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1.
Sci Rep ; 11(1): 24432, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1585772

ABSTRACT

Despite the initial success of some drugs and vaccines targeting COVID-19, understanding the mechanism underlying SARS-CoV-2 disease pathogenesis remains crucial for the development of further approaches to treatment. Some patients with severe Covid-19 experience a cytokine storm and display evidence of inflammasome activation leading to increased levels of IL-1ß and IL-18; however, other reports have suggested reduced inflammatory responses to Sars-Cov-2. In this study we have examined the effects of the Sars-Cov-2 envelope (E) protein, a virulence factor in coronaviruses, on inflammasome activation and pulmonary inflammation. In cultured macrophages the E protein suppressed inflammasome priming and NLRP3 inflammasome activation. Similarly, in mice transfected with E protein and treated with poly(I:C) to simulate the effects of viral RNA, the E protein, in an NLRP3-dependent fashion, reduced expression of pro-IL-1ß, levels of IL-1ß and IL-18 in broncho-alveolar lavage fluid, and macrophage infiltration in the lung. To simulate the effects of more advanced infection, macrophages were treated with both LPS and poly(I:C). In this setting the E protein increased NLRP3 inflammasome activation in both murine and human macrophages. Thus, the Sars-Cov-2 E protein may initially suppress the host NLRP3 inflammasome response to viral RNA while potentially increasing NLRP3 inflammasome responses in the later stages of infection. Targeting the Sars-Cov-2 E protein especially in the early stages of infection may represent a novel approach to Covid-19 therapy.


Subject(s)
Coronavirus Envelope Proteins/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , Bronchoalveolar Lavage Fluid/chemistry , COVID-19/pathology , COVID-19/virology , Coronavirus Envelope Proteins/genetics , Down-Regulation/drug effects , Endoplasmic Reticulum Stress , Humans , Inflammasomes/drug effects , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Janus Kinases/genetics , Janus Kinases/metabolism , Lipopolysaccharides/pharmacology , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/deficiency , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Poly I-C/pharmacology , RNA, Viral/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
2.
Immunity ; 54(11): 2632-2649.e6, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1549842

ABSTRACT

The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.


Subject(s)
Apolipoprotein L1/genetics , COVID-19/genetics , Genetic Predisposition to Disease/genetics , Sepsis/genetics , Animals , Apolipoprotein L1/blood , COVID-19/pathology , DNA, Mitochondrial/metabolism , Endothelial Cells/metabolism , Humans , Inflammation/genetics , Inflammation/pathology , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , Mitophagy/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Risk Factors , Sepsis/pathology , Severity of Illness Index , /statistics & numerical data
3.
Mol Biol Rep ; 48(12): 8221-8225, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1525563

ABSTRACT

Arglabin (l(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),ll(13)-dien-6,12-olide), is a natural sesquiterpene γ-lactone which was first isolated from Artemisia glabella. The compound has been shown to possess anti-inflammatory activity through inhibition of the NLR Family pyrin domain-containing 3 (NLRP3) inflammasome and production of proinflammatory cytokines including interleukin (IL)-1ß and IL-18. A more hydrophilic derivative of the compound also exhibited antitumor activity in the breast, colon, ovarian, and lung cancer. Some other synthetic derivatives of the compound have also been synthesized with antitumor, cytotoxic, antibacterial, and antifungal activities. Since both NLRP3 inflammasome and cytokine storm are associated with the pathogenesis of COVID-19 and its lethality, compounds like arglabin might have therapeutic potential to attenuate the inflammasome-induced acute respiratory distress syndrome and/or the cytokine storm associated with COVID-19.


Subject(s)
COVID-19/drug therapy , SARS-CoV-2/drug effects , Sesquiterpenes, Guaiane/therapeutic use , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Artemisia , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , Cytokines , Humans , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pandemics , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2/pathogenicity , Sesquiterpenes, Guaiane/chemistry , Sesquiterpenes, Guaiane/metabolism , Signal Transduction/drug effects
4.
Int J Mol Sci ; 22(20)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1470895

ABSTRACT

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies.


Subject(s)
Adaptive Immunity , Autoimmune Diseases/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/isolation & purification
7.
Med Hypotheses ; 146: 110396, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1386308

ABSTRACT

We have reviewed a considerable amount of recent scientific papers relating inflammation caused by air pollution with chronic and severe medical conditions. Furthermore, there are evidences relating organ inflammation caused by not only outdoor long-term but also short-term inhaled radioisotopes contained in high polluted air or in household natural radioactive background aerosols, in addition to SARS-COV-2 attached to bioaerosols, which are related with a worst evolution of severe acute respiratory syndrome patients. Reactive oxygen species (ROS) production induced by the interaction with environmental ionizing radiation contained in pollution is pointed out as a critical mechanism that predispose mainly to elder population, but not excluding young subjects, presenting previous chronic conditions of lung inflammation or neuroinflammation, which can lead to the most serious consequences.


Subject(s)
Air Pollution, Radioactive/adverse effects , COVID-19/etiology , Climate Change , Inflammation/etiology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/pathogenicity , Aerosols , Air Microbiology , COVID-19/mortality , Causality , Humans , Inflammasomes/metabolism , Inflammasomes/radiation effects , Models, Biological , Nervous System Diseases/etiology , Pandemics , Particle Size , Particulate Matter/adverse effects , Pneumonia/etiology
8.
Nat Commun ; 12(1): 4664, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1338538

ABSTRACT

Excessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1ß and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.


Subject(s)
COVID-19/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , Inflammasomes/metabolism , Inflammation/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/virology , Cells, Cultured , Cytokines/metabolism , HEK293 Cells , Humans , Inflammasomes/genetics , Lung Injury/genetics , Lung Injury/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Phosphoproteins/metabolism , Protein Binding , SARS-CoV-2/physiology , THP-1 Cells
9.
EMBO J ; 40(18): e108249, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1323479

ABSTRACT

SARS-CoV-2 is an emerging coronavirus that causes dysfunctions in multiple human cells and tissues. Studies have looked at the entry of SARS-CoV-2 into host cells mediated by the viral spike protein and human receptor ACE2. However, less is known about the cellular immune responses triggered by SARS-CoV-2 viral proteins. Here, we show that the nucleocapsid of SARS-CoV-2 inhibits host pyroptosis by blocking Gasdermin D (GSDMD) cleavage. SARS-CoV-2-infected monocytes show enhanced cellular interleukin-1ß (IL-1ß) expression, but reduced IL-1ß secretion. While SARS-CoV-2 infection promotes activation of the NLRP3 inflammasome and caspase-1, GSDMD cleavage and pyroptosis are inhibited in infected human monocytes. SARS-CoV-2 nucleocapsid protein associates with GSDMD in cells and inhibits GSDMD cleavage in vitro and in vivo. The nucleocapsid binds the GSDMD linker region and hinders GSDMD processing by caspase-1. These insights into how SARS-CoV-2 antagonizes cellular inflammatory responses may open new avenues for treating COVID-19 in the future.


Subject(s)
COVID-19/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nucleocapsid/metabolism , Phosphate-Binding Proteins/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Caspase 1/immunology , Caspase 1/metabolism , HEK293 Cells , Host-Pathogen Interactions , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Intracellular Signaling Peptides and Proteins/immunology , Mice , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Phosphate-Binding Proteins/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , THP-1 Cells
10.
Int J Mol Sci ; 22(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1304667

ABSTRACT

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Alzheimer Disease/metabolism , Animals , Coronavirus/pathogenicity , Humans , Immunity, Innate , Microglia/metabolism , Virus Diseases/immunology , Virus Diseases/pathology
11.
Int J Mol Sci ; 22(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1295856

ABSTRACT

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Alzheimer Disease/metabolism , Animals , Coronavirus/pathogenicity , Humans , Immunity, Innate , Microglia/metabolism , Virus Diseases/immunology , Virus Diseases/pathology
13.
Cytokine Growth Factor Rev ; 61: 2-15, 2021 10.
Article in English | MEDLINE | ID: covidwho-1275255

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called "cytokine storm". Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.


Subject(s)
COVID-19/drug therapy , COVID-19/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/pathogenicity , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/metabolism , Humans , Inflammasomes/drug effects
14.
Elife ; 102021 06 21.
Article in English | MEDLINE | ID: covidwho-1278699

ABSTRACT

Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic diet (KD) impacts immune surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue, and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome, and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.


Subject(s)
Coronavirus Infections/diet therapy , Diet, Ketogenic/methods , Murine hepatitis virus/pathogenicity , Age Factors , Aging , Animals , COVID-19/diet therapy , Coronavirus Infections/metabolism , Coronavirus Infections/mortality , Disease Models, Animal , Glycolysis , Humans , Inflammasomes/metabolism , Ketone Bodies/metabolism , Male , Mice , Mice, Inbred C57BL , Murine hepatitis virus/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2
15.
Eur Rev Med Pharmacol Sci ; 25(10): 3898-3907, 2021 May.
Article in English | MEDLINE | ID: covidwho-1264766

ABSTRACT

The World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) advise cancer survivors to follow their lifestyle recommendations for cancer prevention.  Recent research indicates that a proper diet could exerts beneficial metabolic and immune effects in humans through the involvement of several, not yet properly known, metabolic pathways. Here, we argue that following WCRF/AICR recommendations could be a strategy to prevent cardiovascular outcomes [fulminant myocarditis, heart failure, venous thromboembolism (VTE)] and acute respiratory distress syndrome (ARDS) in patients during follow-up post COVID-19 infection. We discuss the metabolic effects of a WCRF/AICR based diet, highlighting on the involved cardio-metabolic pathways related on NLRP3 inflammasome-cytokines axis aimed to improve prognosis of COVID-19, especially in patients with cancer.


Subject(s)
COVID-19/pathology , Diet , Neoplasms/pathology , Alcohol Drinking , Body Weight , COVID-19/complications , COVID-19/virology , Carbonated Beverages , Cytokines/metabolism , Guidelines as Topic , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Neoplasms/complications , Prognosis , Red Meat , Risk Factors , SARS-CoV-2/isolation & purification , Survivors
16.
Immunity ; 54(7): 1463-1477.e11, 2021 07 13.
Article in English | MEDLINE | ID: covidwho-1263294

ABSTRACT

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1ß production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.


Subject(s)
Adenosine Triphosphate/metabolism , DNA, Mitochondrial/biosynthesis , Inflammasomes/drug effects , Metformin/pharmacology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pneumonia/prevention & control , Animals , COVID-19/metabolism , COVID-19/prevention & control , Cytokines/genetics , Cytokines/metabolism , DNA, Mitochondrial/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides/toxicity , Metformin/therapeutic use , Mice , Nucleoside-Phosphate Kinase/metabolism , Pneumonia/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/prevention & control , SARS-CoV-2/pathogenicity
17.
Molecules ; 25(20)2020 Oct 14.
Article in English | MEDLINE | ID: covidwho-1197553

ABSTRACT

The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune diseases. Hibiscus noldeae Baker f. has been widely reported to be traditionally used in the treatment of different ailments, some of which are of inflammatory background such as asthma, wounds, headache, etc. However, the claims have not been supported by evidence at the molecular and functional levels. Here, we report on the bio-guided fractionation of H. noldeae and assessment of the inhibitory properties of some fractions and purified compounds on NLRP3 inflammasome and Interleukin 6 (IL-6). The activation of the NLRP3 inflammasome was determined by detecting the activity of caspase-1 and the production of Interleukin 1ß (IL-1ß) in Lipopolysaccharide (LPS) and ATP-stimulated Tamm-Horsfall Protein 1 (THP-1) macrophages, while the production of IL-6 was studied in LPS-stimulated RAW264.7 mouse macrophages. It was observed that hexane and ethyl acetate fractions of the crude extract of the aerial parts of H. noldeae, as well as caffeic acid, isoquercetin, and ER2.4 and ER2.7 fractions revealed significant inhibitory effects on Caspase-1 activities, and on IL-1ß and IL-6 production. The ER2.4 and ER2.7 fractions downregulated the production of IL-1ß and IL-6, in a similar range as the caspase-1 inhibitor AC-YVAD-CHO and the drug Dexamethasone, both used as controls, respectively. Overall, our work does provide the very first scientific based evidence for Hibiscus noldeae anti-inflammatory effects and widespread use by traditional healers in Rwanda for a variety of ailments.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Hibiscus/chemistry , Inflammasomes/drug effects , Inflammation/drug therapy , Interleukin-6/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , Plant Extracts/pharmacology , Animals , Inflammasomes/immunology , Inflammasomes/metabolism , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Interleukin-6/metabolism , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , RAW 264.7 Cells
18.
Int J Mol Sci ; 22(5)2021 Mar 04.
Article in English | MEDLINE | ID: covidwho-1125259

ABSTRACT

Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).


Subject(s)
COVID-19/therapy , Hydrogen/pharmacology , Hydrogen/therapeutic use , Inflammation/therapy , Mitochondria/physiology , Animals , Chronic Disease , Humans , Inflammation/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism
19.
Int J Mol Sci ; 22(2)2021 Jan 16.
Article in English | MEDLINE | ID: covidwho-1040994

ABSTRACT

The inflammasome is a three-component (sensor, adaptor, and effector) filamentous signaling platform that shields from multiple pathogenic infections by stimulating the proteolytical maturation of proinflammatory cytokines and pyroptotic cell death. The signaling process initiates with the detection of endogenous and/or external danger signals by specific sensors, followed by the nucleation and polymerization from sensor to downstream adaptor and then to the effector, caspase-1. Aberrant activation of inflammasomes promotes autoinflammatory diseases, cancer, neurodegeneration, and cardiometabolic disorders. Therefore, an equitable level of regulation is required to maintain the equilibrium between inflammasome activation and inhibition. Recent advancement in the structural and mechanistic understanding of inflammasome assembly potentiates the emergence of novel therapeutics against inflammasome-regulated diseases. In this review, we have comprehensively discussed the recent and updated insights into the structure of inflammasome components, their activation, interaction, mechanism of regulation, and finally, the formation of densely packed filamentous inflammasome complex that exists as micron-sized punctum in the cells and mediates the immune responses.


Subject(s)
DNA-Binding Proteins/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Animals , CARD Signaling Adaptor Proteins/chemistry , CARD Signaling Adaptor Proteins/metabolism , Caspase 1/chemistry , Caspase 1/metabolism , DNA-Binding Proteins/chemistry , Humans , Inflammasomes/chemistry , NLR Family, Pyrin Domain-Containing 3 Protein/chemistry , Protein Domains , Protein Multimerization
20.
Nutrients ; 13(1)2020 Dec 25.
Article in English | MEDLINE | ID: covidwho-1016213

ABSTRACT

Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1ß and pro-interleukin-18 to active interleukin-1ß and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation-including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity-antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.


Subject(s)
Antioxidants/therapeutic use , COVID-19 , Dietary Supplements , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/diet therapy , COVID-19/metabolism , COVID-19/pathology , Humans
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