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Scleroderma
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
The RhoA/ROCK pathway is important in the activation of myofibroblasts leading to matrix stiffening through STAT3 phosphorylation (101, 102). Similarly, the lysophosphatidic acid (LPA) receptor family can also activate the RhoA/ROCK pathway and induce the differentiation of fibroblasts (103). In a bleomycin- induced mouse model of SSc, a novel autotaxin inhibitor, PAT-048, markedly attenuated dermal fibrosis when treatment was initiated before or after the development of fibrosis (104). This study also highlighted the importance of autotaxin playing a major role in the pathogenic loop of SSc fibrogenesis, including LPA and IL-6, to amplify the production of each other.
Ethnomedicinal Plants of North Eastern Himalayan Region of India to Combat Hypertension
Published in Amit Baran Sharangi, K. V. Peter, Medicinal Plants, 2023
Pintubala Kshetri, K. Tamreihao, Subhra Saikat Roy, Thangjam Surchandra Singh, Susheel Kumar Sharma, Meraj Alam Ansari
Clerodendrum colebrookianum Walp generally grows in the south and south-east Asia. In India it is mostly grown in the NER up to an altitude of 1,700 m (Rajlakshmi et al., 2003). Its hypotensive activity was demonstrated by a study conducted by Lokesh and Amitsankar (2012) where they observed that the ethyl acetate fraction of C. colebrookianum Walp leaves exhibits Rho kinase (ROCK II) and phosphodiesterase-5 (PDE-5) inhibition. ROCK II and PDE-5 are the two important enzymes playing a key role in vasoconstriction. Around 21 compounds have been reported from C. colebrookianum Walp. And from the molecular docking studies, it was revealed that the three compounds (acteoside, martinoside, and osmanthuside b6) could interact with ROCK, ACE, and PDE5 which are well-known anti-hypertensive drug targets. The acteoside and osmanthuside b6 make stable interactions with the anti-hypertensive targets ROCK I/ROCK II and PDE5 (Arya et al., 2018).
Case preparation
Published in Peter A. Schneider, Endovascular Skills: Guidewire and Catheter Skills for Endovascular Surgery, 2019
Your patients will benefit substantially if you go into the procedure with a good sense of how the patient is doing, a good feeling of how strongly indicated the treatment might be, and a reasonable understanding of the whole range of treatment options. Here are some examples of how this information helps. Obtaining a good sense of the history will help to indicate the trajectory of the vascular problem. If it is chronic and the patient is having problems during the procedure, it makes more sense to stop and come back another day. If the problem is more acute, then other factors related to the acute illness may be anticipated. If the patient has profound ischemia, they may not be able to tolerate having the limb on a level surface. If there is significant cardiopulmonary compromise, the patient may not be able to lay flat. It is good to know if palpation of the pulses reveals that the femoral arteries are rock hard. If an antegrade puncture is being considered, does the patient also have a popliteal pulse or could there be occlusive disease near and just inferior to the puncture site? If an upper extremity access is anticipated, it is good to know what the pulses feel like and also whether the bilateral brachial pressures are equal. Is the skin of the groin that is intended for access clean? Factors such as these help to drive the decision-making process that takes place before the procedure even starts.
The effect of transglutaminase-2 inhibitor on pulmonary vascular remodeling in rats with pulmonary arterial hypertension
Published in Clinical and Experimental Hypertension, 2022
Ting Wang, Yan Duan, Dong Liu, Gang Li, Bin Liu
Rho is a member of the Ras superfamily of GTP-binding proteins, with three isoforms, namely RhoA, RhoB, and RhoC, while ROCK is one of the first effective downstream effectors identified for Rho proteins, with two isoforms, namely ROCK1 and ROCK2 (17,18). ROCK can affect cardiovascular disease by regulating the sensitivity of smooth muscle cells to Ca2+ and the expression of nitric oxide synthase in endothelial cells (19). Therefore, the mechanism of the ROCK signaling pathway in cardiovascular diseases has been widely investigated. In the present study, the mRNA expression of ROCK2 in rat pulmonary tissues was detected using RT-PCR, and the protein expression was detected using Western blot. The results revealed that the mRNA and protein expressions of ROCK2 were higher in the model group compared with those in the control group and the intervention group. This further indicates the important role of the Rho/ROCK signaling pathway in the pathogenesis of PAH and its possible involvement in ventricular remodeling and pulmonary vascular remodeling. Moreover, the ROCK has become a new target for intervention in the treatment of cardiovascular diseases, and inhibition of the activation of the signaling pathway has become a hot research topic. Compared to other inhibitors, the widely used inhibitor is fasudil, etc (20,21).
Emerging therapeutic targets for idiopathic pulmonary fibrosis: preclinical progress and therapeutic implications
Published in Expert Opinion on Therapeutic Targets, 2021
Toyoshi Yanagihara, Ciaran Scallan, Kjetil Ask, Martin R. J. Kolb
Rho-associated coiled-coil-forming protein kinase (ROCK) are key mediators of the cellular response to injury through reorganization of the actin cytoskeleton with two isoforms ROCK1 and ROCK2 [72]. The ROCK pathway has been implicated in the development of pulmonary fibrosis where expression of ROCK2 mRNA was increased and selective ROCK inhibition attenuated fibrosis development in bleomycin treated mice [73]. Analysis of human IPF lung myofibroblasts revealed reduced contractility via decreased myosin light chain phosphorylation which is mediated by the ROCK pathway [74]. KD025 (Kadmon Corporation) is an oral agent which specifically inhibits ROCK2. Several Phase I clinical trials in healthy subjects have shown KD025 to be safe and well tolerated [75,76]. An open label Phase II clinical trial in 36 patients with IPF compared KD025 (400 mg) to standard care. The drug was overall well tolerated with no serious adverse effects. KD025 was associated with a reduction in lung function decline (FVC) compared to standard care at 24 weeks (−1.5%(±4.2) vs −5.0%(±5.0) respectively [77].
The Roles of Tissue Rigidity and Its Underlying Mechanisms in Promoting Tumor Growth
Published in Cancer Investigation, 2020
Muhammad Asyaari Zakaria, Nor Fadilah Rajab, Eng Wee Chua, Gayathri Thevi Selvarajah, Siti Fathiah Masre
There are two ROCK homologues that have been identified: ROCK1 and ROCK2. These ROCK homologues share 65% of overall homology and 92% of the kinase domain homology (120). Both ROCK1 and ROCK2 promote actin cytoskeleton contractility through similar and distinct downstream targets. ROCK1 and ROCK2 both generate traction force via phosphorylation of myosin light chain (MLC), but, ROCK2 alone generates traction force by suppressing F-actin depolymerization after phosphorylation of LIMK that inactivates cofilin (Figure 2) (14,121). Taken together, the combined actions of ROCK1 and ROCK2 promote the cross-linking and assembly of filamentous actin with myosin, which enhances cytoskeletal contractility (122–124). In addition, ROCK also increases collagen deposition and β-catenin accumulation in the nucleus, resulting in increased tumor size, number, and rigidity (105,125). This eventually triggers associated signaling pathways, including ROCK per se, leading to a positive feedback mechanism. Table 2 shows that ROCK has been found to be regulated in different types of cancer, which proves the importance of their presence in tumorigenesis. Thus, targeting the ROCK pathway is a promising “bullet” to reduce tumor progression (93).