Oolong tea extract alleviates weight gain in high-fat diet-induced obese rats by regulating lipid metabolism and modulating gut microbiota.

Obesity is a serious global health issue, and the societal interventions during the COVID-19 pandemic may have perturbed energy homeostasis, which affects the condition of obesity. Tea is a traditional beverage in Asia and has been shown to provide many beneficial health effects. Oolong tea is semifermented, with its chemical composition comprising features of green (unfermented) and black (fermented) tea. Although green tea has anti-obesity properties, studies on the anti-obesity ability of oolong tea are still scarce. In this study, we analyzed the chemical composition of oolong tea extract (OTE) and investigated the effects of OTE on high-fat diet-induced obese rats. OTE contained more (-)-epigallocatechin-3-gallate, (-)-epigallocatechin, and (-)-gallocatechin-3-gallate than theaflavins and theasinensins. Rats fed with a high-fat diet (HFD) and treated with 0.5% OTE exhibited significantly reduced body weight and visceral fat weight compared with the HFD-only group. OTE also decreased adipocyte size, lipogenesis-related protein sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) protein expression and increased thermogenesis-related protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and uncoupling protein 1 (UCP1) protein expression in epididymal adipose tissue compared with the HFD group. Moreover, the OTE groups had a significantly higher abundance of Candidatus arthromitus and Hydrogenoanaerobacterium and a lower abundance of Ruminococcus1, Oscillibacter, and Odoribacter compared with the HFD group. All these results show that OTE can alleviate weight gain by regulating lipid metabolism and modulating the distribution of the gut microbiota to decrease lipid accumulation in adipose tissue.

Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8+ T Cells in Elderly Humans.

Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication.

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 is a virus-induced inflammatory disease of the airways and lungs that leads to severe multi-organ damage and death. Here we show that cellular lipid synthesis is required for SARS-CoV-2 replication and offers an opportunity for pharmacological intervention. Screening a short-hairpin RNA sublibrary that targets metabolic genes, we identified genes that either inhibit or promote SARS-CoV-2 viral infection, including two key candidate genes, ACACA and FASN, which operate in the same lipid synthesis pathway. We further screened and identified several potent inhibitors of fatty acid synthase (encoded by FASN), including the US Food and Drug Administration-approved anti-obesity drug orlistat, and found that it inhibits in vitro replication of SARS-CoV-2 variants, including more contagious new variants, such as Delta. In a mouse model of SARS-CoV-2 infection (K18-hACE2 transgenic mice), injections of orlistat resulted in lower SARS-CoV-2 viral levels in the lung, reduced lung pathology and increased mouse survival. Our findings identify fatty acid synthase inhibitors as drug candidates for the prevention and treatment of COVID-19 by inhibiting SARS-CoV-2 replication. Clinical trials are needed to evaluate the efficacy of repurposing fatty acid synthase inhibitors for severe COVID-19 in humans.

Does vitamin C supplementation exert profitable effects on serum lipid profile in patients with type 2 diabetes? A systematic review and dose-response meta-analysis.

Previous studies have reported that vitamin C supplementation may decrease lipid profile in patients with type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis evaluated the influence of vitamin C supplementation on lipid profile in patients with T2DM. Studies examining the effects of vitamin C supplementation on lipid profile in patients with T2DM, published up to November 2020, were identified through PubMed, SCOPUS, and Embase databases. 15 studies, including 872 participants, were included and analyzed using a random-effects model to calculate weighted mean differences (WMDs) with 95% confidence intervals (CI). Findings from 15 studies indicated that vitamin C supplementation significantly decreased Triglyceride (TG) (WMD: -16.48 mg/dl, 95% CI (-31.89, -1.08), P < 0.001) and total cholesterol (TC) (WMD: -13.00 mg/dl, 95% CI (-23.10, -2.91), P < 0.001) in patients with T2DM. However, vitamin C supplementation failed to improve LDL and HDL. The meta-regression analysis suggested that lipid profile improvement was affected by duration of vitamin C treatment. Dose-response analysis showed that vitamin C supplementation changed LDL significantly based on vitamin C dose. According to our findings, vitamin C supplementation significantly improved lipid profile via decreases in TG and TC. However, vitamin C failed to affect LDL and HDL in diabetic populations. It appears that vitamin C supplementation is more beneficial to lipid profile in long-term vs. short term interventions.

Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens.

The ongoing COVID-19 pandemic, periodic recurrence of viral infections, and the emergence of challenging variants has created an urgent need of alternative therapeutic approaches to combat the spread of viral infections, failing to which may pose a greater risk to mankind in future. Resilience against antiviral drugs or fast evolutionary rate of viruses is stressing the scientific community to identify new therapeutic approaches for timely control of disease. Host metabolic pathways are exquisite reservoir of energy to viruses and contribute a diverse array of functions for successful replication and pathogenesis of virus. Targeting the host factors rather than viral enzymes to cease viral infection, has emerged as an alternative antiviral strategy. This approach offers advantage in terms of increased threshold to viral resistance and can provide broad-spectrum antiviral action against different viruses. The article here provides substantial review of literature illuminating the host factors and molecular mechanisms involved in innate/adaptive responses to viral infection, hijacking of signalling pathways by viruses and the intracellular metabolic pathways required for viral replication. Host-targeted drugs acting on the pathways usurped by viruses are also addressed in this study. Host-directed antiviral therapeutics might prove to be a rewarding approach in controlling the unprecedented spread of viral infection, however the probability of cellular side effects or cytotoxicity on host cell should not be ignored at the time of clinical investigations.

Inhibitors of VPS34 and fatty-acid metabolism suppress SARS-CoV-2 replication.

Coronaviruses rely on host membranes for entry, establishment of replication centers, and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we test small molecule inhibitors that target the PI3 kinase VPS34 or fatty acid metabolism for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity. Our studies determine that compounds targeting VPS34 are potent SARS-CoV-2 inhibitors. Mechanistic studies with compounds targeting multiple steps up- and downstream of fatty acid synthase (FASN) identify the importance of triacylglycerol production and protein palmitoylation as requirements for efficient viral RNA synthesis and infectious virus production. Further, FASN knockout results in significantly impaired SARS-CoV-2 replication that can be rescued with fatty acid supplementation. Together, these studies clarify roles for VPS34 and fatty acid metabolism in SARS-CoV-2 replication and identify promising avenues for the development of countermeasures against SARS-CoV-2.

COVID-19: Direct and Indirect Mechanisms of Statins.

The virus responsible for the current COVID-19 pandemic is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a new virus with high infectivity and moderate mortality. The major clinical manifestation of COVID-19 is interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). However, the disease causes a potent systemic hyperin-flammatory response, i.e., a cytokine storm or macrophage activation syndrome (MAS), which is associated with thrombotic complications. The complexity of the disease requires appropriate intensive treatment. One of promising treatment is statin administration, these being 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that exert pleiotropic anti-inflammatory effects. Recent studies indicate that statin therapy is associated with decreased mortality in COVID-19, which may be caused by direct and indirect mechanisms. According to literature data, statins can limit SARS-CoV-2 cell entry and replication by inhibiting the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). The cytokine storm can be ameliorated by lowering serum IL-6 levels; this can be achieved by inhibiting Toll-like receptor 4 (TLR4) and modulating macrophage activity. Statins can also reduce the complications of COVID-19, such as thrombosis and pulmonary fibrosis, by reducing serum PAI-1 levels, attenuating TGF-ß and VEGF in lung tissue, and improving endothelial function. Despite these benefits, statin therapy may have side effects that should be considered, such as elevated creatinine kinase (CK), liver enzyme and serum glucose levels, which are already elevated in severe COVID-19 infection. The present study analyzes the latest findings regarding the benefits and limitations of statin therapy in patients with COVID-19.

Hydroxychloroquine Inhibits the Trained Innate Immune Response to Interferons.

Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.