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Cancer is a genetic disease resulting from genomic changes; however, epigenetic alterations act synergistically with these changes during tumorigenesis and cancer progression. Epigenetic variations are gaining more attention as an important regulator in tumor progression, metastasis and therapy resistance. Aberrant DNA methylation at CpG islands is a central event in epigeneticmediated gene silencing of various tumor suppressor genes. DNA methyltransferase 1 (DNMT1) predominately methylates at CpG islands on hemimethylated DNA substrates in proliferation of cells. DNMT1 has been shown to be overexpressed in various cancer types and exhibits tumor-promoting potential. The major drawbacks to DNMT1-targeted cancer therapy are the adverse effects arising from nucleoside and non-nucleoside based DNMT1 inhibitors. This paper focuses on the regulation of DNMT1 by various microRNAs (miRNAs), which may be assigned as future DNMT1 modulators, and highlights how DNMT1 regulates various miRNAs involved in tumor suppression. Importantly, the role of reciprocal inhibition between DNMT1 and certain miRNAs in tumorigenic potential is approached in this review. Hence, this review seeks to project an efficient and strategic approach using certain miRNAs in conjunction with conventional DNMT1 inhibitors as a novel cancer therapy. It has also been pinpointed to select miRNA candidates associated with DNMT1 regulation that may not only serve as potential biomarkers for cancer diagnosis and prognosis, but may also predict the existence of aberrant methylation activity in cancer cells.

Evidence for gadolinium-based contrast agent- (GBCA-) induced disease continues to mount. Risk factors for gadolinium-induced systemic fibrosis are entirely unexplored. Obesity-related renal injury is characterized by activation of glomerular mesangial cells and podocyte damage with alteration of lipid metabolism/lipid accumulation in both cell types resulting in matrix accumulation and eventual progression to glomerulosclerosis. We examined the consequences of GBCA treatment in the kidneys from mice with normal kidney function and the potential interplay between obesity and gadolinium exposure. We found that administration of GBCA (4 weeks) causes significant renal fibrosis and podocyte injury that are associated with metabolic disorders as evidenced by dyslipidemia. Metabolomic analysis demonstrated that renal lipid metabolism and metabolic markers of collagen turnover are significantly altered by gadolinium. GBCA stimulates myeloid-derived fibrocytes to the kidney. Obesity was induced by feeding a group of mice a high fat diet (HFD) for 22 weeks. Groups were sub-randomized to GBCA treatment versus none for 4 weeks before sacrifice. HFD-induced fibrosis and podocyte injury were worsened by GBCA. Similarly, HFD-mediated hyperlipidemia and lipid metabolites were exacerbated by gadolinium. This is the first evidence that GBCA causes significant metabolic disorders and kidney injury in mice without renal insufficiency and that the injurious actions of GBCA are amplified by obesity. The understanding of the functional interplay between gadolinium and obesity will allow the development of therapeutic interventions or the establishment of effective preventive measures to reduce gadolinium- and obesity-mediated renal pathologies.

A negative correlation exists between environmental temperature and cancer risk based on both epidemiological and statistical analyses. Previously, cold stress was reported to be an effective cause of tumorigenesis. Several studies have demonstrated that cold temperature serves as a potential risk factor in cancer development. Most recently, a link was demonstrated between the effects of extreme cold climate on cancer incidence, pinpointing its impact on tumour suppressor genes by causing mutation. The underlying mechanism behind cold stress and its association with tumorigenesis is not well understood. Hence, this review intends to shed light on the role of associated factors, genetic and/or non-genetic, which are modulated by cold temperature, and eventually influence tumorigenic potential. While scrutinizing the effect of cold exposure on the body, the expression of certain genes, e.g. uncoupled proteins and heat-shock proteins, were elevated. Biological chemicals such as norepinephrine, thyroxine, and cholesterol were also elevated. Brown adipose tissue, which plays an essential role in thermogenesis, displayed enhanced activity upon cold exposure. Adaptive measures are utilized by the body to tolerate the cold, and in doing so, invites both epigenetic and genetic changes. Unknowingly, these adaptive strategies give rise to a lethal outcome i.e., genesis of cancer. Concisely, this review attempts to draw a link between cold stress, genetic and epigenetic changes, and tumorigenesis and aspires to ascertain the mechanism behind cold temperature-mediated cancer risk.

Reduced bioavailability of nitric oxide due to impaired endothelial nitric oxide synthase (eNOS) activity is a leading cause of endothelial dysfunction in diabetes. Enhancing eNOS activity in diabetes is a potential therapeutic target. This study investigated basal cerebral blood flow and cerebrovascular reactivity in wild-type mice, diabetic mice (Ins2Akita+/−), nondiabetic eNOS-overexpressing mice (TgeNOS), and the cross of two transgenic mice (TgeNOS-Ins2Akita+/−) at six months of age. The cross was aimed at improving eNOS expression in diabetic mice. The major findings were: (i) Body weights of Ins2Akita+/− and TgeNOS-Ins2Akita+/− were significantly different from wild-type and TgeNOS mice. Blood pressure of TgeNOS mice was lower than wild-type. (ii) Basal cerebral blood flow of the TgeNOS group was significantly higher than cerebral blood flow of the other three groups. (iii) The cerebrovascular reactivity in the Ins2Akita+/− mice was significantly lower compared with wild-type, whereas that in the TgeNOS-Ins2Akita+/− was significantly higher compared with the Ins2Akita+/− and TgeNOS groups. Overexpression of eNOS rescued cerebrovascular dysfunction in diabetic animals, resulting in improved cerebrovascular reactivity. These results underscore the possible role of eNOS in vascular dysfunction in the brain of diabetic mice and support the notion that enhancing eNOS activity in diabetes is a potential therapeutic target.

Matrix protein accumulation is a prominent feature of diabetic nephropathy that contributes to renal fibrosis and decline in renal function. The pathogenic mechanisms of matrix accumulation are incompletely characterized. We investigated if the matrix metalloprotease a disintegrin and metalloprotease1 7 (ADAM17), known to cleave growth factors and cytokines, is activated in the kidney cortex of OVE26 type 1 diabetic mice and the potential mechanisms by which ADAM17 mediates extracellular matrix accumulation. Protein expression and activity of ADAM17 were increased in OVE26 kidney cortex. Using a pharmacological inhibitor to ADAM17, TMI-005, we determined that ADAM17 activation results in increased type IV collagen, Nox4, and NADPH oxidase activity in the kidney cortex of diabetic mice. In cultured mouse proximal tubular epithelial cells (MCTs), high glucose increases ADAM17 activity, Nox4 and fibronectin expression, cellular collagen content, and NADPH oxidase activity. These effects of glucose were inhibited when cells were pretreated with TMI-005 and/or transfected with small interfering ADAM17. Collectively, these data indicate a novel mechanism whereby hyperglycemia in diabetes increases extracellular matrix protein expression in the kidney cortex through activation of ADAM17 and enhanced oxidative stress through Nox enzyme activation. Additionally, our study is the first to provide evidence that Nox4 is downstream of ADAM17.