[Show abstract][Hide abstract] ABSTRACT: AIMS/HYPOTHESIS: Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. METHODS: We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. RESULTS: SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on pro-inflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. CONCLUSIONS/INTERPRETATION: Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: It should be noted that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a protein encoded by the PDPK1 gene, which plays a key role in the signaling pathways activated by several growth factors and hormones. PDK1 is a crucial kinase that functions downstream of phosphoinositide 3-kinase activation and activates members of the AGC family of protein kinases, such as protein kinase B (Akt), protein kinase C (PKC), p70 ribosomal protein S6 kinases, and serum glucocorticoid-dependent kinase, by phosphorylating serine/threonine residues in the activation loop. AGC kinases are known to play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation, and survival. Changes in the expression and activity of PDK1 and several AGC kinases have been linked to human diseases including cancer. Recent data have revealed that the alteration of PDK1 is a critical component of oncogenic phosphoinositide 3-kinase signaling in breast cancer, suggesting that inhibition of PDK1 can inhibit breast cancer progression. Indeed, PDK1 is highly expressed in a majority of human breast cancer cell lines and both PDK1 protein and messenger ribonucleic acid are overexpressed in a majority of human breast cancers. Furthermore, overexpression of PDK1 is sufficient to transform mammary epithelial cells. PDK1 plays an essential role in regulating cell migration, especially in the context of phosphatase and tensin homologue deficiency. More importantly, downregulation of PDK1 levels inhibits migration and experimental metastasis of human breast cancer cells. Thus, targeting PDK1 may be a valuable anticancer strategy that may improve the efficacy of chemotherapeutic strategies in breast cancer patients. In this review, we summarize the evidence that has been reported to support the idea that PDK1 may be a key target in breast cancer management.
Cancer Management and Research 01/2013; 5:271-280.
[Show abstract][Hide abstract] ABSTRACT: The last quarter of a century has witnessed remarkable progress in the understanding of phosphoinositide 3-kinases (PI3K) signalling and their involvement in different disease such as cancer, diabetes, inflammation. Nevertheless, many questions remain open and among these the role of genetic and epigenetic regulation of PI3K isoforms is one of the most prominent. Emerging evidence indicates that PI3K isoforms levels can be modulated upon stimulation or in both physiological and pathological conditions including increased gene copy number and transcription regulation. In addition, intriguing role for epigenetic regulation of PI3K expression, caused by mechanisms other than changes in the underlying DNA sequence, are starting to get appreciated. In this review, we summarize the genetic and epigenetic regulation of PI3Ks in physiology and the role played by their alterations in different diseases.
[Show abstract][Hide abstract] ABSTRACT: This report reviews evidence on disorders related to inadequate vitamin D repletion in older people. Vitamin D is as essential for bone health in adults as in children, preventing osteomalacia and muscle weakness and protecting against falls and low-impact fractures. Vitamin D is provided by skin synthesis by UVB-irradiation from summer sunshine and to a small extent by absorption from food. However, these processes become less efficient with age. Loss of mobility or residential care restricts solar exposure. Reduced appetite and financial problems often add to these problems. Thus, hypovitaminosis D is common world-wide, but is more common and more severe in older people. Non-classical effects of vitamin D, depending on serum circulating 25-hydroxyvitamin D concentrations, are present in most non-bony tissues; disorders associated with hypovitaminosis D include increased risks of sepsis [bacterial, mycobacterial and viral], cardiovascular and metabolic disorders [e.g. hyperlipidemia, type 2 diabetes mellitus, acute vascular events, dementia, stroke and heart failure]. Many cancer risks are associated with vitamin D inadequacy, though causality is accepted only for colo-rectal cancer. Maintenance of repletion in healthy older people requires intakes of ≥800IU/day [20μg], as advised by the Institute of Medicine [IOM], but achieving such intakes usually requires supplementation. Excessive intakes are dangerous, especially in undiagnosed primary hyperparathyroidism or sarcoidosis, but the IOM finds doses <4000 IU/day are safe. Many experts suggest that ≥1000-2000 IU [25-50μg] of vitamin D daily is necessary for older people, especially when independence is lost, or hypovitaminosis D could add to the clinical problem[s]. Much higher doses than these are needed for treatment of established deficiency or insufficiency.
[Show abstract][Hide abstract] ABSTRACT: Class II isoforms of PI3K (phosphoinositide 3-kinase) are still the least investigated and characterized of all PI3Ks. In the last few years, an increased interest in these enzymes has improved our understanding of their cellular functions. However, several questions still remain unanswered on their mechanisms of activation, their specific downstream effectors and their contribution to physiological processes and pathological conditions. Emerging evidence suggests that distinct PI3Ks activate different signalling pathways, indicating that their functional roles are probably not redundant. In the present review, we discuss the recent advances in our understanding of mammalian class II PI3Ks and the evidence suggesting their involvement in human diseases.
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Multidrug resistance (MDR) is the main cause of failure in cancer therapy. One mechanism responsible for MDR is the active efflux of drugs by ATP-binding cassette (ABC) transporters. Several agents have been developed to block transporter-mediated drug efflux and some of these compounds have entered Phase II/III clinical testing. Evidence is also emerging of the role played by ABC transporters in cancer cell signalling that is likely to be important in disease progression and which is distinct from MDR. AREAS COVERED: This article reviews current literature to analyse the rationale for targeting ABC transporters in cancer. Preclinical and clinical results of ABC transporter inhibitors in early clinical trials, as single agents or in combination with other drugs, are described. The development of new strategies to target MDR and the emerging roles of ABC transporters in cancer signalling are discussed. EXPERT OPINION: The intense active search for safe and effective inhibitors of ABC transporters has led to some success in MDR reversal in preclinical studies. However, there has been little impact on clinical outcome. The discovery of novel, potent and nontoxic inhibitors as well as new treatment strategies is therefore needed.
Expert Opinion on Investigational Drugs 05/2012; 21(5):657-66.
[Show abstract][Hide abstract] ABSTRACT: Cytokines are secreted from macrophages and other cells of the immune system in response to pathogens. Additionally, in autoinflammatory diseases cytokine secretion occurs in the absence of pathogenic stimuli. In the case of TRAPS [TNFR (tumour necrosis factor receptor)-associated periodic syndrome], inflammatory episodes result from mutations in the TNFRSF1A gene that encodes TNFR1. This work remains controversial, however, with at least three distinct separate mechanisms of receptor dysfunction having been proposed. Central to these hypotheses are the NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) families of transcriptional activators that are able to up-regulate expression of a number of genes, including pro-inflammatory cytokines. The present review examines each proposed mechanism of TNFR1 dysfunction, and addresses how these processes might ultimately impact upon cytokine secretion and disease pathophysiology.
[Show abstract][Hide abstract] ABSTRACT: 3-Phosphoinositide dependent protein kinase-1 (PDK1) and phospholipase C (PLC)gamma1 are two key enzymes in signal transduction that control several intracellular processes. Despite the fact that PLCgamma1 has been investigated for several years, the mechanisms of activation of this enzyme are still not completely clear. Similarly, although PDK1 has been mostly investigated for its role in activation of Akt, a crucial enzyme in regulation of several cellular processes, it has become recently evident that the role of PDK1 in physiological and pathological conditions is not limited to Akt activation.Here we demonstrate that PDK1 regulates PLCgamma1 activation in a mechanism involving association of the two enzymes and modulation of PLCgamma1 tyrosine phosphorylation. We further show that this novel PDK1-PLCgamma1 pathway is important for cancer cell invasion. The identification of a PDK1-PLCgamma1 pathway reveals the existence of a previously undetected link between two of the most important enzymes in signal transduction. This is likely to have profound consequences in our understanding of several cellular functions dependent on phosphoinositides and controlled by PDK1 and PLCgamma1.
Journal of Cell Science 03/2012;
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