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FoxO AND Sirt

Hanlin Yao, Zhen Yao, Shaocheng Zhang, Wenjun Zhang, Wen Zhou
Osteoporosis is a disease that significantly influences life expectancy and quality in humans. Oxidative stress may stimulate bone marrow osteoclast differentiation and inhibit osteoblast (OB) differentiation. OB proliferation and differentiation are affected by the forkhead box O (FoxO)1/β‑catenin signaling pathway. The osteogenic differentiation of mesenchymal stem cells (MSCs) may be promoted by silent information regulator type‑1 [sirtuin (SIRT)1]. However, the molecular mechanism of SIRT1 regulation of osteogenic differentiation of MSCs remains unclear, and further elucidation is needed...
May 2018: Molecular Medicine Reports
Jianping Guo, Ji Cheng, Brian J North, Wenyi Wei
Alzheimer's disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated...
December 2017: Biochimica et Biophysica Acta
Longwei Huo, Xiaobin Bai, Yafei Wang, Maode Wang
Glioma is the most common primary malignant tumor of the central nervous system. B10 is a new glycosylated derivative of betulinic acid with enhanced cytotoxic activity. The present study was designed to explore the molecular mechanism underlying the anticancer effect of B10 in glioma cells. 25-50μM B10 resulted in a significant decrease of cell viability and BrdU incorporation. 25-50mg/kg B10 significantly reduced the implanted tumor weight and volume in nude mice. Activation of apoptosis was found in glioma cells when the cells were exposed to B10, as evidenced by increased number of TUNEL-stained cells, increased caspase 3 and 9 activities, and Bax and cleaved PARP expression...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
T C Kenny, P Hart, M Ragazzi, M Sersinghe, J Chipuk, M A K Sagar, K W Eliceiri, T LaFramboise, S Grandhi, J Santos, A K Riar, L Papa, M D'Aurello, G Manfredi, M G Bonini, D Germain
By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis...
August 2017: Oncogene
H Jęśko, R P Strosznajder
Sirtuins (SIRT1 to -7) are unique histone deacetylases (HDACs) whose activity depends on NAD+, thus making them capable of sensing the cellular metabolic status. Sirtuins orchestrate the stress response and damage repair, and are able to modulate the course of ageing and neurodegenerative diseases. Despite their classification as HDACs, sirtuins deacetylate a vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-B, and DNA-PK (DNA-dependent protein kinase)...
2016: Folia Neuropathologica
Jeong-Ju Lee, Hee Jin Lee, Byung-Ho Son, Sung-Bae Kim, Jin-Hee Ahn, Seung Do Ahn, Eun Yoon Cho, Gyungyub Gong
Forkhead box (FOX) proteins constitute an extended family of transcriptional regulators. FOXM1 is ubiquitously expressed in cells undergoing proliferation, and overexpression of FOXM1 is associated with poor prognosis in various malignant tumours. FOXM1 and FOXO3a are often transcriptionally antagonistic. FOXO3a plays a critical tumour-suppressive role in breast cancer. FOXO activity is modulated by its acetylation status, which is regulated by class III histone deacetylases (sirtuins; also known as SIRTs)...
April 2016: International Journal of Experimental Pathology
Shatrunajay Shukla, Ankita Sharma, Vivek Kumar Pandey, Sheikh Raisuddin, Poonam Kakkar
Post-translational modifications i.e. phosphorylation and acetylation are pivotal requirements for proper functioning of eukaryotic proteins. The current study aimed to decode the impact of acetylation/deacetylation of non-histone targets i.e. FoxO1/3a and p53 of sirtuins (NAD(+) dependent enzymes with lysine deacetylase activity) in berberine treated human hepatoma cells. Berberine (100 μM) inhibited sirtuins significantly (P<0.05) at transcriptional level as well as at translational level. Combination of nicotinamide (sirtuin inhibitor) with berberine potentiated sirtuins inhibition and increased the expression of FoxO1/3a and phosphorylation of p53 tumor suppressor protein...
January 15, 2016: Toxicology and Applied Pharmacology
Dipita Bhakta-Guha, Thomas Efferth
In the paradigm of drug administration, determining the correct dosage of a therapeutic is often a challenge. Several drugs have been noted to demonstrate contradictory effects per se at high and low doses. This duality in function of a drug at different concentrations is known as hormesis. Therefore, it becomes necessary to study these biphasic functions in order to understand the mechanistic basis of their effects. In this article, we focus on different molecules and pathways associated with diseases that possess a duality in their function and thus prove to be the seat of hormesis...
2015: Pharmaceuticals
Bo Chen, Yan-Rong Lu, You-Nan Chen, Yu-Jian Kang, Jing-Qiu Cheng
In the endothelium, ROS mainly derive from mitochondria, endothelial nitric oxide synthases and NADPH oxidases 4. Excessive ROS are a major cause of oxidative stress, the primary stimulus of vascular dysfunction and oxidative stress-related diseases. However, cellular evolution has made possible the development of adaptive antioxidant systems that scavenge excessive ROS, such as Nrf2/Keapl-ARE, PPAR-y, SIRT and FOXO, etc. Among them, the Nrf2/Keapl-ARE signaling pathway is perhaps the most prominent. What is more, there are the "crosstalk" among these antioxidant stress-related signaling pathways aim to alleviate oxidative stress injurys and promote cells survival...
February 2015: Sheng Li Ke Xue Jin Zhan [Progress in Physiology]
Adam P Sharples, David C Hughes, Colleen S Deane, Amarjit Saini, Colin Selman, Claire E Stewart
Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals...
August 2015: Aging Cell
Anthony J Donato, R Garrett Morgan, Ashley E Walker, Lisa A Lesniewski
Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults...
December 2015: Journal of Molecular and Cellular Cardiology
Jesus A F Tresguerres, Sara Cuesta, Roman A Kireev, Cruz Garcia, Dario Acuña-Castroviejo, Elena Vara
Abstract This paper will review the effect of aging on glucose metabolism and insulin resistance in pancreas and in peripheral tissues and how melatonin administration could affect these parameters. In SAMP8 mice insulin levels in plasma were found to be increased together with enhanced HOMA-IR values, whereas insulin content in pancreas showed a decrease with aging. Aging in SAMP8 mice was also associated with a significant increase in the relative expression of both protein and mRNA of different pro-inflammatory mediators...
December 2013: Hormone Molecular Biology and Clinical Investigation
Yukio Akasaki, Oscar Alvarez-Garcia, Masahiko Saito, Beatriz Caramés, Yukihide Iwamoto, Martin K Lotz
OBJECTIVE: A major signaling pathway that regulates cellular aging is the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol 3-kinase (PI3K)/Akt/FoxO transcription factor axis. We previously observed that FoxO transcription factors are dysregulated in aged and OA cartilage. The objective of this study was to investigate the impact of down-regulated FoxO transcription factors on chondrocytes. METHODS: Small interfering RNAs (siRNAs) targeting FOXO1 (siFOXO1) and FOXO3 (siFOXO3) were transfected into human articular chondrocytes...
December 2014: Arthritis & Rheumatology
Kartick C Pramanik, Neel M Fofaria, Parul Gupta, Sanjay K Srivastava
Here, we investigated the potential mechanism of capsaicin-mediated apoptosis in pancreatic cancer cells. Capsaicin treatment phosphorylated c-jun-NH2-kinase (JNK); forkhead box transcription factor, class O (FOXO1); and BIM in BxPC-3, AsPC-1, and L3.6PL cells. The expression of BIM increased in response to capsaicin treatment. Capsaicin treatment caused cleavage of caspase-3 and PARP, indicating apoptosis. Antioxidants tiron and PEG-catalase blocked capsaicin-mediated JNK/FOXO/BIM activation and protected the cells from apoptosis...
March 2014: Molecular Cancer Therapeutics
Rongya Tao, Xiwen Xiong, Ronald A DePinho, Chu-Xia Deng, X Charlie Dong
Cholesterol homeostasis is crucial for cellular function and organismal health. The key regulator for the cholesterol biosynthesis is sterol-regulatory element binding protein (SREBP)-2. The biochemical process and physiological function of SREBP-2 have been well characterized; however, it is not clear how this gene is epigenetically regulated. Here we have identified sirtuin (Sirt)6 as a critical factor for Srebp2 gene regulation. Hepatic deficiency of Sirt6 in mice leads to elevated cholesterol levels. On the mechanistic level, Sirt6 is recruited by forkhead box O (FoxO)3 to the Srebp2 gene promoter where Sirt6 deacetylates histone H3 at lysines 9 and 56, thereby promoting a repressive chromatin state...
October 2013: Journal of Lipid Research
Rokhsana Mortuza, Shali Chen, Biao Feng, Subhrojit Sen, Subrata Chakrabarti
In diabetes, some of the cellular changes are similar to aging. We hypothesized that hyperglycemia accelerates aging-like changes in the endothelial cells (ECs) and tissues leading to structural and functional damage. We investigated glucose-induced aging in 3 types of ECs using senescence associated β-gal (SA β-gal) staining and cell morphology. Alterations of sirtuins (SIRTs) and their downstream mediator FOXO and oxidative stress were investigated. Relationship of such alteration with histone acetylase (HAT) p300 was examined...
2013: PloS One
Stefanie Grünwald, Julia Stellzig, Iris V Adam, Kristine Weber, Sarai Binger, Michael Boll, Eileen Knorr, Richard M Twyman, Andreas Vilcinskas, Uwe Wenzel
Diet is generally believed to affect the aging process. The effects of complex foods on life span can be investigated using simple models that produce rapid results and allow the identification of food-gene interactions. Here, we show that 1 % lyophilized broccoli, added to flour as a dietary source, significantly increases the life span of the red flour beetle (Tribolium castaneum) under physiological conditions (32 °C) and under heat stress (42 °C). The beneficial effects of broccoli could also be reproduced by supplementing flour with the isothiocyanate sulforaphane at concentrations found in the broccoli-supplemented diet...
September 2013: Genes & Nutrition
Sang-Heng Kok, Li-Deh Lin, Kuo-Liang Hou, Chi-Yuan Hong, Cheng-Chi Chang, Michael Hsiao, Jyh-Horng Wang, Eddie Hsiang-Hua Lai, Sze-Kwan Lin
OBJECTIVE: To examine the role of sirtuin-1 (SIRT-1)/FoxO3a in the expression of cysteine-rich protein 61 (CYR-61) in rheumatoid arthritis synovial fibroblasts (RASFs) and the influence of simvastatin on this pathway, and to determine the relationship between disease progression and FoxO3a/CYR-61 signaling in synovial fibroblasts in vivo using a rat model of collagen-induced arthritis (CIA). METHODS: In RASFs, the expression of CYR-61 and SIRT-1, the localization of FoxO3a in the nucleus/cytoplasm, and the phosphorylation/acetylation of FoxO3a were examined by Western blotting...
March 2013: Arthritis and Rheumatism
Mikyung Kim, Hyesuk Chung, Changsin Yoon, Eunju Lee, Taenyun Kim, Taekyoon Kim, Minjeong Kwon, Soonhee Lee, Byoungdoo Rhee, Jeonghyun Park
AIMS: Variations of blood glucose level have been reported to be more harmful than sustained high glucose, but the effects on pancreatic β-cells have not yet been clarified. FOXO transcription factors are important for cell fate. We tried to clarify the effect of glucose variability on INS-1 cells, and the potential mechanisms related with FOXO-SIRT pathway. METHODS: INS-1 cells were exposed to control, SHG (sustained high glucose) or IHG (intermittent high glucose) alternating every 12 h for 5 days...
October 2012: Diabetes Research and Clinical Practice
Jeremy S Tilstra, Cheryl L Clauson, Laura J Niedernhofer, Paul D Robbins
Stochastic damage to cellular macromolecules and organelles is thought to be a driving force behind aging and associated degenerative changes. However, stress response pathways activated by this damage may also contribute to aging. The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation...
December 2011: Aging and Disease
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