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The COVID-19 pandemic has altered people's lifestyles around the world. Prevention of recurrent episodes of the disease and mitigation of its consequences are especially associated with effective post-COVID-19 rehabilitation in patients. The aim of the study was to evaluate the effects of the drug Likopid (glucosaminylmuramyl dipeptide, GMDP) for post-COVID-19 rehabilitation in patients. Material and methods. Patients who recovered from mild to moderate COVID-19 (n=60, mean age 54+/- 11.7 years) were randomized into the observation group (n=30, 15 men and 15 women) who received 2 courses of Licopid (1 mg twice a day) and the comparison group (n=30, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the innate immune cellular factors was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months observations. In order to assess the quality of life of all patients, we used the SF-36 Health Status Survey and the Hospital Anxiety and Depression Scale questionnaires. Results. During assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after COVID-19, an increase in the protective cytolytic activity of CD16+ and CD8+Gr+ cells, as well as a persistent increase in TLR2, TLR4 and TLR9 expression was found, which indicates the antigen recognition recovery and presentation at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold reduction in the frequency and severity of respiratory infections due to an increase in the total monocyte count. As a result of assessing patients' quality of life against the background of the therapy, a positive dynamic in role functioning was revealed in patients. In the general assessment of their health status, an increase in physical and mental well-being was noted during 6 months of observation. The comparison group showed no improvement in the psychoemotional state. Discussion. The study demonstrated the effectiveness of GMDP immunomodulatory therapy in correcting immunological parameters for post-COVID-19 rehabilitation in patients. The data obtained are consistent with the previously discovered ability of GMDP to restore impaired functions of phagocytic cells and induce the expression of their surface activation markers, which in turn contributes to an adequate response to pathogens. Conclusion. The study revealed that the correction of immunological parameters with the use of GMDP in COVID-19 convalescents contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.Copyright © Eco-Vector, 2023. All rights reserved.
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The newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has turned into a potentially fatal pandemic illness. Numerous acute kidney injury (AKI) cases have been reported, although diffuse alveolar destruction and acute respiratory failure are the major symptoms of SARS-CoV-2 infection. The AKI, often known as a sudden loss of kidney function, carries a greater risk of mortality and morbidity. AKI was the second most frequent cause of death after acute respiratory distress syndrome (ARDS) in critically ill patients with coronavirus disease 2019 (COVID-19). While most patients with COVID-19 have moderate symptoms, some have severe symptoms, such as septic shock and ARDS. Also, it has been proven that some patients have severe symptoms, such as the failure of several organs. The kidneys are often affected either directly or indirectly. The major signs of kidney involvement are proteinuria and AKI. It is hypothesized that multiple mechanisms contribute to kidney injury in COVID-19. Direct infection of podocytes and proximal tubular cells in the kidneys may lead to acute tubular necrosis and collapsing glomerulopathy. SARS-CoV2 may also trigger a cascade of immunological responses that lead to AKI, including cytokine storm (CS), macrophage activation syndrome, and Toll-like receptor type-4 activation (TLR-4). Other proposed processes of AKI include interactions between organs, endothelial failure, hypercoagulability, rhabdomyolysis, and sepsis.Furthermore, ischemic damage to the kidney might result from the decreased oxygen supply. This article focuses on kidney injury's epidemiology, etiology, and pathophysiological processes. Specifically, it focuses on the CS and the role of TLR-4 in this process. To effectively manage and treat acute kidney damage and AKI in COVID-19, it is crucial to understand the underlying molecular pathways and pathophysiology.
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Swine acute diarrhea syndrome coronavirus (SADS-CoV), a newly discovered enteric coronavirus, is the etiological agent that causes severe clinical diarrhea and intestinal pathological damage in piglets. In this study, Vero E6 and IPI-2I cells were pretreated with different concentrations of glycyrrhizin (GLY) for 2 hours, and then infected with different concentrations of SADSCoV, aiming to investigate the inhibitory effect of GLY on SADS-CoV. Western blot and TCID50 results revealed a significantly decreased N protein expression and viral titer, indicating that GLY can inhibit the infection of SADS-CoV. Vero E6 and IPI-2I cells were pretreated with different concentrations of GLY for 2 hours and infected with SADS-CoV. Western blot results showed that when the concentration of GLY was 0.8 mmol/L, the expression of N protein decreased significantly, indicating that GLY inhibited the invasion of the virus. At first, cells were treated with 0.4 mmol/L GLY, and cell samples were collected at 2 hours, 6 hours and 12 hours after being infected with SADS-CoV for analysis, and the expression of N protein were found to be significantly reduced at all points, indicating that GLY had a significant inhibitory effect on the replication of the virus. GLY is a competitive inhibitor of high mobility group box 1 (HMGB1), and the receptors of HMGB1 mainly include TLR4 and RAGE. Based on this fact, the mutant plasmid at the key sites of HMGB1 (C45S, C106S, C45/106S) and the siRNA of the RAGE receptor were transfected to Vero E6 cells and infected with SADS-CoV, and the cell supernatant and samples were harvested. The western blot and TCID50 results showed that the expression of N protein and the virus titer were decreased, suggesting that GLY exerts its function by affecting the binding of HMGB1/TLR4/RAGE during SADS-CoV infection. To further explore the signaling pathway through which GLY functions, Vero E6 and IPI-2I cells were inoculated with SADS-CoV, and cell samples were harvested, western blot was used to detect the changes of MAPK proteins. The results showed that the protein expression levels of p-p38, p-JNK and p-ERK were up-regulated in the early and late stages, indicating that the MAPK pathway was activated by SADS-CoV infection. Vero E6 and IPI-2I were pretreated with different concentrations of GLY and TLR4 inhibitor TAK for 2 hours and infected with SADS-CoV. Protein samples were harvested and analysed by western blot which showed a decreased p-JNK and N proteins, while other proteins showed no significant changes. These results indicated that GLY and TAK regulated the phosphorylation of JNK but did not regulate the phosphorylation of p38 and ERK. Also, Vero E6 cells were treated with HMGB1 antibody, the siRNA of HMGB1 and HMGB1 mutants plasmid, and infected with SADS-CoV. Protein samples were harvested, western blot results showed that phosphorylation of JNK decreased, indicating that HMGB1 affected JNK phosphorylation. Finally, Vero E6 and IPI-2I cells were pretreated with different concentrations of JNK inhibitor SP600125 to infect SADS-CoV, western blot, TCID50 and IFA results showed that the expression of N protein and virus titer, as well as virus replication were reduced, indicating that SP600125 inhibited virus replication. In conclusion, our results revealed that GLY can inhibit in vitro replication of SADS- CoV, mainly through the HMGB1/TLR4/JNK signaling pathway. The discovery of this pathway provides theoretical support for the research of novel anti-SADS-CoV drugs.
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The coronavirus disease 2019 (COVID-19) pandemic underlines a persistent threat of respiratory tract infectious diseases and warrants preparedness for a rapid response. At present, COVID-19 has had a serious social impact and imposed a heavy global burden on public health. The exact pathogenesis of COVID-19 has not been fully elucidated. Since the outbreak of COVID-19, a renewed attention has been brought to Toll-like receptors (TLRs). Available data and new findings have demonstrated that the interaction of human TLRs and SARS-CoV-2 is a vital mediator of COVID-19 immunopathogenesis. TLRs such as TLR2, 4, 7 and 8 are potentially important in viral combat and activation of immunity in patients with COVID-19. Therapeutics targeting TLRs are currently considered promising options against the pandemic. A number of TLR-targeting immunotherapeutics are now being investigated in preclinical studies and different phases of clinical trials. In addition, innovative vaccines based on TLRs under development could be a promising approach for building a new generation of vaccines to solve the current challenges. In this review, we summarize recent progress in the role of TLRs in COVID-19, focusing the new candidate drugs targeting TLRs, the current technology and potential paths forward for employing TLR agonists as vaccine adjuvants.Copyright © 2023 The Scandinavian Foundation for Immunology.
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The COVID-19 pandemic has altered people's lifestyles around the world. Prevention of recurrent episodes of the disease and mitigation of its consequences are especially associated with effective post-COVID-19 rehabilitation in patients. The aim of the study was to evaluate the effects of the drug Likopid (glucosaminylmuramyl dipeptide, GMDP) for post-COVID-19 rehabilitation in patients. Material and methods. Patients who recovered from mild to moderate COVID-19 (n=60, mean age 54+/- 11.7 years) were randomized into the observation group (n=30, 15 men and 15 women) who received 2 courses of Licopid (1 mg twice a day) and the comparison group (n=30, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the innate immune cellular factors was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months observations. In order to assess the quality of life of all patients, we used the SF-36 Health Status Survey and the Hospital Anxiety and Depression Scale questionnaires. Results. During assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after COVID-19, an increase in the protective cytolytic activity of CD16+ and CD8+Gr+ cells, as well as a persistent increase in TLR2, TLR4 and TLR9 expression was found, which indicates the antigen recognition recovery and presentation at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold reduction in the frequency and severity of respiratory infections due to an increase in the total monocyte count. As a result of assessing patients' quality of life against the background of the therapy, a positive dynamic in role functioning was revealed in patients. In the general assessment of their health status, an increase in physical and mental well-being was noted during 6 months of observation. The comparison group showed no improvement in the psychoemotional state. Discussion. The study demonstrated the effectiveness of GMDP immunomodulatory therapy in correcting immunological parameters for post-COVID-19 rehabilitation in patients. The data obtained are consistent with the previously discovered ability of GMDP to restore impaired functions of phagocytic cells and induce the expression of their surface activation markers, which in turn contributes to an adequate response to pathogens. Conclusion. The study revealed that the correction of immunological parameters with the use of GMDP in COVID-19 convalescents contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.Copyright © Eco-Vector, 2023. All rights reserved.
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Background: Viral infections pose some of the most serious human health concerns worldwide. The infections caused by several viruses, including coronavirus, hepatitis virus, and human immunodeficiency virus, are difficult to treat. Method(s): This review details the findings of a literature search performed on the antiviral properties of luteolin. The keywords engaged in the search are "virus" along with "luteolin." Results: Luteolin possesses antiviral properties, which is the basis for the current review. It is an important natural flavonoid with numerous important biological properties, including anti-inflammatory, immune regulatory, and antitumor effects, and is found in vegetables, fruits, and several medicinal plants. Recent studies have revealed that many traditional Chinese medicines that contain luteolin inhibit the replication of coronaviruses. Conclusion(s): Luteolin effectively inhibits the replication of coronavirus, influenza virus, enterovirus, rotavirus, herpes virus, and respiratory syncytial virus, among others. In particular, it prevents viral infection by improving the body's nonspecific immunity and antioxidation capacity and inhibiting many pathways related to virus infection and replication, such as MAPK, PI3K-AKT, TLR4/8, NF-kappaB, Nrf-2/hemeoxygenase-1, and others. It also regulates the expression of some receptors and factors, including hepatocyte nuclear factor 4alpha, p53, NLRP3, TNF-alpha, and interleukins, thereby interfering with the replication of viruses in cells. Luteolin also promotes the repair of damaged cells induced by proinflammatory factors by regulating the expression of inflammatory molecules. The overall effect of these processes is the reduction in viral replication and, consequently, the viral load. This review summarizes the antiviral effect of luteolin and the mechanism underlying this property.Copyright © The Author(s) 2023.
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Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.
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Background: Effective rehabilitation of patients who have had a SARS CoV-2 infection is essential to prevent re-infections and will improve the quality of life of people and reduce the burden on the healthcare system. Muramylpeptides are used in the prevention of seasonal diseases in children and adults in order to correct immunodeficiency states and prevent infectious complications. The aim of this study was to study the dynamic changes in the state of cellular factors of innate immunity and the levels of anxiety and depression in patients treated with glucosaminyl muramyl dipeptide (GMDP). Method(s): Patients who underwent mild to moderate COVID-19 (N = 60, mean age 54 +/- 11.7 years) were randomized to the study group (30 people, 15 men and 15 women) who received 2 courses of licopid 1 mg twice per day and a comparison group (30 people, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the cellular factors of the innate immune response was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months. observations. To assess the quality of life of all patients, the SF-36 Health Status Survey and HADS questionnaires were used before the use of licopid, at the end of the course and after 6 months of follow-up. Result(s): In the course of assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after suffering COVID-19, an increase in the protective cytolytic activity of CD16+, CD8+Gr+ cells, as well as a persistent increase in the expression of TLR2, TLR4 and TLR9 was found, which indicates the restoration of antigenic recognition and presentations at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold decrease in the frequency and severity of respiratory infections due to an increase in the total monocyte count, which persisted for 6 months from the start of therapy, while the use of systemic antibiotic therapy was not required, while in the comparison group -7 people were forced to resort to this therapy due to the severity of acute respiratory infections. When analyzing the assessment of the quality of life of patients against the background of the therapy, patients showed positive dynamics in role functioning, general assessment of their health status, and an increase in physical and mental well-being during 6 months of observation. In the comparison group, there was no improvement in the psycho-emotional state of patients. Conclusion(s): In this study, for the first time, it was found that the correction of immunological parameters when exposed to GMDP after a previous illness contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.
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COVID-19 has been found to affect the expression profile of several mRNAs and miRNAs, leading to dysregulation of a number of signaling pathways, particularly those related to inflammatory responses. In the current study, a systematic biology procedure was used for the analysis of high-throughput expression data from blood specimens of COVID-19 and healthy individuals. Differentially expressed miRNAs in blood specimens of COVID-19 vs. healthy specimens were then identified to construct and analyze miRNA-mRNA networks and predict key miRNAs and genes in inflammatory pathways. Our results showed that 171 miRNAs were expressed as outliers in box plot and located in the critical areas according to our statistical analysis. Among them, 8 miRNAs, namely miR-1275, miR-4429, miR-4489, miR-6721-5p, miR-5010-5p, miR-7110-5p, miR-6804-5p and miR-6881-3p were found to affect expression of key genes in NF-KB, JAK/STAT and MAPK signaling pathways implicated in COVID-19 pathogenesis. In addition, our results predicted that 25 genes involved in above-mentioned inflammatory pathways were targeted not only by these 8 miRNAs but also by other obtained miRNAs (163 miRNAs). The results of the current in silico study represent candidate targets for further studies in COVID-19.Copyright © 2023 Elsevier B.V.
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Under the COVID-19 pandemic, interest in immune enhancement and anti-obesity is increasing. Thus, in this study, we investigated whether Kadsura japonica fruits (KJF) exhibits immunostimulatory activity and anti-obesity activity. KJF increased the production of immunostimulatory factors and phagocytosis in RAW264.7 cells. Inhibition of TLR2 and TLR4 blocked KJF-mediated production of immunostimulatory factors in RAW264.7 cells. In addition, the inhibition of MAPK and PI3 K/AKT signaling pathway reduced KJF-mediated production of immunostimulatory factors, and the activation of MAPK and PI3 K/AKT signaling pathway by KJF suppressed the inhibition of TLR2/4. KJF attenuated the lipid accumulation and the protein expression such as CEBPa, PPARP, perilipin-1, adiponectin, and FABP4 related to the lipid accumulation in 3T3-L1 cells. In addition, KJF inhibited excessive proliferation of 3T3-L1 cells and protein expressions such as beta-catenin and cyclin D1 related to cell growth. These findings indicate that KJF may have immunostimulatory activity and anti-obesity activity.
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The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D3 (VD3) and 17beta-estradiol (E2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E2 in the context of these diseases. E2 and VD3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD3 and E2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.Copyright © Sociedade Brasileira de Genetica.
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Objective To study the anti-coronavirus effect of Qingre Xiaoyanning Tablet (), and provide experimental basis for evaluating its prevention and treatment of coronavirus infection. Methods A total of 96 BALB/c mice with half male and half female were randomly divided into control group, model group, Lianhua Qingwen Capsules (, 0.546 g/kg) group and Qingre Xiaoyanning Tablet (8.72, 17.44, 34.89 g/kg) groups with 16 mice in each group. BALB/c mice were infected with ip cyclophosphamide combined with HCoV-229E coronavirus to establish a model of coronavirus infection. The therapeutic effect of Qingre Xiaoyanning Tablet was evaluated by body weight, lung index, viral load, hemagglutination titer and pathological changes in lung tissue of mice;Levels of interleukin-1beta (IL-1beta), IL-4, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and vascular cell adhesion molecule-1 (VCAM-1) in alveolar lavage fluid were detected by ELISA;The proportion of macrophages, lymphocytes (CD3+, CD4+) and NK cells in lung tissue was detected by flow cytometry;Western blotting was used to detect Toll like receptor 4 (TLR4), myeloid differentiation factor 88 (MYD88), inhibitor kappa B kinase-beta (IKK-beta), inhibitor kappa B (IkappaB) and p-IkappaB protein expressions in lung tissue. Results Compared with model group, Qingre Xiaoyanning Tablet significantly increased the body weight of virus infected mice (P < 0.05, 0.01), decreased lung index and hemagglutination titer (P < 0.01), improved lung disease (P < 0.05), and significantly inhibited viral mRNA expression (P < 0.01);TNF-alpha, IL-1 beta and VCAM-1 levels in alveolar lavage fluid were decreased (P < 0.05, 0.01), IFN-gamma level was increased (P < 0.05);The percentage of macrophages was significantly decreased (P < 0.05, 0.01), percentage of CD3+, CD4+ lymphocytes and NK cells was increased (P < 0.01);MYD88, TLR4, IkappaB and IKK-beta protein expressions in lung tissue were significantly down regulated (P < 0.05, 0.01). Conclusion Qingre Xiaoyanning Tablet can inhibit the replication of coronavirus in vivo, reduce inflammatory reaction, protect lung tissue, and has obvious anti-coronavirus effect in vivo. Its mechanism may be related to the regulation of TLR4/MyD88/IKK/IkappaB signal pathway and improving immunity.Copyright © 2023 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.
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Monkeypox is a viral zoonotic disease, often transmitted to humans from animals. While the whole world is haggling with the COVID-19 pandemic, the emergence of the monkeypox virus (MPXV) arose as a new challenge to mankind. Till date, numerous cases related to the MPXV have been reported in several countries across the globe, but, its momentary distribution in the current time has left everyone in fright with increasing mortality and limited clinically approved treatments. Therefore, it is of immense importance to develop a potent and highly effective vaccine capable of inducing desired immunogenic responses against the highly contagious MPXV. Herein, using various immunoinformatic and computational biology tools, we made an attempt to develop a multi-epitope vaccine construct against the MPXV which is antigenic, non-allergen and non-toxic in nature and capable of exhibiting immunogenic behavior. The sequence of vaccine construct was designed using the proposed 4 MHC-I, 3 MHC-II and 4 B-cell epitopes linked with suitable adjuvant and linkers. The modeled structure of the vaccine construct was used to assess its interaction with the Toll-like Receptor 4 (TLR4) using ClusPro and HADDOCK. All-atoms molecular dynamics simulation of the MPXV vaccine construct-TLR4 complex followed by a high level of gene expression of the construct within the bacterial system affirmed its stability along with induction of immunogenic response within the host cell. Altogether, our immunoinformatic approach aid in the development of a stable chimeric vaccine construct against MPXV and needs further experimental validation for its immunological relevance and usefulness as a vaccine candidate.Communicated by Ramaswamy H. Sarma.
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ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is one of the fatal complications of respiratory virus infections such as influenza virus and coronavirus, which has high clinical morbidity and mortality. Jinhua Qinggan granules (JHQG) has been approved by China Food and Drug Administration in the treatment of H1N1 influenza and mild or moderate novel coronavirus disease 2019 (COVID-19), which is an herbal formula developed based on Maxingshigan decoction and Yinqiao powder that have been used to respiratory diseases in China for thousands of years. However, the underlying mechanism of JHQG in treating infectious diseases remains unclear. AIM OF THE STUDY: This study investigated the effects of JHQG on neutrophil apoptosis and key signaling pathways in lipopolysaccharide (LPS) -induced ALI mice in order to explore its mechanism of anti-inflammation. MATERIALS AND METHODS: The effect of JHQG on survival rate was observed in septic mouse model by intraperitoneal injection of LPS (20 mg/kg). To better pharmacological evaluation, the mice received an intratracheal injection of 5 mg/kg LPS. Lung histopathological changes, wet-to-dry ratio of the lungs, and MPO activity in the lungs and total protein concentration, total cells number, TNF-α, IL-1ß, IL-6, and MIP-2 levels in BALF were assessed. Neutrophil apoptosis rate was detected by Ly6G-APC/Annexin V-FITC staining. Key proteins associated with apoptosis including caspase 3/7 activity, Bcl-xL and Mcl-1 were measured by flow cytometry and confocal microscope, respectively. TLR4 receptor and its downstream signaling were analyzed by Western blot assay and immunofluorescence, respectively. RESULTS: JHQG treatment at either 6 or 12 g/kg/day resulted in 20% increase of survival in 20 mg/kg LPS-induced mice. In the model of 5 mg/kg LPS-induced mice, JHQG obviously decreased the total protein concentration in BALF, wet-to-dry ratio of the lungs, and lung histological damage. It also attenuated the MPO activity and the proportion of Ly6G staining positive neutrophils in the lungs, as well as the MIP-2 levels in BALF were reduced. JHQG inhibited the expression of Mcl-1 and Bcl-xL and enhanced caspase-3/7 activity, indicating that JHQG partially acted in promoting neutrophil apoptosis via intrinsic mitochondrial apoptotic pathway. The levels of TNF-α, IL-1ß, and IL-6 were significantly declined in LPS-induced mice treated with JHQG. Furthermore, JHQG reduced the protein expression of TLR4, MyD88, p-p65 and the proportion of nuclei p65, suggesting that JHQG treatment inhibited TLR4/MyD88/NF-κB pathway. CONCLUSION: JHQG reduced pulmonary inflammation and protected mice from LPS-induced ALI by promoting neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway, suggesting that JHQG may be a promising drug for treatment of ALI.
Subject(s)
Acute Lung Injury , COVID-19 , Influenza A Virus, H1N1 Subtype , Mice , Animals , NF-kappa B/metabolism , Toll-Like Receptor 4/metabolism , Lipopolysaccharides/toxicity , Myeloid Differentiation Factor 88/metabolism , Neutrophils , Tumor Necrosis Factor-alpha/metabolism , Influenza A Virus, H1N1 Subtype/metabolism , Interleukin-6/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/therapeutic use , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , ApoptosisABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1 production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions.
Subject(s)
COVID-19 Drug Treatment , Interferon Type I , Humans , Acetylation , NF-kappa B/metabolism , Drug Repositioning , Membrane Proteins/metabolism , SARS-CoV-2 , Nucleotidyltransferases/metabolism , Interferon Type I/metabolism , Aspirin , Immunity, Innate/geneticsABSTRACT
Recognition of viral infection by pattern recognition receptors is paramount for a successful immune response to viral infection. However, an unbalanced proinflammatory response can be detrimental to the host. Recently, multiple studies have identified that the SARS-CoV-2 spike protein activates Toll-like receptor 4 (TLR4), resulting in the induction of proinflammatory cytokine expression. Activation of TLR4 by viral glycoproteins has also been observed in the context of other viral infection models, including respiratory syncytial virus (RSV), dengue virus (DENV) and Ebola virus (EBOV). However, the mechanisms involved in virus-TLR4 interactions have remained unclear. Here, we review viral glycoproteins that act as pathogen-associated molecular patterns to induce an immune response via TLR4. We explore the current understanding of the mechanisms underlying how viral glycoproteins are recognized by TLR4 and discuss the contribution of TLR4 activation to viral pathogenesis. We identify contentious findings and research gaps that highlight the importance of understanding viral glycoprotein-mediated TLR4 activation for potential therapeutic approaches.
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Clinical success of Toll-Like receptor-4 (TLR-4) antagonists in sepsis therapy has thus far been lacking. As inhibition of a receptor can only be useful if the receptor is active, stratification of patients with active TLR-4 would be desirable. Our aim was to establish an assay to quantify phosphorylated TLR-4 using the proximity ligation assay (PLA). HEK293 TLR4/MD2/CD14 as well as THP-1 cells were stimulated with LPS and the activation of TLR-4 was measured using the PLA. Furthermore, peripheral blood mononuclear cells (PBMCs) from 25 sepsis patients were used to show the feasibility of this assay in clinical material. Activation of TLR-4 in these samples was compared to the PBMCs of 11 healthy individuals. We could show a transient activation of TLR-4 in both cell lines. Five min after the LPS stimulation, the signal increased 6.7-fold in the HEK293 cells and 4.3-fold in the THP-1 cells. The assay also worked well in the PBMCs of septic patients. Phosphorylation of TLR-4 at study inclusion was 2.9 times higher in septic patients compared to healthy volunteers. To conclude, we established a diagnostic assay that is able to quantify the phosphorylation of TLR-4 in cell culture and in clinical samples of sepsis patients. This makes large-scale stratification of sepsis patients for their TLR-4 activation status possible.
Subject(s)
Sepsis , Toll-Like Receptor 4/metabolism , HEK293 Cells , Humans , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacologyABSTRACT
SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Viral infections can induce an immune cascade which may incite varied autoimmune disease to take action. One such disease is dermatomyositis, a rare inflammatory disease with multisystemic involvement. As we enter the post pandemic era, several unique complications related to COVID-19 are now surfacing. Here we present a case of a 57-year-old female who developed dermatomyositis after recent Covid-19 infection. CASE PRESENTATION: Patient is a 57-year-old female who presented to our pulmonary clinic with complaints of cough and shortness of breath (SOB). Patient reported feeling ill since contracting COVID-19 in November 2020. Two months after being diagnosed with COVID-19 she started to experience generalized muscle and joint pain;she underwent extensive rheumatological workup which was consistent with Sjogren disease for which she was started on hydroxychloroquine. A month after initiation of medication she started to experience worsening cough and SOB and underwent pulmonary function testing (PFT) in our clinic which showed evidence of restrictive lung disease. Chest CT was consistent with interstitial changes, therefore a diagnosis of ILD (interstitial lung disease) due to connective tissue disorder was made. Further assessment revealed positive CPK and anti-Jo1 antibodies indicative of dermatomyositis as a cause of her ILD. She was started on oral steroids which helped improve her symptoms. DISCUSSION: Several viruses including EBV, Hepatitis C, Rubella, HTLV-1 and Parvovirus have been associated with development of autoimmune diseases. Viral infections, like COVID-19 have shown to trigger an intense immune response which in turn may lead to autoimmune activity against host antigen. SARS-CoV2 has been found to enter muscle cells through ACE-2 receptors, allowing for transfer of genetic material and skeletal muscle damage. Another proposed mechanism of COVID induced myopathy has been T-cell clonal expansion by the virus up regulating TLR4 receptors increasing expression of ACE2, therefore facilitating entry of viruses leading to further inflammation. Identification of very specific T cell receptor epitopes for SARS-COv2 in patients with dermatomyositis has suggested COVID-19 as a trigger for CD8-T cells which leads to dermatomyositis in these patients. Autoimmune reactions occur from varying mechanisms like epitope spreading and bystander activation to molecular mimicry triggered by viral infections. CONCLUSIONS: SARS-COv2 presented with several challenges in the field of medicine. As we enter the post COVID period in medicine, we will continue to face several challenges proposed by the inflammatory surge caused by this disease. It is therefore important clinicians recognize and report these rare cases to increase awareness regarding several post covid diseases. Reference #1: HUSSEIN, H. M.;RAHAL, E. A. The role of viral infections in the development of autoimmune diseases. Critical Reviews in Microbiology, [s. l.], v. 45, n. 4, p. 394–412, 2019. DOI 10.1080/1040841X.2019.1614904. Disponível em: https://search-ebscohost-com.proxy.lib.wayne.edu/login.aspx?direct=true&db=a9h&AN=138199390&site=ehost-live&scope=site. Acesso em: 4 abr. 2022. DISCLOSURES: No relevant relationships by Kevser Akyuz No relevant relationships by Ranim Chamseddin No relevant relationships by Padmini Giri No relevant relationships by verisha khanam No relevant relationships by Emad Shehada No relevant relationships by Abdullah Yesilyaprak
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Objective To explore the application pattern and mechanism of medicine and food homologous traditional Chinese medicine (TCM) against modern viral diseases. Methods The method of literature mining was applied based on the characteristics of modern viral diseases, combining with ancient books and modern prescriptions for the prevention and treatment of viral diseases to build a relevant prescription database. Then SPSS and R language were used to analyze the high-frequency medicine and food homologous TCM and high confidence medicine and food homologous prescriptions in these prescriptions, and cluster analysis was carried out. The antiviral characteristic active ingredients of high-frequency medicinal and food homologous TCN were identified and analyzed, and the action mechanism of active ingredients against modern viral diseases was evaluate by network pharmacology. Results In the prevention and treatment of modern viral diseases, Gancao (Glycyrrhizae Radix et Rhizoma)-Chenpi (Citri Reticulatae Pericarpium)-Fuling (Poria) had the highest confidence, Glycyrrhizae Radix et Rhizoma-Jiegeng (Platycodonis Radix) had the highest support. At the same time, the prescriptions were clustered and analyzed to obtain Jinyinhua (Lonicerae Japonicae Flos)-Huangqi (Astragali Radix)-Huoxiang (Agastache rugosa), Glycyrrhizae Radix et Rhizoma-Xingren (Armeniacae Semen Amarum)-Poria-Platycodonis Radix-Citri Reticulatae Pericarpium, Ganjiang (Zingiberis Rhizoma)-Renshen (Ginseng Radix et Rhizoma), Zisu (Perilla frutescens)-Gegen (Puerariae Lobatae Radix), Lugen (Phragmitis Rhizoma)-Sangye (Mori Folium), Shengjiang (Zingiberis Rhizoma Recens)-Dazao (Jujubae Fructus) clustering new prescription. The core action targets of EGFR, CASP3, VEGFA, STAT3, MMP9, HSP90AA1, mTOR, PTGS2, MMP2, TLR4, MAPK14, etc were identified. The action mechanism involved human cytomegalovirus infection, coronavirus disease-coronavirus disease 2019 (COVID-19), etc. The core action pathway were phosphatidylinositol-3/kinase protein kinase B (PI3K/Akt) signal pathway, mitogen activated protein kinase (MAPK) signal pathway, interleukin-17 (IL-17) signal pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signal pathway, etc. Conclusion Through data mining, six new prescriptions for preventing and controlling modern viral diseases were obtained, and the mechanism of action was preliminarily discussed, which provided some reference for the research and development of medicine and food homologous TCM prescriptions for the prevention and treatment of viral epidemics and related health products.
ABSTRACT
The relevance of the current epidemic situation of a new coronavirus infection is determined by new strains of the virus and the registration of cases of re-infection in COVID-19 survivors earlier. In this regard, the questions about the expediency and nature of vaccination of those who have been ill attract close attention, moreover it has affected the formation of the concept of “hybrid immunity”. The aim of this study was to analyze changes in the parameters of the immune system, reflecting their regulatory and functional potential, in response to the introduction of the peptide vaccine EpiVacCorona to persons who have suffered from the new coronavirus infection. To study the features of the formation of hybrid immunity, a retrospective analysis of the observation of 43 study participants was carried out. The inclusion criteria were data confirming COVID-19 in mild and moderate forms of the course in the period from six months to a year ago, a low level or absence of antibodies to the nucleocapsid protein SARS-CoV-2, a negative PCR result for the presence of the SARS-CoV-2 virus, the absence of comorbid pathology. The subpopulation composition, regulatory and functional potential of the immune system were determined by flow cytofluorimetry using a set of monoclonal antibodies corresponding to the goals. 21 days after the administration of a single dose of EpiVacCorona, antibodies to the vaccine peptide antigens were registered in all study participants at the highest coefficient of positivity values for the SARS-CoV-2-IgG-Vector test system used. In addition, there was a fourfold increase in the number of specific IgG to the N protein. A specific immune response to recombinant SARS-CoV-2 antigens was accompanied by a decrease in the circulation of the number of monocytes expressing TLR4, T helper cells expressing the interaction coreceptor with antigen-presenting cells, unconnected B memory with an increase in the number of B lymphocytes expressing the CD40 T-B coreceptor interaction molecule. The remaining differences in the functioning of the immune system identified in patients with COVID-19 before the vaccination in comparison with the control data have not changed. The differences consist in a decrease in the proportion of monocytes expressing HLA-DR, an increase in the expression of interaction molecules on T and B lymphocytes, an increase in the number of Treg, B1 cells, activated B lymphocytes with a decrease in the proportion of suppressor Breg and B memory. The totality of the presented data demonstrates that the COVID-19 infection that preceded vaccination in mild and moderate clinical course contributes to the formation of immunological memory, which made it possible to form a secondary immune response even to a single injection of peptide antigens of the virus.