-
1.
The effect of periodic resistance training on obese patients with type 2 diabetic nephropathy.
Li, S, Yuan, S, Zhang, J, Xu, F, Zhu, F
Scientific reports. 2024;(1):2761
Abstract
Resistance training is an exercise against resistance designed to train the endurance and strength of muscle. To observe the effect of intervention of periodic resistance training on obese patients with type 2 diabetic nephropathy. A total of 60 obese patients with type 2 diabetic nephropathy were randomized into resistance training group and aerobic exercise group (30 patients each group) for observing the changes of blood glucose, body weight, blood lipid, insulin resistance, serum creatinine (Scr), urinary microalbumin, urinary albumin excretion rate (UAER) calculated by urinary creatinine, and glomerular filtration rate (GFR) after 12 weeks of intervention, and relevant significance as well. The number of patients with hypoglycemia during the intervention was also recorded. After 12 weeks of intervention, the weight, Body mass index (BMI), Waist, Triglyceride (TG), Cholesterol (TC), Low-density lipoprotein cholesterol (LDL), Fasting glucose (FBG), Fasting insulin (FINS), Glycosylated hemoglobin (HbA1c) and urine Albumin-Creatinine Ratio (uACR) were decreased and GFR was increased in both groups (P < 0.05), but the effect was more significant in the resistance training group. GFR was increased from 92.21 ± 10.67 mL/(min·1.73 m2) to 100.13 ± 12.99 mL/(min·1.73 m2) in resistance training group (P < 0.05). In the aerobic exercise group, GFR was increased from 89.98 ± 9.48 mL/(min·1.73 m2) to 92.51 ± 11.35 mL/(min·1.73 m2) (P > 0.05). Periodic resistance training can not only control the weight, blood sugar and blood lipid of obese patients with type 2 diabetic nephropathy, but also improve the urinary albumin excretion rate and glomerular filtration rate of early obese patients with type 2 diabetic nephropathy, and delay the progression of diabetic nephropathy. It is an effective non-drug intervention.
-
2.
Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities.
Yuan, S, Xu, F, Zhang, H, Chen, J, Ruan, X, Li, Y, Burgess, S, Åkesson, A, Li, X, Gill, D, et al
Journal of thrombosis and haemostasis : JTH. 2024;(3):738-748
Abstract
BACKGROUND Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. OBJECTIVES We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities. METHODS A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy. RESULTS The network Mendelian randomization analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Low-density lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%-49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. Five proteins (interleukin-6 receptor subunit alpha, LRP12, prothrombin, angiopoietin-1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities. CONCLUSION This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.
-
3.
Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis.
Chen, J, Zhou, Y, Sun, Y, Yuan, S, Kalla, R, Sun, J, Zhao, J, Wang, L, Chen, X, Zhou, X, et al
Journal of Crohn's & colitis. 2023;(5):777-785
-
-
Free full text
-
Abstract
BACKGROUND AND AIMS Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. METHODS We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. RESULTS Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 × 10-10]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 × 10-19] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. CONCLUSION Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.
-
4.
Genetic polymorphisms of CYP24A1 gene and cancer susceptibility: a meta-analysis including 40640 subjects.
Wang, Y, Wang, R, Yuan, S, Liu, X
World journal of surgical oncology. 2023;(1):279
Abstract
BACKGROUND Whether cytochrome P450 24A1 (CYP24A1) polymorphism is associated with cancer susceptibility, the individual study results are still controversial. Therefore, we performed a comprehensive study to identify the association of CYP24A1 polymorphisms (rs4809960, rs6068816, rs2296241, rs4809957, rs2762939) with cancer susceptibility. METHODS Electronic databases including Cochrane Library, PubMed, and Embase were systematically retrieved for relevant publications. Fixed or random-effect model was selected to calculate odds ratios (ORs) with their 95% confidence intervals (95%CI). RESULTS Eighteen published articles were identified. The results indicated that rs4809960 polymorphism was associated with a decreased cancer risk in Caucasian (TT vs. TC+CC: P=0.035; C vs. T: P=0.016) and Asian population (CC vs. TC+TT: OR P=0.044; TT vs. TC+CC: P=0.021; CC vs. TT: P=0.020; C vs. T: P=0.008) and breast cancer risk (TT vs. TC+CC: P = 0.007; TC vs. TT: P=0.004; C vs. T: P=0.033). A significant association was found between rs2296241 polymorphism and esophageal squamous cell carcinoma risk (AA vs. GG+AG: P = 0.023) and prostate cancer susceptibility (A vs. G: P=0.022). Furthermore, rs4809957 polymorphism was associated with prostate cancer susceptibility in Caucasian (GG vs. GA+AA: P=0.029; GA vs. GG: P=0.022) and breast cancer susceptibility (AA vs. GG+GA: P=0.012; AA vs. GG, P=0.010; A vs. G: P=0.024). Additionally, rs6068816 polymorphism significantly decreased the lung cancer (CC vs. CT+TT: P = 0.016; TT vs. CC: P = 0.044; CT vs. CC: P = 0.036; T vs. C: P = 0.016) and breast cancer risk (TT vs. CC+CT: P = 0.043; TT vs. CC: P = 0.039). No association was found for rs2762939 polymorphism with overall cancer risk. However, for rs2296241, rs4809957, and rs6068816 polymorphisms, there were no significant differences after the Bonferroni correction. CONCLUSION The meta-analysis suggested that rs4809960 was associated with cancer risk and might be a genetic marker for predicting cancer risk. More large-scale and large-sample studies are necessary to further confirm these results.
-
5.
Cryo-EM structures of ClC-2 chloride channel reveal the blocking mechanism of its specific inhibitor AK-42.
Ma, T, Wang, L, Chai, A, Liu, C, Cui, W, Yuan, S, Wing Ngor Au, S, Sun, L, Zhang, X, Zhang, Z, et al
Nature communications. 2023;(1):3424
Abstract
ClC-2 transports chloride ions across plasma membranes and plays critical roles in cellular homeostasis. Its dysfunction is involved in diseases including leukodystrophy and primary aldosteronism. AK-42 was recently reported as a specific inhibitor of ClC-2. However, experimental structures are still missing to decipher its inhibition mechanism. Here, we present cryo-EM structures of apo ClC-2 and its complex with AK-42, both at 3.5 Å resolution. Residues S162, E205 and Y553 are involved in chloride binding and contribute to the ion selectivity. The side-chain of the gating glutamate E205 occupies the putative central chloride-binding site, indicating that our structure represents a closed state. Structural analysis, molecular dynamics and electrophysiological recordings identify key residues to interact with AK-42. Several AK-42 interacting residues are present in ClC-2 but not in other ClCs, providing a possible explanation for AK-42 specificity. Taken together, our results experimentally reveal the potential inhibition mechanism of ClC-2 inhibitor AK-42.
-
6.
ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma.
Ferrarese, R, Izzo, A, Andrieux, G, Lagies, S, Bartmuss, JP, Masilamani, AP, Wasilenko, A, Osti, D, Faletti, S, Schulzki, R, et al
Life science alliance. 2023;(1)
Abstract
Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulate the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the co-activator/co-repressor CTBP and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. In line with our findings, metabolic assays and glucose tracing analysis confirm the reduction in several phospholipid species upon ZBTB18 expression. Our study identifies CTBP1/2 and LSD1 as co-activators of SREBP genes and indicates that the functional activity of the CTBP-LSD1 complex is altered by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 demethylase activity of H3K4me2 and H3K9me2 marks. Concomitantly, the interaction between LSD1, CTBP, and ZNF217 is increased, suggesting that ZBTB18 promotes LSD1 scaffolding function. Our results outline a new epigenetic mechanism enrolled by ZBTB18 and its co-factors to regulate fatty acid synthesis that could be targeted to treat glioblastoma patients.
-
7.
Metabolic regulation by biomaterials in osteoblast.
Kang, Z, Wu, B, Zhang, L, Liang, X, Guo, D, Yuan, S, Xie, D
Frontiers in bioengineering and biotechnology. 2023;:1184463
Abstract
The repair of bone defects resulting from high-energy trauma, infection, or pathological fracture remains a challenge in the field of medicine. The development of biomaterials involved in the metabolic regulation provides a promising solution to this problem and has emerged as a prominent research area in regenerative engineering. While recent research on cell metabolism has advanced our knowledge of metabolic regulation in bone regeneration, the extent to which materials affect intracellular metabolic remains unclear. This review provides a detailed discussion of the mechanisms of bone regeneration, an overview of metabolic regulation in bone regeneration in osteoblasts and biomaterials involved in the metabolic regulation for bone regeneration. Furthermore, it introduces how materials, such as promoting favorable physicochemical characteristics (e.g., bioactivity, appropriate porosity, and superior mechanical properties), incorporating external stimuli (e.g., photothermal, electrical, and magnetic stimulation), and delivering metabolic regulators (e.g., metal ions, bioactive molecules like drugs and peptides, and regulatory metabolites such as alpha ketoglutarate), can affect cell metabolism and lead to changes of cell state. Considering the growing interests in cell metabolic regulation, advanced materials have the potential to help a larger population in overcoming bone defects.
-
8.
Effects of a two meals-a-day ketogenic diet on newly diagnosed obese patients with type 2 diabetes mellitus: A retrospective observational study.
Li, S, Yuan, S, Lin, G, Zhang, J
Medicine. 2023;(43):e35753
-
-
Free full text
-
Abstract
To investigate the effects of a two-meals-a-day energy-restricted ketogenic diet (KD) on newly diagnosed obese patients with type 2 diabetes mellitus. In total, 60 obese patients with newly diagnosed type 2 diabetes mellitus were divided into 2 groups: 1 group followed a 2-meals-a-day KD and the other group followed a conventional diabetic diet. Changes in weight, blood glucose, blood lipids, insulin resistance, and uric acid levels were observed before and after 2 months of adhering to the respective diets under energy restriction. Both groups showed significant reductions in weight, waist circumference, body mass index, total cholesterol, triglycerides, high-density lipoproteins, low-density lipoproteins, fasting blood glucose, fasting insulin, and glycated hemoglobin (P < .05). The twice-daily KD group showed more significant improvements in these parameters compared to the conventional diabetic diet group. In addition, the 2-meals-a-day KD group showed a slight increase in uric acid levels compared to the conventional diabetic diet control group (P < .05). The 2-meals-a-day KD can significantly improve weight, blood glucose, and lipid control in newly diagnosed obese patients with type 2 diabetes mellitus.
-
9.
Causal factors underlying diabetes risk informed by Mendelian randomisation analysis: evidence, opportunities and challenges.
Yuan, S, Merino, J, Larsson, SC
Diabetologia. 2023;(5):800-812
-
-
Free full text
-
Abstract
Diabetes and its complications cause a heavy disease burden globally. Identifying exposures, risk factors and molecular processes causally associated with the development of diabetes can provide important evidence bases for disease prevention and spur novel therapeutic strategies. Mendelian randomisation (MR), an epidemiological approach that uses genetic instruments to infer causal associations between an exposure and an outcome, can be leveraged to complement evidence from observational and clinical studies. This narrative review aims to summarise the evidence on potential causal risk factors for diabetes by integrating published MR studies on type 1 and 2 diabetes, and to reflect on future perspectives of MR studies on diabetes. Despite the genetic influence on type 1 diabetes, few MR studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. In type 2 diabetes, MR analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. These studies have also identified biomarkers, some of them derived from the gut microbiota, and molecular processes leading to increased disease risk. These studies provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. Because genetic association studies have mostly been restricted to participants of European descent, multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development.
-
10.
Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome.
Sun, J, Zhao, J, Jiang, F, Wang, L, Xiao, Q, Han, F, Chen, J, Yuan, S, Wei, J, Larsson, SC, et al
Genome medicine. 2023;(1):75
Abstract
BACKGROUND The proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). METHODS Protein quantitative trait loci (pQTLs) were derived from seven published genome-wide association studies (GWASs) on plasma proteome, and summary-level data were extracted for 4853 circulating protein markers. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4957 cases and 304,197 controls), and the UK Biobank (9276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. RESULTS Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which four (GREM1, CLSTN3, CSF2RA, CD86) were prioritized with the most convincing evidence. These protein-coding genes are mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. CONCLUSIONS This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.