Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 42
Filter
1.
Int J Mol Sci ; 23(13)2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1934137

ABSTRACT

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.


Subject(s)
Adipose Tissue , Obesity, Morbid , Adipokines/metabolism , Adipose Tissue/metabolism , Humans , Inflammasomes/metabolism , Inflammation/metabolism , Obesity, Morbid/metabolism
2.
Cells ; 11(6)2022 03 14.
Article in English | MEDLINE | ID: covidwho-1887165

ABSTRACT

The epicardial adipose tissue (EAT) is the visceral fat depot of the heart which is highly plastic and in direct contact with myocardium and coronary arteries. Because of its singular proximity with the myocardium, the adipokines and pro-inflammatory molecules secreted by this tissue may directly affect the metabolism of the heart and coronary arteries. Its accumulation, measured by recent new non-invasive imaging modalities, has been prospectively associated with the onset and progression of coronary artery disease (CAD) and atrial fibrillation in humans. Recent studies have shown that EAT exhibits beige fat-like features, and express uncoupling protein 1 (UCP-1) at both mRNA and protein levels. However, this thermogenic potential could be lost with age, obesity and CAD. Here we provide an overview of the physiological and pathophysiological relevance of EAT and further discuss whether its thermogenic properties may serve as a target for obesity therapeutic management with a specific focus on the role of immune cells in this beiging phenomenon.


Subject(s)
Adipose Tissue , Coronary Artery Disease , Adipokines/metabolism , Adipose Tissue/metabolism , Coronary Artery Disease/metabolism , Humans , Obesity/metabolism , Pericardium/metabolism
3.
Int J Obes (Lond) ; 46(8): 1478-1486, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1852402

ABSTRACT

BACKGROUND: COVID-19 severity varies widely. Although some demographic and cardio-metabolic factors, including age and obesity, are associated with increasing risk of severe illness, the underlying mechanism(s) are uncertain. SUBJECTS/METHODS: In a meta-analysis of three independent studies of 1471 participants in total, we investigated phenotypic and genetic factors associated with subcutaneous adipose tissue expression of Angiotensin I Converting Enzyme 2 (ACE2), measured by RNA-Seq, which acts as a receptor for SARS-CoV-2 cellular entry. RESULTS: Lower adipose tissue ACE2 expression was associated with multiple adverse cardio-metabolic health indices, including type 2 diabetes (T2D) (P = 9.14 × 10-6), obesity status (P = 4.81 × 10-5), higher serum fasting insulin (P = 5.32 × 10-4), BMI (P = 3.94 × 10-4), and lower serum HDL levels (P = 1.92 × 10-7). ACE2 expression was also associated with estimated proportions of cell types in adipose tissue: lower expression was associated with a lower proportion of microvascular endothelial cells (P = 4.25 × 10-4) and higher proportion of macrophages (P = 2.74 × 10-5). Despite an estimated heritability of 32%, we did not identify any proximal or distal expression quantitative trait loci (eQTLs) associated with adipose tissue ACE2 expression. CONCLUSIONS: Our results demonstrate that individuals with cardio-metabolic features known to increase risk of severe COVID-19 have lower background ACE2 levels in this highly relevant tissue. Reduced adipose tissue ACE2 expression may contribute to the pathophysiology of cardio-metabolic diseases, as well as the associated increased risk of severe COVID-19.


Subject(s)
Adipose Tissue , Angiotensin-Converting Enzyme 2 , COVID-19 , Adipose Tissue/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/genetics , Cardiometabolic Risk Factors , Diabetes Mellitus, Type 2/genetics , Endothelial Cells/metabolism , Humans , Obesity , SARS-CoV-2
4.
Cell Metab ; 34(5): 656-657, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1850884

ABSTRACT

Adipose tissue has been linked to inflammation and various physiological processes. In this issue of Cell Metabolism, Caputa et al. describe that perinodal adipocytes adapt their metabolism to actively participate in an immune response against intracellular Listeria monocytogenes.


Subject(s)
Adipocytes , Adipose Tissue , Adipocytes/metabolism , Adipose Tissue/metabolism , Humans , Immunity , Inflammation/metabolism
5.
Cells ; 11(8)2022 04 09.
Article in English | MEDLINE | ID: covidwho-1785540

ABSTRACT

The risk of complications following surgical procedures is significantly increased in patients with SARS-CoV-2 infection. However, the mechanisms underlying these correlations are not fully known. Spinal cord injury (SCI) patients who underwent reconstructive surgery for pressure ulcers (PUs) before and during the COVID-19 pandemic were included in this study. The patient's postoperative progression was registered, and the subcutaneous white adipose tissue (s-WAT) surrounding the ulcers was analyzed by proteomic and immunohistochemical assays to identify the molecular/cellular signatures of impaired recovery. Patients with SCI and a COVID-19-positive diagnosis showed worse recovery and severe postoperative complications, requiring reintervention. Several proteins were upregulated in the adipose tissue of these patients. Among them, CKMT2 and CKM stood out, and CKM increased for up to 60 days after the COVID-19 diagnosis. Moreover, CKMT2 and CKM were largely found in MGCs within the s-WAT of COVID patients. Some of these proteins presented post-translational modifications and were targeted by autoantibodies in the serum of COVID patients. Overall, our results indicate that CKMT2, CKM, and the presence of MGCs in the adipose tissue surrounding PUs in post-COVID patients could be predictive biomarkers of postsurgical complications. These results suggest that the inflammatory response in adipose tissue may underlie the defective repair seen after surgery.


Subject(s)
COVID-19 , Pressure Ulcer , Spinal Cord Injuries , Adipose Tissue/metabolism , COVID-19/complications , COVID-19 Testing , Creatine Kinase/metabolism , Creatine Kinase, Mitochondrial Form/metabolism , Humans , Pandemics , Pressure Ulcer/epidemiology , Pressure Ulcer/etiology , Pressure Ulcer/surgery , Proteomics , SARS-CoV-2 , Spinal Cord Injuries/complications , Spinal Cord Injuries/surgery , Suppuration/complications , Up-Regulation
6.
Int J Infect Dis ; 120: 33-40, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1783422

ABSTRACT

OBJECTIVES: Epicardial adipose tissue (EAT) has been proposed to be an independent predictor of visceral adiposity. EAT measures are associated with coronary artery disease, diabetes, and chronic obstructive pulmonary disease, which are risk factors for COVID-19 poor prognosis. Whether EAT measures are related to COVID-19 severity and prognosis is controversial. METHODS: We searched 6 databases for studies until January 7, 2022. The pooled effects are presented as the standard mean difference (SMD) or weighted mean difference with 95% confidence intervals (CIs). The primary end point was COVID-19 severity. Adverse clinical outcomes were also assessed. RESULTS: A total of 13 studies with 2482 patients with COVID-19 were identified. All patients had positive reverse transcriptase-polymerase chain reaction results. All quantitative EAT measures were based on computed tomography. Patients in the severe group had higher EAT measures compared with the nonsevere group (SMD = 0.74, 95% CI: 0.29-1.18, P = 0.001). Patients with hospitalization requirement, requiring invasive mechanical ventilation, admitted to intensive care unit, or with combined adverse outcomes had higher EAT measures compared to their controls (all P < 0.001). CONCLUSIONS: EAT measures were associated with the severity and adverse clinical outcomes of COVID-19. EAT measures might help in prognostic risk stratification of patients with COVID-19.


Subject(s)
COVID-19 , Adipose Tissue/diagnostic imaging , Adipose Tissue/metabolism , Adiposity , Humans , Pericardium/diagnostic imaging , Pericardium/metabolism , Risk Factors
8.
J Clin Endocrinol Metab ; 107(7): 1799-1811, 2022 06 16.
Article in English | MEDLINE | ID: covidwho-1736468

ABSTRACT

Obesity is associated with an increase in morbidity and mortality from coronavirus disease 2019 (COVID-19). The risk is related to the cytokine storm, a major contributor to multiorgan failure and a pathological character of COVID-19 patients with obesity. While the exact cause of the cytokine storm remains elusive, disorders in energy metabolism has provided insights into the mechanism. Emerging data suggest that adipose tissue in obesity contributes to the disorders in several ways. First, adipose tissue restricts the pulmonary function by generation of mechanical pressures to promote systemic hypoxia. Second, adipose tissue supplies a base for severe acute respiratory syndrome coronavirus 2 entry by overexpression of viral receptors [angiotensin-converting enzyme 2 and dipeptidyl peptidase 4]. Third, impaired antiviral responses of adipocytes and immune cells result in dysfunction of immunologic surveillance as well as the viral clearance systems. Fourth, chronic inflammation in obesity contributes to the cytokine storm by secreting more proinflammatory cytokines. Fifth, abnormal levels of adipokines increase the risk of a hyperimmune response to the virus in the lungs and other organs to enhance the cytokine storm. Mitochondrial dysfunction in adipocytes, immune cells, and other cell types (endothelial cells and platelets, etc) is a common cellular mechanism for the development of cytokine storm, which leads to the progression of mild COVID-19 to severe cases with multiorgan failure and high mortality. Correction of energy surplus through various approaches is recommended in the prevention and treatment of COVID-19 in the obese patients.


Subject(s)
Adipose Tissue , COVID-19 , Obesity , Adipose Tissue/metabolism , COVID-19/complications , Cytokine Release Syndrome , Cytokines/metabolism , Endothelial Cells/metabolism , Humans , Obesity/complications
9.
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
11.
Int J Obes (Lond) ; 46(4): 866-873, 2022 04.
Article in English | MEDLINE | ID: covidwho-1635369

ABSTRACT

BACKGROUND: Increased adiposity and visceral obesity have been linked to adverse COVID-19 outcomes. The amount of epicardial adipose tissue (EAT) may have relevant implications given its proximity to the heart and lungs. Here, we explored the role of EAT in increasing the risk for COVID-19 adverse outcomes. METHODS: We included 748 patients with COVID-19 attending a reference center in Mexico City. EAT thickness, sub-thoracic and extra-pericardial fat were measured using thoracic CT scans. We explored the association of each thoracic adipose tissue compartment with COVID-19 mortality and severe COVID-19 (defined as mortality and need for invasive mechanical ventilation), according to the presence or absence of obesity. Mediation analyses evaluated the role of EAT in facilitating the effect of age, body mass index and cardiac troponin levels with COVID-19 outcomes. RESULTS: EAT thickness was associated with increased risk of COVID-19 mortality (HR 1.18, 95% CI 1.01-1.39) independent of age, gender, comorbid conditions and BMI. Increased EAT was associated with lower SpO2 and PaFi index and higher levels of cardiac troponins, D-dimer, fibrinogen, C-reactive protein, and 4 C severity score, independent of obesity. EAT mediated 13.1% (95% CI 3.67-28.0%) and 5.1% (95% CI 0.19-14.0%) of the effect of age and 19.4% (95% CI 4.67-63.0%) and 12.8% (95% CI 0.03-46.0%) of the effect of BMI on requirement for intubation and mortality, respectively. EAT also mediated the effect of increased cardiac troponins on myocardial infarction during COVID-19. CONCLUSION: EAT is an independent risk factor for severe COVID-19 and mortality independent of obesity. EAT partly mediates the effect of age and BMI and increased cardiac troponins on adverse COVID-19 outcomes.


Subject(s)
COVID-19 , Adipose Tissue/diagnostic imaging , Adipose Tissue/metabolism , Adiposity , Adult , Body Mass Index , Humans , Pericardium/diagnostic imaging , Pericardium/metabolism , Young Adult
12.
Elife ; 112022 01 17.
Article in English | MEDLINE | ID: covidwho-1626761

ABSTRACT

Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.


Developing a new drug that is both safe and effective is a complex and expensive endeavor. An alternative approach is to 'repurpose' existing, safe compounds ­ that is, to establish if they could treat conditions others than the ones they were initially designed for. To achieve this, methods that can predict the activity of thousands of established drugs are necessary. These approaches are particularly important for conditions for which it is hard to find promising treatment. This includes, for instance, heart failure, dementia and other diseases that are linked to the activity of the hormone insulin becoming modified throughout the body, a defect called insulin resistance. Unfortunately, it is difficult to model the complex actions of insulin using cells in the lab, because they involve intricate networks of proteins, tissues and metabolites. Timmons et al. set out to develop a way to better assess whether a drug could be repurposed to treat insulin resistance. The aim was to build a biological signature of the disease in multiple human tissues, as this would help to make the findings more relevant to the clinic. This involved examining which genes were switched on or off in thousands of tissue samples from patients with different degrees of insulin resistance. Importantly, some of the patients had their condition reversed through lifestyle changes, while others did not respond well to treatment. These 'non-responders' provided crucial new clues to screen for active drugs. Carefully piecing the data together revealed the molecules and pathways most related to the severity of insulin resistance. Cross-referencing these results with the way existing drugs act on gene activity, highlighted 138 compounds that directly bind 73 proteins responsible for regulating insulin resistance pathways. Some of the drugs identified are suitable for short-term clinical studies, and it may even be possible to rank similar compounds based on their chemical activity. Beyond giving a glimpse into the complex molecular mechanisms of insulin resistance in humans, Timmons et al. provide a fresh approach to how drugs could be repurposed, which could be adapted to other conditions.


Subject(s)
Drug Repositioning , Metabolic Diseases/drug therapy , Adipose Tissue/metabolism , Biomarkers/metabolism , Humans , Insulin Resistance , Metabolic Diseases/genetics , Muscles/metabolism , Transcriptome
13.
Biochem Soc Trans ; 50(1): 447-457, 2022 02 28.
Article in English | MEDLINE | ID: covidwho-1599610

ABSTRACT

Obesity and its associated metabolic diseases, including diabetes, insulin resistance, and inflammation, are rapidly becoming a global health concern. Moreover, obese individuals are more likely to be infected with COVID-19. New research on adipose tissue is required to help us understand these metabolic diseases and their regulatory processes. Recently, extracellular vesicles (EVs) have been identified as novel intercellular vectors with a wide range of regulatory functions. The miRNAs carried by EVs participate in the regulation of white adipose tissue (WAT) browning, insulin resistance, diabetes, and inflammation. In addition, EV miRNAs demonstrate great potential for helping elucidating the mechanism of metabolic diseases, and for advancing their prevention and treatment. In this review, we focus on the mechanisms underlying the regulation of adipose differentiation and metabolic diseases by adipose-derived EV miRNAs. Understanding the role of these miRNAs should enrich our understanding of the etiology and pathogenesis of metabolic diseases caused by obesity.


Subject(s)
Adipose Tissue/metabolism , Extracellular Vesicles/metabolism , MicroRNAs , Obesity/metabolism , Animals , Humans
14.
Cells ; 10(12)2021 12 08.
Article in English | MEDLINE | ID: covidwho-1597185

ABSTRACT

Beta-3 adrenergic receptor activation via exercise or CL316,243 (CL) induces white adipose tissue (WAT) browning, improves glucose tolerance, and reduces visceral adiposity. Our aim was to determine if sex or adipose tissue depot differences exist in response to CL. Daily CL injections were administered to diet-induced obese male and female mice for two weeks, creating four groups: male control, male CL, female control, and female CL. These groups were compared to determine the main and interaction effects of sex (S), CL treatment (T), and WAT depot (D). Glucose tolerance, body composition, and energy intake and expenditure were assessed, along with perigonadal (PGAT) and subcutaneous (SQAT) WAT gene and protein expression. CL consistently improved glucose tolerance and body composition. Female PGAT had greater protein expression of the mitochondrial uncoupling protein 1 (UCP1), while SQAT (S, p < 0.001) was more responsive to CL in increasing UCP1 (S×T, p = 0.011) and the mitochondrial biogenesis induction protein, PPARγ coactivator 1α (PGC1α) (S×T, p = 0.026). Females also displayed greater mitochondrial OXPHOS (S, p < 0.05) and adiponectin protein content (S, p < 0.05). On the other hand, male SQAT was more responsive to CL in increasing protein levels of PGC1α (S×T, p = 0.046) and adiponectin (S, p < 0.05). In both depots and in both sexes, CL significantly increased estrogen receptor beta (ERß) and glucose-related protein 75 (GRP75) protein content (T, p < 0.05). Thus, CL improves systemic and adipose tissue-specific metabolism in both sexes; however, sex differences exist in the WAT-specific effects of CL. Furthermore, across sexes and depots, CL affects estrogen signaling by upregulating ERß.


Subject(s)
Adipose Tissue, Brown/metabolism , HSP70 Heat-Shock Proteins/genetics , Membrane Proteins/genetics , PPAR gamma/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Uncoupling Protein 1/genetics , Adipose Tissue/metabolism , Adipose Tissue, Brown/growth & development , Adipose Tissue, White/metabolism , Animals , Body Composition/genetics , Dioxoles/pharmacology , Energy Metabolism/genetics , Estrogen Receptor beta/genetics , Estrogens/genetics , Estrogens/metabolism , Female , Glucose Tolerance Test , Humans , Male , Mice , Mitochondria/genetics , Mitochondria/metabolism , Receptors, Adrenergic, beta-3/genetics , Receptors, Adrenergic, beta-3/metabolism , Sex Characteristics
16.
Diabetes ; 70(12): 2745-2755, 2021 12.
Article in English | MEDLINE | ID: covidwho-1556100

ABSTRACT

Aging, obesity, and diabetes are major risk factors for the severe progression and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]), but the underlying mechanism is not yet fully understood. In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in humans and mice with older age, obesity, and diabetes. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including metformin, sodium-glucose cotransporter 2 inhibitor, or ß3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue. Environmental interventions, including exercise, calorie restriction, fasting, or cold exposure, reduced the gene expression of GRP78 in adipose tissue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in patients with older age, obesity, and diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventative target.


Subject(s)
COVID-19/complications , COVID-19/pathology , Diabetes Mellitus , Obesity/complications , SARS-CoV-2 , Adipose Tissue/metabolism , Adrenergic beta-3 Receptor Agonists/pharmacology , Aged , Aging , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cell Line , Humans , Hyperinsulinism/complications , Hyperinsulinism/drug therapy , Hypoglycemic Agents/pharmacology , Metformin/therapeutic use , Mice , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Up-Regulation , Virus Internalization
17.
Mol Metab ; 55: 101409, 2022 01.
Article in English | MEDLINE | ID: covidwho-1540868

ABSTRACT

BACKGROUND: Chronic disease appears connected to obesity. However, evidence suggests that chronic metabolic diseases are more specifically related to adipose dysfunction rather than to body weight itself. SCOPE OF REVIEW: Further study of the first generation "insulin sensitizer" pioglitazone and molecules based on its structure suggests that is possible to decouple body weight from the metabolic dysfunction that drives adverse outcomes. The growing understanding of the mechanism of action of these agents together with advances in the pathophysiology of chronic metabolic disease offers a new approach to treat chronic conditions, such as type 2 diabetes, fatty liver disease, and their common organ and vascular sequelae. MAJOR CONCLUSIONS: We hypothesize that treating adipocyte dysfunction with new insulin sensitizers might significantly impact the interface of infectious disease and chronic metabolic disease.


Subject(s)
Chronic Disease/drug therapy , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Thiazolidinediones/pharmacology , Adipose Tissue/metabolism , COVID-19 , Diabetes Mellitus, Type 2/metabolism , Humans , Inflammation , Insulin/metabolism , Insulin Resistance , Metabolic Diseases/metabolism , Mitochondria , Non-alcoholic Fatty Liver Disease , Pioglitazone/metabolism
18.
J Cell Mol Med ; 26(1): 228-234, 2022 01.
Article in English | MEDLINE | ID: covidwho-1532813

ABSTRACT

The outbreak of COVID-19 has become a serious public health emergency. The virus targets cells by binding the ACE2 receptor. After infection, the virus triggers in some humans an immune storm containing the release of proinflammatory cytokines and chemokines followed by multiple organ failure. Several vaccines are enrolled, but an effective treatment is still missing. Mesenchymal stem cells (MSCs) have shown to secrete immunomodulatory factors that suppress this cytokine storm. Therefore, MSCs have been suggested as a potential treatment option for COVID-19. We report here that the ACE2 expression is minimal or nonexistent in MSC derived from three different human tissue sources (adipose tissue, umbilical cord Wharton`s jelly and bone marrow). In contrast, TMPRSS2 that is implicated in SARS-CoV-2 entry has been detected in all MSC samples. These results are of particular importance for future MSC-based cell therapies to treat severe cases after COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cytokine Release Syndrome/therapy , Mesenchymal Stem Cell Transplantation/methods , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Adipose Tissue/cytology , Adipose Tissue/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Gene Expression Profiling , Gene Expression Regulation , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Primary Cell Culture , Protein Binding , SARS-CoV-2/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Umbilical Cord/cytology , Umbilical Cord/metabolism
19.
Front Immunol ; 12: 712572, 2021.
Article in English | MEDLINE | ID: covidwho-1472386

ABSTRACT

The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.


Subject(s)
Complement Factor D/antagonists & inhibitors , Complement Pathway, Alternative/drug effects , Molecular Targeted Therapy , Adipose Tissue/metabolism , Aging/immunology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Complement Factor D/biosynthesis , Complement Factor D/deficiency , Complement Factor D/physiology , Energy Metabolism , Geographic Atrophy/genetics , Geographic Atrophy/immunology , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/genetics , Hemoglobinuria, Paroxysmal/immunology , Hepatocytes , Humans , Kidney Diseases/immunology , Liver/injuries , Oligonucleotides, Antisense/therapeutic use , Peptides, Cyclic/therapeutic use , Phagocytosis
20.
Diabetes ; 70(12): 2745-2755, 2021 12.
Article in English | MEDLINE | ID: covidwho-1456233

ABSTRACT

Aging, obesity, and diabetes are major risk factors for the severe progression and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]), but the underlying mechanism is not yet fully understood. In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in humans and mice with older age, obesity, and diabetes. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including metformin, sodium-glucose cotransporter 2 inhibitor, or ß3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue. Environmental interventions, including exercise, calorie restriction, fasting, or cold exposure, reduced the gene expression of GRP78 in adipose tissue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in patients with older age, obesity, and diabetes. The management of hyperinsulinemia and the related GRP78 expression could be a therapeutic or preventative target.


Subject(s)
COVID-19/complications , COVID-19/pathology , Diabetes Mellitus , Obesity/complications , SARS-CoV-2 , Adipose Tissue/metabolism , Adrenergic beta-3 Receptor Agonists/pharmacology , Aged , Aging , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cell Line , Humans , Hyperinsulinism/complications , Hyperinsulinism/drug therapy , Hypoglycemic Agents/pharmacology , Metformin/therapeutic use , Mice , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Up-Regulation , Virus Internalization
SELECTION OF CITATIONS
SEARCH DETAIL