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Micronutrients in Improvement of the Standard Therapy in Cancer
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Gastric cancer cells have low expression of miR-133a, miR-128b, miR-9, miR-126, and miR-124, but have high levels of their respective proteins TAGLN2 (transgelin 2), A2bR (adenosine A2b receptor), TNFAIP8 (TNF-alpha-induced protein 8), Crk (vsrc sarcoma virus CT10 oncogene homolog), and ROCK1 (Rho-associated protein kinase 1) compared to normal tissues. These elevated levels of proteins play a role in cell proliferation, migration, and invasion. Overexpression of these microRNAs inhibited their respective target proteins and reduced the growth, migration, and invasion of tumor cells in culture.15–19 The results are summarized in Table 8.1.
Specialization in individual circulations
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
Multiple controversial mechanisms have been suggested to underlie HPV. HPV has been studied in isolated pulmonary vessels and whole lung. There is growing agreement that hypoxia is ‘sensed’ by the vessel mitochondria, which generate reactive O2 species, but how this leads to vasoconstriction is not fully understood. One mechanism involves myocyte depolarization as K+ channels are inhibited (a KV isoform and a potassium channel subfamily K member 3, or TASK channel isoform). A second mechanism is sarcoplasmic reticulum Ca2+ store release via ryanodine receptors (for example, via cyclic adenosine diphosphate ribose or reactive O2 species) and Ca2+ entry through voltage-gated and store-operated channels, a process shown to be critical for early HPV. Over the next 20-40 min, HPV increases further, but cytosolic [Ca2+] does not, indicating a third, slower mechanism, Ca2+ sensitization. The slow phase is partly endothelium-dependent and is mediated by the Ca2+-sensitizing kinase, Rho-associated protein kinase (Section 12.5). Sustained HPV is largely blocked by inhibitors of Rho-associated protein kinase.
Medical Therapy for Glaucoma
Published in Neil T. Choplin, Carlo E. Traverso, Atlas of Glaucoma, 2014
Jennifer E. Williamson, Janet B. Serle
Several potential new targets for antiglaucoma drugs have also been identified in recent years. These include adenosine receptors, angiotensin II receptors, cannabinoid receptors, serotonin receptorsactin receptors and rho-associated protein kinase. It is anticipated that additional receptors will be identified that mediate ocular outflow and aqueous inflow, leading to development of new drugs that act at these receptors. One class of compounds, Rho kinase inhibitors (ROCK) appears promising in preclinical and early clinical trials. The topical Rho kinase inhibitor AR-12286 has been shown in recent clinical trials to produce significant clinical and statistical reductions in IOP in a dose-dependent manner. Mean IOP reductions were 4.4–6.8 mmHg from baseline at peak effect. The only adverse effect of note was transient conjunctival hyperemia.
The herbicide paraquat-induced molecular mechanisms in the development of acute lung injury and lung fibrosis
Published in Critical Reviews in Toxicology, 2021
Rajasekaran Subbiah, Rajnarayan R. Tiwari
MAP kinases, namely, ERK1/2, JNK, and p38 kinase, are involved in a broad range of cellular responses, including activation of inflammatory responses in the lungs following exposure to environmental toxicants. In alveolar epithelial type 2 cells, PQ treatment-induced EMT, which was mediated through the MAPK signaling (Huang, Wang, et al. 2016). However, inhibitors against MAPK attenuated PQ-induced EMT, which implies that the MAPK pathway is a therapeutic target in the PQ-mediated EMT process. Also, JNK inhibitor (SP600125) attenuated PQ-induced ALI by decreasing AP-1 transcriptional activity, ROS generation, apoptosis, and expression of proinflammatory genes (TNF-α and IL-6) (Shen, Wu, Wang, Han, et al. 2017). Similarly, the Rho-associated protein kinase (ROCK) signaling peptide is reported to mediate the inflammatory response, oxidative stress, cell apoptosis, Txnip/Trx (thioredoxin) expressions, and NF-kB activation following PQ exposure (Chen et al. 2016; Zhang, Li, et al. 2018). However, a rock kinase inhibitor (Fasudil) can inhibit the changes mentioned above and prevent PQ-induced ALI.
Therapeutic targets and early stage clinical trials for pulmonary fibrosis
Published in Expert Opinion on Investigational Drugs, 2019
Seidai Sato, Toyoshi Yanagihara, Martin R. J. Kolb
KD025 (or SLX-2119; Kadmon Corporation, LLC) is an orally administered selective Rho-associated protein kinase 2 (ROCK2) inhibitor. Healing responses to tissue injury involve reorganization of the actin cytoskeleton of participating cells, which is directed by the ROCK family of serine/threonine kinases, including ROCK1 and ROCK2 [47]. ROCK activation has been demonstrated in the lungs of patients with IPF and mice with bleomycin-induced lung fibrosis [48]. Myofibroblasts isolated from the lungs of patients with IPF demonstrated high constitutive ROCK activity compared with those from normal lungs [48]. KD025 has anti-inflammatory effects in human T cells and dose-dependently attenuated lung fibrosis in a bleomycin-induced fibrosis model [49].
MiR-199a targeting ROCK1 to affect kidney cell proliferation, invasion and apoptosis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Zhigang Qin, Xin Wei, Ning Jin, Yao Wang, Rui Zhao, Yangqing Hu, Weijian Yan, Junke Li, Qiaoling Zhou
Rho-associated protein kinase 1 (ROCK1), which belongs to the AGC family of serine/threonine protein kinases, plays an important role in the regulation of the actin cytoskeleton through the phosphorylation of downstream substrates leading to actin filament stabilization and the modulation of actin-myosin contractility [13]. Increased expression of ROCK1 has been described in several human cancers and has been correlated with poor survival in breast cancer and in renal cancer [13]. Sequestration of activated ROCK1 into cancer cells prevented ROCK1 from interacting with JNK-interacting protein 3 (JIP-3) and its activation of c-Jun N-terminal kinase (JNK), a pathway triggering apoptosis, thereby protecting cells from apoptosis [14].