scholarly journals A Systems Biology Overview on Human Diabetic Nephropathy: From Genetic Susceptibility to Post-Transcriptional and Post-Translational Modifications

2016 ◽  
Vol 2016 ◽  
pp. 1-23 ◽  
Author(s):  
Francesca Conserva ◽  
Loreto Gesualdo ◽  
Massimo Papale
Keyword(s):  
Diabetic Nephropathy ◽  
Systems Biology ◽  
Genetic Susceptibility ◽  
Molecular Mechanisms ◽  
Disease Onset ◽  
Systematic Analysis ◽  
Post Translational Modifications ◽  
Inflammatory Processes ◽  
End Stage

Diabetic nephropathy (DN), a microvascular complication occurring in approximately 20–40% of patients with type 2 diabetes mellitus (T2DM), is characterized by the progressive impairment of glomerular filtration and the development of Kimmelstiel-Wilson lesions leading to end-stage renal failure (ESRD). The causes and molecular mechanisms mediating the onset of T2DM chronic complications are yet sketchy and it is not clear why disease progression occurs only in some patients. We performed a systematic analysis of the most relevant studies investigating genetic susceptibility and specific transcriptomic, epigenetic, proteomic, and metabolomic patterns in order to summarize the most significant traits associated with the disease onset and progression. The picture that emerges is complex and fascinating as it includes the regulation/dysregulation of numerous biological processes, converging toward the activation of inflammatory processes, oxidative stress, remodeling of cellular function and morphology, and disturbance of metabolic pathways. The growing interest in the characterization of protein post-translational modifications and the importance of handling large datasets using a systems biology approach are also discussed.

scholarly journals Advancing Drug Discovery and Development from Active Constituents of Yinchenhao Tang, a Famous Traditional Chinese Medicine Formula

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Aihua Zhang ◽  
Hui Sun ◽  
Shi Qiu ◽  
Xijun Wang
Keyword(s):  
Systems Biology ◽  
Drug Discovery ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Molecular Networks ◽  
Agile Development ◽  
Therapeutic Effects ◽  
Systematic Analysis

Traditional Chinese medicine (TCM) formula has been playing a very important role in health protection and disease control for thousands of years. Guided by TCM syndrome theories, formula are designed to contain a combination of various kinds of crude drugs that, when combined, will achieve synergistic efficacy. However, the precise mechanism of synergistic action remains poorly understood. One example is a famous TCM formula Yinchenhao Tang (YCHT), whose efficacy in treating hepatic injury (HI) and Jaundice syndrome, has recently been well established as a case study. We also conducted a systematic analysis of synergistic effects of the principal compound using biochemistry, pharmacokinetics and systems biology, to explore the key molecular mechanisms. We had found that the three component (6,7-dimethylesculetin (D), geniposide (G), and rhein (R)) combination exerts a more robust synergistic effect than any one or two of the three individual compounds by hitting multiple targets. They can regulate molecular networks through activating both intrinsic and extrinsic pathways to synergistically cause intensified therapeutic effects. This paper provides an overview of the recent and potential developments of chemical fingerprinting coupled with systems biology advancing drug discovery towards more agile development of targeted combination therapies for the YCHT.

scholarly journals Comprehensive genomic profiling in diabetic nephropathy reveals the predominance of proinflammatory pathways

2013 ◽  
Vol 45 (16) ◽  
pp. 710-719 ◽  
Author(s):  
K. J. Kelly ◽  
Yunlong Liu ◽  
Jizhong Zhang ◽  
Chirayu Goswami ◽  
Hai Lin ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Systems Biology ◽  
Gene Networks ◽  
Inflammatory Cells ◽  
Rna Seq ◽  
Cycle Arrest ◽  
Comprehensive Genomic Profiling ◽  
Novel Therapeutic Strategies ◽  
Stage Renal Disease ◽  
End Stage

Despite advances in the treatment of diabetic nephropathy (DN), currently available therapies have not prevented the epidemic of progressive chronic kidney disease (CKD). The morbidity of CKD, and the inexorable increase in the prevalence of end-stage renal disease, demands more effective approaches to prevent and treat progressive CKD. We undertook next-generation sequencing in a rat model of diabetic nephropathy to study in depth the pathogenic alterations involved in DN with progressive CKD. We employed the obese, diabetic ZS rat, a model that develops diabetic nephropathy, characterized by progressive CKD, inflammation, and fibrosis, the hallmarks of human disease. We then used RNA-seq to examine the combined effects of renal cells and infiltrating inflammatory cells acting as a pathophysiological unit. The comprehensive systems biology analysis of progressive CKD revealed multiple interactions of altered genes that were integrated into morbid networks. These pathological gene assemblies lead to renal inflammation and promote apoptosis and cell cycle arrest in progressive CKD. Moreover, in what is clearly a major therapeutic challenge, multiple and redundant pathways were found to be linked to renal fibrosis, a major cause of kidney loss. We conclude that systems biology applied to progressive CKD in DN can be used to develop novel therapeutic strategies directed to restore critical anomalies in affected gene networks.

scholarly journals Special Issue “Diabetic Nephropathy: Diagnosis, Prevention and Treatment”

2020 ◽  
Vol 9 (3) ◽  
pp. 813 ◽  
Author(s):  
Marta Ruiz-Ortega ◽  
Raul R. Rodrigues-Diez ◽  
Carolina Lavoz ◽  
Sandra Rayego-Mateos
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Damage ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Clinical Medicine ◽  
Histopathological Changes ◽  
Special Issue ◽  
Genetic And Environmental Factors ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is the main cause of end-stage renal disease. DN is a complex disease mediated by genetic and environmental factors, and many cellular and molecular mechanisms are involved in renal damage in diabetes. There are no biomarkers that reflect the severity of the underlying renal histopathological changes and can effectively predict the progression of renal damage and stratify the risk of DN among individuals with diabetes mellitus. Current therapeutic strategies are based on the strict control of glucose and blood pressure levels and, although there are new anti-diabetic drugs, these treatments only retard renal damage progression, being necessary novel therapies. In this Special Issue, there are several comprehensive reviews and interesting original papers covering all these topics, which would be of interest to the growing number of readers of the Journal of Clinical Medicine.

scholarly journals The Role of MicroRNAs in the Pathogenesis of Diabetic Nephropathy

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jian Tang ◽  
Deyi Yao ◽  
Haiying Yan ◽  
Xing Chen ◽  
Linjia Wang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanisms ◽  
Microvascular Complications ◽  
Diabetic Patients ◽  
Hemodynamic Changes ◽  
Clinical Value ◽  
New Ideas ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetic patients; it is also an important cause of renal dysfunction, renal fibrosis, and end-stage renal disease. Unfortunately, the pathogenesis of DN is complex and has not yet been fully elucidated; hence, the pathogenesis of DN to determine effective treatments of crucial importance is deeply explored. Early DN research focuses on hemodynamic changes and metabolic disorders, and recent studies have shown the regulatory role of microRNAs (miRNAs) in genes, which may be a new diagnostic marker and therapeutic target for diabetic nephropathy. In this review, we summarize the recent advances in the clinical value and molecular mechanisms of miRNAs in DN, providing new ideas for the diagnosis and treatment of DN.

scholarly journals Epigenetic Regulations in Diabetic Nephropathy

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Zeyuan Lu ◽  
Na Liu ◽  
Feng Wang
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanisms ◽  
Noncoding Rnas ◽  
Epigenetic Mechanisms ◽  
End Stage Kidney Disease ◽  
Multiple Factors ◽  
Chronic Complication ◽  
Epigenetic Regulations ◽  
End Stage

Diabetic nephropathy (DN) is a chronic complication of diabetes and the most common cause of end-stage kidney disease. It has been reported that multiple factors are involved in the pathogenesis of DN, while the molecular mechanisms that lead to DN are still not fully understood. Numerous risk factors for the development of diabetic nephropathy have been proposed, including ethnicity and inherited genetic differences. Recently, with the development of high-throughput technologies, there is emerging evidence that suggests the important role of epigenetic mechanisms in the pathogenesis of DN. Epigenetic regulations, including DNA methylation, noncoding RNAs, and histone modifications, play a pivotal role in DN pathogenesis by a second layer of gene regulation. All these findings can contribute to developing novel therapies for DN.

scholarly journals Inflammatory Cytokines in Diabetic Nephropathy

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Javier Donate-Correa ◽  
Ernesto Martín-Núñez ◽  
Mercedes Muros-de-Fuentes ◽  
Carmen Mora-Fernández ◽  
Juan F. Navarro-González
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Diabetic Complication ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Molecular Events ◽  
Patients With Diabetes ◽  
Inflammatory Processes ◽  
Stage Renal Disease ◽  
End Stage

Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy.

scholarly journals Natural history and risk factors for diabetic nephropathy in Italy: insights from AMD Annals initiative

2019 ◽  
Vol 22 (4) ◽  
pp. 178
Author(s):  
Piscitelli, P.
Keyword(s):  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Natural History ◽  
Disease Onset ◽  
Diabetic Patients ◽  
Increased Risk ◽  
End Stage

Diabetic patients have a high risk to develop diabetic nephropathy. Diabetic nephropathy represents non only a risk factor for progression toward end stage renal disease but it is also associates with an increased risk to have of major cardiovascular events. Over the last few years, analysis of the AMD annals dataset has contributed several important insights on the clinical features of type 2 diabetes kidney disease and their prognostic and therapeutic implications. First, non-albuminuric renal impairment is the predominant clinical phenotype. Even though associated with a lower risk of progression compared to overt albuminuria, it contributes significantly to the burden of end-stage renaldisease morbidity. Second, optimal blood pressure control provides significant but incomplete renal protection. It reduces albuminuria but there may be a J curve phenomenon with eGFR at very low blood pressure values. Third, hyperuricemia and diabetic hyperlipidemia, namely elevated triglycerides and low HDL cholesterol, are strong independent predictorsof chronic kidney disease onset in diabetes, although the pathogenetic mechanisms underlying these associationsremain uncertain. These data help clarify the natural history of CKD in patients with type 2 diabetes and provide important clues for designing futureinterventional studies. KEY WORDS albuminuria; glomerular filtration rate; hypertension; uric acid; type2 diabetes mellitus.

scholarly journals Pathogenesis and Novel Treatment from the Mouse Model of Type 2 Diabetic Nephropathy

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Masako Furukawa ◽  
Tomohito Gohda ◽  
Mitsuo Tanimoto ◽  
Yasuhiko Tomino
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diabetic Model ◽  
Glycation End Products ◽  
Receptor Blockers ◽  
End Stage

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide. However, current treatments remain suboptimal. Many factors, such as genetic and nongenetic promoters, hypertension, hyperglycemia, the accumulation of advanced glycation end products (AGEs), dyslipidemia, and albuminuria/proteinuria itself, influence the progression of this disease. It is important to determine the molecular mechanisms and treatment of this disease. The development of diabetes results in the formation of AGEs, oxidative stress, and the activation of the renin-angiotensin-aldosterone system (RAAS) within the kidney, which promotes progressive inflammation and fibrosis, leading to DN and declining renal function. A number of novel therapies have also been tested in the experimental diabetic model, including exercise, inhibitors of the RAAS (angiotensin type 1 receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors), inhibitors of AGE (pyridoxamine), peroxisome proliferator-activated receptor (PPAR)γagonists (pioglitazone), inhibitors of lipid accumulation (statins and eicosapentaenoic acid (EPA)), and the vitamin D analogues. This review summarizes the advances in knowledge gained from our studies and therapeutic interventions that may prevent this disease.

The role of epigenetic mechanisms in the pathogenesis of diabetic nephropathy

2021 ◽  
Vol 25 (2) ◽  
pp. 35-42
Author(s):  
K. A. Aitbaev ◽  
I. T. Murkamilov ◽  
V V Fomin ◽  
Zh. A. Murkamilova ◽  
F. A. Yusupov
Keyword(s):  
Diabetic Nephropathy ◽  
High Performance ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Epigenetic Mechanisms ◽  
Chronic Complication ◽  
Non Coding Rnas ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy (DN) is a chronic complication of diabetes and the most common cause of the end-stage renal disease (ESRD). Numerous factors have been considered, both contributing to the development of DN, and participating in its pathogenesis. However, to date, the molecular mechanisms, that lead to the development of DN, remain not fully understood. Recently, with the development of high-performance technologies, evidence demonstrating epigenetic mechanisms of regulation of gene expression, including DNA methylation, non-coding RNAs, and histone modifications that play a key role in the pathogenesis of DN through the secondary regulation of genes are starting to appear. All these data can contribute to the creation of new, more effective diagnostic and therapeutic technologies for DN.

scholarly journals Characterization of the Inducible and Slow-Releasing Hydrogen Sulfide and Persulfide Donor P*: Insights into Hydrogen Sulfide Signaling

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1049
Author(s):  
Modesta Trummer ◽  
Erwan Galardon ◽  
Anita Fischer ◽  
Stefan Toegel ◽  
Bernhard-Michael Mayer ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Antioxidant Properties ◽  
Heme Oxygenase 1 ◽  
Primary Chondrocytes ◽  
Sodium Hydrogen ◽  
Inflammatory Processes ◽  
Complex Chemistry

Hydrogen sulfide (H2S) is an important mediator of inflammatory processes. However, controversial findings also exist, and its underlying molecular mechanisms are largely unknown. Recently, the byproducts of H2S, per-/polysulfides, emerged as biological mediators themselves, highlighting the complex chemistry of H2S. In this study, we characterized the biological effects of P*, a slow-releasing H2S and persulfide donor. To differentiate between H2S and polysulfide-derived effects, we decomposed P* into polysulfides. P* was further compared to the commonly used fast-releasing H2S donor sodium hydrogen sulfide (NaHS). The effects on oxidative stress and interleukin-6 (IL-6) expression were assessed in ATDC5 cells using superoxide measurement, qPCR, ELISA, and Western blotting. The findings on IL-6 expression were corroborated in primary chondrocytes from osteoarthritis patients. In ATDC5 cells, P* not only induced the expression of the antioxidant enzyme heme oxygenase-1 via per-/polysulfides, but also induced activation of Akt and p38 MAPK. NaHS and P* significantly impaired menadione-induced superoxide production. P* reduced IL-6 levels in both ATDC5 cells and primary chondrocytes dependent on H2S release. Taken together, P* provides a valuable research tool for the investigation of H2S and per-/polysulfide signaling. These data demonstrate the importance of not only H2S, but also per-/polysulfides as bioactive signaling molecules with potent anti-inflammatory and, in particular, antioxidant properties.

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