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Mitochondrial pharmacology

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https://www.readbyqxmd.com/read/29150539/ros-and-glutathionylation-balance-cytoskeletal-dynamics-in-neutrophil-extracellular-trap-formation
#1
Darko Stojkov, Poorya Amini, Kevin Oberson, Christiane Sokollik, Andrea Duppenthaler, Hans-Uwe Simon, Shida Yousefi
The antimicrobial defense activity of neutrophils partly depends on their ability to form neutrophil extracellular traps (NETs), but the underlying mechanism controlling NET formation remains unclear. We demonstrate that inhibiting cytoskeletal dynamics with pharmacological agents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA release required for NET formation. Wiskott-Aldrich syndrome protein-deficient neutrophils are unable to polymerize actin and exhibit a block in both degranulation and DNA release...
November 17, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29148034/role-of-p62-sqstm1-beyond-autophagy-a-lesson-learned-from-drug-induced-toxicity-in-vitro
#2
Fernando Alegre, Ángela B Moragrega, Miriam Polo, Alberto Marti-Rodrigo, Juan V Esplugues, Ana Blas-Garcia, Nadezda Apostolova
BACKGROUND AND PURPOSE: SQSTM1/p62 is a multifunctional, stress-induced, scaffold protein involved in multiple cellular processes including autophagic clearance, regulation of inflammatory responses and redox homeostasis. Alterations in its function have been associated with a long list of human pathologies such as neurodegenerative, metabolic and bone diseases (down-regulation), and cancerogenesis (up-regulation). However, its role in the off-target effects of clinically used drugs is still not understood...
November 17, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29146527/osthole-attenuates-right-ventricular-remodeling-via-decreased-myocardial-apoptosis-and-inflammation-in-monocrotaline-induced-rats
#3
Yeli Li, Yiqi Li, Fuguo Shi, Lina Wang, Lisheng Li, Danli Yang
Osthole (Ost) is a coumarin that exhibits wide pharmacological effects in the cardiovascular system. However, whether Ost can inhibit apoptosis and inflammation in right ventricle (RV) cardiomyocytes and prevent RV remodeling is not clear. This study was designed to investigate the effect of Ost on RV remodeling and the underlying mechanism. By applying a monocrotaline (MCT)-induced rat model, the effect of Ost on RV remodeling was investigated. Rats were given a single dose of MCT (50mg⁄kg) subcutaneously (s...
November 13, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29144508/ly6g-neutrophil-derived-mir-223-inhibits-the-nlrp3-inflammasome-in-mitochondrial-damp-induced-acute-lung-injury
#4
Zunyong Feng, Shimei Qi, Yue Zhang, Zhilin Qi, Liang Yan, Jing Zhou, Fang He, Qianqian Li, Yanyan Yang, Qun Chen, Shi Xiao, Qiang Li, Yang Chen, Yao Zhang
MicroRNA (miRNA) mediates RNA interference to regulate a variety of innate immune processes, but how miRNAs coordinate the mechanisms underlying acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with pulmonary inflammatory injury is still unknown. In this study, we demonstrated that miR-223 limits the number of Ly6G+ neutrophils and inhibits the activity of the NLRP3 inflammasome to alleviate ALI induced by mitochondrial damage-associated molecular patterns (DAMPs) (MTDs). miR-223 expression is increased in the lungs of MTD-induced mice or ARDS patients following trauma/transfusion or following the physiological remission of ALI/ARDS...
November 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29141243/trolline-ameliorates-liver-fibrosis-by-inhibiting-the-nf-%C3%AE%C2%BAb-pathway-promoting-hsc-apoptosis-and-suppressing-autophagy
#5
Facheng Bai, Quanfang Huang, Jinlan Nie, Shengjuan Lu, Chunyuan Lu, Xunshuai Zhu, Yuxin Wang, Lang Zhuo, Zhongpeng Lu, Xing Lin
BACKGROUND/AIMS: Previous studies have shown that trolline possesses various forms of pharmacological activity, including antibacterial and antiviral potency. The present paper addressed the putative hepatoprotective effects of trolline. METHODS: Rats received 2 ml/kg CCl4 (mixed 1: 1 in peanut oil) intragastrically twice a week for 8 weeks to induce hepatic fibrosis. The animals were then treated with trolline for additional 4 weeks. Liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively...
November 15, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29138502/crystal-structures-of-the-mitochondrial-deacylase-sirtuin-4-reveal-isoform-specific-acyl-recognition-and-regulation-features
#6
Martin Pannek, Zeljko Simic, Matthew Fuszard, Marat Meleshin, Dante Rotili, Antonello Mai, Mike Schutkowski, Clemens Steegborn
Sirtuins are evolutionary conserved NAD(+)-dependent protein lysine deacylases. The seven human isoforms, Sirt1-7, regulate metabolism and stress responses and are considered therapeutic targets for aging-related diseases. Sirt4 locates to mitochondria and regulates fatty acid metabolism and apoptosis. In contrast to the mitochondrial deacetylase Sirt3 and desuccinylase Sirt5, no prominent deacylase activity and structural information are available for Sirt4. Here we describe acyl substrates and crystal structures for Sirt4...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29136945/mitochondria-protection-as-a-mechanism-underlying-the-hepatoprotective-effects-of-glycine-in-cholestatic-mice
#7
Reza Heidari, Vahid Ghanbarinejad, Hamidreza Mohammadi, Asrin Ahmadi, Mohammad Mehdi Ommati, Narges Abdoli, Fatemeh Aghaei, Athena Esfandiari, Negar Azarpira, Hossein Niknahad
Cholestasis is the stoppage of bile flow which could lead to serious clinical complications if not managed. Cytotoxic bile acids are involved in the pathogenesis of liver injury during cholestasis. There are no promising pharmacological interventions against cholestasis and its associated complications. This study examined the impact of glycine supplementation on liver mitochondria as a major target of bile acids-induced toxicity during cholestasis. Mice underwent BDL operation and received glycine (0.25% and 1% w:v in drinking water)...
November 9, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29136773/the-potential-use-of-melatonin-to-treat-protozoan-parasitic-infections-a-review
#8
REVIEW
Ahmad Daryani, Mahbobeh Montazeri, Abdol Satar Pagheh, Mehdi Sharif, Shahabeddin Sarvi, Azam Hosseinzadeh, Russel J Reiter, Ramtin Hadighi, Mohammad Taghi Joghataei, Habib Ghaznavi, Saeed Mehrzadi
Melatonin (N-acetyl-5-methoxytryptamine) is a circadian hormone produced in vertebrates by the pineal gland and other organs. Melatonin is believed to influence immune cells leading to modulation of the proliferative response of stimulated lymphocytes as well as cytokine production. Due to the antioxidant and immunomodulatory effects of melatonin, it is suggested that this molecule could be a therapeutic alternative agent to fight bacterial, viral, and parasitic infections by a variety of mechanisms. Herein, we review the effects of melatonin on the cell biology of protozoan parasites and host's immune response...
November 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29135158/-the-role-of-pharmacological-preconditioning-in-renal-ischemic-and-reperfusion-injury
#9
D A Kostina, T G Pokrovskaya, Yu V Olefir, A N Yavorskii, V V Elagin
Renal ischemic and reperfusion injury resulting in acute renal failure is a multidisciplinary problem at the junction of pathophysiology, transplantology, urology, nephrology, cardiac surgery and pharmacology. One of renal protection strategies is using the phenomenon of preconditioning. Preconditioning is one of the ways to adopt a tissue to repeated short-term effects of damaging factors to induce an enhanced tolerance to the long period of hypoxia and/or ischemia. There are multiple cellular and molecular mechanisms of the renal protective effects of preconditioning stimuli, but the key effectors and signaling molecules are ATP-dependent potassium channels, nitric oxide synthase, nitric oxide, and mitochondrial pore...
October 2017: Urologii︠a︡
https://www.readbyqxmd.com/read/29133339/decreased-ceramide-underlies-mitochondrial-dysfunction-in-charcot-marie-tooth-2f
#10
Nicholas U Schwartz, Ryan W Linzer, Jean-Philip Truman, Mikhail Gurevich, Yusuf A Hannun, Can E Senkal, Lina M Obeid
Charcot-Marie-Tooth (CMT) disease is the most commonly inherited neurologic disorder, but its molecular mechanisms remain unclear. One variant of CMT, 2F, is characterized by mutations in heat shock protein 27 (Hsp27). As bioactive sphingolipids have been implicated in neurodegenerative diseases, we sought to determine if their dysregulation is involved in CMT. Here, we show that Hsp27 knockout mice demonstrated decreases in ceramide in peripheral nerve tissue and that the disease-associated Hsp27 S135F mutant demonstrated decreases in mitochondrial ceramide...
November 13, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29131445/airyscan-super-resolution-microscopy-of-mitochondrial-morphology-and-dynamics-in-living-tumor-cells
#11
Vladimir L Kolossov, Mayandi Sivaguru, Joseph Huff, Katherine Luby, Kaviamuthan Kanakaraju, H Rex Gaskins
Mitochondrial morphology is regulated by continuous fusion-and-fission events that are essential for maintaining normal function. Despite the prominence of mitochondrial function in energy generation and cell signaling, understanding of processes of fusion and fission dynamics has been hampered by the lack of high-resolution optical systems that accommodate live-cell imaging. We have examined different confocal modalities in terms of resolution and signal-to-noise ratio (SNR) in a point scanning confocal microscope with Airyscan super-resolution (AS-SR)...
November 13, 2017: Microscopy Research and Technique
https://www.readbyqxmd.com/read/29129787/cd38-nad-axis-regulates-immunotherapeutic-anti-tumor-t-cell-response
#12
Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Megan W Wyatt, Payal Dhar, Shanmugam Paneer Selvam, Jianing Fu, Jinyu Zhang, Hung Nguyen, Inhong Kang, Kyle Toth, Mazen Al-Homrani, Mahvash Husain, Gyda Beeson, Lauren Ball, Kristi Helke, Shahid Husain, Elizabeth Garrett-Mayer, Gary Hardiman, Meenal Mehrotra, Michael I Nishimura, Craig C Beeson, Melanie Gubbels Bupp, Jennifer Wu, Besim Ogretmen, Chrystal M Paulos, Jeffery Rathmell, Xue-Zhong Yu, Shikhar Mehrotra
Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD(+)-dependent activity of the histone deacetylase Sirt1...
November 8, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29128343/post-stroke-depression-mechanisms-and-pharmacological-treatment
#13
REVIEW
Roberto Federico Villa, Federica Ferrari, Antonio Moretti
Depression, the most frequent psychiatric disorder following ischaemic stroke, negatively affects survivals' functional outcome, response to rehabilitation and quality of life. Approximately, one-third of them are affected by post-stroke depression (PSD), making it a serious social and public health problem and anti-depressant preventive and curative therapies worth investigating. However, a two-way association between depression and stroke has been also established: stroke increases the risk of PSD, but depression is an independent risk factor for stroke...
November 8, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29127235/cardiac-performance-is-limited-by-oxygen-delivery-to-the-mitochondria-in-the-crystalloid-perfused-working-heart
#14
Sarah Kuzmiak-Glancy, Raul Covian, Armel N Femnou, Brian Glancy, Rafael Jaimes, Anastasia M Wengrowski, Kara Garrott, Stephanie French, Robert S Balaban, Matthew W Kay
The left ventricular (LV) working, crystalloid-perfused heart is used extensively to evaluate basic cardiac function, pathophysiology, and pharmacology. Crystalloid-perfused hearts may be limited by oxygen delivery, as adding oxygen carriers increases myoglobin oxygenation and improves myocardial function. However, whether decreased myoglobin oxygen saturation impacts oxidative phosphorylation (OxPhos) is unresolved since myoglobin has a much lower affinity for oxygen than cytochrome c oxidase (COX). In the present study, a laboratory-based synthesis of an affordable perfluorocarbon (PFC) emulsion was developed to increase perfusate oxygen-carrying capacity without impeding optical absorbance assessments...
November 10, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29118048/rank-rewires-energy-homeostasis-in-lung-cancer-cells-and-drives-primary-lung-cancer
#15
Shuan Rao, Verena Sigl, Reiner Alois Wimmer, Maria Novatchkova, Alexander Jais, Gabriel Wagner, Stephan Handschuh, Iris Uribesalgo, Astrid Hagelkruys, Ivona Kozieradzki, Luigi Tortola, Roberto Nitsch, Shane J Cronin, Michael Orthofer, Daniel Branstetter, Jude Canon, John Rossi, Manolo D'Arcangelo, Johan Botling, Patrick Micke, Linnea La Fleur, Karolina Edlund, Michael Bergqvist, Simon Ekman, Thomas Lendl, Helmut Popper, Hiroshi Takayanagi, Lukas Kenner, Fred R Hirsch, William Dougall, Josef M Penninger
Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts...
November 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/29117569/ros-control-mitochondrial-motility-through-p38-and-the-motor-adaptor-miro-trak
#16
Valentina Debattisti, Akos A Gerencser, Masao Saotome, Sudipto Das, György Hajnóczky
Mitochondrial distribution and motility are recognized as central to many cellular functions, but their regulation by signaling mechanisms remains to be elucidated. Here, we report that reactive oxygen species (ROS), either derived from an extracellular source or intracellularly generated, control mitochondrial distribution and function by dose-dependently, specifically, and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca(2+)], mitochondrial membrane potential, or permeability transition pore opening, known effectors of oxidative stress...
November 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/29115629/oxymatrine-induces-a549-human-non%C3%A2-small-lung-cancer-cell-apoptosis-via-extrinsic-and-intrinsic-pathways
#17
Guang-Zhou Zhou, Yan-Yan Shi, Liu-Su Cui, A-Fang Li, Qing-Qing Wang, Min Liu
Oxymatrine is one of the primary natural compounds extracted from the Sophora flavescens, and has been reported to exhibit numerous pharmacological properties including cancer‑preventive and anti‑cancer effects, however the mechanisms as to how oxymatrine exhibits anti‑proliferative activity in non‑small cell lung carcinoma cells remains uncertain. The present study aimed to explore the mechanism of its anti‑cancer effect, and whether it is due to apoptosis induction and anti‑migration in the A549 lung cancer cell line...
November 6, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29113217/grape-seed-proanthocyanidins-induce-mitochondrial-pathway-mediated-apoptosis-in-human-colorectal-carcinoma-cells
#18
Chen Zhang, Weili Chen, Xuhao Zhang, Yanbing Zheng, Fengli Yu, Yulong Liu, Yi Wang
Grape seed proanthocyanidins (GSPs) have been reported to possess a wide array of pharmacological and biochemical properties. Recently, GSPs have been reported to inhibit various types of colorectal cancer; however, the mechanism(s) involved remain unclear. The present study investigated the effects of GSPs on HCT-116 human colorectal carcinoma cell line. Exposure of these cells to GSPs for 48 h resulted in a significant concentration-dependent inhibition of cell viability. Further investigation indicated that GSPs induced apoptosis of these cells...
November 2017: Oncology Letters
https://www.readbyqxmd.com/read/29109080/central-leptin-regulates-heart-lipid-content-by-selectively-increasing-ppar-%C3%AE-%C3%AE-expression
#19
Cristina Mora, Cristina Pintado, Blanca Rubio, Lorena Mazuecos, Virginia Lopez, Alejandro Fernandez, Aurora Salamanca, Brenda Barcena, Teresa Fernandez-Agullo, Carmen Arribas, Nilda Gallardo, Antonio Andres
The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective up-regulation of gene and protein expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and their target genes, adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), pyruvate dehydrogenase kinase 4 (PDK4), and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization...
November 6, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/29107291/absence-of-the-kinase-s6k1-mimics-the-effect-of-chronic-endurance-exercise-on-glucose-tolerance-and-muscle-oxidative-stress
#20
C Binsch, T Jelenik, A Pfitzer, M Dille, S Müller-Lühlhoff, S Hartwig, S Karpinski, S Lehr, D G Kabra, A Chadt, M Roden, H Al-Hasani, T R Castañeda
OBJECTIVE: Ribosomal protein S6 Kinase-1 (S6K1) has been linked to resistance exercise-mediated improvements in glycemia. We hypothesized that S6K1 may also play a role in regulating glycemic control in response to endurance exercise training. METHODS: S6k1-knockout (S6K1KO) and WT mice on a 60 cal% high-fat diet were trained for 4 weeks on treadmills, metabolically phenotyped, and compared to sedentary controls. RESULTS: WT mice showed improved glucose tolerance after training...
November 2017: Molecular Metabolism
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