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Background There are many studies indicating that alterations in the abundance of certain gut microbiota are associated with colorectal cancer (CRC). However, a causal relationship has not been identified due to confounding factors such as lifestyle, environmental, and possible reverse causal associations between the two. Furthermore, certain host gene mutations can also contribute to the development of CRC. However, the association between genes and gut microbes in patients with CRC has not been extensively studied. Methods We conducted a two-sample Mendelian randomization (MR) study to reveal the causal relationship between gut microbiota and CRC. We obtained SNPs associated with gut microbiome abundance as instrumental variables (IVs) from a large-scale, multi-ethnic GWAS study, and extracted CRC-related datasets from an East Asian Population genetic consortia GWAS (AGWAS) study and FinnGen consortium, respectively. We analyzed a total of 166 bacterial features at four taxonomic levels, including order, family, genus, and species. The inverse-variance-weighted (IVW), weighted median, MR-Egger, and simple median methods were applied to the MR analysis, and the robustness of the results were tested using a series of sensitivity analyses. We extracted IVs of gut microbiota with direct causal association with CRC for SNP annotation to identify the genes in which these genetic variants were located to reveal the possible host gene-microbiome associations in CRC patients. Results The findings from our MR analysis based on CRC-associated GWAS datasets from AGWAS revealed causal relationships between 6 bacterial taxa and CRC at a locus-wide significance level (P < 1 × 10 –5 ). The IVW method found that family Porphyromonadaceae , genera Anaerotruncus , Intestinibacter , Slackia , and Ruminococcaceae UCG004, and species Eubacterium coprostanoligenes group were positively associated with CRC risk, which was generally consistent with the results of other complementary analyses. The results of a meta-analysis of the MR estimates from the AGWAS and the FinnGen datasets showed that family Porphyromonadaceae and genera Slackia , Anaerotruncus , and Intestinibacter replicated the same causal association. Sensitivity analysis of all causal associations did not indicate significant heterogeneity, horizontal pleiotropy, or reverse causal associations. We annotated the SNPs at a locus-wide significance level of the above intestinal flora and identified 24 host genes that may be related to pathogenic intestinal microflora in CRC patients. Conclusion This study supported the causal relationship of gut microbiota on CRC and revealed a possible correlation between genes and pathogenic microbiota in CRC. These findings suggested that the study of the gut microbiome and its further multi-omics analysis was important for the prevention and treatment of CRC.

The atherogenic index of plasma (AIP), a novel composite lipid index, is closely linked to cardiovascular disease (CVD). However, lipid levels fluctuate dynamically, and it is unclear whether there are differences in the association of single-timescale, multiple-timescale, or AIP change trajectories with new-onset cardiovascular disease. Hence, the aim of this study was to investigate the correlation between different AIP parameters and the occurrence of CVD. Data were derived from the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2011, 2015, 2018, and 2020, focusing on middle-aged and elderly populations aged over 45 years. Changes in AIP were classified into three groups using K-means cluster analysis: the low-level growth group (Class 1), the medium-level growth group (Class 2), and the high-level decline group (Class 3). Furthermore, participants were grouped based on tertiles (T) of cumulative AIP (Cum-AIP). Our multivariate logistic regression model integrated adjustments for potential confounders in order to investigate the association between Cum-AIP and the occurrence of CVD. Additionally, we employed restricted cubic spline (RCS) modeling to illustrate the dose-response relationship of baseline AIP, mean AIP, and Cum-AIP with CVD risk. During the 5-year follow-up period, 927 participants experienced the onset of CVD. After controlling for various potential confounding factors, it was observed that individuals in Class 2 demonstrated a notably heightened risk of CVD (OR = 1.23, 95% CI: 1.03, 1.46) and stroke (OR = 1.35, 95% CI: 1.02, 1.80) in comparison to those in Class 1. However, there was no significant difference in the risk of heart disease (OR = 1.21, 95% CI: 0.99, 1.48). In contrast, a noteworthy correlation was solely observed in the Class 3 group concerning the risk of stroke occurrence (OR = 1.60, 95% CI: 1.06, 2.42). The adjusted OR (95% CI) for CVD in the T2 and T3 groups were 1.21 (1.00, 1.46) and 1.30 (1.05, 1.62), respectively, compared to the T1 Cum-AIP group ( P for trend = 0.017). Through the RCS model, we identified a positive and linear relationship between baseline AIP, mean AIP, and Cum-AIP with the incidence of CVD. However, the association between baseline AIP and CVD was weak. Sustained elevation of AIP is linked to a heightened risk of CVD in the general population. The elevated mean, and Cum-AIP levels are associated with a heightened risk of CVD. These findings indicate that AIP can serve as a valuable indicator of dyslipidemia, and continuous monitoring and early intervention targeting AIP may contribute to a further reduction in the incidence of CVD.

The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 ( SLC13A3 ) and ASBT ( SLC10A2 ). Shared genetic determinants of 7,073 metabolite–disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments. Genome-wide studies of 1,916 plasma and urine metabolites from 5,023 participants of the German Chronic Kidney Disease study provide insights into systemic and kidney-specific enzymatic and transport processes.

The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite–locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research. Genome-wide association analysis of 1,172 urinary metabolites identifies 240 metabolite–locus associations that when combined with UK Biobank data suggest novel metabolic mediators of disease and markers of disease risk.

Identifying dependable prognostic indicators is essential for the efficient management of metabolic dysfunction-associated steatotic liver disease (MASLD). The index of hemoglobin glycation (HGI) has been demonstrated to be closely linked to the onset and advancement of MASLD. Currently, no studies have investigated the relationship between HGI and mortality rates among MASLD patients. This study analyzed data from the National Health and Nutrition Examination Surveys (NHANES) covering 1999 to 2018, involving 8,257 adult patients diagnosed with MASLD. The HGI was determined using a linear regression model that correlated hemoglobin A1c (HbA1c) with fasting plasma glucose (FPG). The study employed Kaplan-Meier survival curves and weighted Cox proportional hazards models to evaluate the independent association between HGI and mortality risk. The study utilized restricted cubic splines (RCS) to visually depict the relationship between HGI and mortality risk. Over a median follow-up duration of 97.0 months, there were 1,352 recorded deaths, among which 386 were attributed to cardiovascular disease (CVD). Participants were classified into two groups based on their HGI values: the high HGI group (≥ 0.4605) and the low HGI group (< 0.4605). The results from the weighted Cox proportional hazards model indicated that individuals in the high HGI group faced a significantly higher risk of all-cause mortality (HR 1.47, 95% CI 1.19–1.82, P <  0.001). However, no significant increase in CVD mortality risk was observed (HR 1.38, 95% CI 0.95–1.99, P =  0.090). The RCS analysis identified a U-shaped association between HGI and both all-cause mortality and CVD mortality, with critical points at -0.0564 and − 0.0573, respectively. Below the critical points, HGI was negatively correlated with all-cause mortality (HR 0.82, 95% CI: 0.72–0.92, P <  0.001) and not significantly associated with CVD mortality (HR 0.78, 95% CI: 0.57–1.07, P =  0.126). Above the critical points, HGI was significantly positively correlated with both all-cause mortality (HR 1.36, 95% CI: 1.20–1.53, P <  0.001) and CVD mortality (HR 1.44, 95% CI: 1.11–1.88, P =  0.007). Further subgroup and interaction analyses corroborated the reliability of these findings. HGI could potentially function as a useful and dependable marker for evaluating all-cause mortality and cardiovascular mortality in MASLD patients.

Aberrant signaling in tumor cells induces nonmetabolic functions of some metabolic enzymes in many cellular activities. As a key glycolytic enzyme, the nonmetabolic function of hexokinase 2 (HK2) plays a role in tumor immune evasion. However, whether HK2, dependent of its nonmetabolic activity, plays a role in human pancreatic ductal adenocarcinoma (PDAC) tumorigenesis remains unclear. Here, we demonstrated that HK2 acts as a protein kinase and phosphorylates IκBα at T291 in PDAC cells, activating NF‐κB, which enters the nucleus and promotes the expression of downstream targets under hypoxia. HK2 nonmetabolic activity‐promoted activation of NF‐κB promotes the proliferation, migration, and invasion of PDAC cells. These findings provide new insights into the multifaceted roles of HK2 in tumor development and underscore the potential of targeting HK2 protein kinase activity for PDAC treatment. HK2‐mediated phosphorylation of IκBα at T291 in PDAC cells leads to IκBα degradation and subsequent activation of NF‐κB for the upregulation of downstream target transcription. HK2 nonmetabolic activity‐promoted activation of NF‐κB stimulates the proliferation, migration, and invasion of PDAC cells.

Background Esophageal cancer is a prevalent malignancy with limited treatment options. The study aimed to understand the role and mechanism of NEK7 in esophageal cancer development. Methods RNA sequencing compared esophageal cancer tissues with adjacent tissues, and real-time PCR validated NEK7 expression. Co-IP identified NLRP3 as NEK7’s binding partner. We also study the effects of NEK7 knockdown on cell viability, apoptosis, migration, invasion, and the expression of NLRP3/PD-L1 in esophageal carcinoma cell lines. TIMER 2.0 analyzed immune infiltration. An animal model was used to investigate the impact of NEK7 knockdown on tumor size, survival rates, and immune cell infiltration. Licochalcone B blocked NEK7/NLRP3, enhancing CD8 T cell-mediated tumor killing. PD-1’s role in T cell viability was also assessed. Results NEK7 was observed to be markedly elevated in both tumor tissues of esophageal cancer and EC109 cells. Moreover, silencing NEK7 reduced cell viability, migration, and invasion, while enhancing cell apoptosis in vitro. Knockdown of NEK7 caused a notable reduction in levels of NLRP3 and PD-L1 in EC109 cells. NEK7 expression showed a positive correlation with immune cell infiltration. Knockdown of NEK7 decreased PD-L1 expression, while upregulation of NEK7 increased PD-L1 expression, then reversed by NLRP3 knockdown. In animal studies, NEK7 knockdown reduced tumor size and volume while improving survival. It also promoted CD4 and CD8 T cell infiltration while inhibiting Treg cells and PD-1 + CD4 and CD8 T cells. Licochalcone B blocked NEK7/NLRP3 binding, decreased cell viability of EC109 cells, and enhanced the activity of co-cultured CD8 T cells. Furthermore, Licochalcone B and anti-PD-1 treatment increased the killing ratio of EC109 cells. Conclusion In conclusion, NEK7 is a key regulator in the progression of esophageal cancer and the immune evasion. Targeting the NEK7/NLRP3 pathway may have therapeutic potential for the treatment of esophageal cancer. Graphical abstract

Blood metabolites of the tryptophan pathway were found to be associated with kidney function and disease in observational studies. In order to evaluate causal relationship and direction, we designed a study using a bidirectional Mendelian randomization approach. The analyses were based on published summary statistics with study sizes ranging from 1,960 to 133,413. After correction for multiple testing, results provided no evidence of an effect of metabolites of the tryptophan pathway on estimated glomerular filtration rate (eGFR). Conversely, lower eGFR was related to higher levels of four metabolites: C-glycosyltryptophan (effect estimate = − 0.16, 95% confidence interval [CI] (− 0.22; − 0.1); p  = 9.2e−08), kynurenine (effect estimate = − 0.18, 95% CI (− 0.25; − 0.11); p  = 1.1e−06), 3-indoxyl sulfate (effect estimate = − 0.25, 95% CI (− 0.4; − 0.11); p  = 6.3e−04) and indole-3-lactate (effect estimate = − 0.26, 95% CI (− 0.38; − 0.13); p  = 5.4e−05). Our study supports that lower eGFR causes higher blood metabolite levels of the tryptophan pathway including kynurenine, C-glycosyltryptophan, 3-indoxyl sulfate, and indole-3-lactate. These findings aid the notion that metabolites of the tryptophan pathway are a consequence rather than a cause of reduced eGFR. Further research is needed to specifically examine relationships with respect to chronic kidney disease (CKD) progression among patients with existing CKD.

Background Dyslipidemia plays a pivotal role in the development of diabetes mellitus (DM) and other metabolic disorders. This study aimed to investigate the trends in lipid concentrations among Chinese participants with different blood glucose statuses—ranging from DM and prediabetes mellitus (pre-DM) to normal blood glucose levels—between 2011 and 2015. Additionally, this study sought to provide a comprehensive description of the potential temporal changes in the prevalence of dyslipidemia among these populations in China during this period. Methods The data for this study were derived from the China Health and Retirement Longitudinal Study (CHARLS), encompassing two time points in 2011 and 2015. The 2011 data sample included 11,408 participants aged 45 years and above, whereas the 2015 data sample included 12,224 participants within the same age range. Results In this study, a comparative analysis of data from 2011 to 2015 revealed that individuals diagnosed with DM and pre-DM experienced significant decreases in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and a significant increase in high-density lipoprotein cholesterol (HDL-C) ( P  < 0.05). For participants with pre-DM, the levels of residual cholesterol (RC) significantly increased, whereas the levels of the atherogenic index of plasma (AIP) significantly decreased ( P  < 0.05). Among participants with normal blood glucose, there was a significant decrease in the levels of TC and LDL-C and a significant increase in the levels of triglycerides (TGs), RCs, and the AIP ( P  < 0.05). Between 2011 and 2015, the concentrations of TC, TG, LDL-C, RC, and AIP, both unadjusted and adjusted, were significantly higher in individuals with DM than in those with pre-DM and normal blood glucose, with the opposite being true for HDL-C. In 2015, the prevalence of dyslipidemia among participants with DM, pre-DM, and normal blood glucose was 36.56% (95% CI: 34.49%, 38.66%), 15.78% (95% CI: 14.93%, 16.67%), and 11.23% (95% CI: 10.17%, 12.36%), respectively. The results of the present study revealed a significant decrease in the incidence of dyslipidemia in urban areas between 2011 and 2015 ( P  < 0.05). Conclusion This study revealed that the prevalence of dyslipidemia is greater among DM patients, particularly those in the 55–64 years age group. Notably, over the four-year observation period, lipid profiles improved among DM patients and pre-DM patients. However, TG levels remained elevated, especially in the 45–54 years age group.

Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations. Anti-TIM-3 Ab treatment improved survival of mice bearing leukemia with oncogene-induced TIM-3 ligand expression. Conversely, leukemia cells with low ligand expression were anti-TIM-3 treatment resistant. In vitro, TIM-3 blockade or genetic deletion in CD8+ Tc enhanced Tc activation, proliferation, and IFN-γ production while enhancing GVL effects, preventing Tc exhaustion, and improving Tc cytotoxicity and glycolysis in vivo. Conversely, TIM-3 deletion in myeloid cells did not affect allogeneic Tc proliferation and activation in vitro, suggesting that anti-TIM-3 treatment-mediated GVL effects are Tc induced. In contrast to anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) treatment, anti-TIM-3-treatment did not enhance acute graft-versus-host disease (aGVHD). TIM-3 and its ligands were frequently expressed in acute myeloid leukemia (AML) cells of patients with post-allo-HCT relapse. We decipher the connections between oncogenic mutations found in AML and TIM-3 ligand expression and identify anti-TIM-3 treatment as a strategy for enhancing GVL effects via metabolic and transcriptional Tc reprogramming without exacerbation of aGVHD. Our findings support clinical testing of anti-TIM-3 Ab in patients with AML relapse after allo-HCT.