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1.
Nat Rev Nephrol ; 17(11): 725-739, 2021 11.
Article in English | MEDLINE | ID: covidwho-1821594

ABSTRACT

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.


Subject(s)
Diabetic Nephropathies/metabolism , Inflammation Mediators/metabolism , Inflammation/metabolism , Kidney/metabolism , Lipid Metabolism , Lipids , Renal Insufficiency, Chronic/metabolism , Diabetes Mellitus/metabolism , Diabetic Angiopathies/metabolism , Humans , Obesity/metabolism
2.
Signal Transduct Target Ther ; 6(1): 427, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1795805

ABSTRACT

Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism. In this study, we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases, and found new-onset insulin resistance, hyperglycemia, and decreased HDL-C in these patients. Mechanistically, SARS-CoV-2 infection increased the expression of RE1-silencing transcription factor (REST), which modulated the expression of secreted metabolic factors including myeloperoxidase, apelin, and myostatin at the transcriptional level, resulting in the perturbation of glucose and lipid metabolism. Furthermore, several lipids, including (±)5-HETE, (±)12-HETE, propionic acid, and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation, especially in insulin resistance. Taken together, our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19, and further illustrated the underlying mechanisms, providing potential therapeutic targets for COVID-19-induced metabolic complications.


Subject(s)
COVID-19/blood , Hyperglycemia/blood , Insulin Resistance , Lipid Metabolism , Lipids/blood , SARS-CoV-2/metabolism , Adult , Aged , Biomarkers/blood , COVID-19/complications , Female , Humans , Hyperglycemia/etiology , Male , Middle Aged , Retrospective Studies
3.
Front Public Health ; 10: 850191, 2022.
Article in English | MEDLINE | ID: covidwho-1785450

ABSTRACT

Objective: To investigate whether first-trimester fasting plasma glucose (FPG), blood coagulation function and lipid metabolism could predict gestational diabetes mellitus (GDM) risk. Methods: From October 2020 to May 2021, a total of 584 pregnant women who took prenatal care in Shanghai Jiaotong University Affiliated Sixth People's Hospital were chosen as the observation subjects. The clinical information and serum samples of all pregnant women were collected at 10-13 weeks of gestation and the blood coagulation function, fasting blood glucose and lipid profiles of the pregnant women were detected. A 75 g oral glucose tolerance test was performed up to 24-28 weeks of gestation. One hundred forty-two pregnant women with GDM and 442 pregnant women without GDM were detected. Data were expressed by x ± s or median (interquartile range) and were analyzed using student's t-test, Wilcoxon rank sum test and Logistic regression analysis. The area under the curve (AUC) was calculated by receiver operating characteristic curve (ROC) to analyze the predictive values. Results: Compared with non-GDM group, age, pre-pregnancy BMI, FPG, FIB, D-Dimer, FDP, FPG, TC, TG, LDL-C, sdLDL-C, APOB and APOE in GDM group were significantly higher than those in non-GDM group, while PT, INR, APTT and TT were significantly lower than those in non-GDM group. Univariate logistic regression analysis was used to explore the risk factors of GDM. Gestational age, pre-pregnancy BMI, FPG, PT, INR, APTT, FIB, TT, D-Dimer, TC, TG, LDL-C, sdLDL-C, APOB and APOE were all independent predictors of GDM. Multivariatelogistic regression showed that pre-pregnancy BMI, FPG, APTT, TT, TG, LDL-C, sdLDL-C and APOB were risk factors for GDM. The AUC of the established GDM risk prediction model was 0.892 (0.858-0.927), and the sensitivity and specificity were 80.71 and 86.85%, respectively; which were greater than that of pre-pregnancy BMI, FPG, APTT, TT,TG, LDL-C, sdLDL-C, APOB alone, and the difffference was statistically signifificant (P < 0.05). Conclusions: FPG, APTT, TT, TG, LDL-C, sdLDL-C, APOB and pre-pregnancy BMI in early pregnancy has important clinical value for the prediction of GDM, We combined these laboratory indicators and established a GDM risk prediction model, which is conducive to the early identification, intervention and treatment of GDM, so as to reduce the morbidity of maternal and infant complications.


Subject(s)
Diabetes, Gestational , Apolipoproteins B/metabolism , Apolipoproteins E/metabolism , Blood Coagulation , Blood Glucose/analysis , Blood Glucose/metabolism , Body Mass Index , Cholesterol, LDL/metabolism , Diabetes, Gestational/diagnosis , Early Diagnosis , Female , Glycolipids , Humans , Lipid Metabolism , Pregnancy
4.
Microbiol Spectr ; 10(1): e0127121, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1752773

ABSTRACT

The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global outbreak and prompted an enormous research effort. Still, the subcellular localization of the coronavirus in lungs of COVID-19 patients is not well understood. Here, the localization of the SARS-CoV-2 proteins is studied in postmortem lung material of COVID-19 patients and in SARS-CoV-2-infected Vero cells, processed identically. Correlative light and electron microscopy on semithick cryo-sections demonstrated induction of electron-lucent, lipid-filled compartments after SARS-CoV-2 infection in both lung and cell cultures. In lung tissue, the nonstructural protein 4 and the stable nucleocapsid N-protein were detected on these novel lipid-filled compartments. The induction of such lipid-filled compartments and the localization of the viral proteins in lung of patients with fatal COVID-19 may explain the extensive inflammatory response and provide a new hallmark for SARS-CoV-2 infection at the final, fatal stage of infection. IMPORTANCE Visualization of the subcellular localization of SARS-CoV-2 proteins in lung patient material of COVID-19 patients is important for the understanding of this new virus. We detected viral proteins in the context of the ultrastructure of infected cells and tissues and discovered that some viral proteins accumulate in novel, lipid-filled compartments. These structures are induced in Vero cells but, more importantly, also in lung of patients with COVID-19. We have characterized these lipid-filled compartments and determined that this is a novel, virus-induced structure. Immunogold labeling demonstrated that cellular markers, such as CD63 and lipid droplet marker PLIN-2, are absent. Colocalization of lipid-filled compartments with the stable N-protein and nonstructural protein 4 in lung of the last stages of COVID-19 indicates that these compartments play a key role in the devastating immune response that SARS-CoV-2 infections provoke.


Subject(s)
COVID-19/metabolism , Lipid Metabolism/physiology , Lipids/analysis , Lung/metabolism , Nucleocapsid/analysis , SARS-CoV-2 , Adolescent , Aged , Animals , COVID-19/pathology , Child, Preschool , Chlorocebus aethiops , Disease Outbreaks , Female , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Lung/cytology , Lung/pathology , Lung/ultrastructure , Male , Microscopy, Immunoelectron , Middle Aged , Nucleocapsid/metabolism , Rabbits , SARS-CoV-2/ultrastructure , Vero Cells/virology
5.
Food Funct ; 13(5): 2846-2856, 2022 Mar 07.
Article in English | MEDLINE | ID: covidwho-1700242

ABSTRACT

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.


Subject(s)
Anti-Obesity Agents/pharmacology , Plant Extracts/pharmacology , Tea , Adipose Tissue/metabolism , Animals , Anti-Obesity Agents/chemistry , Diet, High-Fat , Disease Models, Animal , Gastrointestinal Microbiome/drug effects , Lipid Metabolism/drug effects , Male , Plant Extracts/chemistry , Rats , Rats, Sprague-Dawley
6.
Int J Environ Res Public Health ; 19(2)2022 01 12.
Article in English | MEDLINE | ID: covidwho-1637922

ABSTRACT

This study investigated the effects of partial replacement of dietary fat with krill oil (KO) or coconut oil (CO) on dyslipidemia and lipid metabolism in rats fed with a high-fat diet (HFD). Sprague Dawley rats were divided into three groups as follows: HFD, HFD + KO, and HFD + CO. The rats were fed each diet for 10 weeks and then intraperitoneally injected with phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (1 mg/kg). The KO- and CO-fed rats exhibited lower levels of serum lipids and aspartate aminotransferases than those of the HFD-fed rats. Rats fed with HFD + KO displayed significantly lower hepatic histological scores and hepatic triglyceride (TG) content than rats fed with HFD. The KO supplementation also downregulated the adipogenic gene expression in the liver. When treated with LPS, the HFD + KO and HFD + CO groups reduced the adipocyte size in the epididymal white adipose tissues (EAT) relative to the HFD group. These results suggest that KO and CO could improve lipid metabolism dysfunction.


Subject(s)
Dyslipidemias , Euphausiacea , Animals , Coconut Oil/metabolism , Coconut Oil/pharmacology , Diet, High-Fat/adverse effects , Dietary Fats , Euphausiacea/metabolism , Lipid Metabolism , Lipopolysaccharides/toxicity , Liver , Rats , Rats, Sprague-Dawley
7.
J Immunol ; 208(3): 562-570, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1625582

ABSTRACT

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).


Subject(s)
Aging/immunology , CD8-Positive T-Lymphocytes/immunology , Immunocompetence/drug effects , Lipid Metabolism , Adult , Aged , Aged, 80 and over , Apoptosis , CD8-Positive T-Lymphocytes/metabolism , COVID-19/immunology , Cancer Vaccines/immunology , Cell Division , Female , Fenofibrate/pharmacology , Glucose/metabolism , HLA-A2 Antigen/immunology , Humans , Hypolipidemic Agents/pharmacology , Hypolipidemic Agents/therapeutic use , Influenza, Human/immunology , Lipid Metabolism/drug effects , Lymphocyte Activation , MART-1 Antigen/chemistry , MART-1 Antigen/immunology , Male , Middle Aged , Neoplasms/immunology , Peptide Fragments/immunology , Rosiglitazone/pharmacology , Single-Blind Method , Vaccination , Viral Vaccines/immunology , Young Adult
8.
Biomed Res Int ; 2022: 1558860, 2022.
Article in English | MEDLINE | ID: covidwho-1622112

ABSTRACT

Increasing outbreaks of new pathogenic viruses have promoted the exploration of novel alternatives to time-consuming vaccines. Thus, it is necessary to develop a universal approach to halt the spread of new and unknown viruses as they are discovered. One such promising approach is to target lipid membranes, which are common to all viruses and bacteria. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reaffirmed the importance of interactions between the virus envelope and the host cell plasma membrane as a critical mechanism of infection. Metadichol®, a nanolipid emulsion of long-chain alcohols, has been demonstrated as a strong candidate that inhibits the proliferation of SARS-CoV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce viral infectivity, including that of coronaviruses (such as SARS-CoV-2) by modifying their lipid-dependent attachment mechanism to human host cells. The receptor ACE2 mediates the entry of SARS-CoV-2 into the host cells, whereas the serine protease TMPRSS2 primes the viral S protein. In this study, Metadichol® was found to be 270 times more potent an inhibitor of TMPRSS2 (EC50 = 96 ng/mL) than camostat mesylate (EC50 = 26000 ng/mL). Additionally, it inhibits ACE with an EC50 of 71 ng/mL, but it is a very weak inhibitor of ACE2 at an EC50 of 31 µg/mL. Furthermore, the live viral assay performed in Caco-2 cells revealed that Metadichol® inhibits SARS-CoV-2 replication at an EC90 of 0.16 µg/mL. Moreover, Metadichol® had an EC90 of 0.00037 µM, making it 2081 and 3371 times more potent than remdesivir (EC50 = 0.77 µM) and chloroquine (EC50 = 1.14 µM), respectively.


Subject(s)
Fatty Alcohols/pharmacology , SARS-CoV-2/drug effects , Viruses/drug effects , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cell Line , Chlorocebus aethiops , Esters/pharmacology , Guanidines/pharmacology , Humans , Lipid Metabolism/physiology , Lipids/chemistry , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/drug effects , Serine Endopeptidases/metabolism , Serine Proteases/metabolism , Serine Proteinase Inhibitors/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Attachment/drug effects , Virus Internalization/drug effects
10.
Rev Med Virol ; 31(5): 1-13, 2021 09.
Article in English | MEDLINE | ID: covidwho-1573688

ABSTRACT

Viruses have evolved to manipulate host lipid metabolism to benefit their replication cycle. Enveloped viruses, including coronaviruses, use host lipids in various stages of the viral life cycle, particularly in the formation of replication compartments and envelopes. Host lipids are utilised by the virus in receptor binding, viral fusion and entry, as well as viral replication. Association of dyslipidaemia with the pathological development of Covid-19 raises the possibility that exploitation of host lipid metabolism might have therapeutic benefit against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, promising host lipid targets are discussed along with potential inhibitors. In addition, specific host lipids are involved in the inflammatory responses due to viral infection, so lipid supplementation represents another potential strategy to counteract the severity of viral infection. Furthermore, switching the lipid metabolism through a ketogenic diet is another potential way of limiting the effects of viral infection. Taken together, restricting the access of host lipids to the virus, either by using lipid inhibitors or supplementation with exogenous lipids, might significantly limit SARS-CoV-2 infection and/or severity.


Subject(s)
COVID-19/metabolism , Lipid Metabolism , SARS-CoV-2/physiology , Animals , COVID-19/diet therapy , COVID-19/immunology , COVID-19/prevention & control , Humans , Lipids/immunology , SARS-CoV-2/genetics
11.
Viruses ; 13(12)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1572667

ABSTRACT

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.


Subject(s)
COVID-19 , Diet, High-Fat/adverse effects , Dietary Carbohydrates/adverse effects , Lipid Metabolism , Severity of Illness Index , Animals , COVID-19/pathology , Cricetinae , Cytokines/blood , Disease Models, Animal , Edema , Fibrin , Hemorrhage , Humans , Interleukin-10 , Interleukin-6 , Lipidomics , Lipids/blood , Liver/pathology , Lung/pathology , Male , Mesocricetus , Obesity , SARS-CoV-2 , Sugars , Vasculitis/pathology , Virus Shedding
12.
Lipids Health Dis ; 20(1): 179, 2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1571759

ABSTRACT

Lipids have a wide variety and vital functions. Lipids play roles in energy metabolism, intracellular and extracellular signal traffic, and transport of fat-soluble vitamins. Also, they form the structure of the cell membrane. SARS-CoV-2 interacts with lipids since its genetic material contains lipid-enveloped ribonucleic acid (RNA). Previous studies have shown that total cholesterol, high-density lipoprotein, and low-density lipoprotein (LDL) levels are lower in patients with severe novel coronavirus disease 2019 (COVID-19) compared to patients with non-severe COVID-19.Na+/H+ Exchanger (NHE) is an important antiport that keeps the intracellular pH value within physiological limits. When the intracellular pH falls, NHE is activated and pumps H+ ions outward. However, prolonged NHE activation causes cell damage and atherosclerosis. Prolonged NHE activation may increase susceptibility to SARS-CoV-2 infection and severity of COVID-19.In COVID-19, increased angiotensin II (Ang II) due to angiotensin-converting enzyme-2 (ACE2) dysfunction stimulates NHE. Lipids are in close association with the NHE pump. Prolonged NHE activity increases the influx of H+ ions and free fatty acid (FFA) inward. Ang II also causes increased low-density lipoprotein receptor (LDLR) levels by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Thus, intracellular atheroma plaque formation is accelerated.Besides, SARS-CoV-2 may replicate more rapidly as intracellular cholesterol increases. SARS-CoV-2 swiftly infects the cell whose intracellular pH decreases with NHE activation and FFA movement. Novel treatment regimens based on NHE and lipids should be explored for the treatment of COVID-19.


Subject(s)
COVID-19/pathology , Cholesterol/metabolism , Receptors, LDL/metabolism , SARS-CoV-2 , Sodium-Hydrogen Exchangers/metabolism , COVID-19/metabolism , COVID-19/mortality , Cause of Death , Humans , Lipid Metabolism , Patient Acuity , SARS-CoV-2/metabolism
14.
Lipids Health Dis ; 20(1): 141, 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1484314

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 coronavirus started in March 2020. The conclusions from numerous studies indicate that people with comorbidities, such as arterial hypertension, diabetes, obesity, underlying cardiovascular disease, are particularly vulnerable to the severe course of COVID-19. The available data also suggest that patients with dyslipidemia, the most common risk factor of cardiovascular diseases, are also at greater risk of severe course of COVID-19. On the other hand, it has been shown that COVID-19 infection has an influence on lipid profile leading to dyslipidemia, which might require appropriate treatment. Owing to antiviral, anti-inflammatory, immunomodulatory, and cardioprotective activity, statin therapy has been considered as valuable tool to improve COVID-19 outcomes. Numerous observational studies have shown potential beneficial effects of lipid-lowering treatment on the course of COVID-19 with significant improved prognosis and reduced mortality.


Subject(s)
COVID-19/etiology , Dyslipidemias/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipoproteinemia Type II/drug therapy , COVID-19/drug therapy , COVID-19/epidemiology , Comorbidity , Dyslipidemias/epidemiology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/metabolism , Lipid Metabolism , Prognosis
15.
Viruses ; 13(7)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1448932

ABSTRACT

Infection has recently started receiving greater attention as an unusual causative/inducing factor of obesity. Indeed, the biological plausibility of infectobesity includes direct roles of some viruses to reprogram host metabolism toward a more lipogenic and adipogenic status. Furthermore, the probability that humans may exchange microbiota components (virome/virobiota) points out that the altered response of IFN and other cytokines, which surfaces as a central mechanism for adipogenesis and obesity-associated immune suppression, is due to the fact that gut microbiota uphold intrinsic IFN signaling. Last but not least, the adaptation of both host immune and metabolic system under persistent viral infections play a central role in these phenomena. We hereby discuss the possible link between adenovirus and obesity-related nonalcoholic fatty liver disease (NAFLD). The mechanisms of adenovirus-36 (Ad-36) involvement in hepatic steatosis/NAFLD consist in reducing leptin gene expression and insulin sensitivity, augmenting glucose uptake, activating the lipogenic and pro-inflammatory pathways in adipose tissue, and increasing the level of macrophage chemoattractant protein-1, all of these ultimately leading to chronic inflammation and altered lipid metabolism. Moreover, by reducing leptin expression and secretion Ad-36 may have in turn an obesogenic effect through increased food intake or decreased energy expenditure via altered fat metabolism. Finally, Ad-36 is involved in upregulation of cAMP, phosphatidylinositol 3-kinase, and p38 signaling pathways, downregulation of Wnt10b expression, increased expression of CCAAT/enhancer binding protein-beta, and peroxisome proliferator-activated receptor gamma 2 with consequential lipid accumulation.


Subject(s)
Inflammation , Lipid Metabolism , Non-alcoholic Fatty Liver Disease/complications , Obesity/etiology , Obesity/virology , Adenoviridae/immunology , Adenoviridae Infections/complications , Adenoviridae Infections/immunology , Animals , Diet, High-Fat , Glucose/metabolism , Humans , Lipogenesis , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/virology , Obesity/complications , Obesity/immunology , Signal Transduction
16.
Nat Metab ; 3(11): 1466-1475, 2021 11.
Article in English | MEDLINE | ID: covidwho-1440484

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/metabolism , COVID-19/virology , Fatty Acids/biosynthesis , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Virus Replication/drug effects , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/mortality , Cell Line , Disease Models, Animal , Disease Susceptibility , Dose-Response Relationship, Drug , Drug Development , Gene Knockdown Techniques , Host-Pathogen Interactions/genetics , Humans , Lipid Metabolism/drug effects , Mice , fas Receptor/antagonists & inhibitors , fas Receptor/deficiency , fas Receptor/metabolism
18.
Pharmacol Res ; 169: 105665, 2021 07.
Article in English | MEDLINE | ID: covidwho-1433725

ABSTRACT

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.


Subject(s)
Ascorbic Acid/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Lipids/blood , Ascorbic Acid/administration & dosage , Ascorbic Acid/pharmacology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Dietary Supplements , Dose-Response Relationship, Drug , Humans , Lipid Metabolism/drug effects
20.
Cells ; 10(4)2021 04 14.
Article in English | MEDLINE | ID: covidwho-1408630

ABSTRACT

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.


Subject(s)
Embryo, Mammalian/pathology , Neoplasms/pathology , Neoplasms/prevention & control , Tumor-Associated Macrophages/pathology , Glucose/metabolism , Humans , Lipid Metabolism , Neoplasms/metabolism , Single-Cell Analysis
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