Epigenetic mechanisms in metal carcinogenesis.

Many metals exhibit genotoxic and/or carcinogenic effects. These toxic metals can be found ubiquitously - in drinking water, food, air, general use products, in everyday and occupational settings. Exposure to such carcinogenic metals can result in serious health disorders, including cancer. Arsenic, cadmium, chromium, nickel, and their compounds have already been recognized as carcinogens by the International Agency for Research on Cancer. This review summarizes a wide range of epigenetic mechanisms contributing to carcinogenesis induced by these metals, primarily including, but not limited to, DNA methylation, miRNA regulation, and histone posttranslational modifications. The mechanisms are described and discussed both from a metal-centric and a mechanism-centric standpoint. The review takes a broad perspective, putting the mechanisms in the context of real-life exposure, and aims to assist in guiding future research, particularly with respect to the assessment and control of exposure to carcinogenic metals and novel therapy development.

Nickel's Role in Pancreatic Ductal Adenocarcinoma: Potential Involvement of microRNAs.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types with a limited overall survival rate due to the asymptomatic progression of symptoms in metastatic stages of the malignancy and the lack of an early reliable diagnostic biomarker. MicroRNAs (miRs/miRNAs) are small (~18-24 nucleotides), endogenous, non-coding RNAs, which are closely linked to the development of numerous malignancies comprising PDAC. Recent studies have described the role of environmental pollutants such as nickel (Ni) in PDAC, but the mechanisms of Ni-mediated toxicity in cancer are still not completely understood. Specifically, Ni has been found to alter the expression and function of miRs in several malignancies, leading to changes in target gene expression. In this study, we found that levels of Ni were significantly higher in cancerous tissue, thus implicating Ni in pancreatic carcinogenesis. Hence, in vitro studies followed by using both normal and pancreatic tumor cell lines and increasing Ni concentration increased lethality. Comparing LC50 values, Ni-acetate groups demonstrated lower values needed than in NiCl2 groups, suggesting greater Ni-acetate. Panc-10.05 cell line appeared the most sensitive to Ni compounds. Exposure to Ni-acetate resulted in an increased phospho-AKT, and decreased FOXO1 expression in Panc-10.05 cells, while NiCl2 also increased PTEN expression in Panc-10.05 cells. Specifically, following NiCl2 exposure to PDAC cells, the expression levels of miR-221 and miR-155 were significantly upregulated, while the expression levels of miR-126 were significantly decreased. Hence, our study has suggested pilot insights to indicate that the environmental pollutant Ni plays an important role in the progression of PDAC by promoting an association between miRs and Ni exposure during PDAC pathogenesis.

An overview of the safety assessment of medicines currently used in the COVID-19 disease treatment.

On 11th March 2020, the pandemic of the new coronavirus was declared by the World Health Organization. At the moment, there are no new registered medicines that can effectively treat the coronavirus infection. However, a number of ongoing clinical trials are investigating the efficacy and safety of the medicines which have already been registered and used for the treatment of other diseases, in the treatment of the coronavirus infection. The proposed combinations of these medicines could potentially present a safety risk, since most of these medicines have the potential to cause numerous side or toxic effects, even when used in monotherapy. Thus, the aim of this study was to review and evaluate the literature data on the toxicity of the selected individual drugs (ritonavir, lopinavir, remdesivir, chloroquine, and umifenovir) and the available clinical data concerning the possible adverse effects of the selected drug combinations (lopinavir/ritonavir + umifenovir, lopinavir/ritonavir + interferon ß, chloroquine + remdesivir, and chloroquine + azithromycin). The most often reported toxic effects of these medicines such as hepatotoxicity, retinal damage, nephrotoxicity, and cardiotoxicity, together with the fact that the health status of the patients with COVID-19 disease is often complicated by co-existing illnesses and therapy implicate that the decision on the therapeutic strategy should be made with caution.

Binary polymeric amorphous carvedilol solid dispersions: In vitro and in vivo characterization.

Binary polymeric amorphous carvedilol solid dispersions were prepared using solvent method by varying solvent type, polymer type and carvedilol to polymer ratio in order to assess the influence of these factors and maximize carvedilol dissolution rate. Low and high molecular weight polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer were used as polymeric carriers in carvedilol to polymer ratios 1:1, 1:2 or 1:4, while absolute ethanol or acetone were used as solvents. Hard gelatin capsules were prepared with carvedilol solid dispersion and lactose monohydrate, mannitol or microcrystalline cellulose. FTIR and PXRD were used to detect carvedilol crystallinity and identify carvedilol-polymer interactions and carvedilol polymorphs. These techniques confirmed carvedilol transition to amorphous state and suggested that hydrogen bonds were formed between carvedilol and polymer molecules. Carvedilol dissolution rate was significantly higher from solid dispersions with higher carvedilol to polymer ratio and solid dispersions prepared using the solvent in which the polymer was more soluble. Solid dispersion with polyvinylpyrrolidone-vinyl acetate copolymer in 1:4 ratio in absolute ethanol displayed the highest carvedilol dissolution rate with 91.78% carvedilol dissolved in the first 30 min. Capsules prepared with the selected solid dispersion and microcrystalline cellulose as diluent displayed the highest carvedilol dissolution rate, with 93.43% carvedilol dissolved within the first 30 min. Carvedilol bioavailability was significantly increased by formulating solid dispersions, while the analysis of serum biochemical parameters excluded damage on liver and kidney function and the lipid profile of animals exposed to investigated drug delivery system.