BACKGROUND:Osteogenesis and angiogenesis are closely coupled during bone modeling and remodeling, providing a potential direction for treating osteoporosis. Salvia miltiorrhiza Bunge (SM) has been preclinically and clinically used to treat skeletal and cardiovascular diseases in traditional Chinese medicine, but its mechanisms in bone formation and vascularization remain poorly understood. PURPOSE:To elucidate the actions and mechanisms of SM against osteoporosis. METHODS:Osteoporotic mice established by bilateral ovariectomy were orally administered SM aqueous extracts for 14 weeks. Bone quality was evaluated by micro-CT, histomorphometry, and three-point bending assay. Immunofluorescence staining was performed to quantify the proportions of type H vessels (CD31hiEMCNhi) in the femurs. In vitro, SM medicated serum was applied to MC3T3-E1 preosteoblasts and EA.hy926 endothelial cells to evaluate osteogenic and angiogenic capacities. Mechanistic studies involved HIF-1α inhibition and Slit3 knockdown in both cell lines. Moreover, the ingredients of SM aqueous extracts and SM medicated serum were characterized by an UPLC-MS/MS. RESULTS:SM treatment improved bone mass and strength, promoted bone formation and type H vessels formation, and upregulated the expressions of HIF-1α, VEGF and Slit3 in the bones of ovariectomized mice. In vitro, SM enhanced osteogenic and angiogenic activities in MC3T3-E1 and EA.hy926 cells. These actions were dependent on HIF-1α/VEGF and Slit3 pathways, as their inhibition abolished the beneficial outcomes. Additionally, salvianolic acid B (Sal B) was identified as a key bioactive component contributing to these processes. CONCLUSION:SM improves bone quality in osteoporosis by concurrently stimulating osteogenesis and angiogenesis through the HIF-1α/VEGF and Slit3 signaling pathways. These results provide a mechanistic basis for the application of SM in osteoporosis treatment and highlight its potential as a multi-target therapy.

Osteoporosis is becoming one of the major global health concerns with accelerating of the aging population and there is an urgent need for novel countermeasures. Salidroside (SAL) and Apigenin (AP) are compounds identified in Ligustri Lucidi Fructus (LLF), a dietary herb that has historically been used and is currently used in osteoporosis management. However, their effects on bone loss remain largely unexplored. To this end, ovariectomized (OVX) mice and osteoclasts differentiated from RAW 264.7 were used to establish the osteoporotic model in vivo and in vitro. We found that SAL and AP treatments reduce the numbers of TRAP-positive cells, F-actin rings and bone resorption pits, and suppress the expression levels of c-Fos, Nfatc1 and Ctsk in osteoclasts. In addition, SAL and AP can improve bone quality and decrease serum levels of CTX-1 and TRAP-5b in OVX mice. These compounds further increase the expression levels of Sema3A, Nrp1 and PlexinA1 in osteoclasts and osteoporotic animals. In conclusion, SAL and AP limit osteoclastic bone resorption to ameliorate bone quality via upregulation of the Sema3A/Nrp1/PlexinA1 signaling pathway, providing a novel strategy for osteoporosis management.

Sepsis is a systemic inflammatory response syndrome caused by pathogenic microorganisms such as bacteria, fungi, viruses, and parasites invading the body. It is primarily characterized by an immune dysregulation in response to infection, leading to severe complications such as dysfunction of vital organs, shock, and disseminated intravascular coagulation (DIC), thereby threatening the patient's life. Additionally, approximately 3 million surviving patients suffer from cognitive impairment, severely affecting their quality of life. Curcumin, a monomer of traditional Chinese medicine, has extensive pharmacological activity. Numerous studies have shown that curcumin can counteract the inflammatory response in sepsis and protect against organ damage caused by sepsis, suggesting that curcumin may become a new direction for sepsis treatment. In this review, we summarize the therapeutic effects and detailed mechanisms of curcumin in the treatment of sepsis based on current research.

ETHNOPHARMACOLOGICAL RELEVANCE:Sijunzi decoction (SJZD), a traditional Chinese medicinal formula with the functions of invigorating the Spleen and replenishing Qi, has been clinically used for the management of diabetes, but its actions and underlying mechanisms on diabetic lipid metabolism remain largely unknown. AIM OF THE STUDY:To explore the effects of SJZD on lipid metabolism disorders and its association with the Wnt/β-catenin pathway in the white adipose tissue of diabetic mice and 3T3-L1 cells. MATERIALS AND METHODS:The diabetic lipid metabolism disorders models were established by high-fat diet/streptozotocin in mice and palmitic acid in 3T3-L1 cells, respectively. The effects of SJZD on total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and glucose consumption were determined by biochemical assay. Hematoxylin-eosin (H&E) staining was used to examine pathological alterations in adipose tissues. Oil red O staining was used to evaluate the differentiation of lipid droplets in 3T3-L1 adipocytes. The expression levels of Wnt10b, β-catenin, CCAAT enhancer binding protein α (C/EBP-α), sterol regulatory element-binding protein 1 (SREBP-1c), acetyl-CoA carboxylase-1 (ACC1), peroxisome proliferator-activated receptor γ (PPAR-γ), fatty acid synthase (FASN), adipose triglyceride lipase (ATGL) were examined by Western blot and/or qRT-PCR. In addition, the main components of SJZD and SJZD-containing serum (SCS) were identified by UPLC-Q-TOF-MS/MS. RESULTS:SJZD reduces the body fat ratio, fasting blood glucose levels, adipose tissue index and serum levels of TC, TG, and LDL, and increases the body weight, lean ratio, and serum HDL levels, as well as prevents the adipocytes hypertrophy in diabetic mice. In addition, SJZD, SCS and its ingredients (Ginsenoside Rb1 and Glycyrrhetinic acid) inhibit lipid synthesis, TG levels and promote glucose consumption in diabetic mice and 3T3-L1 adipocytes. These interventions decrease the expressions of PPAR-γ, SREBP-1c, C/EBP-α, FASN, ACC1 and P-β-catenin, and increase the expressions of ATGL, Wnt10b and β-catenin. CONCLUSION:SJZD regulates the Wnt/β-catenin signaling pathway to preserve lipid metabolism homeostasis in diabetes. GRb and Gac may constitute the material basis of SJZD in attenuation of diabetic lipid metabolism disorders. These findings highlight a novel strategy for the treatment of diabetes.

Myosin Light Chain Kinase (MLCK) represents a synthetic lethal interaction with the "undruggable" oncoprotein MYC. In this study, we identified Ginsenoside F2 (GF2) as a novel MLCK inhibitor through molecular dockingbased virtual screening of a natural compound library, followed by in vitro cellular validation. GF2 treatment inhibited MLCK kinase activity, as demonstrated by the reduced phosphorylation of its substrate, myosin II regulatory light chain (MLC). The direct binding of GF2 to MLCK was confirmed using the cellular thermal shift assay (CETSA), which revealed decreased MLCK thermotolerance after GF2 treatment. Notably, GF2 selectively induced apoptosis in MYC-transformed cells while sparing normal counterparts. Triple-negative breast cancer (TNBC) and pancreatic cancer cells with high MYC expression are sensitive to GF2 treatment. Moreover, combining GF2 with the Bcl2 inhibitor venetoclax synergistically enhanced apoptosis in MYC-driven cancer cells. These findings establish GF2 as a novel MLCK inhibitor and underscore the therapeutic potential of targeting MLCK in MYC-driven malignancies, particularly TNBC and pancreatic cancer.

BACKGROUND:Diabetic cardiomyopathy (DCM) causes a high risk of heart failure, necessitating effective therapies. The Si-Miao-Yong-An decoction (SMYAD) has been widely applied in the clinical management of diabetes mellitus and cardiovascular diseases within the paradigm of traditional Chinese medicine (TCM), but its active constituents and mechanism of the action against DCM are poorly understood. PURPOSE:The aim of this study was to evaluate the effects of chlorogenic acid (CGA) and ferulic acid (FA), the main active ingredients of SMYAD, on cardiac function and cardiac lipotoxicity in mice with DCM, as well as to investigate their potential molecular mechanisms. METHODS:The cardioprotective effects of CGA and FA on DCM mice were identified by echocardiography, HE, Masson, and Oil Red O. Immunofluorescence, flow cytometry, MitoTracker Green staining, and seahorse analysis were used to study the effects of CGA and FA on palmitic acid (PA)-induced lipotoxicity in cardiomyocytes. Finally, the regulatory effects of CGA and FA on GCGR/PPARα and GCGR/AMPK signalling pathways were detected by Ad GCGR-infection, molecular docking, RT-PCR and western blot. RESULTS:Based on previously identified 20 representative blood prototype components and in vitro multilayer lipid toxicity analysis, chlorogenic acid (CGA) and ferulic acid (FA) were screened as the main active components of SMYAD against DCM. In vivo experiments showed that CGA and FA attenuated lipotoxicity associated with cardiac GLC/GCGR in DCM mice, thereby protecting cardiac function. In vitro results showed that GCGR inhibitor (Adomeglivant) reduces PA-induced apoptosis, indicating that PA leads to cardiomyocyte lipotoxic apoptosis by activating GCGR. Moreover, CGA and FA inhibit PA-induced cardiomyocyte lipotoxic apoptosis, mitochondrial dysfunction, and energy substrate transition through inhibiting GCGR/PPARα and GCGR/AMPK pathways. Furthermore, GLC-stimulated/GCGR-infected H9c2 cardiomyocyte lipotoxic apoptosis and downstream proteins were effectively suppressed by CGA and FA, which is consistent with the effect of Adomeglivant. Docking results showed that ASP1018 and THR1024 of GCGR are the principal molecular targets for both CGA and FA. CONCLUSION:GLC lipotoxic signaling is a crucial target in mediating cardiac lipotoxicity development. CGA and FA could inhibit DCM by regulating the GCGR/PPARα and GCGR/AMPK pathway, offering a novel strategy for the development of anti-DCM drugs.

Osteoporosis (OP) is a prevalent chronic bone disorder that causes reduction of bone mass, deterioration of bone microarchitecture, and increase of fragility and fracture risk. Current therapeutic strategies mainly alleviate these pathological features but often fail to fully restore bone quality. Extracellular vesicles (EVs) are nanoscale mediators of intercellular communication and have recently emerged as groundbreaking candidates for restoring bone homeostasis. This review systematically explores the multifaceted potential of EVs as therapeutics, diagnostic biomarkers, and drug delivery systems for OP. EVs from diverse biological sources (e.g., mammals, plants, and microbial species) are critically evaluated as innovative modulators of bone metabolism. EVs carry dynamic biomarkers of OP progression which not only possess diagnostic value but also provide novel insights into disease mechanisms. Moreover, EVs could be further bioengineered for bone-targeted drug delivery. Indeed, preclinical studies validate the transformative potential of EVs, although challenges remain in clinical translation. We report current advancements, identify translational barriers, and emphasize the need for interdisciplinary collaboration to accelerate the transition from basic research to clinical applications.

Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, ABHD6 mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and db/db mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity per se. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.

Semaphorin 3A (Sema3A) is a signaling protein that has attracted increasing attention in recent years for its important role in regulating bone metabolism. In this review, we searched different databases with various combinations of keywords to analyze the effects of Sema3A on osteoporosis. Sema3A promotes bone formation and inhibits bone resorption by directly affecting the osteoblast and osteoclast or indirectly targeting the nervous system. The sympathetic nervous system may be the main link between the central nervous system and bone metabolism for Sema3A. In the peripheral nervous system, Sema3A may improve bone quality via sensory nervous innervation. In addition, estrogen is found to regulate Sema3A levels to improve bone homeostasis. Lots of Sema3A agonists have been documented to exhibit anti-osteoporotic potential in preclinical investigations. Therefore, Sema3A can be considered a novel therapeutic target for preserving bone mass, highlighting an alternative strategy for the development of anti-osteoporosis drugs.

Ethnopharmacological relevance: Fuling-Zexie (FZ) formula, a traditional Chinese herbal prescription composed of Poria cocos (Schwan.) Wolf. (Poria), Pueraria lobate (Willd.) Howe. (Puerariae Lobatae Radix), Alisma orientale (Sam.) Julep. (Alismatis Rhizoma), and Atractylodes lancea (Thunb.) Dc. (Atractylodis Rhizoma), has been clinically used to ameliorate hyperuricemia (HUA) and its associated renal injury. Aim of study: This study aims to explore the action and mechanism of FZ on renal inflammation and dysfunction caused by HUA. Materials and methods: FZ was orally administered to rapid HUA mouse induced by potassium oxonate (PO) and hypoxanthine (HX) for 7 days. Serum levels of uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), xanthine oxidase (XOD), adenosine deaminase (ADA), alanine aminotransferase (ALT), aspartate aminotrans-ferase (AST), urine levels of UA, CRE and urinary albumin were determined by biochemical assays. Serum levels of interleukin (IL)-1 beta and IL-6 were tested by ELISA. Hematoxylin-eosin and Masson staining were used to examine kidney and liver histopathological alterations. The expressions of renal glucose transporter 9 (GLUT9), ATP-binding cassette subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), phospho-janus kinase 2 (p-JAK2), p-signal transducer and activator of transcription 3 (p-STAT3), suppression of cytokine signaling 3 (SOCS3), NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cleaved-cysteinyl aspartate specific proteinase-1 (cleaved-Cas-1) were detected by western blots. The potential protein targets and pathways of FZ intervention on HUA were predicted by network pharmacology. The con-stituents in FZ aqueous extract were analyzed by UPLC-MS. Results: FZ reduced serum UA, CRE, BUN, and urinary albumin and increased urine UA, CRE levels in HUA mice. In addition, the treatment with FZ to HUA mice inhibited the elevated serum levels of XOD and ADA, and regulated renal urate transports including OAT1, GLUT9 and ABCG2. FZ also attenuated kidney inflammation and fibrosis and downregulated the expressions of IL-1 beta, p-JAK2, p-STAT3, SOCS3, IL-6, NLRP3, ASC, and cleaved-Cas-1. Thirteen compounds were identified in the FG, including L-phenylalanine, D-tryptophan, 3 '- hydroxypuerarin, Puerarin, 3 '-Methoxy Puerarin, Daidzin, Pueroside A, formononetin-8-C-[xylosyl (1 -> 6)]-glucoside, Ononin, Alisol I 23-acetate, 16-oxo-alisol A, Alisol C and Alisol A.Conclusion: FZ inhibits serum UA generation and promotes urine UA excretion as well as attenuates kidney inflammation and fibrosis in HUA mouse with nephropathy. The underlying mechanism of its action may be associated with suppression of the JAK2/STAT3 signaling pathway and NLRP3 inflammasome activation. This formula may offer a novel source for developing anti-HUA drugs.

The increasing incidence of cancer-related deaths highlights the pressing need for effective treatment modalities, particularly in the context of digestive tract cancers, such as gastric, hepatic, esophageal, intestinal, and pancreatic tumors. While conventional drug therapies play a critical role in managing these malignancies, their associated side effects often pose significant challenges to patient quality of life. Thus, there is a growing focus on traditional Chinese medicine (TCM) and its compounds, which are safe, non-toxic, and reliable. During anti-tumor therapy, TCM compounds, based on their multi-target, multi-pathway, and multi-level regulatory effects, fully mobilize multiple mechanisms of the body, presenting significant advantages in inhibiting tumor development, boosting patient welfare, and increasing their lifespan. This article reviews the mechanisms by which TCM inhibits tumor cell proliferation, promotes tumor cell death, suppresses tumor cell invasion and metastasis, regulates the tumor microenvironment, inhibits angiogenesis, and enhances anti-tumor drug resistance. This knowledge might provide a theoretical and scientific basis for preventing and treating tumors using TCM.

Osteoporosis becomes a global public health concern due to its rising prevalence and substantial impact on life quality. Salvia miltiorrhiza Bunge (Salviae Miltiorrhizae Radix et Rhizoma, SM) has been firstly recorded in Shen Nong’s Herbal Classic, and is frequently prescribed in conjunction with other herbs for the management of osteoporosis. This systematic review aims to comprehensively analyze the recent advances of SM on osteoporosis in traditional Chinese clinical uses and preclinical investigations. Literature encompassing pertinent studies were systematically retrieved across multiple databases, including the PubMed, Web of Science, Chinese National Knowledge Infrastructure, Chinese VIP Database, and Chinese Biomedical Literature Database. Original investigations spanning from February 2014 to March 2024, including traditional Chinese medicine (TCM) clinical trials and preclinical studies, were employed to analyze the effects and actions of SM on osteoporosis. Thirty-eight TCM clinical trials were identified to employ SM in combination with other herbs for the management of primary and secondary osteoporosis. The overall efficacy was between 77% and 96.67%. Forty preclinical studies were identified to investigate the effects and actions of SM and/or its ingredients on osteoporosis. The anti-osteoporosis actions of this herb may be attributed to inhibit osteoclastogenesis/bone resorption and promote osteoblastogenesis/osteogenesis. The ethanol extracts and its ingredients (tanshinones) inhibit osteoclastogenesis/bone resorption by inhibiting the MAPK/NF-κB/NFATc1 signaling pathway and cathepsin K-induced collagen degradation. Both ethanol extracts (tanshinones) and water extracts (Sal B and tanshinol) contribute to osteoblastogenesis by promoting osteogenesis and angiogenesis via activation of the Wnt/β-catenin/VEGF and ERK/TAZ pathways, and eliminating ROS production targeting Nrf2/ARE/HO-1 pathway. In conclusions, SM may offer a novel strategy for osteoporosis management. Well-designed clinical trials are still needed to evaluate the actions of this herb and its ingredients on bone remodeling.

Recent interest in preventing the development of osteoporosis has focused on the regulation of redox homeostasis. However, the action of lycopene (LYC), a strong natural antioxidant com-pound, on osteoporotic bone loss remains largely unknown. Here, we show that the administra-tion of LYC to OVX rats reduces body weight gain, improves lipid metabolism and preserves bone quality. In addition, LYC treatment inhibits ROS overgeneration in serum and bone marrow in OVX rats, and in BMSCs upon H2O2 stimulation, leading to inhibiting adipogenesis and pro-moting osteogenesis during bone remodeling. Mechanically, LYC may improve bone quality via an increase in the expressions of FoxO1 and Runx2, and a decrease in the expressions of PPARγ and C/EBPα in OVX rats and BMSCs. Collectively, these findings suggest that LYC attenuates osteoporotic bone loss through promoting osteogenesis and inhibiting adipogenesis via regula-tion of the FoxO1/PPARγ pathway driven by oxidative stress, presenting a novel strategy for os-teoporosis management.

Recent interest in preventing the development of osteoporosis has focused on the regulation of redox homeostasis. However, the action of lycopene (LYC), a strong natural antioxidant compound, on osteoporotic bone loss remains largely unknown. Here, we show that oral administration of LYC to OVX rats for 12 weeks reduced body weight gain, improved lipid metabolism, and preserved bone quality. In addition, LYC treatment inhibited ROS overgeneration in serum and bone marrow in OVX rats, and in BMSCs upon H2O2 stimulation, leading to inhibiting adipogenesis and promoting osteogenesis during bone remodeling. At the molecular level, LYC improved bone quality via an increase in the expressions of FoxO1 and Runx2 and a decrease in the expressions of PPARγ and C/EBPα in OVX rats and BMSCs. Collectively, these findings suggest that LYC attenuates osteoporotic bone loss through promoting osteogenesis and inhibiting adipogenesis via regulation of the FoxO1/PPARγ pathway driven by oxidative stress, presenting a novel strategy for osteoporosis management.

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.

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.

Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp ), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans . However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

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.