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1.
Cell Rep Med ; 3(6): 100652, 2022 06 21.
Article in English | MEDLINE | ID: covidwho-1960088

ABSTRACT

Disease recovery dynamics are often difficult to assess, as patients display heterogeneous recovery courses. To model recovery dynamics, exemplified by severe COVID-19, we apply a computational scheme on longitudinally sampled blood transcriptomes, generating recovery states, which we then link to cellular and molecular mechanisms, presenting a framework for studying the kinetics of recovery compared with non-recovery over time and long-term effects of the disease. Specifically, a decrease in mature neutrophils is the strongest cellular effect during recovery, with direct implications on disease outcome. Furthermore, we present strong indications for global regulatory changes in gene programs, decoupled from cell compositional changes, including an early rise in T cell activation and differentiation, resulting in immune rebalancing between interferon and NF-κB activity and restoration of cell homeostasis. Overall, we present a clinically relevant computational framework for modeling disease recovery, paving the way for future studies of the recovery dynamics in other diseases and tissues.


Subject(s)
COVID-19 , NF-kappa B , Cell Differentiation , Humans , Interferons/metabolism , NF-kappa B/genetics , Neutrophils/metabolism , Signal Transduction
2.
Int J Mol Sci ; 23(11)2022 May 25.
Article in English | MEDLINE | ID: covidwho-1953485

ABSTRACT

The novel SARS-CoV-2 Omicron variant B.1.1.529, which emerged in late 2021, is currently active worldwide, replacing other variants, including the Delta variant, due to an enormously increased infectivity. Multiple substitutions and deletions in the N-terminal domain (NTD) and the receptor binding domain (RBD) in the spike protein collaborate with the observed increased infectivity and evasion from therapeutic monoclonal antibodies and vaccine-induced neutralizing antibodies after primary/secondary immunization. In contrast, although three mutations near the S1/S2 furin cleavage site were predicted to favor cleavage, observed cleavage efficacy is substantially lower than in the Delta variant and also lower compared to the wild-type virus correlating with significantly lower TMPRSS2-dependent replication in the lungs, and lower cellular syncytium formation. In contrast, the Omicron variant shows high TMPRSS2-independent replication in the upper airway organs, but lower pathogenicity in animal studies and clinics. Based on recent data, we present here a hypothesis proposing that the changed charge distribution in the Omicron's spike protein could lead to lower activation of Toll-like receptors (TLRs) in innate immune cells, resulting in lower NF-κB activation, furin expression, and viral replication in the lungs, and lower immune hyper-activation.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Furin/genetics , Furin/metabolism , NF-kappa B , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptors , Virulence
3.
Int J Mol Sci ; 23(9)2022 May 09.
Article in English | MEDLINE | ID: covidwho-1953474

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 19 (COVID-19), a disease that has affected more than 500 million people worldwide since the end of 2019. Due to its high complications and death rates, there is still a need to find the best therapy for SARS-CoV-2 infection. The dysregulation of the inflammatory response in COVID-19 plays a very important role in disease progression. It has been observed that abnormal activity of Nuclear Factor kappa B (NF-κB) is directly associated with, inter alia, increased synthesis of proinflammatory factors. Therefore, this review paper focuses on the functions of NF-κB in the development of SARS-CoV-2 infection and potential application of NF-κB inhibitors in COVID-19 immunotherapy. A comprehensive literature search was performed using the MEDLINE/PubMed database. In the current review, it is highlighted that NF-κB plays important functions in the modulation of an adaptive inflammatory response, including inducing the expression of proinflammatory genes. Increased activation of NF-κB in SARS-CoV-2 infection was observed. The association between NF-κB activation and the expression of SARS-CoV-2 structural and non-structural proteins were also reported. It was observed that modulation of NF-κB using, e.g., traditional Chinese medicine or glucocorticosteroids resulted in decreased synthesis of proinflammatory factors caused by SARS-CoV-2 infection. This review summarizes the role of NF-κB in COVID-19 and describes its potential immunotherapeutic target in treatment of SARS-CoV-2 infection. However, indisputably more studies involving patients with a severe course of COVID-19 are sorely needed.


Subject(s)
COVID-19/pathology , NF-kappa B/metabolism , COVID-19/drug therapy , COVID-19/immunology , Humans , Inflammation/pathology , SARS-CoV-2
4.
Molecules ; 27(13)2022 Jun 23.
Article in English | MEDLINE | ID: covidwho-1934172

ABSTRACT

Iron plays a critical role in the immune response to inflammation and infection due to its role in the catalysis of reactive oxygen species (ROS) through the Haber-Weiss and Fenton reactions. However, ROS overproduction can be harmful and damage healthy cells. Therefore, iron chelation represents an innovative pharmacological approach to limit excess ROS formation and the related pro-inflammatory mediator cascades. The present study was designed to investigate the impact of the iron chelator, DIBI, in an experimental model of LPS-induced acute lung injury (ALI). DIBI was administered intraperitoneally in the early and later stages of lung inflammation as determined by histopathological evaluation. We found that lung tissues showed significant injury, as well as increased NF-κB p65 activation and significantly elevated levels of various inflammatory mediators (LIX, CXCL2, CCL5, CXCL10, IL-1𝛽, IL-6) 4 h post ALI induction by LPS. Mice treated with DIBI (80 mg/kg) in the early stages (0 to 2 h) after LPS administration demonstrated a significant reduction of the histopathological damage score, reduced levels of NF-κB p65 activation, and reduced levels of inflammatory mediators. Intravital microscopy of the pulmonary microcirculation also showed a reduced number of adhering leukocytes and improved capillary perfusion with DIBI administration. Our findings support the conclusion that the iron chelator, DIBI, has beneficial anti-inflammatory effects in experimental ALI.


Subject(s)
Acute Lung Injury , Lipopolysaccharides , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Inflammation Mediators , Iron Chelating Agents/pharmacology , Iron Chelating Agents/therapeutic use , Lipopolysaccharides/pharmacology , Lung , Mice , NF-kappa B , Pyridines , Reactive Oxygen Species
5.
BMC Neurosci ; 23(1): 43, 2022 07 06.
Article in English | MEDLINE | ID: covidwho-1928160

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious, and the neurological symptoms of SARS-CoV-2 infection have already been reported. However, the mechanisms underlying the effect of SARS-CoV-2 infection on patients with central nervous system injuries remain unclear. METHODS: The high-throughput RNA sequencing was applied to analyze the transcriptomic changes in SK-N-SH cells after SARS-CoV-2 infection. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to identify the functions of differentially expressed genes and related pathways. RESULTS: A total of 820 mRNAs were significantly altered, including 671 upregulated and 149 downregulated mRNAs (showing an increase of ≥ 2-fold or decrease to ≤ 0.5-fold, respectively; p ≤ 0.05). Moreover, we verified the significant induction of cytokines, chemokines, and their receptors, as well as the activation of NF-κB, p38, and Akt signaling pathways, in SK-N-SH by SARS-CoV-2. CONCLUSIONS: To our knowledge, this is the first time the transcriptional profiles of the host mRNAs involved in SARS-CoV-2 infection of SK-N-SH cells have been reported. These findings provide novel insight into the pathogenic mechanism of SARS-CoV-2 and might constitute a new approach for future prevention and treatment of SARS-CoV-2-induced central nervous system infection.


Subject(s)
COVID-19 , Neuroblastoma , Cytokines , Humans , NF-kappa B , RNA, Messenger/metabolism , SARS-CoV-2
6.
Nutrients ; 14(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1917652

ABSTRACT

Black rice is a functional food that is high in anthocyanin content, primarily C3G and P3G. It possesses nutraceutical properties that exhibit a range of beneficial effects on human health. Currently, the spike glycoprotein S1 subunit of SARS-CoV-2 (SP) has been reported for its contribution to pathological inflammatory responses in targeting lung tissue and innate immune cells during COVID-19 infection and in the long-COVID phenomenon. Our objectives focused on the health benefits of the C3G and P3G-rich fraction of black rice germ and bran (BR extract) on the inhibition of inflammatory responses induced by SP, as well as the inhibition of NF-kB activation and the NLRP3 inflammasome pathway in an in vitro model. In this study, BR extract was identified for its active anthocyanins, C3G and P3G, using the HPLC technique. A549-lung cells and differentiated THP-1 macrophages were treated with BR extract, C3G, or P3G prior to exposure to 100 ng/mL of SP. Their anti-inflammatory properties were then determined. BR extract at concentrations of 12.5-100 µg/mL exhibited anti-inflammation activity for both A549 and THP-1 cells through the significant suppression of NLRP3, IL-1ß, and IL-18 inflammatory gene expressions and IL-6, IL-1ß, and IL-18 cytokine secretions in a dose-dependent manner (p < 0.05). It was determined that both cell lines, C3G and P3G (at 1.25-10 µg/mL), were compatibly responsible for the significant inhibition of SP-induced inflammatory responses for both gene and protein levels (p < 0.05). With regard to the anti-inflammation mechanism, BR extract, C3G, and P3G could attenuate SP-induced inflammation via counteraction with NF-kB activation and downregulation of the inflammasome-dependent inflammatory pathway proteins (NLRP3, ASC, and capase-1). Overall, the protective effects of anthocyanins obtained from black rice germ and bran can be employed in potentially preventive strategies that use pigmented rice against the long-term sequelae of COVID-19 infection.


Subject(s)
COVID-19 , Oryza , Anthocyanins/pharmacology , COVID-19/complications , Glucosides/pharmacology , Humans , Inflammasomes , Interleukin-18 , Lung/metabolism , Macrophages/metabolism , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Oryza/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
Molecules ; 27(12)2022 Jun 12.
Article in English | MEDLINE | ID: covidwho-1917634

ABSTRACT

Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Lipopolysaccharide (LPS) is known as an endotoxin in the outer membrane of Gram-negative bacteria, and it catalyzes inflammation by stimulating the secretion of inflammatory-mediated cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by stimulated immune cells. Among the pathways involved in inflammation, nuclear factor kappa (NF-кB) and mitogen-activated protein kinases (MAPKs) are important. NF-kB is a diploid composed of p65 and IkBα and stimulates the pro- gene. MAPKs is a family consisting of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, JNK and p38 play a role as proinflammatory mediators. Thus, we aim to determine the scutellarein (SCU) effect on LPS stimulated RAW264.7 cells. Furthermore, since scutellarein has been shown to inhibit the SARS coronavirus helicase and has been used in Chinese medicine to treat inflammatory disorders like COVID-19, it would be required to examine scutellarein's anti-inflammatory mechanism. We identified inflammation-inducing substances using western blot with RAW264.7 cells and SCU. And we discovered that was reduced by treatment with SCU in p-p65 and p-IκBα. Also, we found that p-JNK and p-ERK were also decreased but there was no effect in p-p38. In addition, we have confirmed that the iNOS was also decreased after treatment but there is no change in the expression of COX-2. Therefore, this study shows that SCU can be used as a compound to treat inflammation.


Subject(s)
COVID-19 , NF-kappa B , Animals , Apigenin , Cyclooxygenase 2/metabolism , Cytokines/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/adverse effects , Mice , NF-kappa B/metabolism , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , RAW 264.7 Cells , Signal Transduction
8.
Cell Rep Med ; 3(7): 100680, 2022 Jul 19.
Article in English | MEDLINE | ID: covidwho-1907870

ABSTRACT

The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC]training = 0.799, p = 4.2e-6; multi-class AUCvalidation = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor κB (NF-κB) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression.


Subject(s)
COVID-19 , Humans , NF-kappa B/metabolism , Proteomics , SARS-CoV-2 , Signal Transduction
9.
Viruses ; 14(5)2022 05 13.
Article in English | MEDLINE | ID: covidwho-1903475

ABSTRACT

Currently, there are no evidence-based treatment options for long COVID-19, and it is known that SARS-CoV-2 can persist in part of the infected patients, especially those with immunosuppression. Since there is a robust secretion of SARS-CoV-2-specific highly-neutralizing IgA antibodies in breast milk, and because this immunoglobulin plays an essential role against respiratory virus infection in mucosa cells, being, in addition, more potent in neutralizing SARS-CoV-2 than IgG, here we report the clinical course of an NFκB-deficient patient chronically infected with the SARS-CoV-2 Gamma variant, who, after a non-full effective treatment with plasma infusion, received breast milk from a vaccinated mother by oral route as treatment for COVID-19. After such treatment, the symptoms improved, and the patient was systematically tested negative for SARS-CoV-2. Thus, we hypothesize that IgA and IgG secreted antibodies present in breast milk could be useful to treat persistent SARS-CoV-2 infection in immunodeficient patients.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19/complications , Eating , Female , Humans , Immunoglobulin A , Immunoglobulin G , Milk, Human , NF-kappa B , RNA, Viral , SARS-CoV-2/genetics
10.
JCI Insight ; 7(15)2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-1902172

ABSTRACT

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as ß-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher ß-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, ß-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.


Subject(s)
COVID-19 , beta-Glucans , COVID-19/complications , Humans , Inflammation , Lectins, C-Type/metabolism , NF-kappa B/metabolism , SARS-CoV-2 , Syk Kinase
11.
Phytomedicine ; 101: 154100, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1895371

ABSTRACT

BACKGROUND: A number of studies have shown that gastrointestinal manifestations co-exist with respiratory symptoms in coronavirus disease 2019 (COVID-19) patients. Xuanfei Baidu decoction (XFBD) was recommended by the National Health Commission to treat mild and moderate COVID-19 patients and proved to effectively alleviate intestinal symptoms. However, the exact mechanisms remain elusive. PURPOSE: This study aimed at exploring potential mechanisms of XFBD by utilizing a mouse model of dextran sulfate sodium (DSS)-induced acute experimental colitis, mimicking the disease conditions of intestinal microecological disorders. METHODS: The network pharmacology approach was employed to identify the potential targets and pathways of XFBD on the intestinal disorders. Mice with DSS-induced intestinal disorders were utilized to evaluate the protective effect of XFBD in vivo, including body weight, disease activity index (DAI) score, colon length, spleen weight, and serum tumor necrosis factor-α (TNF-α) level. Colon tissues were used to perform hematoxylin-eosin (H&E) staining, western blot analysis, and transcriptome sequencing. Macrophages, neutrophils and the proportions of T helper cell (Th) 1 and Th2 cells were measured by flow cytometry. Intestinal contents were collected for 16S rRNA gene sequencing. RESULTS: Network pharmacology analysis indicated that XFBD inhibited the progression of COVID-19-related intestinal diseases by repressing inflammation. In mice with DSS-induced intestinal inflammation, XFBD treatment significantly reduced weight loss, the spleen index, the disease activity index, TNF-α levels, and colonic tissue damage, and prevented colon shortening. Transcriptomics and flow cytometry results suggested that XFBD remodeled intestinal immunity by downregulating the Th1/Th2 ratio. Western blot analysis showed that XFBD exerted its anti-inflammatory effects by blocking the nuclear factor-κB (NF-κB) signaling pathway. Indicator analysis of microbiota showed that 75 operational taxonomic units (OTUs) were affected after XFBD administration. Among them, Akkermansia, Muribaculaceae, Lachnospiraceae, and Enterorhabdus were simultaneously negatively correlated with intestinal disorders' parameters, and Bacteroides, Escherichia-Shigella, Eubacterium nodatum,Turicibacter, and Clostridium sensu stricto 1, showed positive correlations with intestinal disorders' parameters. CONCLUSIONS: Our data indicate that XFBD treatment attenuated intestinal disorders associated with inhibiting inflammation, remodeling of intestinal immunity, and improving intestinal flora. These findings provide a scientific basis for the clinical use of XFBD and offer a potential therapeutic approach for the treatment of COVID-19 patients with intestinal symptoms.


Subject(s)
COVID-19 , Colitis, Ulcerative , Colitis , Drugs, Chinese Herbal , Gastrointestinal Microbiome , T-Lymphocytes, Regulatory/immunology , Animals , COVID-19/drug therapy , Colitis/chemically induced , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/pathology , Colon/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Humans , Inflammation/drug therapy , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , RNA, Ribosomal, 16S , Tumor Necrosis Factor-alpha/metabolism
12.
Phytomedicine ; 100: 154083, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1895370

ABSTRACT

BACKGROUND: The high incidence of thrombotic events is one of the clinical characteristics of coronavirus disease of 2019 (COVID-19), due to a hyperinflammatory response caused by the virus. Gegen Qinlian Pills (GQP) is a Traditional Chinese Medicine that is included in the Chinese Pharmacopoeia and played an important role in the clinical fight against COVID-19. Although GQP has shown the potential to treat thrombosis, there is no relevant research on its treatment of thrombosis so far. HYPOTHESIS: We hypothesized that GQP may be capable inhibit inflammation-induced thrombosis. STUDY DESIGN: We tested our hypothesis in a carrageenan-induced thrombosis mouse model in vivo and lipopolysaccharide (LPS)-induced human endothelial cells (HUVECs) in vitro. METHODS: We used a carrageenan-induced mouse thrombus model to confirm the inhibitory effect of GQP on inflammation-induced thrombus. In vitro, studies in human umbilical vein endothelial cells (HUVECs) and in silico network pharmacology analyses were performed to reveal the underlying mechanisms of GQP and determine the main components, targets, and pathways of GQP, respectively. RESULTS: Oral administration of 227.5 mg/kg, 445 mg/kg and 910 mg/kg of GQP significantly inhibited thrombi in the lung, liver, and tail and augmented tail blood flow of carrageenan-induced mice with reduced plasma tumor necrosis factor α (TNF-α) and diminished expression of high mobility group box 1 (HMGB1) in lung tissues. GQP ethanol extract (1, 2, or 5 µg/ml) also reduced the adhesion of platelets to LPS stimulated HUVECs. The TNF-α and the expression of HMGB1, nuclear factor kappa B (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) in LPS stimulated HUVECs were also attenuated. Moreover, we analyzed the components of GQP and inferred the main targets, biological processes, and pathways of GQP in the treatment of inflammation-induced thrombosis through network pharmacology. CONCLUSION: Overall, we demonstrated that GQP could reduce inflammation-induced thrombosis by inhibiting HMGB1/NFκB/NLRP3 signaling and provided an accurate explanation for the multi-target, multi-function mechanism of GQP in the treatment of thromboinflammation, and provides a reference for the clinical usage of GQP.


Subject(s)
Drugs, Chinese Herbal , HMGB1 Protein , Thrombosis , Animals , Carrageenan , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides , Mice , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Thrombosis/chemically induced , Thrombosis/drug therapy , Tumor Necrosis Factor-alpha/metabolism
13.
J Immunol Res ; 2022: 4008991, 2022.
Article in English | MEDLINE | ID: covidwho-1891951

ABSTRACT

Phycocyanobilin (PCB) is a linear open-chain tetrapyrrole chromophore that captures and senses light and a variety of biological activities, such as anti-oxidation, anti-cancer, and anti-inflammatory. In this paper, the biological activities of PCB are reviewed, and the related mechanism of PCB and its latest application in disease treatment are introduced. PCB can resist oxidation by scavenging free radicals, inhibiting the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and delaying the activity of antioxidant enzymes. In addition, PCB can also be used as an excellent anti-inflammatory agent to reduce the proinflammatory factors IL-6 and IFN-γ and to up-regulate the production of anti-inflammatory cytokine IL-10 by inhibiting the inflammatory signal pathways NF-κB and mitogen-activated protein kinase (MAPK). Due to the above biological activities of phycocyanobilin PCB, it is expected to become a new effective drug for treating various diseases, such as COVID-19 complications, atherosclerosis, multiple sclerosis (MS), and ischaemic stroke (IS).


Subject(s)
Phycobilins , Phycocyanin , Spirulina , Anti-Inflammatory Agents/pharmacology , Brain Ischemia , Humans , MAP Kinase Signaling System , NADPH Oxidases , NF-kappa B , Phycobilins/pharmacology , Phycocyanin/pharmacology , Spirulina/chemistry
14.
Biomed Pharmacother ; 152: 113254, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1889242

ABSTRACT

Sang Xing decoction (SXD) is a typical prescription for treating "warm dryness" in traditional Chinese medicine (TCM), which is equivalent to respiratory diseases such as acute bronchitis in modern medicine. However, its mechanism of action remains unclear. In this study, the representative components of SXD were characterized using liquid chromatography-tandem mass spectrometry (LC-MS). The key targets, signaling pathways, and metabolic pathways associated with SXD in the treatment of acute bronchitis were identified via network prediction and metabolomics. A rat model of acute bronchitis was also established using mixed smoke, systematic in vivo experiments such as histopathological analyses, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunohistochemistry and western blotting were conducted to evaluate the network prediction results. An in-depth analysis of the targeted quantitative results was performed using the SIMCA software and MetaboAnalyst website. The results revealed that 50 active compounds and 45 key targets were screened and clustered with 20 approved drugs. The NF-κB signaling pathway, oxidative stress, and glutamine metabolism were associated with the therapeutic mechanism of SXD in acute bronchitis. In vivo experiments showed that SXD may maintain the production of inflammatory factors by regulating the PI3K/Akt/NF-κB signaling pathway, improving the metabolism of glutamine and glutamate to reduce oxidative stress, and inhibiting apoptosis. Simultaneously, the possibility of using SXD as an adjuvant drug for COVID-19 treatment was also revealed. This research will lay the foundation for the modern clinical application of SXD and promote the promotion and innovation of TCM.


Subject(s)
Bronchitis , COVID-19 , Drugs, Chinese Herbal , Animals , Bronchitis/drug therapy , COVID-19/drug therapy , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Glutamine , Humans , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases , Rats , Smoke
15.
Int J Mol Sci ; 23(12)2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1884211

ABSTRACT

The receptor of advanced glycation end products (RAGE) is a receptor that is thought to be a key driver of inflammation in pregnancy, SARS-CoV-2, and also in the comorbidities that are known to aggravate these afflictions. In addition to this, vulnerable populations are particularly susceptible to the negative health outcomes when these afflictions are experienced in concert. RAGE binds a number of ligands produced by tissue damage and cellular stress, and its activation triggers the proinflammatory transcription factor Nuclear Factor Kappa B (NF-κB), with the subsequent generation of key proinflammatory cytokines. While this is important for fetal membrane weakening, RAGE is also activated at the end of pregnancy in the uterus, placenta, and cervix. The comorbidities of hypertension, cardiovascular disease, diabetes, and obesity are known to lead to poor pregnancy outcomes, and particularly in populations such as Native Hawaiians and Pacific Islanders. They have also been linked to RAGE activation when individuals are infected with SARS-CoV-2. Therefore, we propose that increasing our understanding of this receptor system will help us to understand how these various afflictions converge, how forms of RAGE could be used as a biomarker, and if its manipulation could be used to develop future therapeutic targets to help those at risk.


Subject(s)
COVID-19 , Glycation End Products, Advanced , Carrier Proteins , Female , Glycation End Products, Advanced/metabolism , Humans , NF-kappa B/metabolism , Pregnancy , Receptor for Advanced Glycation End Products/metabolism , Receptors, Immunologic/metabolism , SARS-CoV-2
16.
Molecules ; 27(9)2022 May 02.
Article in English | MEDLINE | ID: covidwho-1875712

ABSTRACT

Hydroxylated polyphenols, also called flavonoids, are richly present in vegetables, fruits, cereals, nuts, herbs, seeds, stems, and flowers of numerous plants. They possess numerous medicinal properties such as antioxidant, anti-cancer, anti-microbial, neuroprotective, and anti-inflammation. Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and ß-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions. Flavonoids such as quercetin, genistein, apigenin, kaempferol, and epigallocatechin 3-gallate modulate the expression and activation of a cytokine such as interleukin-1beta (IL-1ß), Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); regulate the gene expression of many pro-inflammatory molecules such s nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and E-selectins; and also inhibits inducible nitric oxide (NO) synthase, cyclooxygenase-2, and lipoxygenase, which are pro-inflammatory enzymes. Understanding the anti-inflammatory action of flavonoids provides better treatment options, including coronavirus disease 2019 (COVID-19)-induced inflammation, inflammatory bowel disease, obstructive pulmonary disorder, arthritis, Alzheimer's disease, cardiovascular disease, atherosclerosis, and cancer. This review highlights the sources, biochemical activities, and role of flavonoids in enhancing human health.


Subject(s)
COVID-19 , Flavonoids , Anti-Inflammatory Agents/adverse effects , Antioxidants/adverse effects , Flavonoids/chemistry , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Inflammation/drug therapy , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/pharmacology
17.
mBio ; 13(3): e0130022, 2022 06 28.
Article in English | MEDLINE | ID: covidwho-1874506

ABSTRACT

Ubiquitin signaling is essential for immunity to restrict pathogen proliferation. Due to its enormous impact on human health and the global economy, intensive efforts have been invested in studying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its interactions with hosts. However, the role of the ubiquitin network in pathogenicity has not yet been explored. Here, we found that ORF9b of SARS-CoV-2 is ubiquitinated on Lys-4 and Lys-40 by unknown E3 ubiquitin ligases and is degraded by the ubiquitin proteasomal system. Importantly, we identified USP29 as a host factor that prevents ORF9b ubiquitination and subsequent degradation. USP29 interacts with the carboxyl end of ORF9b and removes ubiquitin chains from the protein, thereby inhibiting type I interferon (IFN) induction and NF-κB activation. We also found that ORF9b stabilization by USP29 enhanced the virulence of VSV-eGFP and transcription and replication-competent SARS-CoV-2 virus-like-particles (trVLP). Moreover, we observed that the mRNA level of USP29 in SARS-CoV-2 patients was higher than that in healthy people. Our findings provide important evidence indicating that targeting USP29 may effectively combat SARS-CoV-2 infection. IMPORTANCE Coronavirus disease 2019 (COVID-19) is a current global health threat caused by SARS-CoV-2. The innate immune response such as type I IFN (IFN-I) is the first line of host defense against viral infections, whereas SARS-CoV-2 proteins antagonize IFN-I production through distinct mechanisms. Among them, ORF9b inhibits the canonical IκB kinase alpha (IKKɑ)/ß/γ-NF-κB signaling and subsequent IFN production; therefore, discovering the regulation of ORF9b by the host might help develop a novel antiviral strategy. Posttranslational modification of proteins by ubiquitination regulates many biological processes, including viral infections. Here, we report that ORF9b is ubiquitinated and degraded through the proteasome pathway, whereas deubiquitinase USP29 deubiquitinates ORF9b and prevents its degradation, resulting in the enhancement of ORF9b-mediated inhibition of IFN-I and NF-κB activation and the enhancement of virulence of VSV-eGFP and SARS-CoV-2 trVLP.


Subject(s)
Biological Phenomena , COVID-19 , Coronavirus Nucleocapsid Proteins/metabolism , Deubiquitinating Enzymes , Humans , Immunity, Innate , NF-kappa B , Phosphoproteins/metabolism , Proteasome Endopeptidase Complex , SARS-CoV-2/genetics , Ubiquitin-Specific Proteases , Ubiquitins , Virulence
18.
J Med Microbiol ; 71(5)2022 May.
Article in English | MEDLINE | ID: covidwho-1874076

ABSTRACT

Introduction. Coronavirus disease 2019 (COVID-19) has caused a serious threat to public health worldwide, and there is currently no effective therapeutic strategy for treating COVID-19.Hypothesis/Gap Statement. We propose that sophocarpine (SOP) might have potential therapeutic effects on COVID-19 through inhibiting the cytokine storm and the nuclear factor NF-κB signalling pathway.Aim. The objective was to elucidate the potential mechanism of SOP against COVID-19 through a network pharmacology analysis and its experimental validation.Methodology. The BATMAN-TCM database was used to identify the therapeutic targets of SOP, while the GeneCards and DisGeNET databases were used to identify the targets related to COVID-19. A protein-protein interaction (PPI) network was constructed from the STRING and analysed using Cytoscape software. Gene ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG) and disease ontology (DO) enrichment analyses of the co-targets were performed using Metascape. Autodock 4.2.6 and Pymol software were applied for molecular docking. Levels of the proinflammatory cytokines IL-6, TNFα and IL-1ß were measured by ELISA, while mRNA expression levels of intercellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor A (VEGFA) and IFN gamma (IFNG) were detected by real-time quantitative reverse transcription PCR. The protein levels of the molecules involved in the NF-κB signalling pathway were validated by western blot analysis.Results. A total of 65 co-targets of SOP and COVID-19 were determined. GO and KEGG enrichment analyses suggested that SOP affected COVID-19 by regulating the IL-17 signalling pathway, TNF signalling pathway and other signalling pathways. The PPI network and molecular docking showed that p65, ICAM-1 and VEGFA were key targets of SOP against COVID-19 and the underlying mechanism was validated in A549 cells in vitro. SOP attenuated the LPS-induced production of TNF-α and IL-6 and downregulated the LPS-induced mRNA expression of ICAM-1, VEGFA and IFNG. Mechanistically, SOP pretreatment inhibited the phosphorylation of p65 and facilitated the activation of Nrf2.Conclusions. SOP has a potential therapeutic effect on COVID-19 through multiple pathways and targets, and inhibits the production of pro-inflammatory cytokines and molecules involved in the NF-κB signalling pathway.


Subject(s)
COVID-19 , Intercellular Adhesion Molecule-1 , Alkaloids , COVID-19/drug therapy , Cytokines/metabolism , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/metabolism , Interleukin-6 , Lipopolysaccharides , Molecular Docking Simulation , NF-kappa B/metabolism , RNA, Messenger , Tumor Necrosis Factor-alpha , Vascular Endothelial Growth Factor A
19.
Viruses ; 14(5)2022 05 08.
Article in English | MEDLINE | ID: covidwho-1862917

ABSTRACT

This paper presents a molecular characterization of the interaction between the SARS-CoV-2 envelope (E) protein and TLR2. We demonstrated that the E protein, both as a recombinant soluble protein and as a native membrane protein associated with SARS-CoV-2 viral particles, interacts physically with the TLR2 receptor in a specific and dose-dependent manner. Furthermore, we showed that the specific interaction with the TLR2 pathway activates the NF-κB transcription factor and stimulates the production of the CXCL8 inflammatory chemokine. In agreement with the importance of NF-κB in the TLR signaling pathway, we showed that the chemical inhibition of this transcription factor leads to significant inhibition of CXCL8 production, while the blockade of the P38 and ERK1/2 MAP kinases only results in partial CXCL8 inhibition. Overall, our findings propose the envelope (E) protein as a novel molecular target for COVID-19 interventions: either (i) by exploring the therapeutic effect of anti-E blocking/neutralizing antibodies in symptomatic COVID-19 patients, or (ii) as a promising non-spike SARS-CoV-2 antigen candidate for inclusion in the development of next-generation prophylactic vaccines against COVID-19 infection and disease.


Subject(s)
COVID-19 , Coronavirus Envelope Proteins , SARS-CoV-2 , Toll-Like Receptor 2 , Coronavirus Envelope Proteins/metabolism , Humans , Interleukin-8 , NF-kappa B , Toll-Like Receptor 2/metabolism
20.
J Biol Chem ; 298(3): 101695, 2022 03.
Article in English | MEDLINE | ID: covidwho-1851422

ABSTRACT

Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5ß1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNFα, IL-1ß, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5ß1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1ß, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5ß1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5ß1 as a promising target for treating vascular inflammation in COVID-19.


Subject(s)
COVID-19 , Inflammation , Integrin alpha5beta1 , NF-kappa B , Spike Glycoprotein, Coronavirus , Tumor Necrosis Factor-alpha , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Human Umbilical Vein Endothelial Cells , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/virology , Integrin alpha5beta1/metabolism , Interleukin-6/metabolism , NF-kappa B/metabolism , Oligopeptides , SARS-CoV-2 , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Tumor Necrosis Factor-alpha/metabolism
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