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Background: Colorectal cancer is influenced by several factors such as unhealthy habits and genetic factors. C1QB has been linked to a number of malignancies. However, uncertainty surrounds the connection between C1QB and CRC. Therefore, this study aimed to explore a bidirectional causal relationship of C1QB as a drug target in CRC through Mendelian randomization (MR) analysis. Methods: The GWASs for C1QB and CRC were obtained from the Integrative Epidemiology Unit Open GWAS database. There were five strategies to investigate MR. Sensitivity analysis was carried out via tests for heterogeneity, horizontal pleiotropy and leave-one-out effects to evaluate the dependability of the MR analysis results. Furthermore, colocalization analysis of C1QB and CRC, protein-protein interaction network and drug prediction according to exposure factors as well as phenotype scanning were performed. Results: The results of forward MR analysis demonstrated that C1QB was a risk factor for CRC (OR = 1.104, p = 0.033). However, we did not find a causal relationship between CRC and C1QB (reverse MR). Rs294180 and rs291985 corresponded to the same linkage interval and had the potential to influence C1QB and CRC, respectively. The PPI results demonstrated that C1QB interacted with 10 genes (C1QA, C1QC, C1R, C1S, C2, C4A, C4B, CALR, SERPING1, and VSIG4). Additionally, 21 medications were predicted to match C1QB. Molecular docking data, including for benzo(a)pyrene, 1-naphthylisothiocyanate, calcitriol and medroxyprogesterone acetate, revealed excellent binding for drugs and proteins. Moreover, we identified 29 diseases that were associated with C1QB and related medicines via disease prediction and intersection methods. As a therapeutic target for CRC, phenotypic scanning revealed that C1QB does not significantly affect weight loss, liver cirrhosis, or nonalcoholic fatty liver disease, but might have protective impacts on ovarian cancer and melanoma. Conclusion: The results highlight a causal relationship between C1QB and CRC and imply an oncogenic role for C1QB in CRC, as potential drug targets. Drugs designed to target C1QB have a greater chance of success in clinical trials and are expected to help prioritize CRC drug development and reduce drug development costs. That provided a theoretical foundation and reference for research on CRC and C1QB in MR.
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There is a growing body of evidence suggesting that the composition of intestinal flora plays a significant role in regulating lipid metabolism. 2', 3', 5'-tri-O-acetyl-N6-(3-hydroxyphenyl) adenosine (IMMH007) is a new candidate compound for regulating blood cholesterol and other lipids. In this study, we conducted metagenomic and metabolomic analyses on samples from high-fat diet-fed (HFD) hamsters treated with IMMH007. Our findings revealed that IMM-H007 reversed the imbalance of gut microbiota caused by a high-fat diet. Additionally, it activated adiponectin receptor and pantothenate and CoA biosynthesis pathway-related genes, which are known to regulate lipid and glucose metabolism. Furthermore, IMM-H007 promotes cholesterol metabolism by reducing the abundance of genes and species associated with 7α-dehydroxylation and bile salt hydrolase (BSH). Metabolomics and pharmacological studies have shown that IMM-H007 effectively improved glucose and lipid metabolism disorders caused by HFD, reduced the aggregation of secondary bile acids (SBAs), significantly increased the content of hyodeoxycholic acid (HDCA), and also activated the expression of VDR in the small intestine. As a result, there was a reduction in the leakage of diamine oxidase (DAO) into the bloodstream in hamsters, accompanied by an upregulation of ZO-1 expression in the small intestine. The results suggested that IMM-H007 regulated glucose and lipid metabolism, promoted cholesterol metabolism through activating the expression of VDR, inhibiting inflammatory and improving the permeability of the intestinal barrier. Thus, our study provides new understanding of how IMM-H007 interacts with intestinal function, microbiota, and relevant targets, shedding light on its mechanism of action.
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Adenosina , Dieta Hiperlipídica , Microbioma Gastrointestinal , Hiperlipidemias , Metabolismo dos Lipídeos , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Cricetinae , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Adenosina/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Mesocricetus , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Transcriptoma/efeitos dos fármacosRESUMO
PURPOSE: Previous studies have explored the role of immune cells on osteonecrosis. This Mendelian randomization (MR) study further assessed 731 immunocyte phenotypes on osteonecrosis, whether a causal relationship exists, and provides some evidence of causality. METHODS: The 731 immunocyte phenotypes and osteonecrosis data used in this study were obtained from their respective genome-wide association studies (GWAS). The authors used inverse variable weighting (IVW) as the primary analysis method. In addition, the authors simultaneously employed multiple analytical methods, including MR-Egger, weighted mode, simple mode, and weighted median, to strengthen the final results. Finally, sensitivity analyses were conducted to verify the stability and feasibility of the data. RESULTS: The results of the IVW method of MR analysis showed that 8 immunocyte phenotypes were positively associated with osteonecrosis [ P <0.05, odds ratio (OR) > 1]; 18 immunocyte phenotypes were negatively associated with osteonecrosis ( P <0.05, OR<1), none of which were heterogeneous or horizontally pleiotropic ( P > 0.05) or reverse causality. In addition to this, in reverse MR, osteonecrosis was positively associated with 10 additional immunocyte phenotypes ( P <0.05, OR > 1) and negatively associated with 14 immunocyte phenotypes ( P <0.05, OR<1). And none of them had heterogeneity and horizontal pleiotropy ( P > 0.05) or reverse causality. CONCLUSIONS: The authors demonstrated a complex causal relationship between multiple immune phenotypes and osteonecrosis through a comprehensive two-way, two-sample MR analysis, highlighting the complex pattern of interactions between the immune system and osteonecrosis.
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Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Osteonecrose , Fenótipo , Humanos , Osteonecrose/genética , Osteonecrose/imunologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Proximal tubular cells (PTCs) play a critical role in the progression of diabetic kidney disease (DKD). As one of important progenitor markers, CD133 was reported to indicate the regeneration of dedifferentiated PTCs in acute kidney disease. However, its role in chronic DKD is unclear. Therefore, we aimed to investigate the expression patterns and elucidate its functional significance of CD133 in DKD. METHODS: Data mining was employed to illustrate the expression and molecular function of CD133 in PTCs in human DKD. Subsequently, rat models representing various stages of DKD progression were established. The expression of CD133 was confirmed in DKD rats, as well as in human PTCs (HK-2 cells) and rat PTCs (NRK-52E cells) exposed to high glucose. The immunofluorescence and flow cytometry techniques were utilized to determine the expression patterns of CD133, utilizing proliferative and injury indicators. After overexpression or knockdown of CD133 in HK-2 cells, the cell proliferation and apoptosis were detected by EdU assay, real-time cell analysis and flow analysis. Additionally, the evaluation of epithelial, progenitor cell, and apoptotic indices was performed through western blot and quantitative RT-PCR analyses. RESULTS: The expression of CD133 was notably elevated in both human and rat PTCs in DKD, and this expression increased as DKD progressed. CD133 was found to be co-expressed with CD24, KIM-1, SOX9, and PCNA, suggesting that CD133+ cells were damaged and associated with proliferation. In terms of functionality, the knockdown of CD133 resulted in a significant reduction in proliferation and an increase in apoptosis in HK-2 cells compared to the high glucose stimulus group. Conversely, the overexpression of CD133 significantly mitigated high glucose-induced cell apoptosis, but had no impact on cellular proliferation. Furthermore, the Nephroseq database provided additional evidence to support the correlation between CD133 expression and the progression of DKD. Analysis of single-cell RNA-sequencing data revealed that CD133+ PTCs potentially play a role in the advancement of DKD through multiple mechanisms, including heat damage, cell microtubule stabilization, cell growth inhibition and tumor necrosis factor-mediated signaling pathway. CONCLUSION: Our study demonstrates that the upregulation of CD133 is linked to cellular proliferation and protects PTC from apoptosis in DKD and high glucose induced PTC injury. We propose that heightened CD133 expression may facilitate cellular self-protective responses during the initial stages of high glucose exposure. However, its sustained increase is associated with the pathological progression of DKD. In conclusion, CD133 exhibits dual roles in the advancement of DKD, necessitating further investigation.
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Antígeno AC133 , Diabetes Mellitus , Nefropatias Diabéticas , Animais , Humanos , Ratos , Linhagem Celular , Proliferação de Células , Diabetes Mellitus/patologia , Nefropatias Diabéticas/metabolismo , Células Epiteliais/patologia , Glucose/metabolismo , Hiperplasia/patologia , Antígeno AC133/genética , Antígeno AC133/metabolismoRESUMO
Patient-derived gene expression signatures induced by cancer treatment, obtained from paired pre- and post-treatment clinical transcriptomes, can help reveal drug mechanisms of action (MOAs) in cancer patients and understand the molecular response mechanism of tumor sensitivity or resistance. Their integration and reuse may bring new insights. Paired pre- and post-treatment clinical transcriptomic data are rapidly accumulating. However, a lack of systematic collection makes data access, integration, and reuse challenging. We therefore present the Cancer Drug-induced gene expression Signature DataBase (CDS-DB). CDS-DB has collected 78 patient-derived, paired pre- and post-treatment transcriptomic source datasets with uniformly reprocessed expression profiles and manually curated metadata such as drug administration dosage, sampling time and location, and intrinsic drug response status. From these source datasets, 2012 patient-level gene perturbation signatures were obtained, covering 85 therapeutic regimens, 39 cancer subtypes and 3628 patient samples. Besides data browsing, download and search, CDS-DB also supports single signature analysis (including differential gene expression, functional enrichment, tumor microenvironment and correlation analyses), signature comparative analysis and signature connectivity analysis. This provides insights into drug MOA and its heterogeneity in patients, drug resistance mechanisms, drug repositioning and drug (combination) discovery, etc. CDS-DB is available at http://cdsdb.ncpsb.org.cn/.
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Antineoplásicos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Neoplasias , Humanos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transcriptoma/genética , Microambiente Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genéticaRESUMO
OBJECTIVE: This study aimed to examine whether diabetes mellitus is causally associated with osteonecrosis. METHOD: Using publicly accessible genome-wide association study statistics, a bidirectional two-sample Mendelian randomization analysis was carried out. In order to determine whether diabetes has a causal effect on osteonecrosis and whether osteonecrosis has a causal effect on diabetes, we extracted six date on diabetes in Europeans from IEU OpenGWAS and GWAS Catalogue and osteonecrosis in Europeans from FinnGen. We then evaluated the data using inverse variance weighting, MR-Egger regression, weighted median, weighted mode, and simple mode. The results' stability and dependability were then evaluated using sensitivity analysis and heterogeneity analysis. Finally, meta-analysis is used to further confirm if there is a relationship between diabetes and osteonecrosis. RESULTS: When diabetes was used as an exposure factor, MR-Egger regression showed that directional fold product was unlikely to bias the results. Cochran's Q test showed only minor heterogeneity in a few data sets. Multidirectional tests Egger-intercept, MR-PRESSO and funnel plots for most data did not show multidirectional and asymmetry at the gene level. Most of the IVW results showed no causal relationship between diabetes mellitus and osteonecrosis. The results of meta-analysis of IVW methods further confirmed the absence of a causal relationship. Inverse MR analysis also showed no causal relationship between osteonecrosis and diabetes. CONCLUSION: Results of bidirectional MR analysis show no evidence of causal relationship between diabetes and osteonecrosis.
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Diabetes Mellitus , Osteonecrose , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Diabetes Mellitus/genética , NonoxinolRESUMO
Drug resistance currently poses the greatest barrier to cancer treatments. To overcome drug resistance, drug combination therapy has been proposed as a promising treatment strategy. Herein, we present Re-Sensitizing Drug Prediction (RSDP), a novel computational strategy, for predicting the personalized cancer drug combination A + B by reversing the resistance signature of drug A. The process integrates multiple biological features using a robust rank aggregation algorithm, including Connectivity Map, synthetic lethality, synthetic rescue, pathway, and drug target. Bioinformatics assessments revealed that RSDP achieved a relatively accurate prediction performance for identifying personalized combinational re-sensitizing drug B against cell line-specific intrinsic resistance, cell line-specific acquired resistance, and patient-specific intrinsic resistance to drug A. In addition, we developed the largest resource of cell line-specific cancer drug resistance signatures, including intrinsic and acquired resistance, as a byproduct of the proposed strategy. The findings indicate that personalized drug resistance signature reversal is a promising strategy for identifying personalized drug combinations, which may guide future clinical decisions regarding personalized medicine.
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Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biologia Computacional , Resistencia a Medicamentos Antineoplásicos , Combinação de MedicamentosRESUMO
Background: Studies have revealed that the transplantation of mesenchymal stem cells (MSCs) might be a potential star candidate for premature ovarian failure (POF) in animal experiments. However, individual studies with a small sample size cannot be used to draw a clear conclusion. Therefore, we conducted a systematic review and meta-analysis to explore the potential of using MSCs in the treatment of POF in animals. Methods: Seven databases were searched for studies exploring the effect of the transplantation of MSCs on POF in animal models. The PRISMA guideline was followed, and the methodological quality was ensured using SYRCLE's risk of bias tool. RevMan 5.4 and STATA 12.0 software was performed to meta-analysis. Results: In total, 37 studies involving 1,079 animals were included. Significant associations were found for MSCs with the levels of E2 (SMD 2.69 [95% CI 1.97, 3.41]), FSH (-2.02, [-2.74, -1.30]), primary follicles (2.04, [1.17, 2.92]), secondary follicles (1.93, [1.05, 2.81]), and primordial follicles (2.38, [1.19, 3.57]. Other outcomes, such as AMH, LH, INHB, antral follicles, growing follicles, mature follicles, and early antral were also found to be significant. There was no difference in FSH/LH, corpus leteum, follicles, and estruc cycle. Conclusions: Our meta-analysis result indicated that the transplantation of MSCs might exert therapeutic effects on animal models of POF, and these effects might be associated with improving the disorder of the sexual cycle, modulating serum hormone expressions to a better state, and restoring ovarian function.
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Menopausa Precoce , Células-Tronco Mesenquimais , Insuficiência Ovariana Primária , Feminino , Humanos , Animais , Folículo Ovariano , Hormônio Foliculoestimulante/metabolismoRESUMO
AIMS: Diabetic kidney disease (DKD) is a severe microvascular complication frequently associated with type 1 and type 2 diabetes mellitus. The objective of this work was to evaluate the relevance of PI3K/Akt pathway polymorphisms and DKD susceptibility by a meta-analysis. METHODS: Case-control studies related to the relationship between PI3K/Akt pathway polymorphisms and DKD risk were searched from Pubmed, Embase, Cochrane Library, SINOMED, CNKI, and Wanfang databases. Statistical analysis and heterogeneity test were conducted by Review Manager 5.4. RESULTS: Totally, 52 eligible studies were enrolled, including seven single nucleotide polymorphisms (SNPs) for four genes in the PI3K/AKT pathway (GNB3: rs5443; eNOS: rs1799983, rs869109213, rs2070744; IL-6: rs1800795, rs1800796; TNFα: rs1800629). The "M" allele of eNOS rs1799983 was related to the increased risk of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 75%, OR = 1.29, 95%CI 1.07-1.56; MM + WM vs. WW: I2 = 75%, OR = 1.50, 95%CI 1.21-1.86). The "M" allele of eNOS rs869109213 was implicated with higher prevalence of DKD under random effects model, especially in Asian population (Overall:M vs. W: I2 = 63%, OR = 1.43, 95%CI 1.22-1.68; MM + WM vs. WW: I2 = 50%, OR = 1.36, 95%CI 1.16-1.58; MM vs. WM + WW: I2 = 59%, OR = 2.20, 95%CI 1.41-3.43). The "M" allele of eNOS rs2070744 was implicated with higher prevalence of DKD under random effects model, especially in Indian population (Overall: M vs. W: I2 = 47%, OR = 1.35, 95%CI 1.15-1.59; MM + WM vs. WW: I2 = 45%, OR = 1.32, 95%CI 1.07-1.62; MM vs. WM + WW: I2 = 65%, OR = 2.29, 95%CI 1.39-3.77). The "M" allele of IL-6 rs1800796 was predominately associated with higher DKD risks under random effects model, especially in Asian population (Overall: M versus W: I2 = 23%, OR = 1.49, 95%CI 1.21-1.84; MM + WM vs. WW: I2 = 1%, OR = 1.43, 95%CI 1.15-1.77; MM + WM vs. WW: I2 = 71%, OR = 2.77, 95%CI 1.09-7.06). CONCLUSIONS: This meta-analysis indicated that polymorphisms in the PI3K/Akt pathway in eNOS rs1799983, rs869109213, rs2070744, and IL-6 rs1800796 were related to the increased risk of DKD.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Interleucina-6/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A growing stream of research suggests that probiotic fermented milk has a good effect on nonalcoholic fatty liver disease. This work aimed to study the beneficial effects of Lactobacillus rhamnosus hsryfm 1301 fermented milk (fermented milk) on rats with nonalcoholic fatty liver disease induced by a high-fat diet. The results showed that the body weight and the serum levels of total cholesterol, total glyceride, low-density lipoprotein, alanine transaminase, aspartate aminotransferase, free fatty acid, and reactive oxygen species were significantly increased in rats fed a high-fat diet (M) for 8 wk, whereas high-density lipoprotein cholesterol and superoxide dismutase were significantly decreased. However, the body weight and the serum levels of total cholesterol, total glyceride, alanine transaminase, aspartate aminotransferase, free fatty acid, reactive oxygen species, interleukin-8, tumor necrosis factor-α, and interleukin-6 were significantly decreased with fermented milk (T) for 8 wk, and the number of fat vacuoles in hepatocytes was lower than that in the M group. There were significant differences in 19 metabolites in serum between the M group and the C group (administration of nonfermented milk) and in 17 metabolites between the T group and the M group. The contents of 7 different metabolites, glycine, glycerophosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, thioetheramide-PC, d-aspartic acid, oleic acid, and l-glutamate, were significantly increased in the M group rat serum, and l-palmitoyl carnitine, N6-methyl-l-lysine, thymine, and 2-oxadipic acid were significantly decreased. In the T group rat serum, the contents of 8 different metabolites-1-O-(cis-9-octadecenyl)-2-O-acetyl-sn-glycero-3-phosphocholine, acetylcarnitine, glycine, glycerophosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, d-aspartic acid, oleic acid, and l-glutamate were significantly decreased, whereas creatinine and thymine were significantly increased. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that 50 metabolic pathways were enriched in the M/C group and T/M group rat serum, of which 12 metabolic pathways were significantly different, mainly distributed in lipid metabolism, amino acid, and endocrine system metabolic pathways. Fermented milk ameliorated inflammation, oxygenation, and hepatocyte injury by regulating lipid metabolism, amino acid metabolic pathways, and related metabolites in the serum of rats with nonalcoholic fatty liver disease.
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Lacticaseibacillus rhamnosus , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/veterinária , Leite/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Alanina Transaminase , Ácido Glutâmico , Ácido D-Aspártico/metabolismo , Ácido D-Aspártico/farmacologia , Ácido Oleico/metabolismo , Timina/metabolismo , Timina/farmacologia , Glicerídeos/metabolismo , Glicerídeos/farmacologia , Aspartato Aminotransferases , Peso Corporal , Glicina/metabolismo , Glicina/farmacologia , Colesterol/metabolismo , Dieta Hiperlipídica , Fígado/metabolismoRESUMO
The energy needs of tubular epithelial components, especially proximal tubular epithelial cells (PTECs), are high and they heavily depend on aerobic metabolism. As a result, they are particularly vulnerable to various injuries caused by factors such as ischemia, proteinuria, toxins, and elevated glucose levels. Initial metabolic and phenotypic changes in PTECs after injury are likely an attempt at survival and repair. Nevertheless, in cases of recurrent or prolonged injury, PTECs have the potential to undergo a transition to a secretory state, leading to the generation and discharge of diverse bioactive substances, including transforming growth factor-ß, Wnt ligands, hepatocyte growth factor, interleukin (IL)-1ß, lactic acid, exosomes, and extracellular vesicles. By promoting fibroblast activation, macrophage recruitment, and endothelial cell loss, these bioactive compounds stimulate communication between epithelial cells and other interstitial cells, ultimately worsening renal damage. This review provides a summary of the latest findings on bioactive compounds that facilitate the communication between these cellular categories, ultimately leading to the advancement of tubulointerstitial fibrosis (TIF).
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Nefropatias , Rim , Humanos , Células Epiteliais , Células Endoteliais , Interleucina-1beta , FibroseRESUMO
Background: The study was designed to investigate the mechanism of Hongjingtian injection (HJT) in treating tubulointerstitial fibrosis (TIF) in chronic kidney diseases (CKD) based on network pharmacology and experimental verification. Methods: First, active ingredients of HJT obtained from literature were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and putative targets of active ingredients were predicted using the Chemmapper, SEA and Swiss Target Prediction database. Subsequently, the "compound-target" network for HJT was established. In addition, TIF disease targets were obtained from the GEO gene chips (accession number GSE20247). The intersecting targets of HJT and TIF obtained through Venny 2.1.0. The key targets and signaling pathways were determined by protein-protein interaction (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, quantitative polymerase chain reaction (qPCR) and Western blot (WB) were used to validate the predicted five key genes targets (GAD1, SPHK1, P4HA2, AKR1B1, PTGES). And immunofluorescence, wound healing assay and transwell assay were used to verify the anti-fibrosis effect of HJT on TGFß1-induced HK-2 cells. Results: The network pharmacology analysis results showed that there are 36 active compounds and 1,044 putative target genes in HJT. HJT may exert its inhibitory effects against TIF by acting on 79 key targets. Besides, KEGG analysis indicated that the anti-TIF effect of HJT was mediated by multiple pathways, such as the metabolic pathway, pathways in cancer and gap junction. Among them, GAD1, SPHK1, P4HA2, AKR1B1 and PTGES are enriched in the metabolic pathway. In vitro induced cell model experiments, the immunofluorescence experience showed that HJT could restore EMT of HK-2 cells. In addition, the qPCR and WB results showed that HJT significantly restored the expression of the SPHK1 in HK-2 cells induced by TGF-ß1. Conclusions: This study comprehensively illuminated the active compounds, potential targets, and molecular mechanism of HJT against TIF. HJT treatment of TIF may reverse EMT caused by TGF-ß1 by targeting SPHK1.
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Objectives: To evaluate the effect of Yugengtongyu granules on reducing the incidence of adverse cardiovascular events and improving quality of life (QOL) in patients with stable coronary artery disease (SCAD). Methods: A double-blind randomized controlled trial was conducted among SCAD population. One hundred fourteen patients were randomly assigned to experimental group (n = 57) and control group (n = 57) following randomized block design. Combined with the basis of standard treatment of SCAD, the experimental group and control group received Yugengtongyu granules or placebo, respectively, twice daily for 6 months and were followed for another 1 year (18 months in total from enrollment). Major outcomes (any occurrence of cardiovascular death, nonfatal myocardial infarction, or coronary revascularization), minor outcomes (any occurrence of all-cause death, ischemic stroke, readmission due to unstable angina, heart failure, or malignant arrhythmia), and composite outcomes (union of major and minor outcomes) were used to evaluate prognosis; Seattle Angina Questionnaire (SAQ) was applied to evaluate QOL, and levels of low density lipoprotein-cholesterol (LDL-C) and high sensitive C reacting protein (HS-CRP) in serum were tested. Results: The incidence of composite outcomes in the experimental group was significantly lower than that in the control group (3 [5.2%] vs. 11 [19.2%], hazard ratio: 0.273, 95% confidence interval: 0.080-0.926, p = 0.022); major outcomes, minor outcomes, and independent events such as nonfatal myocardial infarction showed lowering trend in experimental group. Experimental group scored significantly higher than control group in four dimensions of SAQ: physical limitation, angina frequency, treatment satisfaction, and disease perception at the third- and sixth-month follow-up; there was no significant difference in serum level of LDL or HS-CRP at all scheduled timepoints. Conclusion: The addition of Yugengtongyu granules based on current standard treatment reduced the incidence of composite outcomes and improved QOL in patients with SCAD. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-13004370).
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Doenças Cardiovasculares , Doença da Artéria Coronariana , Medicamentos de Ervas Chinesas/uso terapêutico , Idoso , Angina Pectoris , Proteína C-Reativa/análise , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
PURPOSE: The conventional interventions of anaplastic thyroid carcinoma (ATC) patients are mainly through surgery, chemotherapy, and radiotherapy; however, it is hardly to improve survival rate. We aimed to investigate the differential expressed genes (DEGs) between ATC and normal thyroid gland through bioinformatics analysis of the microarray datasets and find new potential therapeutic targets for ATC. METHODS: Microarray datasets GSE9115, GSE29265, GSE33630, GSE53072, and GSE65144 were downloaded from Gene Expression Omnibus (GEO) database. Compared with the normal tissue, GEO2R was conducted to screen the DEGs in each chip under the condition of |log FC| > l, adjusted P-values (adj. P) < 0.05. The Retrieval of Interacting Genes (STRING) database was used to calculate PPI networks of DEGs with a combined score >0.4 as the cut-off criteria. The hub genes in the PPI network were visualized and selected according to screening conditions in Cytoscape software. In addition, the novel genes in ATC were screened for survival analysis using Kaplan-Meier plotter from those hub genes and validated by RT-qPCR. RESULTS: A total of 284 overlapping DEGs were obtained, including 121 upregulated and 161 downregulated DEGs. A total of 232 DEGs were selected by STRING database. The 50 hub genes in the PPI network were chosen according to three screening conditions. In addition, the Kaplan-Meier plotter database confirmed that high expressions of ANLN, CENPF, KIF2C, TPX2, and NDC80 were negatively correlated with poor overall survival of ATC patients. Finally, RT-qPCR experiments showed that KIF2C and CENPF were significantly upregulated in ARO cells and CAL-62 cells when compared to Nthy-ori 3-1 cells, TPX2 was upregulated only in CAL-62 cells, while ANLN and NDC80 were obviously decreased in ARO cells and CAL-62 cells. CONCLUSION: Our study suggested that CENPF, KIF2C, and TPX2 might play a significant role in the development of ATC, which could be further explored as potential biomarkers for the treatment of ATC.
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Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease. However, the treatment is limited. The aim of this meta-analysis was to evaluate the effects and safety of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4 (DPP-4I), in treating NAFLD. Studies were sourced from electronic databases including PubMed, CENTRAL (Cochrane Controlled Trials Register), Embase, Medline, Web of Science, Clinical Trials, and CNKI to identify all randomized controlled clinical trials (RCTs) and non-RCTs in adult patients with NAFLD. Key outcomes were changes in serum levels of liver enzymes and improvement in hepatic histology and fat content measured by imaging or liver biopsy. Stata14.0 and RevMan5.3 were used for the meta-analysis. Seven studies with 269 NAFLD patients were included. Compared to the control group, sitagliptin treatment improved serum gamma-glutamyl transpeptidase (GGT) levels in the RCT subgroup (SMD = 0.79, 95% CI: 0.01-1.58). However, there was no significant improvement in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels following sitagliptin treatment. Four of the included studies performed liver imaging, but sitagliptin treatment did not result in a significant reduction in liver fat content. Only five participants developed sitagliptin-related gastrointestinal discomfort. Our study suggests that sitagliptin effects individuals with NAFLD by improving serum GGT. Although sitagliptin is safe and well tolerated in NAFLD patients, it exerts no beneficial effects on liver transaminase and liver fat content in these patients.
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Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Fosfato de Sitagliptina/efeitos adversos , Fosfato de Sitagliptina/farmacologia , Idoso , Ensaios Clínicos como Assunto/estatística & dados numéricos , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Fígado/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfato de Sitagliptina/administração & dosagem , Resultado do TratamentoRESUMO
Intestinal mucosal barriers help the body resist many intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). In this study, we identified a novel bacterium promoting the repair of intestinal mucosa and investigated the potential mechanisms underlying its activity. Culture supernatant of Bacillus subtilis RZ001 upregulated the expression of mucin 2 (MUC2) and tight junction (TJ) proteins in HT-29 cells in vitro. Oral administration of B. subtilis RZ001 may have significantly reduced symptoms such as the dextran sulfate sodium (DSS)-induced decrease in body weight, shortening of colon length and overproduction of proinflammatory factors. The number of goblet cells and levels of MUC2 and TJ proteins were significantly increased in adult mice fed with B. subtilis RZ001. B. subtilis RZ001 cells upregulated the levels of MUC2 in the intestinal organoids. Furthermore, culture supernatant of B. subtilis RZ001 could suppress the Notch signalling pathway and activate the expression of atonal homolog 1 (Atoh1). The transcription factor Atoh1 is required for intestinal secretory cell differentiation and activates transcription of MUC2 via binding to E-boxes on the MUC2 promoter. Taken together, B. subtilis strain RZ001 has the potential for treating IBD. The present study is helpful to elucidate the mechanisms of B. subtilis action.
Assuntos
Bacillus subtilis/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Colite/etiologia , Colite/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Biópsia , Linhagem Celular Tumoral , Sobrevivência Celular , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Mucina-2/genética , Mucina-2/metabolismo , Proteínas de Junções ÍntimasRESUMO
In aortic endothelial cells, the TGFß signaling pathway is involved in the regulation of vascular endothelial growth factor (VEGF), which encodes a potent angiogenic factor crucial for the development of ovarian hyperstimulation syndrome. Growth differentiation factor 9 (GDF9) is a member of the TGFß family and its effect on VEGF expression in human granulosa cells is unknown. In this study, human granulosa cells were collected from patients during the course of oocyte retrieval for in vitro fertilization and were cultured in vitro. After the first 48 h of culture, cells were treated with GDF9 with or without SB431542 (an ALK5 inhibitor) at various doses. The medium was then collected to determine the concentration of VEGF by ELISA. Cellular RNA was collected and extracted for quantification by real-time quantitative fluorescence PCR. Our study showed that GDF9 suppressed VEGF release from human granulosa cells in a dose-dependent manner and also downregulated VEGF mRNA levels in these cells. Furthermore, SB431542 antagonized the suppression of VEGF mRNA by GDF9 and diminished the inhibitory effect of GDF9 on VEGF release by human granulosa cells. Our results indicated that GDF9 can inhibit VEGF expression in human granulosa cells and ALK5 might mediate this process.
Assuntos
Células da Granulosa/metabolismo , Fator 9 de Diferenciação de Crescimento/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Benzamidas , Dioxóis , Feminino , HumanosRESUMO
Purpose: We compare anterior segment parameters and the risk of malignant glaucoma between nanophthalmos with secondary chronic angle closure glaucoma (NSCACG) and chronic primary angle-closure glaucoma (CPACG). Methods: This retrospective case-control study included 32 NSCACG (32 eyes) and 36 CPACG (36 eyes) patients. Anterior segment parameters, including anterior chamber depth (ACD) and width (ACW), pupil diameter (PD), lens vault (LV), ciliary process-ciliary process distance (CCD), angle opening distance500 (AOD500), trabecular-iris angle (TIA), trabecular-ciliary processes distance (TCPD), ciliary body max thickness (CBMT), iris convexity (IC), peripheral iris thickness (PIT), iris-zonule distance (IZD), trabecular ciliary process angle (TCPA), and anterior vault (AV), were measured by ultrasound biomicroscopy. A-scan ultrasonography measurements, including lens thickness (LT) and axial length (AL), also were reviewed. Results: ACD, ACW, CCD, TCPD, and AL were smaller, whereas the LV, LT/AL, LV/LT, LV/ACD, LT/ACD, LV/AV, and AV/AL were larger in NSCACG compared to CPACG eyes (all Bonferroni-corrected P < 0.05). Eyes with NSCACG had a higher risk of malignant glaucoma postoperatively than eyes with CPACG (P = 0.018). Conclusions: Characterized by narrower anterior segment, forward movement of larger lens, more anteriorly rotated ciliary bodies, and smaller CCD, NSCACG eyes have a higher risk of malignant glaucoma than CPACG eyes.
Assuntos
Segmento Anterior do Olho/patologia , Glaucoma de Ângulo Fechado/patologia , Microftalmia/patologia , Adulto , Idoso , Comprimento Axial do Olho/patologia , Estudos de Casos e Controles , Corpo Ciliar/patologia , Feminino , Humanos , Iris/patologia , Cristalino/patologia , Masculino , Microscopia Acústica , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: No effective treatment is currently available for poorly differentiated thyroid cancer which is resistant to radioiodine, especially with migration and invasion. A great number of researches have revealed the anticancer effects of salidroside, but none have studied the effects of salidroside on thyroid cancer. This study aimed to investigate the effect of salidroside on migration and invasion of poorly differentiated thyroid cancer cells. METHODS: The effects of salidroside on migration, invasion and apoptosis of poorly differentiated thyroid cancer WRO cells and normal thyroid follicular epithelial Nthy-ori 3-1 cells were measured by wound-healing assay, transwell migration/invasion assay and flow cytometry, respectively. The expression levels of MMP2 and MMP9 at RNA and protein levels in WRO cells were detected by qRT-PCR and western blot. The phosphorylation levels of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and the apoptosis-related protein levels of Bax, cleaved caspase 3 and Bcl-2 were assessed by western blot. RESULTS: Salidroside significantly suppressed migration/invasion and induced apoptosis in poorly differentiated thyroid cancer WRO cells. We further illustrated that salidroside significantly inhibited expressions of MMP2 and MMP9 at mRNA and protein levels and the phosphorylation activation of JAK2/STAT3 in WRO cells. In addition, salidroside increased expressions of pro-apoptotic factors (Bax and cleaved caspase 3) and decreased expression of anti-apoptotic factor (Bcl-2) significantly in WRO cells. CONCLUSION: The present study demonstrates that salidroside inhibits migration and invasion of WRO cells (a kind of poorly differentiated cancer cell line) significantly, which might be via suppressing JAK2-STAT3 signaling pathway.
Assuntos
Glucosídeos/farmacologia , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Janus Quinase 2/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
Persistent high-risk HPV infection is considered as a major cause of cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The RIG-I pathway in innate immunity plays an important role in antivirus response. Here, we hypothesized that altered function of mitochondrial antiviral signaling protein (MAVS) and mitochondrial TNF receptor-associated factor 3(TRAF3), key molecules downstream of the viral sensors RIG-I, may impair their ability of clearing HPV and thereby influence the risk for cervical precancerous lesions. To investigate the effects of MAVS and TRAF3 polymorphisms on susceptibility to cervical precancerous lesions, 8 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-environment interactions were also calculated. We found that CA genotype of rs6052130 in MAVS gene were at 1.48 times higher risk of developing cervical precancerous lesion than individuals with CC genotype (CA vs. CC: ORadjusted = 1.48, 95% CI, 1.02-2.16). In addition, a significant synergetic interaction between high-risk HPV infection and rs6052130 was found on an additive scale. A significantly decreased risk of cervical precancerous lesions for the TC genotype of rs12435483 in the TRAF3 gene (ORadjusted = 0.67, 95% CI, 0.45-0.98) was also found. Moreover, MDR analysis identified a significant three-locus interaction model, involving high-risk HPV infection, TRAF3 rs12435483 and number of full-term pregnancies. Our results indicate that the MAVS rs6052130 and TRAF3 rs12435483 confer genetic susceptibility to cervical precancerous lesions. Moreover, MAVS rs6052130-mutant individuals have an increased vulnerability to high-risk HPV-induced cervical precancerous lesions.