Author: Umemura, Masahiro ; Kawata, Kazuhito ; Hanaoka, Tomohiko ; Noritake, Hidenao ; Kitsugi, Kensuke ; Ulmasov, Barbara ; Ohta, Kazuyoshi ; Takatori, Shingo ; Ito, Jun ; Suda, Takafumi ; Matsumoto, Moe ; Neuschwander-Tetri, Brent A ; Yamashita, Maho ; Chida, Takeshi

BACKGROUND & AIMSHepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence.METHODSThe immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins.RESULTSCWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs.CONCLUSIONSPharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs.

01 Nov 2022·Cellular Signalling

Arg-Gly-Asp-binding integrins activate hepatic stellate cells via the hippo signaling pathway

Article

BACKGROUND & AIMSLiver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs.METHODSImmortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins.RESULTSCWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK.CONCLUSIONSThese results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis.

01 Aug 2022·Journal of Interferon & Cytokine Research

CWHM-12, an Antagonist of Integrin-Mediated Transforming Growth Factor-Beta Activation Confers Protection During EarlyMycobacterium tuberculosisInfection in Mice

Article

Author: Khader, Shabaana A. ; Rangel-Moreno, Javier ; Griggs, David W. ; Scott, Ninecia R. ; Thirunavukkarasu, Shyamala

Tuberculosis (TB) caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) is one of the most lethal infectious diseases in the world. Presently, Bacillus Calmette-Guerin, the vaccine approved for use against TB, does not offer complete protection against the disease, which necessitates the development of new therapeutics to treat this infection. Overexpression of transforming growth factor beta (TGF-β) is associated with pulmonary profibrotic changes. The inactive TGF-β secreted is activated through its cleavage and release by αv integrins. Integrin-mediated regulation of TGF-β is considered as a master switch in the profibrotic process and a potential therapeutic target. Thus, in this study, we sought to determine if treatment with a broad range antagonist of integrins, CWHM-12, has the potency to inhibit pulmonary fibrosis and enhance Mtb control in a highly susceptible mouse model of Mtb infection, namely the C3Heb/FeJ (FeJ). CWHM-12 treatment at the early stages of Mtb infection was efficacious in reducing disease severity and inflammation associated with decreased iNOS, MIP-2, and IL-10 production without degradation of collagen. This suggests a potential for CWHM-12 targeting of TGF-β to be explored as an adjunct therapeutic for early Mtb infection.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Fibrosis	Discovery	US	University of California, Santa Barbara	01 Dec 2013
Pulmonary Fibrosis	Discovery	GB	The University of Edinburgh	01 Dec 2013
Pulmonary Fibrosis	Discovery	US	San Francisco Conservatory of Music	01 Dec 2013

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