Research progress of ulinastatin in treatment of COVID-19.

Coronavirus disease 2019 (COVID-19) is still spreading worldwide. At present, no specific drug has been developed for the virus. Ulinastatin plays an important role in anti-inflammatory. Clinically, it is mainly used in acute pancreatitis, shock and disseminated intravascular coagulation. It also has the effects of antioxidant stress, anticoagulation and immune regulation, which may be of great significance to reduce the severity and mortality of COVID-19. Combined with the pharmacological effect of ulinastatin and its clinical application in the treatment of COVID-19 complications such as acute respiratory distress syndrome and sepsis lung injury, this paper discusses the feasibility of its application in COVID-19, so as to provide help for the clinical treatment and new drug research and development of this disease.Copyright © 2022 Tianjin Press of Chinese Herbal Medicines. All Rights Reserved.

Neuro-PASC is characterized by enhanced CD4+ and diminished CD8+ T cell responses to SARS-CoV-2 Nucleocapsid protein.

Introduction: Many people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents. Results: We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4+ T cell responses and diminished CD8+ memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8+ T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction. Discussion: We conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions.

Beneficial or detrimental activity of regulatory T cells, indoleamine 2,3-dioxygenase, and heme oxygenase-1 in the lungs is influenced by the level of virulence of Mycobacterium tuberculosis strain infection.

Tuberculosis (TB) caused by the complex Mycobacterium tuberculosis (Mtb) is the main cause of death by a single bacterial agent. Last year, TB was the second leading infectious killer after SARS-CoV-2. Nevertheless, many biological and immunological aspects of TB are not completely elucidated, such as the complex process of immunoregulation mediated by regulatory T cells (Treg cells) and the enzymes indoleamine 2,3-dioxygenase (IDO) and heme oxygenase 1 (HO-1). In this study, the contribution of these immunoregulatory factors was compared in mice infected with Mtb strains with different levels of virulence. First Balb/c mice were infected by intratracheal route, with a high dose of mild virulence reference strain H37Rv or with a highly virulent clinical isolate (strain 5186). In the lungs of infected mice, the kinetics of Treg cells during the infection were determined by cytofluorometry and the expression of IDO and HO-1 by RT-PCR and immunohistochemistry. Then, the contribution of immune-regulation mediated by Treg cells, IDO and HO-1, was evaluated by treating infected animals with specific cytotoxic monoclonal antibodies for Treg cells depletion anti-CD25 (PC61 clone) or by blocking IDO and HO-1 activity using specific inhibitors (1-methyl-D,L-tryptophan or zinc protoporphyrin-IX, respectively). Mice infected with the mild virulent strain showed a progressive increment of Treg cells, showing this highest number at the beginning of the late phase of the infection (28 days), the same trend was observed in the expression of both enzymes being macrophages the cells that showed the highest immunostaining. Animals infected with the highly virulent strain showed lower survival (34 days) and higher amounts of Treg cells, as well as higher expression of IDO and HO-1 one week before. In comparison with non-treated animals, mice infected with strain H37Rv with depletion of Treg cells or treated with the enzymes blockers during late infection showed a significant decrease of bacilli loads, higher expression of IFN-g and lower IL-4 but with a similar extension of inflammatory lung consolidation determined by automated morphometry. In contrast, the depletion of Treg cells in infected mice with the highly virulent strain 5186 produced diffuse alveolar damage that was similar to severe acute viral pneumonia, lesser survival and increase of bacillary loads, while blocking of both IDO and HO-1 produced high bacillary loads and extensive pneumonia with necrosis. Thus, it seems that Treg cells, IDO and HO-1 activities are detrimental during late pulmonary TB induced by mild virulence Mtb, probably because these factors decrease immune protection mediated by the Th1 response. In contrast, Treg cells, IDO and HO-1 are beneficial when the infection is produced by a highly virulent strain, by regulation of excessive inflammation that produced alveolar damage, pulmonary necrosis, acute respiratory insufficiency, and rapid death.

Early Inflammatory Profiles Predict Maximal Disease Severity in Covid-19

Background: Better understanding of host inflammatory changes that precede development of severe COVID-19 could improve delivery of available antiviral and immunomodulatory therapies, and provide insights for the development of new therapies. Method(s): In plasma from individuals with COVID-19, sampled <=10 days from symptom onset from the All-Ireland Infectious Diseases Cohort study, we measured 61 biomarkers, including markers of innate immune and T cell activation, coagulation, tissue repair, lung injury, and immune regulation. We used principal component analysis (PCA) and k-means clustering to derive biomarker clusters, and univariate and multivariate ordinal logistic regression to explore association between cluster membership and maximal disease severity, adjusting for risk factors for severe COVID-19, including age, sex, ethnicity, BMI, hypertension and diabetes. Result(s): From March 2020-April 2021, we included 312 individuals, (median (IQR) age 62 (48-77) years, 7 (4-9) days from symptom onset, 54% male) in the analysis. PCA and clustering derived 4 clusters. Compared to cluster 1, clusters 2-4 were significantly older and of higher BMI but there were no significant differences in sex or ethnicity. Cluster 1 had low levels of inflammation, cluster 2 had higher levels of markers of tissue repair and endothelial activation (EGF, VEGF, PDGF, TGFalpha, serpin E1 and p-selectin). Cluster 3 and 4 were both characterised by higher overall inflammation, but compared to cluster 4, cluster 3 had downregulation of growth factors, markers of endothelial activation, and immune regulation (IL10, PDL1), but higher alveolar epithelial injury markers (RAGE, ST2). In univariate analysis, compared to cluster 1, cluster 3 had the highest odds of severe disease (OR (95% CI) 9.02 (4.62-18.31), followed by cluster 4: 5.59 (2.75-11.72) then cluster 2: 4.5 (2.38-8.81), all p < 0.05). Cluster 3 remained most strongly associated with severe disease in fully adjusted analyses;cluster 3: OR(95% CI) 5.99 (2.69-13.35), cluster 2: 3.14 (1.54-6.42), cluster 4: 3.13 (1.36-7.19), all p< 0.05). Conclusion(s): Distinct early inflammatory profiles predicted maximal disease severity independent of known risk factors for severe COVID-19. A cluster characterised by downregulation of growth factor and endothelial markers and early evidence of alveolar injury was associated with highest risk of developing severe COVID19. Whether this reflects a dysregulated inflammatory response that could improve targeted treatment requires further study. Heatmap of biomarker derived clusters and forest plot of association between clusters and disease severity. A: Heatmap demonstrating differences in biomarkers between clusters B: Forest plot demonstrating odds ratio of specific clusters for progressing to moderate or severe disease (reference Cluster 1), calculated using ordinal logistic regression. Odds ratio (95% CI) presented as unadjusted and fully adjusted (for age, sex, ethnicity, BMI, hypertension, diabetes, immunosuppression, smoking and baseline anticoagulant use). Maximal disease severity graded per the WHO severity scale.

Therapeutic Effect of Gegentang Granules on Mouse Model with hCoV-229E Pneumonia and Hanshi Yidu Xifei Syndrome.

Objective:To determine the therapeutic effect of Gegentang granules on a disease-syndrome mouse model combining human coronavirus 229EhCoV-229Epneumonia with Hanshi Yidu Xifei syndrome in vivo. Method(s): Mice were randomly divided into normal group,infection group,cold-dampness group,model group,chloroquine phosphate group0.18 g.kg-1,interferon-alpha2bIFN-alpha2bgroup1.83x106 U.kg-1, Gegentang granules high-dose and low-dose groups6.6,3.3 g.kg-1with 10 mice in each group. Cold-dampness environment and hCoV-229E infection were used for modeling,and the general status and lung index of mice in each group were observed. The viral load in lung tissue was detected by real-time fluorescent quantitative polymerase chain reactionReal-time PCR,the pathological changes in lung tissue were evaluated by hematoxylin-eosinHEstaining,the levels of serum gastrointestinal hormones and inflammatory factors in lung tissue were detected by enzyme-linked immunosorbent assayELISA,and the percentage of peripheral blood lymphocytes was detected by flow cytometry. Result(s):Comparing with model group,Gegentang granules could significantly alleviate the physical signs of Hanshi Yidu Xifei syndrome,including listlessness,weakness of limbs,sticky stool,etc. Comparing with model group,Gegentang granules high-dose group significantly reduced lung index,histopathological score of interstitial lung and bronchus,and the level of serum motilinP< 0.05,P<0.01,two doses of Gegentang granules could significantly increase the level of serum gastrinP< 0.05,P<0.01,the percentage of CD4+ ,CD8+ T lymphocytes in peripheral bloodP<0.05,P<0.01,and the level of tumor necrosis factor-alphaTNF-alphain lung tissue was significantly decreasedP<0.01,and the level of interleukin-6IL-6showed decreasing tendency. Conclusion(s): Gegentang granules has therapeutic effect on model mice. It can improve the appearance and behavior characterization,regulate the level of gastrointestinal hormones,decrease lung index and histopathological score,and possibly play an immunomodulatory role by inhibiting the expression of inflammatory cytokines in lung tissue and restoring the percentage of peripheral blood lymphocytes.Copyright © 2022, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica. All rights reserved.

NAD+ metabolism-based immunoregulation and therapeutic potential.

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.

Changes in Juvenile Dermatomyositis after the Covid-19 Pandemic

Background. Prior research has shown that viruses may trigger JDM, although the degree to which COVID-19 may serve as a trigger for JDM remains unknown. We present two case reports of JDM occurring after COVID-19 infection. We also provide case numbers of new JDM diagnoses pre-and post-COVID-19 as well as an analysis of JDM population characteristics pre-and post-COVID-19. A 5year-old female developed upper respiratory infection (URI) symptoms and was diagnosed with COVID-19 in December of 2020. She developed Gottron's sign, heliotrope rash, and weakness resulting in admission in February of 2021. She had elevated CK, AST, ALT, LDH, and aldolase. Her CMAS (childhood myositis assessment scale) was 24. An MRI showed diffuse myositis. Myositis specific antibody (MSA) testing revealed a positive MJ antibody. She was diagnosed with JDM and started on steroids, methotrexate, hydroxychloroquine, and IVIG with improvement. The second patient was a 4year-old female who was diagnosed with COVID-19 in October 2020. In January 2021, she developed heliotrope rash and Gottron's papules. She developed decreased exercise tolerance in May 2021 found to have elevated Aldolase and LDH. Her CMAS was 34. An MRI showed diffuse myositis. MSA testing was significant for a positive P155/140 antibody. She was started on hydroxychloroquine, steroids, IVIG and methotrexate with improvement. Due to the aforementioned cases a retrospective analysis was performed assessing the characteristics of JDM pre-and post-COVID-19 at Lurie Children's Hospital. Methods. The Cure JM biorepository houses clinical data, laboratory data, and patient samples obtained at the onset of JDM. The following information was obtained from newly diagnosed JDM patients: MSA, DAS (disease activity score), flow cytometry results, vWF antigen, neopterin, CMAS, capillary end row loop(ERL), LDH, Aldolase, ESR, CRP, IgG, complements, ANA, and age at diagnosis. We identified 10 patients with a diagnosis of JDM from January 1st 2020 -July 1st 2021 who were designated as the post-COVID-19 group. This population was compared to a total of 51 patients diagnosed with JDM between Jan 1st 2010 and December 31st 2019 who were designated as the pre-COVID-19 group. Data analysis was performed using Welch T-testing. Research enrollment was impacted due to the COVID-19 pandemic. To better assess JDM rates, chart review and EMR reports were obtained to determine the total number of JDM diagnoses. Results. T-testing showed no significant change in DAS, ERL count, T or B cell flow cytometry, vWF antigen, CK, CMAS, CRP, Aldolase, LDH, IgG, complements or ANA titer between the pre-and post-COVID-19 JDM groups. The analysis showed a significant change in NK cell population with a decrease in the absolute NK cell number (pre 163, post 90.75. P value 0.03), and NK cell percentage (pre 6.6%, post 3.625%, P value 0.008). Both of the patients presented in this case report showed a low NK cell number (1% and 3% respectively). The total number of new JDM cases rose from an average of 6.3 cases per year to an average 9 cases per year from January 1st 2020 to December 31st 2021. Conclusion. This study provides two case reports of COVID-19 likely triggering JDM. This study also shows a modest increase in the number of new JDM cases since the onset of the pandemic. Interestingly, the NK cell population in the post-COVID-19 JDM patients were significantly decreased. NK cells have multiple roles in not only immune regulation, but also the immune response to viruses. This study suggests that NK cells play a role in the development of in virally mediated JDM, specifically in cases triggered by COVID-19. Future studies will be important to further delineate the function of NK cells in these patients. Markers of JDM disease severity, including DAS, Neopterin, CK, and CMAS, did not significantly change in our institution's JDM population after the onset of the COVID-19 pandemic.

Trained innate immunity and diseases: Bane with the boon

Emerging research shows that innate immunity can also keep the memory of prior experiences, challenging the long-held notion that immunological memory is only the domain of the adaptive immune cells. However, the absence of immunological memory in innate immune responses has recently been brought into question. Now it is known that after a few transient activations, innate immune cells may acquire immunological memory phenotype, resulting in a stronger response to a subsequent secondary challenge. When exposed to particular microbial and/or inflammatory stimuli, trained innate immunity is characterized by the enhanced non-specific response, which is regulated by substantial metabolic alterations and epigenetic reprogramming. Trained immunity is acquired by two main reprogramming, namely, epigenetic reprogramming and metabolic adaptation/reprogramming. Epigenetic reprogramming causes changes in gene expression and cell physiology, resulting in internal cell signaling and/or accelerated and amplified cytokine release. Metabolic changes due to trained immunity induce accelerated glycolysis and glutaminolysis. As a result, trained immunity can have unfavorable outcomes, such as hyper inflammation and the development of cardiovascular diseases, autoinflammatory diseases, and neuroinflammation. In this review, the current scenario in the area of trained innate immunity, its mechanisms, and its involvement in immunological disorders are briefly outlined.Copyright © 2022

Ayurvedic and Other Herbal Remedies for Dengue: An Update

Dengue fever is a flu-like ailment propagated by female mosquitos of the Aedes aegypti species. It is also known as dandaka jwara in Ayurveda. It is most common in the world's subtropical and tropical climate zones. Vomiting, severe headache, nausea, rashes, joint pain, pain behind the eyes, muscle pain, and swollen glands are all common dengue symptoms. If not handled promptly, these symptoms can lead to more severe issues such as exhaustion, blood in the vomit, continuous vomiting, bleeding gums, restlessness, severe abdominal pain, and rapid bleeding. Because there is no specific medication for dengue fever, the disease is treated by eliminating and managing the symptoms. Fortunately, there are a variety of ayurvedic remedies (like Carica papaya L., Cissampelos pareira L., etc.) that can help to tackle the same by strengthening the immune system and controlling hyperthermia. This review article provides a comprehensive overview of dengue virus infections, clinical symptoms, diagnosis, mitigation, and treatments, focusing on ayurvedic and herbal remedies.Copyright © 2022 The Author(s)

Immunomodulatory effects of complex probiotics on the immuno-suppressed mice induced by cyclophosphamide.

Introduction: Previous studies have reported the beneficial effects of Bifidobacterium animalis subsp. lactis XLTG11, Lacticaseibacillus casei Zhang, and Lactiplantibacillus plantarum P8, respectively. However, studies on the immunomodulatory enhancing effects of three complex probiotics have not been conducted. The aim of our study is to investigate the immunomodulatory effects of complex probiotics effect on the immunosuppressed mice induced by cyclophosphamide (CTX). Methods: An immunocompromised mouse model was established by intraperitoneal injection of cyclophosphamide, which was gavage of different doses of complex probiotics and levamisole hydrochloride. The splenic and thymic indices, intestinal barrier, leukocyte and lymphocyte counts, percentage of splenic lymphocyte subpopulations, cytokine levels, and gut microbiota were determined. Results: Results showed that the complex probiotics significantly elevated the spleen and thymus indices, increased the villi and crypt depth and the goblet cells. The leukocyte and lymphocyte counts and the percentage of splenic lymphocyte subpopulations in the CTX-treated mice were significantly elevated by the complex probiotics. In addition, the cytokines (IL-6, IL-10, IL-1ß, and IFN-γ) were significantly increased after complex probiotic treatment. The complex probiotics restored the gut microbiota structure to the pattern of the control group by reducing the ratio of Firmicutes/Bacteroidetes and enhancing the relative abundances of specific microbiota that produced short-chain fatty acids. Discussion: This study provides theoretical support for the immunity-enhancing function of the complex probiotics as well as a pharmacological basis for its further development and utilization.

Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes

BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic. OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS: Articles were searched on PubMed and CNKI with the key words of "SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review. RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. © 2023, Publishing House of Chinese Journal of Tissue Engineering Research. All rights reserved.

Exploring Feature Genes for Ischemic Stroke Based on Bioinformatics and Machine Learning

Background and Aims: This study aims to screen the feature genes of ischemic stroke (IS) by bioinformatics and machine learning (ML) and explore the possible pathophysiological mechanism of the genes in IS. Method(s): Two RNA sequencing datasets were downloaded from NCBI Gene Expression Omnibus (GEO) database. The GSE122709 dataset with a larger sample size was used as the training set and analyzed for differentially expressed genes (DEGs), while the GSE140275 dataset was used as the test set. The DEGs were further analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) enrichment analyses. Then, feature genes selection was performed by two ML algorithms. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of the ML algorithms. Result(s): A total of 378 DEGs (Fold Change>=2 and p value<=0.05) were identified. The GO and KEGG analyses demonstrated that the majority of DEGs were associated with inflammatory response, immune regulation and COVID-19. The DO analysis revealed that the DEGs were mainly linked to demyelinating disease and cancer. The TVP23C and B3GAT1 were identified as feature genes by ML algorithms, and the AUCs of them were closer to 1 both in the training and test set. It is found that B3GAT1 may be involved in brain injury of IS by regulating AMRA glutamate receptors. Conclusion(s): The integrated approach of bioinformatics and ML could be a novel approaches for screening feature genes, and the B3GAT1 gene may be a possible therapeutic target in IS.

Dual Roles of Tumor Necrosis Factor Superfamily 14 in Antiviral Immunity.

Tumor necrosis factor superfamily 14 (TNFSF14) (LIGHT) is an interesting costimulatory molecule associated with T lymphocyte activation, and it mainly exerts its biological effects by binding to its receptors herpesvirus invasion mediator (HVEM) and lymphotoxin-ß receptor. Research shows that TNFSF14 plays a critical regulatory role in immune responses to viral infection, but its role is different in different diseases. TNFSF14 can be a cytokine neutralization target during novel coronavirus infection, and anti-TNFSF14 monoclonal antibody treatment can reduce the risk of respiratory failure and mortality. When the host is infected with adenovirus, TNFSF14 can be used as an inflammatory biomarker to indicate whether there was an adenovirus infection in the host and the degree of disease caused by viral infection. When hosts suffer influenza virus infection, the TNFSF14-HVEM signaling pathway can stimulate the maturation and proliferation of memory CD8+ T cells, which helps the host immune system stimulate a second immune response against respiratory virus infection. TNFSF14 can act as an immune adjuvant and enhance the immunogenicity of the human papillomavirus (HPV) DNA vaccine when the host is infected with HPV. During hepatitis virus infection, TNFSF14 acts as a proinflammatory factor, participates in inflammation and causes tissue damage. In conclusion, TNFSF14 plays different and significant roles in diverse viral infections. This article reviews the current research on TNFSF14 in antiviral immunity.

Pregnant Women Infected with Coronavirus Disease 2019 Pneumonia: A Case Series in Medan, Indonesia

BACKGROUND: Pregnancy state affects the immune regulation including physical barrier, innate, and adaptive immunity-related to susceptibility of infections and increasing risk for severe to critical case of COVID-19. Further, high risk of thrombosis becomes a challenge in the management of COVID19 in pregnancy due to the strong association with worse outcome. CASE REPORT: Here, we present three cases of pregnant women infected with COVID-19 pneumonia with different outcomes in maternal and fetal condition related to high-risk thrombosis. Serial inflammatory markers were needed to the early detect the disease progressivity in pregnant women with COVID-19. Further, complete assessment of fetus including reverse transcriptase-polymerase chain reaction and chest X-ray must be performed to the early diagnosis of COVID-19 in neonatal whose mother was infected by SARS-CoV-2. CONCLUSION: Pregnancy state affects the immune regulation including physical barrier, innate, and adaptive immunity-related to susceptibility of infections and increasing risk for severe to critical case of COVID-19. Further, high risk of thrombosis becomes a challenge in the management of COVID19 in pregnancy due to the strong association with worse outcome. Although fetal transmission of COVID-19 to fetus remains unclear, complete assessment of fetus including RT-PCR, and chest X-ray must be performed to the early diagnosis of COVID-19 in neonatal whose mother was infected by SARS-CoV-2.

ROLE OF VITAMIN C IN THE TREATMENT AND PREVENTION OF COVID-19

Pathophysiologically, SARS-CoV-2 is similar to SARS-CoV-1, causing a strong characteristic inflammatory reaction that damages the airways [8]. [...]combined antiviral and host responses contribute to disease severity, as seen in cases of SARS-CoV-1 and MERS-CoV infections [9]. [...]a spurt of cytokines released in response to viral infection results in cytokine storm and sepsis, leading to a mortality rate of 28% in critical COVID-19 cases [10]. [...]SARS-CoV-2 decreases ACE2 receptor expression, which is associated with acute lung injury and disease pathology. Since ACE2 controls the renin-angiotensin system (RAS), its suppression can impair RAS homeostasis and influence blood pressure, electrolyte equilibrium, inflammation, and vascular permeability in the airways [14]. The enhanced requirement for antioxidants and consumption of vitamin C by leukocytes could explain the reduction in vitamin C levels observed during infections in general, during lung infections specifically [29], and in critically ill patients [30]. Besides the antioxidative effects of vitamin C, its beneficial functions during pneumonia act via signaling pathways associated with inflammation suppression and enhancement of immunoregulation [31].

Immune regulation of AP-N, DDP4 and ACE2 receptors and the susceptibility to infections with coronavirus 229E, MERS-CoV and SARS-CoV2

The Coronaviridae family includes the seven known human coronavi-ruses (HCoV) that cause mild to moderate respiratory infections (HCo-V-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1) as well as severe illness and death (MERS-CoV, SARS-CoV, SARS-CoV-2). Severe infections in-duce inflammatory responses that are often intensified by host ada-ptive immune pathways. Proinflammatory responses are triggered by CoV entry mediated by host cell surface receptors. Interestingly, four of the seven strains use cell surface metallopeptidases as receptors. The entry receptors for specific coronaviruses are: aminopeptidase N (AP-N), dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme 2 (ACE2) for HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV2, respectively. In addition, these receptors perform many physiological functions, including the regulation of the circulatory and immune sys-tems. Coronavirus receptors are also highly expressed in human tissues and organs (intestines, kidneys, heart, lungs). Additionally, some cy-tokines, chemokines, and other proteins and immune cells influence the modulation of the expression of coronavirus receptors. This review presents the biological role of receptor proteins in the regulation of human physiological systems, the impact of the immune response on susceptibility to coronavirus infections, and the potential effects of glucocorticosteroids (GCS) and specific allergen immunotherapy (AIT) used in the treatment of asthma and allergy on the suscpetibility to coronaviral infections.

Therapeutic Plants with Immunoregulatory Activity and Their Applications: A Scientific Vision of Traditional Medicine in Times of COVID-19.

The progression of SARS-CoV-2 (COVID-19) in humans heavily depends on the patient's overall health status, especially on its immunoregulatory capacity. Different plants and plant-derived preparations (infusions, encapsulated, etc.) have been used as immunoregulators, several of them with scientific support. Nevertheless, due to the composition complexity of such plant-derived preparations, the molecular and physiological mechanisms involved in their beneficial effects remain, in some cases, unclear. In this review article, the most reported plants used in traditional medicine to enhance immunoregulatory capacity are presented, and their effect on the innate immune response is discussed and correlated with their respective phytochemical profile. Understanding how the plant phytochemical profile relates to the observed impact on the innate and adaptative immune response is fundamental to designing plant-derived co-treatments to lessen the symptoms and favor the recovery of COVID-19 patients. In this regard, we propose a prospective guideline for using plants and plant-derived preparations as co-treatments for COVID-19 (and similar viral infections), which could be helpful in the context of the worldwide effort to end the current SARS-CoV-2 pandemic.

Coinhibition: A self Q&A

There are two approaches to scientific investigation, the common approach (proving one’s theory) and Popper’s approach (falsification of one’s theories). Popper’s approach has advantages as well as dangers (being perceived as not sure of one’s theories, or even be hostile to them—an ‘auto-traitor’). Nevertheless, the Popper approach can bridge the gap between inhibition (directly observable) and inhibitory regulation (not directly observable). Suppression of immune responses by antigen-specific antibody has led to theories regarding immunoregulation by immune products. There are many immune products capable of regulating immune responses. The inhibitory outcomes of this regulation have been called coinhibition and immune checkpoint inhibition. Coinhibition should be used when regulation begins at the cell surface or in the cell cytoplasm, which opens up the possibility of antigen-specific regulation. Immune checkpoint inhibition should be used when the initiating inhibitory event occurs in the nucleus, such as by directly affecting the cell cycle, where the concept of antigen-specific regulation is more difficult to invoke. These forms of immunoregulation could be corrupted by viral infections, such as in COVID-19 infections.

Oral manifestations in patients with COVID- 19 disease

The aim is to determine oral manifestations in patients with COVID-19 disease and in the postcovid period. Methods: A special survey (questionnaire) was made in 424 people who had COVID-19 confirmed by RT-PCR, ELISA for specific IgM and IgG antibodies and Chest CT scan (168 people). 123 people had complaints and clinical symptoms in the oral cavity 2-6 months after the illness and they came to the University dental clinic. Laboratory tests have been performed (clinical blood test, blood immunogram, virus and fungal identification). Results: Survey results showed that 16,0% participants had asymptomatic COVID-19, 23,6% - mild and 48,1% moderate disease. 12,3% with severe COVID-19 were treated in a hospital with oxygen support. In the first 2 weeks 44,3% indicated xerostomia, dysgeusia (21,7%), muscle pain during chewing (11,3%), pain during swallowing (30,2%), burning and painful tongue (1,9%), tongue swelling (30,2%), catharal stomatitis (16,0%), gingival bleeding (22,6%), painful ulcers (aphthae) (8,5%) and signs of candidiasis - white plaque in the tongue (12,3%). After illness (3-6 months), patients indicated dry mouth (12,3%), progressing of gingivitis (20,7%) and periodontitis (11,3%). In patients who applied to the clinic we identified such diagnoses: desquamative glossitis - 16 cases, glossodynia (11), herpes labialis and recurrent herpetic gingivostomatitis (27), hairy leukoplakia (1), recurrent aphthous stomatitis (22), aphthosis Sutton (4), necrotising ulcerative gingivitis (13), oral candidiasis (14), erythema multiforme (8), Stevens-Johnson syndrome (2), oral squamous cell papillomas on the gingiva (4) and the lower lip (1). According to laboratory studies, virus reactivation (HSV, VZV, EBV, CMV, Papilloma viruces) was noted in 52 patients (42,3%), immunodeficiency in 96 people (78,0%), immunoregulation disorders (allergic and autoimmune reactions) in 24 people (19,5%). Conclusions: Lack of oral hygiene, hyposalivation, vascular compromise, stress, immunodeficiency and reactivation of persistent viral and fungal infections in patients with COVID-19 disease are risk factors for progression of periodontal and oral mucosal diseases.

Immunomodulatory properties of triterpenes.

The immune system is one of the main defence mechanisms of the human body. Inadequacy of this system or immunodeficiency results in increased risk of infections and tumours, whereas over-activation of the immune system causes allergic or autoimmune disorders. A well-balanced immune system is important for protection and for alleviation of these diseases. There is a growing interest to maintain a well-balanced immune system, especially after the Covid-19 pandemic. Many biological extracts, as well as natural products, have become popular due to their wide array of immunomodulatory effects and influence on the immune system. Triterpenes, one of the secondary metabolite groups of medicinal plants, exhibit immunomodulatory properties by various mechanisms. Different triterpenes, including components of commonly consumed plants, can promote some protection and alleviation of disease symptoms linked with immune responses and thus enhance overall well-being. This review aims to highlight the efficacy of triterpenes in light of the available literature evidence regarding the immunomodulatory properties of triterpenes. We have reviewed widely investigated immunomodulatory triterpenes; oleanolic acid, glycyrrhizin, glycyrrhetinic acid, pristimerin, ursolic acid, boswellic acid, celastrol, lupeol, betulin, betulinic acid, ganoderic acid, cucumarioside, and astragalosides which have important immunoregulatory properties. In spite of many preclinical and clinical trials were conducted on triterpenes related to their immunoregulatory actions, current studies have several limitations. Therefore, especially more clinical studies with optimal design is essential.