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https://www.readbyqxmd.com/read/27800715/molecular-modeling-dynamics-studies-and-density-functional-theory-approaches-to-identify-potential-inhibitors-of-sirt4-protein-from-homo-sapiens-a-novel-target-for-the-treatment-of-type-2-diabetes
#1
Sanjay K Choubey, Dhamodharan Prabhu, Mutharasappan Nachiappan, Jayshree Biswal, Jeyaraman Jeyakanthan
Type 2 Diabetes is one of the biggest health challenges in the world and WHO projects it to be the 7(th) leading cause of death in 2030. It is a chronic condition affecting the way our body metabolizes sugar. Insulin resistance is high risk factor marked by expression of Lipoprotein Lipases and Peroxisome Proliferator-Activated Receptor that predisposes to type 2 diabetes. AMP-dependent protein kinase in AMPK signaling pathway is a central sensor of energy status. Deregulation of AMPK signaling leads to inflammation, oxidative stress and deactivation of autophagy which are implicated in pathogenesis of insulin resistance...
November 1, 2016: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/27698834/decreased-sirtuin-4-expression-is-associated-with-poor-prognosis-in-patients-with-invasive-breast-cancer
#2
Qingyu Shi, Tong Liu, Xianyu Zhang, Jingshu Geng, Xiaohui He, Ming Nu, Da Pang
Aberrant metabolism is a hallmark of human cancer. Glutamine metabolism has been identified as a central metabolic pathway in cancer and thus, targeting glutamine metabolism may exhibit therapeutic potential. Sirtuin 4 (SIRT4) is an important molecule that mediates the blockade of glutamine catabolism by inhibiting glutamate dehydrogenase. In the present study, SIRT4 protein expression levels were analyzed in 409 breast cancer tissues and 241 paired adjacent non-cancerous tissues by immunohistochemical analysis and the correlation between SIRT4 expression and the clinicopathological features was evaluated...
October 2016: Oncology Letters
https://www.readbyqxmd.com/read/27650728/easy-to-use-strategy-for-reference-gene-selection-in-quantitative-real-time-pcr-experiments
#3
Stefanie Klenke, Kristina Renckhoff, Andrea Engler, Jürgen Peters, Ulrich H Frey
Real-time PCR is an indispensable technique for mRNA expression analysis but conclusions depend on appropriate reference gene selection. However, while reference gene selection has been a topic of publications, this issue is often disregarded when measuring target mRNA expression. Therefore, we (1) evaluated the frequency of appropriate reference gene selection, (2) suggest an easy-to-use tool for least variability reference gene selection, (3) demonstrate application of this tool, and (4) show effects on target gene expression profiles...
September 20, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27628218/a-novel-role-for-sirt3-in-regulating-mediators-involved-in-the-terminal-pathways-of-human-labor-and-delivery
#4
Ratana Lim, Gillian Barker, Ramkumar Menon, Martha Lappas
Preterm birth remains the major cause of neonatal mortality and morbidity, mediated largely by an inflammatory process. The sirtuin (SIRT) family of cellular regulators have been implicated as key inhibitors of inflammation. We have previously reported a role for SIRT1, SIRT2 and SIRT6 in regulating inflammation-induced pro-labor mediators. In this study, we determined the effect of term labor and pro-inflammatory cytokines on SIRT3, SIRT4, SIRT5 and SIRT7 expression in human myometrium. Functional studies were also employed to investigate the effect of siRNA knockdown of SIRTs in regulating inflammation-induced pro-labor mediators...
September 14, 2016: Biology of Reproduction
https://www.readbyqxmd.com/read/27592202/tissue-specific-regulation-of-sirtuin-and-nicotinamide-adenine-dinucleotide-biosynthetic-pathways-identified-in-c57bl-6-mice-in-response-to-high-fat-feeding
#5
Janice E Drew, Andrew J Farquharson, Graham W Horgan, Lynda M Williams
The sirtuin (SIRT)/nicotinamide adenine dinucleotide (NAD) system is implicated in development of type 2 diabetes (T2D) and diet-induced obesity, a major risk factor for T2D. Mechanistic links have not yet been defined. SIRT/NAD system gene expression and NAD/NADH levels were measured in liver, white adipose tissue (WAT) and skeletal muscle from mice fed either a low-fat diet or high-fat diet (HFD) for 3 days up to 16 weeks. An in-house custom-designed multiplex gene expression assay assessed all 7 mouse SIRTs (SIRT1-7) and 16 enzymes involved in conversion of tryptophan, niacin, nicotinamide riboside and metabolic precursors to NAD...
August 14, 2016: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/27457618/acetylation-of-mitochondrial-trifunctional-protein-%C3%AE-subunit-enhances-its-stability-to-promote-fatty-acid-oxidation-and-is-decreased-in-nonalcoholic-fatty-liver-disease
#6
Liang Guo, Shui-Rong Zhou, Xiang-Bo Wei, Yuan Liu, Xin-Xia Chang, Yang Liu, Xin Ge, Xin Dou, Hai-Yan Huang, Shu-Wen Qian, Xi Li, Qun-Ying Lei, Xin Gao, Qi-Qun Tang
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation...
October 15, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27431591/tissue-specific-gene-expression-and-fasting-regulation-of-sirtuin-family-in-gilthead-sea-bream-sparus-aurata
#7
Paula Simó-Mirabet, Azucena Bermejo-Nogales, Josep Alvar Calduch-Giner, Jaume Pérez-Sánchez
The seven sirtuin (SIRT) counterparts of higher vertebrates were identified and molecularly characterized in a farmed fish of the Sparidae family, order Perciformes. These proteins are NAD(+)-dependent deacetylases that couple protein deacetylation with the energy status of the cell via the cellular NAD(+)/NADH ratio with a strict conservation of the characteristic catalytic domain surrounded by divergent N- and C- terminal regions. Phylogenetic analysis showed three major clades corresponding to SIRT1-3, SIRT4-5, and SIRT6-7 that reflected the present hierarchy of vertebrates and the accepted classification of SIRTs...
July 18, 2016: Journal of Comparative Physiology. B, Biochemical, Systemic, and Environmental Physiology
https://www.readbyqxmd.com/read/27246218/identification-of-sirtuin4-sirt4-protein-interactions-uncovering-candidate-acyl-modified-mitochondrial-substrates-and-enzymatic-regulators
#8
Rommel A Mathias, Todd M Greco, Ileana M Cristea
Recent studies have highlighted the three mitochondrial human sirtuins (SIRT3, SIRT4, and SIRT5) as critical regulators of a wide range of cellular metabolic pathways. A key factor to understanding their impact on metabolism has been the discovery that, in addition to their ability to deacetylate substrates, mitochondrial sirtuins can have other prominent enzymatic activities. SIRT4, one of the least characterized mitochondrial sirtuins, was shown to be the first known cellular lipoamidase, removing lipoyl modifications from lysine residues of substrates...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27207907/acute-and-chronic-electroconvulsive-seizures-ecs-differentially-regulate-the-expression-of-epigenetic-machinery-in-the-adult-rat-hippocampus
#9
Madhavi Pusalkar, Shreya Ghosh, Minal Jaggar, Basma Fatima Anwar Husain, Sanjeev Galande, Vidita A Vaidya
BACKGROUND: Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape. METHODS: We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis...
May 17, 2016: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27164052/the-role-of-mitochondrial-sirtuins-in-health-and-disease
#10
Brenna Osborne, Nicholas L Bentley, Magdalene K Montgomery, Nigel Turner
Mitochondria play a critical role in energy production, cell signalling and cell survival. Defects in mitochondrial function contribute to the ageing process and ageing-related disorders such as metabolic disease, cancer, and neurodegeneration. The sirtuin family of deacylase enzymes have a variety of subcellular localisations and have been found to remove a growing list of post-translational acyl modifications from target proteins. SIRT3, SIRT4, and SIRT5 are found primarily located in the mitochondria, and are involved in many of the key processes of this organelle...
May 6, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/27099261/sirt4-accelerates-ang-ii-induced-pathological-cardiac-hypertrophy-by-inhibiting-manganese-superoxide-dismutase-activity
#11
Yu-Xuan Luo, Xiaoqiang Tang, Xi-Zhou An, Xue-Min Xie, Xiao-Feng Chen, Xiang Zhao, De-Long Hao, Hou-Zao Chen, De-Pei Liu
AIMS: Oxidative stress contributes to the development of cardiac hypertrophy and heart failure. One of the mitochondrial sirtuins, Sirt4, is highly expressed in the heart, but its function remains unknown. The aim of the present study was to investigate the role of Sirt4 in the pathogenesis of pathological cardiac hypertrophy and the molecular mechanism by which Sirt4 regulates mitochondrial oxidative stress. METHODS AND RESULTS: Male C57BL/6 Sirt4 knockout mice, transgenic (Tg) mice exhibiting cardiac-specific overexpression of Sirt4 (Sirt4-Tg) and their respective controls were treated with angiotensin II (Ang II, 1...
April 20, 2016: European Heart Journal
https://www.readbyqxmd.com/read/27082627/downregulation-of-sirt4-expression-is-associated-with-poor-prognosis-in-esophageal-squamous-cell-carcinoma
#12
Yujiro Nakahara, Makoto Yamasaki, Genta Sawada, Yasuhiro Miyazaki, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Shuji Takiguchi, Koshi Mimori, Masaki Mori, Yuichiro Doki
OBJECTIVE: SIRT4, a mitochondria-localized sirtuin, represses glutamine metabolism by inhibiting glutamate dehydrogenase (GDH). The current study aimed to evaluate the clinical and biological significance of SIRT4 in esophageal squamous cell carcinoma (ESCC). METHODS: The study comprised 172 patients with surgically resected ESCC in two independent cohorts. SIRT4 mRNA expression was analyzed in Cohort 1 (n = 79) and SIRT4 protein expression in Cohort 2 (n = 93)...
2016: Oncology
https://www.readbyqxmd.com/read/27080717/high-throughput-screening-of-sirtuin-family-of-genes-in-breast-cancer
#13
Mehri Igci, Mehmet Emin Kalender, Ersin Borazan, Ibrahim Bozgeyik, Recep Bayraktar, Esra Bozgeyik, Celaletdin Camci, Ahmet Arslan
Mammalian Sirtuins have been shown to perform distinct cellular functions and deregulated expression of these genes was reported to be involved in the development of various malignancies including breast cancer. An increasing number of evidence indicates that Sirtuins have both tumor promoter and tumor suppressor functions. However, the roles of Sirtuins have not been well-reported in breast cancer. In the present study, quantitative expression levels of Sirtuins (SIRT1-7) in breast cancer patients and breast cancer cell lines (MCF-7 and SKBR3) and control cell line (CRL-4010) were assessed by using a high-throughput real-time PCR method...
July 15, 2016: Gene
https://www.readbyqxmd.com/read/27038700/effects-of-intrinsic-aerobic-capacity-aging-and-voluntary-running-on-skeletal-muscle-sirtuins-and-heat-shock-proteins
#14
Sira Karvinen, Mika Silvennoinen, Petra Vainio, Lea Sistonen, Lauren G Koch, Steven L Britton, Heikki Kainulainen
AIM: Sirtuins are proteins that connect energy metabolism, oxidative stress and aging. Expression of heat shock proteins (Hsps) is regulated by heat shock factors (HSFs) in response to various environmental and physiological stresses, such as oxidative stress. Oxidative stress accumulates during aging which makes cells more prone to DNA damage. Although many experimental animal models have been designed to study the effects of knockdown or overexpression of sirtuins, HSFs and Hsps, little is known about how aging per se affects their expression...
June 15, 2016: Experimental Gerontology
https://www.readbyqxmd.com/read/26986234/clinical-and-therapeutic-significance-of-sirtuin-4-expression-in-colorectal-cancer
#15
Guoyu Huang, Jun Cheng, Fudong Yu, Xisheng Liu, Chenwei Yuan, Chenchen Liu, Xiaolei Chen, Zhihai Peng
Several members of the sirtuin family (SIRT1-7), which are a highly conserved family of NAD+-dependent enzymes, play an important role in tumor formation. Recent studies indicate that SIRT4 acts as a tumor suppressor by regulating glutamine metabolism. In the present study, we investigated the expression and activity of SIRT4 in colorectal cancer. Using a tissue microarray of 89 colorectal cancer cases, we found that SIRT4 was significantly downregulated in colorectal cancer tissues compared with that noted in the corresponding normal tissue (P<0...
May 2016: Oncology Reports
https://www.readbyqxmd.com/read/26959556/microrna-15b-regulates-mitochondrial-ros-production-and-the-senescence-associated-secretory-phenotype-through-sirtuin-4-sirt4
#16
Alexander Lang, Susanne Grether-Beck, Madhurendra Singh, Fabian Kuck, Sascha Jakob, Andreas Kefalas, Simone Altinoluk-Hambüchen, Nina Graffmann, Maren Schneider, Antje Lindecke, Heidi Brenden, Ingo Felsner, Hakima Ezzahoini, Alessandra Marini, Sandra Weinhold, Andrea Vierkötter, Julia Tigges, Stephan Schmidt, Kai Stühler, Karl Köhrer, Markus Uhrberg, Judith Haendeler, Jean Krutmann, Roland P Piekorz
Mammalian sirtuins are involved in the control of metabolism and life-span regulation. Here, we link the mitochondrial sirtuin SIRT4 with cellular senescence, skin aging, and mitochondrial dysfunction. SIRT4 expression significantly increased in human dermal fibroblasts undergoing replicative or stress-induced senescence triggered by UVB or gamma-irradiation. In-vivo, SIRT4 mRNA levels were upregulated in photoaged vs. non-photoaged human skin. Interestingly, in all models of cellular senescence and in photoaged skin, upregulation of SIRT4 expression was associated with decreased levels of miR-15b...
March 2016: Aging
https://www.readbyqxmd.com/read/26948035/sirtuins-cell-senescence-and-vascular-aging
#17
REVIEW
Yujiro Kida, Michael S Goligorsky
The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors...
May 2016: Canadian Journal of Cardiology
https://www.readbyqxmd.com/read/26918605/glutamate-dehydrogenase-gdh-regulates-bioenergetics-and-redox-homeostasis-in-human-glioma
#18
Jiannan Zhang, Guisong Wang, Qin Mao, Shanquan Li, Wenhao Xiong, Yingying Lin, Jianwei Ge
The mitochondrial enzyme, glutamate dehydrogenase (GDH), is commonly upregulated in human cancers. Whether and how GDH contributes to the development of glioma remains unknown. Here we report that GDH is a mitochondrial regulator for alpha-ketoglutarate (α-KG) in glioma cells. GDH expression and activity are up-regulated in human glioma cell lines and tissues, and high level of GDH predicts poor outcome. We demonstrate that GDH is an oncogenic factor in vitro and in vivo by using loss-of-function and gain-of-function strategies...
February 24, 2016: Oncotarget
https://www.readbyqxmd.com/read/26785117/loss-of-mitochondrial-tumor-suppressor-genes-expression-is-associated-with-unfavorable-clinical-outcome-in-head-and-neck-squamous-cell-carcinoma-data-from-retrospective-study
#19
Ishrat Mahjabeen, Mahmood Akhtar Kayani
Mitochondrial genes play important roles in cellular energy metabolism, free radical generation, and apoptosis. Dysregulation of these genes have long been suspected to contribute to the generation of reactive oxygen species (ROS), increased proliferation and progression of cancer. A family of orthologues of yeast silent information regulator 3 (SIRT3), 4 (SIRT4) and mitochondrial tumor suppressor 1 (MTUS1) are important mitochondrial tumor suppressor genes which play an important role in the progression of multiple cancers...
2016: PloS One
https://www.readbyqxmd.com/read/26775843/sirt4-regulates-cancer-cell-survival-and-growth-after-stress
#20
Seung Min Jeong, Sunsook Hwang, Rho Hyun Seong
Cellular stresses initiate well-coordinated signaling response pathways. As the proper regulation of stress is essential for cellular homeostasis, the defects of stress response pathways result in functional deficits and cell death. Although mitochondrial SIRT4 has been shown to be involved in cellular stress response and tumor suppression, its roles in survival and drug resistance of cancer cells are not well determined. Here we show that SIRT4 is a crucial regulator of the stress resistance of cancer cells...
February 5, 2016: Biochemical and Biophysical Research Communications
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