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Introduction: Traditional Chinese medicine (TCM) has the advantages of syndrome differentiation and rapid determination of etiology, and many TCM prescriptions have been applied to the clinical treatment of coronavirus disease 2019 (COVID-19). Among them, Jinbei Oral Liquid (Jb.L) has also shown an obvious curative effect in the clinic, but the related material basic research is relatively limited. Methods: Therefore, in this process, a systematic data acquisition and mining strategy was established using ultra-high- performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Results and Discussion: With the optimized conditions, a total of 118 peaks were tentatively characterized, including 43 flavonoids, 26 phenylpropanoids, 14 glycosides, 9 phthalides, 8 alkaloids and others. To determine the content of relevant pharmacological ingredients, we firstly exploited the ultra-performance liquid chromatography method coupled with triple-quadrupole tandem mass spectrometry (UPLC-QqQ-MS/MS) method for simultaneous detection of 31 active ingredients within 17 min, and the validation of methodology showed that this method has good precision and accuracy. Moreover, analyzing the pharmacology of 31 individual of the medicinal material preliminarily confirmed the efficacy of Jb.L and laid a foundation for an in-depth study of network pharmacology.
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Background: The long-term implications of COVID-19 attract global attention in the post-COVID-19 pandemic era. Impaired lung function is the main sequelae in adults' survivors of SARS-CoV-2 infection. Methods and Results: The plasma proteomic pattern provides novel evidence on multiple biological domains relevant to monitoring lung function and targeting the clinical application in adults with acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 infection (SARS-CoV-2-ARDS). Preliminary studies support the evidence of pulmonary function tests (PFT) and computed tomography (CT) scan as routine follow-up tools. Combining the early fibrotic indicators and D-dimer levels could prove the validity and reliability of the proactive management of lung function assessment during the long-term recovery in SARS-CoV-2 infection. Conclusion: In summary, protocolized PFT and CT scan and effective biomarkers for early fibrotic changes should be applied to clinical practice during the long follow-up in patients with severe COVID-19.
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Objective The aim of this study was to assess the prognostic value of the lung ultrasound (LUS) score in patients with pediatric acute respiratory distress syndrome (pARDS) who received extracorporeal membrane oxygenation (ECMO). Methods A prospective cohort study was conducted in a pediatric intensive care unit (PICU) of a tertiary hospital from January 2016 to June 2021. The severe pARDS patients who received ECMO were enrolled in this study. LUS score was measured at initiation of ECMO (LUS-0 h), then at 24 h (LUS-24 h), 48 h (LUS-48 h), and 72 h (LUS-72 h) during ECMO, and when weaned from ECMO (LUS-wean). The value of LUS scores at the first 3 days of ECMO as a prognostic predictor was analyzed. Results Twenty-nine children with severe pARDS who received ECMO were enrolled with a median age of 26 (IQR 9, 79) months. The median duration of ECMO support was 162 (IQR 86, 273) h and the PICU mortality was 31.0% (9/29). The values of LUS-72 h and LUS-wean were significantly lower in survivors than that in non-survivors (both P < 0.001). Daily fluid balance volume during the first 3 days of ECMO support were strongly correlated with LUS score [1st day: r = 0.460, P = 0.014;2nd day: r = 0.540, P = 0.003;3rd day: r = 0.589, P = 0.001]. The AUC of LUS-72 h for predicting PICU mortality in these patients was 1.000, and the cutoff value of LUS-72 h was 24 with a sensitivity of 100.0% and a specificity of 100.0%. Furthermore, patients were stratified in two groups of LUS-72 h ≥ 24 and LUS-72 h < 24. Consistently, PICU mortality, length of PICU stay, ratio of shock, vasoactive index score value, and the need for continuous renal replacement therapy were significantly higher in the group of LUS-72 h ≥ 24 than in the group of LUS-72 h < 24 (all P < 0.05). Conclusion Lung ultrasound score is a promising tool for predicting the prognosis in patients with ARDS under ECMO support. Moreover, LUS-72 h ≥ 24 is associated with high risk of PICU mortality in patients with pARDS who received ECMO.
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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent for the coronavirus disease 2019 (COVID-19) pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin 1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 26 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate PI3KC3-C1 (Beclin-1-Vps34-Atg14) but selectively inhibit PI3KC3-C2 (Beclin-1-Vps34-UVRAG). Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raise the possibility of targeting the autophagic pathway for the treatment of COVID-19.
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BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a global public health concern due to relatively easy person-to-person transmission and the current lack of effective antiviral therapy. However, the exact molecular mechanisms of SARS-CoV-2 pathogenesis remain largely unknown. METHODS: Genome-wide screening was used to establish intraviral and viral-host interactomes. Quantitative proteomics was used to investigate the peripheral blood mononuclear cell (PBMC) proteome signature in COVID-19. FINDINGS: We elucidated 286 host proteins targeted by SARS-CoV-2 and >350 host proteins that are significantly perturbed in COVID-19-derived PBMCs. This signature in severe COVID-19 PBMCs reveals a significant upregulation of cellular proteins related to neutrophil activation and blood coagulation, as well as a downregulation of proteins mediating T cell receptor signaling. From the interactome, we further identified that non-structural protein 10 interacts with NF-κB-repressing factor (NKRF) to facilitate interleukin-8 (IL-8) induction, which potentially contributes to IL-8-mediated chemotaxis of neutrophils and the overexuberant host inflammatory response observed in COVID-19 patients. CONCLUSIONS: Our study not only presents a systematic examination of SARS-CoV-2-induced perturbation of host targets and cellular networks but it also reveals insights into the mechanisms by which SARS-CoV-2 triggers cytokine storms, representing a powerful resource in the pursuit of therapeutic interventions. FUNDING: National Key Research and Development Project of China, National Natural Science Foundation of China, National Science and Technology Major Project, Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, Shanghai Science and Technology Commission, Shanghai Municipal Health Commission, Shanghai Municipal Key Clinical Specialty, Innovative Research Team of High-level Local Universities in Shanghai, Interdisciplinary Program of Shanghai Jiao Tong University, SII Challenge Fund for COVID-19 Research, Chinese Academy of Sciences (CAS) Large Research Infrastructure of Maintenance and Remolding Project, and Chinese Academy of Sciences Key Technology Talent Program.
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COVID-19 , SARS-CoV-2 , China/epidemiology , Humans , Interleukin-8 , Leukocytes, Mononuclear , Proteomics , Virulence FactorsABSTRACT
The pandemic of the Coronavirus Disease 2019 (COVID-19) has spread around the world. COVID-19 is one of the most serious infectious disease threats in the past 100 years. Epidemiological and clinical studies have shown that early diagnosis of infectious COVID-19 cases is of great help to slow down the spread of disease and reduce mortality. Therefore, the diagnosis of SARS-CoV-2 infection is of great significance in the control of the pandemic. However, because patients with COVID-19 show partially similar symptoms to diseases such as influenza-like illness, it is impossible to diagnose SARS-CoV-2 infection by relying solely on the patient's clinical features. Meanwhile, there are a number of asymptomatic patients, who are capable of spreading the infection while passing general surveillance. The early diagnosis of such cases is also critical for the prevention of the outbreak and control of the pandemic. Given there is no effective SARS-CoV-2-specific anti-viral agents, chemists are engaging in the development of analytical strategies for the SARS-CoV-2 detection and antiviral drug to combat the spread of the COVID-19. In order to support the innovation in the ongoing research on fighting COVID-19 pandemic, we summarized part of the achievements in SARS-CoV-2 detection and drug development engaged by chemists in China. By summarizing the available products and patents with practical potentials in fast analysis, we discussed the recent advances in the techniques for SARS-CoV-2 detection and their application potentials in diagnosis of COVID-19. For the diagnosis of COVID-19, the most specific analysis method is polymerase chain reaction (PCR) based nucleic acid assay. At the end of March, National Medical Products Administration has approved more than 20 products aiming at SARS-CoV-2 test, most of which are kits based on the principle of real-time quantitative reverse transcription PCR (RT-qPCR). Because PCR-based method needs complex manual operation steps, the technique is limited due to the time-consuming reaction steps. Later on, techniques with multiple procedures including nucleic acid extraction, amplification, and virus detection have been integrated for rapid detection. In order to solve the problems caused by disadvantages of complex thermal cycling process in PCR, isothermal amplification has been applied for nucleic acid detection. Combined with isothermal amplification, rapid point-of-care test is applicable for the detection of collected SARS-CoV-2 viral RNA. Although viral RNA assay is the most specific method for diagnosis of COVID-19, it cannot be used to determine the post-infection or monitor the immunity of general populations. The immunological assays could be applied for the detection of antibodies themselves several days after the infection by SARS-CoV-2. Therefore, lateral flow assay, microfluidics, and other technologies have successfully applied for the immune assay. Some reagents, detection kits, and devices have been certificated and marketed internationally. Specific anti-SARS-CoV-2 agents have been designed and tested. Moreover, several small-molecule drug candidates with high efficacy and low toxicity showed great potential in clinical application. Facing the outbreak of epidemic of COVID-19, Department of Chemical Sciences, Department of Mathematical and Physical Sciences of National Natural Science Foundation of China have jointly funded three innovative projects to support the research on the effective and expedite control of the epidemic. These projects include "Research on rapid detection of new coronavirus in aerosol on site", "A pre-clinical study of using small molecules to treat SARS-CoV-2-induced excessive inflammation and injury", and "Polymer micro-/nano-fibrous non-woven fabrics prepared via flash-pressure-released technology and reusable high-quality medical protective suits produced with these fabrics". The pandemic of COVID-19 is a major public health emergency, which poses a major challenge to health system worldwide and also has a m jor impact on economy and society. In response to sudden large-scale outbreaks, rapid, accurate and high-throughput detection technology is undoubtedly the priority of "anti-epidemic". Focusing on the present and serving the long-term requirement, we still need to innovatively propose new ideas to meet the major needs in the diagnosis and treatment of major diseases based on a global perspective.