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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.

The gut bacterial community is involved in the metabolism of bile acids and short-chain fatty acids (SCFAs). Bile acids are involved in the absorption of fat and the regulation of lipid homeostasis through emulsification and are transformed into unconjugated bile acids by the gut microbiota. The gut microbiota is actively involved in the production of bile acid metabolites, such as deoxycholic acid, lithocholic acid, choline, and SCFAs such as acetate, butyrate, and propionate. Metabolites derived from the gut microbiota or modified gut microbiota metabolites contribute significantly to host pathophysiology. Gut bacterial metabolites, such as deoxycholic acid, contribute to the development of hepatocellular carcinoma and colon cancer by factors such as inflammation and oxidative DNA damage. Butyrate, which is derived from gut bacteria such as Megasphaera, Roseburia, Faecalibacterium, and Clostridium, is associated with the activation of Treg cell differentiation in the intestine through histone acetylation. Butyrate averts the action of class I histone deacetylases (HDAC), such as HDAC1 and HDAC3, which are responsible for the transcription of genes such as p21/Cip1, and cyclin D3 through hyperacetylation of histones, which orchestrates G1 cell cycle arrest. It is essential to identify the interaction between the gut microbiota and bile acid and SCFA metabolism to understand their role in gastrointestinal carcinogenesis including colon, gastric, and liver cancer. Metagenomic approaches with bioinformatic analyses are used to identify the bacterial species in the metabolism of bile acids and SCFAs. This review provides an overview of the current knowledge of gut microbiota-derived bile acid metabolism in tumor development and whether it can stand as a marker for carcinogenesis. Additionally, this review assesses the evidence of gut microbiota-derived short-chain fatty acids including butyric acid in antitumor activity. Future research is required to identify the beneficial commensal gut bacteria and their metabolites which will be considered to be therapeutic targets in inflammation-mediated gastrointestinal cancers.

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.

Complexity in tissues affected by cancer arises from somatic mutations and epigenetic modifications in the genome. The mutation susceptible hotspots present within the genome indicate a non-random nature and/or a position specific selection of mutation. An association exists between the occurrence of mutations and epigenetic DNA methylation. This study is primarily aimed at determining mutation status, and identifying a signature for predicting mutation prone zones of tumor suppressor (TS) genes. Nearby sequences from the top five positions having a higher mutation frequency in each gene of 42 TS genes were selected from a cosmic database and were considered as mutation prone zones. The conserved motifs present in the mutation prone DNA fragments were identified. Molecular docking studies were done to determine putative interactions between the identified conserved motifs and enzyme methyltransferase DNMT1. Collective analysis of 42 TS genes found GC as the most commonly replaced and AT as the most commonly formed residues after mutation. Analysis of the top 5 mutated positions of each gene (210 DNA segments for 42 TS genes) identified that CG nucleotides of the amino acid codons (e.g., Arginine) are most susceptible to mutation, and found a consensus DNA "T/AGC/GAGGA/TG" sequence present in these mutation prone DNA segments. Similar to TS genes, analysis of 54 oncogenes not only found CG nucleotides of the amino acid Arg as the most susceptible to mutation, but also identified the presence of similar consensus DNA motifs in the mutation prone DNA fragments (270 DNA segments for 54 oncogenes) of oncogenes. Docking studies depicted that, upon binding of DNMT1 methylates to this consensus DNA motif (C residues of CpG islands), mutation was likely to occur. Thus, this study proposes that DNMT1 mediated methylation in chromosomal DNA may decrease if a foreign DNA segment containing this consensus sequence along with CG nucleotides is exogenously introduced to dividing cancer cells.

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.

Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Pharmacological doses of the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduce albuminuria in diabetes. We explored the hypothesis that mTOR mediates podocyte injury in diabetes. High glucose (HG) induces apoptosis of podocytes, inhibits AMP-activated protein kinase (AMPK) activation, inactivates tuberin, and activates mTOR. HG also increases the levels of Nox4 and Nox1 and NADPH oxidase activity. Inhibition of mTOR by low-dose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase activity, and podocyte apoptosis. Inhibition of mTOR had no effect on AMPK or tuberin phosphorylation, indicating that mTOR is downstream of these signaling molecules. In isolated glomeruli of OVE26 mice, there is a similar decrease in the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 and NADPH oxidase activity. Inhibition of mTOR by a small dose of rapamycin reduces podocyte apoptosis and attenuates glomerular injury and albuminuria. Our data provide evidence for a novel function of mTOR in Nox4-derived reactive oxygen species generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes. Thus, mTOR and/or NADPH oxidase inhibition may represent a therapeutic modality of diabetic kidney disease.

Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes.