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Purpose: Vitamin D deficiency has been associated with the occurrence of obstructive sleep apnea syndrome (OSAS). Megalin (LRP2) and cubilin (CUBN) are implicated in vitamin D metabolism, whereas LRP2 and CUBN polymorphisms have been previously associated with variable serum vitamin D levels. The present study aimed to evaluate the role of LRP2 rs2228171 c.8614C > T and CUBN rs1801222 c.758A > G polymorphisms in OSAS susceptibility, independently or in synergy with vitamin D levels. Methods: Vitamin D serum concentration of consecutive individuals was measured. PCR–RFLP was used for LRP2 rs2228171 and CUBN rs1801222 genotyping. Results: A total of 176 individuals was enrolled, including 144 patients with OSAS and 32 controls. Frequency of LRP2 rs2228171 c.8614 T and CUBN rs1801222 c.758G alleles was estimated at 22.4% and 79.8%, respectively. LRP2 and CUBN polymorphisms were not associated with OSAS occurrence (rs2228171Τ allele: 22.9% in OSAS group vs. 20.3% in controls, p = 0.651; rs1801222A allele 19.4% in OSAS group vs. 23.4% in controls, p = 0.471). Frequency of CUBN rs1801222A allele carriers was increased in patients with moderate or severe OSAS compared to mild OSAS (p = 0.028). Patients with OSAS homozygous for LRP2 CC and CUBN GG genotypes had lower vitamin D serum concentration compared to controls carrying the same genotype (18.0 vs 27.0 ng/mL, p = 0.006 and 19.0 vs 27.5 ng/mL, p = 0.007, respectively). Conclusion: CUBN rs1801222 polymorphism may affect OSAS severity. Among other factors, low vitamin D concentration is associated with OSAS occurrence, irrespectively of LRP2 and CUBN polymorphisms. [ABSTRACT FROM AUTHOR]

Aim: The COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells. Method: We scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin. Results: Several drugs/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil). Conclusion: Several agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies. [ABSTRACT FROM AUTHOR]

Background and Objective: Inter-individual variability exists in the statin (HMG-CoA reductase inhibitor) lipid-lowering response, which is partially attributed to genetic factors. The polymorphic enzyme P450 oxidoreductase (POR) transfers electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to cytochrome P450 (CYP) 3A enzymes, which metabolize atorvastatin and simvastatin. The POR*28 allele is associated with increased activity of CYP3A enzymes. We analyzed the association of the POR*28 allele with response to atorvastatin and simvastatin. Methods: A total of 207 atorvastatin-treated adults were included in the study. An independent population of 210 simvastatin-treated adults served as a replication cohort. Total cholesterol (TChol) and low-density lipoprotein cholesterol (LDL-C) were measured at baseline and after 6 months of treatment. The POR*28 allele was analyzed with a TaqMan assay. Results: The POR*28 allele was associated with a non-significant trend towards lower percentage mean reduction of TChol (−35.5 % in *1/*1, −33.7 % in *1/*28, and −29.5 % in *28/*28 individuals) and LDL-C (−42.6 % in *1/*1, −41.7 % in *1/*28, and −37.8 % in *28/*28 individuals) in response to atorvastatin. This trend was not observed in the replication cohort of simvastatin-treated patients. No sex-gene interaction was observed regarding the effect of the POR*28 allele on the statin lipid-lowering response in either statin-treated patient cohort. Conclusion: The POR*28 allele was not associated with the lipid-lowering effect of atorvastatin and the results were replicated in an independent simvastatin-treated population. The hypothesized effect of the POR*28 allele on the lipid-lowering response to CYP3A-metabolized statins can potentially be masked by relevant confounding or uncontrolled factors; therefore, further studies in different populations are required. [ABSTRACT FROM AUTHOR]

Monocyte chemoattractant protein-1 (MCP-1) is implicated in promoting atherosclerotic diseases, including stroke. Therefore, several studies have investigated the association between variants of the MCP-1 gene and risk of atherosclerotic diseases. We sought to determine the occurrence of MCP-1 −2518A>G polymorphism in patients with ischemic stroke (IS), and studied its association with the severity of disease and functional outcome after an acute IS. One hundred and forty-five consecutive patients with first ever IS and 145 age- and sex-matched control subjects were recruited. Stroke severity and functional outcome were assessed on admission and at one month post-stroke, respectively. Genotyping for the MCP-1 −2518A>G polymorphism was performed by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No significant difference in the frequency of MCP-1 −2518A>G genotypes between IS patients and controls was found, with OR = 0.69 (95 % CI 0.46-1.04, P = 0.08). Moreover, carriage of the G allele was not associated with stroke severity (Scandinavian stroke scale score 33.1 vs. 32.5, respectively, P = 0.71), or poor outcome at 1 month post-stroke (63.9 vs. 59.7 %, respectively, P = 0.61). In conclusion, we were unable to demonstrate a significant association of the MCP-1 −2518A>G gene polymorphism with IS occurrence, severity or functional outcome in a Caucasian population. However, larger studies are necessary to fully elucidate the role of this polymorphism in IS. [ABSTRACT FROM AUTHOR]