PACT-mediated pkr activation acts as a hyperosmotic stress intensity sensor weakening osmoadaptation and enhancing inflammation

The inability of cells to adapt to increased environmental tonicity can lead to inflammatory gene expression and pathogenesis. The Rel family of transcription factors TonEBP and NF-κB p65 play critical roles in the switch from osmoadaptive homeostasis to inflammation, respectively. Here we identified PACT-mediated PKR kinase activation as a marker of the termination of adaptation and initiation of inflammation in Mus musculus embryonic fibroblasts. We found that high stress-induced PACT-PKR activation inhibits the interaction between NF-κB c-Rel and TonEBP essential for the increased expression of TonEBP-dependent osmoprotective genes. This resulted in enhanced formation of TonEBP/NF-κB p65 complexes and enhanced proinflammatory gene expression. These data demonstrate a novel role of c-Rel in the adaptive response to hyperosmotic stress, which is inhibited via a PACT/PKR-dependent dimer redistribution of the Rel family transcription factors. Our results suggest that inhibiting PACT-PKR signaling may prove a novel target for alleviating stress-induced inflammatory diseases

The practice of hepatocellular cancer surveillance in Nigeria

Background: Hepatocellular cancer is a disease of global and public health importance due to the widespread distribution of risk factors and associated high case fatality. Hepatocellular Cancer (HCC) in Sub-Saharan Africa is commonly seen among the younger age groups (<45 years) who present mostly in the terminal stage, when the disease is not amenable to any curative therapy. Hepatocellular Carcinoma surveillance employs the use of simple, cheap and readily available investigations, to detect early curable cancer in individuals with risk factors for HCC.Objectives:The aim of this study is to assess the practice of hepatocellular cancer screening among physicians.Methodolgy:This is a nationwide online survey carried out among physicians who care for patients with HCC. A questionnaire was sent out via a web link to all consenting doctors in Nigeria. The responses were collated in a cloud-based application and data was analysed using Epi-info version 20.Results:Atotal of 218 respondents, 142 were males (65.1 %) with a mean age of 37.6 ± 5.7 years. The modal age group was 31-40 years 153 (69.5%). The main factors considered as a hindrance to surveillance were; the cost of the tests (57.7%), failure of return of patients (50.5%) and not being aware of a surveillance program (45.2 %). The majority of the respondents were Gastroenterologists and Family Physicians. 54% of the gastroenterologists and 64% of the family physicians have never offered HCC surveillance to their patients.Conclusion:This survey highlights a knowledge gap in HCC surveillance among physicians. There is a need to make HCCsurveillance a daily routine among patients at risk by all physicians. Keywords: Surveillance, Hepatocellular Carcinoma, HBV, HCV, Cancer screening

Circulating Naturally-Occurring Anticoagulants before Treatment and after Recovery from SARS-CoV-2 Infection in Ghana

Background: Disturbance in naturally-occurring anticoagulants may contribute to the hypercoagulable state in COVID-19. This study determined the plasma antigen levels of protein C (PC), protein S (PS), antithrombin-III (AT-III), and thrombomodulin (TM) before treatment and after recovery from COVID-19. Materials and Methods: This cross-sectional study, conducted from February to August 2022 at Kumasi South Hospital, recruited sixty-five RT-PCR-confirmed COVID-19 participants. A venous blood sample was taken for full blood count (FBC) analysis using a 3-part fully automated haematology analyzer, and PC, PS, AT-III, and TM antigen levels measured using ELISA. The data were analyzed using SPSS version 26.0. P<0.05 was considered statistically significant. Results: Severe COVID-19 participants had relatively lower haemoglobin (p<0.001), RBC (p<0.001), HCT% (p<0.001) and platelets (p<0.001), but higher RDW-CV% (p=0.013), WBC (p<0.001), and absolute lymphocyte counts (p<0.001) compared to those with the non-severe form of the disease. The overall prevalence of anaemia among the participants was 58.5%, and 32 (84.2%) and 6 (15.8%) of the anaemic participants had mild and moderate anaemia respectively. Protein C (p<0.001), PS (p<0.001) and ATIII (p<0.001) levels were lower among the severe COVID-19 participants than in the non-severe group. But severe COVID-19 group had higher TM levels (p<0.001) than the non-severe group. Again, participants had higher haemoglobin (p<0.001), RBC (p<0.001), HCT% (p=0.049), absolute neutrophil count (p<0.001) and platelets (p<0.001) after recovery from COVID-19 than the values on admission. Additionally, after recovery, participants had higher levels of PC (p<0.001), PS (p<0.001), and ATIII (p<0.001), but reduced TM (p<0.001). Conclusion: Severe COVID-19 patients had higher PC, PS, and AT-III, but lower TM levels. The changes in circulating anticoagulants may contribute to the hypercoagulable state of COVID-19. Blood cell indices are negatively affected during COVID-19. Complete recovery from the SARS-CoV-2 infection normalised the haematological indices. Assessment of naturally-occurring anticoagulants and the provision of anticoagulants are recommended in the management of COVID-19.   Doi: 10.28991/SciMedJ-2022-04-04-01 Full Text: PD

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress

To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions