The role of advanced glycation end products in fracture risk assessment in postmenopausal type 2 diabetic patients.

Objective: The objective of this study was to analyze the quantitative association between advanced glycation end products (AGEs) and adjusted FRAX by rheumatoid arthritis (FRAX-RA) in postmenopausal type 2 diabetic (T2D) patients. The optimal cutoff value of AGEs was also explored, which was aimed at demonstrating the potential value of AGEs on evaluating osteoporotic fracture risk in postmenopausal T2D patients. Methods: We conducted a cross-sectional study including 366 postmenopausal participants (180 T2D patients [DM group] and 186 non-T2D individuals [NDM group]). All the subjects in each group were divided into three subgroups according to BMD. Physical examination, dual-energy x-ray absorptiometry (DXA), and serum indicators (including serum AGEs, glycemic parameters, bone turnover markers and inflammation factors) were examined. The relationship between FRAX-RA, serum laboratory variables, and AGEs were explored. The optimal cutoff value of AGEs to predict the risk of osteoporotic fracture was also investigated. Results: Adjusting the FRAX values with rheumatoid arthritis (RA) of T2D patients reached a significantly increased MOF-RA and an increasing trend of HF-RA. AGEs level was higher in the DM group compared to the NDMs, and was positively correlated with MOF-RA (r=0.682, P<0.001) and HF-RA (r=0.677, P<0.001). The receiver operating characteristic curve analysis revealed that the area under the curve was 0.804 (P<0.001), and the optimal AGEs cut-off value was 4.156mmol/L. Subgroup analysis for T2D patients revealed an increase in TGF-ß, IL-6 and SCTX in the osteoporosis group, while a decreased PINP in the osteoporosis group compared to the other two subgroups. AGEs were positively associated with FBG, HbA1c, HOMA-IR, S-CTX, IL-6 and TGF-ß in T2D patients, and negatively associated with PINP. Conclusions: RA-adjusted FRAX is a relevant clinical tool in evaluating fracture risk of postmenopausal T2D patients. Our study analyzed the relationship between AGEs and FRAX-RA, and explored the threshold value of AGEs for predicting fracture risk in postmenopausal T2D patients. AGEs were also associated with serum bone turnover markers and inflammation factors, indicating that the increasing level of AGEs in postmenopausal T2D patients accelerated the expression of inflammatory factors, which led to bone metabolism disorders and a higher risk of osteoporotic fractures.

Astragaloside IV improved antioxidative stress capacity and related gene expression of the Keap1-Nrf2 pathway in grass carp (Ctenopharyngodon idella) hepatocytes under heat stress.

This study aims to investigate the protective effects of astragaloside IV (AS-IV) on the hepatocytes of grass carp (Ctenopharyngodon idella) on heat stress. Cultured cells were treated with AS-IV (0, 50, 100 and 200 µg/ml) at 28°C for 24 h and then exposed to heat stress by increasing the culturing temperature (32 ± 0.5°C) for 6 h. The increased temperatures significantly reduced cell viability and superoxide dismutase (SOD) activity, and increased malondialdehyde (MDA) levels in the 0 µg/ml AS-IV treatment group at 32°C, but the grass carp hepatocytes treated with 100 and 200 µg/ml AS-IV had significantly increased cell viability and SOD activity and decreased MDA levels. The mRNA levels of keap1a, keap1b, nrf2, gsh-px, cat, cu-zn sod, mgst1 and il-6 were significantly lower in the 0 µg/ml AS-IV treatment group at 32°C, while those of keap1a, nrf2, gsh-px, cat, cu-zn sod, gstp1, ho-1 and il-6 were significantly higher in cells treated with 100 or 200 µg/ml AS-IV. Our findings indicate that AS-IV could enhance the antioxidative stress capacity of grass carp hepatocytes under heat stress, and its mechanism may be associated with the activation of the Keap1-Nrf2 pathway. Thus, these results provide new insights into how to alleviate heat stress in grass carp.

Betulin Targets Lipin1/2-Meidated P2X7 Receptor as a Therapeutic Approach to Attenuate Lipid Accumulation and Metaflammation.

The present study focused on the potential mechanism of betulin (BT), a pentacyclic triterpenoid isolated from the bark of white birch (Betula pubescens), against chronic alcohol-induced lipid accumulation and metaflammation. AML-12 and RAW 264.7 cells were administered ethanol (EtOH), lipopolysaccharide (LPS) or BT. Male C57BL/6 mice were fed Lieber-DeCarli liquid diets containing 5% EtOH for 4 weeks, followed by single EtOH gavage on the last day and simultaneous treatment with BT (20 or 50 mg/kg) by oral gavage once per day. In vitro, MTT showed that 0-25 mM EtOH and 0-25 µM BT had no toxic effect on AML-12 cells. BT could regulate sterolregulatory-element-binding protein 1 (SREBP1), lipin1/2, P2X7 receptor (P2X7r) and NOD-like receptor family, pyrin domains-containing protein 3 (NLRP3) expressions again EtOH-stimulation. Oil Red O staining also indicated that BT significantly reduced lipid accumulation in EtOH-stimulated AML-12 cells. Lipin1/2 deficiency indicated that BT might mediate lipin1/2 to regulate SREBP1 and P2X7r expression and further alleviate lipid accumulation and inflammation. In vivo, BT significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and triglyceride (TG) levels, and regulated lipin1/2, SREBP1, peroxisome proliferator activated receptor α/γ (PPARα/γ) and PGC-1α expression compared with the EtOH group. BT reduced the secretion of inflammatory factors and blocked the P2X7r-NLRP3 signaling pathway. Collectively, BT attenuated lipid accumulation and metaflammation by regulating the lipin1/2-mediated P2X7r signaling pathway.

Allium victorialis L. Extracts Promote Activity of FXR to Ameliorate Alcoholic Liver Disease: Targeting Liver Lipid Deposition and Inflammation.

Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber-DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro, AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.

BMSC-Derived Exosomes Inhibit Dexamethasone-Induced Muscle Atrophy via the miR-486-5p/FoxO1 Axis.

Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging, injury, hormone imbalance and other catabolic conditions. Recently, exosomes were considered to regulate muscle regeneration and protein synthesis. In order to confirm the effect of BMSC-derived exosomes (BMSC-Exos) on muscle, dexamethasone-induced muscle atrophy was built both in vitro and in vivo. In the present research, BMSC-Exos attenuated the decrease of myotube diameter induced by dexamethasone, indicating that BMSC-Exos played a protective role in skeletal muscle atrophy. Further mechanism analysis exhibited that the content of miR-486-5p in C2C12 myotubes was up-regulated after treated with BMSC-Exos. Meanwhile, BMSC-Exos markedly downregulated the nuclear translocation of FoxO1, which plays an important role in muscle differentiation and atrophy. Importantly, the miR-486-5p inhibitor reversed the decreased expression of FoxO1 induced by BMSC-Exos. In animal experiments, BMSC-Exos inhibited dexamethasone-induced muscle atrophy, and miR-486-5p inhibitor reversed the protective effect of BMSC-Exos. These results indicating that BMSC-derived exosomes inhibit dexamethasone-induced muscle atrophy via miR486-5p/Foxo1 Axis.

Association of the polymorphisms in FOXO1 gene and diabetic nephropathy risk.

PURPOSE: This study was aimed to study the hypothesis that forkhead box O1 (FOXO1) gene rs17446614 and rs17592236 single nucleotide polymorphisms (SNPs) influenced the development of diabetic nephropathy (DN). METHODS: This study included 138 DN patients and 149 healthy controls. Controls were matched with the patients in age and gender. The method of polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) was used to detect FOXO1 gene polymorphisms. Haploview software was conducted to analyze the linkage disequilibrium and haplotypes of FOXO1 gene polymorphisms. Relative risk of DN was expressed by odds ratios (ORs) and 95% confidence intervals (95% CIs), then the results were adjusted by clinical characteristics of the study subjects using logistic regression analysis. Subgroup analysis was performed according to gender. RESULTS: AA genotype of rs17446614 SNPs was significantly associated with the risk of DN (P = .037, adjusted OR = 5.412, 95% CI = 1.103-26.559), especially in female (OR = 8.700, 95% CI = 1.008-75.062, P = .021). FOXO1 rs17446614 A allele positively associated with the development of DN (P = .027, adjusted OR = 1.680, 95% CI = 1.060-2.662), particularly in women (OR = 2.003, 95% CI = 1.070-3.749, P = .028). A-C haplotype formed by FOXO1 gene rs17446614 and rs17592236 SNPs was significantly associated with the increased risk of DN (P = .011, OR = 1.850, 95% CI = 1.146-2.986). CONCLUSION: FOXO1 gene rs17446614 SNP, and the A-C haplotype of rs17446614 and rs17592236 polymorphisms were risk factors for the development of DN.

IRS-1 targets TAZ to inhibit adipogenesis of rat bone marrow mesenchymal stem cells through PI3K-Akt and MEK-ERK pathways.

Gene modification of mesenchymal stem cells (MSCs) offers a promising approach for clinical stem cell therapy. Transcriptional co-activator with PDZ-binding motif (TAZ) plays a vital role in MSCs' differentiation. We aim to explore the interaction of insulin receptor substrate-1 (IRS-1) with TAZ to regulate MSCs' adipogenesis in this study. Initially, IRS-1 and TAZ followed similar decreasing expression pattern at the early stage of adipogenesis. And, overexpression of IRS-1 decreased the CCAAT/enhancer binding protein ß (C/EBPß) and peroxi-some proliferator-activated receptor gamma (PPARγ) expression with TAZ upregulation. Accordingly, knockdown of IRS-1 induced the upexpression of C/EBPß and PPARγ with TAZ downregulation. Indeed, IRS-1 targeted TAZ to downregulate the C/EBPß and PPARγ expression, while knockdown of TAZ attenuated the IRS-1 inhibited adipogenesis. Furthermore, both LY294002 (the PI3K-Akt inhibitor) and U0126 (the MEK-ERK inhibitor) blocked the regulation of IRS-1 on TAZ during adipogenesis. Additionally, IRS-1 and TAZ influenced the cell proliferation in the above process. Taken together, this study suggests for the first time that IRS-1 is a key regulator of the MSCs' adipogenesis and may serve as a potential therapeutic target for differential alterations in bone marrow.