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Background: Obesity is a global public health concern linked to chronic diseases such as cardiovascular disease and type 2 diabetes (T2D). Emerging evidence suggests that epigenetic modifications, particularly DNA methylation, may contribute to obesity. However, the molecular mechanism underlying the longitudinal change of BMI has not been well-explored, especially in East Asian populations. Methods: This study performed a longitudinal epigenome-wide association analysis of DNA methylation to uncover novel loci associated with BMI change in 533 individuals across two Chinese cohorts with repeated DNA methylation and BMI measurements over four years. Results: We identified three novel CpG sites (cg14671384, cg25540824, and cg10848724) significantly associated with BMI change. Two of the identified CpG sites were located in regions previously associated with body shape and basal metabolic rate. Annotation of the top 20 BMI change-associated CpGs revealed strong connections to obesity and T2D. Notably, these CpGs exhibited active regulatory roles and located in genes with high expression in the liver and digestive tract, suggesting a potential regulatory pathway from genome to phenotypes of energy metabolism and absorption via DNA methylation. Cross-sectional and longitudinal EWAS comparisons indicated different mechanisms between CpGs related to BMI and BMI change. Conclusion: This study enhances our understanding of the epigenetic dynamics underlying BMI change and emphasizes the value of longitudinal analyses in deciphering the complex interplay between epigenetics and obesity. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world's population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-[kappa]B/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention., Introduction In the past decade, the prevalence of obesity has substantially increased in both the adults and children (1) due to rapid changes in lifestyle. Obesity is associated with high [...]

Poly(vinyl alcohol) (P)/alginate (A)/MMT (M) (PAM) composite aerogels was modified through interpenetrating cross-linking of methyltriethoxysilane (Ms) or γ-aminopropyltriethoxysilane (K) and calcium ion (Ca2+) as a cross-linking agent, respectively. The compressive moduli of the cross-linked PAM/MsCa and PAM/KCa aerogels greatly increased to 17.4 and 22.1 MPa, approximately 10.5- and 8.2-fold of that of PAM aerogel, respectively. The limited oxygen index (LOI) values for PAM/MsCa and PAM/KCa composite aerogels increased from 27.0% of PAM aerogel to 40.5% and 56.8%. Compared with non-cross-linked PAM aerogel, the peak heat release rate (PHRR) of PAM/MsCa and PAM/KCa composite aerogels dramatically decreased by 34% and 74%, respectively, whereas the PAM/KCa aerogel presented better flame retardancy and lower smoke toxicity than the PAM/MsCa aerogel because of the release of more inert gases and the barrier action of more compact char layer during the combustion. The highly efficient flame-retardant PAM-based composite aerogels with excellent mechanical properties are promising as a sustainable alternative to traditional petroleum-based foams. [ABSTRACT FROM AUTHOR]

Aims: The study aimed to develop a novel noninvasive model to detect advanced fibrosis based on routinely available clinical and laboratory tests. Materials and Methods: A total of 309 patients who underwent liver biopsy were randomly divided into the estimation group (n = 201) and validation group (n = 108). The model was developed using multiple regression analysis in the estimation group and further verified in the validation group. Diagnostic accuracy was evaluated using the receiver operating characteristic (ROC) curve. Results: The model was named NAFLD Fibrosis Index (NFI): −10.844 + 0.046 × age − 0.01 × platelet count + 0.19 × 2h postprandial plasma glucose (PG) + 0.294 × conjugated bilirubin − 0.015 × ALT + 0.039 × AST + 0.109 × total iron binding capacity −0.033 × parathyroid hormone (PTH). The area under the ROC curve (AUC) of NFI was 0.86 (95% CI: 0.79–0.93, p < 0.001) in the estimation group and 0.80 (95% CI: 0.69–0.91, p < 0.001) in the validation group, higher than NFS, FIB4, APRI, and BARD, and similar to FibroScan (NFI AUC = 0.77, 95% CI: 0.66–0.89, p = 0.001 vs. FibroScan AUC = 0.76, 95% CI: 0.62–0.90, p = 0.002). By applying the low cut‐off value (−2.756), advanced fibrosis could be excluded among 49.3% and 48% of patients in the estimation group (sensitivity: 93.1%, NPV: 97.9%, specificity: 55.2%, and PPV: 26.0%) and validation group (sensitivity: 81.3%, NPV: 94.2%, specificity: 53.3%, and PPV: 23.2%), respectively, allowing them to avoid liver biopsy. Conclusions: The study has established a novel model for advanced fibrosis, the diagnostic accuracy of which is superior to the current clinical scoring systems and is similar to FibroScan. [ABSTRACT FROM AUTHOR]

Background and Purpose: Salvianolic acid B (SalB) is effective for treating cardiovascular diseases. However, the molecular mechanisms underlying its therapeutic effects remain unclear. Mechanosensitive Piezo1 channels play important roles in vascular biology, although their pharmacological properties are poorly defined. Here, we aimed to identify novel Piezo1 inhibitors and gain insights into their mechanisms of action. Experimental Approach Intracellular Ca2+ ions were measured in HUVECs, murine liver endothelial cells (MLECs), THP‐1 and RAW264.7 cell lines and bone marrow‐derived macrophages (BMDMs). Isometric tensions in mouse thoracic aorta were recorded. Shear‐stress assays with HUVECs were conducted. Patch‐clamp recordings with mechanical stimulation were performed with HUVECs in whole‐cell mode. Foam cell formation was induced by treating BMDMs with oxidised LDL (oxLDL). Atherosclerotic plaque assays were performed with Ldlr−/− and Piezo1 genetically depleted mice on a high‐fat diet. Key Results: Salvianolic acid B inhibited Yoda1‐induced Ca2+ influx in HUVECs and MLECs. Similar results were observed in macrophage cell lines and BMDMs. Furthermore, we demonstrated that salvianolic acid B inhibited Yoda1‐ and mechanically activated currents. Salvianolic acid B suppressed Yoda1‐induced aortic ring relaxation and inhibited HUVECs alignment in the direction of shear stress. Additionally, Yoda1 enhanced the formation of foam cells, which was reversed by salvianolic acid B. Salvianolic acid B also inhibited formation of atherosclerotic plaques and was insensitive to Piezo1 genetic depletion. Conclusion and Implications: Our study provides novel mechanistic insights into the inhibitory role of salvianolic acid B against Piezo1 channels and improves our understanding of salvianolic acid B in preventing atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

Nanocellulose has lately emerged as one of the most promising "green" materials due to its unique properties. Nanocellulose can be mainly divided into three types, i.e., cellulose nanocrystals (CNCs), cellulose nanofibrils (CNFs), and bacterial cellulose (BC). With the rapid development of technology, nanocellulose has been designed into multidimensional structures, including 1D (nanofibers, microparticles), 2D (films), and 3D (hydrogels, aerogels) materials. Due to its adaptable surface chemistry, high surface area, biocompatibility, and biodegradability, nanocellulose-based composite materials can be further transformed as drug delivery carriers. Herein, nanocellulose-based composite material used for drug delivery was reviewed. The typical drug release behaviors and the drug release mechanisms of nanocellulose-based composite materials were further summarized, and the potential application of nanocellulose-based composite materials was prospected as well. [ABSTRACT FROM AUTHOR]

Summary: Background: The PNPLA3 and TM6SF2 gene variants have been found to cause NAFLD with a favourable cardiovascular risk profile. Aims: To investigate the effects of the NAFLD risk alleles on the all‐cause and cause‐specific mortality in 5581 Chinese adults. Methods: The genome‐wide genotypes were detected using a genotyping array and serum lipoprotein profiles were examined using 1H NMR platform. Liver fat content (LFC) was measured using a quantitative ultrasound method. The vital status was determined using official registration data. Results: Genome‐wide association analysis showed that a series of variants in PNPLA3 were associated with LFC, including rs738409 C>G variant (P = 8.6 × 10−7). Further analyses validated the associations of TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants with NAFLD. During 29 425.1 person‐years of follow‐up, the overall mortality was 816 per 100 000 person‐years, where 299 deaths were attributable to cardiovascular disease and 85 to liver disease. The PNPLA3 rs738409 C>G variant was independently associated with increased liver‐specific mortality (P for trend = 0.034) but reduced cardiovascular mortality (P for trend = 0.047). A composite genetic‐predisposition score of PNPLA3, TM6SF2, and MBOAT7 risk alleles presented similar opposite effects on liver‐specific and cardiovascular mortality. Moreover, interactions of the NAFLD risk alleles with adiposity for liver‐specific mortality were found (Pinteraction < 0.05). The reduced serum VLDL1 concentration was responsible for the increased liver‐specific mortality related to NAFLD risk alleles. Conclusion: The PNPLA3 rs738409 C>G variant and its combination with TM6SF2 rs58542926 C>T and MBOAT7 rs641738 C>T variants increase liver‐specific mortality but reduce cardiovascular mortality in overweight/obese Chinese. [ABSTRACT FROM AUTHOR]

Recent advances indicate that bone and energy metabolism are closely related. However, little direct evidence on causality has been provided in humans. We aimed to assess the association of three bone‐related biomarkers—25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and osteocalcin (OCN)—with several metabolic phenotypes and investigate any causal relevance to the associations using a Mendelian randomization (MR) study. Serum 25OHD, PTH, and total OCN were measured at baseline in 5169 eligible Chinese participants in Changfeng study. Partial correlation and bivariate GREML analysis were used to estimate phenotypic and genetic correlations, respectively. Multiple linear regression and logistic regression were used to assess linear associations. Genomewide association analysis (GWAS) was performed. Bidirectional two‐sample MR analyses were conducted to examine causal relationships between OCN and body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), high‐density lipoprotein cholesterol (HDL‐C), glycated hemoglobin A1c (HbA1c), and type 2 diabetes (T2DM), using our GWAS result of OCN and GWAS statistics from Biobank Japan project (BBJ) and the largest meta‐analysis of T2DM GWAS in East Asian population. Circulating OCN was significantly associated with higher DBP and HDL‐C and decreased TG, blood glucose level, insulin resistance, liver fat content, bone mineral density, BMI, and a favorable body fat distribution pattern. GWAS identified one novel serum PTH locus and two novel serum OCN loci, explaining 0.81% and 1.98% of variances of PTH and OCN levels, respectively. MR analysis suggested a causal effect of T2DM on lower circulating OCN concentration (causal effect: −0.03; −0.05 to −0.01; p = 0.006 for T2DM_BBJ and −0.03; −0.05 to −0.01; p = 0.001 for T2DM_EAS). These findings indicate that T2DM might impact bone remodeling and provide a resource for understanding complex relationships between osteocalcin and metabolic (and related) traits in humans. © 2021 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Xia et al papers. To view these articles, visit https://doi.org/10.1111/apt.16772 and https://doi.org/10.1111/apt.16818 [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) contributes to disability and imposes heavy burdens, while subclinical DPN is lack of attention so far. We aimed to investigate the relationship between vitamin D and distinct subtypes of subclinical DPN in type 2 diabetes (T2DM) patients., Methods: This cross-sectional study included 3629 T2DM inpatients who undertook nerve conduction study to detect subclinical DPN in Zhongshan Hospital between March 2012 and December 2019. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25(OH)D) level < 50 nmol/L., Results: 1620 (44.6%) patients had subclinical DPN and they were further divided into subgroups: distal symmetric polyneuropathy (DSPN) (n=685), mononeuropathy (n=679) and radiculopathy (n=256). Compared with non-DPN, DPN group had significantly lower level of 25(OH)D (P < 0.05). In DPN subtypes, only DSPN patients had significantly lower levels of 25(OH)D (36.18 ± 19.47 vs. 41.03 ± 18.47 nmol/L, P < 0.001) and higher proportion of vitamin D deficiency (78.54% vs. 72.18%, P < 0.001) than non-DPN. Vitamin D deficiency was associated with the increased prevalence of subclinical DPN [odds ratio (OR) 1.276, 95% confidence interval (CI) 1.086-1.501, P = 0.003] and DSPN [OR 1. 646, 95% CI 1.31-2.078, P < 0.001], independent of sex, age, weight, blood pressure, glycosylated hemoglobin, T2DM duration, calcium, phosphorus, parathyroid hormone, lipids and renal function. The association between vitamin D deficiency and mononeuropathy or radiculopathy was not statistically significant. A negative linear association was observed between 25(OH)D and subclinical DSPN. Vitamin D deficiency maintained its significant association with subclinical DSPN in all age groups., Conclusions: Vitamin D deficiency was independently associated with subclinical DSPN, rather than other DPN subtypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Yang, Zhu, Ma, Li, Zhang, Liu, Fan, Zhang, Xu, Xu, Gao, Dong, Xia and Bian.)

Bariatric surgery (BS), recognized as the most effective intervention for morbid obesity and associated metabolic comorbidities, encompasses both weight loss-dependent and weight loss-independent mechanisms to exert its metabolic benefits. In this study, we employed plasma proteomics technology, a recently developed mass spectrometric approach, to quantitatively assess 632 circulating proteins in a longitudinal cohort of 9 individuals who underwent sleeve gastrectomy (SG). Through time series clustering and Gene Ontology (GO) enrichment analysis, we observed that complement activation, proteolysis, and negative regulation of triglyceride catabolic process were the primary biological processes enriched in down-regulated proteins. Conversely, up-regulated differentially expressed proteins (DEPs) were significantly associated with negative regulation of peptidase activity, fibrinolysis, keratinocyte migration, and acute-phase response. Notably, we identified seven proteins (ApoD, BCHE, CNDP1, AFM, ITIH3, SERPINF1, FCN3) that demonstrated significant alterations at 1-, 3-, and 6-month intervals post SG, compared to baseline. These proteins play essential roles in metabolism, immune and inflammatory responses, as well as oxidative stress. Consequently, they hold promising potential as therapeutic targets for combating obesity and its associated comorbidities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Shi, Wu, Yan, Xia, Jiao, Zhou, Wu, Zhong, Lou, Gao, Bian and Chang.)

Diabetes mellitus is prevalent worldwide and affects 1 in 10 adults. Despite the successful development of glucose-lowering drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors recently, the proportion of patients achieving satisfactory glucose control has not risen as expected. The heterogeneity of diabetes determines that a one-size-fits-all strategy is not suitable for people with diabetes. Diabetes is undoubtedly more heterogeneous than the conventional subclassification, such as type 1, type 2, monogenic and gestational diabetes. The recent progress in genetics and epigenetics of diabetes has gradually unveiled the mechanisms underlying the heterogeneity of diabetes, and cluster analysis has shown promising results in the substratification of type 2 diabetes, which accounts for 95% of diabetic patients. More recently, the rapid development of sophisticated glucose monitoring and artificial intelligence technologies further enabled comprehensive consideration of the complex individual genetic and clinical information and might ultimately realize a precision diagnosis and treatment in diabetics., Competing Interests: All authors declare that there is no duality of interest., (© The Author(s) 2023.)

Context: Previous genome-wide association studies (GWASs) of bone mineral density (BMD) were mainly conducted in Europeans., Objective: To explore genetic variants that affect BMD and sex differences in a Chinese population., Methods: A total of 5428 middle-aged and elderly Chinese were included. Dual-energy X-ray absorptiometry was used to measure BMD at the lumbar spine, and total and specific sites of the hip. A mixed linear model was used to analyze the associations between BMD and autosomal genetic variants, adjusting for age, age squared, sex, and menopausal women (model 1); model 2 was further adjusted for height and weight. A GWAS of osteoporosis in the Biobank Japan (BBJ) project was used for replication. GWAMA software was used to detect the statistical significance of sex differences of estimated effects. Gene annotation and pathway enrichment analysis were performed., Results: Women lost BMD at earlier ages and faster than men. The 2 models identified a total of 12 loci that were associated with BMD at any site. Single nucleotide polymorphisms rs72354346, rs2024219, rs1463093, rs10037512, and rs5880932 were successfully replicated in the BBJ. Variations of rs79262027 G>A (VKORC1L1) and rs4795209 A>G (DDX52) were associated with BMD only in men, and rs1239055408 G>GA (KCNJ2) was associated with BMD only in women. Gene enrichment analysis showed that BMD in a Chinese elderly population was mainly related to ossification, bone resorption, sex hormones, and kidney physiology., Conclusion: The present GWAS identified 12 loci that were significantly associated with BMD at any site in a Chinese population, and 3 of them showed sex differences in their effects., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vascular remodeling (VR) is a structural and functional change of blood vessels to adapt to the changes of internal and external environment. It is one of the common pathological features of many vascular proliferative diseases. The process of VR is mainly manifested in the changes of vascular wall structure and function, including intimal hyperplasia, thickening or thinning of media, fibrosis of adventitia, etc. These changes are also the pathological basis of aging and various cardiovascular diseases. Mechanical force is the basis of cardiovascular biomechanics, and the newly discovered mechanical sensitive ion channel Piezo1 is widely distributed in the whole cardiovascular system. Studies have confirmed that Piezo1, a mechanically sensitive ion channel, plays an important role in cardiovascular remodeling diseases. This article reviews the molecular mechanism of Piezo1 in atherosclerosis, hypertension and pulmonary hypertension, in order to provide a theoretical basis for the further study of vascular remodeling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, He, Hong, Bi, Li and Xia.)

At present, many experiments provide support for the cardiovascular protective effect of hawthorn ( Crataegus oxyacantha ) flower, leaf and fruit extracts. The aim of this study was to investigate the intervention mechanism of hawthorn fruit extract on spontaneously hypertensive rats (SHR) and its effect on their lipid metabolic pattern. After SHR was intervened by hawthorn extract (1.08 g/kg/d) for 6 weeks, the blood pressure and liver histopathology of rats were evaluated. An UHPLC-Q Extractive metabolomics approach was used to collect information on rat liver lipid metabolites, combined with multivariate data analysis to identify significantly different substances and potential biomarkers through mass spectrometry and database searches. Histomorphology of the liver was partially restored in the hawthorn-treated group. Hawthorn extract interferes with sphingolipid metabolism, glycerophospholipid metabolism and glycerolipids metabolism, improving partially disturbed metabolic pathways. This study showed that hawthorn could partially restore liver histomorphology and has anti-hypertensive effect by regulating lipid metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Chi, Xia, Ma, Zhang, Jiang, Zhang and Tian.)

Background: Macrophages play important roles in renal fibrosis, partially by sensing mechanical forces, including shear stress and increased stiffness. The mechanically activated cationic channel Piezo1 drives vascular formation and blood pressure regulation to inflammatory responses, or cancer, but its role in macrophages in fibrotic kidney is elusive. Here, we hypothesized that Piezo1 in macrophages may have functions in renal fibrosis., Methods: We established a genetically engineered mouse model with Piezo1 specific knockout in myeloid cells and challenged with unilateral ureteric obstruction operation and folic acid treatment to induce the renal fibrosis, aiming to investigate the function of the mechanical-sensitive protein Piezo1 in macrophages in renal fibrosis and its underlying mechanisms., Results: Myeloid Piezo1 was indispensable for renal fibrosis generation. Piezo1 gene deletion in the myeloid lineage was protective in mice with renal fibrosis. Further analyses revealed that macrophage accumulation in the injured kidney depended on the Piezo1-regulated C-C motif chemokine ligand 2, C-C motif chemokine receptor 2 pathway, and Notch signaling cascade. Moreover, Piezo1 deletion restrained macrophage inflammation and consequently suppressed kidney fibrosis and epithelial-mesenchymal transition. In vitro assays showed that Piezo1 deficiency blocked lipopolysaccharide and Piezo1 activation-induced inflammatory responses in bone marrow-derived macrophages. Mechanistically, Piezo1 regulated inflammation through the Ca 2+ -dependent intracellular cysteine protease, as the pharmacological inhibition of calpain blocked the proinflammatory role of Piezo1., Conclusions: This study characterized the important function of Piezo1 in renal fibrosis. Targeting the Piezo1 channels by genetic or pharmacological manipulations may be a promising strategy for the treatment of renal fibrosis.

Despite great progress in the management of atherosclerosis (AS), its subsequent cardiovascular disease (CVD) remains the leading cause of morbidity and mortality. This is probably due to insufficient risk detection using routine lipid testing; thus, there is a need for more effective approaches relying on new biomarkers. Quantitative nuclear magnetic resonance (qNMR) metabolomics is able to phenotype holistic metabolic changes, with a unique advantage in regard to quantifying lipid-protein complexes. The rapidly increasing literature has indicated that qNMR-based lipoprotein particle number, particle size, lipid components, and some molecular metabolites can provide deeper insight into atherogenic diseases and could serve as novel promising determinants. Therefore, this article aims to offer an updated review of the qNMR biomarkers of AS and CVD found in epidemiological studies, with a special emphasis on lipoprotein-related parameters. As more researches are performed, we can envision more qNMR metabolite biomarkers being successfully translated into daily clinical practice to enhance the prevention, detection and intervention of atherosclerotic diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ma, Xia and Gao.)