Author: Rembiak, Andreas ; Jankowski, Vera ; Alidousty, Christina ; Enders, Dieter ; Braun, Gerald S ; Kunter, Uta ; Rauen, Thomas ; Ostendorf, Tammo ; Floege, Jürgen ; Wang, Jialin ; Djudjaj, Sonja ; Raffetseder, Ute ; Gibbert, Lydia

Virtually all chronic kidney diseases progress towards tubulointerstitial fibrosis. In vitro, Y-box protein-1 (YB-1) acts as a central regulator of gene transcription and translation of several fibrosis-related genes. However, it remains to be determined whether its pro- or antifibrotic propensities prevail in disease. Therefore, we investigated the outcome of mice with half-maximal YB-1 expression in a model of renal fibrosis induced by unilateral ureteral obstruction. Yb1^+/- animals displayed markedly reduced tubular injury, immune cell infiltration and renal fibrosis following ureteral obstruction. The increase in renal YB-1 was limited to a YB-1 variant nonphosphorylated at serine 102 but phosphorylated at tyrosine 99. During ureteral obstruction, YB-1 localized to the cytoplasm, directly stabilizing Col1a1 mRNA, thus promoting fibrosis. Conversely, the therapeutic forced nuclear compartmentalization of phosphorylated YB-1 by the small molecule HSc025 mediated repression of the Col1a1 promoter and attenuated fibrosis following ureteral obstruction. Blunting of these effects in Yb1^+/- mice confirmed involvement of YB-1. HSc025 even reduced tubulointerstitial damage when applied at later time points during maximum renal damage. Thus, phosphorylation and subcellular localization of YB-1 determines its effect on renal fibrosis in vivo. Hence, induced nuclear YB-1 shuttling may be a novel antifibrotic treatment strategy in renal diseases with the potential of damage reversal.

01 Dec 2015·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Anti-fibrotic effects of a novel small compound on the regulation of cytokine production in a mouse model of colorectal fibrosis

Q3 · BIOLOGY

Article

Author: Abe, Jun ; Higashi, Kiyoshi ; Yazawa, Masaki ; Mine, Tetsuya ; Imai, Jin ; Sumiyoshi, Hideaki ; Inagaki, Yutaka ; Hirano, Ken-ichi ; Hozumi, Katsuto

Intestinal fibrotic stricture is a major complication of inflammatory bowel disease. Despite its clinical importance, anti-fibrotic therapy has not been implemented. Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to tissue fibrosis. We have previously shown that the administration of a small compound, HSc025, which promotes the nuclear translocation of YB-1 as a downstream effector of IFN-γ and antagonizes TGF-β/Smad signaling, improves fibrosis in several murine tissues. In this study, we evaluated the anti-fibrotic effect of HSc025 on colorectal fibrosis in TNBS-induced murine chronic colitis. Daily oral administration of HSc025 (3, 15 and 75 mg/kg) suppressed collagen production and decreased the severity of colorectal fibrosis in a dose-dependent manner. In addition, the local production of TGF-β was decreased after HSc025 treatment, whereas that of IL-13 and TNF-α was not affected. HSc025 administration maintained the level of IFN-γ production, even at a late stage when IFN-γ production was lost without the drug treatment. These results demonstrate that HSc025 could be a therapeutic candidate for intestinal fibrosis in inflammatory bowel disease that acts by altering the local production of cytokines, as well as by directly suppressing collagen production.

01 Jun 2014·Journal of Dermatological ScienceQ2 · MEDICINE

A novel small compound accelerates dermal wound healing by modifying infiltration, proliferation and migration of distinct cellular components in mice

Q2 · MEDICINE

Article

Author: Mabuchi, Tomotaka ; Nakao, Sachie ; Sumiyoshi, Hideaki ; Inagaki, Yutaka ; Ozawa, Akira ; Yamaoka, Hanako ; Saito, Koichi ; Minakawa, Kaori ; Ikoma, Norihiro ; Higashi, Kiyoshi ; Sumida, Kayo

BACKGROUNDImpaired wound healing in skin ulcer is one of the major medical issues in the aged society. Wound healing is a complex process orchestrated by a number of humoral factors and cellular components. TGF-β is known to stimulate collagen production in dermal fibroblasts while inhibiting proliferation of epidermal keratinocyte. A screening of small compounds that suppress type I collagen production in fibroblasts has identified HSc025 that antagonizes the TGF-β/Smad signal.OBJECTIVEWe examined the effects of HSc025 on dermal wound healing and elucidated the underlying mechanisms.METHODSEffects of HSc025 on the wound closure process were evaluated in a murine full-thickness excisional wound healing model. Cell proliferation and migration were estimated using primary cultures of human keratinocytes and fibroblasts. Comprehensive analyses of gene expression profiles were performed using untreated and HSc025-treated fibroblasts.RESULTSOral HSc025 administration suppressed macrophage infiltration and accelerated wound closure as early as at day 2 after the dermal excision. Treatment of cultured keratinocytes with HSc025 counteracted the inhibitory effects of TGF-β on cell proliferation and migration. On the other hand, HSc025 stimulated migration, but not proliferation, of dermal fibroblasts independently of TGF-β. Experiments using an artificial dermis graft revealed that HSc025 stimulated migration of collagen-producing cells into the graft tissue. A cDNA microarray analysis of untreated and HSc025-treated fibroblasts identified pirin as a critical mediator accelerating fibroblast migration.CONCLUSIONHSc025 accelerates wound healing by modifying infiltration, proliferation and migration of distinct cellular components, which provides a novel insight into the therapy for intractable skin ulcer.

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Preclinical	JP	Sumitomo Chemical Co., Ltd.	-

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