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Glomerular diseases afflict millions of people and impose an enormous burden on public healthcare costs worldwide. Identification of potential therapeutic targets for preventing glomerular diseases is of considerable clinical importance. CHILKBP is a focal adhesion protein and modulates a wide array of biological functions. However, little is known about the role of CHILKBP in glomerular diseases. To investigate the function of CHILKBP in maintaining the structure and function of podocytes in a physiologic setting, a mouse model (CHILKBP cKO) was generated in which CHILKBP gene was conditionally deleted in podocytes using the Cre-LoxP system. Ablation of CHILKBP in podocytes resulted in massive proteinuria and kidney failure in mice. Histologically, typical podocyte injury including podocyte loss, foot process effacement, and glomerulosclerosis was observed in CHILKBP cKO mice. Mechanistically, we identified ZO-1 as a key junctional protein that interacted with CHILKBP. Loss of CHILKBP in podocytes exhibited a significant reduction of ZO-1 expression, leading to abnormal actin organization, aberrant slit diaphragm protein expression and compromised podocyte filtration capacity. Restoration of CHILKBP or ZO-1 in CHILKBP-deficient podocytes effectively alleviated podocyte injury induced by the loss of CHILKBP in vitro and in vivo. Finally, we showed the glomerular expression of CHILKBP and ZO-1 was decreased in patients with proteinuric kidney diseases. Our findings reveal a novel signaling pathway consisting of CHILKBP and ZO-1 that plays an essential role in maintaining podocyte homeostasis and suggest novel therapeutic approaches to alleviate glomerular diseases.

Cholinergic system conducts signal transmission in brain and muscle. Besides nervous system, the nonneuronal functions of cholinergic system have been proposed in various tissues. The expression of cholinergic proteins and release of acetylcholine in human skin have been reported, but its mechanism and influence on dermatological functions is not elucidated. Here, the expression profile of cholinergic markers was further investigated in skin and keratinocyte. The expression levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), and synaptophysin, were upregulated during differentiation of keratinocytes. In cultured keratinocytes, a transient exposure of solar light induced the release of acetylcholine, which was mediated by intracellular Ca2+ mobilization. The light-induced acetylcholine release was mediated by the present of opsin. The light-induced melanogenesis was inhibited by acetylcholine or AChE inhibitor in melanocyte in vitro and mouse skin ex vivo. These results indicated that the potential role of cholinergic system could be a negative regulator in skin pigmentation.

Androgen receptor (AR) signaling plays important roles in breast cancer progression. We show here that Kindlin-2, a focal adhesion protein, is critically involved in the promotion of AR signaling and breast cancer progression. Kindlin-2 physically associates with AR and Src through its two neighboring domains, namely F1 and F0 domains, resulting in formation of a Kindlin-2-AR-Src supramolecular complex and consequently facilitating Src-mediated AR Tyr-534 phosphorylation and signaling. Depletion of Kindlin-2 was sufficient to suppress Src-mediated AR Tyr-534 phosphorylation and signaling, resulting in diminished breast cancer cell proliferation and migration. Re-expression of wild-type Kindlin-2, but not AR-binding-defective or Src-binding-defective mutant forms of Kindlin-2, in Kindlin-2-deficient cells restored AR Tyr-534 phosphorylation, signaling, breast cancer cell proliferation and migration. Furthermore, re-introduction of phosphor-mimic mutant AR-Y534D, but not wild-type AR reversed Kindlin-2 deficiency-induced inhibition of AR signaling and breast cancer progression. Finally, using a genetic knockout strategy, we show that ablation of Kindlin-2 from mammary tumors in mouse significantly reduced AR Tyr-534 phosphorylation, breast tumor progression and metastasis in vivo. Our results suggest a critical role of Kindlin-2 in promoting breast cancer progression and shed light on the molecular mechanism through which it functions in this process.

Background During melanogenesis, melanocytes produce melanin through enzymatic reactions. Microphthalmia-associated transcription factor (MITF) is a major regulator in controlling the expressions of melanogenic enzymes tyrosinase (TYR), tyrosine-related protein-1 (TRP1), and dopachrome tautomerase (DCT). Self-Growth Colony (SGC) is prepared from human platelet-rich plasma (PRP) having an enrichment of growth factors, and which has claimed skin regeneration function. Aim In this study, we aim to identify and investigate the novel role of SGC in skin melanogenesis. Methods MTT assay was performed to determine the cytotoxicity of applied SGC. Melanin assay was adopted to quantify the intracellular melanin after SGC treatment. Promoter-driven luciferase assay, real-time PCR, and Western blotting were performed to determine the expressions of melanogenic enzymes and MITF in SGC-treated cultured Melan-A cells, being treated with or without UV induction. Ex vivo mouse skin was treated with SGC, and then was subjected to Western blotting and histochemical staining. Results We identified that SGC inhibited melanogenesis in cultured melanocytes and ex vivo mouse skin. The phenomena were attributed to a reduction of MITF expression, which subsequently down-regulated the melanogenic enzymes, that is, TYR, TRP1, and DCT. Moreover, ERK signaling was activated in the SGC-inhibited melanogenesis. Conclusions The findings suggest that SGC extracting from human blood can be a safe and potential agent in promoting skin whitening.

Acetylcholinesterase (AChE) hydrolyses acetylcholine to choline and acetate, playing an important role in terminating the neurotransmission in brain and muscle. Recently, the non-neuronal functions of AChE have been proposed in different tissues, in which there are various factors to regulate the expression of AChE. In mammalian skin, AChE was identified in melanocytes and keratinocytes. Our previous study has indicated that AChE in keratinocyte affects the process of solar light-induced skin pigmentation; however, the expression of AChE in keratinocytes in responding to sunlight remains unknown. Here, we provided several lines of evidence to support a notion that AChE could be upregulated at transcriptional and translational levels in keratinocytes when exposed to solar light. The light-mediated AChE expression was triggered by Ca2+, supported by an induction of Ca2+ ionophore A23187 and a blockage by Ca2+ chelator BAPTA-AM. In addition, this increase on AChE transcriptional expression was eliminated by mutagenesis on the activating protein 1 (AP1) site in ACHE gene. Hence, the solar light-induced AChE expression is mediated by Ca2+ signalling through AP1 site. This finding supports the role of solar light in affecting the cholinergic system in skin cells, and which may further influence the dermatological function.