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Recurrent respiratory infections (RRIs) represent a significant health concern among children, affecting 6% within their first six years and 25% before reaching one year old. Despite often presenting mild symptoms, these infections persist to varying degrees, typically decreasing in frequency until complete resolution by the age of twelve. However, the transient nature of RRIs disguises the considerable medical and social burdens they impose, notably diminishing the quality of life for affected children and their families. This comprehensive review aims to distil and synthesize findings from extensive research conducted over the past seventeen years, with a particular focus on understanding the role of probiotics in both preventing and treating RRIs. By compiling key insights from these studies, the review sheds light on the complex dynamics of RRIs and explores the potential of probiotics as a promising avenue for reducing the frequency and severity of these infections. Probiotics, defined as live microorganisms conferring health benefits, have garnered attention due to their immunomodulatory properties. Recent studies have investigated the efficacy of probiotics in preventing and treating RRIs, emphasizing their ability to modulate immune responses, enhance mucosal immunity, and maintain a balanced microbial environment within the respiratory tract. Through critical examination of accumulated evidence, this review aims to provide a nuanced understanding of the intricate interplay between RRIs, the evolving immune systems of children, and the potential therapeutic contributions of probiotics. By synthesizing findings from recent research, it seeks to contribute meaningfully to ongoing discussions on effective strategies for alleviating the burden of RRIs in pediatric populations. The insights gleaned from this review are poised to inform future interventions, guiding healthcare practitioners in devising targeted and effective approaches to managing and mitigating the impact of RRIs in children.
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Tuberculosis remains the leading cause of death among global infectious diseases with increasing challenges of antimicrobial resistance. Conventional anti-tuberculosis chemotherapy is aggravated by a limited success rate, a long course of treatment, and numerous side effects. Once again, we highlighted the significance of immuno-therapy. In this review, we focus on assessing the efficacy and safety of thymosin alpha 1 (Tα1) as a valuable adjunctive therapy for tuberculosis. We aim to examine the potential mechanism through which Tα1 influences the immune system of tuberculosis patients, intending to provide a theoretical foundation for its clinical applications. After reviewing the articles published in PubMed, Web of Science, Embase, BIOSIS Library, and China-national-knowledge-internet, we identified 21 clinical cohort studies investigating Tα1 as an auxiliary treatment for tuberculosis. These studies included 11 articles on pulmonary tuberculosis, 2 articles on tuberculous pleurisy, and 8 articles on intestinal tuberculosis. These studies have demonstrated the safety and effectiveness of Tα1, an immunomodulator, in the treatment of tuberculosis. The probable immune mechanism of Tα1 might involve the up-regulation of T lymphocyte (CD3+, CD4+), helper T 17 (Th17), natural killer (NK), interferon-γ (IFN-γ), and interleukin-2 (IL-2) levels. Consequently, Tα1 may be suggested as an effective and safe auxiliary treatment for mycobacterium tuberculosis infection in clinical settings. However, several key aspects regarding Tα1 remain unclear, including the molecular mechanism involved in Tα1's upregulation of immune cell differentiation and cytokine secretion, the synergistic association between Tα1 and anti-tuberculosis drugs, and its therapeutic dose and treatment duration for tuberculosis. Therefore, there is an urgent need to investigate these aspects and explore more scientific and effective treatment strategies to provide a reference for the treatment of tuberculosis.
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The gut-liver axis has emerged as a fundamental concept in elucidating liver diseases. Central to this axis is the intestinal barrier, which exerts a significant influence on the progression of various liver conditions, including non-alcoholic fatty liver disease, alcoholic liver disease, viral liver diseases, autoimmune liver diseases, and cirrhosis. This review synthesizes domestic and international literature to explore the intricate association between the intestinal barrier and liver diseases. Mechanistic insights into how the intestinal barrier modulates liver pathology are elucidated, emphasizing its role in mediating the systemic effects of intestinal contents on liver health. Additionally, this paper sheds light on the potential clinical and scientific implications of targeting the intestinal barrier in liver disease management. The review highlights the imperative for continued research efforts to unravel the intricate connections between the intestinal barrier and liver diseases to unveil novel therapeutic strategies to alleviate the burden of these conditions.
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Multiple myeloma (MM) is a clonal plasma cell proliferation disease characterized by an abnormal monoclonal protein, leading to specific-organ damage. Nowadays, significant knowledge about the pathophysiology and the treatment of MM has been gained. Unique lesions regarding reactive oxygen species (ROS) and reactive nitrogen species (RNS) production in MM's pathobiology have been reported due to new technologies. On the one hand, in most stages of MM, an overproduction of free radicals and a deregulation of the human antioxidant system can be found, leading to intense myeloma cell proliferation. On the other hand, in advanced disease with comorbidities, oxidative stress suppression leads to further growth of neoplastic clone. Novel agents that have been emerged for MM treatment, such as proteasome inhibitors, immunomodulatory drugs, epigenetic drugs and monoclonal antibodies have improved patients' survival and quality of life. These drugs increase oxidative stress, resulting in myeloma cell apoptosis, via activation of a molecular pathway called Unfolded Protein Response (UPR). Nowadays, the research focuses on the discovery of novel factors that can enhance their anti-myeloma effects, by modulation of oxidative stress.
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The human vagina harbors various types of microorganisms, and the normal female vaginal microbiota is in a dynamic balance ecosystem, with Lactobacillus as the predominant organism. Vaginal microbiota dysbiosis is influenced by disordered hormone regulation, autoimmune imbalance, and pathogen invasion. This dysbiosis not only adversely affects women's health and fertility but also has a negative impact on the development of babies during pregnancy, especially in terms of inflammatory responses and complications. The inflammatory response within the vagina is the first to reflect vaginal microbiota dysbiosis. Therefore, understanding the mechanisms by which host inflammatory responses triggered by changes in the microbiota lead to disease progression is critical for prevention and treatment strategies. In this review, we conducted a search of the PubMed electronic databases for studies published before August 2023 with keywords “vaginal microbiota”, “inflammation”, “reproductive”, “fertility”, and “pregnancy”. We also manually searched relevant references from retrieved manuscripts and review articles. We aim to summarize the research focused on inflammation and complications induced by dysbiosis of the vaginal microbiota and the impact on female fertility and pregnancy outcomes.
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Copper (Cu), an essential trace element, plays a crucial role in various physiological processes within the human body. Recently, cuproptosis, a novel form of cell death induced by copper overload, has been identified. Despite numerous studies investigating the association between copper and gastric cancer (GC), a comprehensive review of the existing literature on this topic is notably lacking. This review provides a retrospective analysis of the correlation between copper and gastric cancer, outlines the aberrant copper metabolism in gastric cancer and its potential mechanisms, and synthesizes current bioinformatics research on cuproptosis in gastric cancer. Furthermore, the review delves into copper-related synthetic materials and drugs that have been pivotal in the diagnosis and treatment of gastric cancer. We have emphasized that the association between copper and gastric cancer has not been fully investigated, indicating the possibility of discovering copper-related synthetic materials, chelating agents, and complexing agents as potential therapeutic approaches for gastric cancer.
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Inflammatory mediators are important molecules that adjust the inflammatory response and prevent tissue damage. Cytokines are relevant mediators involved in inflammation. The interleukin-1 (IL-1) family is a well-known cytokine group that regulates inflammatory responses, in which IL-1β plays a pivotal role in the promotion of inflammation. Although there are several underlying mechanisms, the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) pathway is the most studied pathway for the secretion of IL-1β. The NLRP3 inflammasome is a protein complex formed after extracellular adenosine triphosphate (eATP) binds to the P2X family purinergic receptor 7 (P2X7R), and NLRP3 inflammasome activation results in IL-1β release. The P2X7 receptor plays a crucial role in the immune response, and its modulation may trigger the development of pathological conditions characterized by inflammation. Therefore, it is important to highlight the P2X7 receptor as a potential therapeutic target in diseases in which an inflammatory profile is observed due to high concentrations of secreted IL-1β. This study aimed to elucidate the mechanism by which the P2X7 receptor may affect IL-1β cytokine release.
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Tetraspanins, characterized by their four transmembrane domains, function as versatile platforms for interactions with a wide range of molecules. Recent research has increasingly focused on the utility of tetraspanins as potential prognostic markers and indicators of metastatic likelihood, varying according to the type of cancer. This review comprehensively examines the multifaceted functions of tetraspanins, highlighting their dual roles as enhancers and inhibitors in cancer development. Furthermore, it provides a detailed exploration of the signaling pathways and interactions associated with tetraspanins that could significantly impact the course and treatment of cancer.
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Reductive stress is a cellular insult stemming from the overgeneration of reducing equivalents and heightened antioxidant potential within the body. Maintaining redox homeostasis necessitates a delicate balance between oxidant and antioxidant production. Key indicators of this balance include ratios such as Reduced glutathione (GSH) to Oxidized glutathione (GSSG), Nicotinamide adenine dinucleotide phosphate (NADP) to Reduced nicotinamide adenine dinucleotide phosphate (NADPH), and Nicotinamide adenine dinucleotide (NAD+) to Reduced nicotinamide adenine dinucleotide (NADH). Glutathione, an endogenous antioxidant, can also be supplemented through natural food sources such as okra, spinach, broccoli, and sweet potatoes among others. These reducing equivalents primarily stem from cellular metabolic processes such as the Krebs cycle and glycolysis. When present in excess, they can modulate signaling pathways, disrupt transcriptional activity, and reduce cellular metabolism, paving the way for various diseases. Conditions associated with reductive stress include cancer, protein aggregation cardiomyopathy, muscular dystrophy, and Alzheimer's disease, among others. Moreover, prolonged use of antioxidant supplements like Vitamins and/or flavonoids may have pro-oxidant effects, disturbing cellular redox balance, inducing reductive stress, and potentially shortening life expectancy. Therefore, the consumption of antioxidant supplements should be moderate and appropriate, as excessive or haphazard intake can be detrimental to overall health.
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Background: Chronic non-communicable diseases are a growing public health concern worldwide, presenting a significant global challenge to address. Mexico has a high level of prevalence of chronic non-communicable diseases. Studies indicate that dietary fiber (DF) in foods such as vegetables, whole grains, fruits, and legumes protects against chronic non-communicable diseases. This review centers on finding scientific evidence regarding the DF properties and functional characteristics in chronic non-communicable diseases and the importance of its consumption in chronic non-communicable disease management and prevention in Mexico.
Methods: We conducted a comprehensive search for relevant articles on the effect of DF on chronic non-communicable diseases. Our search spanned multiple reputable databases, including PubMed, Scopus, Google Scholar, and Web of Science, ensuring a thorough and reliable review of the existing literature.
Results: Studies and clinical trials with isolated and extracted fibers from different sources have shown alterations in the composition and activity of the intestinal microbiota, which have important implications for the development and control of chronic non-communicable diseases. Thus, promoting DF within dietary guidelines could be an option to improve public health.
Conclusions: This article not only presents scientific evidence but also offers a practical tool for healthcare professionals. By promoting DF and educating the public to meet the recommended intake of ≥25 g/day, we can potentially prevent the development and enhance the control of chronic non-communicable diseases among Mexican adults.
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Background: The phosphatidylinositol binding clathrin assembly protein interacting mitotic regulator (PIMREG) is highly expressed in osteosarcoma, cholangiocarcinoma, breast cancer, pancreatic cancer, and other cancer types, with its high expression being associated with poor cancer survival. At the same time, some studies have explored the association between PIMREG expression and glioma, but the results are controversial. Therefore, this study aimed to conduct a meta-analysis to systematically evaluate the effect of PIMREG expression on the prognosis of glioma patients.
Methods: The relevant literature published in English was accessed through various databases, including PubMed, Embase, Web of Science, and The Cochrane Library from September 2023. The research articles were screened based on the predetermined inclusion and exclusion criteria. The quality of the literature was assessed using the Newcastle-Ottawa Scale (NOS). Furthermore, hazard ratio (HR) and its corresponding 95% confidence interval (CI) for overall survival (OS) were either directly obtained from the original sources or derived from the Kaplan-Meier survival graphs using Engauge Digitizer 4.3. STATA 15.0 was selected for meta-analysis. Moreover, sensitivity analysis was performed to evaluate the stability of the included studies. Additionally, the Begg rank correlation method and Egger regression method were employed to evaluate the publication bias of the included literature.
Results: Following a thorough screening process, 6 research articles were included in this study. Meta-analysis results showed that patients with high PIMREG expression had poorer OS (HR = 2.77, 95% CI: 1.83–3.71). The subgroup analysis revealed that the HR of OS was 2.32 (95% CI: 1.59–3.06) in the Asian population and 3.12 (95% CI: 0.80–5.44) in the non-Asian population. In subgroups of tumor types, the HR for OS was 2.71 (95% CI: 1.88–3.54) for patients with glioma type and 2.60 (95% CI: 0.87–4.34) for those with glioblastoma type. Furthermore, sensitivity analysis revealed that the stability of the included studies was good. Begg and Egger tests showed that in the meta-analysis, publication bias of the included literature was not significant (p = 0.630).
Conclusion: The high expression of PIMREG is associated with poor prognosis of glioma patients, indicating its application as a potential prognostic indicator for these patients.
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Background: This study aims to summarize the evidence regarding the effects of polyunsaturated fatty acids (PUFAs) supplementation on both amateur and professional athletes.
Objective: The aim is to elucidate the impacts of PUFAs supplementation on physical performance, inflammatory response, biochemical profile, anthropometric/body composition, and performance outcomes in athletes.
Methods: Articles published up to December 2023 were retrieved from databases including Cochrane Library, PubMed/Medline, Scopus, and Embase. Selected articles met eligibility criteria and quality methodology. Data on inflammatory response, biochemical markers, anthropometric/body composition, and neuromuscular indicators were extracted.
Results: Twenty-one studies were included in this systematic review. PUFAs supplementation resulted in decreased levels of certain inflammatory markers (interferon-gamma, interleukin 1, prostaglandin E2, and tumor necrosis factor alpha). However, no significant differences were observed in interleukin 4, 6, 8, 10, and matrix metalloproteinase 9. Additionally, there were no differences in glycemic (glucose and insulin) and lipid metabolism (high density lipoprotein (HDL)) cholesterol, low density lipoprotein (LDL), triglycerides). A reduction in reactive oxygen species levels was noted. No significant differences were found in muscle fatigue markers and anthropometry. Some performance parameters (neuromuscular and aerobic) improved following supplementation, including performance on the Yo-Yo distance test, resting energy expenditure, exercise time to exhaustion, and maximum oxygen consumption/maximum heart rate.
Conclusion: Supplementation with PUFAs (600–3150 mg) in athletes led to reductions in inflammation and oxidative stress markers, as well as improvements in specific aerobic performance parameters. However, no significant effects were observed on glycemic and lipid profiles, anthropometric profiles, or body composition.
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Since their introduction to the US market in 2016, oral nicotine pouches have grown in popularity. These small fiber pouches of an appealing taste deliver nicotine to the narrow space between the gum and the lip, precisely at the interface of the mucosa of the vestibulum oris and the oral moisture derived from saliva. This delivery mechanism leads to a systemic effect as the substances bypass gastrointestinal enzymatic degradation and the hepatic first-pass effect. While a portion of the nicotine from these products undergoes enzymatic changes in the liver due to the first-pass effect, some nicotine manages to evade this process. The gut environment appears to influence the first-pass effect within the portal circulation system. Despite their ease of use, these products exhibit variability in nicotine levels and concentrations, potentially leading to poisoning and addiction. The increases in use, marketing, and appeal of nicotine pouches have notably elevated their popularity among younger people. However, it is crucial to note that oral nicotine pouches are not risk-free. Given their potential for overdose, a review of medical literature was conducted to explore whether the microbiota could play a role in influencing nicotine overdose among users of oral nicotine pouches.
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Background: Although some studies have highlighted the potential tumor-suppressive role of Ankyrin repeat and BTB/POZ domain-containing protein 1 (ABTB1) in various malignancies, its significance in B-cell acute lymphoblastic leukemia (B-ALL) remains unclear. This study aimed to explore the potential of ABTB1 as a prognostic marker for B-ALL.
Methods: Firstly, we identified differentially expressed genes (DEGs) in a patient with recurrent B-ALL, encompassing recurrence and complete remission, using bioinformatics methods. A protein-protein interaction (PPI) network for the identified DEGs was constructed using the Search Tool for Recurring Instances of Neighbouring Genes (STRING) database and visualized using Cytoscape software. Hub gene analysis was conducted utilizing three distinct algorithms (Degree, Maximal Clique Centrality (MCC), and Density of Maximum Neighborhood Component (DMNC)) via the cytoHubba plugin. The top 15 genes identified by each algorithm were designated as hub genes. Subsequently, transcriptome and clinical data from the TARGET database were then retrieved. mRNA expression profiles from 199 B-ALL cases were subjected to univariate Cox analysis to identify prognostic gene markers. Hub genes (p < 0.05) were then isolated from this gene pool. Kaplan-Meier analysis was conducted to examine the association between the extracted hub genes and overall survival (OS). Further screening of OS-related hub genes, considering hazard ratios from univariate Cox analysis and the regulatory patterns of DEGs, identified potential prognostic biomarkers. Finally, the expressions of the screened hub genes were validated, and their clinical significance was assessed in paediatric B-ALL patients.
Results: A total of 2666 DEGs were identified, comprising 930 upregulated and 1736 downregulated genes. Three candidate hub genes, namely ABTB1 (Hazard Ratio (HR) = 0.683, p < 0.05), a disintegrin and a metalloproteinase domain-8 (ADAM8) (HR = 0.729, p < 0.05), and G protein-coupled 84 (GPR84) (HR = 0.868, p < 0.05), were markedly downregulated and associated with poor prognosis in B-ALL. Subsequent validation revealed that only ABTB1 was differentially expressed between newly diagnosed B-ALL patients and those with complete remission. Furthermore, ABTB1 exhibited significant associations with white blood cell count and risk stratification. Additionally, the protein expression of ABTB1 was reduced in newly diagnosed B-ALL patients.
Conclusions: ABTB1 emerges as a promising novel prognostic biomarker in B-ALL, shedding light on its potential role in disease progression and prognosis.
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Background: Hyperlipidemic acute pancreatitis (HAP) is characterized by high triglyceride (TG) and acute pancreatitis (AP), and is closely related to intestinal microflora. MiR-124 was found to have a significant regulatory relationship with chronic pancreatitis. Here, the study aimed to investigate the protection effect of miR-124 agonist in HAP.
Methods: HAP was induced in mice using a high-fat diet (HFD) and cerulein. We evaluated the biochemical and morphological protective effects of miR-124 in HAP mice. miR-124 expression in the serum and pancreas was quantified by real-time quantitative PCR (qRT-PCR). Cluster of differentiation 68 (CD68) expression in pancreatic macrophages was detected by immunohistochemistry. Colonic flora was analyzed using High-Throughput Sequencing. Flow cytometry was performed to determine macrophage polarization. Serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Western blot (WB) was performed to detect protein expression.
Results: The results revealed that miR-124 expression was downregulated in HAP mice (p < 0.001), which exhibited pathological injury and inflammatory cell infiltration in the pancreas. However, this status was inhibited by miR-124 agonist treatment. High-throughput sequencing of 16S rDNA demonstrated that miR-124 agonist treatment significantly reversed HAP-induced gut dysbiosis. Using Linear discriminant analysis Effect Size (LEfSe) analysis, we found that Rikenellaceae was the key species in the miR-124 agonist treatment of HAP. Finally, we found that the treatment with the miR-124 agonist promoted macrophage polarization toward M2 (p < 0.05) and inhibited the inflammatory response (p < 0.05) in HAP mice.
Conclusion: MiR-124 agonists improve HAP by attenuating inflammatory reactions, regulating macrophage polarization, and rebalancing the intestinal microbiota.
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Background: The leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) functions to regulate cell cytoskeleton. This study assessed LRPPRC expression in colorectal cancer (CRC) for association with the clinicopathological features from patients and then investigated the impact of LRPPRC expression on CRC cells in vitro and in vivo.
Material and Methods: Tissue microarrays were built using 75 cases of each really normal and CRC tissues or 75-paired normal and CRC tissues for immunohistochemical analysis of LRPPRC expression. CRC cell lines were grown and assessed for tumor cell migration and invasion using wound healing and transwell assays. Changes in mRNA and protein expression in CRC cells were assayed using western blot and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), respectively. Knockdown or overexpression of LRPPRC was conducted using siRNA and cDNA transfections, respectively. Next, a nude mouse xenograft assay was performed to verify the impact of LRPPRC expressions in vivo.
Results: LRPPRC was overexpressed in CRC vs. real normal and paired normal tissues (p < 0.05), which was associated with CRC lymph node and distant metastases, and advanced clinical stages. In vitro, knockdown of LRPPRC expression inhibited CRC LOVO cell migration and invasion, whereas LRPPRC overexpression promoted CRC HCT116 cell migration and invasion. Moreover, LRPPRC overexpression upregulated Vimentin, N-cadherin, and Snail, and downregulated E-cadherin protein, whereas knockdown of LRPPRC expression had opposite results, suggesting increase in CRC cell epithelial-mesenchymal transition (EMT). In addition, knockdown of LRPPRC expression suppressed growth of colorectal cancer cell xenografts in mice.
Conclusions: LRPPRC could be an oncogene or had an oncogenic activity in CRC.
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Purpose: Recent studies have shown that fatty acid-binding protein 6 (FABP6) is not only a risk factor for digestive tract tumors, but also a diagnostic marker for digestive tract tumors. This study aimed to extend our understanding by investigating the potential significance of FABP6 in urinary tract tumors, particularly its role in the bladder cancer progression. We aimed to assess whether FABP6 influences bladder cancer progression through immune cell interactions.
Methods: Utilizing data from the cancer genome atlas (TCGA) database, the association between FABP6 expression level and clinical data of bladder cancer was analyzed. This investigation aimed to determine the feasibility of FABP6 as a marker gene for the diagnosis and prognosis of bladder cancer. Additionally, the correlation between FABP6 and immune cells in bladder cancer was analyzed.
Results: FABP6 was highly expressed in bladder cancer (p < 0.05). The overall survival (OS), progression-free interval (PFI) and disease-specific survival (DSS) in the high FABP6 expression group were higher than those in the low FABP6 expression group (all p < 0.05). The expression of FABP6 was negatively correlated with the infiltration of Th2 cells, macrophages, and Th1 cells (all p < 0.05). Conversely, the expression level of FABP6 was positively correlated with the infiltration of NK CD56bright cells (all p < 0.05).
Conclusion: FABP6 emerges as a promising prognostic marker for bladder cancer. FABP6 may have an impact on the disease progression of bladder cancer by interacting with different types of immune cells in bladder cancer.
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Background: Due to its good softness, silica gel is now widely used in radiotherapy tissue compensation adhesives, but its relative electron density is high and its CT value is high, so many experts have doubts about its clinical application. This study aimed to explore how silicone can be used as a radiotherapy tissue filler.
Methods: Based on the 6-megavolt (MV) X-ray phase-space file, 30 × 30 × 30 cm cube models of water, silicone, and different human tissues were constructed in Geant4 Monte Carlo (MC) software to simulate the transport process of X-rays in those media. The study obtained the central axial energy deposition in silicone and the particle-phase-space information at a depth of 1 cm and 2 cm when the rays passed through all the media.
Results: The radiation attenuation in silicone was greater than in water. At a depth of 5 cm, the thickness of the silicone was equivalent to 1.12 times the thickness of the water. In dose built-up area and approximate charged-particle equilibrium, the particle-phase-space composition in silicone were similar to that in water, skin, soft tissue, and adipose tissue, although the particle-phase-space concentration of positrons was slightly higher, and the energy spectrum of each particle was distributed more uniformly. The particle-phase-space composition in silicone was quite different from that in compact bone and cortical bone, and the particle-phase-space concentration of positrons was lower in silicone than in the two bones media. The MC and Pinnacle algorithms were in good agreement in terms of the dose calculation behind the silicone. After the rays had passed through the different thicknesses of silicone, the differences in the two algorithms were within 2.5%.
Conclusion: There was negligible impact of secondary dose build-up between the silicone and the body's surface, and the values calculated by the different treatment planning system (TPS) algorithms were in good agreement. Therefore, silicone is deemed suitable for use as a tissue filler from the perspective of dosage.
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Background: Migraine is a prevalent neurovascular headache characterized by recurring pain episodes. Previous research indicates that managing the expression of the cAMP response element-binding protein/Brain-derived neurotrophic factor/Tyrosine receptor kinase B (CREB/BDNF/TrkB) pain signaling pathway may enhance migraine conditions. This study delves into the pharmacological effects and analgesic mechanisms of emodin in treating nitroglycerin-induced migraines in animal models, focusing on the CREB/BDNF/TrkB signaling pathway.
Methods: Sixty-six male Sprague Dawley (SD) rats were randomly divided into six groups: Control, Model, positive control, and low, medium and high doses of emodin treatment groups. All groups, except the control, underwent the establishment of experimental migraine animal models and received treatment for seven consecutive days. Subsequently, behavioral evaluations and heat pain threshold assessments were conducted. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the levels of Brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide (CGRP) in rat serum. Reverse Transcription-Quantitative Polymerase Chain Reaction (RT-qPCR) was performed to detect the mRNA expression levels of CGRP and cAMP response element-binding protein (CREB). Western blot analysis was utilized to assess the protein expression levels of Tyrosine receptor kinase B (TrkB) and Cyclooxygenase-2 (COX-2).
Results: Behavioral assessment, measurement of thermal pain threshold, and mechanical pain thresholds indicated that, in comparison to the Model group, the emodin treatment group exhibited a significant improvement in abnormal behavior in migraine rats (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, there was an increase in thermal pain threshold and mechanical pain thresholds in the emodin treatment group (p < 0.05, p < 0.01, p < 0.0001). ELISA experiments revealed that, when compared to the Model group, the emodin-high-dose (emodin-H) treatment group exhibited reduced serum levels of BDNF and CGRP (p < 0.01). Additionally, RT-qPCR and Western blot (WB) experiments demonstrated the downregulation of CGRP (p < 0.001) and CREB (p < 0.05) mRNA expression levels. Furthermore, there were decreased expression levels of TrkB and COX-2 proteins in the rat brainstem (p < 0.05, p < 0.01).
Conclusion: This study confirms that emodin can markedly enhance abnormal behavioral activities and elevate the thermal pain threshold in the migraine rat model. Its effects appear to be mediated by the downregulation of upstream COX-2 and CGRP, along with the inhibition of the CREB/BDNF/TrkB pain signaling pathway.
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Background: The changing lifestyles and dietary patterns in recent years have led to an increased incidence rate of colorectal cancer, posing a significant threat to the well-being and safety of patients. Therefore, the objective of this study was to investigate the therapeutic efficacy of the combination treatment of Aspirin and curcumin in a colorectal cancer model. The aim is to provide insights into potential approaches for managing this disease.
Methods: All mice were randomly assigned to different groups, including sham, dextran sulphate sodium (DSS) + azoxymethane (AOM), Aspirin, Curcumin, and Union group, with six mice in each group. In vitro experiments utilized the human colon adenocarcinoma cell lines (HCT-116) as a model. For HCT-116 cells, TAp63alpha (TAp63α), si-TAp63α, negative control, or si-negative were transfected using Lipofectamine 2000, with three replicates per group. Quantitative polymerase chain reaction (qPCR) was performed to assess the expression levels of Lrg5 and TAp63α after treatment with Aspirin combined with curcumin, both in vivo and in vitro. The Cell Counting Kit-8 (CCK8) assay and 5-ethynyl-2'-deoxyuridine (EDU) staining were used to evaluate the proliferation of colorectal cancer cells following combination treatment.
Results: The combination treatment of Aspirin and curcumin resulted in a significant reduction in tumor numbers and tumor size in the colorectal cancer mouse model (p < 0.05). Moreover, this combination treatment led to reduced mRNA expressions of interleukin-6 (IL-6), IL-17α, and Prostaglandin-Endoperoxide Synthase 2 (Ptgs2) in the tumor tissue of the mouse model (p < 0.05). In HCT-116 cells, the combination treatment of Aspirin and curcumin demonstrated inhibitory effects on cell proliferation and migration rates. It also reduced the rate of EDU-positive cells and increased Caspase-3/9 activity levels (p < 0.05). Additionally, this combination treatment resulted in decreased glucose consumption, lactate production, and adenosine triphosphate (ATP) quantity in HCT-116 cells (p < 0.05). Furthermore, it reduced extracellular acidification rate and increased oxygen consumption relative to basal levels (OCR, oxygen consumption rate) in HCT-116 cells (p < 0.05). The combination treatment of Aspirin and curcumin suppressed the mRNA expressions of TAp63α and Lgr5 in both the mouse model and in vitro models (p < 0.05). It also downregulated the protein expressions of TAp63α, Lgr5, and p-β-catenin in both models (p < 0.05). Notably, Aspirin had no effect on TAp63α ubiquitination, while curcumin promoted TAp63α ubiquitination in HCT-116 cells. Furthermore, compared to curcumin alone, the combination treatment of Aspirin and curcumin further enhanced TAp63α ubiquitination in HCT-116 cells (p < 0.05). The regulation of TAp63α played a crucial role in mediating the effects of Aspirin combined with curcumin on colorectal cancer cell growth and the progression of the Warburg effect.
Conclusions: The combination treatment of Aspirin and curcumin effectively suppresses the proliferation and migration of colorectal cancer cells both in vitro and in vivo by targeting the Warburg effect. This modulation of the Warburg effect is mediated through the TAp63a/Lgr5 signaling pathway. These findings highlight the potential therapeutic value of Aspirin combined with curcumin for the treatment of colorectal cancer.
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Background: Gestational diabetes mellitus (GDM) is defined as any degree of dysglycaemia that occurs for the first time or is first detected during pregnancy. GDM causes various complications for both the mother and fetus. Immature granulocytes (IGs) may enter the peripheral blood in response to infection, inflammation, or other stimuli. In this study, we delve into the role of IGs in the occurrence and development of GDM as well as their correlation with pregnancy outcomes.
Purpose: This study aimed to investigate the risk factors for gestational diabetes mellitus (GDM) as well as the correlation between immature granulocytes (IGs) and maternal pregnancy outcome.
Methods: This study was conducted between January 1, 2019 and December 31, 2019 at the Women's Hospital, School of Medicine, Zhejiang University. We collected maternal demographic data and clinical information on major adverse pregnancy outcomes from medical records. We implemented multiple logistic regression models to determine the association between maternal IGs and adverse pregnancy outcomes.
Results: A total of 9558 pregnant women, including 7613 controls (those without GDM) and 1945 pregnant women diagnosed with GDM. We found that compared to those without GDM (control group), GDM patients exhibited a significantly higher percentage of immature granulocytes (1.22% ± 1.03% vs. 1.34% ± 1.26%, p < 0.01), and absolute immature granulocyte count (0.12 ± 0.13 × 109/L vs. 0.14 ± 0.15 × 109/L, p < 0.001). Furthermore, GDM patients manifested substantially higher rates of premature birth (6.96% vs. 10.13%, p < 0.001), macrosomia (4.39% vs. 5.55%, p < 0.05), and cesarean section (34.6% vs. 41.8%, p < 0.001). We found that after adjusting for potential confounding variables, IGs were found to be associated with a high risk for GDM (absolute value of IGs, adjusted odds ratio [aOR] = 2.265; percentage of IGs [aOR = 1.100]), preterm birth (absolute value of IGs, aOR = 5.325; percentage of IGs, aOR = 1.209), and macrosomia (absolute IG count, aOR = 1.503).
Conclusions: Our study demonstrates an association between IGs and GDM. Furthermore, IGs can serve as a risk factor associated with preterm delivery and macrosomia.
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Background: Osteoarthritis (OA) is a frequently occurring degenerative joint disease. As the primary bioactive ingredient extracted from Epimedium, icariin (ICA) is reported to promote osteogenic differentiation and bone formation. Nonetheless, the specific mechanisms of ICA in treating OA warrant further elucidation. The current study is targeted at ascertaining the mechanism of ICA in modulating the phenotypes of chondrocytes with an in-vitro model.
Methods: To construct an in-vitro model of OA, we used interleukin (IL)-1β to induce human chondrocytes (C-28/I2). Nuclear paraspeckle assembly transcript 1 (NEAT1) and miR-27a-3p expressions were examined through qRT-PCR. Cell viability was determined through Cell Counting Kit-8 (CCK-8) assay; flow cytometry was employed to analyze cell cycle progression; cell migration was examined by Transwell assay; enzyme-linked immunosorbent assay (ELISA) was conducted to measure the levels of inflammation-related factors (IL-8 and IL-6). The binding relationship of miR-27a-3p with NEAT1 was verified through dual-luciferase reporter gene assay; Western blot assay was conducted to measure the expressions of extracellular matrix-related proteins (ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS-5), collagen II, matrix metalloproteinase 13 (MMP-13), and aggrecan) and mitogen-activated protein kinase (MAPK) signaling pathway-associated proteins (p-p38, p-Jun N-terminal kinase (JNK), and phosphorylated MAPK1 and MAPK2 (p-ERK1/2)). MiR-27a-3p's downstream target genes were predicted using the miRwalk, StarBase, miR-Database (DB), TargetScan databases, and the DAVID database was adopted to perform a Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis of the target genes.
Results: ICA significantly boosted chondrocyte viability and migration, as well as suppressed the apoptosis, inflammatory response and extracellular matrix degradation of C-28/I2 cells. ICA down-regulated NEAT1 expression in chondrocytes. MiR-27a-3p was recognized as NEAT1's downstream target, and bioinformatics analysis implied that miR-27a-3p's potential target genes might be related to the MAPK signaling pathway activation. ICA could inhibit p-ERK1/2, p-p38, and p-JNK expressions through promoting miR-27a-3p expression.
Conclusions: ICA protects chondrocyte via modulating the NEAT1/miR-27a-3p/MAPK axis, and our findings partly explain the mechanism of ICA in ameliorating OA.
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Background: Loganein, the primary active ingredient of Cornus officinalis, has been recognized for its anti-tumor effects in many cancer types, exerting an inhibitory effect on the Wnt/β-catenin pathway. However, its precise impact and underlying mechanism in lymphoma progression are still unclear. This study aimed to investigate whether loganetin regulated lymphoma progression through the Wnt/β-catenin pathway.
Methods: To explore the regulatory impact of loganetin on lymphoma progression, we divided lymphoma cells (Jurkat) into three groups: the Control group (treated with 0 μmol/L loganetin), the Loganetin group (treated with 40, 80, 160 μmol/L loganetin), and the Loganetin+LiCl group (treated with 20 mM Wnt/β-catenin signal activator LiCl and 160 μmol/L loganetin). Subsequently, we assessed Jurkat cell viability, cell cycle, and apoptosis rate to reveal the effect of loganetin and Wnt/β-catenin pathway activator on lymphoma cell growth using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining assay, and flow cytometry. Moreover, the protein levels of CyclinD1, P21, C-Caspase-3, β-catenin, and c-myc were examined employing RT-qPCR and western blot analysis.
Results: With the increasing of loganetin concentration, Jurkat cell viability, CyclinD1, Bcl-2, β-catenin, and c-myc levels were gradually decreased (p < 0.05), while the G0/G1 ratio, P21 level, cell apoptosis rate, TUNEL positive cell rate, as well as the levels of Fas, FASL, Bax and C-Caspase-3/total-caspase 3 were gradually improved (p < 0.05). Compared to the Loganetin group, Jurkat cell viability, CyclinD1, Bcl-2, β-catenin and c-myc levels were enhanced (p < 0.05), while the G0/G1 ratio, P21 level, cell apoptosis rate, TUNEL positive cell rate, Fas, FASL, Bax and C-Caspase-3/total-caspase 3 levels were reduced in the Loganetin+LiCl group (p < 0.05).
Conclusions: Loganetin inactivated the Wnt/β-catenin pathway to restrain lymphoma cell proliferation and promote apoptosis.
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Background: Diabetic retinopathy (DR) is a complication of diabetes that impacts the vision and quality of life of patients. Sodium aescinate (SA) has been widely used in resisting exudation and treating inflammation and vascular diseases, which is consistent with the disease symptoms of DR. However, the therapeutic effect and molecular mechanism of SA on DR are lacking. Therefore, this study is aimed at examining the palliative impact of SA on DR rats induced by streptozotocin (STZ).
Methods: DR model was established by injecting STZ (80 mg/kg) into the Sprague Dawley (SD) rats (7-week-old). Later, SA was administered via the tail vein at a dosage of 1 mg/kg/per, 7 days/cycle, totaling 21 days. During this period, the changes in the rats' body weight and blood sugar levels were observed, and their glucose tolerance was monitored. The fundus conditions of the rats were then examined using fundus photography, focusing on the diameter and permeability of blood vessels. Retinal pathology was assessed using hematoxylin-eosin (HE) staining, and the changes in DR-related markers vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) in the retinas were assayed. The changes in reactive oxygen species (ROS), lipid peroxidation (Lip-ROS), malondialdehyde (MDA), glutathione (GSH), and insulin-like growth factor 1 (IGF1) in retinal protein, as well as the changes of IGF1 in the serum, were also evaluated. Additionally, the changes in the advanced glycation end products (AGE)-receptor for AGEs (RAGE) signaling pathway were investigated.
Results: The treatment group with SA slowed down the diameter of fundus blood vessels and reduced angiogenesis in DR. It inhibited the expression of VEGF and TNF-α. At the same time, SA could also inhibit the activation of ROS, MDA, GSH, and IGF1, and reduce the protein content of IGF1. Additionally, the expression of AGE and RAGE in the advanced glycation end products (AGE)-receptor for AGEs (RAGE) signaling pathway was decreased, and the phosphorylated Janus kinase-signal transd ucer and activator of transcription 3 (JAK/STAT3) in its downstream pathway was also downregulated.
Conclusions: SA has the capacity to diminish DR by inhibiting oxidative stress and AGE-RAGE signaling pathway.
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Background: The role of Short-chain fatty acids (SCFAs) and their G-protein-coupled receptors (GPRs) in mitigating diabetic nephropathy (DN) has been recognized. This study aimed to investigate the impact of SCFAs on inflammation in DN via G-protein-coupled receptors 41 and 43 (GPR41/43).
Methods: Human kidney tubular HK-2 cells were transfected to silence GPR41/43 and treated with sodium acetate (Ac, 48 mmol/L)/sodium propionate (Pr, 24 mmol/L)/sodium butyrate (But, 8 mmol/L) under high glucose (HG, 30 mM) or normal glucose conditions. Rats were administered lentivirus solution to silence GPR41/43 and streptozotocin (STZ, 60 mg/kg) to induce DN, followed by treatment with But (100 mmol/L). Diabetic symptoms and renal function were evaluated, kidney weight/body weight (KW/BW) was calculated, and renal histopathology was examined using hematoxylin-eosin, periodic acid-Schiff, and Masson staining. Quantitative real-time polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, and immunohistochemistry were employed to assess epithelial-mesenchymal transition (EMT)-related proteins, GPR41, GPR43, NLR family pyrin domain containing 3 (NLRP3), and inflammatory factor levels in HK-2 cells and kidney tissues.
Results: Ac/Pr/But reversed HG-induced downregulation in GPR41/GPR43 and upregulation of NLRP3/tumor necrosis factor-α (TNF-α)/interleukin-18 (IL-18)/IL-6/IL-1β in HK-2 cells (p< 0.001). But attenuated HG-induced decrease in epithelial cadherin (E-cadherin) (p < 0.001) and increase in alpha-smooth muscle actin (α-SMA) (p < 0.05) in HK-2 cells. Silencing GPR41/43 reversed the effects of But (p < 0.05). STZ induced diabetic symptoms, increased urine albumin level, serum creatinine/ blood urea nitrogen (BUN) level, KW/BW, α-SMA, NLRP3, and inflammatory factor levels in kidney tissues, exacerbated kidney morphology, and downregulated E-cadherin and GPR41/GPR43 in kidney tissues in rats (p < 0.001). But attenuated these effects of STZ, which were reversed by silencing GPR41/43 (p < 0.05).
Conclusions: SCFAs inhibit NLRP3 inflammasome activation, thus alleviating inflammation and EMT in DN by upregulating GPR41/43.
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Background: Ficus semicordata Buch. is a well-known ethnomedicinal plant that is used to treat various ailments such as colic pain, urogenital difficulties, gastrointestinal disorders, visceral blockage, leprosy, jaundice, diabetes, and hepatitis. This study aims to investigate the phytochemical contents of the metabolites extracted (methanol) from the fruits of Ficus (F.) semicordata, and determine their neuropharmacological, anti-diarrhoeal, and cytotoxic potencies, using in vivo, in vitro, and in silico methods.
Methods: The pharmacological properties of methanol extract of Ficus semicordata fruits (MEFSF) were assessed at different concentrations and its toxicity was determined using the in vitro brine shrimp lethality test. Tail suspension and forced swimming tests were used to investigate the antidepressant activity of MEFSF in mice and elevated plus maze and hole board test models were used to uncover its anxiolytic potentiality. The in vivo anti-diarrhoeal properties of MEFSF were tested on castor oil-induced diarrhoea and gastrointestinal motility models. Gas chromatography-mass spectrometry (GC-MS) analysis was conducted using a mass spectrometer. Based on the GC-MS analysis, 19 phytochemicals were investigated using molecular docking techniques against various target proteins to determine whether they mediate cytotoxic, depressive, anxiolytic, and anti-diarrhoeal effects.
Results: MEFSF exhibited moderate toxicity (median lethal dose (LD50): 267.23 μg/mL). In the antidepressant assessment, MEFSF demonstrated a significant (p < 0.0001) dose-dependent decrease in immobility compared to fluoxetine. Similarly, MEFSF exhibited a dose-dependent reduction in anxiolytic-like behaviour in mice, with a 400 mg/kg dose exhibiting vigorous activity. MEFSF also significantly inhibited motility in both anti-diarrhoeal models, with a 400 mg/kg dose exhibiting highly significant (p < 0.0001) suppression. The GC-MS analysis revealed 81 bioactive components. Seven phytochemicals exhibited a strong affinity for various target proteins in the molecular investigation. Notably, beta-D-glucopyranose and 4-O-beta-D-galactopyranosyl manifested a high affinity for hER, K+ channel, SERT3, and M3MAR and exhibited cytotoxic, anxiolytic, antidepressant, and anti-diarrhoeal potential.
Conclusion: The findings indicate that MEFSF can potentially contribute to the development of innovative anti-cancer, neuropharmacological, and anti-diarrhoeal treatments. However, additional research is necessary to explore this possibility.
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Background: Glioblastoma (GBM) is the most prevalent primary malignant brain tumor. However, current prognostic indicators do not accurately predict the prognostic and therapeutic benefits of GBM patients, therefore we proposed a new immune-based classification of GBM and find out patients more sensitive to immunotherapy.
Methods: This study established a novel immune-based classification, the immune-related prognostic score (IRPS), by utilizing four GBM cohorts comprising 302 samples. Furthermore, a comprehensive immunogenomic analysis was conducted to assess the relationship between IRPS and clinical prognosis, immune cell infiltration, immune checkpoints, and potential mechanisms of immune evasion. The Chinese Glioma Genome Atlas (CGGA) GBM cohort was also used to validate the IRPS. The findings of this research demonstrate the potential of IRPS as a biomarker for predicting the overall survival (OS) of GBM patients. Additionally, the analysis of Tumor Immune Dysfunction and Exclusion (TIDE) and mRNA stemness index (mRNAsi) has suggested that patients with high IRPS may exhibit increased responsiveness to immunotherapy.
Results: The patients were ranked according to the IRPS score and stratified into high and low IRPS groups. Kaplan-Meier survival analysis revealed a significant difference in prognosis within the two subgroups in both the training and testing datasets. The results showed that the low IRPS subgroup higher degree of immune cell infiltration compared to those of the high IRPS subtype. Tumors in the low IRPS group may express more immune checkpoint molecules as a means of evading immune killing following immune stimulation. In the high IRPS subtype of GBM, TP53 (49%) was the most frequently mutated gene, while in the low IRPS subtype, only 31% showed this mutation. Moreover, the high IRPS subtype GBM is also more susceptible to mut-p53 therapy degradation compared to GBM of the low IRPS subtype. Additionally, the analysis of TIDE and mRNAsi has suggested that patients with high IRPS may exhibit increased responsiveness to immunotherapy.
Conclusions: These findings suggest that IRPS could function as a reliable prognostic biomarker, facilitate the development of novel immunotherapeutic interventions, and assist in clinical decision-making for GBM patients.
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Background: Spinal cord injury (SCI) is a spinal nerve dysfunction caused by trauma, resulting in irreversible and destructive spinal cord impairments. The present research was formulated to identify the biological functions of metformin in SCI and to probe into the intrinsic mechanisms.
Methods: SCI rat models were established using Allen's method and SCI rats were intraperitoneally injected with 20 or 100 mg/kg metformin. Besides, endoplasmic reticulum (ER) stress was induced in PC12 cells by administration of 1 μM thapsigargin. Then, 100 μmol/mL metformin was given to PC12 cells. Afterwards, Basso-Beattie-Bresnahan (BBB) locomotor scoring for detecting hindlimb locomotor function, hematoxylin and eosin (H&E) staining for detecting pathological changes, cell counting kit-8 (CCK-8) assay for detecting viability, TdT-mediated dUTP nick-end labeling (TUNEL) staining for detecting apoptosis, immunofluorescence and western blot for detecting autophagy and ER stress response were performed.
Results: Results of in vivo experiments revealed that metformin promoted functional recovery, reduced lesion size, attenuated apoptosis in spinal cord tissues, strengthened autophagy and repressed ER stress after SCI. Additionally, in vitro experimental results evidenced that elevation of ER stress partly abolished the suppressing effects of metformin on neuronal apoptosis and reversed the promoting effects of metformin on autophagy.
Conclusions: To sum up, metformin can protect against SCI by repressing neuronal apoptosis and enhancing autophagy, depending on inhibition of X-box binding protein 1 (XBP-1)-mediated ER stress.
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Background: N6-methyladenosine (m6A) modification predominantly occurs in cancer cells mRNA. The X-box binding protein 1 (XBP1) influences hepatocellular carcinoma (HCC) progression, but its m6A regulatory mechanism remains unclear. Furthermore, the dysregulation of CCAAT/enhancer binding proteins alpha (C/EBPα) in liver cancer is influenced by fat mass and obesity-associated protein (FTO) and acts downstream of XBP1. Therefore, this study aims to investigate how FTO catalyzes XBP1 m6A demethylation in HCC regulation.
Methods: Initially, HepG2 cells were used to construct FTO overexpression and knockdown cells. The cells were divided into the FTO overexpression group (oe-FTO), overexpression control group (oe-NC), FTO knocked-down group (sh-FTO), and control of FTO knocked-down group (sh-NC) groups. RNA immunoprecipitation quantitative polymerase chain reaction (RIP-qPCR) was used to determine the interaction between FTO and XBP1. Furthermore, quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) analysis were utilized to assess the expression levels of XBP1 and C/EBPα. Additionally, subcutaneous transplanted tumor models were constructed and the tumor size, weight, and occurrence time were monitored. Moreover, Hematoxylin-Eosin (H&E) staining was employed to observe the pathological changes of tumors. m6A immunoprecipitation (MeRIP)-qPCR was used to evaluate the XBP1 m6A modification levels. qRT-PCR and WB analysis were used to determine the expression levels of XBP1 and C/EBPα.
Results: We observed that FTO specifically binds to XBP1 mRNA in HCC cells, indicating a potential regulatory role at the RNA level. At the cellular level, compared to the sh-NC and oe-NC groups, the m6A methylation level of XBP1 was significantly increased in the sh-FTO group, while it was decreased in the oe-FTO group (p < 0.05). Furthermore, the mRNA and protein expression levels of FTO, XBP1, and C/EBPα were altered following FTO manipulation. Functional assays demonstrated that FTO overexpression promoted cell proliferation and invasion while inhibiting apoptosis. Conversely, FTO knockdown resulted in decreased cell proliferation and invasion and increased apoptosis. In a mouse xenograft tumor model, we observed rapidly growing tumors in the oe-FTO group, whereas sh-FTO tumors exhibited slower growth. Histological analysis revealed distinct patterns of tumor growth and damage. Collectively, these findings suggest that FTO plays a crucial role in HCC progression through its effects on XBP1 and C/EBPα, providing insights into the potential therapeutic intervention of FTO in hepatocellular carcinoma.
Conclusion: FTO overexpression leads to m6A demethylation of XBP1, thereby modulating the expression of XBP1-C/EBPα and suppressing cell apoptosis. This, in turn, facilitates the progression of hepatocellular carcinoma by promoting cell growth.
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Background: Lung cancer stands as the leading cause of cancer-related mortality globally, with non-small cell lung carcinoma (NSCLC) accounting for approximately 85% of all lung cancer cases. Despite advancements in diagnostic techniques and therapeutic interventions, the 5-year survival rate for NSCLC remains low due to the recurrence and dissemination of malignant cells. There is an urgent need to identify novel biomarkers and therapeutic targets to address this challenge. Therefore, this study aims to identify common genes associated with tumor-related immune cells and investigate their potential clinical utility in both early and advanced NSCLC.
Methods: Early-stage and advanced NSCLC expression data, mutation data, and associated medical records were obtained and refined for subsequent examination from The Cancer Genome Atlas (TCGA). Differential expression analysis, gene ontology (GO), transcription factors and pathway enrichment analysis, and gene set enrichment analysis (GSEA) were implemented to discern molecular function and regulatory relationship across differentially expressed genes (DEGs). Single-sample gene set enrichment analysis (ssGSEA) was employed to analyze immune cell abundance. Furthermore, the weighted gene co-expression network analysis (WGCNA) of DEGs was utilized to screen out gene modules related to tumor-associated immune cells in early-stage and advanced NSCLC. This was achieved by the tumor immune estimation resource (TIMER) algorithm to assess immune cell abundance. Subsequently, consensus genes associated with drug sensitivity and pathways activity were analyzed using the Gene Set Cancer Analysis Literate (GSCALite) platform. Notably, we also evaluated the correlation between consensus genes expression and TP53 mutant (TP53mut) and TP53 wild-type (TP53wt). Finally, the KMPlotter online tool was used to evaluate the prognostic implications of consensus genes exhibiting different correlation patterns in NSCLC.
Results: In early and advanced NSCLC, there were 996 (445 upregulations and 551 downregulations) and 822 (398 upregulations and 424 downregulations) DEGs from lung adenocarcinoma (LUAD) versus lung squamous cell carcinoma (LUSC), respectively, following differential expression analysis. In the interferon signal pathway, functional enrichment analysis showed significant enrichment of DEGs. A correlation between immune infiltration and NSCLC was found using ssGSEA. WGCNA analysis revealed a strong association between tumor-immune infiltration characteristics and the blue and turquoise modules. Notably, a total of 27 consensus genes linked to tumor-related immune cells were identified in both early and advanced NSCLC. Furthermore, differential expression patterns were observed for these consensus genes, such as melanoma-associated antigen A 4 (MAGEA4) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1), between TP53 mutant (TP53mut) and TP53 wild-type (TP53wt).
Conclusions: This study revealed the crucial role of immune cell infiltration, especially dendritic cells, in the onset and progression of early and advanced NSCLC, providing potential targets for immune therapy.
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Background: A chemotherapy regimen based on biomarkers in patients might be more efficient than standard therapy. In this study, we evaluated the extensive correlation between the 21-recurrence score (RS), candidate genes, patient demographics, histopathologic factors, and prognosis. We identified the risk factors that affect breast cancer progression, providing evidence for the breast cancer treatment.
Methods: In this study, a total of 150 patients were analyzed, all of whom underwent a 21-gene RS score evaluation. The candidate genes evaluated in this study included thymidylate synthase (TYMS), ribonucleotide reductase M1 (RRM1), tubulin beta 3 class III (TUBB3), topoisomerase II alpha (TOP2A), and phosphatase and tensin homolog (PTEN) deleted on chromosome ten. Subsequently, we collected patient information regarding the types of endocrine therapy they received.
Results: The 21-gene RS score was significantly correlated with the sentinel lymph node status (p = 0.045). Further investigations into the TYMS and RRM1 genes revealed that the genes are distinct factors involved in the progression of breast cancer. Additionally, human epidermal growth factor receptor 2 (HER2) staining was found to be a compelling indicator of disease progression. Specifically, grade ≥2 staining implies an advanced risk of disease progression. It was demonstrated that the combination of tumor node metastasis (TNM) stage, sentinel lymph node, and 21-gene RS data provides very convincing evidence for clinical application. Moreover, TYMS, RRM1, and HER2 are all independent factors that separately affect the progression of breast cancer.
Conclusions: The 21-gene RS was closely associated with the sentinel lymph nodes status in breast cancer. Besides, TYMS, RRM1, and HER2 were identified as independent factors affecting breast cancer progression.
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Background: Acute kidney injury (AKI) is an acute renal insufficiency syndrome, often associated with high morbidity and mortality. Currently, there is a lack of early diagnostic biomarkers. Urine Tissue inhibitor of metalloproteinases 2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7) serve as markers of G1 cell cycle arrest and foretell AKI development. Therefore, this study aimed to investigate the diagnostic efficacy of these two markers in detecting AKI.
Method: We analysed urine and serum samples obtained from the normal control, patients without AKI (NO-AKI), and AKI groups. We assessed the levels of Neutrophil gelatinase-associated lipocalin (NGAL), TIMP2, and IGFBP7 in urine and serum creatinine (Scr) levels utilizing corresponding enzyme linked immunosorbent assay (ELISA) kits. The diagnostic values of urinary NGAL, TIMP2, IGFBP7, and serum Scr were evaluated through receiver operating characteristic (ROC) curve analysis. Moreover, the hypoxia model of renal tubule cells was used to simulate AKI in vitro, and the expression levels of TIMP2 and IGFBP7 were determined at different time following hypoxia induction.
Results: There were significant differences in urinary TIMP2, IGFBP7, and NGAL levels as well as Scr levels among the three experimental groups. The urinary TIMP2, IGFBP7, and NGAL levels, as well as Scr levels were significantly higher in the AKI group than those in the normal and the NO-AKI groups (p < 0.01). However, the urinary IGFBP7 and Scr levels were elevated in NO-AKI group compared to the normal group. Moreover, there was no substantial difference in urinary TIMP2 and NGAL levels between the NO-AKI and normal groups (p > 0.05). Additionally, ROC curve analysis revealed that the urinary IGFBP7 had excellent diagnostic performance for AKI, followed by urinary TIMP2, NGAL, and Scr. Furthermore, the TIMP2 and IGFBP7 levels elevated in a time dependent manner, reaching the peak at 120 minutes after hypoxia induction, followed by a gradual decline (p < 0.001).
Conclusions: The present study shows that IGFBP7 and TIMP2 have good diagnostic value for early AKI, which are potential biomarkers for early screening of high-risk AKI patients.
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Background: The impact of Gambogenic acid (GNA), a bioactive component derived from Gamboge, on osteosarcoma (OS) has not been properly investigated. However, whether GNA could induce autophagy in osteosarcoma cells and its role in inducing autophagy of osteosarcoma remains unclear. Therefore, this study aimed to elucidate apoptosis and autophagy in GNA-treated-143B cells and to explore the association between apoptosis and autophagy in these cells after treatment.
Methods: The inhibitory effect of GNA on 143B cells was assessed using Cell Counting Kit-8 (CCK-8) assay. Hoechst staining and flow cytometric analysis were used to examine the apoptosis rate, and Ad-GFP-LC3B transfection was employed to evaluate autophagy in treated cells. Intracellular reactive oxygen species (ROS) level and mitochondrial membrane potential were determined through 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetramethylbenzimidazolylcarbocyanine iodide (JC-1) staining, respectively. Additionally, Western blot analysis was utilized to assess the expression of apoptosis-related proteins, autophagy, c-Jun N-terminal kinase (JNK) signaling pathway, and mitochondrial apoptosis pathway.
Results: The GNA treatment significantly inhibited 143B cell viability and Colony formation (p < 0.05). We observed the involvement of mitochondrial pathways in GNA-induced cell apoptosis (p < 0.05). Furthermore, GNA treatment induced autophagy, which was suppressed by reactive oxygen species (ROS) scavenger and JNK inhibitor (p < 0.05). Thus, the ROS scavenger hindered JNK phosphorylation (p < 0.05). Inhibition of autophagy by knockdown of AGT5 enhanced both apoptosis rate and cytotoxicity of 143B cells following GNA treatment (p < 0.05).
Conclusions: GNA induced apoptosis and autophagy in 143B cells, with apoptosis being associated with the mitochondrial pathway and autophagy being regulated by the ROS-JNK signaling pathway. Additionally, autophagy played a cell-protective role against apoptosis.
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Background: Bronchopulmonary dysplasia (BPD) remains the most frequent chronic lung disease among infants, characterized by multifactorial pathogenesis. Necroptosis represents a caspase-independent mode of programmed cell death, and its deregulation is associated with lung diseases, but the mechanisms of necroptosis in BPD are still unclear. This work was conducted to unveil the post-transcriptional regulatory mechanisms of necroptosis in BPD.
Methods: We sequenced messenger RNA (mRNA) (BPD, n = 4; controls, n = 4) and microRNA (miRNA) (BPD, n = 5; controls, n = 5) profiles in peripheral blood specimens. The GSE125873 dataset comprising mRNA profiles from 11 BPD individuals and 10 controls was obtained. The circular RNA (circRNA)-miRNA-mRNA networks and a necroptosis-based subnetwork were constructed on the basis of the circBank and starBase databases. The diagnostic efficacy of eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) was assessed using receiver operator characteristic curve (ROC). EIF2AK2-relevant molecules were analyzed with weighted correlation network analysis (WGCNA), followed by molecular classification through consensus clustering method. In vitro experiments were conducted for validating the main findings.
Results: Aberrantly expressed mRNAs and miRNAs were determined in peripheral blood of BPD relative to controls. Specifically, hsa_circ_0075945/hsa_circ_0038897/hsa_circ_0038898/hsa_circ_0041143 were found to mediate hsa-miR-143-3p, while hsa_circ_0075924/hsa_circ_0075925/hsa_circ_0033776/hsa_circ_0089761 were associated with hsa-miR-589-5p, both of which post-transcriptionally regulated EIF2AK2 expression. EIF2AK2 can effectively diagnose BPD (area under the curve (AUC) = 0.938). Thirty-one EIF2AK2-related genes were selected, which classified BPD into two molecular subtypes. EIF2AK2 knockdown alleviated apoptosis of hyperoxia-induced BEAS-2B cells (p < 0.0001).
Conclusions: Collectively, necroptosis gene EIF2AK2 acts as a molecular determinant of BPD, and our findings uncover the contribution of post-transcriptional regulation to its aberrant expression.
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Background: Prostate cancer (PC) is a solid tumour that is highly prevalent worldwide, ranking as the second most common tumour in humans. The N6-methyladenosine modification of ribonucleic acid (RNA) (m6A) is the most prevalent epigenetic internal modification of both non-coding RNAs (ncRNAs) and messenger RNAs (mRNAs). This study aimed to investigate the link between m6A-related long non-coding RNAs (lncRNAs) and PC to provide a new solution for treating this disease.
Methods: This study used a Pearson's correlation analysis to identify m6A-related lncRNAs. The expression and function of AC020907.4, one of the four selected m6A-related lncRNAs, were verified through experimental validation in PC tissue samples and cell lines. In addition, univariate Cox regression was employed to screen these m6A-related lncRNAs for PC. In the validation and entire groups, a least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to establish and validate the prognostic model for biochemical recurrence (BCR), and small interfering RNA (siRNA) was used to knockdown AC020907.4. Real-time quantitative polymerase chain reaction assay was used to detect the mRNA expression level. A cell counting kit-8 assay was used to detected cell viability.
Results: In total, this study identified 204 m6A-related lncRNAs and found that 64 of the 204 were linked with BCR in patients diagnosed with PC. The LASSO Cox regression was employed to establish a BCR model containing four lncRNAs (AC020907.4, AC022364.1, AC099850.3 and AP001505.1). Kaplan–Meier curves confirmed the different outcomes in the low-risk and high-risk groups. The effectiveness of the model was evaluated using receiver operating characteristic and concordance index curves. The independence of the model for the prognosis prediction was analysed using univariate and multivariate Cox regression analyses. The knockdown of AC020907.4 reduced the cell viability of PC cells.
Conclusions: This study constructed and validated an m6A-related lncRNA model for BCR prediction in patients with PC, providing new insights for research related to m6A and the clinical treatment of PC.
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Background: Chemokines and receptor (CCR) genes are closely associated with tumorigenesis and progression. However, their function in the malignant progression of glioblastoma (GBM) is unknown. The present study aims to reveal prognostic factors, molecular subtypes, and prognostic indicators in chemokine genes and receptor genes in GBM.
Methods: In this study, expression profiles in The Cancer Genome Atlas (TCGA), The Chinese Glioma Genome Atlas (CGGA), and University of Cingifornia Sisha Cruz (UCSC xnea) were utilized for expression analysis of chemokine/receptor genes in pan-cancer and GBM. Univariate COX models identified chemokine/receptor genes with prognostic value. Chemokine/receptor-related gene types in GBM were determined by consistency clustering analysis. This study constructed a prognostic model (CCR Score) using differentially expressed genes (DEGs) between genotypes. Differences between prognosis, tumor mutation burden (TMB), immune checkpoint genes, tumor microenvironment (TME), and drug sensitivity were explored in CCR Score groups and gene types.
Results: Expression models of chemokine/receptor genes were explored, and two differentially characterized genotypes (CCR1 and CCR2) were identified in pan-cancer and GBM. CCR1 and CCR2 exhibited different prognoses, TMB, and TME activity. RTK-RAS (56.2%), PI3K (50.4%), TP53 (30.8%), NOTCH (28.8%), and Hippo (25.2%) pathways had a higher percentage of variants. Next, based on the DEGs in CCR1 and CCR2, we constructed a prognostic model (CCR Score) for predicting the prognosis of GBM patients. The CCR Score showed excellent prognostic and predictive performance, and patients with high CCR Score and CCR1 showed better immune activity and were more sensitive to immunotherapy. In addition, the CCR Score was significantly correlated with cancer chemotherapy sensitivity.
Conclusion: Overall, we identified the CCR characteristics of GBM patients' prognosis, and the CCR Score helps elucidate the potential link between GBM progression and chemokines/receptors and helps explore the mechanisms of carcinogenesis and therapeutic strategies.
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Background: Kidney disease is usually complicated by multiple organ dysfunctions, such as cognitive impairment and neuropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors decrease the degradation of glucagon-like peptide-1 (GLP-1), improving glycemic control.
This study investigated the effect of acute kidney injury (AKI) on social interaction and investigated the underlying role of inflammation, altered energetics, and the possible mode of action of a DPP-4 inhibitor on the brain in AKI.
Methods: Forty rats constituted the animal model and were distributed into four groups (control, untreated, and treated AKI groups). We evaluated sociability; social novelty preferences in a three-chamber social apparatus; platelet counts; hippocampal mitochondrial enzyme complex (I–V) content by calorimetric methods; serum urea, blood urea nitrogen (BUN), and creatine phosphokinase levels by enzyme-linked immunoassay (ELISA); hippocampal adenosine triphosphate (ATP) content measured by ELISA; hippocampal glial fibrillary acidic protein (GFAP) expression; activity-regulated cytoskeleton-associated protein (Arc); Toll-like receptor 4 (TLR4) expression; and nuclear factor kappa B (NF-κB) expression by real-time polymerase chain reaction (RT‒PCR).
Results: The sociability and social novelty indices, all hippocampal mitochondrial complexes (I to V), and platelet, ATP content, were significantly (p value ≤ 0.05) lower in the AKI group than in the control group. Serum creatinine, BUN, and creatine phosphokinase (CPK) levels, the relative expression of hippocampal GFAP, Arc, TLR4, and NF-κB were significantly (p value ≤ 0.05) increased in the AKI control group compared to those in the control group. Sections from the hippocampal cornu ammonis (CA) 1 (CA1) and 3 (CA3) regions and CA3 regions showed degeneration of pyramidal cells with microglial cell in filtration and the appearance of congested blood capillaries. Vildagliptin exerted a protective effect on uremic encephalopathy induced by AKI, as revealed by social behavior and biochemical measurements in the serum and hippocampus and confirmed by histological examination of the CA1 and CA3 hippocampal areas. The statistical significance was stated in parallel with intergroup variability.
Conclusions: The present study showed the protective effect of vildagliptin on uremic encephalopathy induced by AKI, as revealed by social behavior and biochemical measurements in the serum and hippocampus and confirmed by histological examination of the CA1 and CA3 hippocampal areas. This improvement was attributed to improved mitochondrial function, which positively affects the energetics of the brain, attenuates the inflammatory response and alters the expression of synaptic proteins.
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Background: Fidgetin-like 1 (FIGNL1) is overexpressed in hepatocellular carcinoma (HCC), and its high expression is correlated with the poor prognosis of patients. However, the exact role of FIGNL1 in the progression of HCC remains unclear. The purpose of this research was to investigate the role of FIGNL1 in the malignant biological behaviors of HCC and its potential mechanism.
Methods: In this study, the expressions of FIGNL1 and sex determining region Y (SRY)-related High Mobility Group (HMG) box-containing gene 9 (SOX9) were evaluated by quantitative Real-Time polymerase chain reaction (qRT-PCR) and western blot. JASPAR database was applied to predict the binding site between SOX9 and FIGNL1 promoter region. The proliferation, migration and invasion of Huh7 cells were detected by means of Cell Counting Kit-8 (CCK-8), colony formation assay, wound healing and transwell assays. Flow cytometry and western blot were employed to estimate cell apoptosis and cell cycle. With the application of luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay, the combination of SOX9 with FIGNL1 was verified.
Results: FIGNL1 level was greatly elevated in HCC tissues (p < 0.01, p < 0.001) and cells (p < 0.01, p < 0.001). FIGNL1 knockdown suppressed Huh7 cell proliferation (p < 0.001), migration (p < 0.01) and invasion (p < 0.001) but induced cell cycle arrest (p < 0.001). Meanwhile, FIGNL1 silencing promoted cell apoptosis and repressed cisplatin resistance in Huh7 cells (p < 0.001). SOX9 expression was abundant in HCC tissues and cells (p < 0.001). SOX9 could bind to the FIGNL1 promoter and upregulate FIGNL1 expression. SOX9 elevation counteracted the impacts of FIGNL1 knockdown on Huh7 cell proliferation (p < 0.001), migration (p < 0.01), invasion (p < 0.001), apoptosis (p < 0.05, p < 0.01, p < 0.001), cell cycle arrest and cisplatin resistance (p < 0.05, p < 0.01, p < 0.001).
Conclusion: In conclusion, upregulation of FIGNL1 mediated by the transcription factor SOX9 accelerated HCC cell proliferation, metastasis and cisplatin resistance but suppressed cell apoptosis and cell cycle arrest, which might shed novel insights into the targeted therapy for HCC.
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Background: The efferocytosis-related genes (EGs) have been associated with the progression of cancers. However, their precise role in basal cell carcinoma (BCC) remains unclear. Therefore, this study aimed to identify biomarkers associated with efferocytosis in BCC.
Methods: BCC-related datasets GSE125285 and GSE42109 were extracted. Target genes were identified by intersecting differentially expressed genes (DEGs) identified by “limma”. Moreover, the module genes were screened by “weighted gene co-expression network analysis (WGCNA)” and EGs were obtained from the previous literature. Subsequently, the enrichment analysis was conducted employing “ClusterProfiler”. Additionally, diagnostic biomarkers for BCC were screened and BCC risk was predicted through a nomogram. Furthermore, an analysis of gene set enrichment analysis (GSEA) was performed to examine possible mechanisms of BCC.
Results: A total of 18 target genes were identified by intersecting 7314 DEGs, 6052 module genes, and 71 EGs. These genes were found to be associated with transmembrane transport and phagocytosis. Moreover, five biomarkers (ADAM10, MBTPS1, P2RY2, SLC2A1, and UCP2) were identified and the diagnostic model was constructed using these biomarkers. Importantly, MBTPS1 and P2RY2 were found to be associated with adaptive immune response.
Conclusions: This study identified five efferocytosis-related biomarkers that might be used to diagnose BCC. By understanding the regulatory mechanism of EGs in BCC, this study might contribute to further research.
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Background: Stem cell exhaustion is a primary factor in human aging. The ability to delay aging by maintaining the steady state of stem cells has emerged as a crucial area of concern. However, the regulatory impact of Cinnamaldehyde (Cina) on stem cell senescence remains unknown. Therefore, this study aimed to elucidate the regulatory effect of Cina on the senescence of mesenchymal stem cells (MSCs).
Methods: Physiological cell senescence model was established by cell subculture. Cell counting kit-8 (CCK-8) proliferation assay, continuous doubling experiment, Ki67 staining, and cell cycle assay were used to examine the impact of Cina on the proliferation of MSCs. Senescence-associated β-galactosidase (SA-β-gal) staining was used to evaluate the senescence of MSCs. Histone H3 trimethylated at lysine 9 (H3K9me3) staining was used to assess the stability of MSCs chromatin. Osteogenic and adipogenic induction tests were used to evaluate the differentiation potential of MSCs, and 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining was used to evaluate the mitochondrial membrane potential. Glutathione (GSH) assay was used to assess the intracellular redox status. Adenosine triphosphate (ATP) detection and the Seahorse test were used to detect the energy metabolism of cells. Additionally, real-time quantitative PCR (RT-PCR) was used to quantify the indexes associated with senescence, proliferation, and differentiation of MSCs. Moreover, changes in MSCs senescence-related signaling pathways were analyzed using transcriptome.
Results: Cina significantly promoted the proliferation of MSCs, maintained their proliferation rate in prolonged exposure, and delayed their senescence (p < 0.05). Cina reduced the number of SA-β-gal posit mycoplasmaive cells, decreased the levels of senescence markers such as cyclin dependent kinase inhibitor 2A (P16), cyclin dependent kinase inhibitor 1A (P21), interleukin 6 (IL-6), and IL-8, and increased the level of Recombinant lamin B1 (LMNB1). Furthermore, Cina treatment increased the expression of H3K9me3, increased the number of Ki67 positive cells, and reversed cell cycle arrest (p < 0.05). Additionally, Cina upregulated the expression of pluripotency-related genes and downregulated senescence-related signaling pathways, such as P53 and RAS-associated protein 1 (RAP1). In osteogenic and adipogenic experiments, Cina was found to promote the differentiation of MSCs (p < 0.05). Furthermore, we observed that Cina substantially protected mitochondrial membrane potential from damage caused by passage replication, maintained intracellular redox balance, and promoted mitochondrial ATP production (p < 0.05).
Conclusions: This study indicates that Cinnamaldehyde (Cina) can delay the senescence of MSCs by maintaining mitochondrial homeostasis, suggesting that Cina has a potential anti-aging effect.
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Background: Previous research has indicated that platelet-rich plasma (PRP) promotes fracture healing and aids in the treatment of nonunion. A key component of PRP, platelet-derived growth factor BB (PDGF-BB), may play a crucial role in PRP, enhancing the biological functions of bone marrow mesenchymal stem cells (BMSCs). This study aims to investigate whether PDGF-BB is a key effector in PRP that promotes proliferation and osteogenic differentiation of BMSCs.
Methods: Rat BMSCs were isolated and cultured, then expanded to the third generation for morphological observation. Flow cytometry analysis was conducted to assess the expression of CD44, CD29, CD45, and CD11b. The BMSCs were cultured under different conditions: the control group received only basic culture medium, while experimental groups received 10 ng/mL, 25 ng/mL, 50 ng/mL, 100 ng/mL, and 200 ng/mL PDGF-BB. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay at 1, 3, 5, 7, and 10 days. The optimal PDGF-BB concentration was determined based on the CCK-8 results for subsequent experiments. Blood was collected from the rat's heart and used to prepare and activate platelet-rich plasma (PRP), which was then stored in liquid nitrogen for later use. According to the culture conditions for BMSCs, the experimental groups were as follows: a blank control group, a 10% PRP group, a 50 ng/mL PDGF-BB group, and a 10% PRP + 100 μM AG1295 [platelet-derived growth factor β receptor (PDGFR-β) inhibitor] group. Each experimental group was replicated three times. Cell proliferation was assessed using the CCK-8 assay, the cell cycle was analyzed using flow cytometry, and the expression of osteogenic differentiation markers was evaluated by Western blot.
Results: The cell viability of BMSCs treated with 50 ng/mL of PDGF-BB for 5 days was significantly higher than that of other concentration groups and time points. CCK-8 and flow cytometry results indicated that compared to the control group, both 10% PRP and 50 ng/mL PDGF-BB significantly promoted BMSCs proliferation and increased the proportion of BMSCs in the S phase of the cell cycle. Western blot results demonstrated that compared to the control group, both 10% PRP and 50 ng/mL PDGF-BB significantly upregulated the protein expression levels of osteogenic differentiation markers. The use of the PDGFR-β inhibitor AG1295 markedly attenuated the proliferative and osteogenic effects of 10% PRP on BMSCs.
Conclusions: A concentration of 50 ng/mL PDGF-BB significantly enhances the proliferation and osteogenic differentiation of rat BMSCs. PDGF-BB may play a key role in PRP, contributing to the enhancement of BMSCs' proliferation and osteogenic differentiation.
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Background: Diabetic cardiomyopathy (DCM) is a common complication among diabetic patients, yet its pathogenesis is not fully understood. Mitochondrial dysfunction and oxidative stress play important roles in the development of DCM. Pachymaran (PPS), a natural compound with various biological properties, has not been extensively investigated in DCM. This study aims to explore the role and mechanism of PPS in DCM.
Methods: DCM model mice were initially divided into control, DCM, and PPS treatment groups (50 mg/kg and 100 mg/kg). Subsequently, we evaluated the effects of PPS on DCM via myocardial histopathological analysis, cardiac function assessment, and mitochondrial function detection. In addition, Western blot and real-time quantitative PCR were used to study the regulatory effects of PPS on mitochondrial biogenesis and Sirtuin 3 (SIRT3).
Results: PPS treatment in DCM mice exhibited significant myocardial protection, evident from reduced myocardial fibrosis upon histopathological examination (p < 0.05). Furthermore, cardiac function assessment revealed a significant improvement in myocardial contractile function in the PPS treatment group (p < 0.01). Moreover, enhanced activity of mitochondrial respiratory chain complexes and ATP synthesis capacity was observed in the PPS treatment group (p < 0.01), indicating improved mitochondrial function. Further research revealed that PPS significantly increased the expression level of SIRT3 and promoted expression of key regulators of mitochondrial biogenesis (p < 0.01).
Conclusion: The results of this study indicate that PPS protects against DCM by activating mitochondrial biogenesis and SIRT3. PPS can inhibit myocardial fibrosis, enhance myocardial contractile function, and improve mitochondrial function. Additionally, PPS can regulate SIRT3 expression and promote mitochondrial biogenesis. Therefore, PPS may be a potential drug for DCM treatment, proposing a new strategy for DCM treatment.
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Background: Effect of HA380 perfusion combined with continuous venovenous hemofiltration (CVVH) on sepsis and prognosis.
Methods: 60 patients with sepsis admitted to our hospital from November 2020 to March 2022 were selected as the research objects and divided into two groups by simple random method. The two groups were given medical treatment according to the sepsis diagnosis and treatment guidelines jointly issued by the American Society of Critical Care Medicine and the European Society of Critical Care Medicine. The control group was treated with CVVH, and the observation group was treated with HA380 perfusion combined with CVVH.
Results: Intestinal fatty acid binding protein, diamine oxidase, D-lactic acid, interleukin-6, tumor necrosis factor-α, endotoxin, C-reaction protein, white blood cell, procalcitonin, blood lactic acid, serum creatinine, blood urea nitrogen, bilirubin, intra-abdominal pressure, one-day body temperature peak, sequential organ function score at 24 h, 48 h, and 72 h after treatment were lower than those at baseline, mean arterial pressure and oxygenation index were higher than those at baseline, with statistical significance (p < 0.05).
Conclusion: HA380 perfusion combined with CVVH in the treatment of sepsis can reduce intestinal barrier function damage and inflammation, and improve short-term prognosis.
Clinical Trial Registration: Chinese clinical trial registry. Number: ChiCTR2400082281.
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Background: The global incidence of thyroid carcinoma (THCA) is gradually increasing. Our investigation aims to establish a signature relevant to pyroptosis and mitophagy, which could provide new insights into prognostic biomarkers and therapeutic targets associated with THCA.
Methods: Gene sequencing data and clinical information were obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. A six-gene prognosis signature of pyroptosis- and mitophagy-related differentially expressed genes (PMRDEGs) was constructed using least absolute shrinkage and selection operator (LASSO) regression analysis. The prognostic efficacy of the risk score model in the TCGA-THCA cohort was evaluated using Kaplan-Meier (KM) survival plots and receiver operating characteristic (ROC) curve analysis. Functional enrichment analysis identified the potential for differential expression of biological pathways across various subgroups of risk scores. The features of the tumor microenvironment associated with the risk score were investigated using the CIBERSORT algorithm for immune infiltration analysis. The pyroptosis and mitophagy score was calculated to predict the response to immune-checkpoint inhibitor (ICI) treatment in thyroid cancer. Additionally, real-time quantitative PCR (qPCR) and Western Blot (WB) were utilized to investigate the expression levels of hub genes.
Results: A prognostic signature consisting of six pyroptosis- and mitophagy-related genes (Apolipoprotein E (APOE), Ephrin type-A receptor 2 (EPHA2), DEAD-box helicase 3 (DDX3X), Centrosome protein 55 (CEP55), Kinesin family member 23 (KIF23), H2B clustered histone 9 (H2BC9)) was established, and participants were stratified into high- and low-risk groups based on their risk levels. When comparing the progression-free interval (PFI) of the high-risk group with that of the low-risk group, Kaplan-Meier (KM) analysis revealed a statistically significant reduction in PFI for the high-risk group (p < 0.05). Gene Set Variation Analysis (GSVA) illustrated differential expression of 20 pathways between the high- and low-risk groups, including activation of Neurotrophic receptor tyrosine kinase 2 (NTRK2) signals through the Phosphoinositide 3-kinase (PI3K) pathway (p < 0.001). Immune infiltration analysis demonstrated significant variations in immune cell distribution between the two investigated groups (p < 0.05). According to quantitative real-time PCR (qRT-PCR) findings, mRNA expression levels of APOE, EPHA2, CEP55, and KIF23 were significantly higher in tumor cells (p < 0.01). Additionally, expression levels of the pyroptosis-associated proteins NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Gasdermin-D, and Caspase-1 were significantly downregulated in the si-KIF23 group (p < 0.05).
Conclusions: Our study developed a prognostic risk model for thyroid cancer, comprising six pyroptosis- and mitophagy-related genes. This model serves as a valuable marker for prognosis, diagnosis, and predicting the response to immunotherapy in individuals with THCA.
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Background: The chloride intracellular channel 1 (CLIC1) plays a pivotal role in the progression of various cancers as a significant anion channel within the human body. With the rising global cancer incidence, this study aims to elucidate the regulatory mechanisms of CLIC1 to prognosis, the tumor immune microenvironment, and immunotherapy.
Methods: We acquired expression matrices and corresponding clinicopathological data for pan-cancer from The Cancer Genome Atlas (TCGA) and UCSC Xena databases. To thoroughly investigate the significance of CLIC1 in pan-cancer, we conducted analyses encompassing genetic information, mutations, and the distribution of CLIC1. Subsequently, we validated differential expression of CLIC1 through experimental methods. Prognostic evaluation was performed using univariate cyclooxygenase (COX) regression, Kaplan-Meier curves, and two primary algorithms. Employing the median CLIC1 expression level as a grouping criterion, we explored biological pathways associated with CLIC1 expression, conducted single-cell transcriptome sequencing, examined immune-infiltrating cells, and investigated immunotherapy. Additionally, we utilized the Connectivity Map (CAMP) to identify potential drugs targeting CLIC1.
Results: CLIC1 is overexpressed in a majority of tumors, with specific validation in stomach and thyroid cancers. Notably, a significant correlation between CLIC1 and immune checkpoints, tumor mutational burden, and high-frequency microsatellite stability was observed in certain patients (p < 0.001), indicating potential for CLIC1 in immunotherapy. Moreover, CLIC1 serves as a significant predictor of poor prognosis across various malignant tumors, impacting overall survival, disease-specific survival, disease-free interval, and progression-free interval. Based on CLIC1's expression profile, it was found to be prominently expressed in immunometabolic and biosynthetic pathways. Furthermore, high expression levels of CLIC1 were identified in monocytes, macrophages, and malignant cells, suggesting its potential as a specific marker for these cell types. Notably, a strong correlation was observed between CLIC1 expression levels and immune cell infiltration (p < 0.001). Lastly, a drug database screened for small-molecule drugs related to CLIC1, highlighting potential anticancer applications.
Conclusion: This study represents the inaugural demonstration of CLIC1 as a prognostic factor across numerous cancers. Furthermore, it elucidates CLIC1's regulatory role in biological pathways, single-cell landscapes, and the tumor immune microenvironment within pan-cancer contexts. Hence, CLIC1 emerges as a potential biomarker for cancer immunotherapy.
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Background: Fetal chromosomal abnormalities predispose the fetus to developmental malformations, which can reduce the quality of newborn births. This study aimed to investigate the clinical utility of chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in fetuses with thickened nuchal translucency (NT).
Methods: A total of 62 singleton pregnant women were enrolled in this study. Ultrasonography showed increased fetal NT (≥3.0 mm) with or without structural malformations. The subjects were divided into four groups based on the NT value: 3.0–3.4 mm (33 cases), 3.5–4.4 mm (21 cases), 4.5–5.4 mm (3 cases), and 5.5 mm (5 cases). Chromosomal abnormalities were initially analyzed using CMA, followed by trio familial whole-exome sequencing (Trio-WES) in 15 subjects with CMA-negative results. All the subjects were monitored for pregnancy outcomes.
Results: Out of 62 cases, CMA identified 12 cases of aneuploidy, 1 case of pathogenic copy number variation (CNV-P), and 5 cases of unknown copy number variation (CNV-VOUS). The detection rate of fetal chromosomal abnormality was 21.0% (13/62). Fifteen CMA-negative fetuses without structural deformities were analyzed by Trio-WES, which produced six VOUS results with two loci each in SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) and collagen type II alpha 1 chain (COL2A1) and one locus each in leucine-zipper-like transcription regulator 1 (LZTR1) and B-Raf proto-oncogene, serine/threonine kinase (BRAF).
Conclusions: This study supports the application of CMA in prenatal diagnosis. It suggests that the positive detection rate of WES may be low in CMA-negative cases with increased NT without structural malformation. Therefore, appropriate genetic counseling should be provided to optimize the use of CMA and WES in prenatal diagnosis.
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Background: Anoikis, a process crucial for maintaining tissue homeostasis, is implicated in tumor initiation and progression, particularly in pancreatic ductal adenocarcinoma (PDAC), known for its dismal prognosis. Understanding the molecular mechanisms underlying anoikis is imperative for unraveling PDAC pathogenesis. This study aimed to investigate the role of anoikis-related genes (ARgs) in PDAC prognosis and their interaction with the tumor immune environment.
Methods: Differential expression analysis of ARgs between tumor tissues and normal tissues was conducted utilizing The Cancer Genome Atlas (TCGA) dataset. Then, utilizing weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression analysis, ARgs with prognostic relevance were discovered as differentially expressed hub genes. Subsequently, these hub ARgs were employed to construct risk signatures, and a consensus cluster analysis was conducted. Predictive values of risk groups and molecular subtypes, alongside characteristics of tumor immune microenvironment, were analyzed to accurately predict the prognosis. Combined with risk signatures and molecular subtypes, validation of prognostic classification models was achieved through external datasets and RT-PCR experiments.
Results: We identified six hub ARgs, divided patients into two groups according to their expression as the basis of consensus cluster analysis, established an ARgs risk signature based on four of these ARgs, divided patients into high-risk and low-risk groups, and accurately predicted their prognosis. Furthermore, by combining the above classification, the two subgroups showed significant differences in their prognostic outcomes and immune microenvironment characteristics. To further validate our findings, we utilized data from the International Cancer Genome Consortium (ICGC). RT-PCR was performed to verify the expressions of hub ARgs.
Conclusion: Our findings underscore the role of anoikis in shaping the tumor microenvironment and PDAC progression. Moreover, the established risk signature and classification exhibit close associations with the immune microenvironment, showing potential for prognostic predictions in PDAC patients.
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Background: Qianghuo is the root and rhizome of the umbelliferae plant Notopterygium incisum Ting ex H.T. Chang (NI) or N. franchetii H. de Boiss. Notopterol (linear furocoumarin) is the most effective component of Notopterygium incisum. Notopterol exhibits antipyretic, analgesic, anti-inflammatory, anti-oxidation, and anti-apoptosis effects. However, the effects of notopterol on skeletal muscle cells are unclear. This study aims to evaluate the influence of notopterol on the activity of myoblast as well as its inhibiting effect on apoptosis induced by tumor necrosis factor-alpha (TNF-α).
Method: We assessed the effect of notopterol on TNF-α-induced C2C12 apoptosis and its underlying mechanisms. Cell viability and apoptosis were evaluated using the CCK-8 and Annexin V-FITC/PI, respectively. The expressions of apoptosis-related proteins and pathways were assessed utilizing western blot (WB) analysis. Additionally, the role of notopterol in the phosphatidylinositol 3-kinases/AKT (PI3K/AKT) pathway was explored using specific inhibitors of PI3K.
Results: We observed that notopterol increased the activity of TNF-α-treated myoblasts (p < 0.05). Furthermore, flow cytometry, Hoechst-33258 staining, and WB analysis revealed that notopterol reduced TNF-α-induced apoptosis of C2C12 myoblasts by increasing B Cell Lymphoma 2 (BCL-2) levels and decreasing BCL-2-associated X protein (BAX), caspase-3, and caspase-9 levels (p < 0.05). Additionally, notopterol can activate the PI3K/AKT pathway in the first place, then can increase AKT phosphorylation and BCL-2 expression and decrease BAX and caspase-3 expression sequentially. These effects were reversed with the introduction of LY294002, which is a specific inhibitor of PI3K (p < 0.05).
Conclusions: Notopterol can affect C2C12 through PI3K/AKT, thus protecting against TNF-α-induced C2C12 myoblast apoptosis. Therefore, notopterol can be used to treat amyotrophy, providing insights into Sarcopenia prevention and treatment.
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Background: Extrapyramidal side effects are a considerable risk associated with most drugs used to treat psychotic illnesses, and they can negatively impact treatment outcomes. Consequently, there is an ongoing requirement to investigate alternative medicines for managing the side effects. Triphala consists of Terminalia chebula Retz. (Haritaki), Terminalia bellirica (Gaertn.) Roxb. (Bibhitaki) and Emblica officinalis Gaertn. (Amlaki) in equal ratio (1:1:1) is one of the most important polyherbal formulations used in the Indian system of medicine. The objective of the present study was to investigate the preventive efficacy of graded doses of different ratios of Triphala (formulations) and antioxidant effects against haloperidol in Swiss albino mice.
Methods: Graded doses (2.5, 6.25, 12.5 mg/kg) of Triphala in the ratio of 1:1:1, 1:2:3, and 1:2:4 proportions of the three myrobalans, or scopolamine (1.0 mg/kg) or ondansetron (0.5 mg/kg) were pretreated daily (per oral) for 7 days, before administration of haloperidol (5.0 mg/kg, i.p, on 7th day) to induce catalepsy in Swiss albino mice. The behavioral parameters were recorded using the standard bar test, akinesia, and rotarod test at various time points. The animals were euthanized, and the brain was used to study the levels of superoxide dismutase and lipid peroxidation. The data was subjected to a one-way analysis of variance (ANOVA) followed by the Dunnett test and a p-value of <0.05 was considered significant.
Results: The findings show that Triphala enhanced superoxide dismutase and decreased lipid peroxidation, and it significantly (p < 0.001) decreased the cataleptic, rotarod, and akinesia scores. The results were comparable with the observations recorded for standard drugs. Besides, lower (2.5 mg/kg) and higher (12.5 mg/kg) doses of Triphala formulations exhibited enhanced efficacy (p < 0.001) than standards at the initial periods after haloperidol exposure. Further, the improvement in antioxidant status was also found to be better than standards.
Conclusion: The data suggested that the Triphala formulations might possess better efficacy than scopolamine and ondansetron in preventing haloperidol-induced complications. More research in this direction might identify an alternative safe herbal medicine for preventing as well as treating the extrapyramidal side effects of antipsychotics.
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Background: Febrile convulsions in children are often triggered by high fever and can lead to acute neurological episodes with potential long-term consequences on cognitive function. Probiotics, particularly bifidobacteria, have demonstrated promising potential in modulating immune function and intestinal health. However, their role in neurological disorders, including febrile convulsions, is yet to be fully explored. Therefore, this study aimed to investigate the therapeutic impacts of Bifidobacterium bifidum on mitigating brain tissue damage and inflammation utilizing a mouse model experiencing febrile convulsions.
Methods: To assess the impact of Bifidobacterium bifidum on febrile convulsions, a mouse model was established by administering dry yeast suspension and pentylenetetrazol solution. Using this model, we examined the changes in anal temperature, convulsion onset time, and convulsion duration. Histological analysis through Hematoxylin and Eosin (H&E) staining was employed to study the neuronal morphology in the mouse hippocampus. Furthermore, the levels of serum Cyclic Adenosine Monophosphate (cAMP) and Prostaglandin E2 (PGE2) were assessed using Enzyme-Linked Immunosorbent Assay (ELISA). Additionally, protein expressions of cyclooxygenase-2 (COX-2), Inducible Nitric Oxide Synthase (iNOS), Gamma-Aminobutyric Acid Type A Receptor (GABAAR), and glial fibrillary acidic protein (GFAP) were determined through western blot analysis, while mRNA expressions of inflammatory markers Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and Tumor Necrosis Factor alpha (TNF-α) in hippocampal tissue were determined by quantitative Polymerase Chain Reaction (qPCR).
Results: In comparison to the model group, mice in the Bifidobacterium group exhibited a significant reduction in anal temperature (p < 0.05), an increase in the time to onset of convulsions (p < 0.05), a shorter duration of convulsive episodes (p < 0.05), and an enhanced expression of GABAAR protein (p < 0.05). Additionally, the Bifidobacterium group showed lowered serum levels of cAMP and PGE2 (p < 0.05), improved neuronal cell morphology in the hippocampus, and a decrease in the expression of COX-2, iNOS, and GFAP proteins in the brain tissue (p < 0.05). Furthermore, there was a substantial reduction in the hippocampal tissue levels of pro-inflammatory factors IL-1β, IL-6, and TNF-α mRNA (p < 0.05).
Conclusion: Bifidobacterium bifidum exhibits an effective antipyretic and anti-convulsant activity. Its mechanism may be attributed to its ability to reduce fever and inflammation in the brain.
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Objective: Neuroinflammation-induced cognitive dysfunction (NICD) relies on symptomatic treatment, with no causative treatment strategies available yet. Therefore, comprehensive investigations on the pathogenesis of NICD are crucial for the development of novel and effective therapeutic drugs. Hence, we aimed to elucidate the impact of Dexmedetomidine (Dex) in modulating nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing-3 (NLRP3) inflammatory vesicles for improving cognitive dysfunction.
Methods: The study employed both cellular and animal models. The HT22 cells were utilized to assess the impact of Dex on Lipopolysaccharide (LPS)-induced neuroinflammation. Cell viability was examined using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and changes in mitochondrial membrane potential were evaluated using the JC-1 kit. Furthermore, the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and NLRP3 were analyzed using Enzyme-Linked Immunosorbnent Assay (ELISA) and qPCR techniques. Additionally, NICD was induced in mice using LPS, and cognitive functions were assessed through the Morris water maze experiment. The expression levels of inflammatory markers in the hippocampal tissues of the mice were evaluated using the qPCR method.
Results: The Dex treatment was found to restore the LPS-induced reduction in HT22 cell viability (p < 0.05), as well as significantly reduced the cellular levels of TNF-α, IL-1β, IL-6, and NLRP3 (p < 0.05). Furthermore, Dex treatment restored the mitochondrial membrane potential of HT22 cells (p < 0.05). Additionally, we observed that Dex treatment significantly improved the declining cognitive ability of NICD mice (p < 0.05).
Conclusion: Dex can protect the learning and memory capabilities of cognitively impaired mice by inhibiting the expression of NLRP3 inflammatory vesicles as well as inflammatory factors.
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Background: The immune cells play a substantial role in the development and advancement of asthma. Therefore, we utilized mendelian randomization (MR) analysis to investigate the correlation between immune cells and asthma.
Objective: Given that immune cells play a crucial role in the onset and progression of the condition, this study aimed to elucidate the unclear links between immune cells and asthma.
Methods: The publicly available genetic data regarding asthma were obtained from the IEU database, and genetic variation points were selected as instrumental variables (IVS). Moreover, genetic information concerning immune cells was obtained from published literature. We used five different methods for dual sample mendelian randomization (MR) analysis, including inverse variance weighted (IVW), weighted median (WMI), MR-Egger regression, simple mode (SM), and weighted mode (WM). Furthermore, sensitivity analysis was utilized to examine the heterogeneity, horizontal pleiotropy, and stability of the outcomes.
Results: IVW results showed that B-cell Activating factor of the TNF family receptor (BAFF–R) on B cell, BAFF–R on IgD- CD27- B cell, BAFF–R on IgD+ CD24- B cell, BAFF–R on IgD+ CD38dim B cell, CD33br HLA DR+ CD14dim myeloid cell, CD25 on B cell, CD25 on IgD+ CD24- B cell, CD25 on IgD+ CD38- naive B cell, CD25 on naive-mature B cell, CD25 on transitional B cell, CD33 on basophil, CD33 on CD14+ monocyte, CD33dim HLA DR+ CD11b- myeloid cell, CD33 on CD66b+ myeloid cell, CD38 on IgD- CD38dim B cell, CD86 on myeloid dendritic cells (DC), HLA DR on CD14- CD16+ monocyte, IgD+ CD38br lymphocyte, and transitional lymphocyte may be the risk factors of asthma. Moreover, CD11b on CD14+ monocyte, CD24 on IgD+ CD38br B cell, CD28 on CD45RA+ CD4+ Treg, CD45 on NK, HLA DR+ CD3- NK, HLA DR+ NK cell, IgD- CD38- B cell, PDL–1 on CD14+ CD16- monocyte, and plasmacytoid dendritic cells (DC) were identified as protective factors for asthma.
Conclusion: This study explored the causal relationship between asthma and immune cells and identified immune cells correlated with asthma development. These immune cells may become new biomarkers or therapeutic targets, provide better treatment options for the prevention and treatment of asthma, and promote the understanding of asthma.
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Background: Coronary heart disease (CHD) is a common cardiovascular disease in clinical settings, which often combines with psychological disorders. Therefore, this study aimed to investigate the impact of flupentixol-melitracen in combination with psychotherapy on CHD patients complicated with psychological disorders.
Methods: A total of 120 CHD patients with psychological disorders were divided into two groups: the control group (n = 60) and the observation group (n = 60). The patients in the former group received flupentixol-melitracen based on conventional therapy, while the latter group was additionally treated with psychotherapy on the basis of the control group. Moreover, before and after treatment, the depression and anxiety levels in patients were evaluated utilizing the scores of the Beck Depression Inventory (BDI), the Spielberg State-Trait Anxiety Inventory form 1 (STAI-state), and Spielberg State-Trait Anxiety Inventory form 2 (STAI-trait). Furthermore, the quality-of-life scoring was assessed using the questionnaire, and serum factor levels were determined by commercial kits.
Results: Compared to the levels before treatment, the BDI, STAI-state, and STAI-trait scores, hypersensitive C-reactive protein (hs-CRP), lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-α), nuclear factor-kappa B (NF-κB), and substance P (SP) were significantly decreased in both groups after treatment (p < 0.05). However, their levels were substantially alleviated in the observation group compared to the control group (p < 0.01). Furthermore, the interleukin-10 (IL-10) and 5-hydroxytryptamine (5-HT) levels were higher in the observation group compared to the control group (p < 0.001). After treatment, there were no abnormalities in blood pressure, blood and urine routine, and hepatorenal function in the two groups.
Conclusion: Flupentixol-melitracen in combination with psychotherapy can relieve depression and anxiety in CHD patients with psychological disorders. Furthermore, this method can improve the inflammatory level and quality of life of patients.
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Background: Heart failure (HF) is one of the most common complications of diabetes mellitus. This study aimed to investigate the potential roles of dual specificity phosphatase 5 (DUSP5), a negative regulator of mitogen-activated protein kinase signaling, in diabetes-related HF.
Methods: Sprague dawley rats were randomly divided into the sham group, streptozotocin (STZ) group, STZ + vector group, STZ + Ad-DUSP5 group and vehicle group, and a group that was intravenously administered DUSP5-nanoparticle (NP) that carried the peroxisome proliferator-activated receptor alpha (PPARα) antagonist GW-6471. Triphenyl tetrazolium chloride staining was used to analyze the infarct area. The apoptosis of cardiomyocytes was determined using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling assay. For in vitro assays, mRNA expression was determined using quantitative reverse transcription-PCR; protein expression was detected using western blotting; protein localization was determined using immunofluorescence assay; and cell apoptosis was analyzed using flow cytometry.
Results: DUSP5 expression was decreased in patients with diabetes-related HF, as well as in the in vitro model (p < 0.05). However, overexpression of DUSP5 inhibited the apoptosis of cardiomyocytes and fatty acid oxidation (p < 0.05). Moreover, DUSP5 mediated the nuclear translocation of PPARα (p < 0.05). By contrast, overexpression of PPARα promoted fatty acid oxidation and the apoptosis of cardiomyocytes (p < 0.05). The in vivo assay showed that DUSP5 overexpression inhibited the infarct area and death of cardiomyocytes (p < 0.05). Additionally, DUSP5-NP that delivered GW-6471 markedly alleviated heart damage induced by diabetes mellitus (p < 0.05).
Conclusions: Our findings suggest that DUSP5 exerts a protective effect on diabetes-related HF by suppressing PPARα-dependent fatty acid oxidation. Therefore, DUSP5 may be a potential target for diabetes-related HF.
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Background: In the context of glucocorticoid-induced femoral head necrosis, the overexpression of peroxisome proliferator-activated receptor γ (PPARγ), induced by glucocorticoid (GC), inhibits adipogenesis and promotes osteogenesis. Some studies have found that the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) pathway mediates the homing of bone marrow mesenchymal stem cells (BMSCs). However, the mechanism of BMSCs homing regulated by GC is not fully understood. In this study, we aim to investigate the mechanism of how GC regulates BMSCs homing through PPARγ from the glucocorticoid receptors (GR) downstream, based on the regulatory signal ahead of the CXCR4.
Methods: BMSCs were cultured, dexamethasone (DXMS) was applied to intervene the BMSCs, and the expression sites of GRα, PPARγ and CXCR4 were detected by immunofluorescence. The expression changes of cytokines GRα, PPARγ and CXCR4 after cell intervention were detected by quantitative real time polymerase chain reaction (qRT-PCR) and Western blot (WB) to explore cellular chemokines and their signaling pathways.
Results: DXMS enhanced the expression of PPARγ and inhibited the expression of SDF-1 and CXCR4. The results revealed that the G protein-coupled receptor was involved in DXMS-regulated expression of SDF-1 and CXCR4, but did not play a major role, and this effect was GR dependent. The Western blot results showed that the downstream SDF-1/CXCR4 was significantly enhanced after GR silencing, suggesting that GR was involved in the BMSCs homing (p < 0.05). After DXMS treatment, the expression of SDF-1 and CXCR4 in BMSCs was inhibited, while PPARγ expression was significantly increased (p < 0.05). The fluorescence quantitation and the Western blot results showed a significant increase in the expression of SDF-1 and CXCR4 after PPARγ silencing (p < 0.05), suggesting the involvement of PPARγ in the expression of BMSCs. No significant change was observed in GR expression when PPARγ was inhibited, suggesting that GR is located in upstream of PPARγ. Additionally, the expression of SDF-1 and CXCR4 decreased significantly upon the addition of DXMS (p < 0.05). The inhibition of SDF-1 and CXCR4 by PPARγ is not complete, indicating the existence of other regulatory mechanisms. The PPARγ gene plays a crucial regulatory role in the DXMS-regulated expression of SDF-1 and CXCR4.
Conclusions: DXMS inhibited the homing of BMSCs by upregulating PPARγ through genomic pathways. PPARγ plays a significant regulatory role in the downregulated expression of SDF-1 and CXCR4.
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Background: Cell pyroptosis and dysbiosis of the gut microbiota are closely related to the pathogenesis of Ankylosing Spondylitis (AS). Capsaicin, an active component in chili peppers, has demonstrated anti-inflammatory and antioxidant potential. This study aims to explore the therapeutic effects of capsaicin on a mouse model of AS and its underlying mechanisms.
Methods: The AS mouse model was established and divided into control, AS model, capsaicin-treated, and sulfasalazine (positive control drug) treated groups. Cytokines in serum were detected by Enzyme-Linked Immunosorbent Assays (ELISA). The activation status of pyroptosis-related proteins and the nuclear factor kappa-B (NF-κB) pathway in spinal joint tissues were analyzed by Western blot. The function of the intestinal mucosal barrier was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Additionally, the composition of the gut microbiota was analyzed.
Results: Capsaicin inhibited tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-17A in the serum of AS mice and increased IL-10 (p < 0.01). In the spinal joint tissues, capsaicin effectively inhibited pyroptosis-related proteins such as NOD-like receptor thermal protein domain associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD) (p < 0.01), thus reducing cell pyroptosis. Furthermore, capsaicin inhibited the activation of the NF-κB pathway (p < 0.01), improved the function of the intestinal mucosal barrier, increased levels of beneficial probiotics such as Lactobacillus and Bifidobacterium (p < 0.001), and decreased levels of harmful bacteria including Enterococcus faecalis (p < 0.05) and Escherichia coli (p < 0.001).
Conclusion: This study confirms that capsaicin alleviates inflammation and pathological damage in AS mice by inhibiting the pyroptosis pathway, repairing the intestinal barrier, and regulating the composition of the gut microbiota.
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Background: Our study aimed to examine the causal relationship between total bilirubin and albumin levels and the risk of developing lung cancer (LC). Previous studies have suggested that the antioxidant properties of these two biomarkers may potentially inhibit cancer development. However, the available evidence on the relationship between total bilirubin and albumin levels and the risk of LC remains inconsistent.
Method: We conducted a two-sample Mendelian randomization (TSMR) study to investigate the association between total bilirubin and albumin levels and the risk of developing LC and assess their causality. We retrieved aggregate statistical datasets from publicly accessible genome-wide association studies (GWAS) of bilirubin and albumin and utilized them as the exposure.
Results: Our findings indicated that bilirubin and albumin levels were associated with an increased risk of LC. The findings were as follows: bilirubin: odds ratio (OR) = 1.341%, 95% confidence interval (CI): 1.076–1.672, p = 0.009; albumin: OR = 1.582%, 95% CI: 1.077–2.323, p = 0.019.
Conclusion: This TSMR analysis indicates that bilirubin and albumin levels positively correlate with an increased risk of LC. These findings contribute to a deeper comprehension of the causes of LC and offer insights into its prevention.
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Background: Cytokines are molecules that play a crucial role in the development of childhood pneumonia. This study aims to investigate the relationship between gene polymorphisms of interleukin (IL)-6 and IL-10 and the susceptibility to childhood pneumonia.
Methods: A total of 200 child patients with pneumonia and 200 healthy children were assigned to the disease group and control group, respectively. Peripheral blood was collected from both groups, and the polymorphisms were analyzed by sequencing. Additionally, the serum levels of IL-6, IL-10, and C-reactive protein were analyzed.
Results: The frequencies of certain alleles and genotypes of IL-6 and IL-10 gene polymorphisms were found to be higher in the disease group compared to the control group (p < 0.05). Specifically, the allele C of IL-6 gene polymorphism rs762371056, allele A of IL-6 gene polymorphism rs762759043, and allele A of IL-10 gene polymorphism rs570186303 were more frequent in the disease group. Additionally, the disease group exhibited higher frequencies of genotype CC of rs762371056, genotype AA of polymorphism rs762759043, and genotype AA of rs570186303 (p < 0.05). The two groups also differed in the distributions of the dominant model of rs762759043 and the recessive model of rs570186303 (p < 0.05). Besides, there were differences in the distributions of haplotype CA of rs762371056 and rs762759043 and haplotypes AA, AG and GG of rs570186303 and rs575853731 between the two groups (p < 0.05). Child patients with genotype TC had higher levels of serum IL-6, while the levels of serum IL-10 were lower in child patients carrying genotype AA. Child patients with genotype AA had a distinctly higher level of serum C-reactive protein (p < 0.05).
Conclusions: IL-6 and IL-10 gene polymorphisms have been found to be correlated with susceptibility to childhood pneumonia.
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Background: Colorectal cancer (CRC) ranks as the second most common gastrointestinal malignancy globally, surpassed only by stomach cancer in incidence. Colorectal cancer (CRC) is recognized as the second most prevalent gastrointestinal cancer worldwide, with stomach cancer being the only cancer that surpasses it in terms of incidence.
Purpose: This research aims to examine the possible anti-carcinogenic effects of Urolithins A, B, C, and D, which are metabolites present in pomegranate juice. These metabolites will be compared to established drugs such as folinic acid, doxorubicin, and 5-fluorouracil (5-FU), often used in treating CRC.
Method: In this study, we investigated the interactions between the epidermal growth factor receptor (EGFR) and three proteins, namely human epidermal growth factor receptor HER3 (Protein Data Bank (PDB) code: 3LMG), HER2 (PDB code: 3PP0), and HER1 (PDB code: 4AG8), utilizing the Protein Data Bank (PDB) principles. The findings of our study demonstrate the presence of persistent and reliable interactions within the protein-ligand complexes, specifically in the cases of 3PP0, 3LMG, and 4AG8, as indicated by the root mean square deviation (RMSD) values.
Results: The 3PP0 complex demonstrated RMSD values spanning from 1.17 to 3.23 Å. The 3LMG complex exhibited root RMSD values ranging from 1.16 to 2.93 Å, with a standard deviation of 0.25. Similarly, the 4AG8 complex showed root mean square deviation of RMSD values ranging from 1.27 to 3.35 Å, accompanied by a standard deviation of 0.42. The root mean square fluctuations (RMSFs) observed in these complexes exhibited a range spanning from 0.42 to 7.65 Å, providing more evidence of the stability of the interactions. The endurance of Urolithin A (Uro A) was established through an investigation using density functional theory (DFT), yielding an E value of 4.2700 eV, energy of the highest occupied molecular orbital (EHOMO) of –5.8560 eV, and energy of the lowest unoccupied molecular orbital (ELUMO) of –1.5860 eV. Uro A's in vitro anticancer potential has been evaluated through human colon adenocarcinoma cell line (HT-29) cell lines. The results of anticancer potential revealed that Uro A exhibited an half maximal inhibitory concentration (IC50) value of 120.4087 ± 1.113, whereas doxorubicin showed a slightly lower IC50 = 117.89 ± 0.537. Uro A has demonstrated promising therapeutic effectiveness by engaging many pathways, such as inducing apoptosis, increasing the expression of pro-apoptotic genes (p53 and p21), inhibiting B-cell lymphoma 2 (Bcl-2), activating caspase and inhibiting protein kinase B (AKT) 1 and 2, and reducing levels of reactive oxygen species (ROS) in CRC cells. Our study in the field of network pharmacology has revealed encouraging possibilities for the treatment of CRC. This study offers a complete analysis of the mechanisms contributing to the possible anti-CRC effects of urolithin polyphenol complexes. Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADMET) analysis reveals the promising potential of Uro A required for future drug development.
Conclusions: Our findings offer valuable insights for future CRC research and therapeutic strategy development, particularly in inhibiting AKT 1 and 2 and activating caspases to promote apoptosis, thereby contributing to effective CRC management.
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Background: Toll-like receptor (TLR) 7 suppresses non-small cell lung cancer (NSCLC) progression and enhances natural killer (NK) cell function. Therefore, this study aimed to elucidate the underlying mechanism of TLR7 enhancing the influences of NK cells on the viability and proliferation of NSCLC cells.
Methods: Identification of NK cells was conducted using flow cytometry. The expression levels of TLR7 and spliced form of x-box binding protein 1 (XBP1s) in lung adenocarcinoma, NK cells, and NSCLC cells were assessed through online website, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blot. After overexpressing or silencing TLR7 in NK cells, their impact on the activity and proliferation (immunofluorescence) of NSCLC cells was determined. Furthermore, after transfecting NSCLC cells with TLR7 overexpression plasmid and short hairpin RNA targeting XBP1s (shXBP1s), the colony formation capabilities of NSCLC cells and their sensitivity to NK cells were evaluated.
Results: NK cells overexpressing TLR7 exhibited increased viability, high XBP1s expression, and enhanced inhibitory effect on the viability and proliferation of NSCLC cells (p < 0.01). Furthermore, TLR7-overexpressing NSCLC cells demonstrated stronger sensitivity to NK cells, but this effect was reversed upon XBP1s silencing (p < 0.05). The vitality and proliferation of NSCLC cells were inhibited by TLR7 overexpression and/or XBP1s silencing (p < 0.05). TLR7 or XBP1s expression in NSCLC cells was upregulated by TLR7 overexpression or XBP1s silencing (p < 0.05).
Conclusion: This study confirmed that TLR7 enhances the inhibitory effect of NK cells on the viability and proliferation of NSCLC cells by upregulating XBP1s expression.
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Background: Lung adenocarcinoma (LUAD), a malignant tumor, poses a significant threat to human life, with easy metastasis being the primary reason for its low survival rate. Therefore, this study aimed to identify specific biomarkers and molecular mechanisms underlying early metastasis, providing a solid foundation for developing novel LUAD therapies.
Methods: The potential modules associated with LUAD metastasis were analyzed through weighted gene co-expression network analysis, and genes in the key modules were used for functional enrichment. Differentially expressed genes between metastatic and non-metastatic LUAD patients were analyzed using the “limma” package. Blood samples were collected to analyze and validate the expression of target genes. Functional assays were performed to investigate the impacts of cell division cycle 25 A (CDC25A) knockdown on cancer cell proliferation, migration, and cell cycle progression.
Results: CDC25A was upregulated in LUAD metastasis, and its overexpression was associated with poorer survival. CDC25A was significantly overexpressed in patients with LUAD metastasis (p < 0.0001). Furthermore, CDC25A knockdown inhibited LUAD cell proliferation (p < 0.01), migration (p < 0.0001), and invasion (p < 0.0001), as well as induced G1 cell cycle arrest. Additionally, suppressing CDC25A expression significantly reduced the expression of cyclin D1 (p < 0.001), cyclin-dependent kinase 4 (CDK4) (p < 0.001), and cyclin-dependent kinase 6 (CDK6) (p < 0.0001).
Conclusion: Our findings demonstrate that CDC25A enhances early LUAD metastasis by promoting cell cycle progression. Therefore, targeting CDC25A could be a potential therapeutic approach to suppress metastasis in LUAD patients.
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Background: Rhizoma paridis total saponins (RPTS) constitute the principal bioactive compound in Rhizoma paridis, demonstrating anticancer properties in various tumor types. However, its mechanism of action in osteosarcoma (OS) remains unclear. This study aimed to elucidate the role of RPTS on OS cells and tumor progression, focusing on its modulation of Solute Carrier Family 7 Member 11 (SLC7A11)-mediated ferroptosis.
Methods: 143B cells were cultured in vitro, and assays were conducted to assess cell viability, proliferation, apoptosis, migration, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential, ferroptosis-related proteins, and epithelial-mesenchymal transition (EMT) markers. Nude mice were subcutaneously injected with 143B cells to establish an osteosarcoma mouse model. Tumor volume and weight were recorded. EMT process markers and ferroptosis-related protein expression were detected in the tumor tissues.
Results: In vitro experiments revealed that RPTS significantly inhibited cell viability, proliferation, and migration and promoted apoptosis (p < 0.05). Moreover, RPTS increased intracellular ROS accumulation and reduced mitochondrial membrane potential (p < 0.05). RPTS inhibited the EMT process, upregulated p53 protein expression, and downregulated glutathione peroxidase 4 (GPX4) and SLC7A11 expression in 143B cells (p < 0.05). Overexpression of SLC7A11 rescued RPTS-induced ROS accumulation and ferroptosis in 143B cells (p < 0.05), and significantly increased RPTS-induced inhibition of cell proliferation and migration (p < 0.05). In vivo, RPTS significantly suppressed tumor growth and EMT markers, upregulated p53 protein expression and decreased GPX4 and SLC7A11 protein expressions (p < 0.05).
Conclusion: RPTS induced ferroptosis in osteosarcoma by inhibiting SLC7A11 expression and regulated cell viability, proliferation, apoptosis, migration, and EMT processes, demonstrating an inhibitory effect on osteosarcoma.
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Background: LncRNA taurine up-regulated gene1 (TUG1) is a valuable lncRNA that is abnormally expressed in a number of tumor types. However, investigations into its expression, prognostic implications, and associations with the tumor microenvironment and immunity remain limited. In this study, we evaluated the prognostic value and oncogenic potential of TUG1, and its relationship with pathological parameters, immune infiltration, and cancer drug sensitivity.
Methods: Using data from The Cancer Genome Atlas (TCGA), Sangerbox, and the Cancer Cell Line Encyclopedia (CCLE), we analyzed TUG1 expression. Kaplan-Meier and Cox regression analyses were employed to evaluate the prognostic significance of TUG1 in pan-cancer. The association between TUG1 expression and methylation, tumor mutational burden (TMB), microsatellite instability (MSI), immune infiltration, immune checkpoints, and drug sensitivity was examined.
Results: In adrenocortical carcinoma (ACC) and liver hepatocellular carcinoma (LIHC), TUG1 overexpression was related to poorer overall survival (OS). In glioblastoma multiforme (GBM), lower grade glioma (LGG) and pheochromocytoma and paraganglioma (PCPG), increased TUG1 was related to better OS. In ACC and LGG, TUG1 may be an independent prognostic factor. Gene set enrichment analysis (GSEA) highlights the involvement of TUG1 in various tumorigenic and signaling pathways. Additionally, TUG1 was associated with TMB in 12 tumor types and with MSI in 11 cancer types. TUG1 expression was positively correlated with Chelerythrine, Nelarabine, Methylprednisol, AZD-9496, and ZM-336372, while it negatively correlated with CG-806, BPTES, Vincristine, AZD-4547, CFI-400945, XR-5944, and Danusertib.
Conclusions: Our findings revealed dysregulated TUG1 expression in the human pan-cancer dataset. Drug sensitivity analysis suggested a potential association between TUG1 and drug resistance of specific drugs. Moreover, TUG1 expression was correlated with immune checkpoint genes, immune cell infiltration, and the tumor microenvironment across various cancers, underscoring its potential as a promising target for tumor prognosis and treatment. Our findings highlight the fundamental impact of TUG1 across multiple cancer types, offering insights that could pave the way for novel therapeutic strategies in cancer patients.
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Background: Induction of immunogenic cell death (ICD) breaks down the immunosuppressive tumor microenvironment (TME) and controls tumor progression, but the correlation between glioblastoma (GBM) and ICD is unclear. Therefore, this study aims to investigate the potential prognostic value of ICD-associated genes in GBM.
Methods: We collected 34 ICD-related genes from various sources. Utilizing public databases, we extracted relevant GBM data and delineated prognosis-related ICD gene modules using weighted gene co-expression network analysis (WGCNA). Least absolute shrinkage and selection operator (LASSO) algorithm was employed to develop a risk model, whose accuracy was confirmed by including an independent Gene Expression Omnibus (GEO) dataset. The biological functions and pathways associated with these signals were analyzed by performing enrichment analysis, and the tumor immune infiltration capacity was evaluated. The R package oncoPredict was used to infer the drug sensitivity of patients in different risk groups using data from the Genomics of Drug Sensitivity in Cancer 2 (GDSC2) database with expression profiling.
Results: Thirty-four ICD-associated genes were differentially expressed in GBM samples and two gene modules significantly associated with prognosis were identified. Based on these gene modules, vitamin D receptor (VDR) and cell death-inducing DFF45-like effector B (CIDEB) were identified as two signature genes for the prognostic prediction of GBM. Subsequently, multivariate Cox analysis confirmed the validity of this signature as an independent factor for evaluating overall survival in GBM. Receiver operating characteristic (ROC) curves also supported an effective prediction of the signature (1-year area under the ROC curve (AUC): 0.667; 3-year AUC: 0.727; 5-year AUC: 0.762). We observed that the high-risk group had higher immune cell infiltration and sensitivity to some drugs.
Conclusions: This work developed a novel ICD-related prognostic model for GBM patients. Our findings highlight the potential of using ICD as a promising prognosis indicator in GBM, contributing to the current understanding of the intricate interplay between ICD and tumor microenvironment.
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Background: We aimed to explore the risk factors and differences in decreased kidney function across the different subtypes of patients with prediabetes and diabetes among rural Chinese residents.
Methods: A total of 7581 residents of a community in Songjiang District, Shanghai, who were older than 40 years, were enrolled in this cross-sectional survey. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and eGFR <60 mL/min/1.73 m2 was defined as decreased kidney function. Subjects were divided into normal glucose tolerance (NGT), prediabetes, and diabetes groups according to a 75-g oral glucose tolerance test (OGTT) or self-reported diagnosis of diabetes.
Results: Of the 7581 subjects, 3578 had NGT, 1581 had diabetes and 2422 had prediabetes. In our study, 2.9% (47/1581) of diabetic patients and 2.4% (60/2422) of prediabetes patients in our study had decreased kidney function. The eGFR in the diabetes (94.1 ± 14.4 mL/min/1.73 m2), combined glucose intolerance (CGI) (94.1 ± 13 mL/min/1.73 m2) and impaired glucose tolerance (IGT) (93.1 ± 13.7 mL/min/1.73 m2) groups was significantly lower than that in the NGT (95.7 ± 12.3 mL/min/1.73 m2) and impaired fasting glucose (IFG) (95.6 ± 12.4 mL/min/1.73 m2) groups (p < 0.001). Older age, age ≥60 years, female sex, and higher uric acid (UA) levels were common risk factors for decreased kidney function in the prediabetes and diabetes groups. Elevated levels of high-density lipoprotein cholesterol (HDL-C) were identified as a risk factor, while body mass index (BMI) ≥24 kg/m2 was a protective factor against decreased kidney function in the prediabetes group. The area under the receiver operating characteristic (ROC) curve (AUC) of UA for predicting decreased kidney function was 0.7935 (95% Confidence interval (CI) 0.7058, 0.8329) in patients with diabetes and 0.7694 (95% CI 0.7058, 0.8329) in patients with prediabetes.
Conclusions: The prevalence of decreased kidney function in patients with different abnormal glycemic statuses was similar, whereas there were significant differences in eGFR levels among the different subtypes of prediabetes and diabetes. Older age, age ≥60 years, female sex, and hyperuricemia were common risk factors for decreased kidney function in prediabetes and diabetes patients. Reducing UA levels in prediabetes and diabetes patients may protect kidney function among rural Chinese residents.
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Background: Lung cancer (LC), a leading cause of cancer-related mortality worldwide, is a major health concern. The N6-methyladenosine (m6A) methylation, a pivotal RNA modification, plays a crucial role in the progression of LC. Therefore, this study aimed to identify m6A modification-related mechanisms underpinning LC progression.
Methods: Expression levels of chloride intracellular ion channel 5 (CLIC5), fat mass and obesity-associated protein (FTO), and the proto-oncogene tyrosine-protein kinase SRC (SRC) in LC cells and xenograft tumors were assessed utilizing bioinformatics tools, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot analysis. Furthermore, their interactions were predicted and validated using bioinformatics tools and/or Methylated RNA immunoprecipitation (MeRIP) assay. After CLIC5/FTO overexpression in LC cells, their roles in LC cell proliferation, migration, invasion, and tumorigenesis were examined employing cell counting kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU), Transwell, and murine xenograft assays.
Results: CLIC5 was downregulated in LC cells (p < 0.001). CLIC5 overexpression inhibited cell viability, proliferation, migration, invasion, and tumorigenesis in LC (p < 0.01). The m6A level was decreased while the FTO level was increased in LC cells (p < 0.001). FTO could interact with the m6A modification site on CLIC5, and the m6A methylation of CLIC5 was potentiated following FTO knockdown in LC cells (p < 0.001). Furthermore, FTO overexpression reversed the inhibitory effect of CLIC5 overexpression on the proliferation, migration, invasion, and tumorigenesis in LC (p < 0.05). Additionally, elevated SRC expression in LC could interact with CLIC5 (p < 0.001). CLIC5 overexpression diminished SRC expression, and the effect of CLIC5 on the SRC expression was reversed by FTO overexpression.
Conclusions: The downregulation of CLIC5, induced by FTO-mediated m6A demethylation, facilitates LC progression both in vitro and in vivo.
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Background: Preoperative staging is of great significance in determining treatment strategies and outcome evaluation. This study aims to investigate the diagnostic value of 64-slice spiral computed tomography (CT) in combination with serum tumor markers for lymph nodes and distant metastasis in gastric cancer.
Methods: We retrospectively analyzed the clinical data of 124 gastric cancer patients who underwent surgical treatment between April 2015 and April 2020. Based on the occurrence of lymph nodes and distant metastasis, the differences in CT examination results and tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and CA125 were compared.
Results: The serum CEA and CA199 levels and the rate of positive lymph node identified through CT were significantly lower in the N0 group compared to the N1-3 group (p < 0.05). Similarly, the serum CEA, CA125 levels, and the rate of the positive lymph node were significantly lower in the M0 group than those in the M1 group (p < 0.05). Additionally, in diagnosing preoperative lymph node metastasis in gastric cancer, the areas under the curve of serum CEA, CA199 levels, and their combined detection were 0.602, 0.694, and 0.708, respectively. The areas under the curve of serum CEA and CA125 levels and their combined detection in the diagnosis of preoperative distant metastasis of gastric cancer were 0.657, 0.838, and 0.888, respectively. The sensitivity, specificity, and accuracy of 64-slice spiral CT in the diagnosis of preoperative lymph node metastasis in gastric cancer were 87.32%, 90.56%, and 88.71%, respectively. The combined diagnosis with serum CEA and CA199 levels exhibited a sensitivity of 91.55%, a specificity of 86.79%, and an accuracy of 89.52%. The sensitivity, specificity, and accuracy of 64-slice spiral CT in the diagnosis of preoperative distant metastasis in gastric cancer were 71.43%, 90.63%, and 86.29%, respectively. The combined diagnosis with serum CEA and CA125 levels demonstrated a sensitivity of 92.86%, a specificity of 88.54%, and an accuracy of 89.52%.
Conclusion: 64-slice spiral CT combined with serum tumor markers can improve the diagnostic value of lymph node and distant metastasis of gastric cancer.
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Background: Extracellular vesicles (EVs) are carriers of DNA derived from parental cells, presenting a promising avenue for monitoring tumor progression. This aimed to investigate the relationship between EV DNA and the parental cell genome to establish a theoretical foundation for utilizing EVs to dynamically monitor tumor progression.
Methods: Utilizing a classical model of cell tumor evolution, B16 melanoma cell lines (B16-F0, B16-F1, and B16-F10) with varying metastatic potentials, we demonstrated that EVs derived from these cells harbor stable double-stranded (dsDNA) fragments ranging from 15 to 10,000 bp. DNase I enzyme digestion, SYBR Green I staining, and TapeStation system were employed for characterization. Whole genome profiling analysis revealed a high concordance between EV DNA and the mutant spectrum of parent cells, particularly regarding single nucleotide polymorphisms (SNPs). EVs contained evolutionary relevant mutation profile of melanoma cells with different metastatic potentials and had a comparable evolutionary relationship with the parent cells.
Results: (1) EVs derived from B16 melanoma cells contained stable dsDNA fragments ranging from 15 to 10,000 bp. (2) EVs DNA comprehensively covered the entire genome of parent cells. (3) EVs DNA exhibited strong consistency with small fragment mutations (SNPs, Inserts/Deletions) of parent cells, with decreasing consistency as mutation length increased. (4) EVs carried mutant gene profiles associated with melanoma cell progression and had similar evolutionary relationships with parent cells.
Conclusions: This study underscores the ability of EVs DNA to reflect the mutation status of parental cells and emphasizes their potential as biomarkers for monitoring tumor evolution. These findings offer a theoretical foundation for the dynamic monitoring of tumor progression using EVs DNA.
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Background: Dermatofibrosis diseases (e.g., keloids) are abnormal pathological results of the tissue healing process. They are characterized by the excessive proliferation of fibroblasts in the dermis and the excessive deposition of extracellular matrix. Existing treatments for dermatofibrosis have not achieved satisfactory results. The therapeutic efficacy of Binimetinib as a clinical agent for treating cutaneous malignancies in the field of fibrosis has not been extensively studied. Therefore, this study aims to investigate the antifibrotic activity of Binimetinib both in vitro and in vivo against dermal fibrosis, as well as elucidate its underlying mechanism.
Methods: In this study, we explored the potential effects and underlying mechanisms of Binimetinib on dermal fibrosis both in vitro and in vivo. In the in vitro experiments, we applied the Cell Counting Kit-8 (CCK-8) assay, wound healing assay, and western blotting to examine the inhibitory effects of Binimetinib on the proliferation, migration, and activation of mouse primary dermal fibroblasts (PSFs) and human keloid fibroblasts (KFs). In the in vivo experiments, we established a bleomycin mouse dermal fibrosis model and a nude mouse subcutaneous keloid model to verify the inhibitory effect of Binimetinib on dermal thickening in bleomycin model mice and on growth in subcutaneous keloid model in nude mice. Additionally, we investigated the expressions of proteins related to the transforming growth factor-β1 (TGF-β1) signaling pathway.
Results: In vitro experiments showed that Binimetinib effectively suppressed the proliferation, migration, and activation of KFs and PSFs in a dose-dependent manner (p < 0.05). In vivo experiments revealed that Binimetinib attenuated dermal thickening induced by bleomycin (BLM), reduced hydroxyproline content, and reduced the expression of fibrosis markers in a bleomycin-induced dermal fibrosis model (p < 0.05). Moreover, in a nude mouse subcutaneous keloid model, Binimetinib not only inhibited keloid proliferation and weight gain but also suppressed the expression of fibrosis markers (p < 0.05). Further mechanistic studies indicated that Binimetinib inhibited both TGF-β1/recombinant SMAD family member (Smad) signaling and TGF-β1/non-Smad signaling pathways associated with fibrosis (p < 0.05).
Conclusions: In summary, our results confirm that Binimetinib effectively suppresses fibrosis both in vivo and in vitro by inhibiting the TGF pathway, demonstrating significant potential for fibrosis treatment.
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Background: Escherichia coli (E. coli O157:H7), a Shiga-like toxin-producing Escherichia coli (STEC) serotype, is harmful, especially for children, elderly people, and immunocompromised persons. This strain can induce serious enterocyte problems, requiring careful mitigation. We intend to study Lactobacillus' prophylactic ability against E. coli O157:H7-induced cellular damage in mouse enterocytes.
Methods: The binding affinity of bacterial intimin and its human target, integrin, was assessed using a docking study. Next, Lactobacillus supplementation was tested in E. coli O157:H7-infected mice enterocytes using transmission electron microscopy (TEM) and light microscope (LM). The rats, weighing between 100 and 200 g, were randomly categorized into three groups (n = 6): uninfected (control), STEC-infected, and probiotics + STEC-infected. The randomization process was conducted using a computer-generated method that considered factors such as age, sex, and initial body weight. This approach was employed to minimize potential biases during the grouping process. Subsequently, specimens from the ileum were meticulously examined utilizing both transmission electron microscopy (TEM) and light microscopy (LM).
Results: ClusPro showed Lactobacillus bound more efficiently than E. coli (–632.5). In STEC-infected mice, LM revealed intestinal epithelial cells (IECs) compromises that probiotic improved. Moreover, TEM showcased structural disruptions in infected mice, rectified by probiotics. Statistical scrutiny, using parameters such as the number of intact microvilli per enterocyte and the extent of membrane damage, underscored significant improvements in STEC-infected mice treated with probiotics, emphasizing their pivotal role in preserving cellular integrity.
Conclusions: Certain probiotics may protect enterocytes from pathogens. These results imply that probiotics may reduce pathogenicity, offering new avenues for enteric infection research.
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Background: Asthma, a prevalent respiratory condition, is characterized by hyperresponsiveness and airway inflammation, and mitochondrial dysfunction and inflammation can exacerbate these symptoms. Therefore, this study aims to investigate whether matrine, known for its anti-inflammatory properties, attenuates mitochondrial fragmentation in asthmatic mice by activating the adenosine 5′-monophosphate-activated protein kinase (AMPK)/Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) pathway.
Methods: An asthma model was induced in BALB/c mice through sensitization with ovalbumin (OVA). The mice were given matrine (50 mg/kg, 100 mg/kg) and dexamethasone (2 mg/kg) through gavage feeding. Serum, lung tissue, and bronchoalveolar lavage fluid (BALF) were collected. Hematoxylin-eosin (H&E), Periodic Acid-Schiff (PAS) and immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blot analyses were used to assess changes in inflammation and oxidative stress levels in the airways and lung tissues. Furthermore, the expression levels of AMPK-dynamin-related protein 1 (DRP1)-NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) pathway proteins were evaluated in the lung tissues.
Results: Matrine treatment significantly reduced airway inflammation and mucus secretion in OVA-induced asthmatic mice (p < 0.05). Notably, inflammatory cell infiltration around the airway and mucus secretion in the airway, as evidenced by H&E and PAS staining, was substantially decreased in matrine-treated mice compared to the OVA group. Additionally, matrine significantly reduced T-helper cell type 2 (Th2) cytokine levels in mediastinal lymph nodes and BALF, as well as serum immunoglobulin (Ig)E levels (p < 0.05). Moreover, matrine exhibited antioxidant effects by enhancing superoxide dismutase (SOD) and catalase (CAT) activity while reducing malondialdehyde (MDA) expression and reactive oxygen species (ROS) accumulation in lung tissues (p < 0.05). Furthermore, the suppression of Caspase-1, NLRP3, and interleukin (IL)-1β by matrine indicated its anti-inflammatory properties (p < 0.05). Mechanistically, matrine increased AMPK phosphorylation, inhibited DRP1-mediated mitochondrial fission, and promoted mitochondrial fusion, suggesting its potential to alleviate airway inflammation (p < 0.05).
Conclusions: Matrine alleviates allergic airway inflammation in OVA-induced asthmatic mice by regulating the AMPK-DRP1-NLRP3 pathway.
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Background: Neuropathic pain poses a considerable challenge in clinical practice, affecting a significant portion of the global population. Existing treatments often provide only symptomatic relief and are associated with limited efficacy and adverse effects, highlighting the need for novel therapeutic strategies.
Methods: This study investigates the repurposing potential of digoxin for neuropathic pain management. Digoxin works as a soluble epoxide hydrolase (sEH) enzyme inhibitor, traditionally given for cardiac conditions. The neuropathic pain management (anti-nociceptive and anti-inflammatory role) of digoxin at 0.1 & 0.2 mg/kg was studied in a rat model having chronic constriction injury (CCI) and oxaliplatin-induced neuropathy. The reduction in pain was assessed through multiple behavioural assays like the acetone drop test, hot plate test, and pin-prick test. The mitochondrial functions, oxidative stress, & inflammation condition were estimated by biochemical analyses & gene expression studies of relevant markers. The histopathological examination depicts the morphology of tissue damage.
Results: Digoxin administration attenuated neuropathic pain behaviour and reduced neuroinflammation in both CCI and oxaliplatin-induced models. Additionally, digoxin treatment significantly improved mitochondrial function and decreased oxidative stress levels in rat models. Histopathological analysis revealed a reduction in axonal damage in the sciatic nerve. Gene expression analysis indicates downregulation of pro-inflammatory markers such as tumor necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-κB).
Conclusion: This study concludes that digoxin acts as a sEH inhibitor and holds promise for repurposing for neuropathic pain management.
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