Hydrogen Sulfide Ameliorates Angiotensin II-Induced Atrial Fibrosis Progression to Atrial Fibrillation Through Inhibition of the Warburg Effect and Endoplasmic Reticulum Stress

Atrial fibrosis is the basis for the occurrence and development of atrial fibrillation (AF) and is closely related to the Warburg effect, endoplasmic reticulum stress (ERS) and mitochondrion dysfunctions-induced cardiomyocyte apoptosis. Hydrogen sulfide (H2S) is a gaseous signalling molecule with cardioprotective, anti-myocardial fibrosis and improved energy metabolism effects. Nevertheless, the specific mechanism by which H2S improves the progression of atrial fibrosis to AF remains unclear. A case-control study of patients with and without AF was designed to assess changes in H2S, the Warburg effect, and ERS in AF. The results showed that AF can significantly reduce cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate thiotransferase (3-MST) expression and the H2S level, induce cystathionine-β-synthase (CBS) expression; increase the Warburg effect, ERS and atrial fibrosis; and promote left atrial dysfunction. In addition, AngII-treated SD rats had an increased Warburg effect and ERS levels and enhanced atrial fibrosis progression to AF compared to wild-type SD rats, and these conditions were reversed by sodium hydrosulfide (NaHS), dichloroacetic acid (DCA) or 4-phenylbutyric acid (4-PBA) supplementation. Finally, low CSE levels in AngII-induced HL-1 cells were concentration- and time-dependent and associated with mitochondrial dysfunction, apoptosis, the Warburg effect and ERS, and these effects were reversed by NaHS, DCA or 4-PBA supplementation. Our research indicates that H2S can regulate the AngII-induced Warburg effect and ERS and might be a potential therapeutic drug to inhibit atrial fibrosis progression to AF.

Evaluation of combination protocols of the chemotherapeutic agent FX-9 with azacitidine, dichloroacetic acid, doxorubicin or carboplatin on prostate carcinoma cell lines

The isoquinolinamine FX-9 is a novel potential chemotherapeutic agent showing antiproliferative effects against hematologic and prostate cancer cell lines such as B- and T-acute lymphoblastic leukemia and prostate cancer (PC) of different species. Interestingly, FX-9 shows no hemolytic activity and low toxicity in benign adherent cells. The detailed FX-9 molecular mode of action is currently not fully understood. But application on neoplastic cells induces pro-apoptotic and antimitotic effects. Canine prostate cancer (cPC) represents a unique spontaneous occurring animal model for human androgen-independent PC. Human androgen-independent PC as well as cPC are currently not satisfactorily treatable with chemotherapeutic protocols. Accordingly, the evaluation of novel agent combinations bears significant potential for identifying novel treatment strategies. In this study, we combined FX-9 with the currently approved therapeutic agents doxorubicin, carboplatin, the demethylating substance azacitidine as well as further potentially antitumorigenic agents such as dichloroacetic acid (DCA) in order to evaluate the respective synergistic potential. The combinations with 1–5 μM FX-9 were evaluated regarding the effect after 72 hours on cell viability, cell count and apoptotic/necrotic cells in two human prostate cancer cell lines (LNCaP, PC-3) and a canine prostate cancer cell line (Adcarc1258) representing androgen-dependent and -independent PC/cPC forms. FX-9 in combination with azacitidine decreases cell viability and increases cell death with positive Bliss values. Furthermore, this decreases the cell count with neutral Bliss values on PC-3. Carboplatin in combination with FX-9 reduces cell viability with a neutral Bliss value and increases cell death on LNCaP with calculated positive Bliss values. DCA or doxorubicin in combination with FX-9 do not show synergistic or additive effects on the cell viability. Based on these results, azacitidine or carboplatin in combination with FX-9 offers synergistic/additive efficacy against prostate adenocarcinoma cell lines in vitro. The beneficial effects of both combinations are worth further investigation.

Changes in the indicators of chemical safety of drinking water in Ufa during its transportation to consumers

Introduction. To conduct a total assessment of carcinogenic, non-carcinogenic, and organoleptic risks to public health and cover both normalized and non-normalized pollutants of potable water, based on the results of long-term monitoring studies, it is possible using an integral indicator of chemical harmlessness of water. Material and methods. Authors studied potable water of water intakes of surface and infiltration types from potable water reservoirs and remote zones of Ufa water distribution networks. Impurities were determined by chromatography, inductively coupled plasma mass spectrometry, photometric, nephelometric, and titrimetric methods. Results. The main effect on the amount of carcinogenic risk in potable water of the surface water intake are chloroform, bromodichlethane, dichloroacetic acid, in the infiltration water intake - in addition to these compounds zinc, lead and chromium are in addition influenced. Organic compounds (phthalates, benz(a)pyrene, volatile aromatic compounds, etc.) have no effect on this type of risk due to the presence in water in low background concentrations. The identified number of individual carcinogenic risks for bromodichloroacetic acid and dichloroacetic acid according to the WHO classification corresponds to the second range. As the surface type water intake is removed from the potable water reservoir, the total carcinogenic risk of water decreases by 13-30%, and the infiltration type increases by 41-84%. Values of noncancerogenic and organoleptic risks are constant for potable water of different water intakes and correspond to recommended limit values. The excess of the maximum permissible concentrations (SanPin 1.2.3685-21) of individual substances in the potable water of the city has not been detected for the whole period of observation. In terms of the integral indicator of chemical harmlessness, the most favorable is the po-table water of the infiltration water intake, in the technology of which is mainly used the UV for decontamination of water. Conclusion. Using a risk assessment methodology complements the traditional approach to assessing water quality under modern hygiene standards. It becomes possible to evaluate the effect of pollutants of various classes on water quality when they are present together.