IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo.

Vitiligo is a depigmentary disorder that develops as a result of the progressive disappearance of epidermal melanocytes. Stress can precipitate or exacerbate a skin disease through psychosomatic mechanisms. Stress exposure induces vitiligo-like symptoms in mice, as cellular damage to melanocytes causes synthetic pigment loss. Stress also increases IL-17, IL-1ß, and antimelanocyte IgG in model mouse serum. Up-regulation of the IL-1ß transcript in patients suggests its possible role in autoimmune pathogenesis of vitiligo. We demonstrate that IL-17 promoted IL-1ß secretion from keratinocytes. Mitochondrial dysfunction, which can induce the excessive production of reactive oxygen species (ROS), is emerging as a mechanism that underlies various inflammatory and autoimmune diseases. In this study, we demonstrate that IL-17 inhibits melanogenesis of zebrafish, normal human epidermal melanocytes, and B16F10 cells. IL-17 increased mitochondrial dysfunction and ROS accumulation, which was related to autophagy induction. Autophagy is needed for autophagic apoptosis of B16F10 cells induced by IL-17. To inhibit ROS generation, B16F10 cells were pretreated with N-acetyl-l-cysteine (NAC), which inhibited autophagy. 3-Methyladenine (3-MA) also had an inhibiting effect on autophagy. NAC or 3-MA pretreatments inhibited IL-17-mediated cell apoptosis. In summary, IL-17 induces the cellular stress microenvironment in melanocytes to promote autophagic cell apoptosis in vitiligo.-Zhou, J., An, X., Dong, J., Wang, Y., Zhong, H., Duan, L., Ling, J., Ping, F., Shang, J. IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo.

Preparation of thermo/redox/pH-stimulative poly(N-isopropylacrylamide-co-N,N'-dimethylaminoethyl methacrylate) nanogels and their DOX release behaviors.

Stimuli-sensitive drug delivery systems show beneficial features of both medical and pharmaceutical fields. In this article, polymeric nanogel P (N-isopropylacrylamide-N,N '-dimethylaminoethyl methacrylate [NIPAM-DMAEMA]) (PND) with pH/redox/thermo-responsivenesses was synthesized by the in situ polymerization of NIPAM and DMAEMA for the controlled release of doxorubicin hydrochloride (DOX) and N,N '-bis(acryloyl)cystamine (BAC) and N,N '-methylenebisacrylamide (MBA) act as the crosslinkers, respectively. The structure, size, and zeta potential of PND-BAC and PND-MBA were further characterized. Moreover, after loading DOX, the encapsulation efficiency and the in vitro release behavior of PND-BAC/DOX and PND-MBA/DOX nanogels were discussed in detail. Compared to PND-MBA NGs, PND-BAC nanogels have redox degradability due to the presence of the crosslinker BAC. After loading DOX, the PND-BAC/DOX nanogel showed a higher encapsulation efficiency (81.6 ± 1.2)% and thermo- and pH-responsiveness as well as redox-responsive in vitro release. These properties together with excellent environmentally sensitive properties make PND-BAC as an attractive candidate for application in drug nanocarriers for the targeted drug delivery of model payloads. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1195-1203, 2019.

A Small ß-Carboline Derivative "B-9-3" Modulates TGF-ß Signaling Pathway Causing Tumor Regression in Vivo.

Targeting tumor microenvironment (TME) is crucial in order to overcome the anti-cancer therapy resistance. In this study, we report the antitumor activity of a newly synthesized ß-carboline derivative "B-9-3." Here, this small molecule showed a promising antitumor activity in vivo along with an enhanced immune response as reflected by a reduction of regulatory T cells and increased CD4+/CD8+ T cells. Further, B-9-3 decreased the number of myofibroblasts not only in the tumor but also in the lung suggesting an anti-metastatic action. The reduction of myofibroblasts was associated with lower expression of epithelial-to-mesenchymal transition markers and a decrease of phosphorylated SMAD2/3 complex indicating the implication of TGF-ß signaling pathway in B-9-3's effect. The blockade of myofibroblasts induction by B-9-3 was also verified in vitro in human fibroblasts treated with TGF-ß. To elucidate the mechanism of B-9-3's action on TGF-ß pathway, first, we investigated the molecular interaction between B-9-3 and TGF-ß receptors using docking method. Data showed a weak interaction of B-9-3 with the ATP-binding pocket of TGFßRI but a strong one with a ternary complex formed of extracellular domains of TGFßRI, TGFßRII, and TGF-ß. In addition, the role of TGFßRI and TGFßRII in B-9-3's activity was explored in vitro. B-9-3 did not decrease any of the two receptors' protein level and only reduced phosphorylated SMAD2/3 suggesting that its effect was more probably due to its interaction with the ternary complex rather than decreasing the expression of TGF-ß receptors or interfering with their ATP-binding domains. B-9-3 is a small active molecule which acts on the TGF-ß signaling pathway and improves the TME to inhibit the proliferation and the metastasis of the tumor with the potential for clinical application.