Vitamin A‐coupled liposomal Rho‐kinase inhibitor ameliorates liver fibrosis without systemic adverse effects

Okimoto, Sho; Kuroda, Satoshi; Tashiro, Hirotaka; Kobayashi, Tsuyoshi; Taogoshi, Takanori; Matsuo, Hiroaki; Ohdan, Hideki

doi:10.1111/hepr.13317

Cited by 15 publications

(9 citation statements)

References 36 publications

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“…Later studies confirmed that Rho-kinase signaling regulates HSC activation and migration [ 146 , 147 , 148 ]. Several other studies demonstrated the beneficial effects of selective delivery of Rho kinase inhibitor to HSCs on the development of hepatic fibrosis in vivo [ 146 , 149 , 150 , 151 ].…”

Section: Camp Signaling In Aldmentioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling. Hence, disturbances in cAMP homeostasis could arise at multiple levels, from changes in G protein coupled receptors and production of cAMP to the rate of degradation by phosphodiesterases. cAMP signaling plays critical roles in metabolism, inflammation and development of fibrosis in several tissues. Alcohol-associated liver disease (ALD) is a multifactorial condition ranging from a simple steatosis to steatohepatitis and fibrosis and ultimately cirrhosis, which might lead to hepatocellular cancer. To date, there is no FDA-approved therapy for ALD. Hence, identifying the targets for the treatment of ALD is an important undertaking. Several human studies have reported the changes in cAMP homeostasis in relation to alcohol use disorders. cAMP signaling has also been extensively studied in in vitro and in vivo models of ALD. This review focuses on the role of cAMP in the pathobiology of ALD with emphasis on the therapeutic potential of targeting cAMP signaling for the treatment of various stages of ALD.

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Section: Camp Signaling In Aldmentioning

confidence: 99%

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

et al. 2020

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“…As attenuated fibrosis in response to ROCK1/2 inhibition was shown to be associated with HSC inactivation 38 and cell-intrinsic ROCK signalling in HSCs drives α-SMA and collagen expression, 39 more recent studies have focused on HSC-targeted delivery of ROCK inhibitors as a therapeutic strategy. 40 , 41 In these studies, the ROCK pathway was confirmed a targetable driver of liver fibrosis in multiple settings and the contribution of cell-intrinsic ROCK signalling in HSCs was demonstrated. However, the contribution of ROCK signalling in upstream immune mediators, and the specific role of ROCK2, the isoform shown to drive pathogenic T-cell, 12 , 42 B-cell, 43 and macrophage 20 differentiation, in liver fibrosis has not previously been established.…”

Section: Discussionmentioning

confidence: 94%

ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis

et al. 2022

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Nonspecific ROCK1 inhibitors fasudil and Y-27632 demonstrate inhibitor pharmacotherapy is beneficial for these diseases; however, adverse effects such as hypotension, insulin resistance, and obesity are observed when ROCK expression/activity is non-specifically altered or systemically downregulated ( 25 , 32 – 35 , 62 , 63 ). This once again highlights the importance of tissue-specific targeting of ROCK1, for example, via mannose-6-phosphate carriers ( 62 , 64 , 65 ), vitamin-A-coupled lysosomes ( 66 ), or genetic engineering. Overall, these tissue-specific approaches will greatly facilitate deciphering the many critical metabolic functions of ROCK1 and, ultimately, may result in the development of novel treatments for metabolic 2974disorders.…”

Section: Discussionmentioning

confidence: 94%

Tissue-Specific Approaches Reveal Diverse Metabolic Functions of Rho-Kinase 1

Landry

Shookster

2021

Front. Endocrinol.

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Rho-kinase 1 (ROCK1) has been implicated in diverse metabolic functions throughout the body, with promising evidence identifying ROCK1 as a therapeutic target in diabetes and obesity. Considering these metabolic roles, several pharmacological inhibitors have been developed to elucidate the mechanisms underlying ROCK1 function. Y27632 and fasudil are two common ROCK1 inhibitors; however, they have varying non-specific selectivity to inhibit other AGC kinase subfamily members and whole-body pharmacological approaches lack tissue-specific insight. As a result, interpretation of studies with these inhibitors is difficult, and alternative approaches are needed to elucidate ROCK1’s tissue specific metabolic functions. Fortunately, recent technological advances utilizing molecular carriers or genetic manipulation have facilitated discovery of ROCK1’s tissue-specific mechanisms of action. In this article, we review the tissue-specific roles of ROCK1 in the regulation of energy balance and substrate utilization. We highlight prominent metabolic roles in liver, adipose, and skeletal muscle, in which ROCK1 regulates energy expenditure, glucose uptake, and lipid metabolism via inhibition of AMPK2α and paradoxical modulation of insulin signaling. Compared to ROCK1’s roles in peripheral tissues, we also describe contradictory functions of ROCK1 in the hypothalamus to increase energy expenditure and decrease food intake via leptin signaling. Furthermore, dysregulated ROCK1 activity in either of these tissues results in metabolic disease phenotypes. Overall, tissue-specific approaches have made great strides in deciphering the many critical metabolic functions of ROCK1 and, ultimately, may facilitate the development of novel treatments for metabolic disorders.

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Vitamin A‐coupled liposomal Rho‐kinase inhibitor ameliorates liver fibrosis without systemic adverse effects

Cited by 15 publications

References 36 publications

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis

Tissue-Specific Approaches Reveal Diverse Metabolic Functions of Rho-Kinase 1

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