Molecular mechanism of resveratrol promoting differentiation of preosteoblastic MC3T3-E1 cells based on network pharmacology and experimental validation.

The purpose of this study was to investigate the mechanism by which resveratrol (Res) inhibits apoptosis and promotes proliferation and differentiation of pre-osteoblastic MC3T3-E1 cells, laying the groundwork for the treatment of osteoporosis (OP). The TCMSP database was used to find the gene targets for Res. The GeneCards database acquire the gene targets for OP. After discovering the potential target genes, GO, KEGG, and Reactome enrichment analysis were conducted. Verifying the major proteins involved in apoptosis can bind to Res using molecular docking. CCK8 measured the proliferative activity of mouse pre-osteoblasts in every group following Res intervention. Alkaline phosphatase staining (ALP) and alizarin red staining to measure the ability of osteogenic differentiation. RT-qPCR to determine the expression levels of Runx2 and OPG genes for osteogenic differentiation ability of cells. Western blot to measure the degree of apoptosis-related protein activity in each group following Res intervention. The biological processes investigated for GO of Res therapeutic OP involved in cytokine-mediated signaling pathway, negative regulation of apoptotic process, Aging, extrinsic apoptotic signaling pathway in absence of ligand, according to potential therapeutic target enrichment study. Apoptosis, FoxO signaling pathway, and TNF signaling pathway are the primary KEGG signaling pathways. Recactome pathways are primarily engaged in Programmed Cell Death, Apoptosis, Intrinsic Apoptotic Pathway, and Caspase activation via extrinsic apoptotic signaling pathways. This research established a new approach for Res treatment of OP by demonstrating how Res controls the apoptosis-related proteins TNF, IL6, and CASP3 to suppress osteoblast death and increase osteoclastogenesis.

GDF11 protects against glucotoxicity-induced mice retinal microvascular endothelial cell dysfunction and diabetic retinopathy disease.

Growth differentiation factor 11 (GDF11) has been implicated in the regulation of embryonic development and age-related dysfunction, including the regulation of retinal progenitor cells. However, little is known about the functions of GDF11 in diabetic retinopathy. In this study, we demonstrated that GDF11 treatment improved diabetes-induced retinal cell death, capillary degeneration, pericyte loss, inflammation, and blood-retinal barrier breakdown in mice. Treatment of isolated mouse retinal microvascular endothelial cells with recombinant GDF11 in vitro attenuated glucotoxicity-induced retinal endothelial apoptosis and the inflammatory response. The protective mechanisms exerted are associated with TGF-ß/Smad2, PI3k-Akt-FoxO1 activation，and NF-κB pathway inhibition. This study indicated that GDF11 is a novel therapeutic target for diabetic retinopathy.

Effect of Type-2 Diabetes Mellitus in Retinopathy Patients on MDA, SOD Activity and its Correlation with HbA1c

Abstract Diabetic retinopathy (DR) is a metabolic disorder of the retina and one of the common problems of Type-2 diabetes mellitus (T-2DM) causing visual loss even at teen ages. In this research article, oxidative stress was the main cause due to reactive oxygen species (ROS) generation at hyperglycemic state and become as the focus point of this study to describe (DR) complication onset. The present study was conducted to compare three groups: T-2DM with complication, T-2DM without complication and control group. For this purpose, number of the individuals participating in this study were n=110 as subject along with T-2DM patients with complication n=50, T-2DM patients without complication n=50 and rest n=10 are taken as control/ normoglycemic individuals. T-2DM patients with/without complication have TAG level is lower than normoglycemic/ control. An observed value of (HbA1c%) glycosylated or glycated hemoglobin type A1c concentration of T2DM with complication group was highest (9.63%) amongst the examined groups. T-2DM with complication has lowest SOD activity (660.96 U/gHb) but the malondialdehyde (MDA) level was found to be higher (5.96 µmol/L) amongst studied groups. Lowest plasma TAG, and higher plasma MDA level indicate the presence of oxidative stress in T2D with/without complications. SOD activity was decreased due to the protein glycation and the surplus level of lipid detoxification especially found in T-2DM cases. Good glycemic control counteracts the response of Lipid peroxidation usually occurs in hyperglycemic state.

An Exceptional Avulsion Fracture Above the Medial Malleolus: A Retrospective Case Series.

The Lauge-Hansen classification does not cover all types of ankle injuries. The present report details three cases of exceptional fragment of the medial tibia that differed from the traditional Lauge-Hansen supination-external rotation and pronation-external rotation fracture patterns. The information obtained from this study will be helpful for conducting basic research of this condition and determining appropriate surgical approaches.

Neuregulin 4 alleviates hepatic steatosis via activating AMPK/mTOR-mediated autophagy in aged mice fed a high fat diet.

Neuregulin 4 (Nrg4) is a brown fat-enriched endocrine factor that exerts beneficial metabolic effects on insulin resistance and hepatic steatosis. Autophagy is a mechanism that is essential for preventing hepatic steatosis. The aim of this study was to explore whether Nrg4 ameliorates hepatic steatosis by inducing autophagy. Aged C57BL/6 mice were maintained on a high fat diet with or without Nrg4 intervention for 3 months. Lipid accumulation in the liver was investigated. Autophagy related protein levels along with related signaling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured L-02 cells. Nrg4 decreased high-fat induced intrahepatic lipid content both in vivo and in vitro. Autophagy level in the liver also decreased in obese mice and Nrg4 intervention reactivated autophagy. Further, Nrg4 intervention was found to have activated autophagy via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Moreover, when the AMPK/mTOR pathway was suppressed or autophagy was inhibited, the beneficial effects of Nrg4 intervention on hepatic steatosis were diminished. These results indicated that Nrg4 intervention attenuated hepatic steatosis by promoting autophagy in the liver of aged obese mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signaling pathway.

MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease.

AIMS/HYPOTHESIS: Myeloid-derived growth factor (MYDGF), mainly secreted by bone marrow-derived cells, has been known to promote glucagon-like peptide-1 production and improve glucose/lipid metabolism in mouse models of diabetes, but little is known about the functions of MYDGF in diabetic kidney disease (DKD). Here, we investigated whether MYDGF can prevent the progression of DKD. METHODS: In vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of MYDGF on albuminuria and pathological glomerular lesions. We used streptozotocin-treated Mydgf knockout and wild-type mice on high fat diets to induce a model of DKD. Then, albuminuria, glomerular lesions and podocyte injury were evaluated in Mydgf knockout and wild-type DKD mice treated with adeno-associated virus-mediated Mydgf gene transfer. In vitro and ex vivo experiments, the expression of slit diaphragm protein nephrin and podocyte apoptosis were evaluated in conditionally immortalised mouse podocytes and isolated glomeruli from non-diabetic wild-type mice treated with recombinant MYDGF. RESULTS: MYDGF deficiency caused more severe podocyte injury in DKD mice, including the disruption of slit diaphragm proteins (nephrin and podocin) and an increase in desmin expression and podocyte apoptosis, and subsequently caused more severe glomerular injury and increased albuminuria by 39.6% compared with those of wild-type DKD mice (p < 0.01). Inversely, MYDGF replenishment attenuated podocyte and glomerular injury in both wild-type and Mydgf knockout DKD mice and then decreased albuminuria by 36.7% in wild-type DKD mice (p < 0.01) and 34.9% in Mydgf knockout DKD mice (p < 0.01). Moreover, recombinant MYDGF preserved nephrin expression and inhibited podocyte apoptosis in vitro and ex vivo. Mechanistically, the renoprotection of MYDGF was attributed to the activation of the Akt/Bcl-2-associated death promoter (BAD) pathway. CONCLUSIONS/INTERPRETATION: The study demonstrates that MYDGF protects podocytes from injury and prevents the progression of DKD, providing a novel strategy for the treatment of DKD. Graphical abstract.

Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism.

OBJECTIVE: Perivascular adipose tissue (PVAT) regulates vascular function in a paracrine manner and the vasodilatory effect of PVAT on vessels is completely abolished in obesity. In addition, autophagy is required for maintaining biological function of PVAT and has been shown to be inhibited in obesity. The aim of this study was to explore whether alogliptin improves endothelial function by promoting autophagy in PVAT in obese mice. METHODS: C57BL/6 mice were maintained on high fat diet with or without alogliptin intervention for 3 months. Vasorelaxation function of thoracic aorta with or without PVAT was determined. Autophagy related protein level of p62 and LC3B, along with phosphorylated mTOR (p-mTOR) were evaluated. In addition, the effects of alogliptin on autophagy were also investigated in cultured adipocytes. RESULTS: The presence of PVAT significantly impaired endothelium-dependent vasodilation in obese mice and alogliptin intervention corrected this defect. Autophagy in PVAT was decreased in obese mice and alogliptin intervention activated autophagy. Activating autophagy in PVAT improved endothelium-dependent vasodilation while blocking it in PVAT impaired vasodilation function. Further, addition of glucagon-like peptide-1 (GLP-1) but not alogliptin alone activated autophagy. Moreover, GLP-1 and alogliptin co-treatment did not show additive effect on activating autophagy. CONCLUSIONS: These results revealed that promoting autophagy in PVAT improved endothelial function in response to alogliptin intervention. Additionally, the beneficial effect of alogliptin intervention on PVAT was GLP-1 dependent.

Costs for hospitalized patients with diabetes mellitus in China.

AIM: To evaluate direct hospitalization costs attributable to diabetes and their determinants in a tertiary care hospital in mainland China between 2007 and 2008. METHODS: A retrospective study of the hospitalization expenses for 489 inpatients with diabetes from June 2007 to July 2008 was conducted. All related cost components were defined and valued at the most detailed levels. RESULTS: Median cost was 5307.8 RMB (range 3672.8-8193.2 RMB). The costs for biochemical tests (28%), pharmacy (26%), and therapies and supplies (21%) were the top 3, about 75% in total expenses. The expenses for the antihyperglycemic treatment alone accounted for 27.6% of total hospitalization expenses. Insulin treatment (P < .001), complication number (P < .001), length of hospitalization (P < .001), diabetes duration (P = .023), and hemoglobin A1C (P = .040) were the main factors affecting costs. CONCLUSIONS: Antihyperglycemic treatment expenses represent a minority of total costs; major costs are due to treatment of complications.