Functional Role of miR-155 in the Pathogenesis of Diabetes Mellitus and Its Complications.
TL;DR: This work systematically describes the reports investigating the role of miR-155 in DM and discusses the recent results from in vivo and in vitro models of type 1 diabetes (T1D and T2D), discussing the differences between clinical and preclinical studies and shedding light on the molecular pathways mediated by miR -155 in different tissues affected by DM.
Abstract: Substantial evidence indicates that microRNA-155 (miR-155) plays a crucial role in the pathogenesis of diabetes mellitus (DM) and its complications. A number of clinical studies reported low serum levels of miR-155 in patients with type 2 diabetes (T2D). Preclinical studies revealed that miR-155 partakes in the phenotypic switch of cells within the islets of Langerhans under metabolic stress. Moreover, miR-155 was shown to regulate insulin sensitivity in liver, adipose tissue, and skeletal muscle. Dysregulation of miR-155 expression was also shown to predict the development of nephropathy, neuropathy, and retinopathy in DM. Here, we systematically describe the reports investigating the role of miR-155 in DM and its complications. We also discuss the recent results from in vivo and in vitro models of type 1 diabetes (T1D) and T2D, discussing the differences between clinical and preclinical studies and shedding light on the molecular pathways mediated by miR-155 in different tissues affected by DM.
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01 Jan 2016
TL;DR: Large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes, but most fell within regions previously identified by genome-wide association studies.
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
698 citations
01 Jan 2009
TL;DR: In this article, a review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.
Abstract: MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.
646 citations
TL;DR: In this paper, a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy is presented, and an excursus on the relative contribution of CARs, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes is provided.
Abstract: Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.
51 citations
18 Sep 2015
TL;DR: The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization, and miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair.
Abstract: The response of the retina to ischemic insult typically leads to aberrant retinal neovascularization, a major cause of blindness The epigenetic regulation of angiogenic gene expression by miRNAs provides new prospects for their therapeutic utility in retinal neovascularization Here, we focus on miR-155, a microRNA functionally important in inflammation, which is of paramount importance in the pathogenesis of retinal neovascularization Whereas constitutive miR-155-deficiency in mice results in mild vascular defects, forced expression of miR-155 causes endothelial hyperplasia and increases microglia count and activation The mouse model of oxygen-induced retinopathy, which recapitulates ischemia-induced aberrant neovessel growth, is characterized by increased expression of miR-155 and localized areas of microglia activation Interestingly, miR-155 deficiency in mice reduces microglial activation, curtails abnormal vessel growth, and allows for rapid normalization of the retinal vasculature following ischemic insult miR-155 binds to the 3′-UTR and represses the expression of the CCN1 gene, which encodes an extracellular matrix-associated integrin-binding protein that both promotes physiological angiogenesis and harnesses growth factor-induced abnormal angiogenic responses Single CCN1 deficiency or double CCN1 and miR-155 knock-out in mice causes retinal vascular malformations typical of faulty maturation, mimicking the vascular alterations of miR-155 gain of function During development, the miR-155/CCN1 regulatory axis balances the proangiogenic and proinflammatory activities of microglia to allow for their function as guideposts for sprout fusion and anastomosis Under ischemic conditions, dysregulated miR-155 and CCN1 expression increases the inflammatory load and microglial activation, prompting aberrant angiogenic responses Thus, miR-155 functions in tandem with CCN1 to modulate inflammation-induced vascular homeostasis and repair
46 citations
Book•
01 Jan 2006
TL;DR: Clinical Epidemiology, Evidence-Based Medicine and the Treatment of Endophthalmitis Seenu M. Mieler, and Retinopathy of Prematurity: Approaches to Management.
Abstract: CLINICAL EPIDEMIOLOGY AND HEALTH ECONOMICS Clinical Epidemiology Hussein Hollands and Sanjay Sharma Health Economics Hussein Hollands and Sanjay Sharma CORNEA/EXTERNAL DISEASE Anterior Segment Ayad Farjo and Qais A. Farjo Refractive Surgery Lou Probst GLAUCOMA Clinical Trials in Glaucoma Paul Rafuse RETINA Diabetic Retinopathy Dean Eliott Diabetic Macular Edema Dean Eliott Proliferative Diabetic Retinopathy Dean Eliott Age-Related Macular Degeneration Sophie Bakri and Peter Kaiser Treatment of Central Retinal Vein Occlusion: Lessons from Clinical Trials Henry Tseng and Sharon Fekrat Treatment of Branch Retinal Vein Occlusion: Lessons from Clinical Trials Henry Tseng and Sharon Fekrat Retinal Detachment and Proliferative Vitreoretinopathy Amani Fawzi, Jay M. Stewart, and Michael Samuel Evidence-Based Medicine and the Treatment of Endophthalmitis Seenu M. Hariprasad and William F. Mieler PEDIATRIC OPHTHALMOLOGY Retinopathy of Prematurity Anna Ells Amblyopia Jonathan M. Holmes, Michael X. Repka, and Raymond T. Kraker OCULAR ONCOLOGY Uveal Melanoma: Approaches to Management E. Rand Simpson NEURO-OPHTHALMOLOGY Optic Neuritis Jonathan D. Trobe OCULOPLASTICS Thyroid Eye Disease Louise A. Mawn Traumatic Optic Neuropathy Louise A. Mawn
43 citations
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TL;DR: The current understanding of miRNA target recognition in animals is outlined and the widespread impact of miRNAs on both the expression and evolution of protein-coding genes is discussed.
18,036 citations
TL;DR: In this paper, the authors compared a lifestyle intervention with metformin to prevent or delay the development of Type 2 diabetes in nondiabetic individuals. And they found that the lifestyle intervention was significantly more effective than the medication.
Abstract: Background Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes. Methods We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups. Results The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin. Conclusions Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
17,333 citations
TL;DR: In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of the gene set.
11,624 citations
"Functional Role of miR-155 in the P..." refers background in this paper
...and hundreds of such interactions have been experimentally proven so far [20,21]....
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...Thousands of mammalian mRNAs have been predicted to be targeted by miRNAs and hundreds of such interactions have been experimentally proven so far [20,21]....
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TL;DR: A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older and safety over a median of 2 months was similar to that of other viral vaccines.
Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a world...
10,274 citations
TL;DR: Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects by means of individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity.
Abstract: Background Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. Methods We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. Results The mean (±SD) amount of weight lost between base line and the end of ye...
10,178 citations