Myeloid-derived growth factor (MYDGF) protects bone mass through inhibiting osteoclastogenesis and promoting osteoblast differentiation.

Whether bone marrow regulates bone metabolism through endocrine and paracrine mechanism remains largely unknown. Here, we found that (i) myeloid cell-specific myeloid-derived growth factor (MYDGF) deficiency decreased bone mass and bone strength in young and aged mice; (ii) myeloid cell-specific MYDGF restoration prevented decreases in bone mass and bone strength in MYDGF knockout mice; moreover, myeloid cell-derived MYDGF improved the progress of bone defects healing, prevented ovariectomy (OVX)-induced bone loss and age-related osteoporosis; (iii) MYDGF inhibited osteoclastogenesis and promoted osteoblast differentiation in vivo and in vitro; and (iv) PKCß-NF-κB and MAPK1/3-STAT3 pathways were involved in the regulation of MYDGF on bone metabolism. Thus, we concluded that myeloid cell-derived MYDGF is a positive regulator of bone homeostasis by inhibiting bone resorption and promoting bone formation. MYDGF may become a potential novel therapeutic drug for osteoporosis, and bone marrow may become a potential therapeutic target for bone metabolic disorders.

Inflammatory Cell-Derived MYDGF Attenuates Endothelial LDL Transcytosis to Protect Against Atherogenesis.

BACKGROUND: Inflammation contributes to the pathogenesis of atherosclerosis. But little is known about the potential benefits of inflammatory cells to atherosclerosis. The aim of this study was to investigate the function of inflammatory cells/endothelium axis and determine whether and how inflammatory cell-derived MYDGF (myeloid-derived growth factor) inhibited endothelial LDL (low-density lipoprotein) transcytosis. METHODS: In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of inflammatory cell-derived MYDGF on LDL transcytosis. We generated monocyte/macrophage-targeted MYDGF-null mice on an Ldlr (LDL receptor)-/- background in the loss-of-function strategy and restored the inflammatory cell-derived MYDGF by bone marrow transplantation and inflammatory cell-specific overexpression of MYDGF mice model in the gain-of-function strategy. In in vitro experiments, coculture experiments between primary mouse aortic endothelial cells and macrophages and mouse aortic endothelial cells supplemented with or without recombinant MYDGF were conducted. RESULTS: Inflammatory cell-derived MYDGF deficiency aggravated endothelial LDL transcytosis, drove LDL uptake by artery wall, and thus exacerbated atherosclerosis in vivo. Inflammatory cell-derived MYDGF restoration by bone marrow transplantation and inflammatory cell MYDGF overexpression alleviated LDL transport across the endothelium, prevented LDL accumulation in the subendothelial space, and subsequently ameliorated atherosclerosis in vivo. Furthermore, in the in vitro study, macrophages isolated from MYDGF+/+ mice and recombinant MYDGF attenuated LDL transcytosis and uptake in mouse aortic endothelial cells. Mechanistically, MYDGF inhibited MAP4K4 (mitogen-activated protein kinase kinase kinase kinase isoform 4) phosphorylation, enhanced activation of Akt (protein kinase B)-1, and diminished the FoxO (forkhead box O) 3a signaling cascade to exert protective effects of MYDGF on LDL transcytosis and atherosclerosis. CONCLUSIONS: The findings support a role for inflammatory cell-derived MYDGF served as a cross talk factor between inflammatory cells and endothelial cells that inhibits LDL transcytosis across endothelium. MYDGF may become a novel therapeutic drug for atherosclerosis, and the beneficial effects of inflammatory cell in atherosclerosis deserve further attention.

The roles of lipids and inflammation in the association between the triglyceride-glucose index and arterial stiffness: evidence from two large population-based surveys.

BACKGROUND: The triglyceride-glucose (TyG) index is a risk marker for arterial stiffness; however, the extent to which the TyG index is associated with arterial stiffness via lipids and inflammation remains unknown. The first aim was to probe the relationship between the TyG index and arterial stiffness in two surveys. The second aim was to clarify whether lipids and inflammation mediate this relationship. METHODS: The sample size of 13,726 U.S. individuals from the National Examination Survey (NHANES) and 3,964 Chinese individuals from the China Health and Retirement Longitudinal Study (CHARLS 2015) were enrolled. Weighted multivariate logistic and linear regression models, as well as restricted cubic spline (RCS) and mediation analyses, were utilized to estimate complex relationships between the TyG index, arterial stiffness, lipids (non-high-density lipoprotein cholesterol [non-HDL-C]) and inflammation (C-reactive protein [CRP]) biomarkers. RESULTS: A total of 3,420 U.S. patients and 992 Chinese patients were diagnosed with increased arterial stiffness. Regression analyses demonstrated that higher quartiles of the TyG index were associated with a greater incidence of increased arterial stiffness (NHANES: OR = 2.610, 95% CI = 2.043-3.334, P < 0.001; CHARLS: OR = 1.579, 95% CI = 1.057-2.360, P < 0.001). Participants with a higher TyG index/higher CRP level or with a higher TyG index/higher non-HDL-C level had the highest incidence of increased arterial stiffness in the two surveys. The results were still consistent when the sensitivity analysis was implemented with stricter clinical cut-off values of non-HDL-C. Mediation analysis verified that lipids (mediated effect: ß = 0.012, P < 0.001 in NHANES; ß = 0.020, P < 0.001 in CHARLS) and inflammation (mediated effect: ß = 0.003, P < 0.001 in NHANES; ß = 0.006, P < 0.001 in CHARLS) partially mediated this relationship. CONCLUSIONS: These results indicated a positive linear correlation between the TyG index, non-HDL-C level, CRP level and increased arterial stiffness in two surveys. Furthermore, lipids and inflammation could partly mediate the correlation of the TyG index with arterial stiffness in both surveys.

[Phenotypic and genetic analysis of a Chinese pedigree affected with type 1 Otopalatodigital syndrome].

OBJECTIVE: To analyze the clinical phenotype and genetic basis of a Chinese pedigree affected with Otopalatodigital syndrome type 1 (OPD1). METHODS: A pedigree which was evaluated at the Department of Endocrinology, General Hospital of the Central Theater Command on December 3, 2020 was selected as the study subject. Clinical phenotype and genetic features of the proband were analyzed. Whole exome sequencing was employed to screen for genetic variants in the proband, and Sanger sequencing was used to verify the candidate variants in the proband's mother, uncle, maternal aunt, and paternal aunt. Pathogenicity analysis was also conducted for the candidate variants. RESULTS: The proband, a 16-year-old male, had shown distinctive facial features including mildly prominent eyebrows, down-slanting palpebral fissures, hypertelorism, and depressed nasal bridge. Additionally, he had clubbing of bilateral thumbs and big toes, and central type diabetes insipidus. Genetic sequencing revealed that he has harbored a heterozygous c.586C>T (p.R196W) missense variant of the FLNA gene (NM_001110556.2), which was also carried by his mother and uncle. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), this variant was classified as likely pathogenic (PM1+PM2_Supporting+PP2+PP3+PS4 Supporting). CONCLUSION: The heterozygous c.586C>T (p.R196W) variant of the FLNA gene probably underlay the pathogenesis in this OPD1 family. The central type diabetes insipidus in the proband may represent a newly discovered phenotype of OPD1. Above finding has contributed crucial information for the comprehensive understanding of the clinical manifestations and pathogenic mechanisms of OPD1.

Identification of signalling downstream of the transcription factor forkhead box protein M1 that protects against endoplasmic reticulum stress in a diabetic foot ulcer model.

AIMS: Diabetic foot ulcer (DFU) has a significant impact on the quality of life of diabetic mellitus (DM) patients. Here, we aimed to explore the molecules with aberrant expression and their regulatory mechanisms in DFU. METHODS: The expression of gene and protein was examined using quantitative polymerase chain reaction (qPCR) and western blot. Pearson's correlation analysis was used to analyse interactions among FOXM1, GAS5 and SDF4. Immunofluorescence was used to detect PDI and GRP78 expression. Flow cytometry was used to assess cell apoptosis. Tube formation assay was used to determine angiogenic capacity. Fluorescence in situ hybridization (FISH) assay was employed to determine the cellular localization of GAS5 and SDF4 in human umbilical vein endothelial cells (HUVECs). The interactions among FOXM1, GAS5 and SDF4 were validated by chromatin immunoprecipitation (ChIP), luciferase, RNA pull-down and RNA immunoprecipitation (RIP) assays. RESULTS: FOXM1, GAS5 and SDF4 were decreased in the skin tissues of DFU patients. High glucose (HG) stimulation induced endoplasmic reticulum (ER) stress and cell apoptosis but suppressed angiogenesis in HUVECs, which were abolished by FOXM1 overexpression. FOXM1 promoted GAS5 transcriptional activity, resulting in increased GAS5 expression, and GAS5 knockdown reversed the effects of FOXM1 overexpression in HG-treated HUVECs. Moreover, GAS5 recruited TAF15 to promote SDF4 expression in HUVECs. GAS5 overexpression inhibited ER stress, cell apoptosis and induced angiogenesis in HG-treated HUVECs which could be reversed by silencing SDF4. CONCLUSION: Our results revealed that FOXM1 suppressed ER stress, cell apoptosis and promoted angiogenesis in HG-induced HUVECs via mediating GAS5/TAF15/SDF4 axis, providing a novel therapeutic molecule mechanism for DFU.

Neuregulin 4 Attenuates Osteoarthritis Progression by Inhibiting Inflammation and Apoptosis of Chondrocytes in Mice.

Osteoarthritis (OA) is characterized by chondrocyte apoptosis and increased degradation of type II collagen. Inflammation is one of the major risk factors involved in the pathophysiology of OA. Neuregulin 4 (Nrg4) plays a protective role in a variety of low-level inflammatory diseases, such as non-alcoholic fatty liver disease, inflammatory bowel disease, or type 2 diabetes mellitus. Here we found that (1) Nrg4 deficiency aggravated the destruction and inflammation of articular cartilage and the apoptosis of chondrocytes in vivo. (2) Nrg4 restoration reversed these changes in vivo. (3) Murine recombinant Nrg4 (rNrg4) suppressed inflammation and apoptosis of chondrocytes and decreased the degradation of extracellular matrix in vitro. (4) Mechanistically, the mitogen-activated protein kinase/c-jun N-terminal kinase (MAPK/JNK) signaling pathway may be involved in the regulation of Nrg4 in the pathophysiology of OA. Therefore, we concluded that Nrg4 alleviated the progression of OA by inhibiting the inflammation, protecting against apoptosis of chondrocyte, and decreasing the degradation of extracellular matrix in a manner involving MAPK/JNK signaling.

LncRNA GAS5 activates the HIF1A/VEGF pathway by binding to TAF15 to promote wound healing in diabetic foot ulcers.

A diabetic foot ulcer (DFU) is one of the most devastating complications of diabetes. It has been reported that lncRNA GAS5 plays a vital role in wound healing in DFUs. However, the specific mechanism remains unclear. In this research, we aimed to investigate the role of GAS5 in wound healing in DFUs as well as the underlying mechanism. qPCR or western blotting was performed to measure the expression levels of GAS5, HIF1A, VEGF and TAF15. CCK-8 or EdU assays, flow cytometry, wound healing assays and tube formation assays were carried out to assess the proliferation, apoptosis, wound healing and in vitro angiogenesis of HUVECs, respectively. RNA pull-down and RIP assays were performed to verify the interaction between GAS5 and TAF15. ChIP and luciferase assays were conducted to verify the binding of TAF15 to the HIF1A promoter. In the DFU mouse model, H&E and Masson staining were used to determine epidermal and dermal thickness and collagen formation. GAS5 and HIF1A were downregulated in the skin tissues of DFU patients, and GAS5 overexpression promoted cell proliferation, wound healing and tubule formation in HG-treated HUVECs. In addition, GAS5 facilitated HIF1A expression by interacting with TAF15. Rescue assays demonstrated that the suppression of HIF1A/VEGF pathway activation partially reversed the functional roles of GAS5 in HUVECs. Furthermore, GAS5 accelerated wound healing by activating the HIF1A/VEGF pathway in mice with DFUs. GAS5 activates the HIF1A/VEGF pathway by binding to TAF15, resulting in accelerated wound healing in DFUs. Our findings may provide a theoretical basis for the clinical treatment of DFUs.

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.

Sweroside-mediated mTORC1 hyperactivation in bone marrow mesenchymal stem cells promotes osteogenic differentiation.

This paper aims to probe into the effect of sweroside (SOS) in osteoporosis (OP) and explains mechanisms of its molecular. Applying the ovariectomized (OVX) mouse model investigates the preventive effect of SOS against postmenopausal OP after 3 months of SOS treatment (120 mg/kg/day). Using hematoxylin and eosin (HE) staining and micro computed tomography (CT) observed the morphology of OP in each group. Immunohistochemical staining (IHC) was used to examine osteoblast markers. Experiments in vitro, bone marrow mesenchymal stem cells (BMSCs) from C57/BL6 mice were treated with SOS for 14 days. The staining of alizarin red and alkaline phosphatase activity were measured, and the presentation of osteoblast markers was detected by quantitative reverse transcription PCR. BMSCs were also treated with 1 µg/mL SOS with or without rapamycin, the expression of protein S6 (PS6), P-mTOR, runt-related transcription factor 2 (RUNX2), OSX, and osteocalcin (OCN) was detected by Western blotting. Experiments in vivo, HE results show that SOS can alleviate OP, CT results show that there are lower trabecular thickness, bone mineral density, and trabecular number in control OVX mice than those in the OVX + SOS group. IHC results showed that SOS can promote the expression of osteogenic markers and immunofluorescent results show that SOS can promote mTORC1 signal activation. Experiments in vitro revealed that SOS stimulated the activation of the mTORC1 signaling pathway and upregulated RUNX2, OSX, and OCN, rapamycin can reverse it. Our findings demonstrated that differentiated BMSCs into osteoblasts can be promoted by SOS via upregulating the expression of P-mTOR, PS6, RUNX2, OSX, and OCN. SOS effectively prevented OP by hyperactivation of the mTORC1/PS6 signaling pathway.

The Correlation Between Circulating Betatrophin and Insulin Resistance in General Population: A Meta-Analysis.

Many inconsistent findings are reported on the correlation between circulating betatrophin and insulin resistance in the different population. The aim of this analysis was to explore the correlation between the level of betatrophin and insulin resistance in the general population. The databases of PubMed, EMBASE, and the Cochrane Library (inception to October 26, 2016) were searched without language restrictions for publications that reported studies on associations between betatrophin and insulin resistance in adults. Subgroup analyses were performed to investigate potential sources of heterogeneity. The pooled effect size was calculated using a random-effects model. Twenty-five studies were included in this meta-analysis. Meta-analysis showed that betatrophin was positively and significantly correlated with insulin resistance (r=0.16, 95% CI: 0.08-0.25). When all participants were divided into DM, GDM, and Non-DM groups, this association was also significant in T2DM, GDM, and Non-DM participants (T2DM: r=0.09, 95% CI: 0.01-0.17; I 2=45.1%; GDM: r=0.39, 95% CI: 0.24-0.55; I 2=0.0%; non-DM: r=0.15, 95% CI: 0.04-0.26; I 2=89.3%), and it was obvious that heterogeneity existed in Non-DM group (I 2=89.3%, p<0.001). Subgroup analysis revealed that gender, serum sample and ELISA kits for full-length betatrophin had significant influence on the association between betatrophin and insulin resistance. In conclusion, the level of circulating betatrophin is positively associated with insulin resistance in the general population, especially in T2DM and GDM patients. Gender, serum sample, and ELISA kits for full-length betatrophin may affect this association. More large-scale studies are needed to determine whether improving insulin resistance concomitantly declines betatrophin levels in different diseases.

GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice.

Growth differentiation factor 11 (GDF11) reduces cardiac hypertrophy, improves cerebral vasculature and enhances neurogenesis in ageing mice. Higher growth differentiation factor 11/8 (GDF11/8) is associated with lower risk of cardiovascular events in humans. Here, we showed that adeno-associated viruses-GDF11 and recombinant GDF11 protein improve endothelial dysfunction, decrease endothelial apoptosis, and reduce inflammation, consequently decrease atherosclerotic plaques area in apolipoprotein E-/- mice. Moreover, adeno-associated viruses-GDF11 and recombinant GDF11 stabilize atherosclerotic plaques by selectively decreasing in macrophages and T lymphocytes, while increasing in collagen and vascular smooth muscle cells within plaques. In addition, GDF11 inhibit palmitic acid-induced endothelial apoptosis and ameliorate palmitic acid-induced inflammatory response in RAW264.7 macrophages in vitro. Mechanistically, GDF11 activates the TGF-ß/Smad2/3, AMPK/endothelial nitricoxide synthase (eNOS) while suppresses JNK and NF-κB pathways. In humans, circulating GDF11/8 is positively associated with flow-mediated endothelium-dependent dilation in overweight subjects. We concluded that adeno-associated viruses-GDF11 and recombinant GDF11 protect against endothelial injury and reduce atherosclerosis in apolipoprotein E-/- mice, thus may be providing a novel approach to the treatment of atherosclerosis.

High Human Cytomegalovirus IgG Level is Associated with Increased Incidence of Diabetic Atherosclerosis in Type 2 Diabetes Mellitus Patients.

BACKGROUND At present, whether human cytomegalovirus (HCMV) infection is associated with type 2 diabetes mellitus (T2DM) is debatable. The effect of active HCMV infection on glucose regulation has been poorly studied. Although HCMV infection is correlated with atherosclerosis in cardiovascular disease, the role of HCMV infection in the development of diabetic atherosclerosis in T2DM is unclear and is usually neglected by endocrinologists. The aim of this study was to assess the effects of HCMV infection on glucose regulation and the development of diabetic atherosclerosis in T2DM patients. MATERIAL AND METHODS A total of 222 hospitalized T2DM patients were enrolled. Nested polymerase chain reactions were used to detect HCMV DNA extracted from peripheral blood leukocytes. Quantitative real-time PCR was used to determine viral load. HCMV IgG antibody concentrations were analyzed by chemiluminescence immunoassay. RESULTS HCMV active infection, viral load, and HCMV IgG titers were not correlated with glucose regulation. Binary logistic regression demonstrated that the highest quartile of HCMV IgG concentration (>500 U/ml) was correlated with the incidence of diabetic atherosclerosis (OR: 8.0, 95%CI: 2.3-27.2), and that titer >127 U/ml of HCMV IgG is an independent predictor for the development of diabetic atherosclerosis in T2DM patients (OR: 4.6, 95%CI: 1.9-11.3) after adjustment for all potential confounding factors. CONCLUSIONS Active HCMV infection is unlikely to influence glucose regulation in T2DM. However, HCMV IgG titers are associated with the incidence of diabetic atherosclerosis, and titer >127 U/ml of HCMV IgG might be an independent risk factor for the development of diabetic atherosclerosis in T2DM patients.

Changes of plasma concentration of osteoprotegerin and its association with endothelial dysfunction before and after hypouricemic therapy in patients with hyperuricemia.

OBJECTIVE: Osteoprotegerin (OPG) is a secreted glycoprotein in the regulation of bone turnover. Recently, many studies showed that OPG acts as an important regulatory molecule in the vascular systems. Our objective was to examine the plasma OPG levels alteration and its association with endothelial function before and after hypouricemic therapy in patients with hyperuricemia. METHODS: Thirty patients (28 males and 2 females, serum uric acid > 7.0 mg/dl) with hyperuricemia were selected. Thirty healthy individuals (28 males and 2 females) with normal serum uric acid were also selected as control. Patients were administered with hypouricemic therapy for 6 months. Plasma OPG concentration was measured in duplicate using a sandwich ELISA and high-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia and after sublingual glyceryltrinitrate. RESULTS: Plasma OPG levels in patients with hyperuricemia before hypouricemic therapy was significantly higher than those in controls (3.39 ± 0.25 vs. 2.05 ± 0.74 ng/L, p < 0.01). After hypouricemic therapy, OPG levels decreased markedly (2.54 ± 0.38 ng/L, p < 0.01). Flow-mediated dilation (FMD) in patients with hyperuricemia was 3.07 ± 1. 23%, which was significantly lower than that in control subjects (4.62 ± 0.69%, p < 0.01), and it improved significantly after hypouricemic therapy (3.91 ± 1.37%, p < 0.01). The absolute changes in OPG showed a significant positive correlation with the changes in serum uric acid (p < 0.05) and negative correlation with the changes in FMD (p < 0.01) in patients with hyperuricemia during the course of hypouricemic therapy. CONCLUSION: The current study demonstrates that plasma OPG levels increased significantly in patients with hyperuricemia and decreased significantly after hypouricemic therapy, and are correlated with FMD. These findings support the growing concept that elevated plasma OPG levels may be involved with the development of endothelial dysfunction in patients with hyperuricemia.

Circulating level of TRAIL concentration is positively associated with endothelial function and increased by diabetic therapy in the newly diagnosed type 2 diabetic patients.

OBJECTIVE: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is associated with atherosclerosis. This study was to investigate the changes of circulating TRAIL and its association with flow-mediated endothelium-dependent arterial dilation (FMD) before and after diabetic treatment in newly diagnosed type 2 diabetes. MATERIALS AND METHODS: The study subjects included 55 newly diagnosed type 2 diabetes and 52 healthy subjects. Circulating TRAIL concentration was measured by an ELISA, and high-resolution ultrasound was used to measure FMD of brachial artery. RESULTS: The circulating TRAIL in patients before treatment was 64·46 pg/ml, which was significantly lower than that in control (80·70 pg/ml, P < 0·001). After 6 months of diabetic treatment, TRAIL level increased markedly (75·11 pg/ml), which was still lower than that in control (P < 0·001). FMD was reduced compared with controls at baseline and increased after diabetic therapy (P < 0·001). In multivariate analysis, circulating TRAIL was significantly associated with FMD, fasting blood glucose (FBG), 2-h blood glucose (2-h BG), haemoglobinA1c (HbA1c) and C-reactive protein (CRP) at baseline (P < 0·01). The absolute change in TRAIL was correlated with the changes in FMD, FBG, 2-h BG, HbA1c and CRP (P < 0·01) before and after diabetic treatment. CONCLUSION: Circulating TRAIL level decreased in newly diagnosed type 2 diabetes and increased after 6 months of diabetic treatment significantly. The circulating TRAIL level is positively associated with endothelial function. Our data showed that circulating TRAIL level may be a protective maker of endothelial function in type 2 diabetes.

Myeloid-derived growth factor and its effects on cardiovascular and metabolic diseases.

Myeloid-derived growth factor (MYDGF) is a paracrine protein produced by bone marrow-derived monocytes and macrophages. Current research shows that it has protective effects on the cardiovascular system, such as repairing heart tissue after myocardial infarction, enhancing cardiomyocyte proliferation, improving cardiac regeneration after myocardial injury, regulating proliferation and survival of endothelial cells, reducing endothelial cell damage, resisting pressure overload-induced heart failure, as well as protecting against atherosclerosis. Furthermore, regarding the metabolic diseases, MYDGF has effects of improving type 2 diabetes mellitus, relieving non-alcoholic fatty liver disease, alleviating glomerular diseases, and resisting osteoporosis. Herein, we will discuss the biology of MYDGF and its effects on cardiovascular and metabolic diseases.

Dapagliflozin promotes white adipose tissue browning though regulating angiogenesis in high fat induced obese mice.

Browning of white adipose tissue (WAT) is become an appealing target for therapeutics in the treatment of obesity and related metabolic diseases. Dapagliflozin is widely used in the treatment of type 2 diabetes, and it is also found that the drug exhibits regulate systemic metabolism such as obesity, insulin resistance and hepatic steatosis. However, the precise role of dapagliflozin on WAT remodeling remains to be elucidated. The current study aimed to explore the role of dapagliflozin on WAT browning in high-fat diet (HFD)-induced obese mice. Male C57BL/6J mice (n = 6 per group) were used to establish obesity model by following feeding with HFD for 6 weeks. The mice were randomly treated with or without dapagliflozin for the experimental observation. The volume and fat fraction of WAT were quantified, H&E, UCP-1 staining and immunohistochemistry were conducted to investigate the white-to-brown fat conversion and angiogenesis in WAT respectively. Quantitative real-time polymerase chain reaction (qPCR) was employed to explore the mRNA expression levels of genes related to fat browning and angiogenesis in WAT. Subsequently, 3T3-L1 cells were used to explore the effect of dapagliflozin on preadipocytes differentiation in vitro. Our results demonstrated that dapagliflozin could reduce body weight gain and promote WAT browning in HFD induced obese mice via regulating lipogenesis and angiogenesis in WAT. Furthermore, dapagliflozin reduce cells differentiation, up-regulate the expression of WAT browning and angiogenesis genes in 3T3-L1 adipocytes in vitro. In conclusion, dapagliflozin can potentially promote WAT browning in HFD induced obese mice via improving lipogenesis and angiogenesis in WAT.

Continuous intrafemoral artery infusion of urokinase improves diabetic foot ulcers healing and decreases cardiovascular events in a long-term follow-up study.

INTRODUCTION: Diabetic foot ulcer (DFU) is a disabling complication of diabetes mellitus. Here, we attempted to assess whether long-term intrafemoral artery infusion of low-dose urokinase therapy improved DFUs and decreased cardiovascular events in patients with DFUs. RESEARCH DESIGN AND METHODS: This trial was a single-center, randomized, parallel study. A total of 195 patients with DFU were randomized to continuous intrafemoral thrombolysis or conventional therapy groups. The continuous intrafemoral thrombolysis group received continuous intrafemoral urokinase injection for 7 days, and conventional therapy just received wound debridement and dressing change. Then, a follow-up of average 6.5 years was performed. RESULTS: Compared with conventional therapy, at the first 1 month of intervention stage, the ulcers achieved a significant improvement in continuous intrafemoral thrombolysis group including a complete closure (72.4% vs 17.5%), an improved ulcer (27.6% vs 25.8%), unchanged or impaired ulcer (0% vs 56.7%). During the 6.5-year follow-up, for the primary outcome of ulcer closure rate, continuous intrafemoral thrombolysis therapy obtained a better complete healing rate (HR 3.42 (95% CI 2.35 to 4.98, p<0.0001)). For the secondary outcome of cardiovascular disease events, continuous intrafemoral thrombolysis therapy had a lower incidence of cardiovascular events (HR 0.50 (95% CI 0.34 to 0.74, p<0.0001)). Importantly, intrafemoral thrombolysis therapy decreased the incidence of cardiovascular death (HR 0.42 (95%CI 0.20 to 0.89, p=0.0241)). Additionally, continuous intrafemoral thrombolysis therapy improved local skin oxygenation and peripheral neuropathy as well as glycolipid metabolic profiles when compared with conventional therapy group (p<0.05). CONCLUSIONS: Continuous intrafemoral thrombolysis therapy has a better therapeutic efficacy to improve DFUs and decrease cardiovascular events. TRIAL REGISTRATION NUMBER: NCT01108120.

Stress hyperglycemia is associated with disease severity in COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is a global pandemic that has affected millions of people worldwide. In this paper, we analyse the relationship between stress hyperglycaemia and disease severity in patients with COVID-19. MATERIAL AND METHODS: A total of 252 patients with COVID-19 were included in this study. The patients were divided into the following groups: COVID-19 with stress hyperglycaemia (SHG), COVID-19 with diabetes (DM), and COVID-19 with normal blood glucose (NG). The stress hyperglycaemia rate (SHR) was calculated using the fasting blood glucose (FBG)/glycated haemoglobin (HbA1c) ratio. To further compare the disease characteristics of different SHRs, we divided the SHR into low SHR and high SHR according to the SHR median. Correlations between the severity of the disease and other factors were analysed after adjusting for sex and age. Multivariate analysis was performed using logistic regression to analyse the risk factors predicting the severity of COVID-19. RESULTS: Compared with the NG group, the SHG group had higher disease severity (p < 0.001); the SHG group had higher HbA1c, FBG, SHR, blood urea nitrogen (BUN), interleukin 6 (IL-6), and neutrophil levels, while lymphocyte, CD3+ T cell, CD8+ T cell, CD4+ T cell, CD16+CD56 cell, and CD19+ cell counts were lower (p < 0.05). Compared with the NG group, the DM group had higher HbA1c, blood glucose, BUN, lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and neutrophils, while CD8+ T cell counts were lower (p < 0.05). Compared with the DM group, the SHG group had higher SHR and lower HbA1c, CD3+ T cell, CD4+ T cell, CD16+CD56 cell, and T cell ratio levels (p < 0.05). Compared to the low SHR group, the high SHR group had patients with more severe COVID-19 (p = 0.004). Also, the high SHR grouphad higher age, HbA1c, FBG, asparate aminotransferaze (AST), BUN, LDH, uric acid (UA), CRP, IL-6, and procalcitonin (PCT), while lymphocyte, CD3+ T cell, CD4+ T cell, CD8+ T cell, and CD19+ cell counts were lower (p < 0.05).Binary logistic regression analysis showed that SHR, gender, and lymphocyte count wererisk factorsfor the severity of COVID-19. CONCLUSION: Stress hyperglycaemia, as indicated by a higher SHR, is independently associated with the severity of COVID-19.

Myeloid-derived growth factor alleviates non-alcoholic fatty liver disease alleviates in a manner involving IKKß/NF-κB signaling.

Whether bone marrow modulates systemic metabolism remains unknown. Our recent study suggested that myeloid-derived growth factor (MYDGF) improves insulin resistance. Here, we found that myeloid cell-specific MYDGF deficiency aggravated hepatic inflammation, lipogenesis, and steatosis, and show that myeloid cell-derived MYDGF restoration alleviated hepatic inflammation, lipogenesis, and steatosis. Additionally, recombinant MYDGF attenuated inflammation, lipogenesis, and fat deposition in primary mouse hepatocytes (PMHs). Importantly, inhibitor kappa B kinase beta/nuclear factor-kappa B (IKKß/NF-κB) signaling is involved in protection of MYDGF on non-alcoholic fatty liver disease (NAFLD). These data revealed that myeloid cell-derived MYDGF alleviates NAFLD and inflammation in a manner involving IKKß/NF-κB signaling, and serves as a factor involved in the crosstalk between the liver and bone marrow that regulates liver fat metabolism. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.