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Recently, there has been increasing interest in the complex function of insulin, not only in its familiar role as a blood glucose-regulating hormone but also as a growth factor and biological regulator. This publication reviews the literature related to insulin resistance (IR) as a causative and exacerbating element in functional urological disorders, including overactive bladder syndrome (OAB). Patients with OAB or similar disorders often present with seemingly unrelated medical issues, such as metabolic syndrome (MetS), fibromyalgia (FM), psoriatic arthritis (PsA), and polycystic ovary syndrome (PCOS). However, these conditions interact with one another and can result in complex clinical scenarios. The literature reviewed delineates a pathophysiological circuit among these disorders, which share the chronic inflammation and underlying oxidative stress caused by IR. Growing evidence from both animal model studies and randomized clinical trials indicates that certain molecules, such as myo-inositol (MI), magnesium (Mg2+), folic acid (FoA), vitamin C (Vc), ferulic acid (FA), and vitamin D (Vd), are effective in treating functional bladder disorders and other syndromes linked to IR. Their success is attributable first and foremost to their insulin-sensitizing actions and, therefore, to their antioxidant and anti-inflammatory properties. Moreover, these treatments are generally safe and well-tolerated, whether used alone or in combination with existing therapies. Therefore, administering these substances to patients with conditions in which IR is known to be a key etiologic factor holds scientific justification and represents a promising therapeutic approach with potential future applications.
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The osteoblasts and the adipocytes share a common progenitor cell so there is a relationship between the bone and the adipose tissue. The differentiation between the adipocytes and the osteoblasts is regulated by extracellular signaling, coordination of many receptors, and by a series of nuclear interactions. The adipose tissue produces the adipokines that affect the activity of many organs. Leptin (LEP), in particular, can influence bone metabolism, acting on both the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). The effects are not yet fully defined. The Body Mass Index (BMI) affects bone density: as a result, low body weight is considered a risk factor involved in osteoporosis fractures with variable effects for the different skeletal sites. Leptin has an anabolic and anti-resorptive role on the bone but also a catabolic effect through the CNS. This hormone is able to influence bone metabolism indirectly through its influence on body weight and sex hormones. LEP is a basic hormone in the maintenance of functional balance not only in the osteoarticular system but in the entire organism acting as a messenger of the information concerning the long-time energy reserves indispensable for the most adequate responses to the maintenance of organic homeostasis. Physical exercise can be useful in the rehabilitation of sarcopenic obesity, linked to hyperleptinemia. In this review, we liked to highlight the many aspects exerted by leptin, so as to also covered some gaps found in other reviews. In addition, we also examined aspects of leptin activity other than bone, as the second purpose of this paper which is also evident from the title: “pleiotropic effects”.
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Several studies have demonstrated the heightened prevalence of colorectal cancer (CRC) among young black men. Most of these men present with already metastasized CRC. Cancer stem cells (CSCs) play a pivotal role in CRC metastasis and drug resistance. The plasticity of CSCs promotes therapeutic resistance by continuously dividing into different phenotypes thwarting therapeutic targets. Phenotypic changes affect the expression of highly heterogeneous surface biomarkers. Identifying molecular and cell surface biomarkers is important for diagnosis, decision-making, and determining clinical outcomes. Furthermore, CSCs promote cancer initiation, development, advancement, relapse, and therapeutic resistance by altering the tumor microenvironment (TME). Cancer-favoring molecular signaling pathways may contribute to differentiating CSCs into TME components that create favorable conditions conducive to cancer progression. In turn, different TME components may differentially stimulate CSCs, prompting proliferation into diverse cancer cell phenotypes. This review describes the mechanisms of CSCs in promoting CRC and elucidates how the TME and CSCs work synergistically to sustain cancer development, evoke relapse, and promote therapeutic resistance. These cancer-promoting mechanisms can be antagonized by identifying different CSC phenotypes and targeting them for cancer therapy.
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Abstract: Polycystic ovarian syndrome (PCOS) is a complicated metabolic and endocrine disorder characterized by androgen excess and chronic anovulation. Depending upon the diagnostic criteria 2% to 26% of women of reproductive ages have been diagnosed with PCOS. The etiology of PCOS is still unclear, but some evidence-based data exhibited multiple causes including ovarian hyperandrogenism, adrenal hyperandrogenism, hypothalamic-pituitary-ovarian dysfunction, obesity, insulin resistance and neuroendocrine dysfunction. PCOS is associated with elevated oxidative stress and anti-Müllerian hormone (AMH) levels. The imbalance of Myo-inositol/D-chiro-inositol also played a pivotal role in its etiology. The diagnosis of PCOS mainly depends on a few disease characteristics such as., oligo-ovulation or anovulation, clinical and or biochemical signs of hyperandrogenism, and polycystic ovaries. Polycystic ovarian patients have multiple clinical abnormalities such as chronic menstrual irregularities, oligo-ovulation or anovulation, recurrent abortions, sleep apnea, obesity, reactive hypoglycemia, hypertension, hirsutism, and male-pattern alopecia. Additional complications of PCOS are infertility, acne, oligomenorrhea, obesity, endometrial cancer, glucose intolerance, hyperlipidemia, pre-eclampsia, acanthosis nigricans, depression and anxiety, etc. The management and treatment of PCOS are typically symptom-based. Allopathic treatments include anti-diabetic, ovulation induction agents, glucocorticoids, statins, oral contraceptive pills (OCPs), anti-androgens, and eflornithine, with a lot of adverse effects and complications. Most recently, there are a lot of natural and alternative medicines available that have the potential to manage the syndrome. Homeopathic medicines are also very safe and effective with fewer side effects for patients. The aims of the present review are to provide an in-depth understanding of the pathogenesis of PCOS along with the comprehensive review of natural and alternative medicines that have excellent potential to manage the disease.
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Background: Currently, the combination of atezolizumab, chemotherapy and bevacizumab is used to treat patients with metastatic colorectal cancer, but the effects on overall survival and safety are controversial. Therefore, this study systematically evaluated the efficacy and safety of bevacizumab, chemotherapy and atezolizumab in the treatment of this disease.
Method: The English literature on treatment of colorectal cancer with bevacizumab and atezolizumab combined with chemotherapy from PubMed, Embase, Web of Science and the Cochrane Library 2023 was systematically searched until June. References were screened according to strictly defined inclusion and exclusion criteria. The included studies were evaluated for quality using Cochrane risk of bias Manual 5.3, and a meta-analysis was performed using Revman5.3. Included outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), ≥3 Grade adverse events, and immune-related adverse events.
Results: Three randomized controlled trials (RCTs) which included 791 colorectal cancer patients met the criteria. Meta-analysis results showed that bevacizumab and chemotherapy plus atezolizumab led to significantly greater PFS (hazard ratio (HR) = 0.75, 95% confidence interval (CI): 0.66~0.85, p < 0.00001) than bevacizumab and chemotherapy, with similar OS (HR = 0.97, 95% CI: 0.72~1.31, p = 0.84), ORR (odds ratio (OR) = 1.00, 95% CI: 0.67~1.49, p = 0.98), ≥3 Grade adverse events (OR = 1.37, 95% CI: 1.00~1.88, p = 0.05), and immune-related adverse events (OR = 3.47, 95% CI: 0.52~23.33, p = 0.20).
Conclusions: Bevacizumab and chemotherapy combined with atezolizumab can prolong PFS in patients with metastatic colorectal cancer, and its safety is comparable to that of bevacizumab and chemotherapy. However, there is no significant improvement in OS and ORR of patients, more studies are needed to prove it.
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Background: Parkinson's disease (PD) is the second most complex neurodegenerative disorder associated with the loss of dopaminergic neurons and has an unknown etiology. Several pathogenic mechanisms including inflammation, oxidative stress, protein dysfunction, apoptosis, mitochondrial dysfunction, abnormal α-synuclein, and autophagy are associated with this disorder. The current existing medications show limited efficacy and adverse health effects. Hence, in such a scenario, phytocompounds can provide an alternate way of effective treatment by repurposing these natural molecules using computational based approaches.
Methods: In this study, we explored various plant bioactives as possible inhibitors against the Parkin gene using in silico approaches. In the present study, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the bioactives were determined via predicting small-molecule pharmacokinetic properties (pkCSM). Moreover, the evaluation of molecular docking, dynamics, binding pockets, and protein-protein interactions of the protein was determined via AutoDock Vina, WEBnm@, Computed Atlas of Surface Topography of Proteins (CASTp), and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING).
Results: The findings obtained from molecular docking analysis revealed that Cytochalasin E was the most effective bioactive compound that showed the highest binding affinity of –8.6 kcal/mol when docked against the selected protein. In this study, all the bioactives followed Lipinski's rule of five except Sitoindoside IX. The CASTp tool identified the binding pockets in the protein with the top binding site having an accessible surface (AS) area of 250.39 Å2 and an accessible surface (AS) volume of 203.03 Å3 respectively. STRING tool determined the protein-protein interactions by visualizing protein structure.
Conclusion: The findings obtained from this study suggest that Cytochalasin E could be repurposed as a potential inhibitor targeting Parkin and these outcomes may prove significant in the process of drug designing. However, further in vitro and in vivo studies are required to validate these results.
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Background: Several reports have highlighted the beneficial impacts of caffeine on performance in various disciplines of Paralympic Powerlifting (PP), a sport renowned for its emphasis on maximal strength. Moreover, caffeine consumption within the context of PP has been found to be safe.
Objective: To examine the effects of caffeine intake before, during, and after PP training sessions at national level in Brazil.
Methods: Thirteen male PP athletes competing at national level (31.31 ± 10.13 years, 80.77 ± 22.66 kg) participated in the study. They were provided with either 9.0 mg/kg of Caffeine Anhydrous (CA) or Placebo (PL) and were evaluated using 45% of their one-repetition maximum (1RM) before and after training sessions, as well as 24 and 48 hours after sessions. Additionally, they performed five sets of five repetitions maximum (5x5), with assessments carried out during the first and fifth sets for all five repetitions. Evaluations focused on Mean Propulsive Velocity (MPV), Maximum Velocity (MaxV), and Power.
Results: No significant differences were observed with 45% 1RM. However, at 80% 1RM, CA demonstrated significant improvement compared to PL during Set 1 and Set 5 (p < 0.05).
Conclusions: CA exhibits promising ergogenic properties, enabling athletes to sustain training intensity throughout the session, even when working with heavier PP loads.
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Background: Proline-rich protein 11 (PRR11) is moderately expressed in the placenta and dysregulated in women with idiopathic recurrent pregnancy loss. The study aims to assess the role of PRR11 in early pregnancy loss (EPL).
Methods: The in vivo expression of PRR11 in chorionic villi of patients with EPL was evaluated using immunohistochemistry, western blotting, and Quantitative Reverse Transcription PCR (qRT-PCR). The in vitro effects of PRR11 on proliferation, apoptosis, migration and angiogenesis of human first-trimester extravillous trophoblast cell line (HTR-8/SVneo) were determined using 2,5-diphenyl-2H-tetrazolium bromide (MTT), flow cytometry, Transwells, and tube formation assays.
Results: PRR11 was reduced in in vivo chorionic villi of patients with EPL. PRR11 over-expression enhanced cell proliferation, while silencing of PRR11 promoted apoptosis of HTR-8/SVneo. Migration and angiogenesis of HTR-8/SVneo were promoted by PRR11. Early growth response protein 1 (EGR1), which positively correlated with PRR11, was also down-regulated in chorionic villi of patients with EPL. Knockdown of EGR1 attenuated PRR11 over-expression-induced up-regulation of transforming growth factor-beta 1 (TGF-β1), p-mothers against decapentaplegic homolog 2 (Drosophila) (p-Smad2) and p-Smad3, and EGR1 attenuated PRR11 silencing-induced down-regulation of TGF-β1, p-Smad2 and p-Smad3.
Conclusion: PRR11 increased EGR1 and promoted the activation of TGF-β/Smad to facilitate proliferation, migration and angiogenesis of HTR-8/SVneo.
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Background: This study aimed to investigate the role and possible mechanisms by which indole-3-acetic acid (IAA) mitigates inflammation in rheumatoid arthritis (RA).
Method: Bovine type II collagen was injected to construct mice with collagen-induced arthritis (CIA) to simulate RA. IAA was adopted for the treatment of CIA mice by oral administration. The involvement of aryl hydrocarbon receptor (AhR) in the therapeutic efficacy of IAA was investigated through CH223191 (an AhR antagonist). The severity of paw inflammation was assessed using qualitative clinical scoring. In addition, we measured Cytochrome P450 1A1 (CYP1A1) expression and AhR mRNA and protein levels, along with the serum levels of cytokines. The percentage of Regulatory T (Treg) and T helper 17 (Th17) cells in spleens was examined by flow cytometry.
Result: IAA treatment reduced paw swelling, erythema, and inflammation in CIA mice. CH223191 reduced the therapeutic effect of IAA, and reversed the decrease of serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-1β, IL-17A and IL-6 in IAA-induced CIA mice. The immunological imbalance was improved after IAA treatment in CIA mice. CH223191 reversed the decrease of Th17 cells in the spleen induced by IAA.
Conclusion: IAA treatment reduced paw swelling, erythema, and inflammation of CIA mice and restored the immunological balance in the spleen by regulating AhR.
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Objective: To determine the clinical efficacy of keyhole surgery for intracranial tumors, and its effect on tumor-specific growth factors.
Methods: In this retrospective study, clinical data of 86 patients with intracranial tumors admitted to our hospital between April 2019 and April 2022 were analyzed. The patients were assigned to either an observation group that received traditional craniotomy, or an experimental group treated with keyhole surgery. The indices of outcome measured were perioperative indices, clinical efficacy, cerebrospinal fluid neuropeptide level, tumor-specific growth factor level, inflammatory factor levels, and complications.
Results: The experimental group had shorter operative time, lower volume of intraoperative bleeding, shorter hospital stay and higher treatment efficiency than the observation group (p < 0.05). The experimental group had markedly higher levels of oxytocin (OT), arginine vasopressin (AVP), and beta-endorphin (β-EP), and lower levels of tumor-supplied group factor (TSGF), C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α), than the observation group (p < 0.05). There was a lower incidence of complications in the experimental group than in the observation group (p < 0.05).
Conclusions: Keyhole surgery effectively reduced operation time, volume of intraoperative bleeding, and levels of tumor-specific growth factor and inflammatory factors, and it improved levels of cerebrospinal fluid neuropeptide in patients with intracranial tumors.
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Background: Accurate and rapid detection of human T-cell lymphotropic virus type 1 (HTLV-1) is a critical aspect in monitoring and developing prevention strategies to reduce its transmission rates in blood donors. However, there are two challenges, the expensive reagents and labor-intensive process, faced by the development of HTLV-1 testing. Thus, a real-time loop-mediated isothermal amplification (RT-LAMP)-based method was used for the rapid detection of HTLV-1 in this article.
Methods: The PX gene (GenBank: L36905.1) of HTLV-1 was cloned into Escherichia coli DH5a plasmid pUC57 to construct a reference strain for HTLV-1 detection. RT-LAMP primers were designed for the PX gene, the experimental reaction system was optimized, and the specificity and sensitivity of the method were investigated.
Results: The optimal reaction system of 25 μL RT-LAMP contained 0.2 μM each of primers outer forward (F3) and backward (B3) primers, 1.6 μM each of forward inner primers (FIP) and backward inner primers (BIP), 0.8 μM each of loop forward (LF) and loop back (LB) primers, 1.2 mM deoxynucleotide triphosphates (dNTPs), 1.0 M betaine, 6 mM MgSO4, and 8 U Bst 3.0 DNA polymerase.
Conclusions: The HTLV-1 LAMP method was sensitive, specific, simple-to-operate, and inexpensive, and could be a new method for the rapid detection of HTLV-1.
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Background: Bacterial resistance to antibiotics and cancer cells resistance to chemotherapeutic drugs are two major public health issues. Thymus algeriensis Boiss. & Reut. and Artemisia herba-alba Asso are two common medicinal plants used to combat several pathologies, including bacterial infections and different types of cancer. This study aims to assess the cytotoxic, antibacterial and antifungal activities of each single essential oil and their combination in vitro and in silico.
Methods: The cytotoxicity was evaluated in vitro towards three cell lines: liver human hepatocyte carcinoma cell line, metastatic adenocarcinoma Michigan Cancer Foundation-7, and Anderson-Metastatic Breast 231. Antibacterial activity was tested by the disc diffusion method on three bacterial and two fungal strains. The subacute oral toxicity was performed to assess the potential toxicity of the studied Essential Oils (EOs) followed by an analysis of the blood biochemical parameters. Lastly, docking studies were performed to assess the antimicrobial effect of Thymol, Chrysanthenone, Camphor and Borneol.
Results: The results of the cytotoxicity test showed that there is a good dose-effect correlation between the essential oils and their mixture for the range of concentrations tested (0–50 μg/mL). However, the mixture induced a greater antiproliferative effect compared to the two oils tested separately against the three cell lines. The antibacterial and antifungal activities have revealed that the essential oil of Thymus (T.) algeriensis has an interesting antibacterial and antifungal activity against Bacillus subtilis and Penicillium digitatum with complete inhibition at 3.125 and 6.25 μg/mL, respectively. Similarly, Staphylococcus (S.) aureus had a very high sensitivity to the essential oil of Artemisia (A.) herba-alba with an inhibitory concentration of 3.125 μg/mL, as well as potent activity against Candida albicans and Penicillium digitatum, which were inhibited at 6.250 μg/mL. The subacute toxicity results showed no toxic effects in mice treated with the essential oils mixture (150 mg/kg) compared to the control group (p < 0.05). The molecular docking showed that thymol exhibited the highest activity among the molecules studied.
Conclusions: These studies show that the essential oils of T. algeriensis and A. herba-alba have great antiproliferative power important synergistic effect, and good antibacterial and antifungal activities.
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Background: Obsessive-compulsive disorder (OCD) is a chronic, general, and usually disabling disorder. A family-based study has illustrated that the risk of OCD was related to genetics. This meta-analysis aims to assess the association between solute carrier family 1 member 1 polymorphisms (rs301430 and rs301434) and OCD susceptibility.
Methods: The study comprehensively searched various databases without language restrictions, including the Cochrane Library database, PubMed, Embase, Web of Science, CNKI, CBM, VIP, and WanFang Data. The data were obtained before April 1, 2023, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were utilized and pooled in the analysis using Stata 17.0 software. Sensitivity analysis was conducted to analyze the robustness and reliability of the results, and Egger's test was used to examine the publication bias. Trial Sequential Analysis (TSA) was performed by TSA 0.9.5.10 Beta software to assess the required information size.
Results: Based on the data derived from eight articles with 3932 participants (2147 OCD subjects and 1785 controls), the risk of OCD and its subtypes were observed to be associated with solute carrier family 1 member 1 (SLC1A1) rs301434 polymorphism (overall OCD: G vs. A: OR = 1.19, 95% CI = 1.06–1.34; GG vs. AA: OR = 2.18, 95% CI = 1.36–3.49; GG+GA vs. AA: OR = 1.21, 95% CI = 1.01–1.45; early-onset OCD: G vs. A: OR = 1.19, 95% CI = 1.04–1.37; GG vs. AA: OR = 1.79, 95% CI = 1.03–3.10; late-onset OCD: GG vs. AA: OR = 3.25, 95% CI = 1.36–7.78; GG vs. GA+AA: OR = 3.22, 95% CI = 1.34–7.76; OCD in Asians: G vs. A: OR = 1.20, 95% CI = 1.00–1.44; GG vs. AA: OR = 3.72, 95% CI = 1.61–8.56; GG vs. GA+AA: OR = 3.70, 95% CI = 1.61–8.51). Meanwhile, no association was found between OCD susceptibility and SLC1A1 rs301430 polymorphism.
Conclusion: This meta-analysis demonstrates that the SLC1A1 rs310434 may be associated with OCD susceptibility, and more studies are needed to corroborate the conclusions.
Systematic Review Registration: PROSPERO: CRD42023426696.
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Background: Though sperm-associated antigen 5 (SPAG5) is highly expressed during the tumorigenesis and progression of various cancers, the impact of SPAG5 upon the most prevalent gynecologic cancer, endometrial cancer (EC), remains undefined. This study aims to investigate the impact of SPAG5 on EC cells.
Methods: SPAG5 expression in EC tissues and its correlation with the overall survival of EC patients were inspected by bioinformatics. Exogenously upregulating or downregulating SPAG5 expression in EC cells was realized via transfection. Examination of EC cell viability, invasion, migration and apoptosis was accomplished by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), Transwell and scratch assays and flow cytometry. Western blot and quantitative real-time polymerase chain reaction were used to measure the expression levels of SPAG5 and mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) pathway-associated proteins and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway-linked markers in EC cells.
Results: High expression pattern of SPAG5 was observed in EC tissues (p < 0.05) and cells (p < 0.001), and was associated with a shorter survival time of EC patients. SPAG5 expression was successfully upregulated and downregulated via transfection with SPAG5 overexpression plasmid and shSPAG5, respectively (p < 0.01). Overexpression of SPAG5 increased the viability, migration, and invasion, reduced the apoptosis, and elevated the levels of phosphorylated (p)-AKT, p-PI3K, p-AKT/AKT and p-PI3K/PI3K. SPAG5 downregulation resulted in the opposite results (p < 0.05). However, changes in SPAG5 expression were not correlated with the level of p-ERK or ERK.
Conclusion: Overexpression of SPAG5 drives in-vitro EC progression via activating the PI3K/AKT pathway.
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Background: Gestational diabetes mellitus (GDM) is a prevalent pregnancy-related metabolic disorder marked by impaired glucose tolerance. We investigated the expression of sodium-dependent glucose transporters 2 (SGLT-2) and their impact on glucose and lipid metabolism and autophagy in GDM mice. We used inhibition of SGLT-2 in GDM mice to observe the effects of Amp-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). The goal of this experiment was to explore the relationship between SGLT-2 and AMPK/SIRT1.
Methods: GDM model (Model group) and control group were established in pregnant mice. Mice in the Model group were treated daily with dagliflozin (Dapagliflozin), AMPK inhibitor, Dorsomorphin (BML-275) and AMPK activator, Acadesine (AICAR). After completion, a blood sample was drawn to test the fasting plasma glucose (FPG) and fasting insulin (FINS) values to calculate the homeostatic model assessment of insulin resistance (HOMA-IR). The expression of SGLT-2 and AMPK/SIRT1 was measured by Quantitative Real-time polymerase chain reaction (qRT-PCR), and the levels of glucose and lipid metabolism-related indexes were measured by the biochemistry instrument. Hematoxylin-Eosin (HE) staining was used to observe histopathological changes in placental tissue.
Results: The Model group exhibited higher levels of FPG, HOMA-IR, and FINS compared to the control group. AMPK/SIRT1 expression was downregulated, while SGLT-2 expression was upregulated (p < 0.05). Histopathological examination revealed severe placental tissue damage in the Model group. Inhibiting SGLT-2 led to increased expression of AMPK/SIRT1 (p < 0.05). Activation of AMPK decreased the expression level of SGLT-2, significantly ameliorating placental tissue damage in GDM mice, reducing FPG, FINS, HOMA-IR, and lipid metabolism (p < 0.05). Inhibition of AMPK had the opposite effects.
Conclusion: Elevated expression of SGLT-2 in GDM contributes to the accelerated pathological progression of the disease. Targeted molecular therapy focused on reducing SGLT-2 presents a promising avenue for future GDM treatment.
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Background: Diarrhea secondary to pediatric pneumonia is often caused by the imbalance of intestinal microbiota due to prolonged use of antibiotics in children, and is characterized by symptoms such as abdominal pain, diarrhea, and vomiting. In severe cases, significant electrolyte and fluid imbalance may occur, which can be life-threatening. It is of great importance to prevent diarrhea secondary to pediatric pneumonia.
Objective: This study was designed to evaluate the efficacy of probiotics in preventing diarrhea secondary to pediatric pneumonia by investigating the intestinal microecology and immune function recovery of patients.
Methods: A total of 308 children with pediatric pneumonia were recruited from January 2019 to March 2021, among them 300 cases were studied after exclusion of 8 cases of dropouts. The children were assigned to receive either routine treatment (control group) or probiotics (treatment group) at a ratio of 1:1, resulting in 150 children in each group. The primary outcome was clinical efficacy, and the secondary endpoint included intestinal microecology and immune function. We used enzyme-linked immunosorbent assay (ELISA) to determine the levels of cluster differentiation 4+ (CD4+) T cell and CD8+ T cell and assessed the immune function.
Results: A lower frequency of diarrhea and a shorter time-lapse before diarrhea episodes were shown in children treated with probiotics (14.66%) as compared to those with routine treatment (40.66%) (p < 0.05). Moreover, probiotics treatment resulted in markedly fewer and shorter diarrhea episodes and abridged length of hospital stay than routine management (p < 0.05). Probiotics provided significant improvement in the number of intestinal florae for the patients, as demonstrated by higher levels of bifidobacteria, lactobacilli, and enterococci and lower yeast levels than those with routine treatment (p < 0.05). Children in the probiotics treatment group showed markedly improved immune function than those in the routine management group, as evidenced by the higher CD4+ T cell and CD4+ T cell/CD8+ T cell levels and lower CD8+ T cell levels (p < 0.05).
Conclusion: Probiotics were shown to have preventative and therapeutic effect in the treatment of diarrhea secondary to pediatric pneumonia, such as shortening the length of hospital stay of patients, and enhancing their intestinal microecology and immunity, thereby improving the prognosis of patients.
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Background: Osteoporosis (OP) is a common disease in the elderly, which can easily lead to fractures. Curcumin can promote osteogenic differentiation to treat OP by regulating certain genes. The expression of related genes in the Wnt/β-catenin pathway is of great significance for osteogenic differentiation. However, the mechanism by which Curcumin regulates genes related to Wnt/β-catenin pathway has not been clarified.
Methodology: The target genes of Curcumin that regulate osteogenic differentiation were determined using network pharmacology, Protein-Protein Interaction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking. The toxicity of Curcumin was studied by Methyl Thiazolyl Tetrazolium (MTT) assay and cell cloning. The macroscopic regulation of Curcumin on osteogenic differentiation was further investigated by alkaline phosphatase (ALP) staining and activity assay, alizarin red staining and quantification. The microscopic expression differences of Wnt/β-catenin pathway-related mRNA and protein were detected by RT-qPCR and Western Blot.
Results: A total of 92 target genes were screened for Curcumin-regulated osteogenic differentiation. Among them, three target genes act on the Wnt/β-catenin signaling pathway. In addition, low concentrations of Curcumin (5 μM, 10 μM) were not toxic to the proliferation of rat bone marrow mesenchymal stem cells (rBMSCs) and enhanced ALP activity (p < 0.001), increased calcium salt deposition (p < 0.01), upregulated mRNA expression of catenin beta 1 (β-catenin), CREB-binding protein (Cbp), Protein kinase A (Pka), Lymphoid Enhancer-binding Factor 1 (Lef-1), Runt-related transcription factor 2 (Runx2), Myc proto-oncogene protein (C-myc) and Cyclin D1 (p < 0.05), downregulated the expression of glycogen synthase kinase-3β (Gsk-3β) (p < 0.05), upregulated the protein expressions of CBP, PKA, LEF-1, Runx2, c-myc, Cyclin D1 and β-catenin in the nucleus (p < 0.05), and downregulated the expression of GSK-3β (p < 0.05), thus boosting osteogenesis. By contrast, 15 μM Curcumin inhibited ALP activity (p < 0.05), downregulated the mRNA expression of β-catenin and Cbp (p < 0.05), upregulated mRNA expression of Gsk-3β (p < 0.05) and downregulated the protein expression of c-myc and Runx2 (p < 0.05), thereby inhibiting the osteogenic differentiation of rBMSCs.
Conclusions: Curcumin at 5 μM and 10 μM can promote the osteogenic differentiation of rBMSCs by activating the Wnt/β-catenin signaling pathway. Curcumin at 15 μM can inhibit the Wnt/β-catenin signaling pathway, thereby inhibiting the osteogenic differentiation of rBMSCs.
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Background: Amino acid metabolism (AAM) plays a significant role in the biological processes of cancer. However, the role of AAM in terms of prognosis, tumor-related immunity, and therapy effectiveness in patients with clear cell renal cell carcinoma (ccRCC) has not been thoroughly explored. Therefore, the present study aimed to explore the role of AAM in ccRCC from the aforementioned aspects.
Methods: In this study, we used RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) to construct an AAM-related risk model (AAMRSM) for ccRCC. We employed the least absolute shrinkage and selection operator (LASSO), Cox regression analyses, and random forest algorithm to develop the model.
Results: We discovered a strong correlation between the AAMRS and prognosis (p < 0.05). The nomogram, which was built using the AAMRS and several clinical parameters, demonstrated significant predictive power. In addition, individuals categorized by the AAMRS showed distinguishable immune status, T-cell-related immune factors, tumor mutation burden (TMB), and medical sensitivity (p < 0.05).
Conclusions: In conclusion, the association between AAMRS and prognosis, immunological landscape, and therapy effectiveness has been established. The use of AAMRSM can aid doctors in selecting more individualized and accurate treatments for patients with ccRCC.
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Background: Tropomyosin 1 (TPM1) is an important actin-binding protein and has been identified as a tumor suppressor in various malignant tumors. However, the role of TPM1 in colorectal cancer remains to be explored. This study aimed to clarify the specific function and mechanism of TPM1 in colorectal cancer.
Methods: To investigate the effect of TPM1 on cell proliferation, migration, and invasion, we constructed cell models with TPM1 knockdown and overexpression. Cytoskeletal changes were observed by phalloidin staining, and changes in epithelial-mesenchymal transition (EMT) markers were detected by Western blot.
Results: This study revealed that TPM1 expression was decreased in human colorectal cancer. Downregulation of TPM1 promoted cell migration, invasion, and proliferation. Moreover, loss of TPM1 decreased the stability of the cytoskeleton. Overexpression of TPM1 significantly inhibited the EMT process of colorectal cancer cells, while downregulation of TPM1 significantly promoted this key process involved in tumor metastasis.
Conclusions: The results showed that downregulation of TPM1 promotes colorectal cancer progression. The underlying mechanism may involve the reduction in actin stability, cytoskeletal rearrangement, and enhancement of cell migration and EMT.
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Background: Diabetes, a disease identified by high glucose levels in the bloodstream, is caused due to irregularities in insulin secretion or its action. These irregularities can have detrimental effects on various organs impacting vision; renal, nerve, and cardiac functions. The aim of the project was to investigate the ameliorative effect of aerial parts of Teucrium royleanum in the form of extracts on the biochemical alterations associated with oxidative stress and hyperglycemia.
Methods: After extraction and fractionations, the extracts were subjected to antioxidant and antidiabetic potential evaluations against diphenylpicrylhydrazyl (DPPH) free radical and alpha-glucosidase following the standard protocols. The extract was then fed to experimental animals after toxicity evaluations. The animals' blood glucose levels and other blood biochemical parameters, liver function, and renal function parameters were monitored throughout the 28-day treatment period in Streptozotocin (STZ) induced diabetic animals. The oxidative stress markers were also evaluated in the diabetic animal's blood.
Results: Ethyl acetate extract more potently inhibited DPPH radical and alpha-glucosidase with IC50 values of 76.12 and 55.12 μg mL-1 correspondingly. At the second and third weeks of treatment (14th and 21st day), the groups received Teucrium royleanum crude extract (Tr-Crd) at 150 and 300 mg/kg body weight (b.w), and Teucrium royleanum chloroform fraction (Tr-Chl) and Teucrium royleanum ethyl acetate (Tr-Eta) at 75 and 150 mg/kg b.w exhibited a significant reduction in blood glucose levels. At the end of the 28-day treatment, significant reductions in glucose levels were observed, with values of 138.9 ± 4.6 mg/dL and 115.7 ± 4.6 mg/dL (p < 0.001) for Tr-Eta at doses of 75 and 150 mg/kg b.w doses, respectively, approaching the levels of the normal control group (104.5 ± 5.4 mg/dL). The impact of treatment on the body weight of the rats was assessed during the 28 days. In the diabetic group, significant weight regain upon treatment with extract was observed like that of the control group. The diabetic groups administered with the samples significantly reduced Glycated hemoglobin A1c (HbA1c) levels compared to the control group. The administration of streptozotocin increased plasma levels of total cholesterol, low-density lipoprotein (LDL), and triglycerides (TG), as well as a decrease in the level of high-density lipoprotein (HDL), when compared to the normal group. Administration of samples significantly (p < 0.05, 0.01, and 0.001, n = 8) reduced the elevated levels of serum alanine transaminase (ALT) and alkaline phosphatase (ALP). Additionally, administering of the samples significantly reduced the elevated creatinine levels, indicating improved kidney function. The activity of superoxide dismutase (SOD), an antioxidant enzyme, was significantly increased in the sample-treated groups, reaching levels comparable to the normal control group (p < 0.001, n = 8). Similar results were observed in the activity of catalase (CAT), suggesting the antioxidant and antidiabetic potentials of the plant.
Conclusions: These findings suggested that Tr-Crd extract and its fractions could be used as an antidiabetic drug as ameliorate the alterations caused by streptozotocin injection. However, further studies in this connection are needed to evaluate its toxicological profile and isolate the responsible compounds in a pure state.
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Background: A previous study found that Kidney and Spleen Supplement Formula could induce apoptosis in renal cell cancer cells by enhancing autophagy. Atractylenolide I (AT-I), as one of the main active ingredients of Kidney and Spleen Supplement Formula, is believed to have anticancer and chemotherapy-enhancing effects. We mainly focused on the role and mechanism of AT-I in cisplatin chemotherapy of renal cell carcinoma.
Methods: Renal cell carcinoma cells were treated with different concentrations of AT-I or cisplatin, and the effects of cell viability and proliferation were determined using Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine (EdU) staining assays. Forkhead box-1 (FOXO1) mRNA levels were detected using quantitative real-time polymerase chain reaction, and autophagy-associated proteins were determined using Western bolt.
Results: AT-I concentration-dependently decreased cell viability and proliferation and enhanced the inhibitory effect of cisplatin on cell growth in renal cell carcinoma cells (p < 0.05). AT-I upregulated light chain 3 (LC3) II/LC3 I, Beclin 1, FOXO1, and autophagy-related gene 5 (ATG5) expression and decreased P62 protein levels (p < 0.05). Overexpression of FOXO1 enhanced the inhibitory effect of cisplatin on cell viability and proliferation, while FOXO1 silencing reversed the chemosensitizing effect of AT-I (p < 0.05). Moreover, AT-I promotion of ATG5, Beclin 1, LC3 II/LC3 I, and attenuation of P62 were also partially subverted by FOXO1 silencing (p < 0.01).
Conclusion: AT-I enhances cisplatin sensitivity in renal cell carcinoma cells through activation of FOXO1-ATG5 pathway-mediated excessive autophagy.
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Background: Gracillin has been shown to have anti-inflammatory activity, but its role in inflammatory bowel disease (IBD) remains unclear. This study aimed to examine the effects of Gracillin on IBD and its possible regulatory mechanisms.
Methods: NCM460 cell viability was measured using cell counting kit-8 assay after treatment with different concentrations of Gracillin or lipopolysaccharide (LPS). The levels of inflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tight junction proteins (zonula occludens-1 (ZO-1), Occludin, Claudin-1), succinate dehydrogenase subunit B (SDHB) and nuclear factor kappa B (NF-κB) pathway (p-P65, P65) were determined by quantitative real-time Polymerase Chain Reaction (qRT-PCR) or western blot. The monolayer integrity of the cells was measured using trans-epithelial electrical resistance. Additionally, the production of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release were examined using specific assay kits. After silencing SDHB via cell transfection, rescue experiments were carried out.
Results: Gracillin did not show any cytotoxicity to NCM460 cells. Upon administration of Gracillin, the cell viability, monolayer integrity, tight junction proteins (ZO-1, Occludin, and Claudin-1) and SDHB protein level were increased, whereas the mRNA level of inflammatory cytokines (IL-6 and TNF-α), mRNA and protein levels of iNOS and COX-2 were down-regulated in LPS-treated cells (p < 0.05). Furthermore, the activation of NF-κB pathway and the increased ROS production and LDH release induced by LPS, were suppressed by Gracillin in the cells (p < 0.05). Additionally, SDHB silencing reversed the regulatory effects of Gracillin on cell viability, inflammation, tight junction and NF-κB pathway in LPS-treated cells (p < 0.05).
Conclusion: Gracillin can block NF-κB pathway to reduce inflammation and improve intestinal barrier in IBD in vitro by up-regulating SDHB.
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Background: The field of pulmonary rehabilitation (PR) is gaining attention and research in clinical application year by year. This study aims to analyze the current status, hot topics, research frontiers and future trends of research in the field of pulmonary rehabilitation.
Methods: Based on the Web of Science Core Collection (WoSCC) database, articles on pulmonary rehabilitation published between January 1st, 2010, and July 1st, 2023, were retrieved. Only articles published in English were included. Collaborative network analysis of the annual number of publications, countries/regions, institutions, journals, keywords, authors, and co-citation analysis of references were conducted using CiteSpace 6.2.R2 Advanced and VOSviewer1.6.18 software.
Results: A total of 5408 articles related to pulmonary rehabilitation were included in the study, with 703 keywords. The United States is the leading country with the most annual publications, and Maastricht University is the most active institution. The International Journal of Chronic Obstructive Pulmonary Disease is the most published, while the American Journal of Respiratory and Critical Care Medicine is the most cited. Spruit Martijn A, Franssen, and Frits ME are the most published researchers in this field. The keywords co-occurrence analysis showed that the current research hotspots and frontiers are: ① fully revealing the clinical effect and potential of pulmonary rehabilitation, and deeply exploring its influence on related indicators and comorbidities of various chronic respiratory diseases, ② continuing to improve the pulmonary rehabilitation treatment strategy, chronic obstructive pulmonary disease (COPD), exercise training, and lung cancer status before and after surgery are still the main research directions, ③ due to the Corona Virus Disease 2019 (COVID-19) pandemic, not only pulmonary rehabilitation in hospitals, but also home pulmonary rehabilitation has attracted wide attention.
Conclusions: At present, pulmonary rehabilitation strategies, various chronic respiratory diseases, exercise methods and quality of life assessment are still hot research topics in this field. In the future, it is suggested to gradually improve the pulmonary rehabilitation strategy, improve the applicability and accessibility of the pulmonary rehabilitation program, and continue to pay attention to the long-term outcome of pulmonary rehabilitation.
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Background: Polycystic ovary syndrome (PCOS) is the leading cause of infertility induced by ovarian disorders. The promising pharmacological activities of clove buds in gynecological disorders have been mentioned in traditional Persian medicine and in recent studies. Since no studies have been conducted on the role of clove aqueous extract (CAE) in the management of PCOS, this study was designed to evaluate its effects on some biochemical and histopathological parameters in letrozole-induced PCOS in rats.
Methods: Thirty-six rats were used for this study: 6 were in the control group, and in the other 30, PCOS was induced by letrozole (1 mg/kg/day). After 3 weeks of induction, PCOS was approved by conducting vaginal smears. Then PCOS-induced rats were divided into five groups, letrozole-induced polycystic ovary syndrome (PCOS), clomiphene citrate 1 mg/kg/day (CLO), and CAE50, 100, 200, which received 50, 100, and 200 mg/kg/day of standardized clove aqueous extract based on eugenol, respectively. The treatment kept going for 30 days. Estrous cyclicity, body weight, oxidative stress-related markers, sex hormones, and ovarian histological parameters were measured.
Results: Disrupted estrous cyclicity, increased body weight, follicular cyst, ovarian level of malondialdehyde (MDA), total oxidant status (TOS), luteinizing hormone (LH), and testosterone levels, as well as decreased estradiol, progesterone, superoxide dismutase (SOD) and total antioxidant capacity (TAC) levels, were demonstrated in PCOS group. The aforementioned parameters were improved following the CAE administration. The estrous phase was observed in the vaginal smear following all doses of CAE administration. The serum level of LH (at doses 50 and 200 mg/kg), LH/follicle-stimulating hormone (FSH) (at all doses), testosterone (at doses 100 and 200 mg/kg) and estradiol (at doses 100 and 200 mg/kg) was significantly decreased. The serum level of progesterone (100 and 200 mg/kg) was increased significantly following CAE administration. Moreover, CAE reduced cystic follicles and ameliorated oxidative parameters.
Conclusions: In conclusion, clove can be a complementary medicine for PCOS patients, but clinical studies are needed to demonstrate its efficacy and safety.
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Background: Piperlongumine (PL) regulates the production of cellular reactive oxygen species (ROS), and ROS can affect the differentiation of mesenchymal stem cells. In order to add to the medicinal value of PL, this study aimed to explore whether and how PL induces chondrogenic differentiation of human bone marrow mesenchymal stem cells (BMSCs).
Methods: To determine the PL concentrations for drug intervention, BMSCs were exposed to varying concentrations of PL, the effects on cell viability were measured by Cell Counting Kit (CCK)-8. After the IC50 (intervention concentration) of PL was determined, the BSMCs were analyzed for changes in morphology (microscopy), degree of chondrogenic differentiation (Alcian blue staining), oxidative stress levels (reactive oxygen species (ROS) assay) and mRNA and protein expressions (quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot) at varying times of treatment. To prove the reliability of the results, the effects of PD98059, an extracellular-signal-regulated kinase (ERK)1/2 inhibitor, and N-acetylcysteine (NAC), an inhibitor of ROS production were also studied.
Results: The IC50 of PL was <50%, when PL concentration was greater than 5 μmol/L (p < 0.001) and 5 μmol/L PL used in subsequent experiments. PL promoted the chondrogenic differentiation of BMSCs and increased glycosaminoglycan deposition and ROS production (p < 0.001). At the molecular level, PL increased the expressions of chondrogenic differentiation-related genes and activated the phosphorylation of ERK1/2 (p < 0.001). These effects of PL were partially prevented by NAC (p < 0.01). PD98059 exerted similar effects as NAC (p < 0.001) but did not affect ROS production.
Conclusions: ROS and ERK1/2 pathway may be part of the mechanism by which PL enhances chondrogenic differentiation of BMSCs.
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Background: Recently, Langya henipavirus (LayV), an animal virus, was found in humans in Eastern China. The single-stranded, negatively oriented RNA genome of the LayV virus from the Henipavirus genus is a member of the Paramyxoviridae family.
Methods: The LayV genome analysis showed that the virus is closely related to the Mojiang henipavirus. The whole protein sequence of the glycoprotein G of the Langya henipavirus UUV47241.1 was retrieved. These proteins were further examined to predict epitopes and were found to be remarkably non-toxic, immunogenic, antigenic, and non-allergic.
Results: These sequences allowed the extraction of T-cell (major histocompatibility complex class 1 and class 2) and B-cell epitopes which yielded vaccine constructs, then further examined the population coverage to determine their global acceptability. Major histocompatibility complex (MHC)-1 and MHC-2 had population coverage of 69.47% and 45.33%, respectively. The structural prediction was validated using physicochemical, molecular, and immunological features to develop a durable and efficient vaccine candidate.
Conclusion: This method could make computational vaccines an effective option against dangerous microbes because they successfully cover a huge population. These results could ultimately help vaccine researchers to create a highly effective peptide-based vaccine.
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Background: Bronchiolitis, which is primarily caused by respiratory syncytial virus (RSV) infecting the lower respiratory tract, is a problematic condition for the health of infants and young children. This study aims to provide deeper insight into RSV-induced bronchiolitis and potential effective treatments.
Methods: Sprague Dawley (SD) rats were randomly divided into three groups: rats without RSV infection (NC), rats with RSV infection (RSV) and rats with RSV infection and azithromycin treatment (RSV-A). The changes of lung pathology were evaluated by observing lung sections stained with hematoxylin and eosin (H&E) through the microscope and inflammatory cells in bronchoalveolar lavage fluid (BALF). In addition, fluorescence-activated cell sorting (FACS) and flow cytometry were used to measure percentage of the regulatory T-cell (Treg) and T helper 17 cell (Th17). Treg/Th17-related cytokines were measured by enzyme-linked immunosorbent assays (ELISA), and their related transcription factors were examined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blot.
Results: Lung tissues from rats in the RSV group presented symptoms of inflammatory cell infiltration, wide alveolar septa, pulmonary interstitial hyperemia and edema, and bronchial collapse and deformation. Additionally, total white blood cells (WBCs), and the percentages of eosinophils, lymphocytes and neutrophils in all WBCs were increased in the RSV group. The percentage of Treg cells, and the levels of transforming growth factor beta (Tgf-β), Interleukin (Il)-17, Il-10, forkhead box P3 (Foxp3) in the RSV group were decreased. In contrast, the percentage of Th17 cells, the concentrations of Il-17 and Il-23, and the retinoic acid-related orphan receptor (RoR)γt in the RSV group were increased. All these changes caused by RSV infection could be attenuated by azithromycin treatment.
Conclusion: RSV-induced bronchiolitis could cause severe histological changes and inflammation, which was associated with a decrease in Treg cells and related cytokines and an increase in Th17 cells and related cytokines. Azithromycin could effectively attenuate those symptoms by restoring Treg cells, Th17 cells, and their related cytokines. These findings suggest that azithromycin has the potential to treat RSV-induced bronchiolitis in humans.
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Background: Parkinson's disease (PD) is a degenerative neurological disorder that could affect body and cognitive functions. Previous research has reported the beneficial role of exercise in the treatment of PD-linked motor defects. This study aimed to explore the role of aerobic exercise in neuroinflammation in PD and further investigated the underlying molecular mechanisms.
Methods: C57BL/6 mice (n = 36) were randomly divided into the Control group (n = 12), PD group (n = 12), and PD+Aerobic exercise (P+E) group (n = 12). Using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the PD mice model was established. In the P+E group, aerobic exercise was delivered after the PD model establishment. The motor function was evaluated using rotarod and pole tests. Immunofluorescence was utilized for evaluating α-synuclein-mediated neurotoxicity and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation in MPTP-induced PD mice. Immunohistochemistry (IHC) was performed to examine glial cell activation and the loss of dopaminergic neurons in MPTP-induced PD mice. Western blot was conducted to assess the expression of the signal transducer and activator of transcription 3 (STAT3)/NLRP3 pathway and pro-inflammatory cytokines, including interleukin-18 (IL-18) and interleukin-1β (IL-1β). Fura-2/AM was used to detect the intracellular concentration of Ca2+ in the striatum.
Results: Aerobic exercise alleviated motor deficits and decreased α-synuclein expression, a neurotoxicity protein in PD (p < 0.05). Moreover, aerobic exercise suppressed MPTP-caused glial cell activation and rescued MPTP-induced loss of dopaminergic neurons in PD mice (p < 0.05). Aerobic exercise negatively regulated the STAT3-mediated activation of NLRP3 inflammasome in MPTP-induced PD mice (p < 0.05), leading to the decreased expression of pro-inflammatory cytokines (p < 0.05). Besides, aerobic exercise in PD mice reversed the upregulated intracellular concentration of Ca2+ in the striatum induced by MPTP (p < 0.05).
Conclusion: These findings indicate that the inhibition effects of aerobic exercise on neuroinflammation through the STAT3/NLRP3 pathway contribute to the improvement of MPTP-caused motor deficits in PD mice.
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Background: Type 2 diabetes may cause chronic kidney disease and damage podocytes, but Astragaloside II (AS II) may protect the function of podocytes. This study aims to verify whether AS II can exert protective effects on podocytes and explore the underlying mechanism.
Method: MPC5 cells were treated with high glucose and AS II or transfected with siParkin. The cell counting kit-8 was used to detect the viability of MPC5 cells. Western blot was used to detect the expressions of Beclin1, microtubule associated protein 1 light chain 3 alpha (LC3)I, LC3II, wilms tumor type 1 (WT1), podocalyxin, mitochondrial fission 1 (Fis1), mitofusin-2 (Mfn2), PTEN induced kinase 1 (PINK1) and parkin RBR E3 ubiquitin protein ligase (Parkin). The MPC5 cells were infected with green fluorescent protein-red fluorescent protein-LC3 (GFP-RFP-LC3) adenovirus to evaluate the effect of AS II and silencing Parkin on autophagy. Mitophagy was detected by the co-localization of mitochondria with autophagosome via immunofluorescent staining.
Result: High glucose damaged MPC5 cells and inhibited the expression of PINK1 and Parkin. AS II (0.33, 1, 3 μM) could improve cell viability, upregulate the expression of WT1 and podocalyxin, and reduce autophagy and cell damage. Among these treatments, 1 μM AS II had the best effect (p < 0.05). In addition, AS II could protect the mitochondrial dynamics and promote the co-localization of Parkin and mitochondria. However, silencing Parkin reversed the effects of AS II (p < 0.05).
Conclusion: AS II promotes the viability, functions, mitophagy and mitochondrial dynamics but inhibits the autophagy of podocytes by activating the PINK1/Parkin signaling pathway.
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Background: Cerebral ischemia-reperfusion (CI/R) injury poses significant threats to human health due to its high disability, morbidity, and mortality rates. This study investigates the effects of Butein in oxidative stress-induced injuries in PC12 cells and its underlying mechanism on CI/R injury.
Methods: An oxygen-glucose deprivation/reoxygenation (OGD/R) model was established using PC12 cells to examine the impact of Butein on CI/R injury. Cell viability and apoptosis were assessed using Cell Counting Kit-8 (CCK-8) and flow cytometry (FCM) techniques, respectively. Protein expressions of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), B-cell lymphoma-2 (Bcl-2) and BCL-2-associated X protein (Bax) were determined by Western blot assay. Additionally, Butein's effects on the levels of superoxide dismutase (SOD), malondialdehyde (MDA), and reactive oxygen species (ROS) in OGD/R cells were evaluated using xanthine oxidase, thiobarbituric acid methods, and flow cytometry, respectively.
Results: Butein augmented the viability of PC12 cells under OGD/R conditions and diminished cell apoptosis. It notably suppressed ROS and MDA production while increased SOD levels. Furthermore, Butein treatment led to a marked reduction in TLR4 and NF-κB expressions. Notably, combining Butein with si-TLR4 enhanced the protective effect of Butein against CI/R injury.
Conclusions: Butein mitigates oxidative stress and reduces apoptosis by inhibiting the TLR4/NF-κB pathway, offering potential therapeutic benefits against CI/R injury.
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Background: This study aimed to assess the effects of hydro-alcoholic extract of Fumaria parviflora (FP) on metabolic parameters, anthropometric measures, and serum concentrations of leptin, adiponectin, and resistin in patients with type 2 diabetes mellitus (T2DM).
Method: Seventy patients with T2DM participated in the present clinical trial. The patients were randomly assigned to one of two groups, receiving either a 500 mg dose of hydro-alcoholic extract of FP or a placebo for 8 weeks. Anthropometric parameters, serum levels of metabolic factors, and serum concentrations of leptin, adiponectin and resistin were assessed pre-and post-intervention. The assessment of dietary intakes was conducted through three-day food records, which were subsequently analyzed via Nutritionist IV software.
Results: FP treatment significantly led to decreased serum concentrations of fasting blood glucose (p = 0.008), insulin (p = 0.011), triglyceride (p = 0.037), total cholesterol (p = 0.008), low-density lipoprotein cholesterol (p = 0.016), leptin (p = 0.003) and resistin (p = 0.026), and homeostatic model assessment for insulin resistance (HOMA-IR) (p = 0.003). However, there was a statistically significant increase in serum concentrations of high-density lipoprotein cholesterol (HDL-C) (p = 0.019) and adiponectin (p = 0.032), as well as quantitative insulin sensitivity check index (p = 0.014) in the FP group compared to the placebo. No significant differences were observed between the groups for anthropometric indices, hemoglobin A1c (HbA1c), serum levels of liver enzymes, blood urea nitrogen, urea, creatinine, and daily dietary intakes at week eight.
Conclusion: FP supplementation (500 mg/day) combined with calorie restriction for 8 weeks effectively improved glycemic indices, lipid profile, and serum levels of leptin, resistin and adiponectin in T2DM patients.
Trial registration: Iranian Registry of Clinical Trials: IRCT20130610013612N11.
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Background: Although the number of therapies for hepatocellular carcinoma has increased, the survival rate is still unsatisfactory. Cancer-associated fibroblasts have been reported to regulate hepatocellular carcinoma progression via various mechanisms. We aimed to investigate an effective prognostic tool related to cancer-associated fibroblasts for decision-making in patients with hepatocellular carcinoma.
Methods: Bioinformatics analyses were used to identify cancer- and fibroblast-associated genes based on data from the Cancer Genome Atlas and Gene Expression Omnibus datasets. Following Cox and least absolute shrinkage and selection operator analyses, the optimal prognostic genes were identified, and a prognostic cancer-associated fibroblast signature was established based on these genes. Receiver operator characteristic analysis was used to validate the performance of the signature. In addition, the correlation between the cancer-associated fibroblast signature and clinical, immune, and mutational features was analyzed. Finally, a prognostic nomogram was developed and evaluated.
Results: Six cancer- and fibroblast-associated prognostic genes (PZP (pregnancy zone protein), TSPYL5 (testis-specific protein Y-encoded-like 5), ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin motifs like 2), SAMD12 (sterile alpha motif domain containing 12), PNMA2 (paraneoplastic Ma antigens family member 2), and N4BP3 (NEDD4 binding protein 3)) in hepatocellular carcinoma were identified to construct the cancer-associated fibroblast risk score. The receiver operating characteristic curve showed that the signature exhibited good performance in predicting the survival of patients with hepatocellular carcinoma (with an area under the curve >0.75). Furthermore, the low-risk group showed better stromal and immune scores and a lower tumor mutation burden. Finally, a nomogram model was constructed to predict the survival of hepatocellular carcinoma patients.
Conclusions: This study shows a promising cancer-associated fibroblast signature that might be useful in predicting the survival and personalized management of patients with hepatocellular carcinoma in the clinic.
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Background: Liuwei Dihuang pills contain quercetin, which has been found to alleviate postmenopausal osteoporosis (PMOP) progression. This study aimed to investigate the effects of quercetin on the intestinal microbiota and microbial metabolism in rats suffering from PMOP.
Methods: The Sprague Dawley female rats were randomly divided into four groups (n = 5): sham, ovariectomized (OVX), quercetin-low dose (50 mg/kg/d), and quercetin-high dose (100 mg/kg/d). The optimal dose group (quercetin-high dose group) was used as the quercetin group for follow-up experiments. The histopathological changes in the tibia of rats were observed using hematoxylin-eosin (HE) and Masson staining. The composition and abundance of intestinal microbiota were determined using 16S rRNA sequencing, while metabolite levels were assessed using metabolomics. Pearson's correlation analysis was used to investigate the relationship between microbiota abundance and metabolite levels.
Results: The administration of quercetin helped to prevent the degradation of the collagen fiber layer on the surface and the formation of fibrosis of femur tissue caused by OVX. Additionally, treatment with quercetin significantly increased species abundance and evenness in the OVX group. In contrast to the OVX group, quercetin treatment increased Muribaculaceae abundance and decreased the Clostridium sensu stricto 1 abundance. Major differential metabolites, such as pregnenolone, 3-aminobutyric acid, 2-aminoisobutyrate, N-methyl-L-alanine, and aminoisobutanoate, were found between the OVX and quercetin groups. Correlations between the abundance of Muribaculaceae and Clostridia UCG 014 and the major differential metabolites were found, respectively. Furthermore, the amino acid metabolic pathways were found to be the primary pathway for intestinal microbiota.
Conclusions: The active ingredient quercetin regulates intestinal microbiota and microbial metabolism, helping to alleviate the symptoms of PMOP in rats.
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Background: Chlorfenapyr (Chlo) is a pyrrole-based insecticide. It has proven effective in controlling a range of pests. This study examined the impact of Chlo on myocardial mitochondrial injury in mice and the underlying mechanisms involved.
Methods: C57BL/6 mice were categorized into groups of saline, doxorubicin (DOX), and low, medium, and high doses of Chlo. The cardiac function of the mice in each group was evaluated using cardiac biomarkers. Hematoxylin and eosin (HE) staining was employed to observe changes in the myocardial tissue, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was used to detect cardiomyocyte apoptosis. Proteins associated with mitochondrial damage were identified by western blotting. Furthermore, cardiomyocytes were isolated and divided into the Dimethyl sulfoxide (DMSO) group, medium and low Chlo groups, DOX group, and Chlo group. Transmission electron microscopy (TEM) was utilized to investigate the mitochondria, and the mitochondrial membrane potential was analyzed using a JC-1 kit. Lactate dehydrogenase (LDH) and reactive oxygen species (ROS) secretion were quantified to evaluate oxidative stress.
Results: The results indicate that Chlo can impair cardiac function in vivo (p < 0.01). Chlo leads to a marked decrease in the mitochondrial membrane potential, resulting in mitochondrial damage (p < 0.05). In cardiomyocytes, Chlo significantly downregulates death-associated protein 3 (Dap3) expression (p < 0.01). However, overexpression of Dap3 effectively mitigated the oxidative stress, apoptosis, and mitochondrial damage induced by Chlo in cardiomyocytes (p < 0.05).
Conclusions: Overall, high concentrations of Chlo trigger cardiotoxicity by downregulating Dap3, leading to mitochondrial damage.
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Background: Ferroptosis is a novel form of nonapoptotic regulatory cell death that is involved in the pathogenesis of diabetic complications, including diabetic cardiomyopathy (DCM). Recent studies have shown that spermine (SPM) may have a protective effect against hyperglycemia in mammals. However, it is still unclear whether SPM can negatively regulate ferroptosis in diabetic mice.
Methods: We investigated the effects of SPM on ferroptosis in diabetic mice induced by streptozotocin (STZ) in vivo, as well as its impact on high glucose (HG)-stimulated HL-1 cardiomyocytes injury in vitro. We used various methods to evaluate cardiomyocyte ferroptosis injury and the effects of SPM, including echocardiographic analysis, electron microscopy, serum-related markers, immunohistochemistry, immunofluorescence, and immunoblotting. We also explored the effect of thioredoxin-interacting protein (TXNIP) on SPM in regulating the ferroptosis in HG-induced HL-1 cells through TXNIP siRNA transfection.
Results: Mice induced with STZ showed a significant increase in blood glucose, food, and water intake (p < 0.05), but decreased body weight and weakened cardiac function (p < 0.05). The level changes of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), iron (Fe2+), lipid reactive oxygen species (ROS) production as well as the expression of ferroptosis marker proteins (acyl-CoA synthetase long-chain family 4 (ACSL4), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11)) and redox-related protein (TXNIP, nuclear factor erythroid 2-related factor 2 (NRF2), and heme oxygenase 1 (HO-1)) verified that diabetes or HG level aggravated lipid peroxidation, iron overloading and oxidative damage, thereby leading to ferroptosis in cardiomyocytes (p < 0.05). However, SPM treatment or interference with TXNIP expression significantly ameliorated cardiac injury in DCM mice caused by ferroptosis and HG-induced injury in cardiomyocytes.
Conclusions: In general, these findings suggest that SPM can be used to prevent DCM by inhibiting the TXNIP-ferroptosis signaling loop. This treatment strategy is brand-new and potentially effective for DCM.
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Background: Oxidative stress and inflammation play the central roles in the pathophysiological process of diabetic retinopathy. Our purpose was to elaborate the effect and regulatory mechanism of ferulic acid (FA) in mitigating diabetic retinopathy as well as the functional roles of mitochondrial calcium uniporter (MCU) and NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and their interplay.
Methods: Human retinal pigment epithelial cells ARPE-19 were pre-treated with 10 mmol/L FA, or transfected with NLPR3 or MCU siRNA or overexpression plasmids. Afterwards, ARPE-19 cells were exposed to 30 mmol/L high glucose for simulating diabetic retinopathy. Intracellular reactive oxygen species (ROS) generation, cytosolic Ca2+ level, endoplasmic reticulum (ER) and mitochondrial stress, mitochondrial membrane potential were assayed with 2,7-dichlorofluorescein diacetate (DCFH-DA), Fluo-4 acetoxymethyl ester (Fluo-4 AM), ER-Tracker Red, Seahorse XFe96 Analyzer and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimi-dazolylcarbocyanine iodide (JC-1) staining, respectively. MCU, NLRP3, Interleukin-1beta (IL-1β), toll-like receptor 4 (TLR4), nuclear factor κB (NFκB), AKT serine/threonine kinase1 (AKT1) and phosphorylated-Akt1 (p-AKT1) were measured with western blots or immunohistochemistry.
Results: Both FA pre-treatment and blockage of NLRP3 mitigated apoptosis, intracellular ROS, cytosolic Ca2+ level as well as ER and mitochondria stress in hyperglycemia-induced ARPE-19 cells. Additionally, MCU-mediated mitochondrial oxidative stress and NLRP3 inflammasome- and TLR4-dependent AKT/NFκB oxidative and inflammatory signaling were alleviated. Blockage of MCU alleviated hyperglycemia-induced NLRP3 inflammasome activation. Conversely, up-regulation of MCU exacerbated hyperglycemia-induced NLRP3 inflammasome- and TLR4-mediated oxidative and inflammatory signaling, which can be attenuated by FA. Similarly, MCU-mediated mitochondrial oxidative stress was mitigated by FA through NLRP3 inhibition.
Conclusion: Collectively, we present evidence that NLRP3 and MCU are essential for FA alleviating ER- and mitochondria-dependent oxidative stress and inflammation in hyperglycemia-induced ARPE-19 cells. Disturbance of NLRP3 and MCU transcription regulation opens novel avenues to mitigate diabetic retinopathy.
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Background: The immunological responses to exercise and the corresponding adaptations in high-level sports have become an important issue, from both the health and the physical performance points of view. A better understanding of the immune responses to exercise and chronic exercise training may benefit athletes and improve physical performance and health. The purpose of this study was to investigate the fluctuations in the immune status of young swimmers throughout a training season.
Methods: Twelve well-trained male swimmers (14.08 ± 1.0 yrs) were recruited. Measurements were carried out at the beginning of the training season (T1) and pre- and post the taper of each competitive period (i.e., T2, T3 for the first training macrocycle, and T4, T5 for the second macrocycle, respectively). Blood samples were collected before and 1 hour post a maximal 400 m swimming testing at each of the above time points. Serum interleukin (IL)-1β, IL-6, IL-1rα, IL-4, IL-10, C-reactive protein (CRP) and creatine kinase (CK) levels were measured. Adjustment for exercise-induced plasma volume changes was performed before all data analyses. Two-way analysis of variance (ANOVA) with repeated measures was used for statistics.
Results: An anti-inflammatory profile was induced during the second competitive period characterized by a reduction in the levels of inflammatory indices (T1 compared to T4 and T5, IL-1β: p = 0.019, p = 0.034 respectively; T1 compared to T4, CRP: –43%, p > 0.05) along with a tendency of increase in anti-inflammatory ones (T1–T5, IL-6: 75%, T4–T5 IL-10: 122%; p > 0.05). Moreover, acute exercise induced anti-inflammatory responses, causing an increase in anti-inflammatory cytokines (IL-6, IL-10, IL-1rα; p < 0.05). There was a significant decrease in serum CK levels between T1-T4 both in the pre- and post-test condition (p = 0.027, p = 0.005, respectively), while significant differences were found between pre- and post-test at T1, T2, and T4 (p = 0.000, p = 0.011, p = 0.017, respectively).
Conclusions: The findings of this study indicated that swimming training throughout a season induces mild long-term but strong acute effects on the immune profile of the swimmers. These findings should be taken into consideration throughout a training season in young swimmers, adjusting the exercise stimuli accordingly in terms of volume, intensity, and recovery time.
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Objective: To explore the regulatory mechanism of the Chinese medicine Qidan Yifei Tongqiao on T helper (Th)17/regulatory T (Treg) cell immune balance in rat models with allergic rhinitis (AR).
Methods: Thirty-two rats were divided into four groups: a blank group, a model group, a traditional Chinese medicine (TCM) group and a Western medicine group. An AR model was established in the latter three groups using ovalbumin (OVA). After successful modelling, the TCM group was gavaged with Qidan Yifei Tongqiao concentrated solution. The blank group and the model group were given normal saline, and the Western medicine group was administered intragastric normal saline and loratadine for a total of 28 d. The histopathological changes in the rats' nasal mucosa were detected by hematoxylin and eosin staining, the levels of interleukin (IL)-17 and transforming growth factor (TGF)-β1 were detected by enzyme-linked immunosorbent assay, and the protein expression of forkhead box Protein 3 (Foxp3) and retinoid-related orphan receptor gamma t (RORγt) were detected by Western blot.
Results: Compared with the rats in the blank group, the IL-17 content of the rats in the model group increased (p < 0.05), while the content of TGF-β1 decreased (p < 0.01). Compared with the rats in the model group, the content of IL-17 in the rats in the Western medicine group and the Chinese medicine group decreased (p < 0.05), and the content of TGF-β1 increased (p < 0.01); no statistically significant differences were detected between the Chinese and Western medicine groups (p > 0.05).
Conclusion: The TCM Qidan Yifei Tongqiao may play a role in relieving AR symptoms by regulating the immune balance of Th17/Treg cells.
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Background: Hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury aggravates the progression of ischemic heart disease. The aim of this study was to explore the role of 1,8-Cineole on the H/R-induced cardiomyocytes injury.
Methods: Cardiomyocytes (H9c2) were hypoxic for 6 hours (h) followed by 12 h reoxygenation to establish a cardiomyocyte injury model. After treatment with 1,8-Cineole (2.27 and 0.57 μmol/ L) or adenosine 5′-monophosphate activated protein kinase (AMPK) inhibitor (Compound C, 10 μmol/L), H9c2 cell viability, cytotoxicity, apoptosis and mitochondrial membrane potential (MMP) were examined by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), lactate dehydrogenase (LDH) release detection assay, flow cytometry, and MMP assay kit with JC-1. Protein expression of caspase-3, cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), Bcl-2 Associated X Protein (Bax), AMPK, phospho (p)-AMPK, NLR family pyrin domain containing 3 (NLRP3) and interleukin (IL)-1β were detected by Western blot. IL-1β level and caspase-1 activity were evaluated by commercial kit.
Results: The results confirmed that 1,8-Cineole treatment enhanced viability and MMP. It decreased LDH levels and apoptosis in H9c2 cells under H/R induction (p < 0.05). Besides, H/R-triggered inhibition of Bcl-2 and p-AMPK protein expressions, as well as promotion of cleaved caspase-3, Bax, NLRP3 and IL-1β protein expression and caspase-1 activity in H9c2 cells were attenuated by 1,8-Cineole (p < 0.05). Compound C partially counteracted the effects of 1,8-Cineole on increasing cell viability, MMP and p-AMPK protein expression and decreasing LDH level, apoptosis and NLRP3 protein expression of H/R-induced H9c2 cells (p < 0.05).
Conclusions: 1,8-Cineole protecting cardiomyocytes from H/R-induced cell injury is dependent on AMPK/NLRP3 signaling.
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Background: Diabetes mellitus (DM) can be characterized by over-production and under-utilization of carbohydrates and varying degrees of abnormal lipid and protein metabolism. The complications of diabetes mellitus affect various organs and systems in the body including the reproductive system. Vitamin C (ascorbic acid) is an essential micronutrient for maintaining normal metabolic processes and homeostasis within the human body. In the current study, the diabetes-induced alterations on the nucleic acids of rat testicular tissues and the effects of low and high doses of ascorbic acid administration were investigated using Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy coupled with an unsupervised technique, namely principal component analysis (PCA).
Methods: Male Wistar rats were treated with streptozotocin (STZ) to induce DM. One week after STZ administration, the diabetic rats were treated with a low dose of ascorbic acid (15 mg/kg) and a high dose of ascorbic acid (100 mg/kg) for 6 weeks. The dissected testicular tissues were studied by FTIR spectroscopy. PCA was applied to their spectra.
Results: This study revealed diabetes-induced global contextual alterations on nucleic acids, particularly RNAs and DNAs in diabetic samples. Low dose ascorbic acid administration was found to be more effective than higher doses in restoring the effect of diabetes on nucleic acids. The PCA results presented a successful discrimination of the diabetic group from the control and Vitamin C treated groups, and showed especially the ameliorative effect of low dose Vitamin C.
Conclusion: Low dose Vitamin C was found to be more effective in combating diabetes-induced alterations in nucleic acids. ATR-FTIR spectroscopy combined with multivariate data analyses demonstrated the beneficial effect of Vitamin C administration on nucleic acid content of diabetic testicular tissue based on the spectral differences.
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Background: Valproic acid (VPA), an anticonvulsant used in epilepsy, has deleterious effects on embryonic development and is considered an environmental risk factor for autism spectrum disorders. There is a growing need for easy and rapid ways to study its effects on embryonic development. The zebrafish model is a cost- and time-effective tool able to facilitate mechanistic studies and high-throughput drug screening. Epileptic patients are increasingly looking to natural compounds to avoid the strong side effects of synthetic drugs, and cannabinoids appear promising. We evaluated the potential of cannabidiol to mitigate the negative effects of VPA on developing zebrafish embryos.
Methods: Wild-type AB embryos, untreated or exposed to VPA (5, 10 or 20 μM) and/or cannabidiol (1, 2 or 3 μM), were evaluated at up to 120 hours post-fertilization. Developmental endpoints: survival, hatching, heart rate, morphology, and locomotor behavior (tail coiling and visual motor response test). Three replicates were evaluated per group, for a total of 120 larvae per treatment.
Results: Although VPA-treated groups showed significantly reduced survival rates compared to control group fish (p ≤ 0.01), zebrafish simultaneously treated with VPA (5 and 10 μM) and cannabidiol (3 μM) displayed survival rates similar to those of untreated controls. Hatching rate, body length and eye area were not influenced by any treatment, but the highest VPA dose and all cannabidiol doses caused a significant increase in burst activity (p ≤ 0.0001). Compared with controls, the pericardial area was larger only in larvae treated with VPA at the highest concentration (p ≤ 0.01). Each VPA treatment caused tachycardia (p ≤ 0.0001), while cannabidiol 3 μM induced bradycardia (p ≤ 0.01). Finally, simultaneous treatment with VPA 5 μM and cannabidiol 3 μM avoided almost all the adverse effects of the two compounds administered individually, stabilizing heart rate and locomotor behavior at control levels.
Conclusions: This study adds further information on the embryotoxic effect of VPA in the zebrafish model and offers new insights into the use of cannabidiol as an alternative natural drug able to mitigate the deleterious effects of VPA. Multi-laboratory large-scale validation and new genomic and molecular analyses are required to clarify the mechanism of action of VPA on developing embryos and the role of cannabidiol as a potential natural protective agent against its toxic effects.
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Background: The viability of cardiomyocytes is crucial for maintaining normal myocardial function. Studies have suggested that lncRNA terminal differentiation-induced non-protein coding RNA (TINCR), a long non-coding RNA, played a protective role against cardiac hypertrophy, which was associated with reduced cardiomyocyte viability, as observed in diabetic cardiomyopathy. This study aimed to investigate the mechanisms and role of lncRNA TINCR in cardiomyocyte viability under high glucose conditions.
Methods: A total of 180 individuals, including 60 diabetic cardiomyopathy patients, 60 diabetic patients without complications and 60 healthy controls, were enrolled. RNA was extracted from the blood samples using Trizol reagent, followed by cDNA synthesis of TINCR and Bnip3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3). Amplification of the cDNA was carried out through real-time quantitative PCR. AC16 (human cardiomyocyte cell line) was cultured in Dulbecco's modified Eagle's medium (DMEM) and was transfected with a TINCR expression vector. The viability of the cells and Bnip3 expression level of proteins were determined through 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyl-2H-Tetrazolium Bromide (MTT) assay and western blot analysis, respectively. The optical density (OD) was measured using a spectrophotometer, and cellular apoptosis was determined by flow cytometry. SPSS19.0 was used for statistical analysis.
Results: We found that TINCR was downregulated and Bnip3 was upregulated in diabetic cardiomyopathy patients. Furthermore, high glucose treatment of the cells did not significantly affect TINCR expression in cardiomyocytes. Moreover, there was a significant negative correlation between Bnip3 mRNA expression and TINCR in diabetic cardiomyopathy patients, but not in other two groups. We found that overexpression of TINCR under high glucose conditions inhibited Bnip3 expression, suppressed cell apoptosis and improved cardiomyocyte viability.
Conclusions: LncRNA TINCR suppressed Bnip3 expression, thus enhancing cardiomyocyte viability under high glucose conditions in diabetic cardiomyopathy.
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Background & Purpose: Neuronal PAS domain protein 2 (NPAS2) is a biological rhythm gene involved in cancer progression. This study explored the function of NPAS2 on endometrial cancer (EC), as well as the potential mechanisms involving NPAS2-zinc fingers and homeoboxes-3 (ZHX3) axis.
Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure the level of NPAS2 and ZHX3 in EC cells. Cell proliferation was analyzed using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and colony formation assays. Flow cytometry was used to test cell cycle and apoptosis. The effect of NPAS2 on tumor growth was measured using a mouse xenograft model. The interaction between NPAS2 and ZHX3 was further confirmed by feedback experiments in vitro.
Results: NPAS2 expression was higher in EC cell lines. Knockdown of NPAS2 repressed proliferation, induced gap (G1)/ synthesis (S) arrest, and promoted apoptosis in EC cells. NPAS2 knockdown also suppressed tumor growth. Furthermore, NPAS2 was significantly positively correlated with ZHX3. Overexpression of ZHX3 reverses the anti-tumor effects of NPAS2 silencing on EC cells.
Conclusions: Lower expression of the NPAS2-ZHX3 axis could inhibit cell proliferation and induce apoptosis, thereby attenuating the development of EC.
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Background: Copy number amplification of genomic Chromosome 1q21.1 has emerged as a robust predictor of overall survival in hepatocellular carcinoma (HCC) patients. However, the study of functional long non-coding RNA (lncRNA)s located in 1q21.1 remains unclear. Here, we reported that LINC02802 in Chr 1q21.1 loci exhibit oncogenic roles in HCC patients.
Methods: We analyzed the copy-number gains or RNA expression levels of LINC02802 by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in HCC samples. Loss- or gain-of-function assays were carried out to determine the biological effects on cell growth and metastasis in vitro and in vivo. Furthermore, mass spectrometry analysis from biotinylated LINC02802 pulldown assays revealed that IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a prominent binding partner of LINC02802 in HCC cells.
Results: The progression of HCC cells is robustly mitigated by LINC02802 knockdown and significantly aggravated by its overexpression. Mechanistically, we found that elevated RNA levels of LINC02802 have directly interacted with the polyproline protein-protein domain, the four IQ motifs domain, and the Ras GTPase-activating protein-related domain of IQGAP1. This interaction stabilizes IQGAP1 by disrupting its interactions with tripartite-motif-containing protein 56 (TRIM56). As a consequence, the ubiquitination-mediated degradation of IQGAP1 is inhibited.
Conclusions: LINC02802, an oncogene, has significant potential as a prognostic biomarker, and targeting LINC02802 could provide a promising therapeutic strategy for HCC patients.
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Background: One of the main malignancies endangering the lives and health of women is cervical cancer. The poor prognosis for cervical cancer is mostly due to metastasis and recurrence. The metastatic spread of cervical cancer cells is largely dependent on the epithelial-mesenchymal transition (EMT) mechanism. Two conclusions have been drawn from earlier research on the function of basic transcription element binding protein 2 (BTEB2) in cervical cancer: there is both tumor promotion and tumor repression. Therefore, the role of BTEB2 in cervical cancer cell metastasis and tumor growth was examined in vitro and in vivo in order to examine the expression of transcription factor BTEB2 in cervical cancer and study its influence on epithelial-mesenchymal transition (EMT) of cervical cancer cells.
Methods: Following the collection of samples from 30 cervical cancer patients as well as nearby tissues, BTEB2 expression in cancer tissues was discovered. The acquisition of both cervical cancer cells and healthy cervical cells allowed for the examination of BTEB2 expression in distinct cervical cancer cell lines. Cell lines that showed differential expression were selected and BTEB2 expression was manipulated for grouping. The expression levels of BTEB2 and EMT-associated proteins (E-cadherin, N-cadherin) were assessed, and the viability, proliferation, migration, and invasion of cervical cancer cells were tracked. To create a xenograft tumor model in the mice, BTEB2-regulated cells were obtained and subcutaneously implanted into naked mice. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to find out how much the transcription factor BTEB2 was expressed in the cancer tissues. Lymphocytes that have infiltrated tumors have been identified using hematoxylin-eosin staining. To identify apoptotic cells, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) was used.
Results: The expression of BTEB2 in cervical cancer cells was upregulated (p < 0.05). After interfering with BTEB2, the expression of BTEB2 in cervical cancer cells decreased, cell vitality decreased, and the ability to proliferate, migrate, and invade was weakened (p < 0.05). EMT-related protein detection found that the expression of E-cadherin decreased and the expression of N-cadherin increased (p < 0.05). Nude mouse tumor transplantation experiments found that after interfering with BTEB2, tumor growth was inhibited, the volume decreased, and the expression of BTEB2 in tumor tissues weakened (p < 0.05). Cell apoptosis increased (p < 0.05).
Conclusion: The upregulation of transcription factor BTEB2 is involved in the growth and metastasis of cervical cancer. Interfering with BTEB2 leads to a decrease in the vitality of cervical cancer cells, as well as a weakening of their proliferation, migration, and invasion abilities. Tumor growth is suppressed, and this may occur through the inhibition of the EMT process.
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Background: Nonunion fracture is a serious complication that occurs after fractures, which has significant impacts on the prognosis of patients. Curcumin has been shown to promote bone tissue repair and treat nonunion fractures by regulating the process of osteogenic differentiation. However, the specific mechanism behind this strategy is yet to be explored. This study aims to investigate the potential mechanism of curcumin in regulating the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) by modulating the expression of osteogenic-related factors Bone morphogenetic protein 2 (Bmp2), Osteocalcin (Ocn), Osteopontin (Opn), Osterix and Runt-related transcription factor 2 (Runx2) through in vitro cell experiments.
Methods: Using rBMSCs for cell experiments, the effects of curcumin on cell proliferation were assessed using the cell counting kit-8 (CCK-8) and cell cloning assays. Different concentrations of curcumin were used to establish reasonable experimental groups. Furthermore, the impact of curcumin on osteogenic differentiation and its regulatory mechanism were assessed. The macroscopic regulation of curcumin on osteogenic differentiation was further investigated by alkaline phosphatase (ALP) staining and activity assay, alizarin red staining, and quantification. Finally, the expression levels of related mRNAs and proteins were detected using Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot.
Results: It was found that compared to the control group (no curcumin treatment), the curcumin 5 μM and 10 μM groups did not have any effect on rBMSCs activity within 48 hours (p > 0.05). However, after 72 hours, a significant increase (p < 0.05) was noted in rBMSCs activity. Furthermore, curcumin 5 μM and 10 μM groups revealed increased proliferation of rBMSCs in vitro (p < 0.05), enhanced alkaline phosphatase activity (p < 0.05), and increased calcium deposition (p < 0.05). They also showed upregulated mRNA expressions of Bmp2, Ocn, Opn, and Runx2 genes and the protein expressions of Bmp2, OCN, OPN, Osterix, Runx2 (p < 0.05). Similarly, the curcumin 10 μM group can upregulate the mRNA expression of Osterix (p < 0.05). On the other hand, group of cells treated with 15 μM curcumin inhibited cell activity rBMSCs after 48 hours (p < 0.05), inhibited the proliferation of rBMSCs in vitro (p < 0.05) and inhibited ALP activity (p < 0.05). However, this group did not affect the deposition of calcium salts, the mRNA expressions of Bmp2, Ocn, Osterix, Opn and Runx2 (p > 0.05), and the protein expressions of Bmp2, OCN, Osterix, OPN (p > 0.05). Additionally, curcumin 15 μM group showed an inhibitory effect on Runx2 protein expression.
Conclusions: Curcumin at concentrations of 5 μM and 10 μM can promote the osteogenic differentiation of rBMSCs. Curcumin at a concentration of 15 μM can inhibit the osteoblastic differentiation of rBMSCs.
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Background: Triple fusion (TF) reporter gene is ideal to track transplanted stem cell fate and function in treatment of myocardial infarction (MI) with stem cell transplantation, but its effects on on mitochondrial morphology and function of induced pluripotent stem cells (iPSCs)-derived cardiomyocytes (i-CMs) are still poorly understood. This study aimed to investigate the effects of the TF reporter gene on viability, proliferation, and differentiation ability, and the mitochondrial morphology and function of i-CMs.
Methods: iPSCs were divided into two groups: iPSCs group and TF-iPSCs group (iPSCs transduced with the TF reporter gene). Moreover, iPSCs and TF-iPSCs were differentiated into i-CMs and TF-CMs respectively. γ-counter, micro-positron emission tomography (PET), bioluminescence imaging (BLI) and immunofluorescence were used to test the expression of the TF reporter gene in vitro. PET and BLI were used to verify the expression of the TF reporter gene in a rat myocardial infarction (MI) model 7 days after cardiomyocyte transplantation. Trypan Blue, CyQUANT cell proliferation and immunofluorescence assays were used to determine the effect of the TF reporter gene on the proliferation and differentiation of iPSCs. In vivo fluorescence and transmission electron microscopy (TEM) were performed to test the effects of the TF reporter gene on the mitochondrial morphology and function of i-CMs.
Results: The TF reporter gene was stably expressed in vivo and in vitro. Compared with the iPSCs group, there were no significant differences in cell viability, proliferation, differentiation ability, and mitochondrial morphology and function from the TF-iPSCs group.
Conclusions: This study demonstrated the safety of the TF reporter gene in multimodality imaging of transplanted cells at the mitochondrial level.
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Background: Infertility is becoming a global reproductive health problem. In vitro fertilization/intracytoplasmic sperm injection embryo transfer (IVF/ICSI-ET) has become an important method for infertility treatment. However, repeated implantation failure (RIF) is a major problem in infertility treatment. Here, we aimed to explore the effects of platelet rich plasma (PRP) and granulocyte colony-stimulating factor (G-CSF) combination therapy through single intrauterine perfusion in the embryo implantation dysfunction rats.
Methods: Seventy Sprague-Dawley (SD) female rats and thirty male rats were purchased for free mating. Rats who find vaginal plugs are recorded as the first day of pregnancy of female rats. Then rats with vaginal plugs were randomly divided into 5 groups, control, model, model+PRP, model+G-CSF, and model+PRP+G-CSF. 10 rats in each group. After treatment, the uterine tissue of the rats in each group was collected for subsequent experiments.
Results: The results showed that PRP or G-CSF intrauterine perfusion improved the pregnancy rate and average number of implanted blastocysts in the embryo implantation dysfunctional rats (p < 0.001). Additionally, PRP or G-CSF intrauterine perfusion effectively improved the endometrial receptivity in the embryo implantation dysfunctional rats, as shown by the increase of leukemia inhibitory factor (LIF), vascular endothelial growth factor (VEGF) and interleukin-1 receptor antagonist (IL-1ra) levels and the decrease of growth-regulated oncogene α (GROα) and interferon inducible protein 10 (IP-10) levels (p < 0.001). Importantly, the effects of PRP and G-CSF combination therapy on the pregnancy rate, average number of implanted blastocysts (p < 0.001) and endometrial receptivity (p < 0.001) were more effective than either of them alone.
Conclusion: PRP and G-CSF combination intrauterine perfusion therapy effectively improved the embryo implantation dysfunction, which provided a novel insight for RIF.
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Background: Non-small cell lung cancer (NSCLC) is a common subtype of lung cancer that is usually associated with an increase in iron metabolism disorders and oxidative stress. Adhesion G protein-coupled receptor D1 (ADGRD1) is a receptor protein that plays important roles in a variety of biological processes. Therefore, we investigated the impacts and molecular mechanisms of ADGRD1 on ferroptosis and oxidative stress during the development of NSCLC.
Methods: In this study, we used cells (BEAS-2B and A549) and mouse (specific pathogen-free (SPF) Balb/c nude male mice, n = 24) models. The tumor Gene Atlas (The Cancer Genome Atlas, TCGA) database was utilized to analyze the expression of ADGRD1 in NSCLC. We investigated the expression levels of ADGRD1, protein kinase B (AKT), mechanistic target of rapamycin (mTOR), glutathione peroxidase 4 (GPX4), cyclooxygenase-2 (Cox-2), cell cycle proteins, inflammatory factors and oxidative stress in NSCLC using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). ADGRD1 overexpression plasmid was constructed and transfected into the cells. The cells were treated with an AKT activator or AKT inhibitor. Additionally, subcutaneous implants of the transfected cells were made on the backs of nude mice to generate tumor tissues for further analysis.
Results: In cell experiments, the model group had lower ADGRD1 expression and higher AKT and mTOR levels (p < 0.05). However, in the oe-ADGRD1 (cells with ADGRD1 overexpression) group, cell proliferation, migration, and invasion decreased, cell-cycle arrest in the G0-G1 phase, while apoptosis increased compared to the oe-NC (p < 0.05). Moreover, the oe-ADGRD1 group had lower AKT and mTOR expression (p < 0.05). Regarding inflammatory response and oxidative stress, the oe-ADGRD1 group exhibited significant reductions in interleukins-1β (IL-1β), interleukins-6 (IL-6), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) levels (p < 0.05). Additionally, decreased Cox-2 and increased GPX4 expressions were observed in this group (p < 0.05). In animal experiments, the oe-ADGRD1 group demonstrated a considerable reduction in tumor volume and an improvement in pathological conditions based on hematoxylin-eosin (HE) staining. Moreover, it was revealed that AKT activation can reverse the therapeutic effect of oe-ADGRD1 on non-small cell lung cancer, while AKT inhibition can enhance its effect on NSCLC.
Conclusions: ADGRD1 is downregulated, while AKT and mTOR are upregulated in NSCLC. Therefore, overexpression of ADGRD1 can synergistically inhibit AKT, reduce iron death and oxidative stress, and ultimately improve NSCLC.
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Background: Urena sinuata L. is a shrubby wild plant used for centuries in folk medicine to treat bronchitis, rheumatism, fever, and waist pain. It is evident that it possesses antioxidant, anti-diarrheal, anti-atherothrombotic, sedative, anxiolytic, and analgesic effects in various test systems.
Objectives: The goal of this research was to evaluate the anti-inflammatory, antioxidant, and anxiolytic activity along with the preliminary phytochemical investigation of the ethanolic leaf extract of U. sinuata (ELEUS). Additionally, we also performed an in silico study to see the possible anxiolytic effects of its previously reported phytochemicals.
Methods: Scavenging methods for nitric oxide (NO●), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and hydroxyl radical (●OH) were used to determine antioxidant activity. The egg albumin model was used to assess anti-inflammatory action, while the elevated plus maze tested anxiolytic activity in adult male Swiss albino mice. For the latter case, the control group received vehicle (10 mL/kg), the standard group received diazepam (DZP: 2 mg/kg), and the test groups received ELEUS at 200 and 400 mg/kg. Additionally, both the test groups were combined with DZP 2 mg/kg. All these treatments were given via oral gavage. Finally, we performed an in silico study to check the possible interactions of its literature-claimed compounds with gamma-aminobutyric acid (GABA)A receptor subunits.
Results: Findings suggest that the ELEUS exhibited significant (p < 0.05) concentration-dependent antioxidant and anti-inflammatory effects. The highest activity was observed at 100 μg/mL. In mice, the extract had an anxiolytic effect that was significant (p < 0.05) and was dose-dependent. ELEUS 200 and 400 mg/kg were seen to potentiate the anxiolytic activity of the standard drug DZP (2 mg/kg) significantly (p < 0.05). Quercetagetin-6,7-O-dimethylether-3′-β-D-gluco-pyranoside, querceta-getin-6,7-O-dimethylether-4′-β-D glucopyranoside, and quercetagetin-6,7-O-dimethylether-3-β-D-glucopyranosid of U. sinuata showed better interaction capacity with the GABAA receptor protein (α1, α2, α3, α4, α5, and α6) than the standard drug (diazepam).
Conclusions: ELEUS possesses many important phytochemical groups and exhibits concentration-dependent antioxidant and anti-inflammatory effects as well as dose-dependent anxiolytic effects. U. sinuata may be a good source of plant-based therapeutically active lead compounds for inflammation, oxidative stress, neurological diseases, and disorders like anxiety.
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Objectives: The treatment of sepsis has received widespread attention in recent years, but morbidity and mortality rates are still increasing in clinical practice. This project aims to evaluate the outcome of propofol (PF) on brain injury induced by sepsis and explore its potential mechanism.
Methods: A total of 48 C57BL/6 mice were randomly divided into four subgroups, each containing 12 mice: a control (Con) subgroup, a sepsis lipopolysaccharide (LPS) subgroup, a fat emulsion (LPS + Lip) subgroup, and a propofol (LPS + PF) subgroup. The model was successfully built, and the pathological changes of brain tissue were evaluated using Hematoxylin eosin (HE) staining. Inflammatory indicators, including S-100β protein (S100-β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and neuron specific enolase (NSE), were measured using Enzyme-Linked Immunosorbent Assay (ELISA). The lactic acid (LA) concentration in brain tissue was measured using a colorimetric quantitative method. Acetylcholinesterase (Ach-E) activity was measured using an ELISA kit. Inflammation-related proteins, including Caspase-1, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and Heme oxygenase-1 (HO-1) concentrations, were measured by western blot. The reactive oxygen species (ROS) concentration was measured by immunofluorescence. Oxidative stress-related indicators, including malondialdehyde (MDA), nitric oxide (NO), glutathione peroxidase (GSH) and superoxide dismutase (SOD) concentrations were measured using a biochemical kit.
Results: This study found that the injury to the hippocampal Cornu Ammonis Area 1 (CA1) in the LPS subgroup was severe, with a decrease in the neurobehavioral score (p < 0.001). Additionally, the concentrations of S100-β, LA, IL-6, TNF-α, NSE, ROS, MDA and NO, as well as the activity of Acetylcholinesterase (Ach-E), were significantly increased (p < 0.001). On the other hand, the concentrations of GSH and SOD were significantly decreased (p < 0.001), while the concentrations of Caspase-1 and NLRP3 were increased (p < 0.001), and the mRNA and protein levels of Nuclear factor erythroid2-related factor 2 (Nrf2) and HO-1 were significantly decreased compared to the Con subgroup (p < 0.001). However, after the intervention of PF, the above results were reversed (p < 0.01).
Conclusions: PF has been shown to significantly mitigate sepsis-induced brain injury in mice. The underlying mechanism of this effect may be related to the Nrf2/HO-1 pathway.
