Association between circadian physical activity patterns and cancer incidence through regulation of inflammation: A UK biobank study.

BACKGROUND: Physical activity (PA) has been linked with cancer incidence. However, the effects and mechanisms underpinning circadian PA trajectories on cancer remain elusive. This study aimed to explore the optimal PA patterns in reducing cancer incidence and the associated potential mediators. METHODS: Between 2006 and 2010, 502,400 participants were recruited from the UK Biobank. Out of these, 102,323 participants wore accelerometers, which allowed for collecting acceleration data continuously over 7 days. After excluding participants with previous cancer history, 96,687 participants were included in K-means cluster analysis to identify PA trajectories. The association between PA and cancer incidence was assessed using Cox regression analysis. Additionally, we investigated the mediating role of inflammation. RESULTS: A total of 5995 cancer cases were recorded during a median follow-up of 7.1 years. Four distinct PA trajectories (persistent low, single peak, double peak, and vigorous) were identified. The ideal PA patterns reduced the risk of 7 out of 17 site-specific cancers, with the lowest hazard ratios and 95% confidence intervals of cancer for bladder (0.59, 0.40-0.86), breast (0.73, 0.60-0.89), kidney (0.45, 0.26-0.78), lung (0.59, 0.41-0.84), myeloma (0.49, 0.27-0.88), and oral & pharynx (0.51, 0.26-0.98) in the vigorous pattern and for colorectal (0.71, 0.54-0.93) in the double peak pattern. Moreover, the mediating effects of inflammation were significant. CONCLUSION: Optimal PA trajectories reduced cancer incidence, especially in double peak and vigorous patterns. The protective effect was associated with both intensity and circadian rhythm. Crucially, this protection was mediated by inflammation regulation.

Combined effects of sleep timing and nighttime sleep duration on non-alcoholic fatty liver disease.

BACKGROUND: While short sleep duration is linked to higher risk of non-alcoholic fatty liver disease (NAFLD), the combined effects of sleep timing and sleep duration on NAFLD are less explored. METHODS: In this cross-sectional study of 39,471 participants from Beijing-Tianjin-Hebei region of China, self-reported sleep information and ultrasonography-diagnosed NAFLD were obtained from Jan 2018 to Jan 2020. Sleep timing was categorized based on sleep midpoint: early-type (before 2:00 AM), intermediate-type (2:00-2:30 AM), and late-type (after 2:30 AM). We used multivariable logistic regression to explore the relationship between sleep timing, duration, and NAFLD. We analyzed sleep midpoint and duration categorically and continuously, and conducted stratification analyses by age, sex, body mass index, hypertension, diabetes, and dyslipidemia. RESULTS: Intermediate-type (OR: 1.15, 95% confidence interval: 1.05-1.26) and late-type sleep timing (OR: 1.08, 1.00-1.16) were associated with higher NAFLD risk compared to early-type. Additionally, longer sleep duration was linked to lower risk (OR: 0.92, 0.90-0.95 per hour increase). Notably, intermediate to late-type sleepers with normal sleep duration (7 to <8 h) exhibited a 20% higher NAFLD risk compared to early-type sleepers with the same duration (OR: 1.20, 1.04-1.39). The increased NAFLD risk associated with intermediate to late sleep timing was particularly evident in men, hypertension, and prediabetes or diabetes participants. CONCLUSIONS: Intermediate to late sleep timing, even with normal sleep duration, is associated with increased NAFLD risk. These findings underscore the importance of considering both sleep timing and sleep duration for NAFLD prevention, especially in men and individuals with cardiometabolic conditions.

Research progress on the role of extracellular vesicles in the pathogenesis of diabetic kidney disease.

Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus (DM) and has become the main cause of end-stage renal disease worldwide. In recent years, with the increasing incidence of DM, the pathogenesis of DKD has received increasing attention. The pathogenesis of DKD is diverse and complex. Extracellular vesicles (EVs) contain cell-derived membrane proteins, nucleic acids (such as DNA and RNA) and other important cellular components and are involved in intercellular information and substance transmission. In recent years, an increasing number of studies have confirmed that EVs play an important role in the development of DKD. The purpose of this paper is to explain the potential diagnostic value of EVs in DKD, analyze the mechanism by which EVs participate in intercellular communication, and explore whether EVs may become drug carriers for targeted therapy to provide a reference for promoting the implementation and application of exosome therapy strategies in clinical practice.

Comparative efficacy of exercise modalities for general risk factors, renal function, and physical function in non-dialysis chronic kidney disease patients: a systematic review and network meta-analysis.

BACKGROUND: Exercise therapy can effectively manage chronic kidney disease (CKD) risk factors and improve renal function and physical fitness, but the challenge lies in choosing the right exercise type tailored to patients' condition. METHODS: An electronic search of databases including PubMed, The Cochrane Library, EMBASE, Web of Science, VIP, WanFang, and CNKI was performed. The random effects model was used. Mean difference was employed as the effect size for continuous variables, with 95% confidence interval (CI) provided. RESULTS: A total of 36 RCTs were included in this study. Compared to conventional therapy (CT), the combination of three exercise therapies with CT resulted in notable benefits in enhancing six minutes walk test (6MWT) capacity, 24-h urinary protein quantity (24hUTP), systolic blood pressure (SBP), diastolic blood pressure (DBP). Resistance exercise therapy (RT) + CT were more effective than CT to reduce serum creatinine (Scr), body mass index (BMI), and hemoglobin A1c (HbA1c) and improve estimated glomerular filtration rate (eGFR). In terms of improving peak oxygen uptake (VO2 peak), only two exercise modalities were involved, aerobic exercise therapy (AT) and combined (Resistance-Aerobic) exercise therapy (CBT), both of which were more efficacious than CT. The efficacy ranking overall demonstrated clear benefits for RT in enhancing eGFR and 6MWT, decreasing Scr, BMI, SBP, DBP, and HbA1c, while AT was more suitable for boosting VO2 peak, and CBT had greater potential for reducing 24hUTP. CONSLUSIONS: Exercise therapy combined with CT offers significant advantages over CT in many cases, but no single exercise modality is universally effective for all indicators.

Accurate measurement and enhancement of fiber coil symmetry.

The pure Shupe effect is substantially reduced in a fiber optic gyroscope (FOG) with symmetrical windings. However, the effect of the temperature-induced nonuniformity of the stress in the coil depends on the mean temperature derivative (T-dot). Research on precision winding technology has discovered that the symmetry of optical fiber rings affects the temperature performance of fiber optic gyroscopes. Optical fiber rings with good symmetry also have good temperature performance. This paper first establishes a temperature drift model of optical fiber rings that includes the Shupe effect and T-dot effect and then uses finite element simulation to analyze the drift error of optical fiber rings in a variable temperature environment. Analysis shows that this drift is caused by the variation and uneven distribution of the fiber length and the refractive index in the positive and negative winding of the optical fiber ring, which results in a residual phase difference that is directly related to the symmetry of the optical fiber ring. Simulation and analysis show that balancing the residual phase difference of the optical fiber ring can be achieved by cutting the length of the optical fiber ring at both ends. This paper uses optical frequency domain reflectometry (OFDR) technology to precisely test the symmetry of the optical fiber ring, ensuring accurate adjustment of the lengths at both ends of the optical fiber ring. Experimental tests on two gyroscopes have shown that the optical fiber ring with a smaller drift error can be obtained after testing and adjusting its length. The experimental data indicates that the bias stability of two laboratory gyros are increased by 23.6% and 18.1%, and the bias range are reduced by 22.4% and 30.0%.

Long-term exposure to ambient ozone at workplace is positively and non-linearly associated with incident hypertension and blood pressure: longitudinal evidence from the Beijing-Tianjin-Hebei medical examination cohort.

BACKGROUND: There is limited longitudinal evidence on the hypertensive effects of long-term exposure to ambient O3. We investigated the association between long-term O3 exposure at workplace and incident hypertension, diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), and mean arterial pressure (MAP) in general working adults. METHODS: We conducted a cohort study by recruiting over 30,000 medical examination attendees through multistage stratified cluster sampling. Participants completed a standard questionnaire and comprehensive medical examination. Three-year ambient O3 concentrations at each employed participant's workplace were estimated using a two-stage machine learning model. Mixed-effects Cox proportional hazards models and linear mixed-effects models were used to examine the effect of O3 concentrations on incident hypertension and blood pressure parameters, respectively. Generalized additive mixed models were used to explore non-linear concentration-response relationships. RESULTS: A total of 16,630 hypertension-free working participants at baseline finished the follow-up. The mean (SD) O3 exposure was 45.26 (2.70) ppb. The cumulative incidence of hypertension was 7.11 (95% CI: 6.76, 7.47) per 100 person-years. Long-term O3 exposure was independently, positively and non-linearly associated with incident hypertension (Hazard ratios (95% CI) for Q2, Q3, and Q4 were 1.77 (1.34, 2.36), 2.06 (1.42, 3.00) and 3.43 (2.46, 4.79), respectively, as compared with the first quartile (Q1)), DBP (ß (95% CI) was 0.65 (0.01, 1.30) for Q2, as compared to Q1), SBP (ß (95% CI) was 2.88 (2.00, 3.77), 2.49 (1.36, 3.61) and 2.61 (1.64, 3.58) for Q2, Q3, and Q4, respectively), PP (ß (95% CI) was 2.12 (1.36, 2.87), 2.03 (1.18, 2.87) and 2.14 (1.38, 2.90) for Q2, Q3, and Q4, respectively), and MAP (ß (95% CI) was 1.39 (0.76, 2.02), 1.04 (0.24, 1.84) and 1.12 (0.43, 1.82) for Q2, Q3, and Q4, respectively). The associations were robust across sex, age, BMI, and when considering PM2.5 and NO2. CONCLUSIONS: To our knowledge, this is the first cohort study in the general population that demonstrates the non-linear hypertensive effects of long-term O3 exposure. The findings are particularly relevant for policymakers and researchers involved in ambient pollution and public health, supporting the integration of reduction of ambient O3 into public health interventions.

Gender differences in the association between sleep duration and body mass index, percentage of body fat and visceral fat area among chinese adults: a cross-sectional study.

BACKGROUND: The relationship between sleep duration and anthropometric indices are still unclear. This study aimed to explore the association between sleep duration and body mass index (BMI), percentage of body fat (PBF) and visceral fat area (VFA) among Chinese adults, further to explore gender difference in it. METHODS: We analyzed part of the baseline data of a cohort study among adult attendees at two health-screening centers in China. Sleep duration was self-reported and categorized into short (< 7 h/day), optimal (7-9 h/day) and long sleep (≥ 9 h/day). BMI, PBF and VFA were assessed by bioelectric impedance analysis. Demographic characteristics, chronic diseases and medication history, physical activity, smoking and alcohol drinking behaviors were measured by an investigator-administrated questionnaire. RESULTS: A total of 9059 adult participants (63.08% were females) were included in the analysis. The participants aged from 19 to 91 years with the mean age of 45.0 ± 14.6 years. Short sleep was independently associated with elevated odds of general obesity (defined using BMI) and visceral obesity (defined using VFA) among the total study population, and gender differences were observed in these associations. Among women, short sleep was associated with 62% increased odds of general obesity (OR = 1.62, 95% CI: 1.24-2.12) and 22% increased odds of visceral obesity (OR = 1.22, 95% CI: 1.02-1.45). Among men, long sleep duration was associated with 21% decreased odds of visceral obesity (OR = 0.79, 95% CI: 0.64-0.99). No association was observed between sleep duration and PBF in both sexes. CONCLUSIONS: Sleep duration was associated with increased odds of general and visceral obesity, and this association differed between men and women. No association was observed between sleep duration and PBF among either males or females.

Comparison of bioelectrical body and visceral fat indices with anthropometric measures and optimal cutoffs in relation to hypertension by age and gender among Chinese adults.

BACKGROUND: Few studies have compared bioelectrical body and visceral fat indices with anthropometric measures, or evaluated their optimal cutoffs in relation to hypertension among Asians. We compared the efficiencies of bioelectrical indices (percentage of body fat, PBF; visceral fat area, VFA) with anthropometric measures (body mass index, BMI; waist-hip ratio, WHR) for hypertension and re-evaluated the optimal cutoffs of each index by age and gender. METHODS: We conducted a cross-sectional survey among 8234 adults for health examination. PBF, VFA, BMI, WHR, and data on hypertension and behaviors were collected. Receiver operating characteristic (ROC) curve and areas under curves (AUCs) were used to analyze the efficiencies of the indices for hypertension, optimal cutoffs were estimated using the Youden index. RESULTS: A total of 8234 individuals aged 21-91 with median age 44 (interquartile range [IQR] 33-56) years were included and 40.56% were men. The overall prevalence of hypertension was 27.47%. The studied indices were all associated with hypertension in all age-specific groups both among men and women except for WHR in 21-29 years old men and PBF in in 21-29 years old women. Among males, there were no statistical differences in powers of four indices for hypertension in all age-specific groups, except for 40-49 years, in which WHR was better than VFA. Among females, no differences were found among the indices in 30-39 and 70-79 years groups, while WHR was the best in 21-29 years group, VFA was better than PBF in 30-39 and 50-59 years groups, BMI was better than PBF and WHR in 60-69 years group. The optimal cutoffs of PBF, VFA, BMI and WHR ranged from 23.9 to 28.7%, 86.4 to 106.9cm2, 23.5 to 27.1 kg/m2, 0.92 to 0.96 across the age categories in males, and 32.8 to 36.3%, 75.9 to 130.9cm2, 21.9 to 26.4 kg/m2, 0.84 to 0.95 across the age categories in females, respectively. CONCLUSIONS: The obesity indices' efficiencies for hypertension varied by age and gender, and their cutoff values varied across the age categories and gender. Specific indices and cutoffs based on person's age and gender should be used to identify individuals with hypertension.

Legumain, an asparaginyl endopeptidase, mediates the effect of M2 macrophages on attenuating renal interstitial fibrosis in obstructive nephropathy.

Two distinct macrophage phenotypes contribute to kidney injury and repair during the progression of renal interstitial fibrosis; proinflammatory (M1) and antiinflammatory (M2) macrophages. Legumain, an asparaginyl endopeptidase of the cysteine protease family, is overexpressed in macrophages in some pathological conditions. However, the macrophage subtype and function of macrophage-derived legumain remains unclear. To resolve this we tested whether M2 macrophages contribute to the accumulation of legumain in the unilateral ureteral obstruction model. Legumain-null mice exhibited more severe fibrotic lesions after obstruction compared with wild-type control. In vitro, IL4-stimulated M2 polarization led to the overexpression and secretion of legumain. The levels of fibronectin and collagen I/III, major components of the extracellular matrix, were reduced in the conditioned medium of TGF-ß1-stimulated tubular epithelial cells or fibroblasts after treatment with legumain or conditioned medium from IL4-stimulated macrophages. Administration of the legumain inhibitor RR-11a exacerbated fibrotic lesions following obstruction. Therapeutically, adoptive transfer of legumain-overexpressing macrophages or IL4-stimulated macrophages ameliorated the deposition of collagen and fibronectin induced by ureteral obstruction, either in the wild-type mice or in lgmn-/- mice. Thus, M2 macrophages overexpress and secret legumain and legumain mediates the anti-fibrotic effect of M2 macrophages in obstructive nephropathy.

Influence of bushenhuoxue on podocytes of focal segmental glomerulosclerosis mice.

OBJECTIVE: To observe the effects and mechanisms of Bushenhuoxue on desmin and nephrin expression in mice podocytes, and to investigate its effects on wt1 expression in Wilms' tumor. METHODS: Adriamycin (ADR) was used to induce focal segmental glomerulous sclerosis (FSGS) in mice. Bushenhuoxue was used to treat FSGS for 6 weeks. We measured body mass and right renal mass, and determined serum albumin (ALB) levels, protein content in urine, and urinary protein and albumin creatinine ratio (UACR). Changes in renal tissue morphology were evaluated by microscopy. wt1 and nephrin expression in podocytes were detected using immunofluorescence. Expression levels of desmin, wt1 and nephrin mRNAs in renal tissue were determined using reverse transcription polymerase chain reaction assays. RESULTS: Protein levels in urine and UACR were significantly increased in FSGS model mice compared with Bushenhuoxue-treated and control mice. Body mass and ALB levels were decreased in FSGS mice compared with control and Bushenhuoxue-treated mice. Expression of the wt1 protein was observed in control mice. Compared with controls, wt1 expression levels were reduced in Bushenhuoxue-treated mice, and to a greater extent in FSGS mice. Nephrin protein expression was widespread in FSGS mice, and significantly reduced in control and Bushenhuoxue mice. Expression levels of wt1 and nephrin mRNAs in FSGS mice were lower compared with those in control and Bushenhuoxue-treated mice. Desmin mRNA levels in FSGS mice were reduced compared with those in control and Bushenhuoxue-treated mice. CONCLUSION: Bushenhuoxue ameliorated albuminuria in FSGS mice; this was possibly related to the up-regulation of wt1 and nephrin, and down-regulation of desmin.

Exploring the role of NLRP3 inflammasome in diabetic nephropathy and the advancements in herbal therapeutics.

Diabetic nephropathy (DN), a prevalent complication of diabetes mellitus (DM), is clinically marked by progressive proteinuria and a decline in glomerular filtration rate. The etiology and pathogenesis of DN encompass a spectrum of factors, including hemodynamic alterations, inflammation, and oxidative stress, yet remain incompletely understood. The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a critical component of the body's innate immunity, plays a pivotal role in the pathophysiology of DN by promoting the release of inflammatory cytokines, thus contributing to the progression of this chronic inflammatory condition. Recent studies highlight the involvement of the NLRP3 inflammasome in the renal pathology associated with DN. This article delves into the activation pathways of the NLRP3 inflammasome and its pathogenic implications in DN. Additionally, it reviews the therapeutic potential of traditional Chinese medicine (TCM) in modulating the NLRP3 inflammasome, aiming to provide comprehensive insights into the pathogenesis of DN and the current advancements in TCM interventions targeting NLRP3 inflammatory vesicles. Such insights are expected to lay the groundwork for further exploration into TCM-based treatments for DN.

Association between oxidative balance score and diabetic kidney disease, low estimated glomerular filtration rate and albuminuria in type 2 diabetes mellitus patients: a cross-sectional study.

Objective: The oxidative balance score (OBS) is a comprehensive concept that includes 20 oxidative stressors and can be used to assess individual pro-oxidant versus antioxidant exposure, and the aim of the present study was to investigate the association between OBS and the risk of diabetic kidney disease (DKD), low estimated glomerular filtration rate (low-eGFR) and albuminuria in patients with diabetes mellitus (DM). Methods: This cross-sectional study included nationally representative consecutive National Health and Nutrition Examination Survey DM patients aged 18 years and older from 2003-2018. The continuous variable OBS was converted into categorical variables by quartiles, and weighted multiple logistic regression analyses and restricted triple spline models were used to explore the relationships. We also performed subgroup analyses and interaction tests to verify the stability of the results. Results: A total of 5389 participants were included, representing 23.6 million non-institutionalized US residents. The results from both multivariate logistic regression analysis and restricted cubic spline models indicated that OBS and dietary OBS levels were negatively associated with the risk of DKD, low-eGFR, and albuminuria, without finding a significant correlation between lifestyle OBS and these clinical outcomes. Compared to the lowest OBS quartile group, the prevalence risk of DKD (OR = 0.61, 95% CI: 0.46-0.80), low-eGFR (OR = 0.46, 95% CI: 0.33-0.64) and albuminuria (OR = 0.68, 95% CI: 0.51-0.92) decreased by 39%, 54% and 32%, respectively, in the highest OBS quartile group. The results remained stable in subgroup analyses and no interaction between subgroups was found. Conclusion: Higher levels of OBS and dietary OBS were associated with a lower risk of DKD, low-eGFR, and albuminuria. These findings provided preliminary evidence for the importance of adhering to an antioxidant-rich diet and lifestyle among individuals with diabetes.

Association of different domains of physical activity with diabetic kidney disease: a population-based study.

Background: The aim of this cross-sectional study was to elucidate the associations between various domains of physical activity, such as occupation-related (OPA), transportation-related (TPA), leisure-time (LTPA) and overall physical activity (PA), and diabetic kidney disease. Methods: Our study encompassed 2,633 participants, drawn from the cross-sectional surveys of the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018, and employed survey-weighted logistic regression, generalized linear regression, and restricted cubic spline (RCS) analyses to ascertain the relationship between different domains of physical activity and diabetic kidney disease. Results: After controlling for all confounders, multivariate logistic regression analyses revealed a lack of correlation between the various domains of physical activity and the prevalence of diabetic kidney disease. Multiple generalized linear regression analyses showed that durations of PA (ß = 0.05, 95% CI, 0.01-0.09, P = 0.012) and TPA (ß = 0.32, 95% CI, 0.10-0.55, P = 0.006) were positively associated with eGFR levels; and LTPA durations were inversely associated with UACR levels (ß = -5.97, 95% CI, -10.50 - -1.44, P = 0.011). The RCS curves demonstrated a nonlinear relationship between PA, OPA, and eGFR, as well as a nonlinear correlation between PA and ACR. Subgroup and sensitivity analyses largely aligned with the outcomes of the multivariate generalized linear regression, underscoring the robustness of our findings. Conclusion: Our population-based study explored the association between different domains of physical activity and diabetic kidney disease. Contrary to our expectations, we found no significant association between the duration of physical activity across all domains and the prevalence of diabetic nephropathy. Nonetheless, renal function markers, including eGFR and UACR, exhibited significant correlations with the duration of total physical activity (TPA) and leisure-time physical activity (LTPA), respectively, among diabetic patients. Interestingly, our findings suggest that diabetic patients engage in physical activity to preserve renal function, ensuring moderate exercise durations not exceeding 35 hours per week.

Assessment of the association between genetic factors regulating thyroid function and microvascular complications in diabetes: A two-sample Mendelian randomization study in the European population.

Background: Observational studies have identified a possible link between thyroid function and diabetic microangiopathy, specifically in diabetic kidney disease (DKD) and diabetic retinopathy (DR). However, it is unclear whether this association reflects a causal relationship. Objective: To assess the potential direct effect of thyroid characteristics on DKD and DR based on Mendelian randomization (MR). Methods: We conducted an MR study using genetic variants as an instrument associated with thyroid function to examine the causal effects on DKD and DR. The study included the analysis of 4 exposure factors associated with thyroid hormone regulation and 5 outcomes. Genomewide significant variants were used as instruments for standardized freethyroxine (FT4) and thyroid-stimulating hormone (TSH) levels within the reference range, standardized free triiodothyronine (FT3):FT4 ratio, and standardized thyroid peroxidase antibody (TPOAB) levels. The primary outcomes were DKD and DR events, and secondary outcomes were estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR) in diabetes, and proliferative diabetic retinopathy (PDR). Satisfying the 3 MR core assumptions, the inverse-variance weighted technique was used as the primary analysis, and sensitivity analysis was performed using MR-Egger, weighted median, and MR pleiotropy residual sum and outlier techniques. Results: All outcome and exposure instruments were selected from publicly available GWAS data conducted in European populations. In inverse-variance weighted random-effects MR, gene-based TSH with in the reference range was associated with DKD (OR 1.44; 95%CI 1.04, 2.41; P = 0.033) and eGFR (ß: -0.031; 95%CI: -0.063, -0.001; P = 0.047). Gene-based increased FT3:FT4 ratio, decreased FT4 with in the reference range were associated with increased ACR with inverse-variance weighted random-effects ß of 0.178 (95%CI: 0.004, 0.353; P = 0.046) and -0.078 (95%CI: -0.142, -0.014; P = 0.017), respectively, and robust to tests of horizontal pleiotropy. However, all thyroid hormone instruments were not associated with DR and PDR at the genetic level. Conclusion: In diabetic patients, an elevated TSH within the reference range was linked to a greater risk of DKD and decreased eGFR. Similarly, decreased FT4 and an increased FT3:FT4 ratio within the reference range were associated with increased ACR in diabetic patients. However, gene-based thyroid hormones were not associated with DR, indicating a possible pathway involving the thyroid-islet-renal axis. However, larger population studies are needed to further validate this conclusion.

Causal effects of systemic inflammatory regulators on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study.

Background: While targeted systemic inflammatory modulators show promise in preventing chronic kidney disease (CKD) progression, the causal link between specific inflammatory factors and CKD remains uncertain. Methods: Using a genome-wide association study of 41 serum cytokines from 8,293 Finnish individuals, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. In addition, we genetically predicted causal associations between inflammatory factors and 5 phenotypes, including CKD, estimated glomerular filtration rate (eGFR), dialysis, rapid progression of CKD, and rapid decline in eGFR. Inverse variance weighting (IVW) served as the primary MR method, while MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q test for heterogeneity. Leave-one-out method ensured stability of MR results, and Bonferroni correction assessed causal relationship strength. Results: Seventeen cytokines were associated with diverse renal outcomes. Among them, after Bonferroni correction test, higher tumor necrosis factor alpha levels were associated with a rapid decrease in eGFR (OR = 1.064, 95% CI 1.028 - 1.103, P = 0.001), higher interleukin-4 levels were associated with an increase in eGFR (ß = 0.003, 95% CI 0.001 - 0.005, P = 0.002), and higher growth regulated oncogene alpha (GROα) levels were associated with an increased risk of CKD (OR=1.035, 95% CI 1.012 - 1.058, P = 0.003). In contrast, genetic susceptibility to CKD was associated with an increase in GROa, and a decrease in eGFR may lead to an increase in stem cell factor. We did not find the presence of horizontal pleiotropy during the analysis. Conclusion: We discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.

Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of Schisandra Chinensis Mixture on diabetic nephropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is one of the most common and serious microvascular complications of Diabetes mellitus (DM). The inflammatory response plays a critical role in DN. Schisandra Chinensis Mixture (SM) has shown promising clinical efficacy in the treatment of DN while the pharmacological mechanisms are still unclear. AIM OF THE STUDY: In this study, a network pharmacology approach and bioinformatic analysis were adopted to predict the pharmacological mechanisms of SM in DN therapy. Based on the predicted results, molecular docking and in vivo experiments were used for verification. MATERIALS AND METHODS: In this study, the candidate bioactive ingredients of SM were obtained via Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and supplementing according to the literature. SM putative targets and the verified targets were acquired from TCMSP and SiwssTartgetPrediction Database. DN-related target genes were collected from GeneCards, OMIM, DisGeNET databases, and microarray data analysis. Biological function and pathway analysis were performed to further explore the pharmacological mechanisms of SM in DN therapy. The protein-protein interaction (PPI) network was established to screen the hub gene. The Receiver Operating Characteristic (ROC) analysis and the molecular docking simulations were performed to validate the potential target-drug interactions. The fingerprint spectrum of multi-components of the SM was characterized by UPLC-MS/MS. The signaling pathways associated with inflammation and hub genes were partially validated in SD rats. RESULTS: A total of 36 bioactive ingredients were contained, and 666 component-related targets were screened from SM, of which 50 intersected with DN targets and were considered potential therapeutic targets. GO analyses revealed that the 50 intersection targets were mainly enriched in the inflammatory response, positive regulation of angiogenesis, and positive regulation of phosphatidylinositol 3-kinase(PI3K) signaling. KEGG analyses indicated that the PI3K-Akt signaling pathway was considered as the most important pathway for SM antagonism to the occurrence and development of DN, with the highest target count enrichment. PPI network results showed that the top 15 protein targets in degree value, VEGFA, JAK2, CSF1R, NOS3, CCR2, CCR5, TLR7, FYN, BTK, LCK, PLAT, NOS2, TEK, MMP1 and MCL1, were identified as hub genes. The results of ROC analysis showed that VEGFA and NOS3 were valuable in the diagnosis of DN. The molecular docking confirmed that the core bioactive ingredients had well-binding affinity for VEGFA and NOS3. The in vivo experiments confirmed that SM significantly inhibited the over-release of inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor receptor (TNF)-α in DN rats, while regulating the PI3K-AKT and VEGFA-NOS3 signaling pathways. CONCLUSION: This study revealed the multi-component, multi-target and multi-pathway characteristics of SM therapeutic DN. SM inhibited the inflammatory response and improved renal pathological damage in DN rats, which was related to the regulation of the PI3K-Akt and VEGFA-NOS3 signaling pathways.

Mechanistic Study of Schisandra chinensis Fruit Mixture Based on Network Pharmacology, Molecular Docking and Experimental Validation to Improve the Inflammatory Response of DKD Through AGEs/RAGE Signaling Pathway.

Background: Diabetic kidney disease (DKD) is a major cause of end-stage renal disease (ESRD), and inflammation is the main causative mechanism. Schisandra chinensis fruit Mixture (SM) is an herbal formulation that has been used for a long time to treat DKD. However, its pharmacological and molecular mechanisms have not been clearly elucidated. The aim of this study was to investigate the potential mechanisms of SM for the treatment of DKD through network pharmacology, molecular docking and experimental validation. Methods: The chemical components in SM were comprehensively identified and collected using liquid chromatography-tandem mass spectrometry (LC-MS) and database mining. The mechanisms were investigated using a network pharmacology, including obtaining SM-DKD intersection targets, completing protein-protein interactions (PPI) by Cytoscape to obtain key potential targets, and then revealing potential mechanisms of SM for DKD by GO and KEGG pathway enrichment analysis. The important pathways and phenotypes screened by the network analysis were validated experimentally in vivo. Finally, the core active ingredients were screened by molecular docking. Results: A total of 53 active ingredients of SM were retrieved by database and LC-MS, and 143 common targets of DKD and SM were identified; KEGG and PPI showed that SM most likely exerted anti-DKD effects by regulating the expression of AGEs/RAGE signaling pathway-related inflammatory factors. In addition, our experimental validation results showed that SM improved renal function and pathological changes in DKD rats, down-regulated AGEs/RAGE signaling pathway, and further down-regulated the expression of TNF-α, IL-1ß, IL-6, and up-regulated IL-10. Molecular docking confirmed the tight binding properties between (+)-aristolone, a core component of SM, and key targets. Conclusion: This study reveals that SM improves the inflammatory response of DKD through AGEs/RAGE signaling pathway, thus providing a novel idea for the clinical treatment of DKD.

Comparison of bioelectrical body and visceral fat indices and anthropometric measures in relation to type 2 diabetes by sex among Chinese adults, a cross-sectional study.

Objectives: We aim to compare the efficacies of the bioelectrical indices (percentage of body fat, PBF; visceral fat area, VFA) with the conventional anthropometric measures (body mass index, BMI; waist-hip ratio, WHR) for predicting type 2 diabetes (T2D) risk by sex and to determine the sex-specific optimal adiposity indices to predict the T2D risk. Design: Cross-sectional design. Setting: Tianjin First Central Hospital and Tianjin Union Medical Center, Tianjin, China. Participants: A total of 9,332 adults (41.35% men) undergoing physical examination. Primary and secondary outcome measures: T2D was defined using the WHO's criteria: fasting blood glucose (FBG) ≥7.0 mmol/L and/or previous diagnosis of T2D. Height, weight, waist, hip, PBF, VFA, and fasting plasma glucose were measured. Results: All studied adiposity indices were associated with T2D among both males and females, and the observed associations differed by sex. The standardized aORs of BMI, WHR, PBF and VFA for T2D were 1.60 (95% CI 1.42-1.81), 1.43 (95% CI 1.25-1.64), 1.42 (95% CI 1.23-1.62) and 1.53 (95% CI 1.35-1.75) for females, and 1.47 (95% CI 1.31-1.66), 1.40 (95% CI 1.25-1.58), 1.54 (95% CI 1.36-1.74) and 1.47 (95% CI 1.31-1.65) for males, respectively. The AUCs of VFA, WHR and BMI were 0.743, 0.742 and 0.717 in women, respectively, whereas none of the indices had AUC larger than 0.70 in men. The AUCs were not significantly different between VFA and WHR, while both demonstrate larger AUCs than BMI and PBF in females (all p < 0.05). The optimal cutoff values of VFA, WHR, and BMI for T2D in women were 103.55 cm2, 0.905, and 24.15 kg/m2, respectively. Conclusion: Although BMI, WHR, and PBF and VFA as measured by bioelectrical impedance analysis (BIA) were all positively associated with T2D, their efficacy for predicting the risk of T2D differed by sex. VFA, WHR and BMI could be used as biomarkers to predict T2D risk in women, however none of the study indicators demonstrated favorable efficacy of predicting T2D risk in men.

Preliminary study of the interactive effects of coronary heart disease and lacunar infarction on renal function in patients with type 2 diabetes mellitus by gender.

BACKGROUND: Coronary heart disease (CHD) and lacunar infarction (LI) are the most common cardio- cerebrovascular complications of type 2 diabetes mellitus (T2DM) and a recognized risk factor for renal injury. Although a unidirectional association of CHD or LI with T2DM or the kidney has been demonstrated, however, it remains unknown whether there is an interactive effect of the coexistence of CHD and LI on renal function in T2DM patients. The aim of our study was to investigate the interaction between CHD and LI on renal function in gender-specific patients with T2DM and the association between cardio-cerebrovascular disease-related conventional serum markers and the estimated glomerular filtration rate (eGFR). METHODS: We conducted a cross-sectional study in Beijing and Tianjin from April 2019 to August 2021. Participants with T2DM aged ≥18 years were asked to complete a one-to-one questionnaire and physical examination. RESULTS: In this study, 389 eligible patients with T2DM were included, with a mean age of 63.04 ± 9.41 years, of whom 200 (51.41 %) were male. The proportions of patients with CHD, LI, and both CHD and LI were 28.53 %, 24.42 %, and 11.05 %, respectively. Compared to T2DM patients without either CHD or LI, those with both CHD and LI were found to have a significantly greater risk of reduced eGFR (OR: 12.82, 95 % CI 5.06-32.52, P < 0.001) than those with CHD alone (OR: 2.42, 95 % CI 1.37-3.00, P = 0.004) or LI alone (OR: 1.15, 95 % CI 0.61-2.18, P = 0.664). The combined presence of CHD and LI is associated with a significantly greater risk of decreased eGFR in female T2DM patients compared to their male counterparts. We found both multiplicative and additive effects in all T2DM patients; however, when stratified by sex, only multiplicative effects were observed. After controlling for interference from CHD, LI, and age, we found that total cholesterol (TC) was negatively correlated with eGFR in females (r = -0.156, P = 0.034), and low-density lipoprotein cholesterol (LDL-C) was negatively correlated with eGFR in males (r = -0.229, P = 0.001). CONCLUSION: This study provides novel evidence that the synergistic effect of CHD and LI on renal injury in patients with T2DM is significantly greater than their individual effects. Women with T2DM who have both CHD and LI are at a 4.85-fold higher risk of decreased eGFR than men. Therefore, increased clinical attention should be given to preventing and treating vascular complications in T2DM patients, as well as aggressively reducing lipid levels, particularly TC and LDL-C, to delay or prevent renal dysfunction in T2DM patients.

Habitual night sleep duration is associated with general obesity and visceral obesity among Chinese women, independent of sleep quality.

Purpose: Research on the relationship between sleep duration and obesity defined using multiple anthropometric and bioelectrical indices in women remains scarce. We aimed to explore the association between sleep duration and body mass index (BMI), waist-hip ratio (WHR), body fat percentage (PBF) and visceral fat area (VFA) among females. Methods: We recruited women for medical examination using multistage cluster sampling. Sleep was assessed using Pittsburgh Sleep Quality Index (PSQI) and sleep duration was categorized into short (<7 h), optimal (7 <9 h) and long sleep (≥ 9 h). Weight and height were measured using a calibrated stadiometer. Waist circumference was manually measured. PBF, and VFA were estimated by bioelectrical impedance analysis. Data on sociodemographic characteristics and lifestyle factors were also collected and included in the logistic regression models to explore the independent association between sleep duration and obesity defined by different indices. Results: A total of 7,763 women with a mean age of 42.6 ± 13.5 years were included. The percentage of women reporting short and long sleep was 10.3 and 13.4% respectively. The mean BMI, WHR, PBF and VFA were 23.07 ± 3.30 kg/m2, 0.78 ± 0.06, 32.23 ± 6.08% and 91.64 ± 35.97cm2, respectively. Short sleep was independently associated with 35% (95% CI: 1.05-1.75) increased odds of general obesity (BMI ≥ 28 kg/cm2), and long sleep was associated with 18% (95% CI: 1.01-1.37) increased odds of visceral obesity (VFA > 100 cm2). No association was observed between sleep deprivation or excessive sleep and high WHR or high PBF. Conclusion: In women, short sleep was associated with an increased odds of general obesity, whereas long sleep was associated with an increased odds of visceral obesity. Longitudinal observations are needed to confirm this cross-sectional relationship.