摘要: Objectives EREG (epiregulin), a member of the epidermal growth factor (EGF) family, plays a role in inflammation, wound healing, normal physiology and malignancies. However, little is known about its function on hair growth. Materials and Methods Cell growth assay, QPCR and immunostaining were carried out. Telogen-to-anagen transition and organ culture were conducted. ROS level was monitored by staining DCFDA. Results We investigated the hair inductive effect of EREG and the mechanism of stimulation on DPCs and ORS cells during hair cycling. Whereas EREG promoted hair growth, EREG knockdown inhibited hair growth as evidenced by telogen-to-anagen transition and organ culture models. EREG was expressed in epidermal cells including ORS cells in vivo. EREG activated phospho-ErbB4 in DPCs during hair cycling and stimulated DPCs via ErbB4 activation in vitro. In terms of the underlying mechanism, reactive oxygen species (ROS) played a key role in DPC stimulation. EREG also activated phospho-EGF receptor (EGFR) in epidermal cells including matrix and ORS cells in vivo and stimulated ORS cells via EGFR activation in vitro. Conclusions EREG, which is released from ORS cells, activated EGFR and ErbB4 on epidermal cells and DPCs during hair cycling, respectively. As a result, EREG stimulated epidermal cells a positive feedback and DPCs via regulating ROS generation for hair growth. Therefore, EREG therapy may be a novel solution for hair loss treatment.

摘要: Objectives Postflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms. Materials and Methods Sprague Dawley rats were subjected to 28-day hindlimb-unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T-type Ca(V)3.1 channel was revealed by assessing its blocking effects. MiR-137 was identified as the upstream of Ca(V)3.1 channel by luciferase assay and investigated by gain/loss-of-function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of Ca(V)3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation. Results Simulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T-type Ca(V)3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR-137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T-type Ca(V)3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively. Conclusions The present work demonstrated that miR-137 and its target T-type Ca(V)3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway.

摘要: Objectives Insulin-like growth factor-binding protein 7 (IGFBP7) is a low-affinity insulin growth factor (IGF) binder that may play an important role in bone metabolism. We previously reported that IGFBP7 enhanced osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) via the Wnt/beta-catenin signalling pathway. In this study, we tried to reveal its function in osteoclast differentiation and osteoporosis. Methods We used both in vitro and in vivo studies to investigate the effects of IGFBP7 on RANKL-induced osteoclastogenesis and osteoporosis, together with the underlying molecular mechanisms of these processes. Results We show that IGFBP7 inhibited receptor activation of nuclear factor-kappa B (NF-kappa B) ligand (RANKL)-induced osteoclastogenesis, F-actin ring formation and bone resorption, which was confirmed by using recombinant IGFBP7 protein, lentivirus and siRNA. The NF-kappa B signalling pathway was inhibited during this process. Moreover, in a mouse ovariectomy-induced osteoporosis model, IGFBP7 treatment attenuated osteoporotic bone loss by inhibiting osteoclast activity. Conclusions Taken together, these findings show that IGFBP7 suppressed osteoclastogenesis in vitro and in vivo and suggest that IGFBP7 is a negative regulator of osteoclastogenesis and plays a protective role in osteoporosis. These novel insights into IGFBP7 may facilitate the development of potential treatment strategies for oestrogen deficiency-induced osteoporosis and other osteoclast-related disorders.

摘要: Objectives High glucose (HG)-mediated bone marrow mesenchymal stem cell (BMSC) dysfunction plays a key role in impaired bone formation induced by type 1 diabetes mellitus (T1DM). Morroniside is an iridoid glycoside derived from the Chinese herbCornus officinalis, and it has abundant biological activities associated with cell metabolism and tissue regeneration. However, the effects and underlying mechanisms of morroniside on HG-induced BMSC dysfunction remain poorly understood. Materials and methods Alkaline phosphatase (ALP) staining, ALP activity and Alizarin Red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time PCR and Western blot (WB) were used to investigate the osteo-specific markers, receptor for advanced glycation end product (RAGE) signalling and glyoxalase-1 (Glo1). Additionally, a T1DM rat model was used to assess the protective effect of morroniside in vivo. Results Morroniside treatment reverses the HG-impaired osteogenic differentiation of BMSCs in vitro. Morroniside suppressed advanced glycation end product (AGEs) formation and RAGE expression by triggering Glo1. Moreover, the enhanced osteogenesis due to morroniside treatment was partially blocked by the Glo1 inhibitor, BBGCP2. Furthermore, in vivo, morroniside attenuated bone loss and improved bone microarchitecture accompanied by Glo1 upregulation and RAGE downregulation. Conclusions These findings suggest that morroniside attenuates HG-mediated BMSC dysfunction partly through the inhibition of AGE-RAGE signalling and activation of Glo1 and may be a potential treatment for diabetic osteoporosis.

摘要: Objectives Vascular disorders are associated with phenotypical switching of vascular smooth muscle cells (VSMCs). We investigated the effect of bone morphogenetic protein (BMP)-2 in controlling VSMC phenotype and vascular disorder progression. Lysine (K)-specific demethylase 1A (KDM1A) has been identified to target BMP-2 and is employed as a therapeutic means of regulating BMP-2 expression in VSMCs. Materials and methods VSMCs were stimulated with angiotensin II, and the expression of KDM1A and BMP-2 was detected. VSMC proliferation, apoptosis, and phenotype were evaluated. An in vivo aortic injury model was established, and VSMC behaviour was evaluated by the expression of key markers. The activation of BMP-2-associated signalling pathways was examined. Results We confirmed the inhibitory effect of KDM1A on BMP-2 activity and demonstrated that KDM1A inhibition prevented VSMC transformation from a contractile to synthetic phenotype. In angiotensin II-treated VSMCs, KDM1A inhibition triggered a decrease in cell proliferation and inflammatory response. In vivo, KDM1A inhibition alleviated post-surgery neointimal formation and collagen deposition, preventing VSMCs from switching into a synthetic phenotype and suppressing disease onset. These processes were mediated by BMP-2 through canonical small mothers against decapentaplegic signalling, which was associated with the activation of BMP receptors 1A and 1B. Conclusions The regulatory correlation between KDM1A and BMP-2 offers insights into vascular remodelling and VSMC phenotypic modulation. The reported findings contribute to the development of innovative strategies against vascular disorders.