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Mitochondrial diseases

Suraiya Haroon, Annie Li, Jaye L Weinert, Clark Fritsch, Nolan G Ericson, Jasmine Alexander-Floyd, Bart P Braeckman, Cole M Haynes, Jason H Bielas, Tali Gidalevitz, Marc Vermulst
Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan...
March 20, 2018: Cell Reports
Carlos A Gómez, Jason Sutin, Weicheng Wu, Buyin Fu, Hana Uhlirova, Anna Devor, David A Boas, Sava Sakadžić, Mohammad A Yaseen
Investigating cerebral metabolism in vivo at a microscopic level is essential for understanding brain function and its pathological alterations. The intricate signaling and metabolic dynamics between neurons, glia, and microvasculature requires much more detailed understanding to better comprehend the mechanisms governing brain function and its disease-related changes. We recently demonstrated that pharmacologically-induced alterations to different steps of cerebral metabolism can be distinguished utilizing 2-photon fluorescence lifetime imaging of endogenous reduced nicotinamide adenine dinucleotide (NADH) fluorescence in vivo...
2018: PloS One
Nesibe Peker, Vinay Donipadi, Mridula Sharma, Craig McFarlane, Ravi Kambadur
Parkinson's Disease is a neurodegenerative disease characterized by tremors, muscle stiffness and muscle weakness. Molecular genetic analysis confirmed that mutations in PARKIN and PINK1 genes, which play major roles in mitochondrial quality control and mitophagy, are frequently associated with Parkinson's Disease. PARKIN is an E3 ubiquitin ligase that translocates to mitochondria during loss of mitochondrial membrane potential to increase mitophagy. Although muscle dysfunction is noted in Parkinson's Disease, little is known about the involvement of PARKIN in the muscle phenotype of Parkinson's Disease...
March 21, 2018: American Journal of Physiology. Cell Physiology
Sarah J Pickett, John P Grady, Yi Shiau Ng, Gráinne S Gorman, Andrew M Schaefer, Ian J Wilson, Heather J Cordell, Doug M Turnbull, Robert W Taylor, Robert McFarland
Objective: The pathogenic mitochondrial DNA m.3243A>G mutation is associated with a wide range of clinical features, making disease prognosis extremely difficult to predict. We aimed to understand the cause of this heterogeneity. Methods: We examined the phenotypic profile of 238 adult m.3243A>G carriers (patients and asymptomatic carriers) from the UK MRC Mitochondrial Disease Patient Cohort using the Newcastle Mitochondrial Disease Adult Scale. We modeled the role of risk factors for the development of specific phenotypes using proportional odds logistic regression...
March 2018: Annals of Clinical and Translational Neurology
Ponarulselvam Sekar, Duen-Yi Huang, Shwu-Fen Chang, Wan-Wan Lin
Extracellular adenosine 5'-triphosphate (ATP) is a damage-associated molecular pattern and contributes to inflammation associated diseases including cancer. Extracellular acidosis is a novel danger signal in the inflammatory sites, where it can modulate inflammation, immunity and tumor growth. Extracellular acidification was shown to inhibit P2X7-mediated channel currents, while it remains unknown how acidification and P2X7 together affect cellular responses. Here, we treated BV-2 microglial cells with ATP in a short period (<15 min) or a sustained acidified condition...
February 27, 2018: Oncotarget
Steven A Harris, Elizabeth A Harris
This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer's disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis...
2018: Frontiers in Aging Neuroscience
Hailong Li, Zhongyuan Tang, Peng Chu, Yanlin Song, Ying Yang, Bin Sun, Mengyue Niu, Eskandar Qaed, Abdullah Shopit, Guozhu Han, Xiaodong Ma, Jinyong Peng, Min Hu, Zeyao Tang
Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage...
March 17, 2018: Free Radical Biology & Medicine
Kolla Rajasekhar, Kapilkumar Mehta, Thimmaiah Govindaraju
Amyloid beta (Aβ) aggregation is the key trait responsible for the pathological devastation caused by Alzheimer's disease (AD). Among the various pathways of multifaceted toxicity exhibited by Aβ aggregates in neuronal cells, generation of reactive oxygen species (ROS) by Aβ-CuII complex and mitochondrial damage are prominent. Aβ interferes with mitochondrial transport channels, causing mitochondrial dysfunction. Herein, we present nontoxic hybrid multifunctional modulators (HMMs, TGR86-88) developed by integrating the structural and functional features of the metal chelating aggregation modulator, clioquinol (Clq) and the antioxidant epigallocatechin gallate (EGCG)...
March 20, 2018: ACS Chemical Neuroscience
Jenna L Gollihue, Samir P Patel, Alexander G Rabchevsky
Mitochondria are essential cellular organelles critical for generating adenosine triphosphate for cellular homeostasis, as well as various mechanisms that can lead to both necrosis and apoptosis. The field of "mitochondrial medicine" is emerging in which injury/disease states are targeted therapeutically at the level of the mitochondrion, including specific antioxidants, bioenergetic substrate additions, and membrane uncoupling agents. Consequently, novel mitochondrial transplantation strategies represent a potentially multifactorial therapy leading to increased adenosine triphosphate production, decreased oxidative stress, mitochondrial DNA replacement, improved bioenergetics and tissue sparing...
February 2018: Neural Regeneration Research
James D Weinstein
Despite decades of research, at present there is no curative therapy for Alzheimer's disease. Changes in the way new drugs are tested appear to be necessary. Three changes are presented here and will be discussed. The first change is that Alzheimer's disease must be considered a disease of four major pathological processes, not one. The four processes are: 1) vascular hypoperfusion of the brain with associated mitochondrial dysfunction, 2) destructive protein inclusions, 3) uncontrolled oxidative stress, and 4) proinflammatory immune processes secondary to microglial and astrocytic dysfunction in the brain...
February 2018: Neural Regeneration Research
Tomohiro Kimura, Atsuko Kimura, Mindong Ren, Bob Berno, Yang Xu, Michael Schlame, Richard M Epand
Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in tafazzin cause Barth syndrome, a potentially life-threatening disease with the major symptom of cardiomyopathy. In the tafazzin-deficient heart, cardiolipin (CL) acyl chains become abnormally heterogeneous unlike those in the normal heart with a single dominant linoleoyl species; tetralinoleoyl CL. In addition, the amount of CL decreases and monolysocardiolipin (MLCL) accumulates...
March 20, 2018: Biochemistry
Ramoji Kosuru, Vidya Kandula, Uddipak Rai, Swati Prakash, Zhengyuan Xia, Sanjay Singh
PURPOSE: Oxidative stress has a pivotal role in the pathogenesis of diabetes-associated cardiovascular problems, which has remained a primary cause of the increased morbidity and mortality in diabetic patients. It is of paramount importance to prevent the diabetes-associated cardiac complications by reducing oxidative stress with the help of nutritional or pharmacological agents. Pterostilbene (PT), the primary antioxidant in blueberries, has recently gained attention for its promising health benefits in metabolic and cardiac diseases...
March 20, 2018: Cardiovascular Drugs and Therapy
Soham Sengupta, Rachel Nechushtai, Patricia A Jennings, Jose' N Onuchic, Pamela A Padilla, Rajeev K Azad, Ron Mittler
The iron-sulfur (2Fe-2S) binding motif CDGSH appears in many important plant and animal proteins that regulate iron and reactive oxygen metabolism. In human it is found in CISD1-3 proteins involved in diabetes, obesity, cancer, aging, cardiovascular disease and neurodegeneration. Despite the important biological role of the CDGSH domain, its origin, evolution and diversification, are largely unknown. Here, we report that: (1) the CDGSH domain appeared early in evolution, perhaps linked to the heavy use of iron-sulfur driven metabolism by early organisms; (2) a CISD3-like protein with two CDGSH domains on the same polypeptide appears to represent the ancient archetype of CDGSH proteins; (3) the origin of the human CISD3 protein is linked to the mitochondrial endosymbiotic event; (4) the CISD1/2 type proteins that contain only one CDGSH domain, but function as homodimers, originated after the divergence of bacteria and archaea/eukaryotes from their common ancestor; and (5) the human CISD1 and CISD2 proteins diverged about 650-720 million years ago, and CISD3 and CISD1/2 share their descent from an ancestral CISD about 1-1...
March 19, 2018: Scientific Reports
Ruchi Mishra, Saurabh Sharma, Radhey Shyam Sharma, Savita Singh, Milind Madhav Sardesai, Sadhna Sharma, Vandana Mishra
ETHNOPHARMACOLOGICAL RELEVANCE: Viscum articulatum Burm. f. (leafless mistletoe) has been used in traditional system of medicines in India, China, Taiwan, Cambodia, Laos, and Vietnam, to treat blood-related diseases and various inflammatory and degenerative diseases including cancer. Anticancer activities of some phytomolecules purified from Viscum articulatum Burm. f. have been tested. However scientific evidence for the anticancerous potential of aqueous extract of V. articularum (VAQE) used in traditional medicine is lacking...
March 16, 2018: Journal of Ethnopharmacology
Diana Vargas, Carolina López, Edward Acero, Edgar Benitez, Angélica Wintaco, Jaime Camacho, Marisol Carreño, Juan Umaña, Daniela Jimenez, Said Díaz, Fernando Lizcano
The anatomical location of adipose tissue might have direct implications for its functionality and risk of cardiovascular disease. Adipose tissue surrounding blood vessels may be thermogenically more active in specific areas of the body, releasing substances that regulate vascular metabolism. In humans, the phenotypic characteristics of adipose tissue surrounding the aorta and the cardiovascular disease risk that it might entail remain largely unknown. Here, we compared thermogenesis-related molecular features of human periaortic adipose tissue samples with those of subcutaneous adipose tissue, obtained by sternotomy from 42 patients undergoing cardiovascular surgery...
2018: PloS One
Jing Tian, Rong Lv, Wei Guo
Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy, myocardial fibrosis and diastolic dysfunction, which are uncorrelated with underlying coronary artery disease or hypertension. As an important metabolic organelle, mitochondria directly involve the process of cell growth, proliferation, signal transduction, apoptosis and so on. Recent studies have demonstrated a close correlation between the mitochondrial dysfunction and the pathogenesis of diabetic cardiomyopathy. The underlying effects of mitochondrial dysfunction in the progress of diabetic cardiomyopathy involve disturbed metabolism, oxidative stress, defective calcium handling, mitochondrial uncoupling, apoptosis, imbalance of mitochondrial quality control and regulation of MicroRNAs...
January 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
JinYing Liu, Xiaokang Liu, Wei Ma, Wei Kou, CaiLi Li, Jin Zhao
PURPOSE: Ovarian cancer is one of the deadly causes of gynecological cancer related mortality worldwide. Despite initial responses to chemotherapy, the disease consistently relapses. Therefore there is an urgent need for identification of anticancer lead molecules for treatment and management of ovarian cancer. The present study evaluated the anticancer activity of cucurbitacin-A on ovarian SKVO3 cancer cells. METHODS: The cell viability of SKVO3 cells was evaluated by MTT assay, while clonogenic assay was used to evaluate the effects on cancer cell colony formation...
January 2018: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Lan Luo, Haibo Zhao, Qian Luo
PURPOSE: Ovarian cancer is one of the major causes of death in females around the world. There are several drug regimens available for this type of cancer, but despite initial response to chemotherapy, the disease consistently relapses, showing that there is a need to find more efficient and novel anticancer agents. Plant-derived natural products may prove beneficial in this case due to their lower cytotoxicity. In the present study we evaluated the anticancer activity of swerchirin against human SKOV3 ovarian cancer cell line...
January 2018: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Guanghui Lian, Fujun Li, Yani Yin, Linlin Chen, Junwen Yang
PURPOSE: Artemisia vulgaris (A.vulgaris) belonging to family Compositae, commonly known as mugwort, has been used as a medicinal herb in Chinese traditional medicine for treatment of diseases. Studies have reported a diversity of activities for this plant which include antiseptic, antispasmodic, antigastric, anticancer and nervous system diseases. However, the anticancer activity of A.vulgaris in HCT-15 human colon cancer cells has not been scientifically validated. Therefore the present study aimed at evaluating the anticancer activity of methanolic extract of A...
January 2018: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Chun-Hsiang Tan, Peter A McNaughton
The abilities to detect warmth and heat are critical for the survival of all animals, both in order to be able to identify suitable thermal environments for the many different activities essential for life and to avoid damage caused by extremes of temperature. Several ion channels belonging to the TRP family are activated by non-noxious warmth or by heat and are therefore plausible candidates for thermal detectors, but identifying those that actually regulate warmth and heat detection in intact animals has proven problematic...
March 19, 2018: Pflügers Archiv: European Journal of Physiology
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