mPGES-1: a key regulator of fever and neonatal respiratory depression

Prostaglandins are potent lipid mediators, synthesized de novo from arachidonic acid (AA) upon cell activation. AA is oxidized by the cyclooxygenase isoenzymes (COX-1 and COX-2) to form PGH2, the common substrate for downstream enzymes involved in prostaglandin biosynthesis. COX-1 is constitutively expressed in most cells and regarded as housekeeping protein. In contrast, expression of COX-2 is markedly increased by pro-inflammatory cytokines at sites of inflammation. PGH2 is converted into biologically active prostanoids like PGD2, PGE2, PGF2alpha, TXA2 and PGI2 by specific enzymes in a cell-specific manner. The isomerization of PGH2 to PGE2, a potent mediator of pain and inflammation, is specifically catalyzed by human microsomal prostaglandin E synthase-1 (mPGES-1), a member of the MAPEG (membrane associated proteins in eicosanoid and glutathione metabolism) superfamily. High levels of PGE2 have been found in numerous disease states. Human mPGES-1 was expressed as an N-terminal-histidine-tagged protein in E. coli. The membrane bound enzyme was solubilized using Triton X-100 and purified to apparent homogeneity using a combination of hydroxyapatite and immobilized metal affinity chromatography. Purified mPGES-1 exhibited high glutathione (GSH)-dependent catalytic activity for the conversion of both PGH2 to PGE2 and, PGG2 to 15-hydroperoxy-PGE2. Moreover, mPGES-1 also exhibited GSH-dependent peroxidase activity towards cumene hydroperoxide and 5-HpETE as well as low but significant glutathione transferase activity, possibly reflecting a relationship to other members of the MAPEG family. A 10 Å projection map of mPGES-1 determined using electron crystallography as well as hydrodynamic studies of mPGES-1-Triton X-100 complex, independently demonstrated the trimeric organization of mPGES-1. The role of mPGES-1 in endotoxin-induced fever, as well as aseptic, cytokine-dependent, inflammation-induced fever was investigated. In response to intraperitoneal injection of lipopolysaccharide (LPS), wildtype DBA/1lacJ mice developed a robust fever with markedly increased PGE2 levels in the cerebrospinal fluid (CSF) and significant LPS-induced mPGES-1 activity in membrane fractions isolated from brain tissues. In contrast, the mPGES-1 knockout mice did not develop fever and, the PGE2 levels in the CSF did not differ significantly from the saline-treated wildtype mice, suggesting a critical role for mPGES-1 in the development of endotoxin-induced fever. In a cytokine-dependent fever model, subcutaneous injection of turpentine induced biphasic fever in wildtype mice, whereas mPGES-1 knockout mice displayed a core body temperature similar to the saline-treated wildtype mice, indicating that mPGES-1 activity was indispensable for the induction of cytokine-dependent fever. mPGES-1 did not, however, mediate hyperthermia induced by psychological stress. The role of mPGES-1 in neonatal respiratory depression was investigated using 9-day old DBA/1lacj mice. Wildtype mice treated with IL-1beta exhibited a reduced respiratory frequency during normoxia as well hyperoxia compared to saline treated mice. This effect of IL-1beta was attenuated in mPGES-1 knockout mice. Moreover, IL-1beta treatment induced apneas, irregular breathing pattern and reduced the anoxic survival of the wildtype mice, and these effects were attenuated in mice lacking mPGES-1. Both IL-1beta and hypoxia treatment synergistically induced a rapid 4-fold mPGES-1 activity in the brainstem of wildtype mice compared to the saline treatment. These results suggest a central role for mPGES-1 in the regulation of neonatal breathing. Taken together, these findings provide further support of mPGES-1 as an attractive target for the development of anti-inflammatory and anti-pyretic drugs. It is also possible that such drugs could be used in neonates at risk for respiratory suppression

Solvent-dependent aggregation behavior of a new Ru(II)-polypyridyl based metallosurfactant

Variation of the solvent polarity leads to the formation of vesicles and reverse vesicles of a newly synthesized amphiphilic Ru(II)-polypyridyl complex

A Retrospective Study on Pre Exposure Hydroxychloroquine and Ivermectin Prophylaxis for COVID-19 in Healthcare Workers in a Tertiary Care Hospital

Background:COVID-19 was declared a ‘pandemic’ by the WHO on 11th March, 2020. The high infectivity and unique transmission potentials of the causative agent of COVID-19, namely, SARS-CoV-2 were the reasons behind its wide-scale spread and made health care workers (HCWs), the most ‘at-risk population’ for acquiring the infection.The administration of HCQs and/or Ivermectin prophylaxis was one of the most commonly used stratagems recommended to protect the HCWs prior to the development of an effective vaccine. But data on its effectiveness, if any, were not conclusive. Also the above strategy was not accepted by many HCWs themselves for a plethora of reasons. Hence a systematic enquiry into the above conundrums was felt to be the need of the hour. Objective: 1.To assesses the effectiveness of HCQs and Ivermectin as pre-exposure prophylaxis (PrEP) drugs against SARS-CoV-2 infection among HCWs in a tertiary care hospital. 2. To identify the reason(s) behind avoidance of PrEPamong HCWs. Materials and methods: We conducted a retrospective study based on an online/ offline/ telephonic survey on HCWs directly related to COVID care services. Results: Total 336 HCWs responded to our survey. There were segregated intotwo cohort groups, namely, those taking PrEP (n=148; exposed) and those avoidingPrEP (n=188; control). In the PrEPgroup, 26 (17.56%) out of 148 participants reported to have tested positive for SARS-CoV-2 during some point of time, whereas, in the control group, 38 (20.21%) out of 188 participants reported to have been SARS-CoV-2 positive. We found no significant reduction SARS-CoV-2 cases in exposed group with relative risk of 0.8691 (95% Confidence Intervals 0.5542 to 1.363, p <0.3181).Conclusions: Our study demonstrated that voluntary consumption of PrEP by HCWs is not associated with a statistically significant reduction in risk of SARS-CoV-2