Biomedical subjects

Jie Zheng

Publications and source records attributed to Jie Zheng.

6 recordsLinked to original sources

PubMed2026

Effects of intensive blood pressure control on cardio-kidney outcomes by KDIGO risk categories: a Post Hoc analysis of ACCORD-BP and SPRINT trials.

The effects of intensive systolic blood pressure (SBP) control on cardiovascular (CV) and kidney outcomes across different Kidney Disease Improving Global Outcomes (KDIGO) risk categories remain unclear. We performed a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) and the SPRINT-eligible Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial. Participants were categorized into low, moderate, and high/very-high KDIGO risk groups. The primary outcomes were composite adverse CV events (defined as nonfatal myocardial infarction (MI), nonfatal stroke, fatal or hospitalized heart failure (HF), and CV mortality) and composite adverse kidney events (defined as a sustained decline in eGFR of ≥ 40% and end-stage kidney disease (ESKD)). We found that intensive BP control reduced the risk of composite CV events (HR 0.68; 95% CI 0.59-0.78), with attenuated benefits in higher KDIGO risk categories (P for interaction = 0.055). This interaction was mainly driven by nonfatal MI and fatal or hospitalized HF (both P for interaction < 0.05). Intensive BP control increased the risk of composite kidney events (HR 1.88; 95% CI 1.52-2.33), mainly in low- and moderate-risk groups rather than in high/very-high risk groups (P for interaction = 0.04). Similar patterns were observed for sustained eGFR decline (P for interaction = 0.03), but not for ESKD (HR 1.05; 95% CI 0.74-1.48; P for interaction = 0.71). The KDIGO risk classification modified the effects of intensive BP control. Balancing CV benefits against potential kidney impacts in patients with different KDIGO risks during intensive BP treatment is recommended. Trial Registration: ClinicalTrials.gov Identifiers: NCT01206062 (SPRINT) and NCT00000620 (ACCORD).

Cardiovascular outcome↗

PubMed2026

The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. RESULTS: GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10- 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10- 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10- 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region. CONCLUSIONS: This study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.

Humans↗

PubMed2026

The tissue-specific effects of glucose-lowering drug targets on aging mediated through DNA methylation: a multi-omics genetic study.

BACKGROUND: DNA methylation plays a key role in mediating the anti-aging effects of glucose-lowering drugs. This study aims to systematically explore the potential anti-aging effects of target genes of FDA-approved glucose-lowering drugs and the underlying epigenetic mediators. METHODS: We conducted a two-sample Mendelian randomization (MR) study to investigate the putative causal relationships between the gene expression levels of glucose-lowering drug targets and 10 aging-related phenotypes, followed by a two-step MR to estimate the mediation effect of DNA methylation. Drug candidates were selected according to the latest review of clinical drug use for type 2 diabetes, and their target genes were obtained from the DGIdb. Tissue-specific cis-expression quantitative trait loci (eQTLs) from GTEx Consortium were selected as genetic instruments to proxy the expression level of drug-target genes. Glycemic phenotypes were used as positive controls to validate the instruments. The cis- and trans-methylation QTLs of Cytosine-phosphate-Guanine sites near the drug target genes were obtained from GoDMC Consortium. Additionally, we performed enrichment analyses focused on tissue specificity and aging pathways to further corroborate our findings. RESULTS: We obtained 194 target genes interacting with 36 FDA-approved anti-diabetic drugs, of which the tissue-specific eQTLs were used to proxy the drug target effects. MR showed strong evidence that nine interacting genes of six glucose-lowering drugs showed anti-aging potential on one or more aging-related phenotypes mediated by DNA methylation: EHMT2, HSPA4, IGF2BP2, IRS1, LPL, NDUFAF1, NDUFS3, SLC22A3, and TCF7L2. These genes were distributed in 17 tissues, especially in the central nervous system, suggesting a potential neural component in their anti-aging effects. For instance, expression of EHMT2 in several brain basal ganglia regions, where the gene interacted with Tolazamide, showed a protective effect on frailty (odds ratio (OR) in caudate = 1.02, 95%CI = 1.01-1.04, FDR adjusted P = 1.69 × 10-2; OR in putamen = 1.02, 95% CI = 1.01-1.03, PFDR = 3.37 × 10-2, OR in nucleus accumbens = 1.02, 95% CI = 1.01-1.04, PFDR = 3.37 × 10-2). These associations were externally validated by searching literature evidence in existing EWAS and TWAS studies, as well as evidence from enrichment analyses. CONCLUSIONS: This study prioritizes nine glucose-lowering genes as anti-aging drug targets in specific tissues and prioritizes their epigenetic regulation through DNA methylation for future drug development.

DNA Methylation↗

PubMed2026

Life-course influence of birthweight and subsequent pathways on healthy aging: a Mendelian randomization study.

BACKGROUND: Birthweight readily measurable marker of fetal growth that may influence health across the lifespan. We aimed to investigate the potential causal association between birthweight and healthy aging and to identify the mediating roles of subsequent socioeconomic, behavioral, functional, and disease-related factors to inform life-course strategies to promote healthy aging and reduce health inequities. METHODS: We performed two-sample Mendelian randomization analyses in European-ancestry participants to estimate the effect of birthweight (n = 298,142-423,683) on two robust, composite healthy aging phenotypes (genetically independent phenotype of aging (aging-GIP) and multivariate aging-related genetic factor (mvAge)) and six individual aging phenotypes, including healthspan, resilience, parental lifespan, self-rated health, phenotypic age deceleration, and 90th percentile self-longevity (n = 34,710-1,958,774), and screened for 100 candidate mediators (n = 14,267-1,812,017) using a two-step mediation analysis. RESULTS: Genetically determined each 1-SD higher birthweight was associated with higher aging-GIP (β [95% CI] in different models ranging from 0.131 [0.066-0.196] to 0.162 [0.089-0.235] SDs) and mvAge (0.036 [0.010-0.063] to 0.045 [0.024-0.067]), independent of later-life obesity indicators; also with more interpretable benefits, including 12%-16% higher odds of longer healthspan, a 0.079-0.089 SD improvement in resilience, and a 1.22-1.74 year increase in parental lifespan. Of 100 candidates, 26 and 25 mediated the effect of birthweight on aging-GIP and mvAge, respectively, including socioeconomic indicators (education, household income, occupational attainment; individual mediation proportion: 12.72%-27.79%); behaviors (e.g., cheese intake, age at first sex; 10.38%-29.56%); physical functions (e.g., blood pressure, grip strength; 7.57%-42.65%); and cardiometabolic diseases (e.g., type 2 diabetes, cardiovascular diseases; 25.02%-70.11%). CONCLUSIONS: Higher birthweight within the normal range directly promotes healthy aging, mediated by multifaceted modifiable factors. Our findings advocate adopting a life-course approach to foster healthy aging, starting with optimal birthweight and extending to interventions that enhance socioeconomic status, promote healthy behaviors, strengthen physical functions, and prevent cardiometabolic diseases.

Mendelian Randomization Analysis↗

PubMed2026

DrdR Negatively Modulates the Expression of Flagellar Genes via Interaction With FleQ in Xanthomonas campestris.

Response regulators (RRs) of two-component signalling systems (TCSs) containing tandem receiver (REC) domains are widespread in bacteria, yet their functions and regulatory mechanisms remain poorly understood. In our previous study, DrdR, one such RR in the cruciferous black rot disease pathogen Xanthomonas campestris pv. campestris (Xcc) was demonstrated to positively regulate pilus-dependent motility and negatively regulate flagellum-dependent motility. We showed that DrdR modulates the ATPase activities of pili motor proteins PilT and PilB, thereby enhancing bacterial pilus-dependent swarming motility. However, how DrdR represses flagellar motility remained unknown. Here, we demonstrate that DrdR acts as a transcriptional repressor of flagellar gene expression. We used in vitro and in vivo approaches to identify FleQ, the master transcriptional regulator of flagellar genes, as a novel interaction partner of DrdR. Biochemical analyses revealed that DrdR binding inhibits FleQ's ATPase activity, which is essential for its transcriptional activation function. Microscale thermophoresis assays showed that DrdR reduces FleQ's DNA-binding capability to its cognate promoter. These findings collectively indicate that DrdR modulates FleQ transcriptional activity by reducing both its DNA-binding ability and ATPase activity. Our results demonstrate that DrdR serves as a specialized modulator of FleQ that acts upstream in the signalling cascade controlling the expression of flagellar genes in Xcc. This study exhibits a previously unknown mechanism whereby DrdR regulates bacterial motility. Combined with our previous finding, our data suggest that DrdR most likely acts as a conversion regulator between flagellum-dependent and pilus-dependent motility in Xcc.

Flagella↗

PubMed2025

Structure-activity relationships study on inhibition of CRISPR-Cas9 by glycosaminoglycans.

The CRISPR-Cas9 system is a revolutionary genome editing system known for its precision, simplicity and efficiency, playing a crucial role in gene-editing. It has enabled applications ranging from biomedicine to agriculture. However, the uncontrollable activity of Cas9 has raised significant safety concerns in clinical settings, limiting its broader application. Consequently, regulating CRISPR-Cas9 activity holds substantial promise for enhancing the safety and efficacy of gene-editing technologies. In this study, we demonstrated that sulfated glycosaminoglycans (GAGs) exhibit inhibitory effects of Cas9. Specifically, both chondroitin sulfate (CS) and heparin (HP) can inhibit CRISPR/Cas9 activity, with heparin showing a stronger inhibitory effect that correlates positively with its concentration. Molecular dynamics simulations indicate that sulfated heparin residues might inhibit Cas9 function by binding to essential DNA-binding sites, which are crucial for functional interactions, potentially impairing activity. Additionally, higher molecular weight GAGs exhibit enhanced inhibitory effects under the same sulphation. Notably, the sulfation site also influenced activity. C6-sulfation of chondroitin sulfate is more favorable for Cas9 inhibition, and N-sulfation of heparin enhances its inhibitory effect on Cas9 activity. These findings provide valuable insights into the development of carbohydrate-based inhibitors for CRISPR-Cas9, offering a foundation for further exploration in this field.

CRISPR-Cas Systems↗