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(ROCK OR Rho) AND mitochondri*

Anthony Tolcher, Keith Flaherty, Geoffrey I Shapiro, Jordan Berlin, Thomas Witzig, Thomas Habermann, Andrea Bullock, Edwin Rock, Agnes Elekes, Chester Lin, Dusan Kostic, Naoto Ohi, Drew Rasco, Kyriakos P Papadopoulos, Amita Patnaik, Lon Smith, Gregory M Cote
LESSONS LEARNED: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy...
March 6, 2018: Oncologist
Xin Tan, Aizhang Xu, Tuo Zhao, Qin Zhao, Jun Zhang, Cuihong Fan, Yulin Deng, Andrew Freywald, Harald Genth, Jim Xiang
Simulated microgravity (SMG) was reported to affect tumor cell proliferation and metastasis. However, the underlying mechanism is elusive. In this study, we demonstrate that clinostat-modelled SMG reduces BL6-10 melanoma cell proliferation, adhesion and invasiveness in vitro and decreases tumor lung metastasis in vivo. It down-regulates metastasis-related integrin α6β4, MMP9 and Met72 molecules. SMG significantly reduces formation of focal adhesions and activation of focal adhesion kinase (FAK) and Rho family proteins (RhoA, Rac1 and Cdc42) and of mTORC1 kinase, but activates AMPK and ULK1 kinases...
February 28, 2018: Scientific Reports
A J Idowu, S L Kumar, B Yidong, R Russel
Mitochondrial dysfunction has been shown to be associated with normal ageing and may account for age-related vulnerability to disease. The increasing number of old people worldwide has created the need to find effective therapeutic agents to reduce the incidence of age-related disease. In the current report, we carried out an assessment of mitochondrial function in established young, middle-aged and old synaptosomal mitochondria bearing cybrids without or with melatonin treatment. The cybrids were generated by transferring isolated mitochondria from synaptosomes of brain cortical cells in mice to rho-zero mtDNA-less cells...
December 30, 2017: Nigerian Journal of Physiological Sciences: Official Publication of the Physiological Society of Nigeria
George B Stefano, Fuzhou Wang, Richard M Kream
Over the course of history, human beings have never stopped seeking effective methods for information storage. From rocks to paper, and through the past several decades of using computer disks, USB sticks, and on to the thin silicon "chips" and "cloud" storage of today, it would seem that we have reached an era of efficiency for managing innumerable and ever-expanding data. Astonishingly, when tracing this technological path, one realizes that our ancient methods of informational storage far outlast paper (10,000 vs...
February 26, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Joon Tae Park, Hyun Tae Kang, Chi Hyun Park, Young-Sam Lee, Kyung A Cho, Sang Chul Park
In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells...
February 20, 2018: Experimental Gerontology
Matteo Zampini, Claudia Tregnago, Valeria Bisio, Luca Simula, Giulia Borella, Elena Manara, Carlo Zanon, Francesca Zonta, Valentina Serafin, Benedetta Accordi, Silvia Campello, Barbara Buldini, Andrea Pession, Franco Locatelli, Giuseppe Basso, Martina Pigazzi
The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Zhongwei Liu, Raouf A Khalil
Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca 2+ has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined...
February 13, 2018: Biochemical Pharmacology
Dawei Mu, Gaobiao Zhou, Jianye Li, Bin Su, Heqing Guo
Ursolic acid has various pharmacological activities, and can reduce blood fat as well as having antihepatic, antitumoral, anti-inflammatory and antiviral properties. However, the pro-apoptotic mechanism by which ursolic acid influences human prostate cancer requires additional study. The aim of the present study was to assess whether ursolic acid activates the apoptosis of prostate cancer and to investigate the mechanism by which the Rho-associated protein kinase 1 (ROCK1)/phosphatase and tensin homolog (PTEN) signaling pathway performs a role in ursolic acid-mediated cofilin-1 to induce apoptosis in human prostate cancer...
March 2018: Oncology Letters
Alessandra Antunes Dos Santos, Caridad López-Granero, Marcelo Farina, João B T Rocha, Aaron B Bowman, Michael Aschner
Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes...
February 8, 2018: Food and Chemical Toxicology
Alexandra M Huffman, Haotian Wu, Allyson Rosati, Tayyab Rahil, Cynthia K Sites, Brian W Whitcomb, J Richard Pilsner
BACKGROUND: Phthalates, a chemical class of plasticizers, are ubiquitous environmental contaminants that have been associated with oxidative stress. Mitochondria DNA copy number (mtDNAcn) and DNA deletions (mtDNAdel) are emerging biomarkers for cellular oxidative stress and environment exposures. OBJECTIVES: To examine associations of urinary phthalate metabolite and isoprostane concentrations on sperm mtDNAcn and mtDNAdel in male partners undergoing assisted reproductive technologies (ART)...
February 5, 2018: Environmental Research
Bruno K Rodiño-Janeiro, Cristina Martínez, Marina Fortea, Beatriz Lobo, Marc Pigrau, Adoración Nieto, Ana María González-Castro, Eloísa Salvo-Romero, Danila Guagnozzi, Cristina Pardo-Camacho, Cristina Iribarren, Fernando Azpiroz, Carmen Alonso-Cotoner, Javier Santos, Maria Vicario
Disturbed intestinal epithelial barrier and mucosal micro-inflammation characterize irritable bowel syndrome (IBS). Despite intensive research demonstrating ovarian hormones modulation of IBS severity, there is still limited knowledge on the mechanisms underlying female predominance in this disorder. Our aim was to identify molecular pathways involved in epithelial barrier dysfunction and female predominance in diarrhea-predominant IBS (IBS-D) patients. Total RNA and protein were obtained from jejunal mucosal biopsies from healthy controls and IBS-D patients meeting the Rome III criteria...
February 2, 2018: Scientific Reports
Kingsley Ibhazehiebo, Cezar Gavrilovici, Cristiane L de la Hoz, Shun-Chieh Ma, Renata Rehak, Gaurav Kaushik, Paola L Meza Santoscoy, Lucas Scott, Nandan Nath, Do-Young Kim, Jong M Rho, Deborah M Kurrasch
Despite the development of newer anti-seizure medications over the past 50 years, 30-40% of patients with epilepsy remain refractory to treatment. One explanation for this lack of progress is that the current screening process is largely biased towards transmembrane channels and receptors, and ignores intracellular proteins and enzymes that might serve as efficacious molecular targets. Here, we report the development of a novel drug screening platform that harnesses the power of zebrafish genetics and combines it with in vivo bioenergetics screening assays to uncover therapeutic agents that improve mitochondrial health in diseased animals...
January 24, 2018: Brain: a Journal of Neurology
Haifeng Zhang, Yajun Lian, Nanchang Xie, Yake Zheng
Epilepsy is a common disease of the central nervous system. This study aims to investigate the role of mitochondrial Rho (Miro) 1 in epilepsy using a mouse model of pilocarpine-induced status epilepticus (SE). Intraperitoneal injection of pilocarpine induced epileptic seizure in mice and significantly decreased Miro 1 expression in the hippocampus. Moreover, pilocarpine treatment increased the serum levels of heat shock protein 70 (HSP70) and S100 calcium binding protein B (S100B), and led to hippocampal neuronal injury and apoptosis...
January 24, 2018: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
Nobuyuki Morimoto, Riho Takei, Masaru Wakamura, Yoshifumi Oishi, Masafumi Nakayama, Makoto Suzuki, Masaya Yamamoto, Françoise M Winnik
Mitochondrial targeting and entry, two crucial steps in fighting severe diseases resulting from mitochondria dysfunction, pose important challenges in current nanomedicine. Cell-penetrating peptides or targeting groups, such as Rhodamine-B (Rho), are known to localize in mitochondria, but little is known on how to enhance their effectiveness through structural properties of polymeric carriers. To address this issue, we prepared 8 copolymers of 3-dimethyl(methacryloyloxyethyl)ammonium propane sulfonate and poly(ethyleneglycol) methacrylate, p(DMAPS-ran-PEGMA) (molecular weight, 18...
January 18, 2018: Scientific Reports
Yue-Liang Shen, Ying-Zhou Shi, Gai-Ge Chen, Lin-Lin Wang, Ming-Zhi Zheng, Hong-Feng Jin, Ying-Ying Chen
Dynamin-related peptide 1 (Drpl)-mediated mitochondrial fission is an important process associated with cardiac dysfunction under different pathological conditions. The aim of the present study was to investigate the expression of Drpl during inflammatory myocardial injury. Sprague‑Dawley rats were treated intraperitoneally with lipopolysaccharides (LPS). Furthermore, cultured H9C2 cardiomyocytes were treated with LPS, interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α). Total and mitochondrial proteins were isolated from the heart tissue of rats and from the H9C2 cardiomyocytes...
January 15, 2018: International Journal of Molecular Medicine
Fernando Lopes, Åsa V Keita, Alpana Saxena, Jose Luis Reyes, Nicole Mancini, Ala Al Rajabi, Arthur Wang, Cristiane Baggio, Michael Dicay, Rob van Dalen, Younghee Ahn, Matheus Carneiro, Nathan Peters, Jong M Rho, Wallace MacNaughton, Stephan E Girardin, Humberto Jijon, Dana J Philpott, Johan D Söderholm, Derek M McKay
The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin, and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria...
January 9, 2018: Journal of Biological Chemistry
Guillermo López-Doménech, Christian Covill-Cooke, Davor Ivankovic, Els F Halff, David F Sheehan, Rosalind Norkett, Nicol Birsa, Josef T Kittler
In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double-knockout mouse embryos and single- and double-knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double-knockout cells...
January 8, 2018: EMBO Journal
M Cecilia Pardo-Gandarillas, Felipe I Torres, Dirk Fuchs, Christian M Ibáñez
Two types of spawning strategy have been described for ommastrephid squids: coastal and oceanic. It has been suggested that ancestral ommastrephids inhabited coastal waters and expanded their distribution into the open ocean during global changes in ocean circulation in the Oligocene. This hypothesis could explain the different reproductive strategies in oceanic squids, but has never been tested in a phylogenetic context. In the present study, we assess the coastal-to-open-ocean hypothesis through inferring the evolution of reproductive traits (spawning type) of ommastrephid squids using the phylogenetic comparative method to estimate ancestral states and divergence times...
December 14, 2017: Molecular Phylogenetics and Evolution
Kanji Okumoto, Tatsuaki Ono, Ryusuke Toyama, Ayako Shimomura, Aiko Nagata, Yukio Fujiki
Microtubule-dependent long-distance movement of peroxisomes occurs in mammalian cells. However, its molecular mechanisms remain undefined. In this study, we identified three distinct splicing variants of human mitochondrial Rho GTPase-1 (Miro1), each containing amino acid sequence insertions 1 (named Miro1-var2), 2 (Miro1-var3), and both 1 and 2 (Miro1-var4), respectively, at upstream of the transmembrane domain. Miro1-var4 and Miro1-var2 are localized to peroxisomes in a manner dependent on the insertion 1 that is recognized by the cytosolic receptor Pex19p...
February 5, 2018: Journal of Cell Biology
Lingling Chen, Chunyan Liu, Jianfeng Gao, Zhiwen Xie, Lawrence W C Chan, Damien J Keating, Yibin Yang, Jiazhong Sun, Fuling Zhou, Yongchang Wei, Xiuli Men, Sijun Yang
Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified...
October 31, 2017: Oncotarget
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