Role of autophagy in cancer-associated fibroblast activation, signaling and metabolic reprograming.

Tumors not only consist of cancerous cells, but they also harbor several normal-like cell types and non-cellular components. cancer-associated fibroblasts (CAFs) are one of these cellular components that are found predominantly in the tumor stroma. Autophagy is an intracellular degradation and quality control mechanism, and recent studies provided evidence that autophagy played a critical role in CAF formation, metabolic reprograming and tumor-stroma crosstalk. Therefore, shedding light on the autophagy and its role in CAF biology might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the exploitation of more efficient cancer diagnosis and treatment. Here, we provide an overview about the involvement of autophagy in CAF-related pathways, including transdifferentiation and activation of CAFs, and further discuss the implications of targeting tumor stroma as a treatment option.

The impact of government pandemic policies on the vulnerability of healthcare workers to SARS-CoV-2 infection and mortality in Jakarta Province, Indonesia.

INTRODUCTION: Healthcare workers (HCWs) are on the frontlines of the COVID-19 pandemic, putting them at a higher risk of infection and disease than non-HCWs. We analysed the effects of government policies for the public and for HCWs on the likelihood of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality among HCWs during the first 8 months of the pandemic in Jakarta province, the capital city and COVID-19 hotspot in Indonesia. METHODS: We conducted a retrospective cohort study using secondary data from the Jakarta provincial government from March to October 2020, which included sociodemographic characteristics, symptoms, comorbidities and COVID-19 diagnosis history for all cases. A generalized linear mixed-effect regression model was used to determine the effect of each month on the odds ratio (OR) of COVID-19 cases and deaths for HCW compared with non-HCW, assuming that monthly trends were influenced by varying government policies. RESULTS: A total of 894,487 suspected and confirmed COVID-19 cases in health facilities in Jakarta province were analysed. The OR of confirmed cases for HCW was 2.04 (95% CI 2.00-2.08; p < .001) compared to non-HCW. Despite this higher OR for infection, the case fatality rate (2.32 per 100) and OR (1.02, 95% CI 0.93-1.11; p = .65) of COVID-19 deaths for HCW were similar to those of non-HCW. We observed a trend towards a lower number of COVID-19 patients in hospitals and lower odds of COVID-19 cases among HCWs during the April-to-July 2020 phase compared to the August-to-October phase. This chronologically aligned with more extensive policies to support hospital-based, community-based and well-being-related actions to protect HCW. CONCLUSIONS: HCW had higher odds of having SARS-CoV-2 infection, yet similar odds of death from COVID-19, as compared to non-HCW. Government policies with collective efforts to prevent hospital overcapacity during high transmission and burden periods of the pandemic should be prioritized.

Healthcare workers (HCWs) had higher exposure and odds of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection than non-HCWs but a similar risk of death, consistent with previous studies.Government policies favouring reduced workloads of HCW and interventions to promote resilience can be achieved through combined hospital-based, community-based and well-being-related approaches.Studies to identify the patterns and trends of COVID-19 cases and deaths, hospital admissions and policy dynamics are important to promote evidence-based decision-making by the government.

Cholesterol accumulation in hepatocytes mediates IRE1/p38 branch of endoplasmic reticulum stress to promote nonalcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD), based on the elevating obesity incidence, is one of the major health issue worldwide. Transition from NAFLD to non-alcoholic steatohepatitis (NASH) is driven by increased apoptosis and is relevant to higher morbidity rates. In regard to limited understanding on cholesterol mediated hepatocyte alterations in NALFD/NASH transition, we investigated endoplasmic reticulum (ER) stress and related apoptosis. Our findings suggest that cholesterol upregulates ER stress and enhances C/EBP homologous protein (CHOP) either in hypercholesterolemic rabbits or in hepatocytes treated with liposome-cholesterol complex. Mechanistically, cholesterol accumulation in hepatocytes activates IRE1/p38 branch of ER stress, stimulating CHOP levels. In liver tissues of cholesterol fed rabbits, α-tocopherol supplementation decreased IRE1/p38/CHOP activation and prevented NASH development. Thus, our study provides a critical role of hepatocyte cholesterol in inducing IRE1/p38/CHOP pathway and suggests novel candidates for therapeutic targets against NASH.

Deficiency of SREBP1c modulates autophagy mediated lipid droplet catabolism during oleic acid induced steatosis.

OBJECTIVE: Increased fatty acid and triglyceride synthesis in liver, majorly modulated by Sterol Regulator Elementing Binding Protein 1c (SREBP1c), is one of the main features of non-alcoholic fatty liver disease (NAFLD). In the present study, we aimed to identify the relation between SREBP1c and autophagy mediated lipid droplet (LD) catabolism in oleic acid (OA) induced lipid accumulation. METHODS: Increased LD formation and SREBP1c induction were identified in hepatocytes (AML12 cells) following the OA administration. SREBP1c level was reduced through siRNA against SREBP1c. The amount and the size of LDs were determined by BODIPY, while protein and mRNA expressions were identified by immunoblotting and qRT-PCR, respectively. LD-lysosome colocalization was determined with immunofluorescence. RESULTS: Increased LD formation and SREBP1c levels were determined at 0.06 mM OA concentration. SREBP1c silencing reduced the number of LDs, while increasing mRNA levels of PPARα. On the other hand, SREBP1c silencing in non-OA and OA treated cells enhanced autophagy mediated LD catabolism. CONCLUSION: Our results implicate the effect of SREBP1c deficiency in modulating PPARα signaling and autophagy mediated LD catabolism against OA induced lipid accumulation.