The Association of Programmed Death 1 Gene Polymorphisms of PD1.3 G/A and PD1.5 C/T with Risk of COVID-19 in an Iranian Population: A Case-Control Study.

Programmed death 1 (PD-1) has a central role in maintaining T cell tolerance and terminating cellular responses after eliminating antigens. Variation in PD-1 gene products caused by polymorphisms has been linked to several malignancies and autoimmune diseases. However, there is little known about the effects of its single-nucleotide polymorphisms (SNPs) on viral infections, particularly COVID-19. The primary aim of this study was to explore the function of genotypes, alleles, and haplotypes of two SNPs within the programmed cell death protein 1 (PDCD1) gene at PD1.3 G/A and PD1.5 C/T on susceptibility to COVID-19 in an Iranian population. The secondary objective was to evaluate the effects of these SNPs on the outcome of the disease. We got blood samples from COVID-19 patients (n = 195) and healthy subjects (n = 500) for genotypic determination of PD1.3 G/A (rs11568821) and PD1.5 C/T (rs2227981) SNPs, using the polymerase chain reaction-restriction fragment length polymorphism method, and constructed four haplotypes for PDCD1 SNPs. We used Pearson's chi-squared test, Fisher's exact test, and T-test for this study and incorporated effect sizes of odds ratio (OR) and standardized mean difference. The frequency of CT genotype of PD1.5 was meaningfully higher in COVID-19 patients (49.2%) than in healthy subjects (37.4%) (p = 0.005). However, these significant differences were not observed in the frequencies of PD1.3 genotypes between the two groups (p > 0.05). Of all estimated haplotypes for PDCD1, only AT was significantly and largely associated with COVID-19 susceptibility (p = 0.01, OR: 7.79 [95% confidence interval = 1.56-38.79]), however, this finding is inconclusive. In addition, the present study showed that the PD1.3 and PD1.5 SNPs were not associated with the outcome of the disease (p > 0.05). These results may propose that the PD1.5 CT genotype and AT haplotype of PDCD1 indecisively contribute to COVID-19 susceptibility in the Iranian population.

The plasma Tumor Necrosis Factor-α (TNF-α) does not have any correlation with disease activity in rheumatoid arthritis patients treated with disease modifying anti-rheumatic drugs (DMARDs)

We performed this study to measure the Tumor Necrosis Factor-alpha (TNF-α) plasma level and to survey its correlation with disease activity in the newly diagnosed Rheumatoid Arthritis (RA) patients and those who were under treatment with the combination of Disease-Modifying Anti-Rheumatic Drug (DMARD) plus Prednisolone (PSL).We enrolled 30 newly diagnosed RA patients who received no treatment regarding their disease, 30 patients under treatment with the combination of Methotrexate (MTX) + Hydroxychloroquine (HCQ) + PSL and 30 healthy subjects in this case-control study from September 2017 to December 2017. The level of plasma TNF-α was measured by enzyme-linked immunosorbent assay (ELISA) in each group. For assessment of disease severity, we used Disease Activity Score-28 (DAS-28) formula, and regarding DAS-28, we divided patients into four groups, including remission, low, moderate and high disease activity. There were no significant differences in the plasma level of TNF-α between the newly diagnosed RA patients and subjects who received MTX + HCQ + PSL, as well as healthy controls (p>0.05). There was a significant correlation between plasma levels of TNF-α and DAS-28 in the newly diagnosed patients with RA (r = 0.594, P = 0.001). Targeting TNF-α at the early stage of RA could have more beneficial effects on the amelioration of disease activity

The impaired gene expression of adenosine monophosphate-activated kinase (AMPK), a key metabolic enzyme in leukocytes of newly diagnosed rheumatoid arthritis patients.

The disturbed immune homeostasis is involved in the pathogenesis of an array of autoimmune diseases like rheumatoid arthritis (RA). The adenosine monophosphate-activated protein kinase (AMPK) with a pivotal role in immunometabolism process, also plays a regulatory function in the immune system. This study aims to evaluate the alteration of AMPK gene expression in peripheral blood leukocytes of RA patients and its effects on disease severity as well as plasma levels of anti-inflammatory cytokines. 60 RA patients, including 30 newly diagnosed and 30 patients whose disease were under controlled with the combinational disease-modifying anti-rheumatic drug (DMARD), as well as 30 healthy subjects, were enrolled in our study. The gene expression of AMPK was evaluated using real-time PCR method. The plasma concentrations of IL-10 and TGF-ß1 were measured using sandwich ELISA. The gene expression of AMPK was significantly lower in the newly diagnosed RA patients in comparison with the control group (P = 0.049). Inversely, in RA patients who received DMARD therapy, the gene expression of AMPK was significantly higher than the control group (P = 0.003). There was no significant correlation between AMPK gene expression and plasma levels of IL-10 and TGF-ß1. The plasma levels of TGF-ß1 was significantly higher in both newly diagnosed and under-treatment patients compared with healthy subjects (P < 0.001). The impaired gene expression of AMPK in peripheral blood leukocytes and elevated levels of plasma TGF-ß1 can be contributed in RA pathogenesis.

Autophagy, cancer and angiogenesis: where is the link?

BACKGROUND: Autophagy is a catabolic process for degradation of intracellular components. Damaged proteins and organelles are engulfed in double-membrane vesicles ultimately fused with lysosomes. These vesicles, known as phagophores, develop to form autophagosomes. Encapsulated components are degraded after autophagosomes and lysosomes are fused. Autophagy clears denatured proteins and damaged organelles to produce macromolecules further reused by cells. This process is vital to cell homeostasis under both physiologic and pathologic conditions. MAIN BODY: While the role of autophagy in cancer is quite controversial, the majority of studies introduce it as an anti-tumorigenesis mechanism. There are evidences confirming this role of autophagy in cancer. Mutations and monoallelic deletions have been demonstrated in autophagy-related genes correlating with cancer promotion. Another pathway through which autophagy suppresses tumorigenesis is cell cycle. On the other hand, under hypoxia and starvation condition, tumors use angiogenesis to provide nutrients. Also, autophagy flux is highlighted in vessel cell biology and vasoactive substances secretion from endothelial cells. The matrix proteoglycans such as Decorin and Perlecan could also interfere with angiogenesis and autophagy signaling pathway in endothelial cells (ECs). It seems that the connection between autophagy and angiogenesis in the tumor microenvironment is very important in determining the fate of cancer cells. CONCLUSION: Matrix glycoproteins can regulate autophagy and angiogenesis linkage in tumor microenvironment. Also, finding details of how autophagy and angiogenesis correlate in cancer will help adopt more effective therapeutic approaches.