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1.
Biomolecules ; 12(4)2022 03 31.
Article in English | MEDLINE | ID: covidwho-1776123

ABSTRACT

Intercellular communication between monocytes/macrophages and cells involved in tissue regeneration, such as mesenchymal stromal cells (MSCs) and primary tissue cells, is essential for tissue regeneration and recovery of homeostasis. Typically, in the final phase of the inflammation-resolving process, this intercellular communication drives an anti-inflammatory immunomodulatory response. To obtain a safe and effective treatment to counteract the cytokine storm associated with a disproportionate immune response to severe infections, including that associated with COVID-19, by means of naturally balanced immunomodulation, our group has standardized the production under GMP-like conditions of a secretome by coculture of macrophages and MSCs. To characterize this proteome, we determined the expression of molecules related to cellular immune response and tissue regeneration, as well as its possible toxicity and anti-inflammatory potency. The results show a specific molecular pattern of interaction between the two cell types studied, with an anti-inflammatory and regenerative profile. In addition, the secretome is not toxic by itself on human PBMC or on THP-1 monocytes and prevents lipopolysaccharide (LPS)-induced growth effects on those cell types. Finally, PRS CK STORM prevents LPS-induced TNF-A and IL-1Β secretion from PBMC and from THP-1 cells at the same level as hydrocortisone, demonstrating its anti-inflammatory potency.


Subject(s)
COVID-19 , Mesenchymal Stem Cells , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Coculture Techniques , Culture Media, Conditioned/pharmacology , Humans , Leukocytes, Mononuclear , Lipopolysaccharides/pharmacology , Monocytes
2.
J Control Release ; 345: 214-230, 2022 05.
Article in English | MEDLINE | ID: covidwho-1747828

ABSTRACT

Mesenchymal stem cell-derived small extracellular vesicles (MSC-EVs) are promising nanotherapeutic agent for pneumonia (bacterial origin, COVID-19), but the optimal administration route and potential mechanisms of action remain poorly understood. This study compared the administration of MSC-EVs via inhalation and tail vein injection for the treatment of acute lung injury (ALI) and determined the host-derived mechanisms that may contribute to the therapeutic effects of MSC-EVs in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells (macrophage cell line) and animal models. Luminex liquid chip and hematoxylin and eosin (HE) staining revealed that, compared with the vehicle control, inhaled MSC-EVs outperformed those injected via the tail vein, by reducing the expression of pro-inflammatory cytokines, increasing the expression of anti-inflammatory cytokine, and decreasing pathological scores in ALI. MSC-EV administration promoted the polarization of macrophages towards a M2 phenotype in vitro and in vivo (via inhalation). RNA sequencing revealed that immune and redox mediators, including TLR4, Arg1, and HO-1, were associated with the activity MSC-EVs against ALI mice. Western blotting and immunofluorescence revealed that correlative inflammatory and oxidative mediators were involved in the therapeutic effects of MSC-EVs in LPS-stimulated cells and mice. Moreover, variable expression of Nrf2 was observed following treatment with MSC-EVs in cell and animal models, and knockdown of Nrf2 attenuated the anti-inflammatory and antioxidant activities of MSC-EVs in LPS-stimulated macrophages. Together, these data suggest that inhalation of MSC-EVs as a noninvasive strategy for attenuation of ALI, and the adaptive regulation of Nrf2 may contribute to their anti-inflammatory and anti-oxidant activity in mice.


Subject(s)
Acute Lung Injury , COVID-19 , Extracellular Vesicles , Mesenchymal Stem Cells , Acute Lung Injury/therapy , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/therapeutic use , Antioxidants , Cytokines/metabolism , Disease Models, Animal , Extracellular Vesicles/metabolism , Lipopolysaccharides , Mesenchymal Stem Cells/metabolism , Mice , NF-E2-Related Factor 2/metabolism
3.
Molecules ; 27(5)2022 Mar 03.
Article in English | MEDLINE | ID: covidwho-1732130

ABSTRACT

Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Docosahexaenoic Acids/metabolism , Inflammation/prevention & control , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/metabolism , COVID-19/drug therapy , COVID-19/virology , Docosahexaenoic Acids/biosynthesis , Docosahexaenoic Acids/chemical synthesis , Docosahexaenoic Acids/chemistry , Docosahexaenoic Acids/therapeutic use , Drug Design , Humans , Inflammation/pathology , SARS-CoV-2/isolation & purification
4.
Front Immunol ; 12: 769011, 2021.
Article in English | MEDLINE | ID: covidwho-1650341

ABSTRACT

Asthma patients may increase their susceptibility to SARS-CoV-2 infection and the poor prognosis of coronavirus disease 2019 (COVID-19). However, anti-COVID-19/asthma comorbidity approaches are restricted on condition. Existing evidence indicates that luteolin has antiviral, anti-inflammatory, and immune regulation capabilities. We aimed to evaluate the possibility of luteolin evolving into an ideal drug and explore the underlying molecular mechanisms of luteolin against COVID-19/asthma comorbidity. We used system pharmacology and bioinformatics analysis to assess the physicochemical properties and biological activities of luteolin and further analyze the binding activities, targets, biological functions, and mechanisms of luteolin against COVID-19/asthma comorbidity. We found that luteolin may exert ideal physicochemical properties and bioactivity, and molecular docking analysis confirmed that luteolin performed effective binding activities in COVID-19/asthma comorbidity. Furthermore, a protein-protein interaction network of 538 common targets between drug and disease was constructed and 264 hub targets were obtained. Then, the top 6 hub targets of luteolin against COVID-19/asthma comorbidity were identified, namely, TP53, AKT1, ALB, IL-6, TNF, and VEGFA. Furthermore, the enrichment analysis suggested that luteolin may exert effects on virus defense, regulation of inflammation, cell growth and cell replication, and immune responses, reducing oxidative stress and regulating blood circulation through the Toll-like receptor; MAPK, TNF, AGE/RAGE, EGFR, ErbB, HIF-1, and PI3K-AKT signaling pathways; PD-L1 expression; and PD-1 checkpoint pathway in cancer. The possible "dangerous liaison" between COVID-19 and asthma is still a potential threat to world health. This research is the first to explore whether luteolin could evolve into a drug candidate for COVID-19/asthma comorbidity. This study indicated that luteolin with superior drug likeness and bioactivity has great potential to be used for treating COVID-19/asthma comorbidity, but the predicted results still need to be rigorously verified by experiments.


Subject(s)
Anti-Inflammatory Agents/metabolism , Antioxidants/metabolism , Antiviral Agents/metabolism , Asthma/epidemiology , Asthma/metabolism , COVID-19/epidemiology , COVID-19/metabolism , Immunologic Factors/metabolism , Luteolin/metabolism , SARS-CoV-2/metabolism , Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Antiviral Agents/chemistry , Comorbidity , Computational Biology/methods , Drug Discovery/methods , Humans , Immunologic Factors/chemistry , Interleukin-6/metabolism , Luteolin/chemistry , Molecular Docking Simulation , Protein Interaction Maps/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Serum Albumin, Human/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolism , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factor A/metabolism
5.
Mar Drugs ; 19(10)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1485164

ABSTRACT

Inflammation is the body's defense reaction in response to stimulations and is the basis of various physiological and pathological processes. However, chronic inflammation is undesirable and closely related to the occurrence and development of diseases. The ocean gives birth to unique and diverse bioactive substances, which have gained special attention and been a focus for anti-inflammatory drug development. So far, numerous promising bioactive substances have been obtained from various marine organisms such as marine bacteria and fungi, sponges, algae, and coral. This review covers 71 bioactive substances described during 2015-2020, including the structures (65 of which), species sources, evaluation models and anti-inflammatory activities of these substances. This review aims to provide some reference for the research progress of marine-organism-derived anti-inflammatory metabolites and give more research impetus for their conversion to novel anti-inflammatory drugs.


Subject(s)
Anti-Inflammatory Agents/metabolism , Aquatic Organisms , Biological Products , Animals , Anthozoa , Anti-Inflammatory Agents/chemistry , Humans , Inflammation/prevention & control , Microalgae , Porifera , Research
6.
Int J Mol Sci ; 22(19)2021 Sep 28.
Article in English | MEDLINE | ID: covidwho-1444229

ABSTRACT

Extracellular vesicles (EVs) carry important biomolecules, including metabolites, and contribute to the spread and pathogenesis of some viruses. However, to date, limited data are available on EV metabolite content that might play a crucial role during infection with the SARS-CoV-2 virus. Therefore, this study aimed to perform untargeted metabolomics to identify key metabolites and associated pathways that are present in EVs, isolated from the serum of COVID-19 patients. The results showed the presence of antivirals and antibiotics such as Foscarnet, Indinavir, and lymecycline in EVs from patients treated with these drugs. Moreover, increased levels of anti-inflammatory metabolites such as LysoPS, 7-α,25-Dihydroxycholesterol, and 15-d-PGJ2 were detected in EVs from COVID-19 patients when compared with controls. Further, we found decreased levels of metabolites associated with coagulation, such as thromboxane and elaidic acid, in EVs from COVID-19 patients. These findings suggest that EVs not only carry active drug molecules but also anti-inflammatory metabolites, clearly suggesting that exosomes might play a crucial role in negotiating with heightened inflammation during COVID-19 infection. These preliminary results could also pave the way for the identification of novel metabolites that might act as critical regulators of inflammatory pathways during viral infections.


Subject(s)
COVID-19/metabolism , Extracellular Vesicles/metabolism , Metabolome , SARS-CoV-2/physiology , Adult , Anti-Inflammatory Agents/metabolism , COVID-19/pathology , Extracellular Vesicles/pathology , Female , Humans , Male , Metabolomics , Middle Aged
7.
Front Immunol ; 12: 714177, 2021.
Article in English | MEDLINE | ID: covidwho-1444042

ABSTRACT

Sepsis continues to be a major cause of morbidity, mortality, and post-recovery disability in patients with a wide range of non-infectious and infectious inflammatory disorders, including COVID-19. The clinical onset of sepsis is often marked by the explosive release into the extracellular fluids of a multiplicity of host-derived cytokines and other pro-inflammatory hormone-like messengers from endogenous sources ("cytokine storm"). In patients with sepsis, therapies to counter the pro-inflammatory torrent, even when administered early, typically fall short. The major focus of our proposed essay is to promote pre-clinical studies with hCG (human chorionic gonadotropin) as a potential anti-inflammatory therapy for sepsis.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Chorionic Gonadotropin/therapeutic use , Peptides/therapeutic use , Sepsis/drug therapy , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/metabolism , Bacteria/metabolism , Chorionic Gonadotropin/chemistry , Chorionic Gonadotropin/metabolism , Cytokine Release Syndrome/drug therapy , Glycoproteins/chemistry , Glycoproteins/metabolism , Humans , Inflammation , Peptides/chemistry , Peptides/metabolism
8.
J Biol Chem ; 296: 100630, 2021.
Article in English | MEDLINE | ID: covidwho-1333548

ABSTRACT

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Immunologic Factors/pharmacology , Interleukin-18/genetics , Receptors, Interleukin-18/genetics , Anti-Inflammatory Agents/metabolism , Antibodies, Monoclonal/biosynthesis , Antibodies, Neutralizing/biosynthesis , COVID-19/drug therapy , Candida albicans/growth & development , Candida albicans/pathogenicity , Gene Expression Regulation , HEK293 Cells , Humans , Immunologic Factors/biosynthesis , Inflammation , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-18/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/microbiology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophage Activation Syndrome/drug therapy , NF-kappa B/genetics , NF-kappa B/immunology , Primary Cell Culture , Receptors, Interleukin-18/antagonists & inhibitors , Receptors, Interleukin-18/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
9.
Int J Mol Sci ; 22(15)2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1325685

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively.


Subject(s)
COVID-19/metabolism , NF-E2-Related Factor 2/metabolism , Neoplasms/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , COVID-19/drug therapy , Humans , NF-E2-Related Factor 2/chemistry , Neoplasms/drug therapy , Signal Transduction
11.
Plant J ; 107(5): 1299-1319, 2021 09.
Article in English | MEDLINE | ID: covidwho-1282039

ABSTRACT

Caffeoylquinic acids (CQAs) are specialized plant metabolites we encounter in our daily life. Humans consume CQAs in mg-to-gram quantities through dietary consumption of plant products. CQAs are considered beneficial for human health, mainly due to their anti-inflammatory and antioxidant properties. Recently, new biosynthetic pathways via a peroxidase-type p-coumaric acid 3-hydroxylase enzyme were discovered. More recently, a new GDSL lipase-like enzyme able to transform monoCQAs into diCQA was identified in Ipomoea batatas. CQAs were recently linked to memory improvement; they seem to be strong indirect antioxidants via Nrf2 activation. However, there is a prevalent confusion in the designation and nomenclature of different CQA isomers. Such inconsistencies are critical and complicate bioactivity assessment since different isomers differ in bioactivity and potency. A detailed explanation regarding the origin of such confusion is provided, and a recommendation to unify nomenclature is suggested. Furthermore, for studies on CQA bioactivity, plant-based laboratory animal diets contain CQAs, which makes it difficult to include proper control groups for comparison. Therefore, a synthetic diet free of CQAs is advised to avoid interferences since some CQAs may produce bioactivity even at nanomolar levels. Biotransformation of CQAs by gut microbiota, the discovery of new enzymatic biosynthetic and metabolic pathways, dietary assessment, and assessment of biological properties with potential for drug development are areas of active, ongoing research. This review is focused on the chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity recently reported for mono-, di-, tri-, and tetraCQAs.


Subject(s)
Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Cognitive Dysfunction/prevention & control , Neuroprotective Agents/chemistry , Phytochemicals/chemistry , Plants, Medicinal/chemistry , Quinic Acid/analogs & derivatives , Acyltransferases/genetics , Acyltransferases/metabolism , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Biosynthetic Pathways , Brachypodium/enzymology , Dietary Supplements , Humans , Ipomoea batatas/enzymology , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Phytochemicals/metabolism , Phytochemicals/pharmacology , Plant Proteins/genetics , Plant Proteins/metabolism , Quinic Acid/chemistry , Quinic Acid/metabolism , Quinic Acid/pharmacology , Terminology as Topic
12.
Molecules ; 26(11)2021 Jun 02.
Article in English | MEDLINE | ID: covidwho-1259548

ABSTRACT

In December 2020, the U.K. authorities reported to the World Health Organization (WHO) that a new COVID-19 variant, considered to be a variant under investigation from December 2020 (VUI-202012/01), was identified through viral genomic sequencing. Although several other mutants were previously reported, VUI-202012/01 proved to be about 70% more transmissible. Hence, the usefulness and effectiveness of the newly U.S. Food and Drug Administration (FDA)-approved COVID-19 vaccines against these new variants are doubtfully questioned. As a result of these unexpected mutants from COVID-19 and due to lack of time, much research interest is directed toward assessing secondary metabolites as potential candidates for developing lead pharmaceuticals. In this study, a marine-derived fungus Aspergillus terreus was investigated, affording two butenolide derivatives, butyrolactones I (1) and III (2), a meroterpenoid, terretonin (3), and 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde (4). Chemical structures were unambiguously determined based on mass spectrometry and extensive 1D/2D NMR analyses experiments. Compounds (1-4) were assessed for their in vitro anti-inflammatory, antiallergic, and in silico COVID-19 main protease (Mpro) and elastase inhibitory activities. Among the tested compounds, only 1 revealed significant activities comparable to or even more potent than respective standard drugs, which makes butyrolactone I (1) a potential lead entity for developing a new remedy to treat and/or control the currently devastating and deadly effects of COVID-19 pandemic and elastase-related inflammatory complications.


Subject(s)
4-Butyrolactone/analogs & derivatives , Anti-Allergic Agents/chemistry , Anti-Inflammatory Agents/chemistry , Aspergillus/chemistry , SARS-CoV-2/enzymology , Viral Matrix Proteins/antagonists & inhibitors , 4-Butyrolactone/chemistry , 4-Butyrolactone/isolation & purification , 4-Butyrolactone/metabolism , Anti-Allergic Agents/metabolism , Anti-Inflammatory Agents/metabolism , Aspergillus/growth & development , Aspergillus/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Catalytic Domain , Humans , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/metabolism , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Docking Simulation , Neutrophils/enzymology , SARS-CoV-2/isolation & purification , Seawater/microbiology , Viral Matrix Proteins/metabolism
13.
Eur J Med Chem ; 221: 113514, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1228023

ABSTRACT

While anti-inflammatory properties of isocoumarins are known their PDE4 inhibitory potential was not explored previously. In our effort the non-PDE4 inhibitor isocoumarins were transformed into the promising inhibitors via introducing an aminosulfonyl/aminocarboxamide moiety to the C-3 benzene ring attached to the isocoumarin framework. This new class of isocoumarins were synthesized via a PdCl2-catalyzed construction of the 4-allyl substituted 3-aryl isocoumarin ring starting from the appropriate 2-alkynyl benzamide derivative. Several compounds showed good inhibition of PDE4B in vitro and the SAR indicated superiority of aminosulfonamide moiety over aminocarboxamide in terms of PDE4B inhibition. Two compounds 3q and 3u with PDE4B IC50 = 0.43 ± 0.11 and 0.54 ± 0.19 µM and ≥ 2-fold selectivity over PDE4D emerged as initial hits. The participation of aminosulfonamide moiety in PDE4B inhibition and the reason for selectivity though moderate shown by 3q and 3u was revealed by the in silico docking studies. In view of potential usefulness of moderately selective PDE4B inhibitors the compound 3u (that showed PDE4 selectivity over other PDEs) was further evaluated in adjuvant induced arthritic rats. At an intraperitoneal dose of 30 mg/kg the compound showed a significant reduction in paw swelling (in a dose dependent manner), inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels and increase in body weight. Moreover, besides its TNF-α inhibition and no significant toxicity in an MTT assay the compound did not show any adverse effects in a thorough toxicity studies e.g. teratogenicity, hepatotoxicity, cardiotoxicity and apoptosis in zebrafish. Thus, the isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Isocoumarins/therapeutic use , Phosphodiesterase 4 Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/toxicity , Arthritis, Experimental/pathology , Catalysis , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Embryo, Nonmammalian/drug effects , Female , Isocoumarins/chemical synthesis , Isocoumarins/metabolism , Isocoumarins/toxicity , Knee Joint/drug effects , Knee Joint/pathology , Male , Mice , Molecular Docking Simulation , Molecular Structure , Palladium/chemistry , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/metabolism , Phosphodiesterase 4 Inhibitors/toxicity , Protein Binding , RAW 264.7 Cells , Rats, Wistar , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Sulfonamides/toxicity , Zebrafish
14.
Int J Immunopathol Pharmacol ; 35: 20587384211005645, 2021.
Article in English | MEDLINE | ID: covidwho-1156054

ABSTRACT

Protective effects of peroxiredoxin 6 (PRDX6) in RIN-m5F ß-cells and of thymulin in mice with alloxan-induced diabetes were recently reported. The present work was aimed at studying the efficiency of thymulin and PRDX6 in a type 1 diabetes mellitus model induced by streptozotocin in mice. Effects of prolonged treatment with PRDX6 or thymic peptide thymulin on diabetes development were evaluated. We assessed the effects of the drugs on the physiological status of diabetic mice by measuring blood glucose, body weight, and cell counts in several organs, as well as effects of thymulin and PRDX6 on the immune status of diabetic mice measuring concentrations of pro-inflammatory cytokines in blood plasma (TNF-α, interleukin-5 and 17, and interferon-γ), activity of NF-κB and JNK pathways, and Hsp90α expression in immune cells. Both thymulin and PRDX6 reduced the physiological impairments in diabetic mice at various levels. Thymulin and PRDX6 provide beneficial effects in the model of diabetes via very different mechanisms. Taken together, the results of our study indicated that the thymic peptide and the antioxidant enzyme have anti-inflammatory functions. As increasing evidences show diabetes mellitus as a distinct comorbidity leading to acute respiratory distress syndrome and increased mortality in patients with COVID-19 having cytokine storm, thymulin, and PRDX6 might serve as a supporting anti-inflammatory treatment in the therapy of COVID 19 in diabetic patients.


Subject(s)
COVID-19 , MAP Kinase Kinase 4/metabolism , NF-kappa B/metabolism , Peroxiredoxin VI , Signal Transduction , Thymic Factor, Circulating , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/immunology , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/therapy , Drug Discovery , Interferon-gamma/blood , Interleukins/blood , Mice , Peroxiredoxin VI/metabolism , Peroxiredoxin VI/pharmacology , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/immunology , Thymic Factor, Circulating/metabolism , Thymic Factor, Circulating/pharmacology , Tumor Necrosis Factor-alpha/blood
15.
Biochimie ; 184: 95-103, 2021 May.
Article in English | MEDLINE | ID: covidwho-1101114

ABSTRACT

Coronavirus Disease 2019 or COVID-19 have infected till day 82,579,768 confirmed cases including 1,818,849 deaths, reported by World Health Organization WHO. COVID-19, originated by Severe Acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), contributes to respiratory distress in addition to neurological symptoms in some patients. In the current review, we focused on the neurological complications associated with COVID-19. We discussed different pathways followed by RNA-virus, especially Flaviviridae family in the brain and passage through the Blood-Brain-Barrier BBB. Then, we explored SARS-CoV-2 mechanisms responsible of neuroinvasion and BBB disruption as well as the immunopathogenesis of SARS-CoV-2 in the central nervous system CNS. Since SARS-CoV-2 is an enveloped virus, enclosed in a lipid bilayer and that lipids are essential cell components playing numerous biological roles in viral infection and replication, we investigated the lipid metabolism remodeling upon coronavirus replication. We also highlighted the anti-inflammatory and neuroprotective potential of an omega-3 polyunsaturated fatty acid, docosahexaenoic acid DHA, as well as several bioactive lipid mediators. Altogether, our data allow better understanding of SARS-CoV-2 neuroinvasion and could assist in drug targeting to decline the burden of short-term and long-term neurological manifestations of SARS-CoV-2.


Subject(s)
Blood-Brain Barrier/virology , COVID-19/complications , Central Nervous System Diseases/virology , Docosahexaenoic Acids/metabolism , SARS-CoV-2/metabolism , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/therapeutic use , Blood-Brain Barrier/metabolism , Brain/virology , COVID-19/drug therapy , COVID-19/metabolism , Central Nervous System Diseases/metabolism , Docosahexaenoic Acids/therapeutic use , Flaviviridae/metabolism , Humans , Lipid Metabolism , Neuroprotective Agents/metabolism , Neuroprotective Agents/therapeutic use
16.
Drug Dev Res ; 82(1): 7-11, 2021 02.
Article in English | MEDLINE | ID: covidwho-923258

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 is a deadly disease afflicting millions. The pandemic continues affecting population due to nonavailability of drugs and vaccines. The pathogenesis and complications of infection mainly involve hyperimmune-inflammatory responses. Thus, therapeutic strategies rely on repurposing of drugs aimed at reducing infectivity and inflammation and modulate immunity favourably. Among, numerous therapeutic targets, the endocannabinoid system, particularly activation of cannabinoid type-2 receptors (CB2R) emerged as an important one to suppress the hyperimmune-inflammatory responses. Recently, potent antiinflammatory, antiviral and immunomodulatory properties of CB2R selective ligands of endogenous, plant, and synthetic origin were showed mediating CB2R selective functional agonism. CB2R activation appears to regulate numerous signaling pathways to control immune-inflammatory mediators including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Many CB2R ligands also exhibit off-target effects mediating activation of PPARs, opioids, and TRPV, suggestive of adjuvant use with existing drugs that may maximize efficacy synergistically and minimize therapeutic doses to limit adverse/ side effects. We hypothesize that CB2R agonists, due to immunomodulatory, antiinflammatory, and antiviral properties may show activity against COVID-19. Based on the organoprotective potential, relative safety, lack of psychotropic effects, and druggable properties, CB2R selective ligands might make available promising candidates for further investigation.


Subject(s)
COVID-19/drug therapy , Cannabinoid Receptor Agonists/administration & dosage , Drug Delivery Systems/methods , Immunity, Cellular/drug effects , Receptor, Cannabinoid, CB2/agonists , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/metabolism , COVID-19/immunology , COVID-19/metabolism , Cannabinoid Receptor Agonists/metabolism , Humans , Immunity, Cellular/physiology , Inflammation/drug therapy , Inflammation/immunology , Inflammation/metabolism , Receptor, Cannabinoid, CB2/immunology , Receptor, Cannabinoid, CB2/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism
17.
EBioMedicine ; 59: 102969, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-728523

ABSTRACT

Coronavirus disease-2019 (COVID-19) is associated with severe inflammation in mainly the lung, and kidney. Reports suggest a beneficial effect of the use of heparin/low molecular weight heparin (LMWH) on mortality in COVID-19. In part, this beneficial effect could be explained by the anticoagulant properties of heparin/LMWH. Here, we summarise potential beneficial, non-anticoagulant mechanisms underlying treatment of COVID-19 patients with heparin/LMWH, which include: (i) Inhibition of heparanase activity, responsible for endothelial leakage; (ii) Neutralisation of chemokines, and cytokines; (iii) Interference with leukocyte trafficking; (iv) Reducing viral cellular entry, and (v) Neutralisation of extracellular cytotoxic histones. Considering the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of heparin/LMWH in COVID-19 patients. In addition, identification of specific heparin-derived sequences that are functional in targeting non-anticoagulant mechanisms may have even higher therapeutic potential for COVID-19 patients, and patients suffering from other inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Coronavirus Infections/drug therapy , Heparin/therapeutic use , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Glucuronidase/antagonists & inhibitors , Glucuronidase/metabolism , Heparin/metabolism , Heparin/pharmacology , Heparin, Low-Molecular-Weight/metabolism , Heparin, Low-Molecular-Weight/pharmacology , Heparin, Low-Molecular-Weight/therapeutic use , Histones/blood , Histones/metabolism , Humans , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Virus Internalization/drug effects
18.
ACS Chem Neurosci ; 11(15): 2137-2144, 2020 08 05.
Article in English | MEDLINE | ID: covidwho-636269
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