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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.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.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.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.

Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)–nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.

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) PKCβ-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.

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.

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.

Bone marrow serves as an endocrine organ that regulates the pathophysiological function of arteries via MYDGF., Whether bone marrow modulates systemic metabolism remains unknown. Here, we found that (i) myeloid cell–specific myeloid-derived growth factor (MYDGF) deficiency exacerbated vascular inflammation, adhesion responses, endothelial injury, and atherosclerosis in vivo. (ii) Myeloid cell–specific MYDGF restoration attenuated vascular inflammation, adhesion responses and leukocyte homing and alleviated endothelial injury and atherosclerosis in vivo. (iii) MYDGF attenuated endothelial inflammation, apoptosis, permeability, and adhesion responses induced by palmitic acid in vitro. (iv) MYDGF alleviated endothelial injury and atherosclerosis through mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4)/nuclear factor κB (NF-κB) signaling. Therefore, we concluded that MYDGF inhibits endothelial inflammation and adhesion responses, blunts leukocyte homing, protects against endothelial injury and atherosclerosis in a manner involving MAP4K4/NF-κB signaling, and serves as a cross-talk factor between bone marrow and arteries to regulate the pathophysiology of arteries. Bone marrow functions as an endocrine organ and serves as a potential therapeutic target for metabolic disorders.

Myeloid-derived growth factor (MYDGF), which is produced by bone marrow–derived cells, mediates cardiac repair following myocardial infarction by inhibiting cardiac myocyte apoptosis to subsequently reduce the infarct size. However, the function of MYDGF in the incretin system of diabetes is still unknown. Here, loss-of-function and gain-of-function experiments in mice revealed that MYDGF maintains glucose homeostasis by inducing glucagon-like peptide-1 (GLP-1) production and secretion and that it improves glucose tolerance and lipid metabolism. Treatment with recombinant MYDGF increased the secretion and production of GLP-1 in STC-1 cells in vitro. Mechanistically, the positive effects of MYDGF are potentially attributable to the activation of protein kinase A/glycogen synthase kinase 3β/β-catenin (PKA/GSK-3β/β-catenin) and mitogen-activated protein kinase (MAPK) kinases/extracellular regulated protein kinase (MEK/ERK) pathways. Based on these findings, MYDGF promotes the secretion and production of GLP-1 in intestinal L-cells and potentially represents a potential therapeutic medication target for type 2 diabetes.

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.

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.