scholarly journals Histone Acetylation and Its Modifiers in the Pathogenesis of Diabetic Nephropathy

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaoxia Li ◽  
Chaoyuan Li ◽  
Guangdong Sun
Keyword(s):  
Diabetic Nephropathy ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Vascular Complications ◽  
Therapeutic Approaches ◽  
Nonhistone Proteins ◽  
Amino Terminal ◽  
Cellular Processes ◽  
Diabetic Vascular Complications ◽  
New Evidence

Diabetic nephropathy (DN) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors contributing to DN is required to develop more effective therapeutic options. It is becoming more evident that histone acetylation (HAc), as one of the epigenetic mechanisms, is thought to be associated with the etiology of diabetic vascular complications such as diabetic retinopathy (DR), diabetic cardiomyopathy (DCM), and DN. Histone acetylases (HATs) and histone deacetylases (HDACs) are the well-known regulators of reversible acetylation in the amino-terminal domains of histone and nonhistone proteins. In DN, however, the roles of histone acetylation (HAc) and these enzymes are still controversial. Some new evidence has revealed that HATs and HDACs inhibitors are renoprotective in cellular and animal models of DN, while, on the other hand, upregulation of HAc has been implicated in the pathogenesis of DN. In this review, we focus on the recent advances on the roles of HAc and their covalent enzymes in the development and progression of DN in certain cellular processes including fibrosis, inflammation, hypertrophy, and oxidative stress and discuss how targeting these enzymes and their inhibitors can ultimately lead to the therapeutic approaches for treating DN.

L-carnosine and its Derivatives as New Therapeutic Agents for the Prevention and Treatment of Vascular Complications of Diabetes

2020 ◽  
Vol 27 (11) ◽  
pp. 1744-1763 ◽  
Author(s):  
Stefano Menini ◽  
Carla Iacobini ◽  
Claudia Blasetti Fantauzzi ◽  
Giuseppe Pugliese
Keyword(s):  
Diabetic Nephropathy ◽  
Life Quality ◽  
Vascular Complications ◽  
Carbonyl Stress ◽  
Complications Of Diabetes ◽  
Diabetic Vascular Complications ◽  
Reactive Carbonyl Species ◽  
Stage Renal Disease ◽  
Stress Dependent ◽  
End Stage

Vascular complications are among the most serious manifestations of diabetes. Atherosclerosis is the main cause of reduced life quality and expectancy in diabetics, whereas diabetic nephropathy and retinopathy are the most common causes of end-stage renal disease and blindness. An effective therapeutic approach to prevent vascular complications should counteract the mechanisms of injury. Among them, the toxic effects of Advanced Glycation (AGEs) and Lipoxidation (ALEs) end-products are well-recognized contributors to these sequelae. L-carnosine (β-alanyl-Lhistidine) acts as a quencher of the AGE/ALE precursors Reactive Carbonyl Species (RCS), which are highly reactive aldehydes derived from oxidative and non-oxidative modifications of sugars and lipids. Consistently, L-carnosine was found to be effective in several disease models in which glyco/lipoxidation plays a central pathogenic role. Unfortunately, in humans, L-carnosine is rapidly inactivated by serum carnosinase. Therefore, the search for carnosinase-resistant derivatives of Lcarnosine represents a suitable strategy against carbonyl stress-dependent disorders, particularly diabetic vascular complications. In this review, we present and discuss available data on the efficacy of L-carnosine and its derivatives in preventing vascular complications in rodent models of diabetes and metabolic syndrome. We also discuss genetic findings providing evidence for the involvement of the carnosinase/L-carnosine system in the risk of developing diabetic nephropathy and for preferring the use of carnosinase-resistant compounds in human disease. The availability of therapeutic strategies capable to prevent both long-term glucose toxicity, resulting from insufficient glucoselowering therapy, and lipotoxicity may help reduce the clinical and economic burden of vascular complications of diabetes and related metabolic disorders.

scholarly journals Uncoupling of ER-mitochondrial calcium communication by transforming growth factor-β

2008 ◽  
Vol 295 (5) ◽  
pp. F1303-F1312 ◽  
Author(s):  
Pál Pacher ◽  
Kumar Sharma ◽  
György Csordás ◽  
Yanqing Zhu ◽  
György Hajnóczky
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Complications ◽  
Transforming Growth Factor Β ◽  
Sole Source ◽  
Atp Production ◽  
Permeabilized Cells ◽  
Cellular Processes ◽  
Diabetic Vascular Complications ◽  
Key Factor

Transforming growth factor-β (TGF-β) has been implicated as a key factor in mediating many cellular processes germane to disease pathogenesis, including diabetic vascular complications. TGF-β alters cytosolic [Ca2+] ([Ca2+]c) signals, which in some cases may result from the downregulation of the IP3 receptor Ca2+ channels (IP3R). Ca2+ released by IP3Rs is effectively transferred from endoplasmic reticulum (ER) to the mitochondria to stimulate ATP production and to allow feedback control of the Ca2+ mobilization. To assess the effect of TGF-β on the ER-mitochondrial Ca2+ transfer, we first studied the [Ca2+]c and mitochondrial matrix Ca2+ ([Ca2+]m) signals in single preglomerular afferent arteriolar smooth muscle cells (PGASMC). TGF-β pretreatment (24 h) decreased both the [Ca2+]c and [Ca2+]m responses evoked by angiotensin II or endothelin. Strikingly, the [Ca2+]m signal was more depressed than the [Ca2+]c signal and was delayed. In permeabilized cells, TGF-β pretreatment attenuated the rate but not the magnitude of the IP3-induced [Ca2+]c rise, yet caused massive depression of the [Ca2+]m responses. ER Ca2+ storage and mitochondrial uptake of added Ca2+ were not affected by TGF-β. Also, TGF-β had no effect on mitochondrial distribution and on the ER-mitochondrial contacts assessed by two-photon NAD(P)H imaging and electron microscopy. Downregulation of both IP3R1 and IP3R3 was found in TGF-β-treated PGASMC. Thus, TGF-β causes uncoupling of mitochondria from the ER Ca2+ release. The sole source of this would be suppression of the IP3R-mediated Ca2+ efflux, indicating that the ER-mitochondrial Ca2+ transfer depends on the maximal rate of Ca2+ release. The impaired ER-mitochondrial coupling may contribute to the vascular pathophysiology associated with TGF-β production.

scholarly journals Vasculogenesis and angiogenesis in diabetes mellitus: novel pathogenetic concepts for treatment of vascular complications

2012 ◽  
Vol 15 (4) ◽  
pp. 17-27 ◽  
Author(s):  
Vladimir Iosifovich Konenkov ◽  
Vadim Valer'evich Klimontov
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Metabolic Disorders ◽  
Vascular Complications ◽  
Angiogenesis Inhibitors ◽  
Therapeutic Approaches ◽  
Retinal Angiogenesis ◽  
Vasculogenesis And Angiogenesis ◽  
Large Vessels ◽  
Stimulation Of

Hyperglycemia along with other metabolic disorders may disrupt the balance of pro- and antiangiogenic regulators, thus leading to a maladaptive formation of new blood vessels in the state of diabetes mellitus (DM). In their turn, aberrant angiogenesis and vasculogenesis are important mechanisms of vascular complications in DM. Activation of retinal angiogenesis is a cornerstone of proliferative diabetic retinopathy, though in diabetic nephropathy excessive angiogenesis is only seen at early stages. Quite on the contrary, macrovascular complications are characterized by certain inhibition of both angiogenesis and vasculogenesis. Novel therapeutic approaches, based on correction of angiogenesis, have emerged recently. Clinical trials have shown efficacy of angiogenesis inhibitors (the ?anti-VEGF? agents) for management of diabetic macular edema and proliferative retinopathy. Experimental evidence also indicates that this treatment may hinder the progress of diabetic nephropathy. In addition, stimulation of angiogenesis and vasculogenesis with stem cells or growth factors promise an option for treatment of large vessels in DM.

Phycocyanin and phycocyanobilin fromSpirulina platensisprotect against diabetic nephropathy by inhibiting oxidative stress

2013 ◽  
Vol 304 (2) ◽  
pp. R110-R120 ◽  
Author(s):  
Jing Zheng ◽  
Toyoshi Inoguchi ◽  
Shuji Sasaki ◽  
Yasutaka Maeda ◽  
Mark F. McCarty ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Oral Administration ◽  
Mesangial Cells ◽  
Vascular Complications ◽  
Blue Green Algae ◽  
Beneficial Effects ◽  
Diabetic Vascular Complications ◽  
Tumor Growth Factor ◽  
Antioxidant Effects

We and other investigators have reported that bilirubin and its precursor biliverdin may have beneficial effects on diabetic vascular complications, including nephropathy, via its antioxidant effects. Here, we investigated whether phycocyanin derived from Spirulina platensis, a blue-green algae, and its chromophore phycocyanobilin, which has a chemical structure similar to that of biliverdin, protect against oxidative stress and renal dysfunction in db/db mice, a rodent model for Type 2 diabetes. Oral administration of phycocyanin (300 mg/kg) for 10 wk protected against albuminuria and renal mesangial expansion in db/db mice, and normalized tumor growth factor-β and fibronectin expression. Phycocyanin also normalized urinary and renal oxidative stress markers and the expression of NAD(P)H oxidase components. Similar antioxidant effects were observed following oral administration of phycocyanobilin (15 mg/kg) for 2 wk. Phycocyanobilin, bilirubin, and biliverdin also inhibited NADPH dependent superoxide production in cultured renal mesangial cells. In conclusion, oral administration of phycocyanin and phycocyanobilin may offer a novel and feasible therapeutic approach for preventing diabetic nephropathy.

Histone acetylation: truth of consequences?This paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 87 (1) ◽  
pp. 139-150 ◽  
Author(s):  
Jennifer K. Choi ◽  
LeAnn J. Howe
Keyword(s):  
Histone Acetylation ◽  
Chromatin Structure ◽  
Peer Review Process ◽  
Active Form ◽  
Large Body ◽  
Covalent Modification ◽  
Nonhistone Proteins ◽  
Chromatin Dynamics ◽  
Amino Terminal ◽  
Downstream Effects

Eukaryotic DNA is packaged into a nucleoprotein structure known as chromatin, which is comprised of DNA, histones, and nonhistone proteins. Chromatin structure is highly dynamic, and can shift from a transcriptionally inactive state to an active form in response to intra- and extracellular signals. A major factor in chromatin architecture is the covalent modification of histones through the addition of chemical moieties, such as acetyl, methyl, ubiquitin, and phosphate groups. The acetylation of the amino-terminal tails of histones is a process that is highly conserved in eukaryotes, and was one of the earliest histone modifications characterized. Since its identification in 1964, a large body of evidence has accumulated demonstrating that histone acetylation plays an important role in transcription. Despite our ever-growing understanding of the nuclear processes involved in nucleosome acetylation, however, the exact biochemical mechanisms underlying the downstream effects of histone acetylation have yet to be fully elucidated. To date, histone acetylation has been proposed to function in 2 nonmutually exclusive manners: by directly altering chromatin structure, and by acting as a molecular tag for the recruitment of chromatin-modifying complexes. Here, we discuss recent research focusing on these 2 potential roles of histone acetylation and clarify what we actually know about the function of this modification.

scholarly journals HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis

2019 ◽  
Vol 10 ◽  
pp. 204062231986269 ◽  
Author(s):  
Xing Lyu ◽  
Min Hu ◽  
Jieting Peng ◽  
Xiangyu Zhang ◽  
Yan Y Sanders
Keyword(s):  
Pulmonary Fibrosis ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Wound Repair ◽  
Hdac Inhibitors ◽  
Scar Tissue ◽  
Nonhistone Proteins ◽  
Fibrotic Diseases

Fibrosis usually results from dysregulated wound repair and is characterized by excessive scar tissue. It is a complex process with unclear mechanisms. Accumulating evidence indicates that epigenetic alterations, including histone acetylation, play a pivotal role in this process. Histone acetylation is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are enzymes that remove the acetyl groups from both histone and nonhistone proteins. Aberrant HDAC activities are observed in fibrotic diseases, including cardiac and pulmonary fibrosis. HDAC inhibitors (HDACIs) are molecules that block HDAC functions. HDACIs have been studied extensively in a variety of tumors. Currently, there are four HDACIs approved by the US Food and Drug Administration for cancer treatment yet none for fibrotic diseases. Emerging evidence from in vitro and in vivo preclinical studies has presented beneficial effects of HDACIs in preventing or reversing fibrogenesis. In this review, we summarize the latest findings of the roles of HDACs in the pathogenesis of cardiac and pulmonary fibrosis and highlight the potential applications of HDACIs in these two fibrotic diseases.

An Overview of HDAC Inhibitors and their Synthetic Routes

2019 ◽  
Vol 19 (12) ◽  
pp. 1005-1040 ◽  
Author(s):  
Xiaopeng Peng ◽  
Guochao Liao ◽  
Pinghua Sun ◽  
Zhiqiang Yu ◽  
Jianjun Chen
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cell Cycle Control ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Cellular Processes ◽  
Chaperone Function ◽  
Damage Repair ◽  
Synthetic Routes

Epigenetics play a key role in the origin, development and metastasis of cancer. Epigenetic processes include DNA methylation, histone acetylation, histone methylation, and histone phosphorylation, among which, histone acetylation is the most common one that plays important roles in the regulation of normal cellular processes, and is controlled by histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDACs are involved in the regulation of many key cellular processes, such as DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function, and can lead to oncogene activation. As a result, HDACs are considered to be an excellent target for anti-cancer therapeutics like histone deacetylase inhibitors (HDACi) which have attracted much attention in the last decade. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. The primary purpose of this paper is to summarize recent HDAC inhibitors and the synthetic routes as well as to discuss the direction for the future development of new HDAC inhibitors.

scholarly journals Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yonggang Wang ◽  
Xiao Miao ◽  
Yucheng Liu ◽  
Fengsheng Li ◽  
Quan Liu ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Treatment Options ◽  
Histone Acetyltransferases ◽  
Protein Acetylation ◽  
Cellular Processes ◽  
Disease States ◽  
Novel Approach ◽  
Artery Disease ◽  
New Evidence

Cardiovascular disease (CVD) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs) and deacetylases (HDACs) are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.

scholarly journals Histone Deacetylase Inhibitors from Marine Invertebrates

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 429 ◽  
Author(s):  
Claudio Luparello ◽  
Manuela Mauro ◽  
Vincenzo Arizza ◽  
Mirella Vazzana
Keyword(s):  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Marine Invertebrates ◽  
Marine Invertebrate ◽  
Hdac Inhibitors ◽  
Nonhistone Proteins ◽  
Future Design ◽  
Cellular Processes ◽  
Epigenetic Machinery ◽  
Isoform Selectivity

Histone deacetylases (HDACs) are key components of the epigenetic machinery controlling gene expression. They are involved in chromatin remodeling events via post-translational histone modifications but may also act on nonhistone proteins, influencing many fundamental cellular processes. Due to the key involvement of HDACs in serious human pathologies, including cancer, HDAC inhibitors (HDACis) have received increased attention in recent years. It is known that marine invertebrates produce significant amounts of secondary metabolites showing active pharmacological properties and an extensive spectrum of biomedical applications. The aim of this review is to gather selected studies that report the extraction and identification of marine invertebrate-derived compounds that possess HDACi properties, grouping the producing species according to their taxonomic hierarchy. The molecular, biochemical, and/or physiological aspects, where available, and modes of action of these naturally occurring HDACis will be recapitulated, taking into consideration their possible utilization for the future design of analogs with increased bioavailability and efficacy, less toxicity, and, also, higher isoform selectivity.

scholarly journals Exogenous H2S Preventing PDC-E1 Translocation to Nucleus and Inhibiting Vascular Smooth Muscle Cell Proliferation in Diabetic State

2021 ◽  
Author(s):  
linxue Zhang ◽  
xiaoshu Jiang ◽  
mingyu Li ◽  
jiaxin Kang ◽  
lingxue Chen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Histone Acetylation ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Vascular Complications ◽  
Diabetic Vascular Complications ◽  
Gaseous Molecule ◽  
Vsmcs Proliferation ◽  
Dehydrogenase Complex

Abstract BackgroundThe poliferation of vascular smooth muscle cells (VSMCs) is the main cause of diabetic vascular complications. Hydrogen sulfide (H2S), a gaseous molecule, is involved in modulating multiple physiological functions. H2S could inhibit VSMCs proliferation induced by hyperglycemia and hyperlipidemia, however, the mechanisms are unclear. ResultsOur results showed that H2S level was lower and expression of proliferative protein for PCNA and CyclinD1 was higher in db/db mice aorta and VSMC treated by glucose and palmitate, whereas, exogenous H2S decreased PCNA and CyclinD1 expression. We found that mitochondrial pyruvate dehydrogenase complex-E1 (PDC-E1) was significantly translocated to the nucleus of VSMCs with the treatment of high glucose and palmitate, and it increased the level of acetyl-CoA and histone acetylation (H3K9Ac). Exogenous H2S inhibited PDC-E1 translocation from mitochondria to nucleus, due to PDC-E1 being modified via S-sulfhydration. In addition, PDC-E1 was mutated at Cys101. Overexpression of PDC-E1 mutated at Cys101 enhanced histone acetylation (H3K9Ac) and VSMCs proliferation.ConclusionsThese findings suggested that H2S regulated PDC-E1 S-sulfhydration at Cys101 to prevent its translocation from mitochondria to nucleus and inhibit VSMCs proliferation in diabetic conditions.

Sign in / Sign up

Export Citation Format

Share Document