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1.
Embase; 2022.
Preprint in English | EMBASE | ID: ppcovidwho-335151

ABSTRACT

Variants of coronavirus (SARS-CoV-2) have been spreading in a global pandemic. It is important to understand quick the infectivity of future new variants for effective countermeasure against them. In this research, we aimed to investigate the prediction of infectivity of SARSCoV-2 by using mathematical model with molecular simulation analysis and the evolutionary distance of spike protein gene (S gene) of SARS -CoV-2 in the phylogenetic analysis. We subjected the six variants and wild type (WT) of spike protein and Angiotensin-Converting Enzyme 2 (ACE2) of human to molecular docking simulation analyses in order to understand the binding affinity. Then the regression analysis of the coefficient from our mathematical model and the infectivity of SARS-CoV-2 were investigated for the prediction of infectivity. The evolutionary distance by S gene (spike protein) correlated to the infectivity of SARSCoV-2 variants. And the coefficient of mathematical model by using the results of molecular docking simulation correlated to the infectivity of SARS-CoV-2 variants, too. These results suggests that the provided data from the docking simulation for Receptor Binding Domain (RBD) of variant spike protein and ACE2 of human were valuable to the prediction of SARS-CoV-2 infectivity. Finally, we established the mathematical model for the prediction of infectivity in the SARS-CoV-2 variant by using the binding affinity under the molecular docking experiment and evolutionary distance by S gene.

2.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-334682

ABSTRACT

B-cell epitopes (BCEs) are a set of specific sites on the surface of an antigen that binds to an antibody produced by B-cell. The recognition of BCEs is a major challenge for drug design and vaccines development. Compared with experimental methods, computational approaches have strong potential for BCEs prediction at much lower cost. Moreover, most of the currently methods focus on using local information around target residue without taking the global information of the whole antigen sequence into consideration. We propose a novel deep leaning method through combing local features and global features for BCEs prediction. In our model, two parallel modules are built to extract local and global features from the antigen separately. For local features, we use Graph Convolutional Networks(GCNs) to capture information of spatial neighbors of a target residue. For global features, Attention-Based Bidirectional Long Short-Term Memory(Att-BLSTM) networks are applied to extract information from the whole antigen sequence. Then the local and global features are combined to predict BCEs. The experiments show that the proposed method achieves superior performance over the state-of-the-art BCEs prediction methods on benchmark datasets. Also, we compare the performance differences between data with or without global features. The experimental results show that global features play an important role in BCEs prediction. Our detailed case study on the BCEs prediction for SARS-Cov-2 receptor binding domain confirms that our method is effective for predicting and clustering true BCEs.

3.
Acta Medica Iranica ; 60(4):202-209, 2022.
Article in English | Academic Search Complete | ID: covidwho-1824333

ABSTRACT

The coronavirus disease 2019 (COVID-19) is a single-stranded RNA (+) virus and causes infectious disease by the viral strain "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). Now, COVID-19 has become pandemic, and there are neither potential vaccines nor drugs discovered. Its RNA contains genes for structural (S, E, M, N) and non-structural proteins (PLpro, 3CLpro, RdRp, Hel). Interaction between the S protein of SARS-CoV-2 and the ACE 2 receptor of the host cell plays a vital role in the entry of the virus into the cell. Favipiravir, ribavirin, remdesivir, galidesivir, lopinavir, ritonavir, chloroquine, and hydroxychloroquine are the few effective drugs against SARS-CoV-2. Live attenuated virus (mutant MERS-CoV and SARS-CoV or recombination with another live attenuated virus) can act as vaccine platforms against SARS CoV-2 along with DNA vaccine and subunit vaccine. [ FROM AUTHOR] Copyright of Acta Medica Iranica is the property of Tehran University of Medical Sciences and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

4.
International Journal of Current Pharmaceutical Research ; 14(2):5-10, 2022.
Article in English | EMBASE | ID: covidwho-1822678

ABSTRACT

Covid Virus particles engage with host cells via the ACE-2 and GRP78 receptors, transferring the genome particle to the host cell and transforming it into a replicating machine. RdRP is a key protein in the replication mechanism of all RNA viruses. 3CLpro is a cleavage enzyme that breaks down polyproteins into non-structural polyproteins. All four elements of the Covid viral particle are required for its propagation and action, and blocking any one of them can shut down the entire system. EGCG and Theaflavins are flavonoids that block virus particles from attaching to the host cell's ACE-2 and GRP78 receptors, preventing the genome from being transferred into the cell. EGCG binds to 3CLpro with a molecular docking value of 11.7, while TF3 has a docking score of 10.574, indicating that it prevents host cell contact. TF binds to RdRP with a binding energy of 9.11 kcal/mol, implying that RdRP activities are interfered with. Furthermore, these flavonoids have anti-inflammatory properties and reduce the action of cytokines, which can cause serious respiratory difficulties. Except these two there are many others flavonoids which possess anti-inflammatory and anti-viral properties. All of these data suggest that flavonoids could be a useful treatment for SARS-CoV19;however, the issue of stability and bioavailability arises because it is unstable at lungs pH.

5.
Pathogens ; 11(4), 2022.
Article in English | EMBASE | ID: covidwho-1822431

ABSTRACT

Background: SARS-CoV-2 enters the body through inhalation or self-inoculation to mucosal surfaces. The kinetics of the ocular and nasal mucosal-specific-immunoglobulin A(IgA) responses remain under-studied. Methods: Conjunctival fluid (CF, n = 140) and nasal epithelial lining fluid (NELF, n = 424) obtained by paper strips and plasma (n = 153) were collected longitudinally from SARS-CoV-2 paediatric (n = 34) and adult (n = 47) patients. The SARS-CoV-2 spike protein 1(S1)-specific mucosal antibody levels in COVID-19 patients, from hospital admission to six months post-diagnosis, were assessed. Results: The mucosal antibody was IgA-predominant. In the NELF of asymptomatic paediatric patients, S1-specific IgA was induced as early as the first four days post-diagnosis. Their plasma S1-specific IgG levels were higher than in symptomatic patients in the second week after diagnosis. The IgA and IgG levels correlated positively with the surrogate neutralization readout. The detectable NELF “receptor-blocking” S1-specific IgA in the first week after diagnosis correlated with a rapid decline in viral load. Conclusions: Early and intense nasal S1-specific IgA levels link to a rapid decrease in viral load. Our results provide insights into the role of mucosal immunity in SARS-CoV-2 exposure and protection. There may be a role of NELF IgA in the screening and diagnosis of SARS-CoV-2 infection.

6.
Brain Sciences ; 12(4), 2022.
Article in English | EMBASE | ID: covidwho-1822411

ABSTRACT

Since the outbreak of the SARS-CoV-2 pandemic, olfactory disorders have been reported as a frequent symptom of COVID-19;however, its pathogenesis is still debated. The aim of this review is to summarize the current understanding of the pathogenesis of smell impairment in the course of COVID-19 and to highlight potential avenues for future research on this issue. Several theories have been proposed to explain the pathogenesis of COVID-19-related anosmia, including nasal obstruction and rhinorrhea, oedema of the olfactory cleft mucosa, olfactory epithelial damage either within the olfactory receptor cells or the supporting non-neural cells (either direct or immune-mediated), damage to the olfactory bulb, and impairment of the central olfactory pathways. Alt-hough the pathogenesis of COVID-19-related anosmia is still not fully elucidated, it appears to be mainly due to sensorineural damage, with infection of the olfactory epithelium support cells via the ACE1 receptor and disruption of the OE caused by immense inflammatory reaction, and possibly with direct olfactory sensory neurons infection mediated by the NRP-1 receptor. Involvement of the higher olfactory pathways and a conductive component of olfactory disorders, as well as genetic factors, may also be considered.

7.
Natural Product Communications ; 17(4), 2022.
Article in English | EMBASE | ID: covidwho-1822124

ABSTRACT

Background: Coronavirus disease 2019 (COVID-19) has posed a serious threat to human health and there is an urgent need for drug development. In this study, we explored the potential mechanisms underlying the efficacy of polydatin against COVID-19. Methods: A combined approach of network pharmacology, molecular docking, and experimental verification were employed in this study. Potential targets of polydatin for treating COVID-19 were obtained from multiple drug and disease databases. Protein–protein interaction and enrichment analyses were performed to predict the potential mechanism of action of polydatin against COVID-19. The binding potential of polydatin and key targets was evaluated through molecular docking. Furthermore, experimental methods including flow cytometry and luciferase assay were used to validate the results of computational analyses. Results: The main diseases identified as polydatin targets included metabolic diseases, lung diseases, inflammation, infectious diseases, and tumors. Polydatin may be used to treat COVID-19 through interventions that alter the immune and inflammatory responses, including IL-17 signaling pathway, T-cell activation, cytokines and inflammatory response, lipopolysaccharide-mediated signaling pathway, as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) innate immunity evasion and cell-specific immune response. Polydatin can potentially bind to the target proteins related to COVID-19, such as SARS-CoV-2 Mpro, RdRp, and human angiotensin-converting enzyme 2 (ACE2), while directly exerting its regulatory or therapeutic functions. The experimental results showed that polydatin decreased the infectivity of the SARS-CoV-2 spike pseudovirus in HEK293T-ACE2 cells. Accordingly, polydatin may retard the entry of SARS-CoV-2 into cells by competitively binding to human ACE2. Conclusion: The potential targets and signaling pathways of polydatin against COVID-19 were preliminarily identified. The findings may benefit the development and application of polydatin as a treatment for COVID-19.

8.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821935

ABSTRACT

SARS-COV-2, or COVID-19, is a respiratory virus infecting over 86 million people worldwide. In addition to respiratory infections, SARS-COV-2 has been shown to include cardiovascular (CV) complications, including myocarditis and acute coronary syndrome. Risk of severe complications from SARS-COV-2 in individuals with existing CV and metabolic disease has been shown to be increased. Evidence indicates SARS-COV-2 enters tissues via the angiotensin-converting enzyme 2 (ACE2) receptor and that the virus is primed and activated by transmembrane protease, serine 2 (TMPRSS2). The goal of this study was to determine ACE2 and TMPRSS2 mRNA levels in pre-clinical swine models of heart failure (HF). We hypothesized sex, pressure-overload, and comorbidities would increase ACE2 and TMPRSS2 mRNA levels. A retrospective analysis was conducted in previously completed studies in our lab including: 1) Female, intact Ossabaw swine that were either lean control or western diet-fed aortic-banded (N=4-5/group);2) Female Yucatan mini-swine subject to ovariectomy and/or aortic banding (N=5-8/group);and 3) Sedentary and exercise trained male, intact Yucatan mini-swine that were aortic banded. ACE2 and TMPRSS2 mRNA levels were evaluated in the left ventricle (LV), right ventricle (RV), and coronary vasculature using qRT-PCR. Linear regression analysis was used to determine differences between the following variables: pig species, sex hormones, aortic banding, comorbidities, exercise training, and tissue. Data was log-transformed to meet linear regression assumptions. ACE2 and TMPRSS2 mRNA levels were significantly influenced by sex, comorbidity, and tissue type. TMPRSS2 mRNA levels were also influenced by species and disease status. Specifically, ACE2 mRNA levels decreased 57.1% in the LV and increased 169.9% in the RV of males compared to coronary vessels in intact females. TMPRSS2 mRNA levels increased in the LV and RV of males (1,218.6% and 5,479.8%, respectively) compared to coronary vessels in intact females. ACE2 and TMPRSS2 mRNA levels increased 344% and 453.4%, respectively, in the LV of Ossabaw swine fed a Western Diet compared to coronary vessels from Yucatan and Ossabaw swine without comorbidities. Species differences indicated TMPRSS2 mRNA levels increased 449.2% in the RV and 498.6% in the LV in Yucatan mini-swine compared to coronary vessels in Ossabaw swine. A 107.3% increase in TMPRSS2 mRNA level was observed in male swine without HF compared to female intact swine with HF highlighting the importance of sex and disease state. Exercise training did not impact ACE2 or TMPRSS2 mRNA levels irrespective of tissue. In conclusion, these results suggest differences in RV, LV and coronary mRNA levels of ACE2 and TMPRSS2 are dependent upon sex and comorbidities. TMPRSS2 levels are additionally influenced by pig species and pressureoverload. These results provide insight into how ACE2 and TMPRSS2 mRNA levels may influence the cardiovascular involvement of SARS-COV-2 infection in an experimental setting of pre-clinical HF incorporating different swine species, sex, and comorbidities.

9.
Indian Veterinary Journal ; 98(12):22-29, 2021.
Article in English | EMBASE | ID: covidwho-1820592

ABSTRACT

Spike (S) proteins covering the outer surface of the Coronaviruses are the major hotspots of evolution and are also responsible for attaching the virus to the angiotensin-converting enzyme (ACE2) receptor on the host cells. In this study, we unveiled the evolutionary relics of the S-protein sequences of different beta Coronaviruses, namely, Severe Acute Respiratory Syndrome (SARS-CoV), SARS-CoV-2, and Middle East Respiratory Syndrome (MERSCoV). The present study aims at exploring the sequence divergence of the spike protein (S-protein) of nCov2 viruses to illuminate the evolutionary process. The nucleotide sequences of S-proteins of nCov2 viruses, namely, SARS, MERS and SARS-CoV2, representing different continents of the world, were downloaded from the NCBI Nucleotide databases. The conserved regions have been depicted through multiple sequence alignment (Clustal Omega, Jalview) and the molecular phylogeny has been studied. (using MEGA 7). Comparative analysis of the pairwise distance and selection pressure indicated that the SARS-CoV and SARS-CoV-2 are close to each other, however, distantly related to MERS-CoV and the SARS-CoV2 could have evolved from SARS (Severe Acute Respiratory Syndrome).

10.
International Journal of Research in Ayurveda and Pharmacy ; 13(2):43-48, 2022.
Article in English | EMBASE | ID: covidwho-1818689

ABSTRACT

The publication and worldwide diffusion of the Ayurveda treatment of COVID-19 and the vital role that spices, and medicinal herbals play in this protocol, promoted by the Department of Health and Family Welfare of India (MoHFW), in the context of SARS-CoV2 infection. Encourage us to review updating the knowledge of these herbals' plants' biochemical mechanisms of action. Several biochemical mechanisms of action of spices have been studied and established in the context of COVID-19. It has been described that herbs act as blocking agonists of some cell receptors, such as the ACE2 receptor of the renin-angiotensin system and TRP receptors belonging to the superfamily of sensory neurons, responsible for symptoms the SARS-CoV2 virus. We also find widely recommended medicinal herbs such as Tinospora cordifolia and Withania somnifera in this protocol, which has been described to stimulate the immune system and, at the same time, increase the destructive capacity of macrophages and biochemically block the entry of SARS-CoV-2 to host cells. Other medicinal herbs recommended by the Ayurveda protocol such as Curcuma longa L, Cinnamomum camphora, Eucalyptus globulus, Allium sativum L, Piper nigrum, Glycyrrhiza glabra L, as well as being potent antioxidants and anti-inflammatory are traditionally selected as an adjuvant treatment indicated for "respiratory diseases" as in the current framework of the COVID-19 pandemic. This article explores the Ayurveda protocol and some recently recommended nutraceutical substances and spiced dietary guidelines, as an alternative treatment in concern to SARS-CoV2 infection, for the treatment of long-term side effects of the post-COVID syndrome.

11.
Asian Pacific Journal of Reproduction ; 11(2):53-61, 2022.
Article in English | EMBASE | ID: covidwho-1818348

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected in the blood, urine, facial/anal swabs, semen, and vaginal discharge;all have been shown to contain SARSCoV-2 RNA. Recent findings have highlighted the prospect of SARS-CoV-2 invading the genital system in addition to other tissues, which might give rise to reproductive concerns. This investigation sheds light on male reproductive tract vulnerability to invasion by SARS-CoV-2 and provides a foundation for further researches into male fertility. Males are infected with COVID-19 at a higher rate than females. As a result, some data suggest that this viral infection might affect the male reproductive system. The probable causes for male genital tract abnormalities in COVID-19 are: 1) high expression of angiotensin-converting enzyme 2 in the testes;2) SARS-CoV-2 infection indirectly induces immune response in the testes;3) SARS-CoV-2 directly damages male genital cells by virus-receptor binding activity;4) fever in SARSCoV-2 infected males may cause damages to testicular cells;5) testosterone level decreased in SAR-CoV-2 infected males;6) males are more susceptible to COVID-19 than females, which may be due to differences in the physiology of the genital tract. This review seeks to offer some insights into the potential causes of COVID-19 that affect the male reproductive system, as well as future prospect on this issue.

12.
Chinese Pharmacological Bulletin ; 37(8):1037-1041, 2021.
Article in Chinese | EMBASE | ID: covidwho-1818309

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. The life cycle of SARS-CoV-2 is not clear, which is one of the reasons that only Remdesivir has been approved by FDA for treating COVID-19. Although some new vaccines have been a- vailable, the quick mutations of SARS-CoV-2 affect the effectiveness of vaccines, calling for further assessment of the persistence and safety of vaccines. Therefore, drug treatment and prevention are still effective ways to deal with the epidemic of SARS-CoV-2. The article briefly summarizes the molecular mechanism of SARS-CoV-2 entry based on the existing literature. This virus enters the cell through two main ways, that is, spike protein mediating membrane fusion with plasma membrane or endosome membrane. According to the targets, the article summarizes the reported inhibitors of SARS-CoV-2 entry into cells, aiming to provide a reference for following research and clinical application of anti-SARS-CoV-2 drugs.

13.
Vaccines ; 10(3), 2022.
Article in English | EMBASE | ID: covidwho-1818229

ABSTRACT

Introduction: Onset of oral lichenoid lesions (OLL) or oral lichen planus (OLP) can be rare adverse reactions to vaccines. Recently, the first solitary cases were reported after COVID-19 vaccination. The aim of the present study was to assess if an increased frequency of OLL/OLP can be found after COVID-19 vaccination within a large real-world cohort. It was assumed that the incidence of OLL/OLP was significantly higher in subjects who received COVID-19 vaccine (cohort I) compared to individuals who were not vaccinated (cohort II). Patients and Methods: Initial cohorts of 274,481 vaccinated and 9,429,892 not vaccinated patients were retrieved from the TriNetX database (TriNetX, Cambridge, Massachusetts, USA), and matched for age, gender and the frequency of use of non-steroidal anti-inflammatory drugs, beta blockers, and angiotensin-converting enzyme inhibitors. Results: After matching each cohort, we accounted for 217,863 patients. Among cohort I, 146 individuals had developed OLL/OLP within 6 days after COVID-19 vaccination (88 and 58 subjects had received mRNA-and adenovirus vector-based vaccines), whereas in cohort II, 59 patients were newly diagnosed with OLL/OLP within 6 days after having visited the clinic for any other reason. The risk of developing OLL/OLP was calculated as 0.067% vs. 0.027%, for cohorts I and II, whereby the risk difference was highly significant (p < 0.001;log-rank test). RR and OR were 2.475 (95% CI = 1.829;3.348) and 2.476 (95% CI = 1.830;3.350), respectively. Discussion: The hypothesis was confirmed. Accordingly, the obtained results suggest that the onset of OLL/OLP is a rare adverse drug reaction to COVID-19 vaccines, especially to mRNA vaccines. Thus far, it remains unknown if specific components of the formulations cause a type IV hypersensitive reaction corresponding to OLL, or if the immune response post vaccination triggers a T cell-driven autoimmune reaction directed against the basal layer of keratinocytes of the oral mucosa in terms of OLP. Although OLL and OLP are both classified as premalignant lesions, spontaneous remission may be expected over time, at least in the case of OLL. Therefore, the presented findings should not place any limitation toward the use of COVID-19-vaccines in broad levels of the population.

14.
Frontiers in Physiology ; 12, 2022.
Article in English | EMBASE | ID: covidwho-1818005

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a major concern in critical care medicine with a high mortality of over 30%. Injury to the lungs is caused not only by underlying pathological conditions such as pneumonia, sepsis, or trauma, but also by ventilator-induced lung injury (VILI) resulting from high positive pressure levels and a high inspiratory oxygen fraction. Apart from mechanical factors that stress the lungs with a specific physical power and cause volutrauma and barotrauma, it is increasingly recognized that lung injury is further aggravated by biological mediators. The COVID-19 pandemic has led to increased interest in the role of the renin-angiotensin system (RAS) in the context of ARDS, as the RAS enzyme angiotensin-converting enzyme 2 serves as the primary cell entry receptor for severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. Even before this pandemic, studies have documented the involvement of the RAS in VILI and its dysregulation in clinical ARDS. In recent years, analytical tools for RAS investigation have made major advances based on the optimized precision and detail of mass spectrometry. Given that many clinical trials with pharmacological interventions in ARDS were negative, RAS-modifying drugs may represent an interesting starting point for novel therapeutic approaches. Results from animal models have highlighted the potential of RAS-modifying drugs to prevent VILI or treat ARDS. While these drugs have beneficial pulmonary effects, the best targets and application forms for intervention still have to be determined to avoid negative effects on the circulation in clinical settings.

15.
Frontiers in Immunology ; 13, 2022.
Article in English | EMBASE | ID: covidwho-1817939

ABSTRACT

Vaccines against the severe acute respiratory syndrome coronavirus 2, which have been in urgent need and development since the beginning of 2020, are aimed to induce a prominent immune system response capable of recognizing and fighting future infection. Here we analyzed the levels of IgG antibodies against the receptor-binding domain (RBD) of the viral spike protein after the administration of three types of popular vaccines, BNT162b2, mRNA-1273, or Sputnik V, using the same ELISA assay to compare their effects. An efficient immune response was observed in the majority of cases. The obtained ranges of signal values were wide, presumably reflecting specific features of the immune system of individuals. At the same time, these ranges were comparable among the three studied vaccines. The anti-RBD IgG levels after vaccination were also similar to those in the patients with moderate/severe course of the COVID-19, and significantly higher than in the individuals with asymptomatic or light symptomatic courses of the disease. No significant correlation was observed between the levels of anti-RBD IgG and sex or age of the vaccinated individuals. The signals measured at different time points for several individuals after full Sputnik V vaccination did not have a significant tendency to lower within many weeks. The rate of neutralization of the interaction of the RBD with the ACE2 receptor after vaccination with Sputnik V was on average slightly higher than in patients with a moderate/severe course of COVID-19. The importance of the second dose administration of the two-dose Sputnik V vaccine was confirmed: while several individuals had not developed detectable levels of the anti-RBD IgG antibodies after the first dose of Sputnik V, after the second dose the antibody signal became positive for all tested individuals and raised on average 5.4 fold. Finally, we showed that people previously infected with SARS-CoV-2 developed high levels of antibodies, efficiently neutralizing interaction of RBD with ACE2 after the first dose of Sputnik V, with almost no change after the second dose.

16.
Blood Purification ; 50(SUPPL 1):3, 2021.
Article in English | EMBASE | ID: covidwho-1816957

ABSTRACT

Background: The COVID-19 disease was first reported in December 2019 and has since spread rapidly around the world. This disease manifests in most cases as a lower respiratory tract infection. COVID-19 enters the human body using angiotensin-converting enzyme 2, abundant in the epithelial cells of the renal tubule. Theoretically, this could be significant in many ways: acute kidney injury (AKI), as well as proteinuria, and/or microhematuria could be associated with penetration of the virus into cells. Microalbuminuria is widely recognized as a critical diagnostic tool in the progression of kidney disease. It is increased in tubular and glomerular diseases. The use of microalbuminuria as a marker for AKI was shown in an animal model and correlated with other markers. However, there are few studies that have validated its usefulness as a marker for AKI. NGAL is abundantly expressed in the kidney after renal ischemia. NGAL has been tested in multiple studies of patients at risk of acute kidney injury (AKI) due to sepsis, cardiac surgery, exposure to contrast media, or after kidney transplantation. The most frequently reported causes of admission to the intensive care unit in patients with COVID-19 are hypoxemic respiratory failure that requires invasive mechanical ventilation or hypotension that requires support with vasoactive amines. Data on AKI are scarce since they only report on incidence in these patients. Methods: A prospective observational study. Patients who came to the area for COVID-19 were recruited. Upon admission, a urine sample was analyzed with Getein 1100, by quantitative immunofluorescence to determine levels of microalbuminuria and NGAL in 50 patients with creatinine <1.0. All patients had high oxygen requirements (> 5 liters/minute). All patients who had a positive PCR test for SARS CoV-2 were included and patients with a history of chronic kidney disease, urinary symptoms, underlying urological disease or complications of Diabetes or hypertension were excluded. Laboratories were collected at admission and 5 days after admission to compare with initial Ngal and microalbuminuria levels. Results: The association of the variables was analyzed using the Spearman correlation coefficient, since they are continuous variables. It was found that an elevation of creatinine at day 5 and an initial Ngal> 200 and microalbuminuria >30 have a moderate correlation (rho = 0.46) with a p <0.05, and a low correlation (rho = 0.28) and a p <0.05, respectively. Conclusion: Although there is no ideal biomarker for acute kidney injury, current biomarkers can significantly predict the development of acute kidney injury, especially in critically ill patients. With the emergence of COVID-19 disease, it is necessary to be able to prevent and treat acute kidney injury on time, in order to reduce the morbidity and mortality of these patients. In this study, it is observed that 2 biomarkers have a significant correlation to predict acute kidney injury, and it is necessary to have more availability of these biomarkers to detect it on time.

17.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816909

ABSTRACT

COVID-19 is leading to a global pandemic and invades human cells via ACE2. ACE2 was found to abundantly expressed in many organs and cells. However, there is no evidence about the potential risk of various types of cancer patients vulnerable to the infection of COVID-19. To obtain a risk map which indicating the novel coronavirus vulnerability of different types of cancer, so in this work we analyzed the RNA sequencing datasets of cancer patient. By interrogating the datasets, we not only identified the cancer types which vulnerable to COVID-19 attacks, but also we reported that variations in the mRNA expression level of ACE2 correlate to various prognosis phenomenon in different types of cancer cohorts and illustrated the underlying mechanism involved in may be related to lymphocytes infiltration. From these discoveries, we constructed an infection risk map which indicate the vulnerability of different types of cancer to COVID-19 infection, also elucidated the correlationship between ACE2 and the prognosis of cancer. We found that high ACE2 expression levels leading high risk of COVID-19 infection and poor prognosis of BRCA while better prognosis in OV patient cohorts. Moreover, our study demonstrated that this different pattern may correlate with the immune infiltration level. Note: This was not presented at the conference.

18.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816903

ABSTRACT

Vimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC 50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.

19.
Journal of Aerosol Medicine and Pulmonary Drug Delivery ; 35(2):A2, 2022.
Article in English | EMBASE | ID: covidwho-1815946

ABSTRACT

SARS-CoV-2 is a coronavirus that infects epithelial cells in the naso- and oropharynx before infecting epithelial cells of the lower airways and alveoli and in severe COVID-19 spreading systemically and inducing a systemic inflammatory response. SARS-CoV-2 is spread mainly by virus particles in droplets and aerosols. This suggests that inhaled therapies may be useful in the treatment of early COVID-19 disease before severe respiratory systemic features develop and potentially in reducing transmission of the virus in the community. To be effective any inhaled therapy must be rapidly acting to prevent viral replication in respiratory epithelial cells to prevent the disease spreading down the respiratory tract and into the systemic circulation. It also needs to be safe and available for early prescription in order to prevent severe disease and hospitalisation. The development of inhaled therapies for COVID-19 may involved repurposing of existing inhaled therapies or developing inhaled formulations of new drugs with antiviral effects. Patients with asthma and COPD were reported to be less likely to be hospitalised with SARS-CoV-2 infection despite the concern that this coronavirus would have severe consequences for these patients as coronaviruses are known to trigger severe exacerbations. One possibility was that this may be due to the widespread treatment with inhaled corticosteroids (ICS), which are known to suppress ACE2 and TMPRSS2 on epithelial cells that are key entry receptors for the virus and also reduce virus replication in vitro. A community based open label parallel group phase 2 study of the ICS budesonide (800 lg bid until recovery) in people with early symptoms (within 7 days of onset) of COVID-19 and confirmed by PCR testing (STOIC) showed that only 1/69 people in the ICS group developed severe disease compared with 10/70 in the usual care group.1 Clinical recovery was also shorter in the ICS group. This finding was confirmed in an open label study of inhaled budesonide in individuals over the age of 65 years at risk from severe COVID-19 (PRINCIPLE), which showed a reduction in time to recovery and a trend towards reduced hospitalisation and death.2 Several other trials, including double-blind studies, of ICS in early COVID-19 are currently underway with different corticosteroids, including ciclesonide, which appears to be the most effective against SARS-CoV-2 in vitro.3 However, a recent double-blind study of nasal and inhaled ciclesonide failed to show any benefit in early COVID-19, although the population was mainly young adults who have a low risk of disease progression.4 The mechanism of action of ICS in COVID- 19 has not yet been established, but may involve reduced viral entry due to suppression of ACE2 and TMPRSS2 in airway epithelial cells, reduced viral proliferation or reduced inflammatory mediators secreted by airway epithelial cells that may promote viral spreading. Interferon b1 is currently approve for treating multiple sclerosis. Nebulised IFN-b1a (SNG001) gave a greater degree of clinical improvement in hospitalised COVID-19 patients and a reduction on symptoms (mainly dyspnoea) compared to with placebo and was well tolerated.5 However, studies in early disease are underway but have not yet been reported, although there are logistical problems in the need for a nebuliser to deliver the drug. Inhaled PUL-42 is a combination of a TLR2/6 and a TLR9 inhibitors which is effective in a single inhaled dose against SARS-CoV and MERS-CoV infection in mice and reduces the lung viral load.6 This drug is now in clinical trials for COVID-19. Other inhaled drugs, including antivirals such as remdesivir and niclosamide, are also in development.

20.
Stem Cell Reports ; 17(4):789-803, 2022.
Article in English | MEDLINE | ID: covidwho-1815188

ABSTRACT

Several studies have pointed to retinal involvement in COVID-19, yet many questions remain regarding the ability of SARS-CoV-2 to infect and replicate in retinal cells and its effects on the retina. Here, we have used human pluripotent stem cell-derived retinal organoids to study retinal infection by SARS-CoV-2. Indeed, SARS-CoV-2 can infect and replicate in retinal organoids, as it is shown to infect different retinal lineages, such as retinal ganglion cells and photoreceptors. SARS-CoV-2 infection of retinal organoids also induces the expression of several inflammatory genes, such as interleukin 33, a gene associated with acute COVID-19 and retinal degeneration. Finally, we show that the use of antibodies to block ACE2 significantly reduces SARS-CoV-2 infection of retinal organoids, indicating that SARS-CoV-2 infects retinal cells in an ACE2-dependent manner. These results suggest a retinal involvement in COVID-19 and emphasize the need to monitor retinal pathologies as potential sequelae of "long COVID."

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