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Mini review ATF4 and GRP78 as novel molecular targets in ER-Stress modulation for critical COVID-19 patients.
Shahriari-Felordi, M, Alikhani, HK, Hashemian, SR, Hassan, M, Vosough, M
Molecular biology reports. 2022;(2):1545-1549
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Abstract
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in more than 4.4 million deaths worldwide as of August 24, 2021. Viral infections such as SARS-CoV2 are associated with endoplasmic reticulum (ER) stress and also increased the level of reactive oxygen species. Activating transcription factor 4 (ATF4) is preferentially translated under integrated stress conditions and controls the genes involved in protein homeostasis, amino acid transport and metabolism, and also protection from oxidative stress. The GRP78, regulated either directly or indirectly by ATF4, is an essential chaperone in the ER and overexpressed and appears on the surface of almost all cells during stress and function as a SARS-CoV2 receptor. In this mini-review article, we briefly discuss the effects of SARS-CoV2 infection on the ER stress, and then the stress modulator functions of ATF4 and GRP78 as novel therapeutic targets were highlighted. Finally, the effects of GRP78 inhibitory components as potential factors for targeted therapies for COVID-19 critical cases were discussed.
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Implications of the NADase CD38 in COVID pathophysiology.
Zeidler, JD, Kashyap, S, Hogan, KA, Chini, EN
Physiological reviews. 2022;(1):339-341
Abstract
During the COVID-19 pandemic, efforts have been made worldwide to develop effective therapies to address the devastating immune-mediated effects of SARS-CoV-2. With the exception of monoclonal antibody-mediated therapeutics and preventive approaches such as mass immunization, most experimental or repurposed drugs have failed in large randomized clinical trials (https://www.who.int/publications/i/item/therapeutics-and-covid-19-living-guideline). The worldwide spread of SARS-CoV-2 virus revealed specific susceptibilities to the virus among the elderly and individuals with age-related syndromes. These populations were more likely to experience a hyperimmune response characterized by a treatment-resistant acute lung pathology accompanied by multiple organ failure. These observations underscore the interplay between the virus, the biology of aging, and outcomes observed in the most severe cases of SARS-CoV-2 infection. The ectoenzyme CD38 has been implicated in the process of "inflammaging" in aged tissues. In a current publication, Horenstein et al. present evidence to support the hypothesis that CD38 plays a central role in altered immunometabolism resulting from COVID-19 infection. The authors discuss a critical but underappreciated trifecta of CD38-mediated NAD+ metabolism, aging, and COVID-19 immune response and speculate that the CD38/NAD+ axis is a promising therapeutic target for this disease.
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NAFLD and Infection, a Nuanced Relationship.
Adenote, A, Dumic, I, Madrid, C, Barusya, C, Nordstrom, CW, Rueda Prada, L
Canadian journal of gastroenterology & hepatology. 2021;:5556354
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased significantly over the last few decades mirroring the increase in obesity and type II diabetes mellitus. NAFLD has become one of the most common indications for liver transplantation. The deleterious effects of NAFLD are not isolated to the liver only, for it has been recognized as a systemic disease affecting multiple organs through protracted low-grade inflammation mediated by the metabolic activity of excessive fat tissue. Extrahepatic manifestations of NAFLD such as cardiovascular disease, polycystic ovarian syndrome, chronic kidney disease, and hypothyroidism have been well described in the literature. In recent years, it has become evident that patients suffering from NAFLD might be at higher risk of developing various infections. The proposed mechanism for this association includes links through hyperglycemia, insulin resistance, alterations in innate immunity, obesity, and vitamin D deficiency. Additionally, a risk independent of these factors mediated by alterations in gut microbiota might contribute to a higher burden of infections in these individuals. In this narrative review, we synthetize current knowledge on several infections including urinary tract infection, pneumonia, Helicobacter pylori, coronavirus disease 2019, and Clostridioides difficile as they relate to NAFLD. Additionally, we explore NAFLD's association with hidradenitis suppurativa.
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The snapshot of metabolic health in evaluating micronutrient status, the risk of infection and clinical outcome of COVID-19.
Tsoukalas, D, Sarandi, E, Georgaki, S
Clinical nutrition ESPEN. 2021;:173-187
Abstract
COVID-19 has re-established the significance of analyzing the organism through a metabolic perspective to uncover the dynamic interconnections within the biological systems. The role of micronutrient status and metabolic health emerge as pivotal in COVID-19 pathogenesis and the immune system's response. Metabolic disruption, proceeding from modifiable factors, has been proposed as a significant risk factor accounting for infection susceptibility, disease severity and risk for post-COVID complications. Metabolomics, the comprehensive study and quantification of intermediates and products of metabolism, is a rapidly evolving field and a novel tool in biomarker discovery. In this article, we propose that leveraging insulin resistance biomarkers along with biomarkers of micronutrient deficiencies, will allow for a diagnostic window and provide functional therapeutic targets. Specifically, metabolomics can be applied as: a. At-home test to assess the risk of infection and propose nutritional support, b. A screening tool for high-risk COVID-19 patients to develop serious illness during hospital admission and prioritize medical support, c(i). A tool to match nutritional support with specific nutrient requirements for mildly ill patients to reduce the risk for hospitalization, and c(ii). for critically ill patients to reduce recovery time and risk of post-COVID complications, d. At-home test to monitor metabolic health and reduce post-COVID symptomatology. Metabolic rewiring offers potential virtues towards disease prevention, dissection of high-risk patients, taking actionable therapeutic measures, as well as shielding against post-COVID syndrome.
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COVID-19 vaccination in patients with diabetes mellitus: Current concepts, uncertainties and challenges.
Pal, R, Bhadada, SK, Misra, A
Diabetes & metabolic syndrome. 2021;(2):505-508
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Abstract
BACKGROUND AND AIMS To summarize the available evidence on the use COVID-19 vaccines in patients with diabetes mellitus. METHODS We performed a thorough literature search with regard to COVID-19 vaccines in patients with type 1 and type 2 diabetes mellitus. RESULTS The novel coronavirus disease (COVID-19) tends to portend a poor prognosis in patients with diabetes mellitus (DM). Primary prevention remains the mainstay for mitigating the risks associated with COVID-19 in patients with DM. A significant step in primary prevention is timely vaccination. Routine vaccination against pneumococcal pneumonia, influenza, and hepatitis B is recommended in patients with DM with good efficacy and reasonable safety profile. With clinical data supporting a robust neutralizing antibody response in COVID-19 patients with DM, vaccination in individuals with DM is justified. In fact, as the burden of the disease is borne by people with DM, COVID-19 vaccination should be prioritized in individuals with DM. Multiple unresolved issues with regard to preferred vaccine type, vaccine efficacy and durability, frequency of administration, vaccination in children (<18 years) and pregnant/lactating women however remain, and need to be addressed through future research. CONCLUSIONS Patients with type 1 and type 2 diabetes mellitus are at a high risk of poor prognosis with COVID-19 and vaccination should be prioritized in them. However, many unresolved issues with regard to COVID-19 vaccination need to be addressed through future research.
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The roles of lipids in SARS-CoV-2 viral replication and the host immune response.
Theken, KN, Tang, SY, Sengupta, S, FitzGerald, GA
Journal of lipid research. 2021;:100129
Abstract
The significant morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 infection has underscored the need for novel antiviral strategies. Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Furthermore, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection. Here, we summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. Furthermore, we define the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for severe acute respiratory syndrome coronavirus 2.
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Non-insulin anti-diabetic agents in patients with type 2 diabetes and COVID-19: A Critical Appraisal of Literature.
Singh, AK, Singh, R, Saboo, B, Misra, A
Diabetes & metabolic syndrome. 2021;(1):159-167
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Abstract
BACKGROUND & AIMS Several observational studies have recently reported the outcomes of non-insulin anti-diabetic agents (ADA) in patients with T2DM and coronavirus disease 2019 (COVID-19). We sought to review the literature to appraise the clinicians on these outcomes. METHODS A literature search using the specific keywords was carried out in the database of PubMed, MedRxiv and Google Scholar up till December 11, 2020 applying Boolean method. Full text of all the relevant articles that reported the outcomes of ADA in patients with T2DM and COVID-19 were retrieved. Subsequently, an appraisal of literature report was narratively presented. RESULTS Available studies that reported the outcomes of ADA are either case series or retrospective cohorts or prospective observational studies, in absence of the randomized controlled trials (RCTs). Results from these observational studies suggest that amongst all the non-insulin ADA, metformin users prior to the hospitalization had improved outcomes compared to the non-users. Data for dipeptidyl-peptidase-4 inhibitors (DPP-4i) are encouraging although inconsistent. No documentation of any harm or benefit has been observed for sulfonylureas (SUs), sodium glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide receptor agonists (GLP-1RAs). No data is yet available for pioglitazone. CONCLUSION Metformin and DPP-4i should be continued in patients with T2DM until hospitalization or unless contraindicated. No evidence of harm suggests that SUs, SGLT-2i or GLP-1RAs may not be stopped unless very sick, hospitalized or contraindicated. The results from RCTs are needed to claim any meaningful benefit with either metformin or DPP-4i in patients with T2DM and COVID-19.
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Treatments in Covid-19 patients with pre-existing metabolic dysfunction-associated fatty liver disease: A potential threat for drug-induced liver injury?
Ferron, PJ, Gicquel, T, Mégarbane, B, Clément, B, Fromenty, B
Biochimie. 2020;:266-274
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Abstract
Obese patients who often present metabolic dysfunction-associated fatty liver disease (MAFLD) are at risk of severe presentation of coronavirus disease 2019 (COVID-19). These patients are more likely to be hospitalized and receive antiviral agents and other drugs required to treat acute respiratory distress syndrome and systemic inflammation, combat bacterial and fungal superinfections and reverse multi-organ failure. Among these pharmaceuticals, antiretrovirals such as lopinavir/ritonavir and remdesivir, antibiotics and antifungal agents can induce drug-induced liver injury (DILI), whose mechanisms are not always understood. In the present article, we hypothesize that obese COVID-19 patients with MAFLD might be at higher risk for DILI than non-infected healthy individuals or MAFLD patients. These patients present several concomitant factors, which individually can favour DILI polypharmacy, systemic inflammation at risk of cytokine storm, fatty liver and sometimes nonalcoholic steatohepatitis (NASH) as well as insulin resistance and other diseases linked to obesity. Hence, in obese COVID-19 patients, some drugs might cause more severe (and/or more frequent) DILI, while others might trigger the transition of fatty liver to NASH, or worsen pre-existing steatosis, necroinflammation and fibrosis. We also present the main mechanisms whereby drugs can be more hepatotoxic in MAFLD including impaired activity of xenobiotic-metabolizing enzymes, mitochondrial dysfunction, altered lipid homeostasis and oxidative stress. Although comprehensive investigations are needed to confirm our hypothesis, we believe that the current epidemic of obesity and related metabolic diseases has extensively contributed to increase the number of cases of DILI in COVID-19 patients, which may have participated in presentation severity and death.
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Nutrition Therapy in Critically Ill Patients With Coronavirus Disease 2019.
Martindale, R, Patel, JJ, Taylor, B, Arabi, YM, Warren, M, McClave, SA
JPEN. Journal of parenteral and enteral nutrition. 2020;(7):1174-1184
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Abstract
In the midst of a coronavirus disease 2019 (COVID-19) pandemic, a paucity of data precludes derivation of COVID-19-specific recommendations for nutrition therapy. Until more data are available, focus must be centered on principles of critical care nutrition modified for the constraints of this disease process, ie, COVID-19-relevant recommendations. Delivery of nutrition therapy must include strategies to reduce exposure and spread of disease by providing clustered care, adequate protection of healthcare providers, and preservation of personal protective equipment. Enteral nutrition (EN) should be initiated early after admission to the intensive care unit (ICU) using a standard isosmolar polymeric formula, starting at trophic doses and advancing as tolerated, while monitoring for gastrointestinal intolerance, hemodynamic instability, and metabolic derangements. Intragastric EN may be provided safely, even with use of prone-positioning and extracorporeal membrane oxygenation. Clinicians should have a lower threshold for switching to parenteral nutrition in cases of intolerance, high risk of aspiration, or escalating vasopressor support. Although data extrapolated from experience in acute respiratory distress syndrome warrants use of fiber additives and probiotic organisms, the lack of benefit precludes a recommendation for micronutrient supplementation. Practices that increase exposure or contamination of equipment, such as monitoring gastric residual volumes, indirect calorimetry to calculate requirements, endoscopy or fluoroscopy to achieve enteral access, or transport out of the ICU for additional imaging, should be avoided. At all times, strategies for nutrition therapy need to be assessed on a risk/benefit basis, paying attention to risk for both the patient and the healthcare provider.