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Kaname Akamata, Jun Wei, Mitra Bhattacharyya, Paul Cheresh, Michael Y Bonner, Jack L Arbiser, Kirtee Raparia, Mahesh P Gupta, David W Kamp, John Varga
Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts...
October 6, 2016: Oncotarget
Chao Song, Wei Peng, Songna Yin, Jiamin Zhao, Beibei Fu, Jingcheng Zhang, Tingchao Mao, Haibo Wu, Yong Zhang
Increasing evidence shows that melatonin protected against age-related mitochondrial oxidative damage. However, the protective effects of melatonin against ovarian aging has not been explored. Young Kunming females (aged 2-3 months) were fed with melatonin added to drinking water for 6 or 12 months (mo). We found that long-term (12 mo) melatonin treatment significantly reduced ovarian aging, as indicated by substantial increases in litter size, pool of follicles, and telomere length as well as oocyte quantity and quality...
October 12, 2016: Scientific Reports
Asad Ali Shah, Akihiro Ito, Akiko Nakata, Minoru Yoshida
SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro...
2016: Biological & Pharmaceutical Bulletin
Sang Pil Yoon, Jinu Kim
Enhanced oxidative stress is a hallmark of cisplatin nephrotoxicity, and inhibition of poly(ADP-ribose) polymerase 1 (PARP1) attenuates oxidative stress during cisplatin nephrotoxicity; however, the precise mechanisms behind its action remain elusive. Here, using an in vitro model of cisplatin-induced injury to human kidney proximal tubular cells, we demonstrated that the protective effect of PARP1 inhibition on oxidative stress is associated with sirtuin 3 (SIRT3) activation. Exposure to 400 µM cisplatin for 8 hours in cells decreased activity and expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPX), and SIRT3, while it increased their lysine acetylation...
September 2016: Anatomy & Cell Biology
Elisabetta Bigagli, Carlotta De Filippo, Cinzia Castagnini, Simona Toti, Francesco Acquadro, Francesco Giudici, Marilena Fazi, Piero Dolara, Luca Messerini, Francesco Tonelli, Cristina Luceri
BACKGROUND: DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study. METHODS: Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes...
October 5, 2016: Cellular Oncology (Dordrecht)
Di Chen, Weiping Zheng
In the current study, we discovered that several N-terminus-to-side chain cyclic tripeptides harboring the catalytic mechanism-based SIRT1/2/3 inhibitory warhead N(ε)-thioacetyl-lysine at their central positions exhibited a comparably strong inhibition (nM level) against the SIRT1/2-catalyzed N(ε)-acetyl-lysine deacetylation reactions. Their dual SIRT1/2 inhibitory action was also found to be stronger than that against SIRT3/5/6. Considering the previous demonstration that a SIRT1/2 dual inhibition could be instrumental in achieving an anti-cancer effect on those cancers retaining the wild-type tumor suppresser p53 protein, these compounds could be employed as leads for developing novel anti-cancer agents...
September 22, 2016: Bioorganic & Medicinal Chemistry Letters
Seon Yeong Chae, Sun Young Park, Jin Oh Park, Kyu Jin Lee, Geuntae Park
This study reports a green approach for synthesis of gold nanoparticles using Gardenia jasminoides extract, and specifically, can potentially enhance anti senescence activity. Biological synthesis of gold nanoparticles is ecofriendly and effective for the development of environmentally sustainable nanoparticles compared with existing methods. Here, we developed a simple, fast, efficient, and ecofriendly approach to the synthesis of gold nanoparticles by means of a Gardenia jasminoides extract. These G. jasminoides extract-capped gold nanoparticles (GJ-GNPs) were characterized by UV-vis, high resolution transmission electron microscopy (HR-TEM), X-ray diffraction (XRD), and Furrier transform infrared spectroscopy (FT-IR)...
September 28, 2016: Journal of Photochemistry and Photobiology. B, Biology
Aneesa Ansari, Md Shahedur Rahman, Subbroto K Saha, Forhad K Saikot, Akash Deep, Ki-Hyun Kim
In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes...
September 29, 2016: Aging Cell
Jonathan B Lin, Shunsuke Kubota, Norimitsu Ban, Mitsukuni Yoshida, Andrea Santeford, Abdoulaye Sene, Rei Nakamura, Nicole Zapata, Miyuki Kubota, Kazuo Tsubota, Jun Yoshino, Shin-Ichiro Imai, Rajendra S Apte
Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD(+) biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD(+) deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction...
September 27, 2016: Cell Reports
Nan Hu, Jun Ren, Yingmei Zhang
Insulin resistance contributes to the high prevalence of type 2 diabetes mellitus, leading to cardiac anomalies. Emerging evidence depicts a pivotal role for mitochondrial injury in oxidative metabolism and insulin resistance. Mitochondrial aldehyde dehydrogenase (ALDH2) is one of metabolic enzymes detoxifying aldehydes although its role in insulin resistance remains elusive. This study was designed to evaluate the impact of ALDH2 overexpression on insulin resistance-induced myocardial damage and mechanisms involved with a focus on autophagy...
September 12, 2016: Oncotarget
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
Wen-Yu Zhao, Lei Zhang, Ming-Xing Sui, You-Hua Zhu, Li Zeng
Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD(+) dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model...
September 13, 2016: Scientific Reports
Ignacio Amigo, Sergio Luiz Menezes-Filho, Luis Alberto Luévano-Martínez, Bruno Chausse, Alicia J Kowaltowski
Caloric restriction (CR) protects against many cerebral pathological conditions that are associated with excitotoxic damage and calcium overload, although the mechanisms are still poorly understood. Here we show that CR strongly protects against excitotoxic insults in vitro and in vivo in a manner associated with significant changes in mitochondrial function. CR increases electron transport chain activity, enhances antioxidant defenses, and favors mitochondrial calcium retention capacity in the brain. These changes are accompanied by a decrease in cyclophilin D activity and acetylation and an increase in Sirt3 expression...
September 13, 2016: Aging Cell
J You, Z Yue, S Chen, Y Chen, X Lu, X Zhang, P Shen, J Li, Q Han, Z Li, P Liu
AIM: The transcriptional cofactor receptor-interacting protein 140 (RIP140) is known as a deleterious regulator of cardiac mitochondrial function and energy metabolic homeostasis. This study revealed that RIP140 repressed Sirtuin 3 (SIRT3), a mitochondrial deacetylase that plays an important role in regulating cardiac function. METHODS: RIP140 was overexpressed by adenovirus infection or was knocked down by RNA interference in neonatal rat cardiomyocytes. RESULTS: RIP140 overexpression repressed, while RIP140 silencing elevated the expression and activity of SIRT3...
September 10, 2016: Acta Physiologica
Mingming Zhang, Zhijing Zhao, Min Shen, Yingmei Zhang, Jianhong Duan, Yanjie Guo, Dongwei Zhang, Jianqiang Hu, Jie Lin, Wanrong Man, Lichao Hou, Haichang Wang, Dongdong Sun
Myocardial infarction (MI), which is characterized by chamber dilation and left ventricular (LV) dysfunction, represents a major cause of morbidity and mortality worldwide. Polydatin (PD), a monocrystalline and polyphenolic drug isolated from a traditional Chinese herb (Polygonum cuspidatum), alleviates mitochondrial dysfunction. We investigated the effects and underlying mechanisms of PD in post-MI cardiac dysfunction. We constructed an MI model by left anterior descending (LAD) coronary artery ligation using wild-type (WT) and Sirt3 knockout (Sirt3(-/-)) mice...
September 7, 2016: Biochimica et Biophysica Acta
Junqiang Zhang, Xianbin Song, Wei Cao, Jinseng Lu, Xiaoqing Wang, Gaoyuan Wang, Zhicheng Wang, Xiaoyu Chen
Resveratrol is a polyphenol derivatives which exhibits a pro-apoptotic effect in a variety of human cancers by triggering mitochondria apoptosis pathway and autophagy. However, there are scarcely reports on its apoptosis-promoting effect in abnormal proliferation fibroblast-like synoviocytes (FLSs). In this study, we investigated the underlying mechanism and apoptosis-inducing effects of resveratrol on the abnormal proliferation of FLSs in adjuvant-arthritis (AA) rats. Since using resveratrol for 12 days resulted in a significant decreasing the swelling degree of the paw, reducing malondialdehyde (MDA) content and enhancing superoxide dismutase (SOD) activity, antioxidant capacity, glutathione peroxidase and glutathione reductase ratio in AA rats...
2016: Scientific Reports
Brittany A Edgett, Jacob T Bonafiglia, Brittany L Baechler, Joe Quadrilatero, Brendon J Gurd
This study examined changes in LRP130 gene and protein expression in response to an acute bout of sprint-interval training (SIT) and 6 weeks of SIT in human skeletal muscle. In addition, we investigated the relationships between changes in LRP130, SIRT3, and PGC-1α gene or protein expression. Fourteen recreationally active men (age: 22.0 ± 2.4 years) performed a single bout of SIT (eight, 20-sec intervals at ~170% of VO2peak work rate, separated by 10 sec of rest). Muscle biopsies were obtained at rest (PRE) and 3 h post-exercise...
September 2016: Physiological Reports
Md Razia Sultana, Pankaj K Bagul, Parameshwar B Katare, Soheb Anwar, Raju Padiya, Sanjay K Banerjee
BACKGROUND: Cardiac complications are major contributor in the mortality of diabetic people. Mitochondrial dysfunctioning is a crucial contributor for the cardiac complications in diabetes, and SIRT-3 remains the major mitochondrial deacetylase. We hypothesized whether garlic has any role on SIRT-3 to prevent mitochondrial dysfunction in diabetic heart. METHODS: Rats with developed hyperglycemia after STZ injection were divided into two groups; diabetic (Dia) and diabetic+garlic (Dia+Garl)...
August 30, 2016: Life Sciences
Mitsuyasu Kawaguchi, Shohei Ikegawa, Naoya Ieda, Hidehiko Nakagawa
Sirtuins (SIRTs) are a family of NAD+-dependent histone deacetylases. In mammals, dysfunction of SIRTs is associated with age-related metabolic diseases and cancers, so SIRT modulators are considered attractive therapeutic targets. However, current screening methodologies are problematic, and no tools are available for imaging endogenous SIRT activity in living cells. In this work, we present a series of simple and highly sensitive novel SIRT activity probes. Fluorescence of these probes is activated by SIRT-mediated hydrolytic release of a 4-(4-dimethylaminophenylazo)benzoyl (Dabcyl)-based FRET quencher moiety from the -amino group of lysine in a histone H3K9-derived nonapeptide bearing a C-terminal fluorophore...
August 19, 2016: Chembiochem: a European Journal of Chemical Biology
Haemin Kim, Yong Deok Lee, Hyung Joon Kim, Zang Hee Lee, Hong-Hee Kim
Reactive oxygen species (ROS) are an indispensable element of cellular signal transduction in various cell types, including bone cells. In particular, osteoclasts (OCs), cells specialized for bone resorption, utilize ROS as second messengers during receptor activator of NF-κB ligand (RANKL)-induced differentiation and activation. In addition, because of the high energy demands of bone-resorbing activity, OCs contain large amounts of mitochondria, the source of the majority of total ROS. In this study, we focused on the regulation of ROS generated from mitochondria during osteoclastogenesis...
August 19, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
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