Molecular pharmacology of mineralocorticoid receptor antagonists: The role of co-regulators.

Mineralocorticoid receptor (MR) antagonists have shown remarkable benefits in the treatment of cardiovascular disease. However, their underutilization in clinical practice may be attributed to concerns regarding the risk of hyperkalemia. An ideal selective MR modulator would inhibit the detrimental effects of MR in non-epithelial cells of the cardiovascular system while sparing its physiological function in kidney epithelial cells, thereby reducing the risk of adverse events. To address this issue, a new generation of non-steroidal MR antagonists, including esaxereneone, balcinrenone, ocedurenone, and finerenone, has been developed with distinct molecular structures and pharmacology. They share a mechanism of action that is different from the previously developed steroidal MR antagonists, leading to altered co-regulator interaction, potentially involving conformational changes of the receptor. Interfering with MR co-regulator interaction or the co-regulator itself may enable selective targeting of downstream signaling cascades and - in the long term - lead to more personalized medicine. In this review article, we summarize what is currently known about the mechanisms of action of the different MR antagonists with a focus on MR co-factor interaction and what may be inferred from this for future developments.

Eplerenone Improves Pulmonary Vascular Remodeling and Hypertension by Inhibition of the Mineralocorticoid Receptor in Endothelial Cells.

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Therapeutic Potentials of Inhibition of Jumonji C Domain-containing Demethylases in Acute Myeloid Leukemia

Objective: Acute myeloid leukemia (AML) is a complex disease affected by both genetic and epigenetic factors. Histone methylation and demethylation are types of epigenetic modification in chromatin remodeling and gene expression. Abnormal expression of histone demethylases is indicated in many types of cancer including AML. Although many commercial drugs are available to treat AML, an absolute cure has not been discovered yet. However, inhibition of demethylases could be a potential cure for AML. Methylstat is a chemical agent that inhibits the Jumonji C domain-containing demethylases. Materials and Methods: The cytotoxic and apoptotic effects of methylstat and doxorubicin on HL-60 cells were detected by MTT cell viability assay, double staining of treated cells with annexin-V/propidium iodide, and caspase-3 activity assay. Mitochondrial activity was analyzed using JC-1 dye. The expression levels of the BCL2 and BCL2L1 anti-apoptotic genes in HL-60 cells were determined using real-time polymerase chain reaction (PCR). Lastly, the cytostatic effect was determined by cell cycle analysis. Results: In our research, cytotoxic, cytostatic, and apoptotic effects of methylstat on human HL-60 cells were investigated. Cytotoxic and cytostatic analyses revealed that methylstat decreased cell proliferation in a dose-dependent cytotoxic manner and arrested HL-60 cells in the G2/M and S phases. Methylstat also induced apoptosis through the loss of mitochondrial membrane potential and increases in caspase-3 enzyme activity. The expression levels of BCL2 and BCL2L1 were also decreased according to real-time PCR results. Finally, the combination of methylstat with doxorubicin resulted in synergistic cytotoxic effects on HL-60 cells. Conclusion: Taken together, these results demonstrate that methylstat may be a powerful candidate as a drug component of AML treatment protocols.

Cow Milk Consumption Increases Iodine Status in Women of Childbearing Age in a Randomized Controlled Trial.

Background: Recent evidence has highlighted the prevalence of mild-to-moderate iodine deficiency in women of childbearing age and pregnant women, with important public health ramifications due to the role of iodine, which is required for thyroid hormone production, in neurodevelopment. Cow milk contributes the greatest amount to iodine intakes in several countries. Objective: The objective of this study was to investigate the effect of increased cow milk consumption on iodine status, thyroid hormone concentrations, and selenium status. Methods: A 12-wk randomized controlled trial was conducted in 78 low-moderate milk-consuming (<250 mL/d) healthy women (aged 18-45 y). The intervention group was asked to consume 3 L semiskimmed milk/wk, whereas the control group continued their usual milk consumption (baseline median: 140 mL/d; IQR: 40-240 mL/d). At baseline and weeks 6 and 12, participants provided a spot urine sample [urinary iodine concentration (UIC), creatinine] and a fasting blood sample (thyroid hormone concentrations, serum total selenium, selenoprotein P). Results: At baseline, the median (IQR) UIC of all participants was 78.5 µg/L (39.1-126.1 µg/L). Changes in the median UIC from baseline to week 6 (35.4 compared with 0.6 µg/L; P = 0.014) and week 12 (51.6 compared with -3.8 µg/L; P = 0.045) were significantly greater in the intervention group compared with the control group. However, despite being higher within the intervention group at weeks 6 and 12, the change in the iodine:creatinine ratio from baseline was not significantly different between groups at either week 6 (P = 0.637) or week 12 (P = 0.178). There were no significant differences in thyroid hormone concentrations or selenium status between groups at any time point. Conclusions: The present study shows that the consumption of additional cow milk can significantly increase UIC in women of childbearing age. These results suggest that cow milk is a potentially important dietary source of iodine in this population group. This trial was registered at www.clinicaltrials.gov as NCT02767167.