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NADH AND diabetes

Zhiyi Liu, Dimitra Pouli, Carlo A Alonzo, Antonio Varone, Sevasti Karaliota, Kyle P Quinn, Karl Münger, Katia P Karalis, Irene Georgakoudi
Monitoring subcellular functional and structural changes associated with metabolism is essential for understanding healthy tissue development and the progression of numerous diseases, including cancer, diabetes, and cardiovascular and neurodegenerative disorders. Unfortunately, established methods for this purpose either are destructive or require the use of exogenous agents. Recent work has highlighted the potential of endogenous two-photon excited fluorescence (TPEF) as a method to monitor subtle metabolic changes; however, mechanistic understanding of the connections between the detected optical signal and the underlying metabolic pathways has been lacking...
March 2018: Science Advances
Russell P Goodman, Sarah Calvo, Vamsi K Mootha
Compartmentalization is a fundamental design principle of eukaryotic metabolism.  Here, we review the compartmentalization of NAD+/NADH and NADP+/NADPH with a focus on the liver, an organ that experiences the extremes of biochemical physiology each day.  Historical studies of the liver, using classical biochemical  measurements of redox-coupled metabolites, have given rise to the view that mitochondrial NAD(H) pools tend to be oxidized and important for energy homeostasis, whereas cytosolic NADP(H) pools tend to be highly reduced for reductive biosynthesis...
March 7, 2018: Journal of Biological Chemistry
Melissa Hodeib, Martin P Ogrodzinski, Laurent Vergnes, Karen Reue, Beth Y Karlan, Sophia Y Lunt, Paul-Joseph P Aspuria
Metformin is a widely used agent for the treatment of diabetes and infertility, however, it has been found to have anti-cancer effects in a variety of malignancies including high grade serous ovarian cancer (HGSC). Studies describing the mechanisms by which metformin affects HGSC are ongoing, but detailed analysis of its effect on the cellular metabolism of both HGSC cells and their precursor, normal fallopian tube secretory epithelial cells (FTSECs), is lacking. We addressed the effects of metformin and the more potent biguanide, phenformin, on HGSC cell lines and normal immortalized FTSECs...
January 9, 2018: Oncotarget
Devy Deliyanti, Saeed F Alrashdi, Sih Min Tan, Colin Meyer, Keith W Ward, Judy B de Haan, Jennifer L Wilkinson-Berka
Purpose: Oxidative stress is a causal factor in the development of diabetic retinopathy; however, clinically relevant strategies to treat the disease by augmenting antioxidant defense mechanisms have not been fully explored. We hypothesized that boosting nuclear factor erythroid-2-related factor 2 (Nrf2) antioxidant capacity with the novel Nrf2 activator dh404, would protect the retina in diabetes including vision-threatening breakdown of the blood-retinal barrier (BRB) and associated damage to macroglial Müller cells...
February 1, 2018: Investigative Ophthalmology & Visual Science
Aniket V Mali, Sunita S Bhise, Surendra S Katyare, Mahabaleshwar V Hegde
Recent studies have been noted that the erythrocytes from Type II diabetic patients show significantly altered structural and functional characteristics along with the changed intracellular concentrations of glycolytic intermediates. More recent studies from our laboratory have shown that the activities of enzymes of glycolytic pathway changed significantly in RBCs from Type II diabetic patients. In particular the levels of lactate dehydrogenase (LDH) increased significantly. Lactic acidosis is an established feature of diabetes and LDH plays a crucial role in conversion of pyruvate to lactate and reportedly, the levels of lactate are significantly high which is consistent with our observation on increased levels of LDH...
January 2018: Indian Journal of Clinical Biochemistry: IJCB
Yu Sun, Zhiliang Tian, Ning Liu, Linxue Zhang, Zhaopeng Gao, Xiaojiao Sun, Miao Yu, Jichao Wu, Fan Yang, Yajun Zhao, Huan Ren, He Chen, Dechao Zhao, Yan Wang, Shiyun Dong, Changqing Xu, Fanghao Lu, Weihua Zhang
Hydrogen sulfide (H2S) is involved in diverse physiological functions, such as anti-hypertension, anti-proliferation, regulating ATP synthesis, and reactive oxygen species production. Sirtuin 3 (SIRT3) is a NAD + -dependent deacetylase that regulates mitochondrial energy metabolism. The role of H2S in energy metabolism in diabetic cardiomyopathy (DCM) may be related to regulate SIRT3 expression; however, this role remains to be elucidated. We hypothesized that exogenous H2S could switch cardiac energy metabolic substrate preference by lysine acetylation through promoting the expression of SIRT3 in cardiac tissue of db/db mice...
January 19, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Hayden W Hyatt, Yufeng Zhang, Wendy R Hood, Andreas N Kavazis
BACKGROUND: Human epidemiological data show that breastfeeding reduces the mother's probability of developing several disease conditions, including obesity and type II diabetes compared to mothers that give birth but do not breastfeed. The goal of this investigation was to characterize how lactation changes a rat's body composition, metabolism, mitochondrial function, and oxidative stress. METHODS: Ten-week old female Sprague-Dawley rats were divided into three groups (n = 8 per group): 1) non-reproductive (NR), 2) those that were allowed to mate and give birth, but were not allowed to suckle their pups (PP), and 3) those that were allowed to mate and give birth, and suckled their young until weaning at 21 days (PL)...
January 9, 2018: Reproductive Biology and Endocrinology: RB&E
Akintayo Ogundajo, Anofi Tom Ashafa
Background: Ehretia cymosa Thonn. is a popular medicinal plant used in different parts of West Africa for the treatment of various ailments including diabetes mellitus. Objective: The current study investigates bioactive constituents and in vitro antioxidant and antidiabetic potentials of fractions from extract of E. cymosa. Materials and Methods: Phytochemical investigation and antioxidant assays were carried out using standard procedures...
October 2017: Pharmacognosy Magazine
Micheal S Ward, Nicole B Flemming, Linda A Gallo, Amelia K Fotheringham, Domenica A McCarthy, Aowen Zhuang, Peter H Tang, Danielle J Borg, Hannah Shaw, Benjamin Harvie, David R Briskey, Llion A Roberts, Manuel R Plan, Michael P Murphy, Mark P Hodson, Josephine M Forbes
Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11-13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight...
November 9, 2017: Scientific Reports
Po-Jen Chien, Takuma Suzuki, Masato Tsujii, Ming Ye, Isao Minami, Kanako Toda, Hiromi Otsuka, Koji Toma, Takahiro Arakawa, Kouji Araki, Yasuhiko Iwasaki, Kayoko Shinada, Yoshihiro Ogawa, Kohji Mitsubayashi
This study describes two biosniffers to determine breath acetone and isopropanol (IPA) levels and applies them for breath measurement in healthy subjects and diabetic patients. Secondary alcohol dehydrogenase (S-ADH) can reduce acetone and oxidize nicotinamide adenine dinucleotide (NADH to NAD(+)) in a weak acid environment. NADH can be excited by 340 nm excitation lights and subsequently emit 490 nm fluorescence. Therefore, acetone can be measured by the decrease in NADH fluorescence intensity. S-ADH can also oxidize IPA and reduce NAD(+) to NADH when it is in an alkaline environment...
November 9, 2017: Analytical Chemistry
Wo-Lin Hou, Jun Yin, Miriayi Alimujiang, Xue-Ying Yu, Li-Gen Ai, Yu-Qian Bao, Fang Liu, Wei-Ping Jia
Accumulating evidences showed metformin and berberine, well-known glucose-lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes...
November 6, 2017: Journal of Cellular and Molecular Medicine
Ye Chen, Yuzhen Liang, Tingting Hu, Riming Wei, Congjie Cai, Ping Wang, Lingyu Wang, Wei Qiao, Leping Feng
Nicotinamide phosphoribosyltransferase (Nampt) is a key enzyme in the nicotinamide adenine dinucleotide (NAD(+)) biosynthetic pathway. Exogenous extra cellular Nampt has been reported to increase the synthesis of pro-fibrotic molecules in various types of renal cells. However, the role of endogenous Namptenzymatic activity in diabetic renal cells, particularly those associated with inflammation and fibrosis through the nuclear factor (NF)-κB p65 and sirtuin 1 (Sirt1) pathway is still unknown. In the present study, a possible mechanism by which endogenous Nampt upregulation affects the expression of pro-inflammatory and pro-fibrotic cytokines in vivo and in vitro, is reported...
November 2017: Experimental and Therapeutic Medicine
Sunbin Ling, Qiaonan Shan, Peng Liu, Tingting Feng, Xuanyu Zhang, Penghui Xiang, Kangchen Chen, Haiyang Xie, Penghong Song, Lin Zhou, Jimin Liu, Shusen Zheng, Xiao Xu
Arsenic trioxide (ATO) is a well-accepted chemotherapy agent in managing promyelocytic leukemia. ATO often causes severe health hazards such as hepatotoxicity, dermatosis, neurotoxicity, nephrotoxicity and cardiotoxicity. The production of reactive oxygen species, (ROS) play a significant role in ATO-induced hepatotoxicity. The oral hypoglycemic drug, metformin, is considered to be a potential novel agent for chemoprevention in the treatment of cancer. Moreover, metformin has also been shown to have hepatoprotective effects...
November 2, 2017: Cell Death & Disease
Xiaoxin X Wang, Dong Wang, Yuhuan Luo, Komuraiah Myakala, Evgenia Dobrinskikh, Avi Z Rosenberg, Jonathan Levi, Jeffrey B Kopp, Amanda Field, Ashley Hill, Scott Lucia, Liru Qiu, Tao Jiang, Yingqiong Peng, David Orlicky, Gabriel Garcia, Michal Herman-Edelstein, Vivette D'Agati, Kammi Henriksen, Luciano Adorini, Mark Pruzanski, Cen Xie, Kristopher W Krausz, Frank J Gonzalez, Suman Ranjit, Alexander Dvornikov, Enrico Gratton, Moshe Levi
Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity...
January 2018: Journal of the American Society of Nephrology: JASN
Jessica M Berthiaume, Jacob G Kurdys, Danina M Muntean, Mariana G Rosca
SIGNIFICANCE: Diabetic cardiomyopathy (DCM) is a frequent complication occurring even in well-controlled asymptomatic diabetic patients, and it may advance to heart failure (HF). Recent Advances: The diabetic heart is characterized by a state of "metabolic rigidity" involving enhanced rates of fatty acid uptake and mitochondrial oxidation as the predominant energy source, and it exhibits mitochondrial electron transport chain defects. These alterations promote redox state changes evidenced by a decreased NAD+ /NADH ratio associated with an increase in acetyl-CoA/CoA ratio...
December 11, 2017: Antioxidants & Redox Signaling
Julia C Fitzgerald, Alexander Zimprich, Daniel A Carvajal Berrio, Kevin M Schindler, Brigitte Maurer, Claudia Schulte, Christine Bus, Anne-Kathrin Hauser, Manuela Kübler, Rahel Lewin, Dheeraj Reddy Bobbili, Lisa M Schwarz, Evangelia Vartholomaiou, Kathrin Brockmann, Richard Wüst, Johannes Madlung, Alfred Nordheim, Olaf Riess, L Miguel Martins, Enrico Glaab, Patrick May, Katja Schenke-Layland, Didier Picard, Manu Sharma, Thomas Gasser, Rejko Krüger
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1...
September 1, 2017: Brain: a Journal of Neurology
Joanne Li, Andrew J Bower, Zane Arp, Eric J Olson, Claire Holland, Eric J Chaney, Marina Marjanovic, Paritosh Pande, Aneesh Alex, Stephen A Boppart
Impaired skin wound healing is a significant comorbid condition of diabetes that is caused by poor microcirculation, among other factors. Studies have shown that angiogenesis, a critical step in the wound healing process in diabetic wounds, can be promoted under hypoxia. In this study, an angiogenesis-promoting topical treatment for diabetic wounds, which promotes angiogenesis by mimicking a hypoxic environment via inhibition of prolyl hydroxylase resulting in elevation or maintenance of hypoxia-inducible factor, was investigated utilizing a custom-built multimodal microscopy system equipped with phase-variance optical coherence tomography (PV-OCT) and fluorescence lifetime imaging microscopy (FLIM)...
October 5, 2017: Journal of Biophotonics
Salvatore Raffa, Cristina Scrofani, Sabatino Valente, Andrea Micaloni, Forte Maurizio, Franca Bianchi, Roberta Coluccia, Aron M Geurts, Sebastiano Sciarretta, Massimo Volpe, Maria Rosaria Torrisi, Speranza Rubattu
Ndufc2, a subunit of the NADH:ubiquinone oxidoreductase, plays a key role in the assembly and activity of complex I within the mitochondrial OXPHOS chain. Its deficiency has been shown to be involved in diabetes, cancer and stroke. To improve our knowledge on the mechanisms underlying the increased disease risk due to Ndufc2 reduction, we performed the present in vitro study aimed at the fine characterization of the derangements in mitochondrial structure and function consequent to Ndufc2 deficiency. We found that both fibroblasts obtained from skin of heterozygous Ndufc2 knock-out rat model showed marked mitochondrial dysfunction and PBMC obtained from subjects homozygous for the TT genotype of the rs11237379/NDUFC2 variant, previously shown to associate with reduced gene expression, demonstrated increased generation of reactive oxygen species and mitochondrial damage...
August 30, 2017: Human Molecular Genetics
Shpetim Karandrea, Huquan Yin, Xiaomei Liang, Angela L Slitt, Emma A Heart
Thymoquinone, a natural occurring quinone and the main bioactive component of plant Nigella sativa, undergoes intracellular redox cycling and re-oxidizes NADH to NAD+. TQ administration (20 mg/kg/bw/day) to the Diet-Induced Obesity (DIO) mice reduced their diabetic phenotype by decreasing fasting blood glucose and fasting insulin levels, and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose and insulin tolerance tests (OGTT and ITT). Furthermore, TQ decreased serum cholesterol levels and liver triglycerides, increased protein expression of phosphorylated Akt, decreased serum levels of inflammatory markers resistin and MCP-1, and decreased NADH/NAD+ ratio...
2017: PloS One
Matthew A Stroh, Michelle K Winter, Kenneth E McCarson, John P Thyfault, Hao Zhu
Cytosolic NADH-cytochrome-b5-oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues. We have previously reported that global ablation of NCB5OR in mice results in early-onset lean diabetes with decreased serum leptin levels and increased metabolic and feeding activities. The conditional deletion of NCB5OR in the mouse cerebellum and midbrain (conditional knock out, CKO mice) results in local iron dyshomeostasis and altered locomotor activity. It has been established that lesion to or removal of the cerebellum leads to changes in nutrient organization, visceral response, feeding behavior, and body weight...
September 8, 2017: Cerebellum
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