​Comprehensive mendelian randomization analysis of plasma proteomics to identify new therapeutic targets for the treatment of coronary heart disease and myocardial infarction.

BACKGROUND: Ischemic heart disease is one of the leading causes of mortality worldwide, and thus calls for development of more effective therapeutic strategies. This study aimed to identify potential therapeutic targets for coronary heart disease (CHD) and myocardial infarction (MI) by investigating the causal relationship between plasma proteins and these conditions. METHODS: A two-sample Mendelian randomization (MR) study was performed to evaluate more than 1600 plasma proteins for their causal associations with CHD and MI. The MR findings were further confirmed through Bayesian colocalization, Summary-data-based Mendelian Randomization (SMR), and Transcriptome-Wide Association Studies (TWAS) analyses. Further analyses, including enrichment analysis, single-cell analysis, MR analysis of cardiovascular risk factors, phenome-wide Mendelian Randomization (Phe-MR), and protein-protein interaction (PPI) network construction were conducted to verify the roles of selected causal proteins. RESULTS: Thirteen proteins were causally associated with CHD, seven of which were also causal for MI. Among them, FES and PCSK9 were causal proteins for both diseases as determined by several analytical methods. PCSK9 was a risk factor of CHD (OR = 1.25, 95% CI: 1.13-1.38, P = 7.47E-06) and MI (OR = 1.36, 95% CI: 1.21-1.54, P = 2.30E-07), whereas FES was protective against CHD (OR = 0.68, 95% CI: 0.59-0.79, P = 6.40E-07) and MI (OR = 0.65, 95% CI: 0.54-0.77, P = 5.38E-07). Further validation through enrichment and single-cell analysis confirmed the causal effects of these proteins. Moreover, MR analysis of cardiovascular risk factors, Phe-MR, and PPI network provided insights into the potential drug development based on the proteins. CONCLUSIONS: This study investigated the causal pathways associated with CHD and MI, highlighting the protective and risk roles of FES and PCSK9, respectively. FES. Specifically, the results showed that these proteins are promising therapeutic targets for future drug development.

Association between 19 medication use and risk of common cancers: A cross-sectional and Mendelian randomisation study.

Background: Previous studies have yielded inconsistent results concerning drug use and the risk of cancers. We conducted a large-scale cross-sectional study and a two-sample Mendelian randomisation (MR) study to reveal the causal effect between the use of 19 medications and the risk of four common cancers (breast, lung, colorectal, and prostate). Methods: We obtained information on medication use and cancer diagnosis from National Health and Nutrition Examination Survey participants. After propensity score matching, we conducted survey-weighted multivariate logistic regression and restricted cubic spline analysis to assess the observed correlation between medication use and cancer while adjusting for multiple covariates. We also performed MR analysis to investigate causality based on summary data from genome-wide association studies on medication use and cancers. We performed sensitivity analyses, replication analysis, genetic correlation analysis, and reverse MR analysis to improve the reliability of MR findings. Results: We found that the use of agents acting on the renin-angiotensin system was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.42; 95% confidence interval (CI) = 0.27-0.63, P < 0.001), and there was a nonlinear association of 'decrease-to-increase-to-decrease' (P < 0.0001). The random-effects inverse variance weighted (IVW) model-based primary MR analysis (OR = 0.94, 95% CI = 0.91-0.97, P = 0.0007) and replication MR analysis (OR = 0.90, 95% CI = 0.85-0.96, P = 0.0006) both provided robust evidence of the causality of genetic liability for the use of agents acting on the renin-angiotensin system on a decreased risk of prostate cancer. Conclusions: Our study provides robust evidence that the use of drugs acting on the renin-angiotensin system can reduce prostate cancer risk. Given the high prevalence of prostate cancer, these findings have important implications for drug selection and prostate cancer prevention in patients with cardiovascular disease.

Shenqi Fuzheng Injection Combined With Chemotherapy for Gastric Cancer: An Overview of Systematic Reviews and Meta-Analyses.

BACKGROUND: Gastric cancer (GC) is a prevalent malignant tumor of the digestive tract. Chemotherapy (CT) is the primary treatment for GC, but it is accompanied by toxic side effects. Several systematic reviews and meta-analyses (SRs/MAs) on the combination of Shenqi Fuzheng injection (SFI) with CT for GC have been published; however, the conclusions have been inconsistent. This overview of SRs/MAs aims to assess the effectiveness and safety of SFI for GC, establishing a dependable foundation for its clinical application. METHODS: We utilized 7 databases, namely PubMed, Embase, Cochrane Library, CNKI, Wanfang, VIP, and SinoMed, to conduct our search. The retrieval period spanned from inception to August 2023. The methodological quality, bias risk, reporting quality, and evidence quality of the SRs/MAs were assessed using the evaluation tools AMSTAR-2, ROBIS, PRISMA 2020, and GRADE, respectively. Subsequently, the randomized controlled trials (RCTs) included in the SRs/MAs were quantitatively analyzed through the implementation of RevMan 5.4 software. RESULTS: Eleven SRs/MAs were included in this study, comprising 54 RCTs involving a total of 9539 patients with GC. The studies covered the period from 2012 to 2021, with the number of original RCTs per study ranging from 3 to 20 and sample sizes ranging from 159 to 1413. The methodological quality of all 11 SRs/MAs was assessed as low or very low, and the quality of evidence was determined to range from moderate to very low. The comprehensive quantitative meta-analysis revealed that the combination of SFI with CT improved the objective response rate (ORR) (RR = 1.30, 95% CI = [1.21, 1.41], P < .00001) and disease control rate (DCR) (RR = 1.13, 95% CI = [1.09, 1.18], P < .00001) in GC patients, without heterogeneity observed among the studies. In comparison with CT alone, SFI combined with CT also demonstrated improvements in the Karnofsky performance status (KPS) (RR = 1.36, 95% CI = [1.25, 1.49], P < .00001) and CD4+/CD8+ level (RR = 1.16, 95% CI = [0.87, 1.46], P < .00001) of patients. In terms of adverse reactions, the combination therapy of SFI with CT was associated with a reduced incidence of gastrointestinal reactions (RR = 0.67, 95% CI = [0.58, 0.78], P < .00001) and neurotoxicity (RR = 0.64, 95% CI = [0.50, 0.81], P = .0002). CONCLUSIONS: SFI combined with CT can enhance the clinical effectiveness and enhance the quality of life in patients with GC, while minimizing adverse reactions. Nonetheless, the evaluation of overall quality remains deficient, thus restricting the reliability and stability of the conclusions. High-quality, large-sample RCTs remain crucial for establishing dependable clinical evidence. SYSTEMATIC REVIEW REGISTRATION: INPLASY20239004.

Global research trends in tumor stem cell-derived exosomes and tumor microenvironment: visualization biology analysis.

BANKGROUND: The tumor microenvironment (TME) is an internal environment composed of various cells and an extracellular matrix. Cancer stem cell-derived exosomes (CSC-Exos), as essential messengers involved in various tumor processes, are important carriers for bidirectional communication between the tumor microenvironment and tumor cells and play an important role in the tumor microenvironment. Nevertheless, few bibliometric analyses have been systematically studied in this field. METHODS: Therefore, we aimed to visualize the research hotspots and trends in this field through bibliometrics to comprehend the future evolution of fundamental and clinical research, as well as to offer insightful information and fresh viewpoints. The Scopus database was used to search the research literature related to exosomes and tumor microenvironments after the establishment of this repository. CiteSpace (version 5.8.R3) and VOSviewer (version 1.6.16) were used for visualization and analysis. RESULTS: In this study, a total of 2077 articles and reviews were included, with the number of articles on exosomes and tumor microenvironments significantly increasing yearly. Recent trends showed that the potential value of exosomes as "tumor diagnostics" and "the application prospect of exosomes as therapeutic agents and drug delivery carriers" will receive more attention in the future. CONCLUSIONS: We revealed the current status and hotspots of tumor stem cell-derived exosomes and tumor microenvironments globally through bibliometrics. The prospect of the regulatory role of CSC-Exos in TME, the potential value of diagnosis, and the application of drug delivery vectors will all remain cutting-edge research areas in the field of tumor therapy. Meanwhile, this study provided a functional literature analysis for related researchers.

Association between leptin and NAFLD: a two-sample Mendelian randomization study.

BACKGROUND: The etiology of nonalcoholic fatty liver disease (NAFLD) involves a complex interaction of genetic and environmental factors. Previous observational studies have revealed that higher leptin levels are related to a lower risk of developing NAFLD, but the causative association remains unknown. We intended to study the causal effect between leptin and NAFLD using the Mendelian randomization (MR) study. METHODS: We performed a two-sample Mendelian randomization (TSMR) analysis using summary GWAS data from leptin (up to 50,321 individuals) and NAFLD (8,434 cases and 770,180 controls) in a European population. Instrumental variables (IVs) that satisfied the three core assumptions of Mendelian randomization were selected. The TSMR analysis was conducted using the inverse variance weighted (IVW) method, MR-Egger regression method, and weighted median (WM) method. To ensure the accuracy and stability of the study results, heterogeneity tests, multiple validity tests, and sensitivity analyses were conducted. RESULTS: The findings of the TSMR correlation analysis between NAFLD and leptin were as follows: IVW method (odds ratio (OR) 0.6729; 95% confidence interval (95% CI) 0.4907-0.9235; P = 0.0142), WM method (OR 0.6549; 95% CI 0.4373-0.9806; P = 0.0399), and MR-Egger regression method (P = 0.6920). Additionally, the findings of the TSMR correlation analysis between NAFLD and circulating leptin levels adjusted for body mass index (BMI) were as follows: IVW method (OR 0.5876; 95% CI 0.3781-0.9134; P = 0.0181), WM method (OR 0.6074; 95% CI 0.4231-0.8721; P = 0.0069), and MR-Egger regression method (P = 0.8870). It has also been shown that higher levels of leptin are causally linked to a lower risk of developing NAFLD, suggesting that leptin may serve as a protective factor for NAFLD. CONCLUSIONS: Using TSMR analysis and the GWAS database, we investigated the genetic relationship between elevated leptin levels and lowered risk of NAFLD in this study. However, further research is required to understand the underlying mechanisms.

A two-sample mendelian randomization analysis investigates associations between gut microbiota and infertility.

Observational studies have provided evidence of a correlation between alterations in gut microbiota composition and infertility. However, concrete proof supporting the causal relationship is still lacking. We performed a Mendelian randomization study to assess whether genetically gut microbiota composition influences the risk of infertility. The genetic data pertaining to gut microbiota were obtained from a genome-wide association study meta-analysis, which was conducted among 24 cohorts (18,340 participants) from the international MiBioGen consortium. By the primary method of assessing causality, we have identified 2 family taxa, 2 genus taxa, and 1 order taxa that were linked to a low risk of male infertility, while 1 genus taxa were associated with a high risk of male infertility. Furthermore, we have discovered 6 genus taxa, 1 phylum taxa, 1 class taxa, 1 order taxa, and 1 family taxa that were associated with a low risk of female infertility, while 1 genus taxa were linked to a high risk of female infertility. This study successfully confirmed that there was a causal link between gut microbiota and infertility. The identification of these specific strains through genetic prediction offers a valuable insight for early diagnosis, prevention, and treatment of infertility.

Genetically predicted 486 blood metabolites in relation to risk of colorectal cancer: A Mendelian randomization study.

BACKGROUND: Metabolic disorders are a hallmark feature of cancer. However, the evidence for the causality of circulating metabolites to promote or prevent colorectal cancer (CRC) is still lacking. We performed a two-sample Mendelian randomization (MR) analysis to assess the causality from genetically proxied 486 blood metabolites to CRC. METHODS: Genome-wide association study (GWAS) data for exposures were extracted from 7824 Europeans GWAS on metabolite levels. GWAS data for CRC from the GWAS catalog database GCST012879 were used for the preliminary analysis. The random inverse variance weighted (IVW) is the primary analysis for causality analysis while MR-Egger and weighted median as complementary analyses. Cochran Q test, MR-Egger intercept test, MR-PRESSO, Radial MR, and leave-one-out analysis were used for sensitivity analyses. For significant associations, additional independent CRC GWAS data GCST012880 were used for replication analysis and meta-analysis. For the final identification of metabolites, Steiger test, linkage disequilibrium score regression, and colocalization analysis were performed for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on CRC. RESULTS: The results of this study indicated significant associations between six metabolites pyruvate (odds ratio [OR]: 0.49, 95% confidence interval [CI]: 0.32-0.77, p = 0.002), 1,6-anhydroglucose (OR: 1.33, 95% CI: 1.11-1.59, p = 0.002), nonadecanoate (19:0) (OR: 0.40, 95% C I:0.4-0.68, p = 0.0008), 1-linoleoylglycerophosphoethanolamine (OR: 0.47, 95% CI: 0.30-0.75, p = 0.001), 2-hydroxystearate (OR: 0.39, 95% CI: 0.23-0.67, p = 0.0007), gamma-glutamylthreonine (OR: 2.14, 95% CI: 1.02-4.50, p = 0.040) and CRC. MVMR analysis revealed that genetically predicted pyruvate, 1-linoleoylglycerophosphoethanolamine and gamma-glutamylthreonine can directly influence CRC independently of other metabolites. CONCLUSION: The current work provides evidence to support the causality of the six circulating metabolites on CRC and a new perspective on the exploration of the biological mechanisms of CRC by combining genomics and metabolomics. These findings contribute to the screening, prevention and treatment of CRC.

Assessing the causal relationships between human blood metabolites and the risk of NAFLD: A comprehensive mendelian randomization study.

Background: Non-alcoholic fatty liver disease (NAFLD) is a liver disease associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and metabolic syndrome. The risk factors for NAFLD have not been identified. Metabolic dysfunction has been found to be an important factor in the pathogenesis and progression of NAFLD. However, the causal impact of blood metabolites on NAFLD is unclear. Methods: We performed a two-sample Mendelian randomization (MR) study. A genome-wide association study (GWAS) with 7824 participants provided data on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of NAFLD, which contained 8,434 cases and 770,180 controls of Europeans. The inverse variance weighted (IVW) model was chosen as the primary two-sample MR analysis approach, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. In addition, we performed replication, meta-analysis, and metabolic pathway analysis. We further conducted colocalization analysis to deeply reflect the causality. Results: After rigorous genetic variant selection, IVW, sensitivity analysis, replication, and meta-analysis, two known metabolites were identified as being associated with the development of NAFLD [biliverdin: OR = 1.45; 95% CI 1.20-1.75; p = 0.0001; myristoleate: OR = 0.57; 95% CI 0.39-0.83; p = 0.0030]. Conclusion: By combining genomics with metabolomics, our findings provide a new perspective on the underlying mechanisms of NAFLD and have important implications for the screening and prevention of NAFLD.

Processed meat, red meat, white meat, and digestive tract cancers: A two-sample Mendelian randomization study.

Background: Previous observational studies suggested inconsistent insights on the associations between meat intake and the risk of digestive tract cancers (DCTs). The causal effect of meat intake on DCTs is unclear. Methods: Two-sample Mendelian randomization (MR) was performed based on genome-wide association studies (GWAS) summary data from UK Biobank and FinnGen to evaluate the causal effect of meat intake [processed meat, red meat (pork, beef, and lamb), and white meat (poultry)] on DCTs (esophageal, stomach, liver, biliary tract, pancreatic, and colorectal cancers). The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. MR-PRESSO and Radial MR were performed to identify and remove outliers. To demonstrate direct causal effects, multivariable MR (MVMR) was applied. In addition, risk factors were introduced to explore potential mediators of the relationship between exposure and outcome. Results: The results of the univariable MR analysis indicated that genetically proxied processed meat intake was associated with an increased risk of colorectal cancer [IVW: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.07-4.19; P = 0.031]. The causal effect is consistent in MVMR (OR = 3.85, 95% CI 1.14-13.04; P = 0.030) after controlling for the influence of other types of exposure. The body mass index and total cholesterol did not mediate the causal effects described above. There was no evidence to support the causal effects of processed meat intake on other cancers, except for colorectal cancer. Similarly, there is no causal association between red meat, white meat intake, and DCTs. Conclusions: Our study reported that processed meat intake increases the risk of colorectal cancer rather than other DCTs. No causal relationship was observed between red and white meat intake and DCTs.

[Screening of differentially expressed genes for colorectal cancer and prediction of potential traditional Chinese medicine: based on bioinformatics].

This study screened and analyzed the differentially expressed genes(DEGs) between colorectal cancer(CRC) tissues and normal tissues with bioinformatics techniques to predict biomarkers and Chinese medicinals for the diagnosis and treatment of CRC. The microarray data sets GSE21815, GSE106582, and GSE41657 were downloaded from the Gene Expression Omnibus(GEO), and the DEGs were screened by GEO2 R, followed by the Gene Ontology(GO) tern enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis of the DEGs based on DAVID. The protein-protein interaction network was constructed by STRING, and MCODE and Cytohubba plug-ins were used to screen the significant modules and hub genes in the network. UCSC, cBioPortal, and Oncomine were employed for hierarchical clustering, survival analysis, Oncomine analysis, and correlation analysis of clinical data. Coremine Medical was applied to predict the Chinese medicinals acting on hub genes. A total of 284 DEGs were screened out, with 146 up-regulated and 138 down-regulated. The up-regulated genes were mainly involved in cell cycle, NLRs pathway, and TNF signaling pathway, and the down-regulated genes were related to mineral absorption, nitrogen metabolism, and bicarbonate reabsorption in proximal tubules. The 15 hub genes were CDK1, CDC20, AURKA, MELK, TOP2 A, PTTG1, BUB1, CDCA5, CDC45, TPX2, NEK2, CEP55, CENPN, TRIP13, and GINS2, among which CDK1 and CDC20 were regarded as core genes. The high expression of CDK1 and CDC20 suggested poor prognosis, and they significantly expressed in many cancers, especially breast cancer, lung cancer, and CRC. The expression of CDK1 and CDC20 was correlated with gender, tumor type, TNM stage, and KRAS gene mutation. The potential effective medicinals against CRC were Scutellariae Radix, Scutellariae Barbatae Herba, Arnebiae Radix, etc. The significant expression of CDK1 and CDC20 can help distinguish tumor tissues from normal tissues, and is related to survival prognosis. Thus, the two can be used as biomarkers for the diagnosis and treatment of CRC. This study provides a reference for related drug development.

Effectiveness and safety of light vegetarian diet and Qingjiang Tiaochang Recipe for functional constipation: An exploratory study protocol for randomized controlled trial.

INTRODUCTION: Functional constipation is a chronic disease that is common in children and adults around the world. The treatments for functional constipation include diet and lifestyle interventions, medications, and surgery. The diet pattern plays an important role in the occurrence of constipation. We found in clinical practice that simple application of drugs cannot achieve long-term relief of constipation, and a large number of patients are not satisfied with the existing treatment. We have concluded that Qingjiang Tiaochang Recipe (QJTCR) and light vegetarian diet (LVD) can effectively improve constipation. However, there is no enough evidence for the description of the effect. This protocol aims at exploratorily investigating effectiveness and safety of LVD and QJTCR following a rigorous clinical trial. METHODS AND ANALYSIS: We will recruit 90 patients to participate in this prospective, placebo-controlled, randomized trial, and exploratory study at the China-Japan Friendship Hospital, including traditional Chinese medicine group, placebo + diet group, traditional Chinese medicine + diet group. Patients in the diet intervention group must strictly abide by LVD, and the study will continue for 28 days. During the intervention period, we need to record a designed diary to assess diet quality and defecation. The primary outcomes for this clinical study were weekly complete spontaneous bowel movements. The secondary outcomes were constipation-related symptom rating scale, traditional Chinese medicine syndrome scale, and 48-hour gastrointestinal transit time, high-resolution anorectal manometry, Bristol stool score, constipation quality of life assessment scale, constipation symptoms self-assessment scale, short-chain fatty acids in feces. In addition, the study will determine the safety of the intervention.