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Mitochondrial pharmacology

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https://www.readbyqxmd.com/read/29793167/improvement-of-neuronal-differentiation-by-carbon-monoxide-role-of-pentose-phosphate-pathway
#1
Ana S Almeida, Nuno L Soares, Catarina O Sequeira, Sofia A Pereira, Ursula Sonnewald, Helena L A Vieira
Over the last decades, the silent-killer carbon monoxide (CO) has been shown to also be an endogenous cytoprotective molecule able to inhibit cell death and modulate mitochondrial metabolism. Neuronal metabolism is mostly oxidative and neurons also use glucose for maintaining their anti-oxidant status by generation of reduced glutathione (GSH) via the pentose-phosphate pathway (PPP). It is established that neuronal differentiation depends on reactive oxygen species (ROS) generation and signalling, however there is a lack of information about modulation of the PPP during adult neurogenesis...
May 15, 2018: Redox Biology
https://www.readbyqxmd.com/read/29790582/acetyl-coa-carboxylase-inhibition-reverses-nafld-and-hepatic-insulin-resistance-but-promotes-hypertriglyceridemia-in-rodents
#2
Leigh Goedeke, Jamie Bates, Daniel F Vatner, Rachel J Perry, Ting Wang, Ricardo Ramirez, Li Li, Matthew W Ellis, Dongyan Zhang, Kari E Wong, Carine Beysen, Gary W Cline, Adrian S Ray, Gerald I Shulman
Pharmacologic inhibition of acetyl-CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for non-alcoholic fatty liver disease (NAFLD) via simultaneous inhibition of fatty acid synthesis and stimulation of fatty acid oxidation. However, the effects of ACC inhibition on hepatic mitochondrial oxidation, anaplerosis, and ketogenesis in vivo are unknown. Here, we evaluated the impact of a novel liver-directed allosteric inhibitor of ACC1 and ACC2 (Compound 1) on these parameters, as well as glucose and lipid metabolism, in control and diet-induced rodent models of NAFLD...
May 23, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29790287/synthesis-biological-activity-and-mechanism-of-action-of-2-pyrazyl-and-pyridylhydrazone-derivatives-new-classes-of-antileishmanial-agents
#3
Marcus De Souza, Elaine S Coimbra, Luciana M R Antinarelli, Mariana A Crispi, Thais C M Nogueira, Alessandra C Pinheiro
In this work, we report the antileishmanial activity of twenty three compounds based on 2-pyrazyl and pyridylhydrazones derivatives. Compounds were tested against the promastigotes of Leishmania amazonensis and L. braziliensis, murine macrophages and intracellular L. amazonensis amastigotes. The most potent antileishmanial compound was selected to investigate its mechanism of action. Among the evaluated compounds, five derivatives (2b, 2c, 2s, 2u and 2v) exhibited significant activity against L. amazonensis amastigote forms, with IC50 values below 20 µM...
May 22, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29789578/sk-channel-activation-is-neuroprotective-in-conditions-of-enhanced-er-mitochondrial-coupling
#4
Birgit Honrath, Inge E Krabbendam, Carmen IJsebaart, Valentina Pegoretti, Nadia Bendridi, Jennifer Rieusset, Martina Schmidt, Carsten Culmsee, Amalia M Dolga
Alterations in the strength and interface area of contact sites between the endoplasmic reticulum (ER) and mitochondria contribute to calcium (Ca2+ ) dysregulation and neuronal cell death, and have been implicated in the pathology of several neurodegenerative diseases. Weakening this physical linkage may reduce Ca2+ uptake into mitochondria, while fortifying these organelle contact sites may promote mitochondrial Ca2+ overload and cell death. Small conductance Ca2+ -activated K+ (SK) channels regulate mitochondrial respiration, and their activation attenuates mitochondrial damage in paradigms of oxidative stress...
May 22, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29786646/metabolic-reprogramming-by-3-iodothyronamine-t1am-a-new-perspective-to-reverse-obesity-through-co-regulation-of-sirtuin-4-and-6-expression
#5
Fariba M Assadi-Porter, Hannah Reiland, Martina Sabatini, Leonardo Lorenzini, Vittoria Carnicelli, Micheal Rogowski, Ebru S Selen Alpergin, Marco Tonelli, Sandra Ghelardoni, Alessandro Saba, Riccardo Zucchi, Grazia Chiellini
Obesity is a complex disease associated with environmental and genetic factors. 3-Iodothyronamine (T1AM) has revealed great potential as an effective weight loss drug. We used metabolomics and associated transcriptional gene and protein expression analysis to investigate the tissue specific metabolic reprogramming effects of subchronic T1AM treatment at two pharmacological daily doses (10 and 25 mg/kg) on targeted metabolic pathways. Multi-analytical results indicated that T1AM at 25 mg/kg can act as a novel master regulator of both glucose and lipid metabolism in mice through sirtuin-mediated pathways...
May 22, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29785004/a-direct-tissue-grafting-approach-to-increasing-endogenous-brown-fat
#6
Nicole R Blumenfeld, Hwan June Kang, Anna Fenzl, Ziwei Song, Janice J Chung, Ranjodh Singh, Roshawn Johnson, Ayse Karakecili, Jun B Feranil, Ninna S Rossen, Vivian Zhang, Sahir Jaggi, Bret McCarty, Steven Bessler, Gary J Schwartz, Robert Grant, Judith Korner, Florian W Kiefer, Brian M Gillette, Samuel K Sia
There is widespread evidence that increasing functional mass of brown adipose tissue (BAT) via browning of white adipose tissue (WAT) could potentially counter obesity and diabetes. However, most current approaches focus on administration of pharmacological compounds which expose patients to highly undesirable side effects. Here, we describe a simple and direct tissue-grafting approach to increase BAT mass through ex vivo browning of subcutaneous WAT, followed by re-implantation into the host; this cell-therapy approach could potentially act synergistically with existing pharmacological approaches...
May 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29784665/srebf1-activity-is-regulated-by-an-ar-mtor-nuclear-axis-in-prostate-cancer
#7
Etienne Audet-Walsh, Mathieu Vernier, Tracey Yee, Chloe E Laflamme, Susan Li, Yonghong Chen, Vincent Giguere
Reprogramming of cellular metabolism is an important feature of prostate cancer (PCa), including altered lipid metabolism. Recently, it was observed that the nuclear fraction of mTOR is essential for the androgen-mediated metabolic reprogramming of PCa cells. Herein, it is demonstrated that the androgen receptor (AR) and mTOR bind to regulatory regions of sterol regulatory element binding transcription factor 1 (SREBF1) to control its expression, while dual activation of these signaling pathways also promotes SREBF1 cleavage and its translocation to the nucleus...
May 21, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29782965/membrane-cholesterol-delays-cellular-apoptosis-induced-by-ginsenoside-rh2-a-steroid-saponin
#8
Sandrine L Verstraeten, Marie Albert, Adrien Paquot, Giulio G Muccioli, Donatienne Tyteca, Marie-Paule Mingeot-Leclercq
Saponins exhibit several biological and pharmacological activities, such as antibacterial, anti-inflammatory and anticancer effects. Many studies attribute their activities to their interactions with cholesterol. In this study, we focus on the steroid saponin ginsenoside Rh2, one of the active principles of Panax ginseng root. Some evidence suggests that lipid rafts, defined as nanodomains enriched in cholesterol and sphingolipids, could be involved in the Rh2-induced apoptosis. However, the role of membrane lipids, especially cholesterol, in this process is still poorly understood...
May 18, 2018: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/29774530/cardiomyocyte-programmed-necrosis-mitochondria-death-receptor-and-beyond
#9
REVIEW
Junxia Zhang, Dairu Liu, Mao Zhang, Yan Zhang
Excessive death of cardiac myocytes leads to multiple cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of multiple organs, including the heart...
May 18, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29768044/cocl2-induces-apoptosis-via-ros-dependent-pathway-and-drp1-mediated-mitochondria-fission-in-the-periodontal-ligament-stem-cells
#10
Yuting He, Xueqi Gan, Ling Zhang, Beilei Liu, Zhuoli Zhu, Tao Li, Junfei Zhu, Junsheng Chen, Haiyang Yu
Oxygen deficiency is associated with various oral diseases, including chronic periodontitis, age-related alveolar bone loss and mechanical stress-linked cell injury from orthodontic appliances. Nevertheless, our understanding of the impact of hypoxia on periodontal tissues and its biochemical mechanism is still rudimentary. The purpose of this research was to elucidate the effects of hypoxia on the apoptosis of human periodontal ligament stem cells (PDLSCs) in vitro and the underlying mechanism. Herein, we showed that CoCl2 triggered cell dysfunction in human PDLSCs in a concentration-dependent manner and resulted in cell apoptosis and oxidative stress overproduction and accumulation in PDLSCs...
May 16, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29766157/dual-acting-antitumor-pt-iv-prodrugs-of-kiteplatin-with-dichloroacetate-axial-ligands
#11
Salvatore Savino, Valentina Gandin, James D Hoeschele, Cristina Marzano, Giovanni Natile, Nicola Margiotta
With the aim to obtain dual acting drugs able to target both nuclear DNA and mitochondria, Pt(iv) kiteplatin derivatives having dichloroacetate (DCA) ligands in axial positions have been synthesized. The rather fast hydrolysis (t1/2 of ca. 1 h) and reduction (by ascorbic acid) of these Pt(iv) derivatives did not impede a potent pharmacological effect on tumor cells. Moreover, similarly to kiteplatin, also the Pt(iv)-DCA compounds proved to be capable of overcoming oxaliplatin-resistance, which is particularly important in view of the fact that metastatic colorectal cancer is the third most common cancer in males and the second in females...
May 16, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/29761845/the-o-methylated-isoflavone-formononetin-inhibits-human-ovarian-cancer-cell-proliferation-by-sub-g0-g1-cell-phase-arrest-through-pi3k-akt-and-erk1-2-inactivation
#12
Sunwoo Park, Fuller W Bazer, Whasun Lim, Gwonhwa Song
Formononetin is an isoflavone that is extracted from red clovers or soy. It has anti-oxidant, anti-proliferative, and anti-tumor effects against cells in various diseases. Several cohort studies have indicated that phytoestrogen intake, including formononetin, could reduce the risk of various carcinogenesis. In fact, many case-control studies have indicated the potential value of flavonoids as drug supplements in the treatment of many cancer patients. However, the toxic effects and the anti-cancer mechanism of formononetin in ovarian cancer are unknown...
May 15, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29753686/pharmacological-inhibition-of-the-mitochondrial-nadph-oxidase-4-pkc%C3%AE-gal-3-pathway-reduces-left-ventricular-fibrosis-following-myocardial-infarction
#13
Maria Del Carmen Asensio-Lopez, Antonio Lax Perez, Maria Josefa Fernandez Del Palacio, Yassine Sassi, Roger J Hajjar, Domingo A Pascual-Figal
Although the initial reparative fibrosis after myocardial infarction (MI) is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental. Although metformin prevents adverse cardiac remodeling, as well as provides glycemic control, the underlying mechanisms remain poorly documented. This study describes the effect of mitochondrial NADPH oxidase 4 (mitoNox) and protein kinase C-alpha (PKCα) on the cardiac fibrosis and galectin 3 (Gal-3) expression...
April 23, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/29752433/palmitic-acid-but-not-high-glucose-induced-myocardial-apoptosis-is-alleviated-by-n%C3%A2-acetylcysteine-due-to-attenuated-mitochondrial-derived-ros-accumulation-induced-endoplasmic-reticulum-stress
#14
Yang He, Lingyun Zhou, Zhiqiang Fan, Shikun Liu, Weijin Fang
Pharmacological inhibition of reactive oxygen species (ROS) is a potential strategy to prevent diabetes-induced cardiac dysfunction. This study was designed to investigate precise effects of antioxidant N‑acetylcysteine (NAC) in alleviating diabetic cardiomyopathy (DCM). Echocardiography and histologic studies were performed 12 weeks after streptozocin injection. Protein levels involved in endoplasmic reticulum stress (ERS) and apoptosis were analyzed by western blotting in diabetic hearts or high-glucose (HG, 30 mM)- and palmitic acid (PA, 300 μM)-cultured neonatal rat cardiomyocytes (NRCMs)...
May 11, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29750781/metabolic-benefits-of-inhibition-of-p38%C3%AE-in-white-adipose-tissue-in-obesity
#15
Shengjie Zhang, Hongchao Cao, Yan Li, Yanyan Jing, Shengnan Liu, Cheng Ye, Hui Wang, Shuxian Yu, Chengyuan Peng, Lijian Hui, Yu-Cheng Wang, Haibing Zhang, Feifan Guo, Qiwei Zhai, Hui Wang, Ruimin Huang, Ling Zhang, Jingjing Jiang, Wei Liu, Hao Ying
p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure...
May 11, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29748882/evolution-of-ucp1
#16
Michael J Gaudry, Kevin L Campbell, Martin Jastroch
Brown adipose tissue (BAT), the specialized heat-producing organ found in many placental mammals including humans, may be accessible for clinical drug intervention to help combat metabolic diseases. Understanding the biology of BAT and its thermogenic uncoupling protein 1 (UCP1) will benefit from an assessment of its evolution, answering where UCP1 originated and how it has been modified and integrated into cellular energy metabolism. Here, we review topical insights regarding the molecular evolution of UCP1-also reconstructing the proximate and ultimate factors selecting for brown fat thermogenesis in placental mammals...
May 10, 2018: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29744660/anti-inflammatory-effects-of-melatonin-in-obesity-and-hypertension
#17
REVIEW
Natalia Jorgelina Prado, León Ferder, Walter Manucha, Emiliano Raúl Diez
PURPOSE OF REVIEW: Here, we review the known relations between hypertension and obesity to inflammation and postulate the endogenous protective effect of melatonin and its potential as a therapeutic agent. We will describe the multiple effects of melatonin on blood pressure, adiposity, body weight, and focus on mitochondrial-related anti-inflammatory and antioxidant protective effects. RECENT FINDINGS: Hypertension and obesity are usually associated with systemic and tissular inflammation...
May 9, 2018: Current Hypertension Reports
https://www.readbyqxmd.com/read/29743972/the-good-the-bad-and-the-ugly-of-ros-new-insights-on-aging-and-aging-related-diseases-from-eukaryotic-and-prokaryotic-model-organisms
#18
REVIEW
Ana L Santos, Sanchari Sinha, Ariel B Lindner
Aging is associated with the accumulation of cellular damage over the course of a lifetime. This process is promoted in large part by reactive oxygen species (ROS) generated via cellular metabolic and respiratory pathways. Pharmacological, nonpharmacological, and genetic interventions have been used to target cellular and mitochondrial networks in an effort to decipher aging and age-related disorders. While ROS historically have been viewed as a detrimental byproduct of normal metabolism and associated with several pathologies, recent research has revealed a more complex and beneficial role of ROS in regulating metabolism, development, and lifespan...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29743925/-gynostemma-pentaphyllum-attenuates-the-progression-of-nonalcoholic-fatty-liver-disease-in-mice-a-biomedical-investigation-integrated-with-in-silico-assay
#19
Ming Hong, Zhe Cai, Lei Song, Yongqiang Liu, Qi Wang, Xiangfei Feng
Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease in developed countries. Oxidative stress plays a critical role in the progression of NAFLD. Modern pharmacological study and clinical trials have demonstrated the remarkable antioxidant activity of Gynostemma pentaphyllum (GP) in chronic liver disease. One aim of this study was to explore the potential protective effects and mechanisms of action of GP extract on NAFLD. The in vivo results showed that GP extract could alleviate fatty degeneration and haptic fibrosis in NAFLD mice...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29740925/metformin-directly-targets-the-h3k27me3-demethylase-kdm6a-utx
#20
Elisabet Cuyàs, Sara Verdura, Laura Llorach-Pares, Salvador Fernández-Arroyo, Fedra Luciano-Mateo, Noemí Cabré, Jan Stursa, Lukas Werner, Begoña Martin-Castillo, Benoit Viollet, Jiri Neuzil, Jorge Joven, Alfons Nonell-Canals, Melchor Sanchez-Martinez, Javier A Menendez
Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3-specific demethylase subfamily, KDM6A/UTX...
May 8, 2018: Aging Cell
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