Purpose: Chronic refractory wounds are a multifactorial comorbidity of diabetes mellitus with the characteristic of impaired vascular networks. Currently, there is a lack of effective treatments for such wounds. Various types of mesenchymal stem cell-derived exosomes (MSC-exos) have been shown to exert multiple therapeutic effects on skin regeneration. We aimed to determine whether a constructed combination of human umbilical cord MSC (hUCMSC)-derived exosomes (hUCMSC-exos) and Pluronic F-127 (PF-127) hydrogel could improve wound healing. Materials and Methods: We topically applied human umbilical cord-derived MSC (hUCMSC)-derived exosomes (hUCMSC-exos) encapsulated in a thermosensitive PF-127 hydrogel to a full-thickness cutaneous wound in a streptozotocin-induced diabetic rat model. The material properties and wound healing ability of the hydrogel and cellular responses were analyzed. Results: Compared with hUCMSC-exos, PF-127-only or control treatment, the combination of PF-127 and hUCMSC-exos resulted in a significantly accelerated wound closure rate, increased expression of CD31 and Ki67, enhanced regeneration of granulation tissue and upregulated expression of vascular endothelial growth factor (VEGF) and factor transforming growth factor beta-1 (TGFβ-1). Conclusion: The efficient delivery of hUCMSC-exos in PF-127 gel and improved exosome ability could promote diabetic wound healing. Thus, this biomaterial-based exosome therapy may represent a new therapeutic approach for cutaneous regeneration of chronic wounds.

Background: Increasing evidence suggests that human gut microbiome plays an important role in variation of skeletal muscle mass (SMM). However, specific causal mechanistic relationship of human gut microbiome with SMM remains largely unresolved. Understanding the causal mechanistic relationship may provide a basis for novel interventions for loss of SMM. This study investigated whether human gut microbiome has a causal effect on SMM among Chinese community‐dwelling healthy menopausal women.Methods: Estimated SMM was derived from whole‐body dual‐energy X‐ray absorptiometry. We performed integrated analyses on whole‐genome sequencing, shotgun metagenomic sequencing, and serum short‐chain fatty acids (SCFAs), as well as available host SMM measurements among community‐dwelling healthy menopausal women (N = 482). We combined the results with summary statistics from genome‐wide association analyses for human gut microbiome (N = 952) and SMM traits (N = 28 330). As a prerequisite for causality, we used a computational protocol that was proposed to measure correlations among gut metagenome, metabolome, and the host trait to investigate the relationship between human gut microbiome and SMM. Causal inference methods were applied to assess the potential causal effects of gut microbial features on SMM, through one‐sample and two‐sample Mendelian randomization (MR) analyses, respectively.Results: In metagenomic association analyses, the increased capacity for gut microbial synthesis of the SCFA butyrate was significantly associated with serum butyrate levels [Spearman correlation coefficient (SCC) = 0.13, P = 0.02] and skeletal muscle index (SCC = 0.084, P = 0.002). Of interest was the finding that two main butyrate‐producing bacterial species were both positively associated with the increased capacity for gut microbial synthesis of butyrate [Faecalibacterium prausnitzii (SCC = 0.25, P = 6.6 × 10⁻⁷) and Butyricimonas virosa (SCC = 0.15, P = 0.001)] and for skeletal muscle index [F. prausnitzii (SCC = 0.16, P = 6.2 × 10⁻⁴) and B. virosa (SCC = 0.17, P = 2.4 × 10⁻⁴)]. One‐sample MR results showed a causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.04, 95% confidence interval 0.029 to 0.051, P = 0.003). Two‐sample MR results further confirmed the causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.06, 95% confidence interval 0 to 0.13, P = 0.06).Conclusions: Our results may help the future development of novel intervention approaches for preventing or alleviating loss of SMM.

Although the gut microbiota has been reported to influence osteoporosis risk, the individual species involved, and underlying mechanisms, remain largely unknown. We performed integrative analyses in a Chinese cohort of peri-/post-menopausal women with metagenomics/targeted metabolomics/whole-genome sequencing to identify novel microbiome-related biomarkers for bone health. Bacteroides vulgatus was found to be negatively associated with bone mineral density (BMD), which was validated in US white people. Serum valeric acid (VA), a microbiota derived metabolite, was positively associated with BMD and causally downregulated by B. vulgatus. Ovariectomized mice fed B. vulgatus demonstrated increased bone resorption and poorer bone micro-structure, while those fed VA demonstrated reduced bone resorption and better bone micro-structure. VA suppressed RELA protein production (pro-inflammatory), and enhanced IL10 mRNA expression (anti-inflammatory), leading to suppressed maturation of osteoclast-like cells and enhanced maturation of osteoblasts in vitro. The findings suggest that B. vulgatus and VA may represent promising targets for osteoporosis prevention/treatment.

Although previous studies have examined the hepatotoxicity of single metal exposure, the associations between metal mixture and non-alcoholic fatty liver disease (NAFLD) or fibrosis remain unclear. This study investigated the associations of urinary metal mixture with the risks of NAFLD and liver fibrosis in US adults using data from the National Health and Nutrition Examination Survey (NHANES) from 2017.01 to 2020.03. Vibration-controlled transient elastography was used to detect the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), which are indicators of NAFLD and liver fibrosis respectively. Three novel mixture modeling approaches including the Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression and quantile g-computation (qgcomp) were used to estimate the associations of the urinary fourteen-metal mixture with Ln CAP and Ln LSM. There were 2283 adults aged over 18 years (1209 women and 1074 men) were included. Among women, urinary metal mixture was positively associated with Ln CAP in the BKMR and qgcomp models (both P < 0.05). However, no significantly associations of urinary metal mixture with Ln CAP were observed among men in all models (all P > 0.05). The metal mixture was not associated with Ln LSM in the three models regardless of genders (all P > 0.05). In conclusion, we observed sex-specific associations between urinary metal mixture and the prevalence of NAFLD in US adults. These findings emphasize the role of environmental heavy metal exposure in the development of NAFLD, and confirm the need for more prospective cohort studies on sex-specific manner.

Background: The unique intracranial tumor microenvironment (TME) contributes to the immunotherapy failure for glioblastoma (GBM), thus new functional protein targets are urgently needed. Alternative splicing is a widespread regulatory mechanism by which individual gene can express variant proteins with distinct functions. Moreover, proteins located in the cell plasma membrane facilitate targeted therapies. This study sought to obtain functional membrane protein isoforms from GBM TME. Methods: With combined single-cell RNA-seq and bulk RNA-seq analyses, novel candidate membrane proteins generated by prognostic splicing events were screened within GBM TME. The short isoform of MS4A7 (MS4A7-s) was selected for evaluation by RT-PCR and western blotting in clinical specimens. Its clinical relevance was evaluated in a GBM patient cohort. The function of MS4A7-s was identified by in vitro and in vivo experiments. MS4A7-s overexpression introduced transcriptome changes were analyzed to explore the potential molecular mechanism. Results: The main expression product, isoform MS4A7-s, generated by exon skipping, is an M2-specific plasma membrane protein playing a pro-oncogenic role in GBM TME. Higher expression of MS4A7-s correlates with poor prognosis in a GBM cohort. In vitro cell co-culture experiments, intracranial co-injection tumorigenesis assay, and RNA-seq suggest MS4A7-s promotes activation of glioma-associated macrophages’ (GAMs) PI3K/AKT/GSK3β pathway, leading to M2 polarization, and drives malignant progression of GBM. Conclusions: MS4A7-s, a novel splicing isoform of MS4A7 located on the surface of GAMs in GBM TME, is a predictor of patient outcome, which contributes to M2 polarization and the malignant phenotype of GBM. Targeting MS4A7-s may constitute a promising treatment for GBM.