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1.
Chinese Journal of Pharmaceutical Biotechnology ; 29(3):284-290, 2022.
Article in Chinese | EMBASE | ID: covidwho-2010558

ABSTRACT

Transmembrane serine protease 2 (TMPRSS2) is an androgen-dependent serine protease, and it had previously been reported that it had important pathological functions in tumor metastasis and invasion and virus infection. The entry of coronavirus into host cells is the prerequisite for its transmission and pathogenicity. TMPRSS2 can mediate the invasion of coronavirus into host cells by activating the spike glycoprotein of coronavirus, so it was considered as a potential target for the intervention of coronavirus infection.Current reported effective inhibitors of TMPRSS2 are broad-spectrum drugs targeting the serine protease family, suggesting urgency for exploring and developing novel TMPRSS2-specific inhibitory molecules. The biological characteristics and pathological functions of TMPRSS2 were summarized, with emphasis on the universal function of TMPRSS2 in human pathogenic coronavirus infection and the latest research trends of TMPRSS2 inhibitors in this paper, to highlight the potential of targeting TMPRSS2 as a novel strategy to prevent and limit early infection and transmission of novel coronavirus.

2.
Frontiers in Pharmacology ; 13, 2022.
Article in English | EMBASE | ID: covidwho-2009897

ABSTRACT

Infectious diseases, caused by pathogenic microorganisms, are capable of affecting crises. In addition to persistent infectious diseases such as malaria and dengue fever, the vicious outbreaks of infectious diseases such as Neocon, Ebola and SARS-CoV-2 in recent years have prompted the search for more efficient and convenient means for better diagnosis and treatment. Antibodies have attracted a lot of attention due to their good structural characteristics and applications. Nanobodies are the smallest functional single-domain antibodies known to be able to bind stably to antigens, with the advantages of high stability, high hydrophilicity, and easy expression and modification. They can directly target antigen epitopes or be constructed as multivalent nanobodies or nanobody fusion proteins to exert therapeutic effects. This paper focuses on the construction methods and potential functions of nanobodies, outlines the progress of their research, and highlights their various applications in human infectious diseases.

3.
Current pharmaceutical design ; 2022.
Article in English | MEDLINE | ID: covidwho-2009796

ABSTRACT

Heat shock protein 90 (Hsp90) is a chaperone protein that prevents many other proteins from aggregating by folding them in a certain way. Hsp90 consists of three structural domains: N-terminal, middle and C-terminal domains. Hsp90 has many activities in numerous proteins and signaling pathways like chimeric fusion proteins, steroid hormone receptors, tumor suppressor genes, and cell cycle regulatory proteins. The role of Hsp90 is not only in cancer but also in other diseases like COVID-19, leishmaniasis, diabetes, flavi virus, systemic sclerosis, grass carp reovirus, psoriasis, malaria, cardiac fibrosis, and alcohol-related liver diseases. This review is a compilation of the pharmacological profile of Hsp90 inhibitors, problems associated with them, and suggested remedies for the same.

4.
Biomolecular concepts ; 13(1):298-313, 2022.
Article in English | MEDLINE | ID: covidwho-2009730

ABSTRACT

Growth factors and cytokines activate signal transduction pathways and regulate gene expression in eukaryotes. Intracellular domains of activated receptors recruit several protein kinases as well as transcription factors that serve as platforms or hubs for the assembly of multi-protein complexes. The signaling hubs involved in a related biologic function often share common interaction proteins and target genes. This functional connectivity suggests that a pairwise comparison of protein interaction partners of signaling hubs and network analysis of common partners and their expression analysis might lead to the identification of critical nodes in cellular signaling. A pairwise comparison of signaling hubs across several related pathways might reveal novel signaling modules. Analysis of protein interaction connectome by Venn (PIC-Venn) of transcription factors STAT1, STAT3, NFKB1, RELA, FOS, and JUN, and their common interaction network suggested that BRCA1 and TSC22D3 function as critical nodes in immune responses by connecting the signaling hubs into signaling modules. Transcriptional regulation of critical hubs may play a major role in the lung epithelial cells in response to SARS-CoV-2 and in COVID-19 patients. Mutations and differential expression levels of these critical nodes and modules in pathological conditions might deregulate signaling pathways and their target genes involved in inflammation. Biological connectivity emerges from the structural connectivity of interaction networks across several signaling hubs in related pathways. The main objectives of this study are to identify critical hubs, critical nodes, and modules involved in the signal transduction pathways of innate and adaptive immunity. Application of PIC-Venn to several signaling hubs might reveal novel nodes and modules that can be targeted by small regulatory molecules to simultaneously activate or inhibit cell signaling in health and disease.

5.
PLoS pathogens ; 18(9):e1010809, 2022.
Article in English | MEDLINE | ID: covidwho-2009723

ABSTRACT

Acinetobacter baumannii is an opportunistic pathogen and an emerging global health threat. Within healthcare settings, major presentations of A. baumannii include bloodstream infections and ventilator-associated pneumonia. The increased prevalence of ventilated patients during the COVID-19 pandemic has led to a rise in secondary bacterial pneumonia caused by multidrug resistant (MDR) A. baumannii. Additionally, due to its MDR status and the lack of antimicrobial drugs in the development pipeline, the World Health Organization has designated carbapenem-resistant A. baumannii to be its priority critical pathogen for the development of novel therapeutics. To better inform the design of new treatment options, a comprehensive understanding of how the host contains A. baumannii infection is required. Here, we investigate the innate immune response to A. baumannii by assessing the impact of infection on host gene expression using NanoString technology. The transcriptional profile observed in the A. baumannii infected host is characteristic of Gram-negative bacteremia and reveals expression patterns consistent with the induction of nutritional immunity, a process by which the host exploits the availability of essential nutrient metals to curtail bacterial proliferation. The gene encoding for lipocalin-2 (Lcn2), a siderophore sequestering protein, was the most highly upregulated during A. baumannii bacteremia, of the targets assessed, and corresponds to robust LCN2 expression in tissues. Lcn2-/- mice exhibited distinct organ-specific gene expression changes including increased transcription of genes involved in metal sequestration, such as S100A8 and S100A9, suggesting a potential compensatory mechanism to perturbed metal homeostasis. In vitro, LCN2 inhibits the iron-dependent growth of A. baumannii and induces iron-regulated gene expression. To elucidate the role of LCN2 in infection, WT and Lcn2-/- mice were infected with A. baumannii using both bacteremia and pneumonia models. LCN2 was not required to control bacterial growth during bacteremia but was protective against mortality. In contrast, during pneumonia Lcn2-/- mice had increased bacterial burdens in all organs evaluated, suggesting that LCN2 plays an important role in inhibiting the survival and dissemination of A. baumannii. The control of A. baumannii infection by LCN2 is likely multifactorial, and our results suggest that impairment of iron acquisition by the pathogen is a contributing factor. Modulation of LCN2 expression or modifying the structure of LCN2 to expand upon its ability to sequester siderophores may thus represent feasible avenues for therapeutic development against this pathogen.

6.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2009529

ABSTRACT

Background: ACC is a heterogeneous neoplasm and there is no standard treatment for patients (pts) with recurrent/metastatic (R/M) disease. Vascular endothelial growth factor receptor inhibitors (VEGFRi) are frequently used to treat R/M ACC rendering mostly disease stabilization. ACC is resistant to PD-1/PD-L1 inhibitors (PD-L1i), consistent with its low mutational burden and uninflamed immune microenvironment. We hypothesized that the immunomodulatory role of VEGFRi (axitinib) would enhance PD-L1i (Avelumab) activity and be a more effective therapy for R/M ACC. Methods: Eligible pts had R/M ACC with radiological or clinical progression within 6 months (mos) of enrollment. Treatment consisted of axitinib 5 mg PO bid and avelumab 10 mg/Kg IV every 2 weeks. Primary endpoint was objective response rate (ORR) per RECIST 1.1;secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. Simon 2-stage design was applied to test the null hypothesis of ORR ≤ 5% versus the alternative ORR ≥ 20%;≥ 4 responses out of 29 pts was required to reject the null hypothesis. Results: 41 pts enrolled from 07/24/19 to 06/29/ 21;28 were evaluable for the primary endpoint (7 screen failures, 6 evaluable for safety only due to loss of insurance/logistics issues related to COVID-19 pandemic);16 pts were treated in first-line. Mutation data was available for 23 of 28 evaluable pts;7 had NOTCH1 activating mutations. The ORR was 17.9% (5/28, 95%CI: 6.1-36.9%). One response was unconfirmed (pt progressed in non-target lesions 2 mos after achieving a PR), for a confirmed ORR of 14.3% (95%CI: 4-32.7%). The median follow-up time for the 15 alive pts was 11.6 mos (min-max: 7.7-29.2 mos). Median PFS was 7.2 mos (95%CI: 3.7-11.7 mos) with a 6-mos PFS rate of 57% (95%CI: 41-79%). Median OS was 17.4 mos (95%CI: 13-NA). 5 pts remain on therapy, 2/5 with a PR. The median DOR for the 5 responders was 5.2 mos (95% CI: 3.7-NA mos). The most common treatment-related adverse events (TRAEs) were fatigue (62%), hypertension (32%), diarrhea (29%), and stomatitis (29%). Serious TRAEs occurred in 8 (24%) pts, all grade 3 and manageable. 4 (15%) pts discontinued avelumab and 9 (32%) underwent axitinib dose reduction due to toxicity. Conclusions: The study reached its primary endpoint with ≥ 4 responses out of 28 evaluable pts (ORR of 17.8%;confirmed ORR of 14.3%). The ORR and 6- mos PFS rate of 57% with axitinib and avelumab compares favorably with single agent axitinib and warrants further study of the combination.

7.
Molecular Medicine ; 28(1), 2022.
Article in English | EMBASE | ID: covidwho-2009352

ABSTRACT

Background: Sepsis is defined as a state of multisystem organ dysfunction secondary to a dysregulated host response to infection and causes millions of deaths worldwide annually. Novel ways to counteract this disease are needed and such tools may be heralded by a detailed understanding of its molecular pathogenesis. MiRNAs are small RNA molecules that target mRNAs to inhibit or degrade their translation and have important roles in several disease processes including sepsis. Main body: The current review adopted a strategic approach to analyzing the widespread literature on the topic of miRNAs and sepsis. A pubmed search of “miRNA or microRNA or small RNA and sepsis not review” up to and including January 2021 led to 1140 manuscripts which were reviewed. Two hundred and thirty-three relevant papers were scrutinized for their content and important themes on the topic were identified and subsequently discussed, including an in-depth look at deregulated miRNAs in sepsis in peripheral blood, myeloid derived suppressor cells and extracellular vesicles. Conclusion: Our analysis yielded important observations. Certain miRNAs, namely miR-150 and miR-146a, have consistent directional changes in peripheral blood of septic patients across numerous studies with strong data supporting a role in sepsis pathogenesis. Furthermore, a large body of literature show miRNA signatures of clinical relevance, and lastly, many miRNAs deregulated in sepsis are associated with the process of endothelial dysfunction. This review offers a widespread, up-to-date and detailed discussion of the role of miRNAs in sepsis and is meant to stimulate further work in the field due to the potential of these small miRNAs in prompt diagnostics, prognostication and therapeutic agency.

8.
Annals of the Rheumatic Diseases ; 81:1705-1706, 2022.
Article in English | EMBASE | ID: covidwho-2009175

ABSTRACT

Background: Uncontrolled systemic infammation characterizes COVID-19 and autoinfammatory diseases such as adult-onset Still's disease (AOSD). Biosynthesis of pro-resolving mediators (SPMs), i.e. lipoxins (LX), resolvins (Rv), pro-tectins (PD), and maresins (MaR), ensures infammation shutdown and tissue repair, limiting neutrophils recruitment and stimulating macrophages to remove apoptotic cells. Among protectins, reduction of PD1 was found in the lungs of mice infected with the H5N1 infuenza virus and experimental treatment with PD1 resulted in increased animals' survival (Morita M et al 2013). Objectives: We investigated the effects of SPMs in pathogenesis and clinical evolution of AOSD and compared these data with mild and severe COVID-19. Finally, we analyzed the potential role of PD1 in modulating the infammatory response of macrophages obtained from AOSD patients, COVID-19 patients and healthy donors (HDs). Methods: 21 patients hospitalized for COVID-19 (10 ICU and 11 hospitalized in medical clinical unit) and 13 patients with AOSD were enrolled. Plasma PD1 levels from patients and controls were analyzed by ELISA, and mono-cytes-derived macrophages were polarized into M1 and M2 phenotype. We analyzed the effect of PD-1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays. Peripheral blood mononuclear cells (PBMCS) from 3 AOSD patients, 2 COVID-19 patients and 3 HDs were obtained. Next-generation deep sequencing was then performed to identify the differences in PBMCs transcripts profiles. Results: AOSD patients with systemic scored (SS) ≥1 showed an increase of PD1 levels compared to AOSD patients with lower systemic score (p=0.04) (Figure 1A). Similarly, plasma levels of PD1 were increased in COVID-19 patients independently from their clinical subsets, compared to HDs (p=0.02). In vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a signifcant increase of M2 polarization vs control (p<0.05) (Figure 1B). Furthermore, a signifcant release of IL-10 and CCL4 from M2 macrophages was observed when compared to control (p<0.05) (Figure 1C). In the transcriptomes from 3 AOSD patients (2 mild and 1 severe), 2 COVID-19 patients (1 mild and 1 ICU) and 2 HDs, we observed that genes involved in infammation, lipid catabolism and monocytes activation were spe-cifcally dysregulated in AOSD and COVID-19 patients when compared to HDs. Among them pla2g15, pla2g12a, pla2g2d, involved in mobilization of SPMs precursors, were signifcant upregulated in patients compared to HDs (p<.01, ;log2FoldChange;>1.2) (Figure 1D). The largest part of the genes involved in infammation, lipid catabolism, and monocytes activation are less expressed in AOSD patients when compared to COVID19 patients, as reported in Table 1. Conclusion: The counterbalance by SPMs during infammation is still a largely unexplored pathway. Our study suggests that an imbalance of SPMs in autoin-fammatory diseases as well as COVID-19. The modulation of SPMs as observed in our experiments, might represent a new possible therapeutic strategy during AOSD and COVID-19.

9.
Annals of the Rheumatic Diseases ; 81:1533, 2022.
Article in English | EMBASE | ID: covidwho-2008985

ABSTRACT

Background: Everyone knows that COVID-19 not only has a severe effect on the pulmonary system, but also triggers a whole cascade of autoimmune reactions. The study of the effect of the pro-infammatory cytokine-interleukin 6 (IL6) on the clinical course of patients with ankylosing spondylitis (AS) undergoing COVID-19 is an important problem in rheumatology. Objectives: To study the signifcance of the pro-infammatory cytokine-IL-6 on the clinical features of the course of AS in patients who have undergone COVID-19. Methods: In the period from 2020-2021, 44 patients with a diagnosis (AS) were hospitalized in the City Clinical Hospital # 3 of Tashkent city. The patients were divided into two groups: Group I-20 patients with AS who underwent COVID-19 and Group II of 24 patients with no history of AS who had COVID-19 infection. The average age of patients in group I was 32 ± 4.1 years and in group II-36.5 ± 5.2 years. All patients underwent clinical and laboratory studies, including studies of serum IL-6 levels. Disease activity was assessed using the BASDAI and ASDAS scales, pain was assessed using a numerical rating scale (NRS), and peripheral joint damage was assessed by the presence of pain and swelling in 44 joints. All patients underwent PCR, as well as ELISA-IHLA tests for the presence of antibodies to COVID-19. Results: Clinical examination of the patients revealed the presence of pain in the spine, which was assessed using the numerical rating scale-(NRS) in group I it was 8.5 ± 1.2 points and 5.9 ± 2.3 points in patients of group II. Examination of peripheral joints showed an average number of painful joints (PJ) of 16.9 ± 3.2 in group I and 8.6 ± 2.7 in group II, the number of swollen joints (NSJ) 8.8 ± 2.1 in group I and 4.2 ± 1.7 in group II. group. The study of AS activity using the BASDAI scale showed an average level of 5.1 ± 1.7 points in group I and 4.4 ± 2.1 points in group II. And the study of activity on the ASDAS scale showed an average level of 4.0 ± 1.7 points in group I and 2.5 ± 0.8 points in group II, which indicates a very high activity of the pathological process in group I and medium-high activity in group II. The IL-6 level in group I was 10.2 ± pg/mL, 4.2 pg/mL in group II and 1.39 pg/mL in the control group. Conclusion: 1. The clinical course of AS in patients who have undergone COVID-19 is characterized by a more pronounced disease activity according to the BASDAI and ASDAS scales, a high intensity of pain syndrome according to a NRS, as well as a high level of IL-6. 2. A high level of IL-6 in group I indicates the impact of COVID-19 on the course, activity and severity of the autoimmune process in patients with AS, which is many times higher than in patients of group II, which allows us to consider it as a biomarker of damage to the articular and connective tissue in this infection.

10.
Annals of the Rheumatic Diseases ; 81:331-332, 2022.
Article in English | EMBASE | ID: covidwho-2008925

ABSTRACT

Background: Thrombosis is a unique complication in coronavirus disease 2019 (COVID-19). We have reported that elevated ferritin and D-dimer on admission were the risk factors of thromboses by analyzing the patients sequentially admitted to our hospital due to COVID-19 (1). However, we have not analyzed throm-botic complications in the view of the antiphospholipid antibodies (aPLs), which are frequently detected in the COVID-19 patients. Objectives: To elucidate the thrombogenic effects of aPLs in COVID-19, we analyzed the development of thrombosis in three lupus models after SARS-CoV-2 infection. Additionally, we evaluated the association of thrombotic events and the serum profile of aPLs in Japanese patients with COVID-19. Methods: Three animal models of lupus (MRL-lpr/lpr, NZBxNZW F1 and NZW×BXSB F1) were evaluated in this study. NZW×BXSB F1 was also considered as a model of antiphospholipid syndrome (APS) since aPLs were detected with a high titer (2). Experimental SARS-CoV-2 infection was induced using mouse-passaged virus strain (3). The incidence of thromboses in the lungs and kidneys were identifed by evaluating H&E staining and PTAH staining of paraf-fn-embedded sections. We have experienced 44 thrombotic events in 34 out of 594 patients admitted to our institute. As a non-thrombotic COVID-19, 68 patients were selected to make a 1 to 2 matched-pair based on the propensity score. In total 102 patients, seven types of aPLs (anti-cardiolipin (CL) IgG/IgM, anti-β2GP1 IgG/IgA/IgM, and anti-phosphatidyl serine/prothrombin complex (PS/PT) IgG/IgM) were measured using specifc ELISA kits. The patients' clinical characteristics and serological profile of aPLs were further evaluated. Results: We identifed the development of thromboses in the lungs or kidneys in 6 out of 12 (50%) NZW×BXSB F1 mice after the SARS-CoV-2 infection, whereas no thrombosis was observed in non-infected mice. Further, there was no thrombosis in the other lupus models (0%) after the infection. These fndings might suggest the pathogenic role of aPLs under the SARS-CoV-2 infection. Among our COVID-19 patients, 39 out of 102 (38%) were tested positive for one or more aPLs. The positive ratios of any aPLs were statistically indifferent between the patients with or without thrombosis;anti-CL IgG (8.8% vs 5.9%)/IgM (0% vs 5.9%), anti-β2GP1 IgG (21% vs 12%)/IgA (8.8% vs 15%)/IgM (0% vs 1.5%), and anti-PS/PT IgG (0% vs 2.9%)/IgM (12% vs 13%), respectively. In addition, their titers were relatively lower than those observed in APS patients. The patients' characteristics and the prognosis of COVID-19 were comparable regardless of the detection of any aPLs. These fndings suggested that COVID-19 associated aPLs were irrelevant to thrombotic complications. Conclusion: Thromboses were induced after the infection of SARS-CoV-2 only in the APS model. However, aPLs detected in COVID-19 patients have little impact on the development of thrombosis. SARS-CoV-2 infection might have a high risk of thrombosis, especially in APS patients, as shown in the case report (4). The discrepancy of its thrombogenic effects of aPLs might be explained by the low titer of the antibody or the diversity of antibody epitope. Further analyses are required to clarify the mechanisms of aPLs production and the development of thrombosis in COVID-19.

11.
Annals of the Rheumatic Diseases ; 81:930, 2022.
Article in English | EMBASE | ID: covidwho-2008848

ABSTRACT

Background: In acute COVID-19 infection, growing evidence hints towards a broad activation of plasma cells and the presence of pathologic autoantibodies (abs). A systematic screening for abs confrmed induction of diverse functional abs by SARS-CoV-2 infection (1, 2). Immune-mediated thrombosis, involving platelet activation, has been identifed as one of the key pathogenic mechanisms in COVID-19 and is linked to morbidity and mortality (3). As natural abs against G protein-coupled receptors, functional abs against the thrombin receptor type-1 (PAR-1) might predispose for increased activation of the coagulation system present in COVID-19 infection. Objectives: The aim of this study is to identify the diagnostic value of anti-PAR1 antibodies and their capacity to predict the outcome of COVID-19 infection. Methods: 82 serum samples from 55 individuals with COVID-19 derived from three different hospitals in Schleswig-Holstein, Germany, and 88 single time point samples from healthy controls were subjected to ELISA-based quantifcation of anti-PAR-1 abs (CellTrend GmbH Luckenwalde, Germany). The levels of anti-AT1R abs were compared with clinical and laboratory parameters. Results: COVID-19 patients revealed markedly increased levels of circulating anti-PAR1 abs in hospitalized patients particularly in those required intensive care treatment in comparison to controls (p < 0.0001, Figure 1a). Anti-PAR1 ab levels were highest in patients with fatal outcome (p = 0.006, Figure 1a). Receiver operating characteristic (ROC) analysis of PAR1 abs levels in COVID-19 patients revealed a sensitivity of 84.00% and a specifcity 79.25% for patients requiring intensive care unit (ICU) treatment and a sensitivity of 87.50 % and a specifcity 84.51 % to distinguish fatal vs. non-fatal disease outcome (Figure 1b). We found correlation of circulating anti-PAR1 abs with D dimers. Conclusion: The increased anti-PAR1 abs, their prediction to identify patients requiring ICU and fatal outcome, and the correlation with markers for blood clotting suggest a role for antibodies against PAR1 in the disease development of blood clotting in COVID-19.

12.
Annals of the Rheumatic Diseases ; 81:460-461, 2022.
Article in English | EMBASE | ID: covidwho-2008834

ABSTRACT

Background: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease that primarily affects joints but is also often characterized by extra-articular involvement1. Cardiovascular diseases are the most important causes of sudden death in these patients, which present a risk of developing cardiovascular events increased by 48%2. The causes of increased cardiovascular risk are several and not completely understood, but recent evidence supports the key role of endothelial dysfunction in pathogenesis. In this complex scenario, it is known that IL-6 receptors are present at the endothelial level and can be activated leading to endothelial dysfunction. SARS-Cov-2 is a coronavirus responsible for the disease called 'coronavirus disease 2019' (CoViD-19) characterized by clinical manifestations ranging from a flu-like syndrome up to severe lung damage associated with systemic hyper cytokine syndrome that can lead to multiple organ failure and death. Therefore, both RA and Covid-19 are associated with an increased pro-thrombotic and cardiovascular risk and IL-6 might be crucial in the patho-physiological mechanisms of both diseases. Objectives: The main hypothesis of this study was to evaluate the possible role of IL-6 as a promoter of endothelial dysfunction in RA and CoViD-19. Methods: In vitro experiments were conducted on the endothelial cell line EA. hy926. Cells were treated for 24 h with fetal bovine serum (FBS), a pool of RA patients' sera or a pool of CoViD-19 patients' sera. The expression levels of adhesion molecules (V-CAM1/CD-106, I-CAM/CD-54, p-selectine/CD-62, tissue factor/CD-142) and apoptosis were analyzed using cytofuorimetric technique. In addition, the autophagy level, using the autophagy markers p62 and LC3II, were evaluated through a western-blot analysis. The same experiments were conducted co-treating cells with the same pool of sera in addition to tocilizumab (TCZ), an anti-IL-6 drug, to verify the reversibility of the process and test the role of the aforementioned cytokine. Data are reported as interquartile median values. The Kruskal Wallis test was used for unpaired samples and the Mann-Whitney test for paired samples. P<0.05 values were considered statistically signifcant. Results: EA. hy926 cells, when treated with both RA and CoViD-19 patients' sera, showed increased levels of activation molecules and apoptosis compared to FBS treated cells. In addition, we observed increased levels of both p62 and LC3 proteins after both rheumatoid arthritis and CoViD-19 patients' sera treatment. All these fndings were reversible in the presence of TCZ. The results are presented in Figure 1. Conclusion: Our data showed that treatment with RA and CoViD-19 patients' sera increase the activation and death of endothelial cells in vitro. The increased level of cells death is possibly due to a block of autophagy. The reversibility of the process after blocking IL-6 with TCZ co-treatment confrms the hypothesis that IL-6 can play a key role in the pathogenesis of endothelial damage in patients with RA and CoViD-19.

13.
Journal of virology ; : e0102422, 2022.
Article in English | MEDLINE | ID: covidwho-2008764

ABSTRACT

Zoonotic coronaviruses represent an ongoing threat to public health. The classical porcine epidemic diarrhea virus (PEDV) first appeared in the early 1970s. Since 2010, outbreaks of highly virulent PEDV variants have caused great economic losses to the swine industry worldwide. However, the strategies by which PEDV variants escape host immune responses are not fully understood. Complement component 3 (C3) is considered a central component of the three complement activation pathways and plays a crucial role in preventing viral infection. In this study, we found that C3 significantly inhibited PEDV replication in vitro, and both variant and classical PEDV strains induced high levels of interleukin-1β (IL-1β) in Huh7 cells. However, the PEDV variant strain reduces C3 transcript and protein levels induced by IL-1β compared with the PEDV classical strain. Examination of key molecules of the C3 transcriptional signaling pathway revealed that variant PEDV reduced C3 by inhibiting CCAAT/enhancer-binding protein β (C/EBP-β) phosphorylation. Mechanistically, PEDV nonstructural protein 1 (NSP1) inhibited C/EBP-β phosphorylation via amino acid residue 50. Finally, we constructed recombinant PEDVs to verify the critical role of amino acid 50 of NSP1 in the regulation of C3 expression. In summary, we identified a novel antiviral role of C3 in inhibiting PEDV replication and the viral immune evasion strategies of PEDV variants. Our study reveals new information on PEDV-host interactions and furthers our understanding of the pathogenic mechanism of this virus. IMPORTANCE The complement system acts as a vital link between the innate and the adaptive immunity and has the ability to recognize and neutralize various pathogens. Activation of the complement system acts as a double-edged sword, as appropriate levels of activation protect against pathogenic infections, but excessive responses can provoke a dramatic inflammatory response and cause tissue damage, leading to pathological processes, which often appear in COVID-19 patients. However, how PEDV, as the most severe coronavirus causing diarrhea in piglets, regulates the complement system has not been previously reported. In this study, for the first time, we identified a novel mechanism of a PEDV variant in the suppression of C3 expression, showing that different coronaviruses and even different subtype strains differ in regulation of C3 expression. In addition, this study provides a deeper understanding of the mechanism of the PEDV variant in immune escape and enhanced virulence.

14.
Autoimmunity ; 2022.
Article in English | EMBASE | ID: covidwho-2008396

ABSTRACT

Antagonism of the neonatal Fc receptor (FcRn) by efgartigimod has been studied in several autoimmune diseases mediated by immunoglobulin G (IgG) as a therapeutic approach to remove pathogenic IgGs. Whereas reduction of pathogenic titres has demonstrated efficacy in multiple autoimmune diseases, reducing total IgG could potentially increase infection risk in patients receiving FcRn antagonists. The objective of this study was to analyse the effect of FcRn antagonism with efgartigimod on existing protective antibody titres and the ability to mount an immune response after vaccine challenge. Serum levels of total IgG and protective antibodies against tetanus toxoid (TT), varicella zoster virus (VZV), and pneumococcal capsular polysaccharide (PCP) were measured in all patients enrolled in an open-label trial of efgartigimod for the treatment of pemphigus. Vaccine specific-responses were assessed by measuring changes in IgG titres in patients with generalised myasthenia gravis (gMG) who were treated with efgartigimod and who received influenza, pneumococcal, or coronavirus disease 2019 (COVID-19) vaccines during participation in the double-blind trial ADAPT or open-label extension, ADAPT+ (n = 17). FcRn antagonism reduced levels of protective anti-TT, anti-VZV, and anti-PCP antibodies and total IgG to a similar extent;anti-TT and anti-VZV titres remained above minimally protective thresholds for the majority of patients, (10/12) 83% and (14/15) 93% respectively. Protective antibodies returned to baseline values upon treatment cessation. Antigen-specific IgG responses to influenza, pneumococcal, and COVID-19 immunisation were detected in patients with gMG who received these vaccines while undergoing therapy with efgartigimod. In conclusion, FcRn antagonism with efgartigimod did not hamper generation of IgG responses but did transiently reduce IgG titres of all specificities.

15.
Journal of chemical information and modeling ; 2022.
Article in English | MEDLINE | ID: covidwho-2008239

ABSTRACT

Five major variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged and posed challenges in controlling the pandemic. Among them, the current dominant variant, viz., Omicron, has raised serious concerns about its infectiousness and antibody neutralization. However, few studies pay attention to the effect of the mutations on the dynamic interaction network of Omicron S protein trimers binding to the host angiotensin-converting enzyme 2 (ACE2). In this study, we conducted molecular dynamics (MD) simulations and enzyme linked immunosorbent assay (ELISA) to explore the binding strength and mechanism of wild type (WT), Delta, and Omicron S protein trimers to ACE2. The results showed that the binding capacities of both the two variants' S protein trimers to ACE2 are enhanced in varying degrees, indicating possibly higher cell infectiousness. Energy decomposition and protein-protein interaction network analysis suggested that both the mutational and conserved sites make effects on the increase in the overall affinity through a variety of interactions. The experimentally determined KD values by biolayer interferometry (BLI) and the predicted binding free energies of the RBDs of Delta and Omicron to mAb HLX70 revealed that the two variants may have the high risk of immune evasion from the mAb. These results are not only helpful in understanding the binding strength and mechanism of S protein trimer-ACE2 but also beneficial for drug, especially for antibody development.

16.
Environmental Toxicology ; 2022.
Article in English | EMBASE | ID: covidwho-2007115

ABSTRACT

Since the outbreak of COVID-19, widespread utilization of disinfectants has led to a tremendous increase in the generation of disinfection byproducts worldwide. Bromoacetic acid (BAA), one of the common disinfection byproducts in the environment, has triggered public concern because of its adverse effects on urinary system in mammals. Nevertheless, the BAA-induced nephrotoxicity and potential mechanism in birds still remains obscure. According to the detected content in the Taihu Lake Basin, the model of BAA exposure in chicken was established at doses of 0, 3, 300, 3000 μg/L for 4 weeks. Our results indicated that BAA exposure caused kidney swelling and structural disarrangement. BAA led to disorder in renal function (CRE, BUN, UA) and increased apoptosis (Bax, Bcl-2, caspase3). BAA suppressed the expression of mitochondrial biogenesis genes (PGC-1α, Nrf1, TFAM) and OXPHOS complex I genes (ND1, ND2, ND3, ND4, ND4L, ND5, ND6). Subsequently, BAA destroyed the expression of Nrf2 antioxidant reaction genes (Nrf2, Keap1, HO-1, NQO1, GCLM, GCLC). Furthermore, renal oxidative damage led to disorder in uric acid metabolism genes (Mrp2, Mrp4, Bcrp, OAT1, OAT2, OAT3) and exacerbated destruction in renal function. Overall, our study provided insights into the potential mechanism of BAA-induced nephrotoxicity, which were important for the clinical monitoring and prevention of BAA.

17.
Journal of Cutaneous Immunology and Allergy ; 2022.
Article in English | EMBASE | ID: covidwho-2007095

ABSTRACT

Background: Since the campaign of vaccination against COVID-19 was started, a wide variety of cutaneous adverse effects after vaccination has been documented worldwide. Varicella zoster virus (VZV) reactivation was reportedly the most frequent cutaneous reaction in men after administration of mRNA COVID-19 vaccines, especially BNT162b2. Aims: A patient, who had persistent skin lesions after BNT162b2 vaccination for such a long duration over 3 months, was investigated for VZV virus and any involvement of vaccine-derived spike protein. Materials & Methods: Immunohistochemistry for detection of VZV virus and the spike protein encoded by mRNA COVID-19 vaccine. PCR analysis for VZV virus. Results: The diagnosis of VZV infection was made for these lesions using PCR analyses and immunohistochemistry. Strikingly, the vaccine-encoded spike protein of the COVID-19 virus was expressed in the vesicular keratinocytes and endothelial cells in the dermis. Discussion: mRNA COVID-19 vaccination might induce persistent VZV reactivation through perturbing the immune system, although it remained elusive whether the expressed spike protein played a pathogenic role. Conclusion: We presented a case of persistent VZV infection following mRNA COVID-19 vaccination and the presence of spike protein in the affected skin. Further vigilance of the vaccine side effect and investigation for the role of SP is warranted.

18.
Duzce Medical Journal ; 24(2):176-181, 2022.
Article in English | EMBASE | ID: covidwho-2006632

ABSTRACT

Aim: Fibrinogen and albumin are proteins that play a role in inflammation. In this study, it was aimed to investigate the role of fibrinogen, albumin, and fibrinogen/albumin ratio (FAR) levels as markers of disease severity and prognosis in coronavirus disease 2019 (COVID-19) patients. Material and Methods: Seventy-one patients aged between 19 and 84 years diagnosed with COVID-19 who were hospitalized in Sakarya University Training and Research Hospital, Neurology Department between March and May 2020 were analyzed retrospectively. Fibrinogen, albumin, FAR, D-dimer, platelet, and C-reactive protein (CRP) levels of the patients were compared according to the length of hospitalization duration, survival, and clinical severity of COVID-19. Results: Twenty-eight (%39.4) of the patients were male and 43 (%60.6) were female, and the mean age was 55.7±20.7 years. There was a significant difference between the groups of COVID-19 clinical severity in terms of age, fibrinogen, albumin, FAR, D-dimer, and CRP values (all p values were <0.001). Also, significantly higher fibrinogen, FAR, D-dimer, and CRP values were found in patients hospitalized longer, while the albumin level was lower in these patients (all p values were <0.001). FAR values were higher and albumin values were lower in non-surviving patients compared to surviving patients (p=0.025 and p<0.001, respectively). Conclusion: FAR levels may be useful in predicting mortality risk in COVID-19 patients. In addition, it may be helpful and useful in determining the prognosis since it has higher levels as the severity of the disease and the length of hospital stay increase.

19.
Indian Journal of Critical Care Medicine ; 26:S91, 2022.
Article in English | EMBASE | ID: covidwho-2006379

ABSTRACT

Aim and background: COVID-19 pandemic is still posing a great challenge to the global healthcare system. Accumulating evidence from various studies suggests that the serum levels of inflammatory markers have the potential in determining the severity of disease, and possibly may serve as potential prognostic biomarkers for COVID-19. Increased levels of inflammatory markers such as interleukin-6 (IL-6), procalcitonin (PCT), d-dimer, C-reactive protein (CRP), and ferritin, are found to be associated with poor clinical outcomes in severe patients. Application of scoring system for critically-ill COVID-19 patients facilitates intensivists for prognosis and predicting mortality. However, no such scoring system is yet available for COVID-19. Therefore, the existing scoring systems, Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, and Sequential Organ Failure Assessment (SOFA) score are used to assess disease severity and estimate mortality in critically ill COVID- 19 patients. Objective: To determine the potential of ICU-based scoring system Sequential Organ Failure Assessment (SOFA) score in combination with inflammatory markers as predictors of 28 days mortality in critically-ill COVID-19 patients. Materials and methods: This is a single-center, observational cohort study, conducted in Max Superspeciality Hospital, Vaishali, Ghaziabad, U.P. (India). The study included 80 critically ill COVID-19 patients admitted to ICU from 3rd August to 2nd October 2020. The patients were followed up for 28 days or until their death. The core outcome was 28 days mortality in COVID-19 patients admitted to ICU. SOFA score was calculated from the time of admission (0 hours) up till 96 hours of ICU stay, to predict the severity of the disease. The levels of inflammatory markers (serum levels of IL-6, d-dimer, procalcitonin, C-reactive protein, and ferritin) were measured at the time of admission (0 hours) and 96 hours after admission. The statistical analysis was performed using IBM Statistical Product and Service Solutions (SPSS) version 17.0. Results: Among the 80 patients admitted to the ICU, 56 survived while 24 patients died at the hospital. Comorbidities were present in 60 patients, with diabetes being the most common, followed by hypertension. At 96 hours of admission to ICU, the SOFA score was significantly higher in non-survivors than survivors (3.75 ± 2.94 vs 2.16 ± 0.87;P < 0.001). Multivariable regression analysis showed significantly increased odds of mortality associated with higher SOFA score (OR- 2.228 [95% CI: 1.220-4.068];P = 0.009) and Procalcitonin levels (OR- 1.983 [95% CI: 1.129-3.485];P = 0.017) at 96 hours of admission. The ROC analysis showed SOFA score ≥4 and PCT ≥0.6 as cut-off values. Conclusion: The present study indicates that using SOFA score along with procalcitonin could function as an effective prognostic tool to predict 28-day mortality in critically-ill COVID-19 patients. However, increased PCT levels could be due to bacterial co-infections, hence additional studies are required to assess the validity of PCT in critically ill COVID-19 pts.

20.
Osteoarthritis and Cartilage ; 30:S6, 2022.
Article in English | EMBASE | ID: covidwho-2004251

ABSTRACT

Purpose: The field of osteoarthritis (OA) biology is rapidly evolving and brilliant progress has been made this year as well. Methods: Landmark studies of OA biology published in 2021 and early 2022 were selected through PubMed searches and classified by their molecular mechanisms, and it was largely divided into the intra-cellular mechanisms and the inter-compartment or inter-cellular interaction in OA progression. Results: The intra-cellular mechanisms involving OA progression included 1) Piezo1/TRPV4-mediated calcium signaling, 2) low grade inflammation by TLR-CD14-LBP complex and IKKβ-NFkB signaling, 3) PGRN/TNFR2/14-3-3ε/Elk-1 anabolic cascade, 4) G protein-coupled receptor (GPCR) signaling, 5) mechanical loading-cilia/Ift88-hedgehog signaling, 6) mitochondrial fission by ERK1/2-DRP1 pathway, and 7) hypoxia-DOT1L-H3K79 methylation pathway. The studies on inter-compartment or inter-cellular interaction in OA progression included the following subjects: 1) the anabolic role of Lubricin, a proteoglycan from superficial zone cells, 2) osteoclast-chondrocyte interaction via exosomal miRNA and sphingosine 1-phosphate (S1P), 3) αV integrin-mediated TGFβ activation by mechanical loading, 4) TGFβ-mediated suppression of sclerostin in osteocytes, 5) catabolic role of Flightless I as a DAMPs-triggering molecule, and 6) catabolic role of paracrine signaling from fat. Conclusions: Despite the disastrous Covid-19 pandemic situation, many outstanding studies have expanded the boundary of OA biology. They give us not only critical insight on pathophysiology, but also clue for the treatment of OA.

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