BACKGROUND The early detection of hepatocellular carcinoma (HCC) remains a major clinical challenge due to the limited sensitivity and specificity of current biomarkers. This study sought to develop a diagnostic model based on serum exosomal microRNAs (miRNAs) and to elucidate the functional mechanism of a key miRNA, miR-200b-3p, in HCC pathogenesis. AIM To develop and validate a serum exosomal miRNA-based diagnostic model for HCC. METHODS Serum exosomes were isolated from a discovery cohort (68 HCC, 131 non-HCC) and a validation cohort (66 HCC, 135 non-HCC). Candidate miRNAs were identified via next-generation sequencing and machine learning, and validated by quantitative real-time polymerase chain reaction. A diagnostic model was constructed using logistic regression. The role of miR-200b-3p was examined using in vitro functional assays. RESULTS A diagnostic model incorporating three exosomal miRNAs (miR-200b-3p, miR-215-5p, miR-452-5p) and age was established. It showed strong performance in the training set (area under the curve = 0.863, sensitivity = 86.4%, specificity = 76.5%; all P < 0.001). Mechanistically, miR-200b-3p acted as a tumor suppressor by directly targeting phosphoserine aminotransferase 1. Its overexpression inhibited HCC cell proliferation, migration, and invasion (all P < 0.05), while knockdown promoted these phenotypes (all P < 0.05). CONCLUSION This study establishes and validates a non-invasive exosomal miRNA-based diagnostic model for HCC, reveals that miR-200b-3p directly targets phosphoserine aminotransferase 1, and provides mechanistic support for early detection.

Excessive incorporation of long-chain fatty acids (LCFAs) into triglycerides in adipose tissue is a key contributor to obesity and related metabolic disorders, and pharmacologically modulating this process remains challenging. Here, we synthesized a library of β-indoquinazolinone derivatives via palladium-catalyzed oxidative addition complex chemistry and identified compound b2b as a potent and selective anti-obesity candidate. b2b inhibited triglyceride accumulation in adipocytes in vitro and significantly reduced adiposity, body weight, and lipid metabolic disturbances in diet-induced obese mice without observable toxicity. Mechanistic studies revealed that b2b directly activates nicotinamide phosphoribosyltransferase (NAMPT) and elevates intracellular NAD+ levels to enhance the NAD+-dependent regulatory protein SIRT1 activity. This activation leads to transcriptional repression of acyl-CoA synthetase long-chain family member 1 (ACSL1), thereby inhibiting LCFAs incorporation into triglycerides. These findings demonstrate that pharmacological activation of the NAMPT-NAD+-SIRT1 axis by b2b offers a novel strategy for obesity treatment.

ObjectiveThis exploratory pilot study aimed to investigate the associations of anger-related irritability symptoms with gut microbiota and circulating metabolites in patients with type 2 diabetes mellitus (T2DM) using multi-omics analysis.MethodsWe conducted a cross-sectional study, in which T2DM patients were categorized into a self-reported irritable T2DM group (IDM, n = 29) and a self-reported non-irritable DM group (NIDM, n = 28) based on Visual Analog Scale (VAS) scores, with a healthy control group (HC, n = 30) also established. Fecal 16S rRNA gene sequencing and UPLC-MS/MS-based untargeted metabolomic profiling of blood samples were performed. Differences in microbial community structure between groups were analyzed using alpha and beta diversity metrics and linear discriminant analysis effect size (LEfSe) analysis. Differentially abundant genera were identified by MaAsLin2 with adjustment for confounders. Exploratory metabolite markers were screened based on thresholds for p < 0.05, variable importance in projection (VIP) > 1, |log2 fold change (FC)| > 1. Associations between differentially abundant genera and exploratory metabolite markers were explored using Spearman correlation analysis. Functional prediction was conducted based on differentially represented KEGG orthology (KO) and clusters of orthologous groups (COG) entries to identify altered metabolic pathways.ResultsBoth beta diversity and LEfSe analyses revealed differences in gut microbial community structure and potential discriminatory taxa among the three groups. Five differentially abundant genera and twelve exploratory metabolite markers were identified between IDM and NIDM. A combined model incorporating microbial and metabolomic markers demonstrated superior diagnostic performance (AUC = 0.872) compared with models using either type of marker alone. Twelve statistically significant microbiota–metabolite associations were found in Spearman analysis. Functional prediction analysis indicated enrichment of bile acid and tryptophan metabolism pathways.ConclusionVAS-defined irritability symptoms were associated with specific gut microbial and metabolomic alterations in T2DM, providing exploratory evidence for future studies on emotion-related metabolic dysregulation.

Ischemic cardiomyopathy (ICM) is a special type or end stage of coronary heart disease or other irreversible ischemic myocardial injury. Inflammatory damage to coronary vessels is a crucial factor in causing stenosis or occlusion of coronary arteries, resulting in myocardial ischemia and hypoxia, but it is also an aspect of cardioprotection that is often overlooked. This review discusses the mechanisms of vascular injury during ICM, in which inflammation and oxidative stress interact and trigger cell death as the cause of coronary microvascular injury. Imbalances in endoplasmic reticulum function and mitochondrial quality control are important potential drivers of inflammation and oxidative stress. In addition, many studies have confirmed the therapeutic effects of Chinese herbal medicines and their natural monomeric components on vascular injuries. Their mitochondrial quality control and endoplasmic reticulum protection mechanisms as well as their role in combating improvements in vascular endothelial function and attenuating vascular injury are also summarized, with a perspective to provide a reference for pathologic understanding, drug research, and clinical application of ICM-associated coronary microvascular injury.

Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation (p-4EBP1) has been involved in the production of excess extracellular matrix (ECM) and the fibrosis of various organs. We first confirmed that the p-4EBP1 and HIF-1α expressions were significantly elevated in transforming growth factor β1 (TGF-β1)-activated LX-2 cells and fibrotic liver samples. In vivo experiments supported the antifibrotic effect of targeting p-4EBP1 in the liver. Genetic or drug-targeted p-4EBP1 activity in vitro decreased TGF-β1-induced activation, proliferation, migration, epithelial-mesenchymal transition (EMT), and the HIF-1α protein expression in LX-2 cells and promoted their apoptosis. Moreover, the short hairpin RNA-mediated knockdown of 4EBP1 was the opposite. In conclusion, our findings suggest that p-4EBP1 is a critical signaling node in TGF-β1-induced hepatic fibrosis and identified what we believe to be a previously unrecognized p-4EBP1/HIF-1α signaling for hepatic stellate cell (HSC) fibrosis transformation.

Sepsis is a systemic inflammatory response syndrome triggered by infection, which can lead to multiple organ dysfunction. This study untangles the synergistic multi-mechanistic effects of the natural flavonoid apigenin in ameliorating this pathological process. Utilizing a murine sepsis model and Caco-2 cell line, we systematically investigated the impact of apigenin on intestinal barrier function. Apigenin treatment (50 mg/kg) markedly improved intestinal barrier integrity, as shown by reduced serum FITC-dextran levels and restored expression of tight junction proteins Occludin, Claudin-1, and ZO-1. The compound simultaneously attenuated systemic inflammation by lowering IL-6 and TNF-α levels. Network pharmacology and molecular docking identified AKT1 and MMP-9 as key molecular targets of apigenin, which was experimentally validated through observed suppression of MMP-9 and COX-2 protein expression. These results demonstrate apigenin’s capacity to preserve intestinal barrier function during sepsis through coordinated anti-inflammatory and barrier-repair mechanisms.

BackgroundClinical practice commonly uses the Yi-qi Huo-xue formula (YQHX), a traditional Chinese herbal medicine comprising eight herbal components, to treat liver fibrosis resulting from various etiologies. Nevertheless, this formula's specific active constituents and underlying mechanisms of action remain to be fully elucidated.MethodsThe drug components of YQHX and potential targets for liver fibrosis were identified via the screening of the various databases. Qualitative and quantitative identification of chemical components of drug-containing serum by Ultra Performance Liquid Chromatography (UPLC).Liver fibrosis was induced in mice through the intraperitoneal injection of carbon tetrachloride, followed by oral administration of YQHX. RNA-Seq quantified transcriptomic profiles in liver tissue.The degree of liver fibrosis was assessed via histopathology staining, the transcription and expression of relevant proteins were analyzed. Primary cells were isolated for in vitro experiments to validate the influence of YQHX on the associated signaling pathways.ResultsNetwork pharmacology identified IL-1β, IL-6, and TNF-α as potential targets for YQHX in treating liver fibrosis.The UPLC detected multiple potential active components. In vivo experiments showed that YQHX reduced serum AST and ALT levels in liver fibrosis-induced mice, decreased liverIL-1β, IL-6, and TNF-α levels, and improved liver fibrosis.The results of transcriptomics suggest that YQHX can reduce the expression of "collagen-activated signaling pathway," "MyD88-dependent toll-like receptor signaling pathway," "fibrinolysis" and "toll-like receptor 4 signaling pathway". Furthermore, YQHX reduced the aggregation of M1 macrophages in the portal area and the deposition of α-SMA. Primary bone marrow-derived cells successfully transformed into M1 macrophages after induction, and YQHX reduced the levels of IL-1β, IL-6, and TNF-α in the supernatant of M1 macrophage culture and decreased the activation of primary hepatic stellate cells indirectly co-cultured with the supernatant. Interestingly, TLR4 agonists weakened this inhibitory effect. Both in vitro and in vivo experiments demonstrated that YQHX could inhibit the expression of the TLR4/TRAF6/MyD88 pathway in M1 macrophages.ConclusionWe reveal here the molecular mechanism and signaling pathway of YQHX in treating liver fibrosis by utilizing network pharmacology in conjunction with in vivo and in vitro experiments. The findings offer insights that may advance the clinical application of YQHX.

Ischemic heart disease (IHD) is associated with high morbidity and mortality rates. Reperfusion therapy is the best treatment option for this condition. However, reperfusion can aggravate myocardial damage through a phenomenon known as myocardial ischemia/reperfusion (I/R) injury, which has recently gained the attention of researchers. Several studies have shown that Chinese herbal medicines and their natural monomeric components exert therapeutic effects against I/R injury. This review outlines the current knowledge on the pathological mechanisms through which mitochondria participate in I/R injury, focusing on the issues related to energy metabolism, mitochondrial quality control disorders, oxidative stress, and calcium. The mechanisms by which mitochondria mediate cell death have also been discussed. To develop a resource for the prevention and management of clinical myocardial I/R damage, we compiled the most recent research on the effects of Chinese herbal remedies and their monomer components.

Introduction: Obesity, a global epidemic, is caused by an imbalance between energy intake and expenditure. The induction of white adipose browning to increase heat production has emerged as a potential effective strategy to address obesity. Ling-gui-zhu-gan (LGZG), a traditional Chinese medicine formula, has been proved to achieve promising results to combat obesity and related metabolic diseases, yet the mechanisms remain largely unexplored. This study aimed to elucidate the anti-obesity properties and the mechanisms of LGZG by investigating its browning effect on 3T3-L1 adipocytes.Methods: LGZG-containing serum obtained by oral administration of LGZG to animals was added to 3T3-L1 adipocytes to simulate in vivo conditions.Results: The results showed that 49 compounds were identified in LGZG-containing serum by UHPLC-Q-Orbitrap HRMS, including compounds such as atractylenolides and polyporenic acid C, etc. LGZG-containing serum alleviated the lipid accumulation and decreased both intracellular and extracellular triglyceride contents in a dose-dependent manner. This reduction is accompanied by enhanced mitochondrial respiratory and heat production function. Mechanistically, LGZG-containing serum led to a decrease in miR-27b expression and an increase in the mRNA and protein levels of browning-related markers, including UCP1, PRDM16, PGC-1α, PPARγ, CTBP1, and CTBP2. Further investigation using miR-27b mimic transfection confirmed that miR-27b/PRDM16 pathway might be a potential mechanism by which LGZG-containing serum promotes browning of 3T3-L1 adipocytes.Discussion: These results underscore the therapeutic potential of LGZG in addressing obesity and its associated metabolic disorders through the promotion of adipose browning.

Purpose:Septic cardiomyopathy (SCM) is a significant global public health concern characterized by substantial morbidity and mortality, which has not been improved for decades due to lack of early diagnosis and effective therapies. This study aimed to identify hub biomarkers in SCM and explore their potential mechanisms. Methods:We utilized the GSE53007 and GSE207363 datasets for transcriptome analysis of normal and SCM mice. Hub biomarkers were identified through a protein-protein interaction (PPI) network and validated using LPS-treated C57/BL6 mice. Functional enrichment analysis was performed to uncover relevant signaling pathways, while single-cell RNA sequencing was used to examine key genes and regulatory mechanisms associated with SCM. Results:A total of 374 differentially expressed genes (DEGs) were identified, with 268 genes up-regulated and 106 genes down-regulated. Functional enrichment highlighted chemokine activity and receptor binding, with KEGG pathways revealing significant involvement of the TNF and IL-7 signaling pathways. Deterioration of cardiac function, elevated inflammatory markers such as IL-1β, IL-6, and increased cardiac injury biomarkers such as cTnI indicated the successful establishment of our SCM model. Subsequently, qPCR was conducted to validate the expression of the top 10 genes, through which we identified Cd40, Tlr2, Cxcl10, Ccl5, Cxcl1, Cd14, Gbp2, Ifit2, and Vegfa as key biomarkers. Single-cell sequencing indicated increased neutrophil and macrophage populations, with decreased B cells and cardiomyocytes. Additionally, transcription regulators Irf1 and Stat1 were found to potentially regulate the expression of Gbp2, Cxcl10, Ccl5, and Cd40, linking SCM to immune response, ferroptosis, pyroptosis, cuproptosis, and m6A RNA methylation modification. Conclusion:This study identified nine hub biomarkers and two transcription regulators associated with SCM. Exploring the connections between SCM and immunity, ferroptosis, pyroptosis, cuproptosis, and m6A RNA methylation might provide insights into the underlying mechanisms. These findings enhanced our understanding of SCM's underlying mechanisms and might pave the way for novel therapeutic strategies to improve clinical outcomes.

Background: Osteoporosis (OP) is a prevalent chronic metabolic bone disease for which limited countermeasures are available. Cnidii Fructus (CF), primarily derived from Cnidium monnieri (L.) Cusson., has been tested in clinical trials of traditional Chinese medicine for the management of OP. Accumulating preclinical studies indicate that CF may be used against OP. Materials and methods: Comprehensive documentation and analysis were conducted to retrieve CF studies related to its main phytochemical components as well as its pharmacokinetics, safety and pharmacological properties. We also retrieved information on the mode of action of CF and, in particular, preclinical and clinical studies related to bone remodeling. This search was performed from the inception of databases up to the end of 2022 and included PubMed, China National Knowledge Infrastructure, the National Science and Technology Library, the China Science and Technology Journal Database, Weipu, Wanfang, the Web of Science and the China National Patent Database. Results: CF contains a wide range of natural active compounds, including osthole, bergapten, imperatorin and xanthotoxin, which may underlie its beneficial effects on improving bone metabolism and quality. CF action appears to be mediated via multiple processes, including the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK), Wnt/beta-catenin and bone morphogenetic protein (BMP)/Smad signaling pathways. Conclusion: CF and its ingredients may provide novel compounds for developing anti -OP drugs.

AIMS:Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment. MATERIALS AND METHODS:C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo. RESULTS:L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway. CONCLUSION:L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment.

Introduction: Jiangtang Sanhao Formula (JTSHF), composed of Panax ginseng, Atractylodes macrocephala, Coptis chinensis, Salvia miltiorrhiza and several other herbs, is a traditional Chinese medicine formula commonly used to treat type 2 diabetes. This compound shows significant clinical efficacy in the treatment of diabetic, however, its target and pharmacological mechanism are still unclear. The present study explored the therapeutic effect of JTSHF on diabetic mice and conducted RNA sequencing to investigate the potential mechanism. Methods: The T2DM mice model was established using a high-fat diet combined with an intraperitoneal injection of low-dose STZ. Fasting blood glucose (FBG), serum insulin, glucose tolerance, and blood lipids in mice from different groups were examined. Then the effects of JTSHF on oxidative stress and liver histopathology in diabetic mice were observed. Next, transcriptome analysis was performed to identify differentially expressed genes (DEG), which were validated using real-time quantitative PCR (RT-qPCR). By using pathway enrichment analysis, we identified several key pathways which are essential in the JTSHF effect on T2DM. Finally, we constructed ceRNA network to illustrate the regulatory effect of JTSHF on transcriptional profile in diabetic liver. Results: JTSHF reduced FBG level and blood lipid contents, ameliorated glucose tolerance and improved insulin sensitivity in diabetic mice. It also showed protective effects on fatty livers induced by high-fat diet and diabetes. For the first time, we revealed that JTSHF exerts anti-T2DM role in the liver of diabetic mice, which is associated with multiple molecular targets and signaling pathways. Enrichment analysis and treatment-based mRNA-ncRNA-miRNA ceRNA networks revealed that JTSHF might exerts therapeutic effect by modulating lipid metabolism. Discussion: Our research found that JTSHF exerts anti-T2DM effect by affecting multiple pathways. Among these, lipid metabolism and oxidative stress might be involved. The present study provided novel insights for the mechanism of JTSHF, and the differentially expressed genes identified can be potential therapeutic targets in the treatment of T2DM in future.

Ethnopharmacological relevance: SiJunZi decoction (SJZD), one of the traditional Chinese medicine formulas, has been clinically and traditionally used to improve glucose and lipid metabolism and promote bone remodeling.Aim of the study: To study the actions and mechanisms of SJZD on bone remodeling in a type 2 diabetes mouse model.Materials and methods: Diabetic mice generated with a high-fat diet (HFD) and streptozotocin (STZ) were subjected to SJZD treatment for 8 weeks. Blood glucose and lipid profile, redox status and bone metabolism were determined by ELISA or biochemical assays. Bone quality was evaluated by micro-CT, three-point bending assay and Fourier transform infrared spectrum (FTIR). Bone histomorphometry alterations were evaluated by Hematoxylin-Eosin (H&E), tartrate resistant acid phosphatase (TRAP) staining and Safranin O-fast green stain-ing. The expressions of superoxide dismutase 1 (SOD1), advanced glycation end products (AGEs), receptor for advanced glycosylation end products (RAGE), phosphorylated nuclear factor kappa-B (p-NF-kappa B), NF-kappa B, cathepsin K, semaphorin 3A (Sema3A), insulin-like growth factor 1 (IGF1), p-GSK-3 beta, (p)-beta-catenin, Runt-related transcription factor 2 (Runx2) and Cyclin D1 in the femurs and/or tibias were examined by Western blot or immunohistochemical staining. The main constituents in the SJZD aqueous extract were characterized by a HPLC/MS.Results: SJZD intervention improved glucose and lipid metabolism and preserved bone quality in the diabetic mice, in particular glucose tolerance, lipid profile, bone microarchitecture, strength and material composition. SJZD administration to diabetic mice preserved redox homeostasis in serum and bone marrow, and prevented an increase in AGEs, RAGE, p-NF-kappa B/NF-kappa B, cathepsin K, p-GSK-3 beta, p-beta-catenin expressions and a decrease in Sema3A, IGF1, beta-catenin, Runx2 and Cyclin D1 expressions in tibias and/or femurs. Thirteen compounds were identified in SJZD aqueous extract, including astilbin, liquiritin apioside, ononin, ginsenoside Re, Rg1, Rb1, Rb2, Ro, Rb3, Rd, notoginsenoside R2, glycyrrhizic acid, and licoricesaponin B2.Conclusions: SJZD ameliorates bone quality in diabetic mice possibly via maintaining redox homeostasis. The mechanism governing these alterations are possibly related to effects on the AGEs/RAGE and Wnt/B-catenin signaling pathways. SJZD may offer a novel source of drug candidates for the prevention and treatment of type 2 diabetes and osteoporosis.

BACKGROUND:Type 2 diabetes is a complex metabolic disorder characterized by insulin resistance and impaired insulin secretion, with growing evidence highlighting the critical role of the gut-microbiota-brain axis in modulating glucose and lipid metabolism. OBJECTIVE:To evaluate the effects of Jiang Tang San Hao Formula (JTSHF) on blood glucose control in type 2 diabetic mouse model and to explore its mechanism through the gut- microbiota-brain axis. METHODS:A type 2 diabetes model was established using six-week-old male C57BL6/J mice, induced by a high-fat diet combined with streptozotocin injection. The diabetic mice then randomly assigned to the model group, metformin (Glucophage) group and JTSHF group, receiving 11 weeks of treatment by gavage. Body weight and fasting blood glucose were monitored biweekly. The oral glucose tolerance test was performed during the fifth and 10th weeks of the intervention. The measurements of body composition were conducted pre- and post-treatment. After the intervention, serum insulin, lipid levels, glucagon like peptide-1 (GLP-1), peptide YY, ghrelin, and leptin were detected. The fresh feces of mice were collected before sacrifice for gut microbiota analysis and short chain fatty acids quantification. The colon tissues of mice in each group were collected to observe the morphological structure and to measure the expression levels of GPR41 and GPR43. The hypothalamus was collected to assess the expression of POMC, AgRP and NPY. RESULTS:JTSHF significantly boosted sugar and lipid metabolism and contributed to weight reduction in diabetic mice (p < 0.05). At the genus level, JTSHF increased the relative abundance of Bacteroides, Prevotella, and Parabacteroides, and decreased Clostridium, Lactobacillus, and Oscillibacter in the gut microbiota. JTSHF enhanced the content of short chain fatty acids, improved the expression level of GPR43/41 in colonic tissue (p < 0.05), and increased POMC expression while decreasing AgRP and NPY expression in the hypothalamus (p < 0.05). Serum GLP-1 was increased, and ghrelin was decreased significantly after JTSHF intervention (p < 0.05). CONCLUSION:By affecting the composition, relative abundance, and metabolites of gut microbiota, JTSHF regulates various gut brain peptides, affects the hypothalamic feeding center, improves glucose and lipid metabolism, and thus plays the anti-diabetic role. The study provides novel insights into how traditional Chinese medicine modulates the gut-brain connection to exert anti-diabetic effects, highlighting the innovative potential of JTSHF in metabolic disease management.

ETHNOPHARMACOLOGICAL RELEVANCE:Simiao San (SmS), a famous traditional Chinese formula, is clinically used to treat patients with hyperuricemia (HUA). However, its mechanism of action on lowering uric acid (UA) and inhibiting inflammation still deserves further investigation. AIM OF THE STUDY:To examine the effect and its possible underlying mechanism of SmS on UA metabolism and kidney injury in HUA mouse. MATERIALS AND METHODS:The HUA mouse model was constructed with the combined administration of both potassium oxalate and hypoxanthine. The effects of SmS on UA, xanthine oxidase (XOD), creatinine (CRE), blood urea nitrogen (BUN), interleukin-10 (IL-10), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by ELISA or biochemical assays. Hematoxylin and eosin (H&E) was used to observe pathological alterations in the kidneys of HUA mice. The expression levels of organic anion transporter 1 (OAT1), recombinant urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), nucleotide binding domain and leucine rich repeat pyrin domain containing 3 (NLRP3), Cleaved-Caspase 1, apoptosis-associated speck like protein (ASC), nuclear factor kappa-B (NF-κB), IL-6, janus kinase 2 (JAK2), phosphor (P)-JAK2, signal transducers and activators of transcription 3 (STAT3), P-STAT3, suppressor of cytokine signaling 3 (SOCS3) were examined by Western blot and/or immunohistochemical (IHC) staining. The major ingredients in SmS were identified by a HPLC-MS assay. RESULTS:HUA mouse exhibited an elevation in serum levels of UA, BUN, CRE, XOD, and the ratio of urinary albumin to creatinine (UACR), and a decline in urine levels of UA and CRE. In addition, HUA induces pro-inflammatory microenvironment in mouse, including an increase in serum levels of IL-1β, IL-6, and TNF-α, and renal expressions of URAT1, GULT9, NLRP3, ASC, Cleaved-Caspase1, P-JAK2/JAK2, P-STAT3/STAT3, and SOCS3, and a decrease in serum IL-10 level and renal OAT1 expression as well as a disorganization of kidney pathological microstructure. In contrast, SmS intervention reversed these alterations in HUA mouse. CONCLUSION:SmS could alleviate hyperuricemia and renal inflammation in HUA mouse. The action mechanisms behind these alterations may be associated with a limitation of the NLRP3 inflammasome and JAK2/STAT3 signaling pathways.

Ethnopharmacological relevance: SiJunZi decoction (SJZD), one of the traditional Chinese medicine formulas, has been clinically and traditionally used to improve glucose and lipid metabolism and promote bone remodeling.Aim of the study: To study actions and mechanisms of SJZD on bone remodeling in type 2 diabetic mice.Materials and Methods: Type 2 diabetic mouse was established with a high-fat diet (HFD) and streptozotocin (STZ), and subjected to SJZD treatment for 8 weeks. Blood glucose and lipid profiles, redox status and bone metabolism were determined by ELISA or biochemical assays. Bone quality was evaluated by micro-CT, three-point bending assay and Fourier transform infrared spectrum (FTIR). Bone histomorphometric alterations were evaluated by Hematoxylin-Eosin (H&E), tartrate resistant acid phosphatase (TRAP) staining and Safranin O-fast green staining. The expressions of superoxide dismutase 1 (SOD1), advanced glycation end products (AGEs), receptor for advanced glycosylation end products (RAGE), phosphorylated nuclear factor kappa-B (p-NF-κB), NF-κB, cathepsin K, semaphorin 3A (Sema3A), insulin-like growth factor 1 (IGF1), β-catenin, Runt-related transcription factor 2 (Runx2) in the femurs and/or tibias were examined by western blot or immunohistochemical staining. The main constituents in SJZD aqueous extract were characterized by a HPLC/MS.Results: SJZD intervention improved glucose and lipid metabolism and preserved bone quality in diabetic mice, including glucose tolerance, lipid profiles, bone microarchitectures, strength and material composition. In addition, the administration of SJZD to diabetic mice preserved redox homeostasis in serum and bone marrow, and prevented an increase in AGEs, RAGE, p-NF-κB/NF-κB, cathepsin K, p-β-catenin expressions and a decrease in Sema3A, IGF1, β-catenin and Runx2 expressions in tibias and/or femurs. Thirteen compounds were identified in SJZD, including astilbin, liquiritin apioside, ononin, ginsenoside Re, Rg1, Rb1, Rb2, Ro, Rb3, Rd, notoginsenoside R2, glycyrrhizic acid, and licoricesaponin B2.Conclusions: SJZD ameliorates bone quality possibly via maintaining redox homeostasis in diabetic mice. The mechanism governing these alterations may be related to regulation of the AGEs/RAGE and Wnt/β-catenin signaling pathways. SJZD may offer a novel source of drug candidates for preventing the development of diabetes and its associated-osteoporosis.

MicroRNAs (miRNAs) and transfer RNA-derived small RNAs (tsRNAs) play critical roles in the regulation of different biological processes, but their underlying mechanisms in diabetes mellitus (DM) are still largely unknown. This study aimed to gain a better understanding of the functions of miRNAs and tsRNAs in the pathogenesis of DM. A high-fat diet (HFD) and streptozocin (STZ)-induced DM rat model was established. Pancreatic tissues were obtained for subsequent studies. The miRNA and tsRNA expression profiles in the DM and control groups were obtained by RNA sequencing and validated with quantitative reverse transcription-PCR (qRT-PCR). Subsequently, bioinformatics methods were used to predict target genes and the biological functions of differentially expressed miRNAs and tsRNAs. We identified 17 miRNAs and 28 tsRNAs that were significantly differentiated between the DM and control group. Subsequently, target genes were predicted for these altered miRNAs and tsRNAs, including Nalcn, Lpin2 and E2f3. These target genes were significantly enriched in localization as well as intracellular and protein binding. In addition, the results of KEGG analysis showed that the target genes were significantly enriched in the Wnt signaling pathway, insulin pathway, MAPK signaling pathway and Hippo signaling pathway. This study revealed the expression profiles of miRNAs and tsRNAs in the pancreas of a DM rat model using small RNA-Seq and predicted the target genes and associated pathways using bioinformatics analysis. Our findings provide a novel aspect in understanding the mechanisms of DM and identify potential targets for the diagnosis and treatment of DM.

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