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3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-320695

ABSTRACT

Background: Since 2020 COVID-19 pandemic became an emergent public sanitary incident. The epidemiology data and the impact on prognosis of secondary infection in severe and critical COVID-19 patients in China remained largely unclear. Methods: . We retrospectively reviewed medical records of all adult patients with laboratory-confirmed COVID-19 who were admitted to ICUs from January 18 th 2020 to April 26 th 2020 at two hospitals in Wuhan, China and one hospital in Guangzhou, China. We measured the frequency of bacteria and fungi cultured from respiratory tract, blood and other body fluid specimens. The risk factors for and impact of secondary infection on clinical outcomes were also assessed. Results: . Secondary infections were very common (86.6%) when patients were admitted to ICU for >72 hours. The majority of infections were respiratory, with the most common organisms being Klebsiella pneumoniae (24.5%), Acinetobacter baumannii (21.8%), Stenotrophomonas maltophilia (9.9%), Candida albicans (6.8%), and Pseudomonas spp. (4.8%). Furthermore, the proportions of multidrug resistant (MDR) bacteria and carbapenem resistant Enterobacteriaceae (CRE) were high. We also found that age ≥60 years and mechanical ventilation ≥13days independently increased the likelihood of secondary infection. Finally, patients with positive cultures had reduced ventilator free days in 28 days and patients with CRE and/or MDR bacteria positivity showed lower 28 day survival rate. Conclusions: . In a retrospective cohort of severe and critical COVID-19 patients admitted to ICUs in China, the prevalence of secondary infection was high, especially with CRE and MDR bacteria, resulting in poor clinical outcomes.

4.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-320694

ABSTRACT

Background: Since the clinical correlates, prognosis and determinants of AKI in patients with Covid-19 remain largely unclear, we perform a retrospective study to evaluate the incidence, risk factors and prognosis of AKI in severe and critically ill patients with Covid-19. Methods: : We reviewed medical records of all adult patients (>18 years) with laboratory-confirmed Covid-19 who were admitted to the intensive care unit (ICU) between January 23 rd 2020 and April 6 th 2020 at Wuhan JinYinTan Hospital and The First Affiliated Hospital of Guangzhou Medical University. The clinical data, including patient demographics, clinical symptoms and signs, laboratory findings, treatment [including respiratory supports, use of medications and continuous renal replacement therapy (CRRT)] and clinical outcomes, were extracted from the electronic records, and we access the incidence of AKI and the use of CRRT, risk factors for AKI, the outcomes of renal diseases, and the impact of AKI on the clinical outcomes. Results: : Among 210 subjects, 131 were males (62.4%). The median age was 64 years (IQR: 56-71). Of 92 (43.8%) patients who developed AKI during hospitalization, 13 (14.1%), 15 (16.3%) and 64 (69.6%) patients were classified as stage 1, 2 and 3, respectively. 54 cases (58.7%) received CRRT. Age, sepsis, Nephrotoxic drug, IMV and elevated baseline Scr were associated with AKI occurrence. The renal recover during hospitalization among 16 AKI patients (17.4%), who had a significantly shorter time from admission to AKI diagnosis, lower incidence of right heart failure and higher P/F ratio. Of 210 patients, 93 patients deceased within 28 days of ICU admission. AKI stage 3, critical disease, greater age and minimum P/F <150mmHg independently associated with it. Conclusions: : Among patients with Covid-19, the incidence of AKI was high. age , sepsis, nephrotoxic drug, IMV and baseline Scr were strongly associated with the development of AKI. Time from admission to AKI diagnosis, right heart failure and P/F ratio were independently associated with the potential of renal recovery. Finally, AKI KIDGO stage 3 independently predicted the risk of death within 28 days of ICU admission.

5.
Front Cardiovasc Med ; 8: 757799, 2021.
Article in English | MEDLINE | ID: covidwho-1555742

ABSTRACT

Objective: Cardiac injury is detected in numerous patients with coronavirus disease 2019 (COVID-19) and has been demonstrated to be closely related to poor outcomes. However, an optimal cardiac biomarker for predicting COVID-19 prognosis has not been identified. Methods: The PubMed, Web of Science, and Embase databases were searched for published articles between December 1, 2019 and September 8, 2021. Eligible studies that examined the anomalies of different cardiac biomarkers in patients with COVID-19 were included. The prevalence and odds ratios (ORs) were extracted. Summary estimates and the corresponding 95% confidence intervals (95% CIs) were obtained through meta-analyses. Results: A total of 63 studies, with 64,319 patients with COVID-19, were enrolled in this meta-analysis. The prevalence of elevated cardiac troponin I (cTnI) and myoglobin (Mb) in the general population with COVID-19 was 22.9 (19-27%) and 13.5% (10.6-16.4%), respectively. However, the presence of elevated Mb was more common than elevated cTnI in patients with severe COVID-19 [37.7 (23.3-52.1%) vs.30.7% (24.7-37.1%)]. Moreover, compared with cTnI, the elevation of Mb also demonstrated tendency of higher correlation with case-severity rate (Mb, r = 13.9 vs. cTnI, r = 3.93) and case-fatality rate (Mb, r = 15.42 vs. cTnI, r = 3.04). Notably, elevated Mb level was also associated with higher odds of severe illness [Mb, OR = 13.75 (10.2-18.54) vs. cTnI, OR = 7.06 (3.94-12.65)] and mortality [Mb, OR = 13.49 (9.3-19.58) vs. cTnI, OR = 7.75 (4.4-13.66)] than cTnI. Conclusions: Patients with COVID-19 and elevated Mb levels are at significantly higher risk of severe disease and mortality. Elevation of Mb may serve as a marker for predicting COVID-19-related adverse outcomes. Prospero Registration Number: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020175133, CRD42020175133.

6.
Cell Res ; 32(1): 9-23, 2022 01.
Article in English | MEDLINE | ID: covidwho-1505077

ABSTRACT

In contrast to the extensive research about viral protein-host protein interactions that has revealed major insights about how RNA viruses engage with host cells during infection, few studies have examined interactions between host factors and viral RNAs (vRNAs). Here, we profiled vRNA-host protein interactomes for three RNA virus pathogens (SARS-CoV-2, Zika, and Ebola viruses) using ChIRP-MS. Comparative interactome analyses discovered both common and virus-specific host responses and vRNA-associated proteins that variously promote or restrict viral infection. In particular, SARS-CoV-2 binds and hijacks the host factor IGF2BP1 to stabilize vRNA and augment viral translation. Our interactome-informed drug repurposing efforts identified several FDA-approved drugs (e.g., Cepharanthine) as broad-spectrum antivirals in cells and hACE2 transgenic mice. A co-treatment comprising Cepharanthine and Trifluoperazine was highly potent against the newly emerged SARS-CoV-2 B.1.351 variant. Thus, our study illustrates the scientific and medical discovery utility of adopting a comparative vRNA-host protein interactome perspective.


Subject(s)
COVID-19 , RNA Viruses , Zika Virus Infection , Zika Virus , Animals , Antiviral Agents , Humans , Mice , RNA, Viral , SARS-CoV-2 , Viral Proteins
7.
Anal Chem ; 93(48): 16086-16095, 2021 12 07.
Article in English | MEDLINE | ID: covidwho-1500405

ABSTRACT

It is highly challenging to construct the best SERS hotspots for the detection of proteins by surface-enhanced Raman spectroscopy (SERS). Using its own characteristics to construct hotspots can achieve the effect of sensitivity and specificity. In this study, we built a fishing mode device to detect the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at low concentrations in different detection environments and obtained a sensitive SERS signal response. Based on the spatial resolution of proteins and their protein-specific recognition functions, SERS hotspots were constructed using aptamers and small molecules that can specifically bind to RBD and cooperate with Au nanoparticles (NPs) to detect RBD in the environment using SERS signals of beacon molecules. Therefore, two kinds of AuNPs modified with aptamers and small molecules were used in the fishing mode device, which can specifically recognize and bind RBD to form a stable hotspot to achieve high sensitivity and specificity for RBD detection. The fishing mode device can detect the presence of RBD at concentrations as low as 0.625 ng/mL and can produce a good SERS signal response within 15 min. Meanwhile, we can detect an RBD of 0.625 ng/mL in the mixed solution with various proteins, and the concentration of RBD in the complex environment of urine and blood can be as low as 1.25 ng/mL. This provides a research basis for SERS in practical applications for protein detection work.


Subject(s)
Binding Sites , Metal Nanoparticles , Spike Glycoprotein, Coronavirus/chemistry , COVID-19 , Gold , Humans , SARS-CoV-2
9.
Front Immunol ; 12: 683879, 2021.
Article in English | MEDLINE | ID: covidwho-1369666

ABSTRACT

Diseases caused by pathogenic bacteria in animals (e.g., bacterial pneumonia, meningitis and sepsis) and plants (e.g., bacterial wilt, angular spot and canker) lead to high prevalence and mortality, and decomposition of plant leaves, respectively. Melatonin, an endogenous molecule, is highly pleiotropic, and accumulating evidence supports the notion that melatonin's actions in bacterial infection deserve particular attention. Here, we summarize the antibacterial effects of melatonin in vitro, in animals as well as plants, and discuss the potential mechanisms. Melatonin exerts antibacterial activities not only on classic gram-negative and -positive bacteria, but also on members of other bacterial groups, such as Mycobacterium tuberculosis. Protective actions against bacterial infections can occur at different levels. Direct actions of melatonin may occur only at very high concentrations, which is at the borderline of practical applicability. However, various indirect functions comprise activation of hosts' defense mechanisms or, in sepsis, attenuation of bacterially induced inflammation. In plants, its antibacterial functions involve the mitogen-activated protein kinase (MAPK) pathway; in animals, protection by melatonin against bacterially induced damage is associated with inhibition or activation of various signaling pathways, including key regulators such as NF-κB, STAT-1, Nrf2, NLRP3 inflammasome, MAPK and TLR-2/4. Moreover, melatonin can reduce formation of reactive oxygen and nitrogen species (ROS, RNS), promote detoxification and protect mitochondrial damage. Altogether, we propose that melatonin could be an effective approach against various pathogenic bacterial infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Inflammasomes/metabolism , Melatonin/pharmacology , Sepsis/metabolism , Signal Transduction/drug effects , Animals , Humans , Inflammasomes/drug effects , Mitogen-Activated Protein Kinases/drug effects , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/drug effects , NF-kappa B/metabolism , Plant Leaves , Reactive Oxygen Species , Sepsis/genetics , Sepsis/immunology
11.
Natural Science ; 12(11):717-725, 2020.
Article in English | CAB Abstracts | ID: covidwho-1319796

ABSTRACT

Around the end of 2019, a new viral species caused large-scale transmissions and infections, discovered in Wuhan (WHO Emergencies Preparedness, Response, 2020) and subsequently around the world (WHO COVID-19 Disease Dashboard, 2020). Symptoms caused include coughing, shortness of breath, and fever. Around 1% to 5% (Worldometer, 2020) of confirmed infections have resulted in deaths, mainly due to severe respiratory failure (CDC, 2020). Genealogical tree studies of the new virus strains have later revealed them to be phylogenetically intimate relatives of the Severe Acute Respiratory Syndrome Coronavirus, namely (SARS-CoV), first identified in 2003 [1]. This new virus has been named SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) (Gorbalenya et al., 2020) on February 11th, 2020.

12.
Chemosphere ; 281: 130728, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1233383

ABSTRACT

As the coronavirus disease 2019 continues to spread globally, its culprit, the severe acute respiratory syndrome coronavirus 2 has been brought under scrutiny. In addition to inhalation transmission, the possible fecal-oral viral transmission via water/wastewater has also been brought under the spotlight, necessitating a timely global review on the current knowledge about waterborne viruses in drinking water treatment system - the very barrier that intercepts waterborne pathogens to terminal water users. In this article we reviewed the occurrence, concentration methods, and control strategies, also, treatment performance on waterborne viruses during drinking water treatment were summarized. Additionally, we emphasized the potential of applying the quantitative microbial risk assessment to guide drinking water treatment to mitigate the viral exposure risks, especially when the unregulated novel viral pathogens are of concern. This review paves road for better control of viruses at drinking water treatment plants to protect public health.


Subject(s)
COVID-19 , Drinking Water , Viruses , Water Purification , Humans , SARS-CoV-2 , Water Microbiology
13.
Front Mol Biosci ; 8: 651662, 2021.
Article in English | MEDLINE | ID: covidwho-1211830

ABSTRACT

BACKGROUND: Tocilizumab (TCZ), an interleukin-6 receptor antibody, has previously been used for treating patients with the coronavirus disease 2019 (COVID-19), but there is a lack of data regarding the administration timing of TCZ. OBJECTIVES: This study aimed to evaluate the timing and efficacy of TCZ in the treatment of patients with COVID-19. METHODS: Laboratory-confirmed patients with COVID-19 with an elevated interleukin-6 (IL-6) level (>10 pg/ml) were offered TCZ intravenously for compassionate use. Clinical characteristics, laboratory tests, and chest imaging before and after the administration of TCZ were retrospectively analyzed. RESULTS: A total of 58 consecutive patients who met the inclusion criteria and with no compliance to the exclusion criteria were included. Of these 58 patients, 39 patients received TCZ treatment, and 19 patients who declined TCZ treatment were used as the control cohort. In the TCZ-treatment group, 6 patients (15.4%) were in mild condition, 16 (41.0%) were in severe condition, and 17 (43.6%) were in critical condition. After TCZ treatment, the condition of 27 patients (69.2%) improved and 12 (30.8%) died. Compared with the improvement group, patients in the death group had higher baseline levels of IL-6 (P = 0.0191) and procalcitonin (PCT) (P = 0.0003) and lower lymphocyte percentage (LYM) (P = 0.0059). Patients receiving TCZ treatment had better prognoses than those without TCZ treatment (P = 0.0273). Furthermore, patients with a baseline IL-6 level of ≥100 pg/ml in the TCZ-treatment group had poorer clinical outcomes than those with an IL-6 level of <100 pg/ml (P = 0.0051). CONCLUSION: The administration of TCZ in an early stage of cytokine storm (IL-6 level < 100 pg/ml) may effectively improve the clinical prognosis of patients with COVID-19 by blocking the IL-6 signal pathway.

14.
Cell ; 184(7): 1865-1883.e20, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1071139

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding of the RNA virus and its interactions with host proteins could improve therapeutic interventions for COVID-19. By using icSHAPE, we determined the structural landscape of SARS-CoV-2 RNA in infected human cells and from refolded RNAs, as well as the regulatory untranslated regions of SARS-CoV-2 and six other coronaviruses. We validated several structural elements predicted in silico and discovered structural features that affect the translation and abundance of subgenomic viral RNAs in cells. The structural data informed a deep-learning tool to predict 42 host proteins that bind to SARS-CoV-2 RNA. Strikingly, antisense oligonucleotides targeting the structural elements and FDA-approved drugs inhibiting the SARS-CoV-2 RNA binding proteins dramatically reduced SARS-CoV-2 infection in cells derived from human liver and lung tumors. Our findings thus shed light on coronavirus and reveal multiple candidate therapeutics for COVID-19 treatment.


Subject(s)
COVID-19/drug therapy , Drug Repositioning , RNA, Viral , RNA-Binding Proteins/antagonists & inhibitors , SARS-CoV-2 , Animals , Cell Line , Chlorocebus aethiops , Deep Learning , Humans , Nucleic Acid Conformation , RNA, Viral/chemistry , RNA-Binding Proteins/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/genetics
15.
Preprint in English | bioRxiv | ID: ppbiorxiv-429815

ABSTRACT

A fraction of COVID-19 patients develop the most severe form, characterized by Acute Respiratory Disease Syndrome (ARDS). The molecular mechanisms causing COVID-19-induced ARDS have yet to be defined, though many studies have documented an increase in cytokines known as a "cytokine storm." Here, we demonstrate that cytokines that activate the NF-kappaB pathway can induce Activin A and its downstream marker, FLRG. In hospitalized COVID-19 patients elevated Activin A/FLRG at baseline were predictive of the most severe longitudinal outcomes of COVID-19, including the need for mechanical ventilation, lack of clinical improvement and all-cause mortality. Patients with Activin A/FLRG above the sample median were 2.6/2.9 times more likely to die, relative to patients with levels below the sample median, respectively. The study indicates high levels of Activin A and FLRG put patients at risk of ARDS, and blockade of Activin A may be beneficial in treating COVID-19 patients experiencing ARDS.

16.
Risk Manag Healthc Policy ; 13: 3187-3199, 2020.
Article in English | MEDLINE | ID: covidwho-1060224

ABSTRACT

PURPOSE: This study aimed to assess the psychological impact of the COVID-19 pandemic among the general public in Hunan Province, China, which could help develop psychological interventions and mental health programs. PARTICIPANTS AND METHODS: This online cross-sectional study recruited 571 participants through snowball sampling between February 2 and February 5, 2020. Data were collected through a general information questionnaire, the Public Emergency Psychological State Questionnaire, the Simple Coping Style Questionnaire, and the Public Disease Awareness on COVID-19 Scale. RESULTS: The total mean score of the public emergency psychological state of the sample was 0.27 (0.31) points, with only 5.78% of participants (n = 33) developing psychological distress. Avoidant coping style and disease awareness were weakly positively correlated (rs = 0.257, p < 0.01) and weakly negatively correlated (rs = -0.124, p <0.01) with psychological responses, respectively. There were significant psychological differences among the following variables: occupation, symptoms of fever or fatigue, discernment of the authenticity of COVID-19 information, and level of concern regarding COVID-19 (p < 0.05). CONCLUSION: The COVID-19 pandemic appears to have had a minor psychological impact on the general population in Hunan Province. However, psychological health promotion in the general public is still required, especially for employees (such as company employees, migrant workers, and businessmen), individuals with COVID-19-like symptoms, limited discernment competence and unconcerned attitudes. IMPLICATIONS: The initiatives for improving psychological health among the general public could focus on delivering COVID-19 knowledge and alleviating avoidant coping styles. Our findings could provide important insight for the development of psychological support strategies in China, as well as in other places affected by the epidemic.

17.
Ital J Pediatr ; 46(1): 153, 2020 Oct 14.
Article in English | MEDLINE | ID: covidwho-874036

ABSTRACT

BACKGROUND: Pediatric COVID-19 is relatively mild and may vary from that in adults. This study was to investigate the epidemic, clinical, and imaging features of pediatric COVID-19 pneumonia for early diagnosis and treatment. METHODS: Forty-one children infected with COVID-19 were analyzed in the epidemic, clinical and imaging data. RESULTS: Among 30 children with mild COVID-19, seven had no symptoms, fifteen had low or mediate fever, and eight presented with cough, nasal congestion, diarrhea, headache, or fatigue. Among eleven children with moderate COVID-19, nine presented with low or mediate fever, accompanied with cough and runny nose, and two had no symptoms. Significantly (P < 0.05) more children had a greater rate of cough in moderate than in mild COVID-19. Thirty children with mild COVID-19 were negative in pulmonary CT imaging, whereas eleven children with moderate COVID-19 had pulmonary lesions, including ground glass opacity in ten (90.9%), patches of high density in six (54.5%), consolidation in three (27.3%), and enlarged bronchovascular bundles in seven (63.6%). The lesions were distributed along the bronchus in five patients (45.5%). The lymph nodes were enlarged in the pulmonary hilum in two patients (18.2%). The lesions were presented in the right upper lobe in two patients (18.1%), right middle lobe in one (9.1%), right lower lobe in six (54.5%), left upper lobe in five (45.5%), and left lower lobe in eight (72.7%). CONCLUSIONS: Children with COVID-19 have mild or moderate clinical and imaging presentations. A better understanding of the clinical and CT imaging helps ascertaining those with negative nucleic acid and reducing misdiagnosis rate for those with atypical and concealed symptoms.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnosis , Lung/diagnostic imaging , Pandemics , Pneumonia, Viral/diagnosis , Tomography, X-Ray Computed/methods , Adolescent , COVID-19 , Child , Child, Preschool , Coronavirus Infections/epidemiology , Diagnostic Errors , Female , Humans , Infant , Male , Pneumonia, Viral/epidemiology , SARS-CoV-2
18.
Nucleic Acids Res ; 49(D1): D183-D191, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-873045

ABSTRACT

RNA molecules fold into complex structures that are important across many biological processes. Recent technological developments have enabled transcriptome-wide probing of RNA secondary structure using nucleases and chemical modifiers. These approaches have been widely applied to capture RNA secondary structure in many studies, but gathering and presenting such data from very different technologies in a comprehensive and accessible way has been challenging. Existing RNA structure probing databases usually focus on low-throughput or very specific datasets. Here, we present a comprehensive RNA structure probing database called RASP (RNA Atlas of Structure Probing) by collecting 161 deduplicated transcriptome-wide RNA secondary structure probing datasets from 38 papers. RASP covers 18 species across animals, plants, bacteria, fungi, and also viruses, and categorizes 18 experimental methods including DMS-seq, SHAPE-Seq, SHAPE-MaP, and icSHAPE, etc. Specially, RASP curates the up-to-date datasets of several RNA secondary structure probing studies for the RNA genome of SARS-CoV-2, the RNA virus that caused the on-going COVID-19 pandemic. RASP also provides a user-friendly interface to query, browse, and visualize RNA structure profiles, offering a shortcut to accessing RNA secondary structures grounded in experimental data. The database is freely available at http://rasp.zhanglab.net.


Subject(s)
Computational Biology/statistics & numerical data , Databases, Genetic/statistics & numerical data , High-Throughput Nucleotide Sequencing/statistics & numerical data , Nucleic Acid Conformation , RNA/chemistry , Transcriptome , Animals , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Computational Biology/methods , Genome, Viral/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Pandemics , RNA/genetics , RNA Probes/genetics , RNA, Bacterial/chemistry , RNA, Bacterial/genetics , RNA, Fungal/chemistry , RNA, Fungal/genetics , RNA, Plant/chemistry , RNA, Plant/genetics , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/genetics , SARS-CoV-2/physiology
19.
Preprint in English | medRxiv | ID: ppmedrxiv-20128298

ABSTRACT

ObjectivesWe aimed to explore the frequencies of nasal symptoms in patients with COVID-19, including loss of smell and taste, as well as their presentation as the first symptom of the disease and their association with the severity of COVID-19. MethodsIn this retrospective study, 1,206 laboratory-confirmed COVID-19 patients were included and followed-up by telephone call one month after discharged from Tongji Hospital, Wuhan. Demographic data, laboratory values, comorbidities, symptoms, and numerical rating scale scores (0-10) of nasal symptoms were extracted from the hospital medical records, and confirmed or reevaluated by the telephone follow-up. ResultsFrom COVID-19 patients (N = 1,172) completing follow-up, 199 (17%) subjects had severe COVID-19 and 342 (29.2%) reported nasal symptoms. The most common nasal symptom was loss of taste (20.6%, median score = 6), while 11.4% had loss of smell (median score = 5). The incidence of nasal symptom including loss of smell and loss of taste as the first onset symptom was <1% in COVID-19 patients. Loss of smell or taste scores showed no correlation with the scores of other nasal symptoms. Loss of taste scores, but not loss of smell scores, were significantly increased in severe vs. non-severe COVID-19 patients. Interleukin (IL)-6 and lactose dehydrogenase (LDH) serum levels positively correlated with loss of taste scores. About 80% of COVID-19 patients recovered from smell and taste dysfunction in 2 weeks. ConclusionIn the Wuhan COVID-19 cohort, only 1 out of 10 hospital admitted patients had loss of smell while 1 out 5 reported loss of taste which was associated to severity of COVID-19. Most patients recovered smell and taste dysfunctions in 2 weeks.

20.
Br J Pharmacol ; 177(18): 4147-4165, 2020 09.
Article in English | MEDLINE | ID: covidwho-592492

ABSTRACT

BACKGROUND AND PURPOSE: Immunosuppression is the predominant cause of mortality for sepsis because of failure to eradicate pathogens. No effective and specific drugs capable of reversing immunosuppression are clinically available. Evidences implicate the involvement of the vitamin D receptor (NR1I1) in sepsis-induced immunosuppression. The anti-malarial artesunate was investigated to determine action on sepsis-induced immunosuppression. EXPERIMENTAL APPROACH: The effect of artesunate on sepsis-induced immunosuppression was investigated in mice and human and mice cell lines. Bioinformatics predicted vitamin D receptor as a candidate target for artesunate, which was then identified using PCR and immunoblotting. Vdr, Atg16l1 and NF-κB p65 were modified to investigate artesunate 's effect on pro-inflammatory cytokines release, bacterial clearance and autophagy activities in sepsis-induced immunosuppression. KEY RESULTS: Artesunate significantly reduced the mortality of caecal ligation and puncture (CLP)-induced sepsis immunosuppression mice challenged with Pseudomonas aeruginosa and enhanced pro-inflammatory cytokine release and bacterial clearance to reverse sepsis-induced immunosuppression in vivo and in vitro. Mechanistically, artesunate interacted with vitamin D receptor, inhibiting its nuclear translocation, which influenced ATG16L1 transcription and subsequent autophagy activity. Artesunate inhibited the physical interaction between vitamin D receptor and NF-κB p65 in LPS-tolerant macrophages and then promoted the nuclear translocation of NF-κB p65, which activated the transcription of NF-κB p65 target genes such as pro-inflammatory cytokines. CONCLUSION AND IMPLICATIONS: Our findings provide evidence that artesunate interacted with vitamin D receptor to reverse sepsis-induced immunosuppression in an autophagy and NF-κB-dependent manner, highlighting a novel approach for sepsis treatment and drug repurposing of artesunate has a bidirectional immunomodulator.


Subject(s)
Artesunate , Autophagy , Receptors, Calcitriol , Sepsis , Animals , Artesunate/pharmacology , Female , Male , Mice , Mice, Inbred BALB C , NF-kappa B , Receptors, Calcitriol/drug effects , Sepsis/drug therapy
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