Literature Watch
Overview of Cantharidin and Its Analogues.
Overview of Cantharidin and Its Analogues.
Curr Med Chem. 2017 Apr 14;:
Authors: Wang G, Dong J, Deng L
Abstract
Canthiridin has significant anti-cancer effects and only limited use due to its toxicity. In spite of some side effects such as hematochezia and tenesmus, cantharidin can efficiently inhibit various tumor cell lines, therefore, its importance can never be overemphasized. Several of its analogues show functions similar to cantharidin without high toxicity. In order to utilize cantharidin to treat cancer, some viable methods are found to reduce its side effects. Since cantharidin can inhibit the activity of protein phosphatases, new researches for the inhibition of protein phosphatases have been implemented. This review introduces facts about cantharidin and its analogues, including structure-activity relationship, pharmacogenomics, mechanism of action, some strategies and directions to reduce toxicity. The review also recommends some clinic applications and comparisons of toxicity of cantharidin and its derivatives from the biological perspective or molecular perspective.
PMID: 28413963 [PubMed - as supplied by publisher]
rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis.
rs657075 (CSF2) Is Associated with the Disease Phenotype (BAS-G) of Ankylosing Spondylitis.
Int J Mol Sci. 2017 Jan 03;18(1):
Authors: Chen WC, Wei JC, Lu HF, Wong HS, Woon PY, Hsu YW, Huang JD, Chang WC
Abstract
Ankylosing spondylitis (AS) is a systemic autoimmune disease mainly affecting the lumbar spine and sacroiliac joints, and exhibits peripheral inflammatory arthropathy. More than 25 loci have been identified as associated with AS. Because both AS and rheumatoid arthritis (RA) are autoimmune diseases that may share some common genetic factors, we therefore examined if the newly identified RA genetic polymorphisms were associated with AS in a Taiwanese population. In this study, we enrolled 475 AS patients and 11,301 healthy subjects from a Taiwanese biobank as controls. Although none of single-nucleotide polymorphisms (SNPs) were associated with the susceptibility to AS, the AS disease index Bath AS Global (BAS-G) clinical phenotype was observed as significantly correlated to the AA genotype of rs657075 (CSF2). The significance remains after gender/age/disease duration adjustment and after group categorization by human leukocyte antigen-B 27 (HLA-B27) genotype. We further investigated the possible functions of rs657075 through bioinformatics approaches. Results revealed that polymorphism of rs657075 is able to influence the expression of acyl-CoA synthetase long-chain family member 6 (ACSL6). In conclusion, our study indicated that rs657075 (CSF2) is strongly associated with the AS disease index Bath AS Global (BAS-G) clinical phenotype.
PMID: 28054948 [PubMed - indexed for MEDLINE]
A case of severe movement disorder with GNAO1 mutation responsive to topiramate.
A case of severe movement disorder with GNAO1 mutation responsive to topiramate.
Brain Dev. 2017 May;39(5):439-443
Authors: Sakamoto S, Monden Y, Fukai R, Miyake N, Saito H, Miyauchi A, Matsumoto A, Nagashima M, Osaka H, Matsumoto N, Yamagata T
Abstract
We report the case of a 19-year-old female patient who had progressive chorea associated with a GNAO1 mutation. Chorea was refractory to multiple anticonvulsants, and the patient suffered from tiapride-induced neuroleptic malignant syndrome. After identification of a GNAO1 missense mutation at the age of 18years, topiramate treatment was initiated and the frequency of chorea decreased dramatically. The efficacy of topiramate may have been related to the inhibitory modulation of voltage-activated Ca(2+) channels. Given the side effects and complications associated with neuroleptics and deep brain stimulation, respectively, topiramate is recommended for the first-line management of severe chorea associated with a GNAO1 mutation.
PMID: 27916449 [PubMed - indexed for MEDLINE]
Establishment of a drug evaluation model against light-induced retinal degeneration using adult pigmented zebrafish.
Establishment of a drug evaluation model against light-induced retinal degeneration using adult pigmented zebrafish.
J Pharmacol Sci. 2016 Jul;131(3):215-8
Authors: Saito Y, Tsuruma K, Shimazawa M, Nishimura Y, Tanaka T, Hara H
Abstract
Age-related macular degeneration (AMD) is a major cause of irreversible loss of central vision in the elderly. Zebrafish is an attractive animal model in some respects, lower cost, smaller housing facilities and easier genetic manipulation compared to rodents. The present study aimed to establish a drug evaluation method against light irradiation, as a dry AMD disease model, using adult pigmented zebrafish. Intravitreal administration of an antioxidant, N-acetylcysteine, protected against light-induced retinal degeneration in a concentration-dependent manner. We established a new drug evaluation model against light-induced retinal degeneration that can provide new knowledge about dry AMD pathology and therapy.
PMID: 27430989 [PubMed - indexed for MEDLINE]
Study suggests hidden epidemic in CF patients.
Study suggests hidden epidemic in CF patients.
Science. 2016 Nov 11;354(6313):695
Authors: Kupferschmidt K
PMID: 27846586 [PubMed - indexed for MEDLINE]
Semantic prioritization of novel causative genomic variants.
Semantic prioritization of novel causative genomic variants.
PLoS Comput Biol. 2017 Apr 17;13(4):e1005500
Authors: Boudellioua I, Mahamad Razali RB, Kulmanov M, Hashish Y, Bajic VB, Goncalves-Serra E, Schoenmakers N, Gkoutos GV, Schofield PN, Hoehndorf R
Abstract
Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.
PMID: 28414800 [PubMed - as supplied by publisher]
The role of GLI1 for 5-Fu resistance in colorectal cancer.
The role of GLI1 for 5-Fu resistance in colorectal cancer.
Cell Biosci. 2017;7:17
Authors: Zhang L, Song R, Gu D, Zhang X, Yu B, Liu B, Xie J
Abstract
Colorectal cancer is a leading cause of cancer-related mortality worldwide, with Fluorouracil (5-FU)-based chemotherapy as the major treatment for advanced disease. Many patients with advanced colorectal cancer eventually succumb to the disease despite some patients responded initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat colorectal cancer. In this study, we established an acquired 5-FU resistant cell line, LoVo-R, from LoVo cells. Through exome sequencing, we discovered that elevated GLI1 signaling axis is a major genetic alteration in the 5-FU resistant cells. Hh signaling, a pathway essential for embryonic development, is an important regulator for residual cancer cells. We demonstrated that knockdown of GLI1 or GLI2 sensitized LoVo-R cells to 5-FU treatment, reduced cell invasiveness. The relevance of our studies to colorectal cancer patients is reflected by our discovery that high expression of GLI1 signaling molecules was associated with a high incidence of cancer relapse and a shorter survival in a larger cohort of colorectal cancer patients who underwent chemotherapy (containing 5-FU). Taken together, our data demonstrate the critical role of the GLI1 signaling axis for 5-FU resistance in colorectal cancer.
PMID: 28413604 [PubMed]
A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing.
A SLC24A2 Gene Variant Uncovered in Pancreatic Ductal Adenocarcinoma by Whole Exome Sequencing.
Tohoku J Exp Med. 2017;241(4):287-295
Authors: Wang L, Shao Z, Chen S, Shi L, Li Z
Abstract
Pancreatic ductal adenocarcinoma (PDAC) presents as an aggressive malignancy caused by environmental and genetic factors. In order to identify causal genes for PDAC, we performed whole exome sequencing (WES) to detect gene mutations in seven pairs of PDAC tissue and adjacent non-tumor tissue samples. Finally, we found a new nonsynonymous single nucleotide variant (nsSNV) in solute carrier 24 family member 2 (SLC24A2) gene resulting in the substitution of native glutamic acid (E) into aspartic acid (D) at position of 287 amino acid (E287D) in SLC24A2 protein, and confirmed this variant by Sanger gene sequencing. SLC24A2 is a potassium-dependent sodium-calcium exchanger and can transport metal ion across cell membrane. Multiple in silico variants' effects analyses methods including SIFT, PolyPhen, PROVEAN, and PANTHER demonstrated this variant had probably damaging effects, which was consistent with the results obtained from Mutation Taster software analysis with a probability of 0.99999997 to be "disease causing." The three dimension (3D) structure analysis results suggested this variant had little effects on the solubility and hydrophobicity of the protein; but it could decrease the protein stability by increasing the total protein structure energy (-8874.33 kJ/mol for the mutant and -8963.54 kJ/mol for the native) and by causing the mutant protein decreasing three stabilizing residues. Less stability of the mutant 287D protein than the native E287 protein was also supported by I-Mutant and Western-blotting analysis results. Overall, a new mutation in SLC24A2 gene was identified to decrease the stability of SLC24A2, which may have potential clinical usages.
PMID: 28413183 [PubMed - in process]
Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management.
Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management.
Brain Dev. 2017 May;39(5):369-385
Authors: Ashrafi MR, Tavasoli AR
Abstract
Childhood leukodystrophies are a growing category of neurological disorders in pediatric neurology practice. With the help of new advanced genetic studies such as whole exome sequencing (WES) and whole genome sequencing (WGS), the list of childhood heritable white matter disorders has been increased to more than one hundred disorders. During the last three decades, the basic concepts and definitions, classification, diagnostic approach and medical management of these disorders much have changed. Pattern recognition based on brain magnetic resonance imaging (MRI), has played an important role in this process. We reviewed the last Global Leukodystrophy Initiative (GLIA) expert opinions in definition, new classification, diagnostic approach and medical management including emerging treatments for pediatric leukodystrophies.
PMID: 28117190 [PubMed - indexed for MEDLINE]
NIH Director's Early Independence Awards (DP5)
Notice of Change to RFA-HL-16-024 "NHLBI Outstanding Investigator Award (OIA) (R35)"
Notice of Change to RFA-HL-16-025 "NHLBI Emerging Investigator Award (EIA) (R35)"
Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients.
Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients.
Eur J Cancer. 2017 Apr 13;78:70-81
Authors: Massi D, Romano E, Rulli E, Merelli B, Nassini R, De Logu F, Bieche I, Baroni G, Cattaneo L, Xue G, Mandalà M
Abstract
BACKGROUND: The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified.
PATIENTS AND METHODS: Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients.
RESULTS: We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%.
CONCLUSION: Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs.
PMID: 28412591 [PubMed - as supplied by publisher]
The Molecular Revolution in Cutaneous Biology: EDC and Locus Control.
The Molecular Revolution in Cutaneous Biology: EDC and Locus Control.
J Invest Dermatol. 2017 May;137(5):e101-e104
Authors: Oh IY, de Guzman Strong C
Abstract
The epidermal differentiation complex (EDC) locus consists of a cluster of genes important for the terminal differentiation of the epidermis. While early studies identified the functional importance of individual EDC genes, the recognition of the EDC genes as a cluster with its shared biology, homology, and physical linkage was pivotal to later studies that investigated the transcriptional regulation of the locus. Evolutionary conservation of the EDC and the transcriptional activation during epidermal differentiation suggested a cis-regulatory mechanism via conserved noncoding elements or enhancers. This line of pursuit led to the identification of CNE 923, an epidermal-specific enhancer that was found to mediate chromatin remodeling of the EDC in an AP-1 dependent manner. These genomic studies, as well as the advent of high-throughput sequencing and genome engineering techniques, have paved the way for future investigation into enhancer-mediated regulatory networks in cutaneous biology.
PMID: 28411839 [PubMed - in process]
Use of Nebulized Antimicrobials for the Treatment of Respiratory Infections in Invasively Mechanically Ventilated Adults: A Position Paper from the European Society of Clinical Microbiology and Infectious Diseases.
Use of Nebulized Antimicrobials for the Treatment of Respiratory Infections in Invasively Mechanically Ventilated Adults: A Position Paper from the European Society of Clinical Microbiology and Infectious Diseases.
Clin Microbiol Infect. 2017 Apr 13;:
Authors: Rello J, Solé-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, Luyt CE, Riera J, Palmer LB, Pereira JM, Felton T, Dhanani J, Bassetti M, Welte T, Roberts JA
Abstract
With an established role in cystic fibrosis and bronchiectasis, nebulized antibiotics are increasingly being used to treat respiratory infections in critically ill invasively mechanically ventilated adult patients. Although there is limited evidence describing their efficacy and safety, in an era of need for new strategies to enhance antibiotic effectiveness because of a shortage of new agents and increases in antibiotic resistance, the potential of nebulization of antibiotics to optimize therapy is considered of high interest, particularly in patients infected with multidrug-resistant (MDR) pathogens. This Position Paper of the European Society of Clinical Microbiology and Infectious Diseases provides recommendations based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology regarding the use of nebulized antibiotics in invasively mechanically ventilated adults, based on a systematic review and meta-analysis of the existing literature (last search July 2016). Overall, the panel recommends to avoid use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy and the high potential for underestimated risks of adverse events (particularly, respiratory complications). Higher quality evidence is urgently needed to inform clinical practice. Priorities of future research are detailed in the second part of the Position Paper as a guidance for researchers in this field. In particular, the panel identified an urgent need for randomized clinical trials of nebulized antibiotic therapy as part of a substitution approach to treatment of pneumonia due to MDR pathogens.
PMID: 28412382 [PubMed - as supplied by publisher]
Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population.
Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population.
Oncotarget. 2017 Feb 17;:
Authors: Li J, Yang S, Pu Z, Dai J, Jiang T, Du F, Jiang Z, Cheng Y, Dai G, Wang J, Qi J, Cao L, Cheng X, Ren C, Li X, Qin Y
Abstract
As a rare type of Congenital Heart Defects (CHD), the genetic mechanism of Total Anomalous Pulmonary Venous Return (TAPVR) remains unknown, although previous studies have revealed potential disease-driving regions/genes. Blood samples collected from the 6 sporadic TAPVR cases and 81 non-TAPVR controls were subjected to whole exome sequencing. All detected variations were confirmed by direct Sanger sequencing. Here, we identified 2 non-synonymous missense mutations: c.C652T, p.R218W in activin A receptor type II-like 1 (ACVRL1), c.C717G, p.D239E in sarcoglycan delta (SGCD). Our results offered the landscape of mutations for TAPVR in Chinese population firstly and are valuable in the mutation-based pre- and post-natal screening and genetic diagnosis for TAPVR.
PMID: 28412737 [PubMed - as supplied by publisher]
Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.
Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.
Ophthalmology. 2017 Apr 12;:
Authors: Pierrache LHM, Kimchi A, Ratnapriya R, Roberts L, Astuti GDN, Obolensky A, Beryozkin A, Tjon-Fo-Sang MJH, Schuil J, Klaver CCW, Bongers EMHF, Haer-Wigman L, Schalij N, Breuning MH, Fischer GM, Banin E, Ramesar RS, Swaroop A, van den Born LI, Sharon D, Cremers FPM
Abstract
PURPOSE: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma.
DESIGN: Case series.
PARTICIPANTS: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma.
METHODS: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography.
MAIN OUTCOME MEASURES: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings.
RESULTS: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula.
CONCLUSIONS: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.
PMID: 28412069 [PubMed - as supplied by publisher]
The Molecular Revolution in Cutaneous Biology: The Era of Genome-Wide Association Studies and Statistical, Big Data, and Computational Topics.
The Molecular Revolution in Cutaneous Biology: The Era of Genome-Wide Association Studies and Statistical, Big Data, and Computational Topics.
J Invest Dermatol. 2017 May;137(5):e113-e118
Authors: Anbunathan H, Bowcock AM
Abstract
The investigation of biological systems involving all organs of the body including the skin is in era of big data. This requires heavy-duty computational tools, and novel statistical methods. Microarrays have allowed the interrogation of thousands of common genetic markers in thousands of individuals from the same population (termed genome wide association studies or GWAS) to reveal common variation associated with disease or phenotype. These markers are usually single nucleotide polymorphisms (SNPs) that are relatively common in the population. In the case of dermatological diseases such as alopecia areata, vitiligo, psoriasis and atopic dermatitis, common variants have been identified that are associated with disease, and these provide insights into biological pathways and reveal possible novel drug targets. Other skin phenotypes such as acne, color and skin cancers are also being investigated with GWAS. Analyses of such large GWAS datasets require a consideration of a number of statistical issues including the testing of multiple markers, population substructure, and ultimately a requirement for replication. There are also issues regarding the missing heritability of disease that cannot be entirely explained with current GWAS approaches. Next generation sequencing technologies such as exome and genome sequencing of similar patient cohorts will reveal additional variants contributing to disease susceptibility. However, the data generated with these approaches will be orders of magnitude greater than that those generated with arrays, with concomitant challenges in the identification of disease causing variants.
PMID: 28411841 [PubMed - in process]
Whole genome sequencing of matched tumor, adjacent non-tumor tissues and corresponding normal blood samples of hepatocellular carcinoma patients revealed dynamic changes of the mutations profiles during hepatocarcinogenesis.
Whole genome sequencing of matched tumor, adjacent non-tumor tissues and corresponding normal blood samples of hepatocellular carcinoma patients revealed dynamic changes of the mutations profiles during hepatocarcinogenesis.
Oncotarget. 2017 Feb 17;:
Authors: Mao R, Liu J, Liu G, Jin S, Xue Q, Ma L, Fu Y, Zhao N, Xing J, Li L, Qiu Y, Lin B
Abstract
Hepatocellular carcinoma (HCC) has become the third most deadly disease worldwide and HBV is the major factor in Asia and Africa. We conducted 9 WGS (whole genome sequencing) analyses for matched samples of tumor, adjacent non-tumor tissues and normal blood samples of HCC patients from three HBV positive patients. We then validated the mutations identified in a larger cohort of 177 HCC patients. We found that the number of the unique somatic mutations (average of 59,136) in tumor samples is significantly less than that in adjacent non-tumor tissues (average 83, 633). We discovered that the TP53 R249S mutation occurred in 7.7% of the HCC patients, and it was significantly associated with poor diagnosis. In addition, we found that the L104P mutation in the VCX gene (Variable charge, X-linked) was absent in white blood cell samples, but present at 11.1% frequency in the adjacent tissues and increased to 14.6% in HCC tissues, suggesting that this mutation might be a tumor driver gene driving HCC carcinogenesis. Finally, we identified a TK1-RNU7 fusion, which would result in a deletion of 103 amino acids from its C-terminal. The frequencies of this fusion event decreased from the adjacent tissues (29.2%) to the tumors (16.7%), suggesting that a truncated thymidine Kinase1 (TK1) caused by the fusion event might be deleterious and be selected against during tumor progression. The three-way comparisons allow the identification of potential driver mutations of carcinogenesis. Furthermore, our dataset provides the research community a valuable dataset for identifying dynamic changes of mutation profiles and driver mutations for HCC.
PMID: 28412734 [PubMed - as supplied by publisher]
During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent.
During yeast chronological aging resveratrol supplementation results in a short-lived phenotype Sir2-dependent.
Redox Biol. 2017 Apr 09;12:745-754
Authors: Orlandi I, Stamerra G, Strippoli M, Vai M
Abstract
Resveratrol (RSV) is a naturally occurring polyphenolic compound endowed with interesting biological properties/functions amongst which are its activity as an antioxidant and as Sirtuin activating compound towards SIRT1 in mammals. Sirtuins comprise a family of NAD(+)-dependent protein deacetylases that are involved in many physiological and pathological processes including aging and age-related diseases. These enzymes are conserved across species and SIRT1 is the closest mammalian orthologue of Sir2 of Saccharomyces cerevisiae. In the field of aging researches, it is well known that Sir2 is a positive regulator of replicative lifespan and, in this context, the RSV effects have been already examined. Here, we analyzed RSV effects during chronological aging, in which Sir2 acts as a negative regulator of chronological lifespan (CLS). Chronological aging refers to quiescent cells in stationary phase; these cells display a survival-based metabolism characterized by an increase in oxidative stress. We found that RSV supplementation at the onset of chronological aging, namely at the diauxic shift, increases oxidative stress and significantly reduces CLS. CLS reduction is dependent on Sir2 presence both in expired medium and in extreme Calorie Restriction. In addition, all data point to an enhancement of Sir2 activity, in particular Sir2-mediated deacetylation of the key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (Pck1). This leads to a reduction in the amount of the acetylated active form of Pck1, whose enzymatic activity is essential for gluconeogenesis and CLS extension.
PMID: 28412652 [PubMed - as supplied by publisher]
Pages
