Molecular genetics and genomics of the ABO blood group system

The A and B oligosaccharide antigens of the ABO blood group system are produced from the common precursor, H substance, by enzymatic reactions catalyzed by A and B glycosyltransferases (AT and BT) encoded by functional A and B alleles at the ABO genetic locus, respectively. In 1990, my research team cloned human A, B, and O allelic cDNAs. We then demonstrated this central dogma of ABO and opened a new era of molecular genetics. We identified four amino acid substitutions between AT and BT and inactivating mutations in the O alleles, clarifying the allelic basis of ABO. We became the first to achieve successful ABO genotyping, discriminating between AA and AO genotypes and between BB and BO, which was impossible using immunohematological/serological methods. We also identified mutations in several subgroup alleles and also in the cis-AB and B(A) alleles that specify the expression of the A and B antigens by single alleles. Later, other scientists interested in the ABO system characterized many additional ABO alleles. However, the situation has changed drastically in the last decade, due to rapid advances in next-generation sequencing (NGS) technology, which has allowed the sequencing of several thousand genes and even the entire genome in individual experiments. Genome sequencing has revealed not only the exome but also transcription/translation regulatory elements. RNA sequencing determines which genes and spliced transcripts are expressed. Because more than 500,000 human genomes have been sequenced and deposited in sequence databases, bioinformaticians can retrieve and analyze this data without generating it. Now, in this era of genomics, we can harness the vast sequence information to unravel the molecular mechanisms responsible for important biological phenomena associated with the ABO polymorphism. Two examples are presented in this review: the delineation of the ABO gene evolution in a variety of species and the association of single nucleotide variant (SNV) sites in the ABO gene with diseases and biological parameters through genome-wide association studies (GWAS).Copyright © Annals of Blood. All rights reserved.

Pre-existing chronic liver disease is associated with poor outcome in patients with SARS-CoV2 infection

COVID-19 is characterized by predominant respiratory and gastrointestinal symptoms. Liver enzymes derangement is seen in 15-55% of the patients. Cirrhosis is characterized by immune dysregulation, leading to concerns that these patients may be at increased risk of complications following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with metabolic dysfunction-associated fatty liver (MAFLD) had shown a 4-sixfold increase in severity of COVID-19, and its severity and mortality increased in patients with higher fibrosis scores. Patients with chronic liver disease had shown that cirrhosis is an independent predictor of severity of COVID-19 with increased hospitalization and mortality. An international European registry study included 756 patients with chronic liver disease from 29 countries reports high mortality in patients with cirrhosis (32%). Data of 228 patients collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19 (APCOLIS study) showed that SARSCoV- 2 infection produces acute liver injury in 43% of CLD patients without cirrhosis. Additionally, 20% of compensated cirrhosis patients develop either ACLF or acute decompensation. In decompensated cirrhotics, the liver injury was progressive in 57% of patients, with 43% mortality. Patients with CLD and associated diabetes and obesity had a worse outcome. Liver related complications were seen in nearly half of the decompensated cirrhotics, which were of greater severity and with higher mortality. Increase in Child Turcotte Pugh (CTP) score and model for end-stage liver disease (MELD) score increases the mortality in these patients. In a subsequent study of 532 patients from 17 Asian countries was obtained with 121 cases of cirrhosis. An APCOLIS risk score was developed, which included presence of comorbidity, low platelet count, AKI, HE and respiratory failure predicts poor outcome and an APCOLIS score of 34 gave a sensitivity and specificity of 79.3%, PPV of 54.8% and NPV of 92.4% and predicted higher mortality (54.8% vs 7.6%, OR = 14.3 [95 CI 5.3-41.2], p<0.001) in cirrhosis patients with Covid-19. The APCOLIS score is helpful in triaging and prognostication of cirrhotics with Coivd-19. The impact of COVID-19 on patients with cirrhosis due to non-alcoholic fatty liver disease (NASH-CLD) was separately studied in 177 NASH-CLD patients. Obese patients with diabetes and hypertension had a higher prevalence of symptomatic COVID. Presence of diabetes [HR 2.27], fraility [HR 2.68], leucocyte counts [HR 1.69] and COVID-19 were independent predictors of worsening liver functions in patients with NASH-CLD. Severity of Covid in Cirrhosis could also be assessed by measuring ICAM1 the Intercellular Adhesion Molecule, an indicator of Endothelial Injury Marker. in Cirrhosis with Covid 19 Immunosuppression should be reduced prophylactically in patients with autoimmune liver disease and post-transplantation with no COVID-19. Hydroxychloroquine and remdesivir are found to be safe in limited studies in a patient with cirrhosis and COVID-19. And is safe in cirrhosis patients. However, flare of AIH has been reported in AIH patients. For hepatologists, cirrhosis with COVID-19 is a pertinent issue as the present pandemic cause severe disease in patients with chronic liver disease leading to more hospitalization and decompensation.

Inflammatory Pathways Associated with Covid-19 Severity Differ Based on Obesity Status

Background: Severe COVID-19 and obesity are characterized by higher inflammation. We aimed to examine early inflammatory patterns in people with (Ob) and without (NOb) obesity and COVID-19 and how they relate to COVID-19 disease severity Methods: Ob (BMI >30 Kg/m2) and NOb with COVID-19 matched for age, sex and WHO disease severity provided blood early after diagnosis. Immunoassays measured 57 plasma biomarkers reflecting innate immune and endothelial activation, systemic inflammation, coagulation, metabolism and microbial translocation (Fig 1). Between-group differences were assessed by Mann- Whitney. Associations between subsequent maximal COVID-19 severity (mild vs moderate/severe/critical) and biomarkers were explored by logistic regression adjusted for age, sex, hypertension (HTN) and diabetes (DM). Data are median pg/mL [IQR] or n [%] unless stated Results: Of 100 subjects (50 Ob and 50 Nob) presenting between April 2020 and March 2021, characteristics (Ob vs Nob) included: age 65 [23-91] vs 65 [21-95];female sex 27 (48%) vs 28 (56%);BMI 33.7 [30.0-71.8] vs 23.3 [15.3-25.9];disease severity mild 22 [48%] vs 23 [46%], moderate 15 [30%] vs 13 [26%], severe 6 [12%] vs 7 [14%];HTN 30 (60%) vs 17 (34%);DM 19 [38%] vs 6 [12%];days from symptom onset 7 [2-17] vs 8 [1-15];vaccinated 3 (6%) vs 0 (0%). Compared to NOb, Ob had higher IFN-alpha (1.8 [0.6;11] vs 0.9 [0.1;4.7]), CRP (10 mAU/mL [9.6;10.2] vs 9.7 [7.2;10]), IL-1RA (197 [122;399] vs 138 [88;253]), IL-4 (288 AU/mL [161;424] vs 205 [82;333]), vWF (252 [166;383] vs 163 [96;318]), Zonulin (114 ng/mL [77;131] vs 57 [18;106]), Resistin (956 [569;1153] vs 727 [712;1525]), Leptin (3482 [1513;5738] vs 848 [249;2114]), and lower Adiponectin (1.12 mg/L [0.09;1.5] vs 1.5 [1.18;1.93]), all p< 0.05. In both groups higher, proinflammatory IL-18 and lower levels of antiinflammatory CCL22 and IL-5 were associated with higher odds of disease severity, and lower E-selectin with higher disease severity only in Ob. However, in NOb higher type 3 interferons (IL-28A), macrophage activation (sCD163, CCL3) and vascular inflammation markers (ICAM-1, VCAM-1), along with higher S100B, GM-CSF and leptin were also associated with disease severity, a pattern not observed in Ob (Fig 1) Conclusion(s): Although Ob had higher overall levels of inflammation than NOb, few biomarkers predicted subsequent COVID-19 severity in Ob. These differential inflammatory patterns suggest dysregulated immune responses in Ob with COVID-19. (Figure Presented).

Plasma P-selectin is an early marker of thromboembolism in COVID-19

Objectives: The aim of this study was to explore the association of the plasma levels of coagulation proteins with venous thromboembolic events (VTE) in COVID-19 and identify candidate early markers of VTE. Background(s): Coagulopathy and thromboembolism are known complications of SARS-CoV-2 infection. The mechanisms of COVID-19-associated hematologic complications involve endothelial cell and platelet dysfunction and immunothrombosis and have been intensively studied. Yet, a full understanding of the pathogenesis and factors that lead to COVID-19 associated coagulopathy is lacking. Previous studies investigated only small numbers of coagulation proteins together, and they were limited in their ability to adjust for confounders. Method(s): This study was a post-hoc analysis of a previously published dataset (Filbin et al., 2021). We included in our analysis 305 subjects with confirmed SARS-CoV-2 infection who presented to an urban Emergency Department with acute respiratory distress during the first COVID-19 surge in 2020;13 (4.2%) were subsequently diagnosed with venous thromboembolism during hospitalization. Serial samples were obtained on days 0, 3, and 7 and assays were performed on two highly-multiplexed proteomic platforms, that in combination cover 1472 + 4776 proteins. We included 31 coagulation proteins in our analysis. Result(s): Nine coagulation proteins were differentially expressed in patients with thromboembolic events. In multivariable models, day 0 levels of P-selectin, a cell adhesion molecule on the surface of activated endothelial cells, displayed the strongest association with the diagnosis of VTE, independent of disease severity and other confounders (p=0.0025). P-selectin together with D-dimer upon hospital presentation provided better discriminative ability for VTE diagnosis than D-dimer alone (AUROC = 0.834 vs. 0.783). Conclusion(s): Our results suggest that plasma P-selectin is a potential early biomarker for the risk stratification of VTE in COVID-19 disease. Our findings support the importance of endothelial activation in the mechanistic pathway of venous thromboembolism in COVID-19.Copyright © 2023

Pharmacoinvasive Therapy in Treating Acute STEMI Patients in COVID-19 Era-Thrombolysis by Tenecteplase (TNK) / Streptokinase (STK) Followed by Rescue PCI of the Culprit Vessel

Background: Treating acute STEMI patients by primary PCI has dramatically fallen globally in covid era as there is chances of potential threat of spreading Covid among the non-Covid patient. Thereby, thrombolysis of acute STEMI patient either by Streptokinase (STK) or Tenecteplase (TNK) in grey zone till Covid RT PCR report to come, was the mode of treatment of acute myocardial infarction patient in our hospital. Post thrombolysis, Covid positive cases were managed conservatively in a Covid dedicated unit. Covid negative cases were treated by rescue PCI of the culprit lesion. Exact data on benefit of thrombolysis either by TNK or STK of STEMI patients in Covid era, is not well addressed in our patient population. Thereby, we have carried out this prospective observational study to see the outcomes of thrombolysis and subsequent intervention. Method(s): STEMI Patient who represented to our ER with chest pain and ECG and hs-TROP-I evidenced acute ST segment elevated myocardial infarction (STEMI), were enrolled in the study. Total 139 patients enrolled (Male:120, Female :19);average age for Male: 54yrs., female was: 56yrs. All patients were admitted in the grey zone of CCU where thrombolysis done either by TNK or STK. Positive for COVID-19, were patients excluded from intervention and managed conservatively in Covid-19 dedicated ward. Covid Negative patients were kept transferred to CCU green zone. Result(s): COVID-19 test was carried out on all studied patients. Among them, Covid-19 positive were 7.9% (11) patients and managed conservatively in dedicated Covid ward, Covid-19 negative were 92.1% (128). Primary PCI was performed in 5.03% (7). Rest was managed by Pharmacoinvasive therapy either by TNK or STK. Thrombolysis by Tenecteplase in 64% (89), Streptokinase in 17.9% (25) patient, 12.9% (18) patient did not receive any thrombolysis due to late presentation and primary PCI done in 5.4% (7). On average 2.1 days after Fibrinolysis, elective PCI carried out. Data analysis from 48 patients;chest pain duration (3.71 +/-2.8 hr., Chest pain to contact time 3.3+/-2.8hr., Chest pain to needle time 7.2 +/-12.7hr., thrombolysis to balloon time 117.5+/-314.8hr., as many of the patient develop LVF post thrombolysis. More than 50% stenosis resolution observed in 41.6% (20) patients, chest pain resolution with one hour of thrombolysis observed in 43.8% (21) patients and development of LVF in 20.8% (10) patients. Door to needle time was 30 min. At presentation of STEMI;Ant Wall MI 46.8% (65), Inferior Wall MI 52.5% (73) and high Lateral 0.7% (1). Average Serum hs Trop-I was 16656 for male and 12109 for female. LVEF were 41% for male and 48% for female. HbA1C were in Male 8.34%: Female 8.05%, SBP for Male 120mmHg: Female 128 mmHg. Total, 88 stents were deployed in 83 territories. CABG recommended for 5.03% (7) patients, PCI in 58.3% (81), remaining were kept on medical management. Stented territory was LAD 45.7% (37) and RCA 39.5% (32) and LCX 14.8% (12). Common stent used;Everolimus 61.4% (54), Sirolimus 25% (22), Progenitor cell with sirolimus 2.3%(2) and Zotarolimus 11.4% (10) Conclusion(s): In the era of COVID-19, in this prospective cohort study, on acute STEMI patient management, we found that Pharmaco therapy by Tenecteplase and Streptokinase, reduced patient symptom and ST resolution partially. Therefore, coronary angiogram and subsequent Rescue PCI by Drug Eluting Stents (DES) are key goals of complete revascularization.Copyright © 2023

A review of fibroblast-like synoviocytes in the pathogenesis of Rheumatoid arthritis: Their activation and the inhibition of their apoptosis

Rheumatoid Arthritis (RA) is a systemic, autoimmune, inflammatory disease characterized by synovial hyperplasia, inflammatory cell infiltration in the synovial tissues, and progressive destruction of cartilage and bones. This disease often leads to chronic disability. More recently, activation of synovial fibroblasts (SFs) has been linked to innate immune responses and several cellular signalingpathways that ultimately result in the aggressive and invasive stages of RA. SFs are the major sources of pro-inflammatory cytokines in RA synovium. They participate in maintaining the inflammatory state that leads to synovial hyperplasia and angiogenesis in the inflamed synovium. The altered apoptotic response of synovial and inflammatory cells has been connected to these alterations of inflamed synovium. RA synovial fibroblasts (RASFs) have the ability to inhibit several apoptotic proteins that cause their abnormal proliferation. This proliferation leads to synovial hyperplasia. Apoptotic pathway proteins have thus been identified as possible targets for modifying the pathophysiology of RA. This review summarizes current knowledge of SF activation and its roles in the inhibition of apoptosis in the synovium, which is involved in joint damage during the effector phase of RA development.Copyright © 2022 Biomedpress.

Jing Si Herbal Drink as a prospective adjunctive therapy for COVID-19 treatment: Molecular evidence and mechanisms

Background: SARS-CoV-2 has led to a sharp increase in the number of hospitalizations and deaths from pneumonia and multiorgan disease worldwide;therefore, SARS-CoV-2 has become a global health problem. Supportive therapies remain the mainstay treatments against COVID-19, such as oxygen inhalation, antiviral drugs, and antibiotics. Traditional Chinese medicine (TCM) has been shown clinically to relieve the symptoms of COVID-19 infection, and TCMs can affect the pathogenesis of SARS-CoV-2 infection in vitro. Jing Si Herbal Drink (JSHD), an eight herb formula jointly developed by Tzu Chi University and Tzu Chi Hospital, has shown potential as an adjuvant treatment for COVID-19 infection. A randomized controlled trial (RCT) of JSHD as an adjuvant treatment in patients with COVID-19 infection is underway Objectives: This article aims to explore the efficacy of the herbs in JSHD against COVID-19 infection from a mechanistic standpoint and provide a reference for the rational utilization of JSHD in the treatment of COVID-19. Method(s): We compiled evidence of the herbs in JSHD to treat COVID-19 in vivo and in vitro. Result(s): We described the efficacy and mechanism of action of the active ingredients in JSHD to treat COVID-19 based on experimental evidence. JSHD includes 5 antiviral herbs, 7 antioxidant herbs, and 7 anti-inflammatory herbs. In addition, 2 herbs inhibit the overactive immune system, 1 herb reduces cell apoptosis, and 1 herb possesses antithrombotic ability. Conclusion(s): Although experimental data have confirmed that the ingredients in JSHD are effective against COVID-19, more rigorously designed studies are required to confirm the efficacy and safety of JSHD as a COVID-19 treatment.Copyright © 2021

Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance

Background: The international, multi-center Pancreatic Cancer Early Detection (PRECEDE) Consortium enrolls high-risk individuals (HRIs) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Enrollment began in 2020, and despite challenges related to the COVID-19 pandemic, the PRECEDE Consortium rapidly accrued a large cohort of HRIs. The purpose of this study is to describe the characteristics of this cohort and assess racial, ethnic, and sex-based disparities. Method(s): The PRECEDE Consortium (NCT04970056) is a prospective, multicenter study focused on improving survival from PDAC through early detection. Data from all HRIs who met criteria for PDAC surveillance and enrolled between May 2020 - March 2022 were collected and included in the analysis. Result(s): During the study period, 1299 HRIs enrolled in PRECEDE at 32 centers. HRIs were excluded if enrollment data was incomplete or criteria for PDAC surveillance were not met. Of 1113 who were included, 47.2% met criteria for familial pancreatic cancer (FPC) and 45.4% had a family history of PDAC along with a PV in a PDAC-risk gene (BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). The remainder had familial atypical mole melanoma syndrome (5.7%), Peutz- Jeghers syndrome (1.6%), or hereditary pancreatitis (0.2%). More females than males enrolled (65.9% vs. 33.5%). The distribution of HRIs by race and ethnicity is depicted;the majority identified as white (87.7%). Study participants were primarily from the US (82.7%), the median age was 61 (27-85) and 18.5% had Ashkenazi Jewish ancestry. Nearly all HRIs consented to allow access to imaging data (99.6%), collection of germline DNA (97.7%), and biosample collection (99.5%). There were no race, ethnicity, or sex-based differences in rates of consent for collection of imaging, DNA, or biosamples. Conclusion(s): Enrollment of HRIs in prospective studies of PDAC surveillance is essential for advancing early detection research in PDAC. A distinct advantage of the PRECEDE Consortium for examining enrollment disparities is that recruitment began in 2020, providing a unique and current snapshot of the international PDAC surveillance landscape. Despite the recent attention on addressing disparities in healthcare delivery, significant racial, ethnic, and sex-based disparities persisted in the cohort of HRIs enrolled in the PRECEDE Consortium. Ensuring that the diversity of participants in the PRECEDE Consortium mirrors the communities served by participating centers is crucial. Further examining and addressing the reasons for these disparities is a major focus of the PRECEDE Consortium moving forward.

Endothelial Biomarkers in Critically Ill Patients with Covid-19: Potential Predictors of the Need for Dialysis

Introduction: Endothelial dysfunction and coagulopathy have been reported as the basis of severe Acute Kidney Injury (AKI) associated with COVID-19. Endothelial biomarkers can detect kidney damage early and allow the adoption of efficient measures to prevent the progression of the disease and its complications. This finding could facilitate the follow-up of patients at higher risk, as well as provide early diagnosis strategies and promote the rational use of resources. The aim of this study is to assess the role of vascular biomarkers to predict the need for hemodialysis in critically ill patients with COVID-19. Method(s): This is a prospective study with 58 patients critically ill due to COVID-19 infection admitted to a tertiary hospital in Fortaleza, Northeast Brazil, from 2020 to 2021. General laboratory tests and vascular biomarkers such as VCAM-1, Syndecan-1, ACE-2, ICAM-1, Angiopoietin-1 and Angiopoietin-2 were quantified on admission to the intensive care unit (ICU). Result(s): There was a 40% mortality rate. VCAM and the Ang-2/Ang-1 ratio at ICU admission were associated with the need for hemodialysis. Vascular biomarkers (VCAM-1, Syndecan-1, angiopoietin-2/anogiopoietin-1 ratio) and thrombocytopenia were predictors of dialysis, and their cutoff values were useful to stratify patients with worse prognosis in the Kaplan-Meier analysis. In the cox multivariate regression analysis with models adjusted according to the presence or absence of platelets, VCAM-1 [O.R. 1.13 (95% CI: 1.01 - 1.27);p=0.034] was an independent predictor of dialysis in all models, and the Ang-2/Ang-1 ratio [O.R. 4.87 (95% C.I.: 1.732 - 13.719);p=0.003] was associated with the need for dialysis in the model without platelet input. Conclusion(s): Vascular biomarkers, mainly VCAM-1 and Ang-2/Ang-1 ratio, and coagulation disorders showed important predictive value for the need for hemodialysis in critically ill patients with COVID-19. No conflict of interestCopyright © 2023

The Emergence of Novel Coronavirus Disease, Global Treatment Update and its Containment Strategies in Overpopulated Countries: A Review

The ongoing pandemic of the novel coronavirus SARS-CoV-2 (COVID-19) has created a major challenge for the public health worldwide. The reported cases indicate that the outbreak is more widespread than initially assumed. Around 18 million people have been infected with 689,000 reported deaths (August 2020;the number is increasing daily);with a high mutation rate, this virus poses an even more serious threat worldwide. The actual source of COVID-19 is still un-clear;even if the initial reports link it to the Chinese seafood wet market in Wuhan, other animals such as birds, snakes, and many small mammals including bats are also linked with this novel coro-navirus. The structure of the COVID-19 shows distinctive proteins among which spike proteins have a pivotal role in host cell attachment and virus-cell membrane fusion in order to facilitate virus infection. Currently, no specific antiviral treatment or vaccine is available. Various drug can-didates, including SARS-CoV and MERS-CoV protease inhibitors, neuraminidase inhibitors, RNA synthesis inhibitors, ACE2 inhibitors and lungs supportive therapy, are under trials. Cell-based therapy also appeared with remarkable treatment possibilities. In this article, we endeavored to succinctly cover the current and available treatment options, including pharmaceuticals, cell-based therapy, and traditional medicine. We also focused on the extent of damages by this novel coron-avirus in India, Pakistan, and Bangladesh;the strategies adopted and the research activities initiat-ed so far by these densely populated countries (neighboring China) are explained in this review.Copyright © 2021 Bentham Science Publishers.

Effect and mechanism of Qingre Xiaoyanning Tablet in treatment of coronavirus infection.

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.

Pleiotropic Effects of Nitric Oxide on SARS-CoV-2 Infections

Infection by beta-coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coron-avirus-2) alters the homeostasis of the vascular endothelium, promoting an inflammatory state which causes damage and favors the prothrombotic state. The direct viral cytotoxicity induced by the SARS-CoV-2 leads to endothelial cell death;thus, altering the vessel functions. Moreover, SARS-CoV infection induces endothelial dysfunction (ED) and reduces the levels of nitric oxide (NO);thus, aggravating the vascular injuries, which promotes thrombotic events due to an altera-tion in the homeostasis. NO is a pleiotropic molecule that induces vasodilation, regulates the immune response, inhibits platelet aggregation, and decreases the cellular adhesion to vascular en-dothelium. Moreover, NO acts directly against invasive agents, exhibiting antibacterial, antiviral, and antifungal activity. High levels of NO result in an increase in the ED, causing an inflammatory amplification that aggravates the disease through undesirable positive feedback. The objective of this review was to present and discuss the involvement of NO on ED in SARS-CoV-2 infections. This review may also highlight new perspectives for therapeutic interventions through the supple-mentation of exogenous NO. The maintenance of homeostatic NO levels could represent a useful approach in the prevention of coronavirus-induced ED.Copyright © 2021 Bentham Science Publishers.

SARS-CoV-2 infection and smoking: What is the association? A brief review.

Susceptibility to severe illness from COVID-19 is anticipated to be associated with cigarette smoking as it aggravates the risk of cardiovascular and respiratory illness, including infections. This is particularly important with the advent of a new strain of coronaviruses, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) that has led to the present pandemic, coronavirus disease 2019 (COVID-19). Although, the effects of smoking on COVID-19 are less described and controversial, we presume a link between smoking and COVID-19. Smoking has been shown to enhance the expression of the angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease 2 (TMPRSS2) key entry genes utilized by SARS-CoV-2 to infect cells and induce a 'cytokine storm', which further increases the severity of COVID-19 clinical course. Nevertheless, the impact of smoking on ACE-2 and TMPRSS2 receptors expression remains paradoxical. Thus, further research is necessary to unravel the association between smoking and COVID-19 and to pursue the development of potential novel therapies that are able to constrain the morbidity and mortality provoked by this infectious disease. Herein we present a brief overview of the current knowledge on the correlation between smoking and the expression of SARS-CoV-2 key entry genes, clinical manifestations, and disease progression.

PLASMA FROM SARS-COV-2 PATIENTS INDUCES OXIDATIVE STRESS AND ENDOTHELIAL DYSFUNCTION VIA ANGIOTENSIN II TYPE 1 RECEPTOR (AT1R)/P38 MAPK PATHWAY

Background: Acute respiratory distress syndrome (ARDS) is a distinctive feature of severe COVID-19 infections that occurs mainly in patients with coexisting health problems, such as hypertension, atherosclerosis, and diabetes. Endothelial dysfunction is a major contributing factor during ARDS development in COVID- 19 patients with pre-existing comorbidities. Objective: Studying the mechanism by which endothelial activation and dysfunction could provide a therapeutic target for COVID-19 treatment. Design and method: The current study measured endothelial dysfunction and oxidative stress by incubating human umbilical vein endothelial cells (HUVECs) with plasma from patients with mild, moderate, severe and extremely severe COVID- 19. Using flow cytometry, wound-healing assays and phosphokinase arrays, Results: We detected increases in cell apoptosis;reactive oxygen species (ROS) formation;hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular cell adhesion molecule-1 (VCAM-1), and vascular endothelial growth factor receptor-1 (VEGFR-1) expression;viral entry;and inflammatory-related protein activity. We also found an impairment in the wound-healing process. Moreover, we found that AT1R blockade and P38 MAPK inhibition reversed all of these effects, especially in the severe group. Conclusions: These findings indicate that AT1R/P38 MAPK-mediated oxidative stress and endothelial dysfunction occur during COVID-19 infection.

Clinical and biochemical short-term effects of hyperbaric oxygen therapy on SARS-Cov-2+ hospitalized patients with hypoxemic respiratory failure.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) has been proposed to address COVID-19- associated respiratory failure. However, its biochemical effects are poorly known. METHOD: 50 patients with hypoxemic COVID-19 pneumonia were divided into C group (standard care) and H group (standard care plus HBOT). Blood was obtained at t = 0 and t = 5 days. Oxygen saturation (O2 Sat) was followed up. White blood cell (WC) count, lymphocytes (L) and platelets (P) and serum analysis (glucose, urea, creatinine, sodium, potassium, ferritin, D dimer, LDH and CRP) were carried out. Plasma levels of sVCAM, sICAM, sPselectin, SAA and MPO, and of cytokines (IL-1ß, IL-1RA, IL-6, TNFα, IFNα, IFNγ, IL-15, VEGF, MIP1α, IL-12p70, IL-2 and IP-10) were measured by multiplex assays. Angiotensin Converting Enzyme 2 (ACE-2) levels were determined by ELISA. RESULTS: The average basal O2 Sat was 85 ± 3%. The days needed to reach O2 Sat >90% were: H: 3 ± 1 and C: 5 ± 1 (P < 0,01). At term, H increased WC, L and P counts (all, H vs C: P < 0,01). Also, H diminished D dimer levels (H vs C, P < 0,001) and LDH concentration (H vs C, P < 0.01]. At term, H showed lower levels of sVCAM, sPselectin and SAA than C with respect to basal values (H vs C: ΔsVCAM: P < 0,01; ΔsPselectin: P < 0,05; ΔSAA: P < 0,01). Similarly, H showed diminished levels of TNFα (ΔTNFα: P < 0,05) and increased levels of IL-1RA and VEGF than C respect to basal values (H vs C: ΔIL-1RA and ΔVEGF: P < 0,05). CONCLUSION: Patients underwent HBOT improved O2 Sat with lower levels of severity markers (WC and platelets count, D dimer, LDH, SAA). Moreover, HBOT reduced proinflammatory agents (sVCAM, sPselectin, TNFα) and increased anti-inflammatory and pro-angiogenic ones (IL-1RA and VEGF).

Receptor-binding domain of SARS-CoV-2 is a functional αv-integrin agonist.

Among the novel mutations distinguishing SARS-CoV-2 from similar coronaviruses is a K403R substitution in the receptor-binding domain (RBD) of the viral spike (S) protein within its S1 region. This amino acid substitution occurs near the angiotensin-converting enzyme 2-binding interface and gives rise to a canonical RGD adhesion motif that is often found in native extracellular matrix proteins, including fibronectin. Here, the ability of recombinant S1-RBD to bind to cell surface integrins and trigger downstream signaling pathways was assessed and compared with RGD-containing, integrin-binding fragments of fibronectin. We determined that S1-RBD supported adhesion of fibronectin-null mouse embryonic fibroblasts as well as primary human small airway epithelial cells, while RBD-coated microparticles attached to epithelial monolayers in a cation-dependent manner. Cell adhesion to S1-RBD was RGD dependent and inhibited by blocking antibodies against αv and ß3 but not α5 or ß1 integrins. Similarly, we observed direct binding of S1-RBD to recombinant human αvß3 and αvß6 integrins, but not α5ß1 integrins, using surface plasmon resonance. S1-RBD adhesion initiated cell spreading, focal adhesion formation, and actin stress fiber organization to a similar extent as fibronectin. Moreover, S1-RBD stimulated tyrosine phosphorylation of the adhesion mediators FAK, Src, and paxillin; triggered Akt activation; and supported cell proliferation. Thus, the RGD sequence of S1-RBD can function as an αv-selective integrin agonist. This study provides evidence that cell surface αv-containing integrins can respond functionally to spike protein and raises the possibility that S1-mediated dysregulation of extracellular matrix dynamics may contribute to the pathogenesis and/or post-acute sequelae of SARS-CoV-2 infection.

Study of Adhesion Molecules' (ICAM-1 and VCAM-1) Effects on Immunothrombosis in Severe and Critical COVID-19 Infections in Comparison with Mild Cases

Background: The study aimed to evaluate the association among the adhesion molecules (ICAM1 and VCAM-1) with immunothrombosis in severe and critical COVID-19 patients in comparison with mild cases. Materials and Methods: A cross sectional study was conducted. From 1 October 2021 to 30 May 2022, a total of 82 COVID-19 patients were recruited at the hospital in Imam AL-Hussein Medical City/Kerbala, consisting of 44 males and 38 females, and their ages ranged from 25 to 85 years old. All participants were hospitalized after testing positive for the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2). 27 of those were diagnosed with mild COVID-19 and 27 with severe cases, while 28 patients had critical diseases. Results: In mild cases, ICAM-1 adhesion molecule level increased approximately more than four folds over the normal range, and dramatically elevated with COVID-19 progression (p= < 0.001). VCAM-1 level also significantly elevated (p = 0.002), but his elevation was slower than ICAM-1 elevation. Conclusion: There is a more significant correlation among immunothrombosis, cellular adhesion molecules (ICAM-1, VCAM-1) elevation and COVID-19 severity.

Increased CD62P platelet expression in deceased Covid-19 patients

Background: There is an association between Coronavirus Disease 2019 (COVID-19) and coagulation abnormalities. Platelet monitoring is important for COVID-19 because abnormalities can occur in terms of quantity and quality. Impaired function of platelets can occur at the activation or aggregation stages. An increase in CD62P is associated with a 1.7-fold increased risk of venous thrombosis. In the event of thrombosis, platelet activation causes interactions between fibrinogen and GP IIb/IIIa molecules which will form intracellular bonds between platelets, causing platelet aggregation. This suggests the role of CD62P as a major marker of platelet activation and may mediate cancer cell adhesion, inflammation, and thrombosis Aims: This study aims to determine the description of platelet function as reflected in CD62P platelet expression in COVID-19 patients Methods: This study is a prospective study that take place from November 2020 to September 2021 at RSUP Dr. Sardjito, Yogyakarta, Indonesia. The subjects involved were adult patients aged over 18 years, men and women with confirmed COVID-19 through PCR swab results. Patients with leukemia, history of coagulation disease, and immunodeficiency were excluded from this study. Flowcytometry analysis using FACS Canto was used to measure CD62P expression on platelets. Antibody used was anti human monoclonal CD41 PE and CD62P FITC antibody. The CD62P examination was carried out on the first day of treatment. Patients were grouped according to the severity of COVID-19 as severe and non-severe. Mann Whitney test was used to compare CD62P platelet expression percentage between groups. Result(s): The CD62P platelet expression on day 1 of the deceased subjects were higher compared to the survived subjects (46.77% vs 43.38%;p = 0.04). On day 1, the severe subjects have a higher mean CD62P platelet expression compared to non-severe subjects (47.88 % vs 39.75%). Conclusion(s): CD62P platelet expression in deceased COVID-19 subjects is higher compared to survived subjects. (Figure Presented).

Oxi-inflammatory stress and vascular cell adhesion molecule-1 in post-COVID active rheumatoid arthritis patients

Background: Coronavirus disease-19 (COVID-19) has sparked the deterioration of human health at an unprecedented scale globally and affected the patient's musculoskeletal health also. It is conceivable that active rheumatoid arthritis (ARA) patients recovered from COVID-19 after second wave are at enhanced risk of cardiovascular complications. Aim and Objectives: In this context, the present study was intended to estimate the soluble vascular cell adhesion molecule-1 (sVCAM-1), serum paraoxonase (PON), and markers of oxi-inflammatory stress in ARA patients diagnosed reverse transcriptase-polymerase chain reaction negative after second wave of COVID-19 and to determine their role in predicting cardiovascular disease (CVD) risk. Materials and Methods: Sixty ARA patients (30-45 years) of Delhi-NCR region were recruited and categorized into two groups (n=30 in each group;on the basis of their history of COVID infection). Using standard methods, study group parameters were estimated in ARA patients and statistically compared it with that of 30 healthy controls by using student's t-test. Results: Serum sVCAM-1, malondialdehyde (MDA), and C-reactive protein (CRP) levels were significantly high (P<0.001) in Group II and Group III subjects as compared to healthy controls. Conversely, serum PON activity was found to be significantly low (P<0.001) in Group III as compared healthy controls. However, PON activity was altered insignificantly (P<0.1) with respect to Group II subjects. sVCAM-1 levels were positively correlated with MDA, CRP, and atherogenic index;and negatively correlated with PON activity (P<0.001) in post-COVID ARA patients. Conclusion: Thus, enhanced sVCAM-1 and reduced PON activity along with enhanced oxi-inflammatory stress status are more efficient molecular signatures of CVD risk among post-COVID ARA patients. Therefore, the present study emphasizes the dire need of special attention to provide cardiovascular rehabilitation strategy among post-COVID ARA patients along with reduction of oxi-inflammatory stress to reduce the CVD mortality in ARA population. [ FROM AUTHOR]