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The incidence of endometrial cancer (EC) has been on the rise in recent years. Advanced EC is associated with poor prognosis in patients. Traditional classification methods for EC do not provide satisfactory diagnosis and treatment. With the rapid advancements in molecular biology, studies have associated multi-omics with signaling pathways in the pathogenesis of EC, which is critical for the diagnosis and treatment of patients. Cell signal transduction pathways may lead to the occurrence, development and metastasis of tumors through multiple effectors. The Wnt (Wingless and Int-1) signaling pathway is a highly conserved signaling route that is widely present in multicellular eukaryotes. It is involved in determining cell fate, as well as cell proliferation, differentiation, motility and apoptosis during embryonic development, and its target genes are factors involved in cell development, cell proliferation and cell migration. Abnormal signal transduction may lead to abnormalities in cell growth, differentiation, metabolism and biology, resulting in various diseases. The Wnt pathway may be involved in uterine development and endometrial maintenance, and it is associated with estrogen-induced endometrial proliferation. This paper reviews progress in research on the relationship between Wnt signaling pathway and EC.
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Background: Summarize the available evidence in the literature regarding the repercussions generated by quercetin supplementation in amateur and professional athletes.
Methods: Searches were conducted in four databases, Cochrane Library (23 articles), PubMed/Medline (37 articles), Scopus (70 articles), and Excerpta Medica Database (EMBASE) (72 articles), which were subjected to eligibility criteria.
Results: Out of 202 articles found, 95 duplicates were removed, and 107 articles were analyzed for the inclusion process. Then, 784 studies were excluded after title/abstract evaluation, resulting in 17 articles of which 13 were included in this systematic review. After quercetin supplementation, alterations in aspects related to the inflammatory response were observed, mainly through modifications in the formation of interleukin (IL)-1β, interleukin 2 (IL-2), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor alpha (TNF-α). Responses were also observed in biochemical parameters, such as reduction of xanthine oxidase, and plasma free radicals. There were also changes related to anthropometry and body composition, in lean body mass (LBM). Some repercussions on performance were also observed, such as an increase in Sprint time (s), and training efficacy, a decrease post-run muscular pain through the Visual Analog Score (VAS), and recovery time in hours.
Conclusion: This systematic review indicates that quercetin supplementation does not improve exercise performance, but may exert positive effects on training development, which might trigger better performance as training progresses. On the inflammatory and oxidative-related parameters, just a few evidence pointed to an improved biochemical profile, wherein the slight enhancement may not justify the supplementation costs.
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Background: Obesity as a complex disease significantly impacts life quality and expectancy in older adults. Managing obesity in older adults is particularly challenging. The use of probiotics has been recommended as a potential strategy for weight management. So, this study aims to review the effectiveness of probiotics on weight and body composition in older adults.
Methods: A systematic search was conducted across multiple databases including PubMed, Web of Science, Scopus, and Embase, to retrieve relevant publications up to May 2023. Eligibility criteria were applied to select clinical trials that reported the effects of probiotics on weight and body composition in older adults. Two independent investigators performed data extraction according to a pre-designed table and assessed the quality of the selected studies using the Cochrane risk-of-bias tool.
Results: A total of 705 records were found, and 12 articles were considered for the review. In four studies, the use of probiotics has been demonstrated to decrease on weight and body composition in older adults. However, due to the high diversity of bacterial species and multispecies probiotics used, it cannot be concluded which type of probiotics is recommended for managing obesity in older adults.
Conclusions: While there is evidence suggesting that probiotics may have an impact on weight management, the effectiveness of probiotics on obesity in older adults is a more complex issue and influenced by various factors like aging, underlying diseases and lifestyle. More clinical studies are needed to determine the effective combination of probiotics for managing obesity in older adults.
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Background: Rheumatoid arthritis (RA) is a systemic inflammatory disorder that is usually treated with a cocktail of steroidal and nonsteroidal anti-inflammatory drugs, as well as other therapeutic modalities known as disease-modifying anti-rheumatic drugs (DMARDs), all of which have significant side effects. Our objective was to investigate the potential impact of naringenin on a rat model of RA induced by Complete Freund's Adjuvant (CFA).
Methods: This was achieved by assessing T-helper (Th) cytokines, oxidative stress, and the anti-oxidant defense system. Eighteen Wistar rats were divided into three equal (n = 6) groups: the normal group, the CFA-induced arthritic control group, and the CFA-induced arthritic group treated with naringenin at a dose of 25 mg/kg body weight daily for two weeks. The study used a variety of techniques, including spectrophotometric analysis, enzyme-linked immunosorbent assay (ELISA), and Western blot procedures, as well as ankle histological investigations and measurement of ankle circumference of the right hind leg.
Results: Naringenin treatment significantly decreased the CFA-induced elevated right hind-ankle circumference, serum rheumatoid factor (RF), anti-cyclic citrullinated peptide (ACCP), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and serum interleukin (IL)-1β levels (p < 0.05). Naringenin significantly increased serum IL-4 levels, hepatic glutathione (GSH), and superoxide dismutase (SOD) activity when compared to the CFA-induced RA model (p < 0.05). Naringenin treatment decreased ankle joint protein expression of nuclear factor kappa B (NF-κB) p50, NF-κB p65, inhibitor of NF-κB (IκBα), matrix metalloproteinases (MMPs)-1, 3 and 9, and inducible nitric oxide synthase (iNOS), as well as malondialdehyde (MDA) and nitric oxide (NO) levels (p < 0.05). Additionally, there was a significant increase in the ankle's nuclear factor erythroid 2-related factor 2 (Nrf2) levels (p < 0.05). Morphological signs like leg swelling and redness were also significantly reduced. Naringenin treatment significantly improved RA's histological changes, such as pannus formation, massive inflammatory cell infiltration, synovial membrane hyperplasia, and articular cartilage erosion.
Conclusions: Naringenin has a potent anti-arthritic effect via modulating Th cells cytokines, NF-κB pathway, Nrf2, MMPs, free radical damage, and anti-oxidant defenses.
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Background: Astrocytes are the most abundant cell type in the central nervous system (CNS) and play a crucial role in neuroinflammatory responses to damage and disease in the CNS. High mobility group box 1 (HMGB1) is an immuno-adjuvant factor that acts as a ligand for toll-like receptor (TLR)2/4 and is the receptor for advanced glycation end products (RAGE). It is associated with chronic neurodegeneration and neuroinflammation. We conducted a study to investigate the impact of HMGB1 on astrocytic cytotoxicity and inflammatory evolution.
Method: We cultured rat astrocytes and treated them with lipopolysaccharide (LPS) (TLR4 ligand), zymosan (TLR2 ligand), and HMGB1 or left them untreated as a control. Then, we blocked the activity of TLR2 and TLR4 with monoclonal antibodies. Using Luminex, we conducted measurements of cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and interleukin-10 (IL-10) at various time intervals. Also, we performed a Flow Cytometry analysis to check for any signs of apoptosis or necrosis in the collected cells. Finally, we tested the effect of astrocytes conditioned medium on neurons after TLRS agonists and antagonists treated them.
Results: Our findings showed that the rate of apoptosis was highest after stimulation by HMGB1 (38.8%). However, the antagonists of TLR4 (25.8%) and TLR2 (31.2%) slightly reversed the rate. HMGB1 activated astrocytes to express higher levels of IL-6 and IL-1β, like bacterial ligands. Conversely, the anti-inflammatory cytokine IL-10 was reduced after prolonged interaction with HMGB1. Our data also showed that TLRs antagonists reacted differently according to time intervals for blocking cytokine release after astrocytes were stimulated with HMGB1.
Conclusions: HMGB1 exhibits diversity in astrocyte activation. It can trigger TLR pathways, resulting in inflammation and subsequent neurotoxicity, or it can be involved in tissue regeneration at some stage.
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Background: Doxorubicin (DOX) is a commonly used antineoplastic medication in clinical settings. However, its clinical utility is hampered by pronounced adverse effects such as nephrotoxicity. The interleukin (IL)-13/p-signal transducer and activator of transcription 6 (STAT6) pathway plays a critical role in various renal diseases. Furthermore, Pitavastatin, a statin drug, has been recognized for its protective effects against multiple diseases. Therefore, this study aimed to explore whether Pitavastatin could improve doxorubicin-induced experimental nephrotoxicity by inhibiting the IL-13/p-STAT6 pathway.
Methods: In this study, a doxorubicin-induced mouse model of renal injury was employed, and mice were randomly divided into five groups: the normal control, Pitavastatin, doxorubicin, doxorubicin + dimethyl sulfoxide (DMSO), and doxorubicin + Pitavastatin groups. Their renal function was assessed by observing mouse body weight and serum biochemical markers (urea nitrogen, creatinine, cystatin C). Western blot analysis was used to examine the levels of IL-13 and STAT6, their phosphorylation in renal tissues, and the expression of inflammatory factors. The effects of Pitavastatin on doxorubicin-induced oxidative stress and apoptosis were analyzed through 2,7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.
Results: Compared to the doxorubicin group, the doxorubicin + Pitavastatin group showed a significant reduction in mouse body weight and improvement in serum biochemical markers (p < 0.05), indicating that Pitavastatin effectively ameliorated doxorubicin-induced nephrotoxicity. Furthermore, Pitavastatin suppressed the IL-13/p-STAT6 pathway's activity and reduced the expression of inflammatory factors at the molecular level. Additionally, Pitavastatin alleviated doxorubicin-induced oxidative stress and apoptosis.
Conclusion: This study demonstrates that Pitavastatin can alleviate doxorubicin-induced nephrotoxicity by inhibiting the IL-13/p-STAT6 pathway. This effect may be correlated to its anti-inflammatory, antioxidant, and anti-apoptotic capabilities. Therefore, Pitavastatin can be a promising therapeutic drug for treating doxorubicin-induced nephrotoxicity. Furthermore, these findings offer a novel theoretical foundation for the therapeutic use of Pitavastatin and suggest future avenues for additional clinical investigations.
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Background: Agmatinase (AGMAT) has been specifically reported to be highly expressed in several malignancies. Therefore, this study aims to investigate the role of AGMAT in colorectal cancer (CRC) and assess its potential as a prognostic biomarker.
Methods: We used The Cancer Genome Atlas (TCGA) database to identify differentially expressed genes in CRC compared to the healthy controls. Subsequently, we performed enrichment analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases to gain insights into the biological processes and cellular signaling pathways influenced by these differentially expressed genes (DEGs). The most informative prognostic genes among these DEGs were predicted by combining Least Absolute Shrinkage and Selection Operator (LASSO) regression and best subset selection, ultimately identifying the eight most relevant genes. Furthermore, we developed gene-based risk scores using Cox coefficients for these eight prognostic genes. The prognostic ability of the risk score was evaluated using two methods: time-dependent receiver operating characteristic (ROC) analysis and Kaplan-Meier (KM) survival analysis. Additionally, the correlation between AGMAT expression and prognosis in CRC tissues was investigated utilizing GEPIA 2 and the Human Protein Atlas (HPA) database. Finally, we employed RT-qPCR to quantify AGMAT mRNA expression levels in CRC tissues samples.
Results: Our analysis of TCGA data revealed 1917 DEGs, including 928 upregulated and 989 downregulated genes. Among them, 8 genes, including Matrix Metallopeptidase 1 (MMP1), Serine Protease Inhibitor Kazal-Type 1 (SPINK1), Cluster of Differentiation 24 (CD24), Serine Protease Inhibitor Kazal-Type 4 (SPINK4), AGMAT, EPH Receptor B2 (EPHB2), C2 Calcium-Dependent Domain Containing 4A (C2CD4A), Pituitary Tumor-Transforming Gene 1 (PTTG1), were significantly associated with prognosis in CRC. Furthermore, we observed upregulated AGMAT expression in CRC tissues. Additionally, we found a significant association between elevated AGMAT expression and decreased overall survival (OS) and disease-free survival (DFS) in patients with CRC (p-value < 0.05).
Conclusions: This study demonstrates that AGMAT is highly expressed in CRC tissues and is significantly associated with poorer prognosis in CRC patients. These findings suggest that AGMAT expression could serve as a biomarker for predicting survival in CRC, potentially offering new insights into its role in CRC development and paving the way for future treatment options.
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Background: Dipterocarpus turbinatus is a well-known ethnomedicinal plant species. Traditionally, it has been used to treat various medical ailments, including diabetes, diarrhea, tuberculosis, leprosy, ringworm, gonorrhea, ulcers, skin infections, wounds, and burns. This study aimed to assess the pharmacological properties of the methanol extract of D. turbinatus (MEDT) obtained from leaves, specifically focusing on its potential antidiabetic, anti-inflammatory, anthelminthic, cytotoxic, thrombolytic, antidiarrheal, and antipyretic properties.
Methods: In this study, castor oil-induced diarrhea, gastrointestinal transit, and castor oil-induced enteropooling mice models were used to examine the antidiarrheal potential of MEDT. The alpha-amylase inhibition assay was employed to investigate its antidiabetic attributes. Moreover, human blood samples were analyzed using a rapid clot analysis method to evaluate their thrombolytic properties. Furthermore, the anti-inflammatory attributes of MEDT were assessed using bovine serum albumin and egg albumin denaturation assays. The Brewer's yeast technique was used to evaluate the pyretic potential of MEDT in mouse models. The chemical composition of MEDT was analyzed using gas chromatography-mass spectrometry (GC-MS) analysis. Furthermore, a docking analysis of selected phytochemicals in MEDT was performed using BIOVIA and Schrödinger Maestro (v11.1) methods. Additionally, the absorption, distribution, metabolism, and excretion/toxicity (ADME/T) properties of these compounds were investigated utilizing online tools.
Results: The phytochemical analysis of the MEDT revealed the presence of diverse phytoconstituents such as flavonoids, alkaloids, glycosides, steroids, phytosterols, and resins. MEDT significantly inhibited alpha-amylase in a concentration-dependent manner, with a minimal inhibitory concentration required to inhibit 50% of enzyme activity (IC50) value of 38.40 μg/mL. Furthermore, MEDT significantly exhibited cytotoxicity, as evidenced by the median lethal dose (LC50) value of 439.25 μg/mL. Compared to streptokinase, the thrombolytic activity was statistically significant (p < 0.001). Additionally, the anthelmintic experiment revealed that exposure to MEDT led to a significant reduction in the duration of paralysis and the time to death in a dose-dependent manner. Furthermore, in pyrectic-induced mice, MEDT at 200 and 400 mg/kg doses resulted in a significant decrease in pyrexia. Moreover, GC-MS analysis enabled the detection of 31 compounds in MEDT. Interestingly, the binding predictions showed that 3-azabicyclo[3.2.2]nonane interacted favorably with 1A5H and 1ERR and that 8,11,14-Eicosatrienoic acid (Z,Z,Z)- showed potential interactions with 1SA0 which might mediate their anthelmintic and antidiabetic properties.
Conclusion: Taking into account the above findings and the ethnomedicinal importance of D. turbinatus, further research is needed to isolate and describe the phytoconstituents that underpin its purported biological effects.
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Background: Epilepsy surgery has seen numerous technological advances in diagnostic and therapeutic procedures in recent years. However, further understanding of how to integrate traditional and emerging technologies into epilepsy treatment is needed to develop this area. The purpose of this study is to observe the antiepileptic effect of gamma knife irradiation on chronic epileptic rats and the expression of cyclic adenosine monophosphate response element binding protein (CREB) in the brain.
Methods: Sixty Wistar rats were randomly divided into four groups: the control group, the control + gamma knife group, the pentylenetetrazole (PTZ) group and the PTZ + gamma knife group. The rats were injected intraperitoneally with PTZ to establish the epileptic models. Gamma knife irradiation was performed on the bilateral frontal cortex of rats. After 12 weeks of irradiation, the Morris water maze test was used on each group of rats to test their ability to learn and remember, and the expression of CREB in the cortex and hippocampus was detected.
Results: The epileptic seizures of rats in the PTZ + gamma knife group were significantly reduced by the 12th week after low-dose gamma knife irradiation (p < 0.05). Compared with the PTZ group, the swimming distance was significantly shorter in the PTZ + gamma knife group (p < 0.05). Compared with the PTZ group, the daily escape latency in the Morris water maze of the PTZ + gamma knife group on days 3–5 was significantly shortened (p < 0.05). Compared with the PTZ group, the number of times the Morris water maze crossed the platform and the percentage swimming time in the platform quadrant were both significantly higher in the PTZ + gamma knife group (p < 0.05).
Conclusion: The cognitive function and the expression of CREB decreased in the brains of epileptic rats, which was increased after low-dose gamma knife irradiation. This may suggest a possible molecular mechanism underlying the effects of gamma knife irradiation on epileptic seizures.
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Background: Heparanase (HPSE) is an endo-beta-D-glucuronidase, and its upregulation is associated with many inflammatory diseases, such as atherosclerosis, fibrosis, and cancer. However, the role of HPSE in myocardial infarction remains unclear.
Methods: Cell Counting Kit-8 (CCK8) assay was used to detect the development of the oxygen-glucose deprivation/reoxygenation (OGD/R) model and the effect of HPSE inhibitor OGT2115. Real-time quantitative PCR (RT-qPCR) and western blotting were used to detect HSPE expression in OGD/R model, the effect of HPSE inhibitor OGT2115, and the expression of cell proliferation-related protein, apoptosis-related protein, and fibrosis-related protein. The immunofluorescence assay was used to detect the expression of 5-Ethynyl-2′-Deoxyuridine (EdU) and TdT-mediated dUTP nick-end labeling (TUNEL). Enzyme-linked immunosorbent assay (ELISA) assay was used to detect the secretion of cytokines associated with the OGD/R model.
Results: HPSE was highly expressed in the OGD/R model, and its inhibitor OGT2115 significantly promoted the proliferation and inhibited the apoptosis and fibrosis of H9C2 cells in the OGD/R model. Simultaneously, OGT2115 inhibited the secretion of inflammatory factors—tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-8—in the OGD/R model. Further mechanistic studies demonstrated that OGT2115 could inhibit the phosphorylation of mitogen-activated protein kinases (MAPK) and extracellular signal-regulated kinase (ERK).
Conclusion: HPSE inhibitor OGT2115 alleviates myocardial IR injury in H9c2 cells and inhibits the MAPK/ERK pathway, indicating that HPSE is crucial in regulating myocardial infarction, and its inhibitor OGT2115 may be a potential drug for the treatment of myocardial infarction.
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Background: Due to its low water solubility, Rutin, a crystalline medication used to treat a variety of conditions, has a limited rate of dissolution when given in gastrointestinal fluids. The present study planned to formulate and characterize Rutin using mesoporous silica material (SBA-15) as well as to determine the in-vitro dissolution properties.
Methods: Rutin was formulated using mesoporous silica material such as SBA-15. Particle size distribution analysis, fourier transform-infrared (FT-IR) spectroscopy, scanning electron microscopy, and X-ray diffraction were used to characterize the compound in the complex. Rutin's solubility and in-vitro release characteristics were assessed. Furthermore, the dissolution data (DD) Solver Excel add-in software was used to evaluate several mathematical models to interpret the Rutin dissolution kinetics from the mesoporous materials.
Results: Differential scanning calorimetry was used to confirm Rutin's amorphous state, which resulted in a significantly higher rate of dissolution than pure crystalline Rutin. The release of the drug from the Rutin/SBA-15 complex was well-simulated by the Weibull model. Notably, the SBA-15 carrier-mediated complex of Rutin exhibited the highest drug loading and dissolution rate, showing promising potential for enhancing Rutin bioavailability.
Conclusion: The findings suggested that Rutin/SBA-15 could be easily incorporated into conventional oral pharmaceutical dosage forms such as capsules and therefore can be utilized for treating ailments such as allergies, inflammation, tumors, infections, protozoal diseases, and spasms. To assess the Rutin/SBA-15 complex's in-vivo pharmacokinetic performance and appropriateness for a range of pharmacological actions, more investigation is required.
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Background: β-sitosterol, a plant-derived sterol, shows anti-cancer properties in multiple cancers. However, its biological effects on osteosarcoma are unclear. This study aims to decipher β-sitosterol's biological function in osteosarcoma and its regulatory mechanism.
Methods: Osteosarcoma cell lines 143B and HOS were used as the in vitro models. They were treated with β-sitosterol, and cell counting kit-8 was adopted to assess cell proliferation. Flow cytometry was conducted to examine cell cycle; apoptosis was detected through Terminal Deoxynucleotidyl Transferase dUTP Nick end Labeling (TUNEL) assay and flow cytometry. The targets of β-sitosterol were predicted in the Traditional Chinese Medicine Systems Pharmacology database, and osteosarcoma-associated genes were analyzed with GeneCards database. Cytoscape software and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) database were applied to establish a protein-protein interaction network and perform modular analysis to screen hub genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology pathway enrichment analyses were then performed with the hub genes with DAVID database. Caspase-3 mRNA expression level was determined via quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was performed to detect the expression level of cleaved caspase-3 protein.
Results: β-sitosterol could inhibit 143B and HOS cell growth, and induce cell apoptosis and cell cycle arrest in G1 phase. Caspase-3 was identified as a target of β-sitosterol in osteosarcoma. Additionally, β-sitosterol could significantly promote cleaved caspase-3 expression, and caspase-3 knockdown could markedly reverse the suppressive effect of β-sitosterol on the malignant phenotypes of 143B and HOS cells.
Conclusion: β-sitosterol can suppress osteosarcoma cell proliferation and induce apoptosis by facilitating caspase-3 expression.
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Background: Microfibril-associated protein 2 (MFAP2) plays an oncogenic role in various cancer. The purpose of study is to investigate the roles of MFAP2 in non-small cell lung cancer (NSCLC).
Methods: Frist, bioinformatics were performed to determine MFAP2 expression in lung adenocarcinoma (LUAD) and Lung squamous cell carcinoma (LUSC); next, MFAP2 mRNA expression in clinical samples has been observed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method, and the protein expression of MFAP2 was tested using western blot and immunohistochemistry; moreover, Receiver operating characteristic (ROC) analysis has been performed to determine the potential diagnostic value of MFAP2; furthermore, A549 as well as NCI-H1299 cells were cultured, and the cell viability, proliferation, migration as well as invasion was determined by using Cell-Counting-Kit-8 (CCK-8), colony formation assay, wound healing and Matrigel assays. Finally, the effects of MFAP2 on ferroptosis of NSCLC cells were also determined by commercially available kits or western blot methods.
Results: We found that the expression of MFAP2 was increased in NSCLC, and overexpression of MFAP2 predicted poor clinical outcomes. Furthermore, high levels of MFAP2 in tumor tissues can be used as a sensitive biomarker for NSCLC patients. Moreover, over-expression of MFAP2 may increase the growth and migration of NSCLC cells, and increased expression of MFAP2 also dampened Erastin-induced ferroptosis of A549 and NCI-H1299 (p < 0.001).
Conclusions: In summary, MFAP2 may worked as an oncogene in NSCLC. MFAP2 deficiency suppressed the aggressiveness of NSCLC cells by increasing the ferroptosis.
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Background: The genome of the dengue virus (DENV) encodes a total of ten proteins, three of which are structural and seven of which are non-structural (NS). Among the NS proteins, nonstructural protein 2A (NS2A) and NS2B play pivotal roles in the replication and assembly of DENV. This study aimed to determine the frequency of mutations occurring in the NS2A and NS2B regions of DENV within the Punjab Province of Pakistan.
Methods: About 4 mL of blood was collected from DENV patients. RNA was isolated from serum samples and confirmed using an RNA Kit. The RNA was converted to complementary DNA (cDNA) followed by amplification using polymerase chain reaction. The cDNA was subjected to library preparation for whole genome sequencing. We selected 23 samples to undergo whole genome sequencing. Among these, 19 isolates exhibited a significant number of mutations.
Results: In the NS2A, a total of 25 mutations were detected, with 23 being novel in the N-terminal and domains. The most common mutation, I15V, was found in seven genomic isolates, followed by I171A (n = 4), M150R (n = 2), and T34A (n = 2). Within NS2B, there were 20 different mutations, 18 of which were novel. Notably, the N and C-terminal regions exhibited a higher mutation frequency compared to the central two helices of NS2B. Specifically, seven mutations were located in the α1 helix of NS2B. Additionally, four mutations (A10E, V11F, I73F, and K127E) were detected in two isolates, respectively.
Conclusions: The most conserved region was the C-terminal domains extending beyond the 181 amino acids. This study represents the first comprehensive analysis of mutations in the NS2A and NS2B regions, which may help design effective vaccines and antiviral therapies for DENV.
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Objective: To analyze the efficacy of belimumab in the treatment of systemic lupus erythematosus (SLE) and its effect on improving the quality of life of Chinese patients.
Methods: A retrospective study was conducted using the medical records of 52 SLE patients admitted between March 2021 and April 2022. These patients were divided into two groups: the control group and the monoclonal antibody group, with 26 cases in each group. Patients in the control group received standard SLE treatment, while those in the monoclonal antibody group received standard SLE treatment in addition to belimumab therapy. The clinical treatment effect, dosage of hormone drugs, SLE disease activity index (SLEDAI) score, peripheral blood B cell level, 36-item Short Form health survey questionnaire (SF-36) and adverse reactions before and after treatment were compared between the two groups.
Results: The routine treatment plus belimumab resulted in higher efficacy than routine treatment alone (p < 0.05). The routine treatment plus belimumab led to a lower B cell as compared to the routine treatment alone (p < 0.05). The routine treatment plus belimumab was associated with higher quality of life (p < 0.05). The safety profiles of the two groups were similar (p > 0.05).
Conclusion: Belimumab might be a viable strategy in the treatment of Chinese patients with SLE. Belimumab can significantly reduce the dosage of hormone drugs in patients, and effectively reduce the SLEDAI score and peripheral blood B cell level of patients, and is not linked to adverse reactions. Therefore, it is worth promoting widely.
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Background: Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder, yet its underlying mechanism remains incompletely understood. This study aimed to elucidate gut microbiome dysbiosis and metabolic perturbations among Chinese patients with diarrhea-predominant IBS (IBS-D).
Methods: Fecal samples were collected from 55 IBS-D patients (according to Rome IV criteria) and 29 healthy controls. Gut microbiome-metabolome signatures were obtained through 16S ribonucleic acid (rRNA) amplicon sequencing and untargeted metabolomics. Integrated bioinformatics analysis was conducted to investigate microbiome-metabolome characteristics in IBS-D patients.
Results: Significant differences in microbiome profiles were observed between IBS-D patients and healthy volunteers. Utilizing machine learning algorithms, our investigation revealed a notable increase in gut microbes, including Sutterella, Lachnospira, Bacteroides, and Fusobacterium, in the IBS-D patients (p < 0.05). Conversely, Bifidobacterium, Blautia, and Romboutsia exhibited a decrease in IBS-D patients (p < 0.05). Furthermore, functional analysis indicated potential alterations in gut lipopolysaccharide (LPS) biosynthesis and disruptions in energy metabolism functions among IBS-D patients. In terms of metabolome profiles, significant upregulation was observed in metabolites such as 5′-S-methyl-5′-thioadenosine, S-adenosyl-methionine, creatine, adenine, and gamma-aminobutyric acid (GABA) in individuals with IBS-D (p < 0.05), suggesting a potentially pivotal role of these metabolites in the microbiota-gut-brain axis. Additionally, our study identified several significant associations between metabolites and microbes, further enhancing our understanding of the intricate interplay within the IBS-D microbiome.
Conclusions: Our research highlights a microbiome-metabolome pattern in individuals with IBS-D, indicating that gut microbiome and fecal metabolites can serve as valuable indicators to distinguish between IBS-D patients and healthy individuals.
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Background: Silver and its nanoparticles have gained attention owing to their unique physicochemical properties which contribute to their antimicrobial and anticancer properties. The primary focus of this study was the synthesis of silver nanoparticles (AgNPs) using the cell filtrate of Escherichia coli (E. coli) American Type Culture Collection (ATCC) 8739.
Methods: Silver nanoparticles were synthesized using E. coli and coated with non-toxic, naturally occurring L-arginine. L-arginine-coated AgNPs (L-AgNPs) were tested for purity, elemental composition, morphology, topology, and stability. Subsequently, they were tested for their antibacterial, apoptotic, reactive oxygen species (ROS), and cytotoxic effects on A549 lung cancer cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Results: The study revealed the formation of well-defined nanoparticles with a spherical shape, falling within the size range of 8.8 nm to 44.6 nm. The L-AgNPs exhibited significant antibacterial characteristics, with the largest zone of inhibition observed against Salmonella spp. (18.7 ± 0.9 mm) and the smallest against Bacillus cereus (8.7 ± 0.9 mm). The half maximal inhibitory concentration (IC50) value of L-AgNPs against A549 lung cancer cells was 58.67 μg/mL, while against 3T3-L1 cells, it was measured as 98.03 μg/mL via MTT assay. L-AgNPs induced apoptosis, as confirmed by morphological alterations in the cells, membrane blebbing, and chromatin condensation. These nanoparticles also triggered the production of reactive oxygen species (ROS) due to cellular oxidative stress, as indicated by the increased levels of dichlorodihydrofluorescein (DCF).
Conclusion: This research demonstrates the potential application of these L-AgNPs in the biotechnology and pharmaceutical industries for their antibacterial and anticancer properties.
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Background: Pneumonia is an inflammatory disease characterized by infection in the lung tissue. Transmembrane Protease Serine 2 (TMPRSS2) is implicated in the onset of inflammatory conditions. However, the precise role of TMPRSS2 in regulating the inflammatory response during pneumonia remains unclear. Hence, this research aims to explore the involvement of TMPRSS2 in pediatric pneumonia and unravel the associated mechanisms.
Methods: To induce pneumonia, lipopolysaccharide (LPS) was injected into the lungs of mice, establishing a mouse model of pneumonia. RAW264.7 cells served as an in vitro model for macrophages and underwent a 4-hour LPS stimulation. The expression pattern of TMPRSS2 in the pneumonia model was determined through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. TMPRSS2's impacts on the inflammatory response, lung tissue damage, oxidative stress levels, mitochondrial permeability, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression in pneumonia were assessed through Enzyme-Linked Immunosorbent Assay (ELISA), hematoxylin and eosin (HE) staining, qRT-PCR, and cellular immunofluorescence experiments. The effects of TMPRSS2 knockdown and overexpression on the expression of NLRP3 and Sirtuin 1 (SIRT1) were also investigated using western blotting.
Results: The expression of TMPRSS2 mRNA and protein was significantly upregulated in mouse lung tissues upon LPS treatment. TMPRSS2 was found to enhance inflammation and lung damage in mice with pneumonia. Conversely, suppressing TMPRSS2 expression alleviated inflammation and lung damage in mice with pneumonia. Additionally, overexpressing TMPRSS2 intensified the inflammatory response in LPS-stimulated RAW264.7 cells, whereas silencing TMPRSS2 attenuated inflammation. We further demonstrated that TMPRSS2 influences the development of pneumonia by inhibiting SIRT1 expression and inducing NLRP3 activity.
Conclusions: Our study suggests that TMPRSS2 promotes the inflammatory progression of pneumonia, and modulates the expression of NLRP3 inflammasome and SIRT1.
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Background: Ischemic stroke continues to be a leading cause of mortality globally. Interleukin-1 receptor-associated kinase 1 (IRAK1) plays a critical regulatory role in the onset and progression of stroke. Therefore, this study aimed to explore the molecular function and the underlying mechanisms of IRAK1 in cerebral ischemia-reperfusion (I-R) injury.
Methods: We established a mouse model of cerebral I-R injury to investigate the expression patterns of IRAK1 during the injury process. Its expression levels were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Additionally, the cerebral infarcted area was evaluated through Toluidine Blue Cresyl Violet (TTC) staining. The impact of IRAK1 knockdown on cell death and inflammatory responses in mouse brain tissues was analyzed employing qRT-PCR and immunofluorescence methods. Furthermore, the effects of IRAK1 knockdown on the nuclear factor-kappa B (NF-κB) signaling pathway and Toll-like Receptor 4 (TLR4) expression levels were assessed utilizing Western blot analysis.
Results: We observed a time-dependent elevation in IRAK1 expression following the I-R injury (p < 0.001). Furthermore, IRAK1 knockdown significantly reduced infarcted area in mice (p < 0.01). Moreover, knockdown of IRAK1 alleviated cell death and inflammatory responses in mice following I-R injury (p < 0.01 and p < 0.001). However, this inhibitory effect was linked to the suppression of the Caspase-3 and NF-κB signaling pathways. Additionally, IRAK1 was found to contribute to cerebral I-R injury by regulating TLR4. We observed that suppressing TLR4 during oxygen-glucose deprivation treatment significantly mitigated the exacerbating effects of IRAK1 overexpression on the inflammatory response and cell apoptosis in microglial cells (p < 0.01 and p < 0.001).
Conclusions: These findings underscore the involvement of IRAK1 in cerebral stroke by interacting with TLR4, presenting a promising avenue for therapeutic intervention in cerebral ischemia-reperfusion injury.
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Background: Conventional chemotherapeutic drugs have limitations, including non-specific toxicity and drug resistance. Targeted cancer therapy using recombinant fusion proteins may effectively overcome these challenges. Azurin is a bacteriocin with pro-apoptotic activity, while buforin IIb derivative (BR2) is an antimicrobial peptide exhibiting cell-penetrating ability. This study aims to construct a fusion protein combining Azurin and BR2 to explore its potential against breast cancer cell line (MCF-7).
Methods: We designed, expressed, purified, and evaluated a novel recombinant fusion protein named Azurin-BR2, consisting of Azurin and BR2 domains, for targeted cytotoxicity against breast cancer cells. The fusion gene construct was cloned into a pET30a vector and transformed into E. coli BL21DE3 for expression. The fusion protein was isolated from inclusion bodies, solubilized, and refolded. The purity and identity of the 19 kDa fusion protein were confirmed by Sodium Dodecyl Sulphate-Polyacrylamide Gel Electrophoresis (SDS-PAGE) and Western blot analysis. To evaluate its biological activity, the fusion protein was tested using the 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide (MTT) assay on both MCF-7 breast cancer cells and MCF-10F normal cells.
Results: The fusion protein showed significant cytotoxic effects against MCF-7 cells, outperforming Azurin alone. The cytotoxic impact on normal MCF-10F cells was significantly lower. The half-maximal inhibitory concentration (IC50) value for Azurin-BR2 was 52 μg/mL compared to 102 μg/mL for Azurin alone against MCF-7 cells.
Conclusions: The fusion protein Azurin-BR2 demonstrated enhanced anticancer therapeutic efficacy by combining the pro-apoptotic activity of Azurin with the cell-penetrating properties of BR2. This fusion protein holds promise for targeted cancer therapy in clinical applications and warrants further in vivo studies.
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Background: Determination of myocardial viability is vital for coronary revascularization in patients with ischemic cardiomyopathy (ICM). To select the appropriate strategies for ICM screening, the present study compared the image quality, viability extent, and dyssynchrony of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) myocardial viability imaging in patients with ICM using an oral glucose and intravenous insulin loading (G/I) protocol with a convenient fasting status (FAST).
Methods: 18F-FDG PET metabolic imaging was conducted using the G/I and FAST protocols on different days and 99mTc-methoxyisobutylisonitrile (MIBI) perfusion imaging in all patients (N = 44). Fluorodeoxyglucose (FDG) image quality was assessed using a 5-point scoring system. The semiquantitative analysis included SUVmean of blood pool (SUVmeanBlood), SUVmax of the whole left ventricular muscle (SUVmaxMyo), and the SUVmeanBlood and SUVmaxMyo ratio (M/B). Furthermore, the quantitative analysis involved comparing the extent of mismatch on polar maps and evaluating left ventricle dyssynchrony between the two groups. The Cohen κ-test was used to investigate positive or negative on left anterior descending (LAD), left circumflex (LCX) or right coronary artery (RCA) between the groups.
Results: The imaging quality scores were 4.36 ± 0.94 and 3.55 ± 1.09 using the G/I and FAST protocols, respectively (p < 0.001). Significant differences were found in SUVmeanBlood, SUVmaxMyo, and M/B between the two groups (p < 0.001, 0.007, and <0.001, respectively). G/I and FAST protocols indicated good agreement for positive and negative findings in the LAD, LCX, and RCA (κ = 0.847, 0.858, and 0.74, respectively). Myocardial viability assessment exhibited equivalence between the two groups (all p > 0.05) within the imaging score ranging from 3 to 5. Furthermore, dyssynchrony assessment of left ventricle exhibited no significant difference between the two groups (all p > 0.05). For the G/I method, insulin consumption (95% confidence interval (CI) 0.03–0.27, p = 0.014) and SUVmaxMyo (95% CI 0.07–0.24, p = 0.0005) were identified as significant predictors for metabolic imaging score (coefficient of determination (R2) = 0.6226). Similarly, for the FAST protocol, SUVmaxMyo (95% CI 0.09–0.29, p = 0.0003) was a significant predictor for metabolic imaging score (coefficient of determination (R2) = 0.6787).
Conclusions: Our findings indicate that 18F-FDG PET in assessing myocardial viability using the FAST protocol could be a time-efficient and safe option for clinical personalized practice.
Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR2400083975).
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Background: Postoperative pain is the most common complication following thoracoscopic surgery (TS). Ropivacaine is a commonly used analgesic drug in clinical settings. This study aims to explore the analgesic effects of ultrasound-guided intercostal nerve block (INB) with different concentrations of ropivacaine during postoperative pain management in patients undergoing TS.
Methods: This prospective, randomized, and controlled trial included 100 study participants from May 2019 to May 2022. The patients were equally divided into the ropivacaine (0.5%, 0.25%), the blank, and the control groups. The 0.5% or 0.25% group received 0.5% or 0.25% ropivacaine injection (15 mL) under the induction of ultrasound. However, the blank group received a placebo injection (15 mL saline) under the induction of ultrasound. The control group was administered with a placebo injection (15 mL saline). Furthermore, baseline characteristics, numeric rating scale (NRS) score, Bruggrmann comfort scale (BCS) score, postoperative analgesic drug supplementation, and adverse events were analyzed across the four groups.
Results: At rest or during movement, the NRS score initially increased and then gradually decreased across four groups. Moreover, 12-, 24-, or 36-hour post-surgery, NRS score was significantly reduced in the 0.5% ropivacaine group relative to the 0.25% ropivacaine group. Furthermore, similar trend of NRS score was observed during movement. After surgery 48 h, the BCS score was significantly higher in the 0.5% or 0.25% ropivacaine group compared to the blank group. However, the BCS score was found to be higher in the 0.5% ropivacaine group compared to the 0.25% ropivacaine group. The number of patients with postoperative analgesic drug supplementation was significantly reduced in the 0.5% or 0.25% ropivacaine group than in the blank group (3 or 6 cases vs. 16 cases, p < 0.001).
Conclusions: In summary, 0.5% ropivacaine for INB under ultrasound guidance exhibited a better postoperative analgesic effect for patients undergoing TS, offering a theoretical basis for clinical applications.
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Background: Bladder cancer is a common tumor of the urinary system. Interleukin-25 is highly expressed in a variety of tumors and leads to poor prognosis. However, the expression and biological role of interleukin-25 in bladder cancer remain unclear.
Methods: This study analyzed the differential expression of interleukin-25 (IL-25) and its receptor, interleukin-17 receptor B (IL-17RB), in tumor and adjacent tissues from bladder cancer patients by bioinformatics databases and immunohistochemistry. The impact of IL-25 on bladder cancer cell proliferation and migration was assessed in vitro. Moreover, we used wild-type and IL-25 knockout mice implanted with bladder cancer cells to investigate tumor growth in vivo. Gene set enrichment analysis (GSEA) was employed to elucidate the underlying mechanisms. We further explored the function of interleukin-25 in bladder cancer by cell viability assay and western blot. Angiogenesis was also compared between the wild-type and IL-25 knockout mice.
Results: Immunohistochemistry indicated a significantly higher expression of IL-25 in bladder cancer tissues, which correlated with several prognostic markers. Analysis of The Cancer Genome Atlas (TCGA) database revealed that IL-17RB was highly expressed in bladder cancer, and may be related to overall survival of patients. In vitro, IL-25 enhanced the proliferation and migration of bladder cancer cells. IL-25 knockout markedly reduced tumor growth in a murine subcutaneous bladder cancer model. Mechanistic investigations revealed that IL-25 enhanced bladder cancer cell proliferation by activating the AKT (protein kinase B), mammalian target of rapamycin (mTOR) signaling pathway (AKT/mTOR signaling pathway). Additionally, angiogenesis was suppressed in IL-25 knockout mice bearing bladder tumors.
Conclusion: Our findings suggest that IL-25 promotes bladder cancer cell proliferation by activating the AKT/mTOR signaling pathway and IL-25 knockout inhibits angiogenesis in bladder cancer. These findings suggest that IL-25 is a potential prognostic marker and therapeutic target in bladder cancer management.
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Background: Anxiety, stress, depression, and psychosis are conditions related to mental illnesses which interfere with the quality of life. Conventional interest in the preventive and therapeutic potential of natural products or nutraceuticals in disease management has escalated in recent years due to their relatively high safety index and affordability. Natural products with anxiolytic properties are essential central nervous system (CNS) modulators, which can reduce symptoms of anxiety and other associated psychological factors. This study investigated the neurotherapeutic effects of bioactive components of extracted in the methanol and acetone fractions of Limonia acidissima L. fruit rind in Swiss albino mice.
Methods: The bioactive properties reflecting neurotherapeutic activity were examined with standard protocols that included open field, hole board, hole cross, and sleeping time tests induced by thiopental sodium. The experimental design included 140 Swiss albino mice, randomly subdivided into twenty-eight groups (n = 5) and distributed into blocks for different in vivo protocols.
Results: Results of the thiopental sodium-mediated sleeping time test demonstrated that both extracts showed substantial (p < 0.001) reductions in sleep onset time while concomitantly increasing sleep duration time. The hole cross (p < 0.001) and open-field (p < 0.05, p < 0.01, p < 0.001) studies showed noteworthy reductions in spontaneous locomotor and experimental behaviours. The administration of the extracts significantly reduced the frequency of head dips during the hole-board testing (p < 0.001).
Conclusions: Our findings show that the methanol and acetone fruit rind extracts from Limonia acidissima (L. acidissima) are potentially active in vivo. The study indicates that the fruit's rind exhibits potent CNS functions regarding its hypnotic and anti-depressant effects.
