High-throughput screening of SARS-CoV-2 main and papain-like protease inhibitors.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.

Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study.

Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20-30 µM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.

[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

Therapeutic targets and interventional strategies in COVID-19: mechanisms and clinical studies.

Owing to the limitations of the present efforts on drug discovery against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lack of the understanding of the biological regulation mechanisms underlying COVID-19, alternative or novel therapeutic targets for COVID-19 treatment are still urgently required. SARS-CoV-2 infection and immunity dysfunction are the two main courses driving the pathogenesis of COVID-19. Both the virus and host factors are potential targets for antiviral therapy. Hence, in this study, the current therapeutic strategies of COVID-19 have been classified into "target virus" and "target host" categories. Repurposing drugs, emerging approaches, and promising potential targets are the implementations of the above two strategies. First, a comprehensive review of the highly acclaimed old drugs was performed according to evidence-based medicine to provide recommendations for clinicians. Additionally, their unavailability in the fight against COVID-19 was analyzed. Next, a profound analysis of the emerging approaches was conducted, particularly all licensed vaccines and monoclonal antibodies (mAbs) enrolled in clinical trials against primary SARS-CoV-2 and mutant strains. Furthermore, the pros and cons of the present licensed vaccines were compared from different perspectives. Finally, the most promising potential targets were reviewed, and the update of the progress of treatments has been summarized based on these reviews.

Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein.

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.

COVID-19 laboratory examination and clinical laboratory management

In December 2019, a corona Virus disease 2019 (COVID-l9) occurred in Wuhan, and the epidemic quickly spread in China and even many countries around the world. The disease is caused by a novel coronavirus. On February 11, the International Virus Classification Commission named acute respiratory syndrome coronavirus (SARS-CoV-2). 0n the same day, WHO named the disease as COVID-l9. COVID-19 patients have their Corresponding characteristics of laboratory tests. In case diagnosis. laboratory inspection has important reference value. Combining relevant literature and experience in the prevention and control of COVID-19, the related measures of COVID-l9 laboratory inspection and clinical laboratory management are proposed to provide reference basis for Clinical diagnosis and treatment of COVID-19.

Long-term sero-positivity for IgG, sequelae of respiratory symptoms, and abundance of malformed sperms in a patient recovered from severe COVID-19.

Patients with severe coronavirus disease in 2019 (COVID-19 pneumonia) may have many sequelae, which seriously affect their quality of life and work. Here, we report a case of infection in China, reviewed the course, treatment, and rehabilitation of a patient suffering from severe COVID-19 pneumonia, and collected his examination reports, including chest CT, laboratory examination results, lung function examination, sleep monitoring report, sex hormones, sperm morphology and activity. The patient's antiviral immunoglobulin G (IgG) continued to be positive for more than 11 months, and his small airway function was abnormal, and he suffered from respiratory problems (cough, chest pain, chest tightness, and shortness of breath), unstructured sleep apnea hypopnea syndrome, and nocturnal sleep hypoxemia. His abnormal sperm rate increased obviously, and sperm activity decreased obviously. Patients with severe COVID-19 pneumonia may have respiratory sequela, the abnormal sperm rate is obviously increased, and IgG positive can last for a long time.

[Clinical and laboratory characteristics of 215 cases of coronavirus disease 2019 with different prognosis].

OBJECTIVE: To analyze the clinical and laboratory characteristics of coronavirus disease 2019 (COVID-19) patients with different prognosis, and to provide evidence for the diagnosis and treatment of COVID-19. METHODS: The clinical and laboratory characteristics of 215 cases of confirmed COVID-19 patients admitted in the First People's Hospital of Tianmen City from January 18 to March 10, 2020 were retrospectively analyzed, including blood cell indexes, inflammatory indexes [C-reactive protein (CRP) and procalcitonin (PCT)], liver function, cardiac function, renal function, blood coagulation function, electrolyte, chest CT scan, and 2019 novel coronavirus (2019-nCoV) nucleic acid tests. The differences of above indexes in the two groups were compared and analyzed. In addition, 55 patients with other viral pneumonia were selected as the control group who admitted to the hospital from August 1 to November 30, 2019. The changes of laboratory indexes of COVID-19 group and control group were observed. RESULTS: In the 215 patients, 206 patients survived and 9 patients died. The average age of survival group was significantly lower than that in the death group, and the average length of hospital stay was significantly longer than the death group. (1) Clinical features: the proportion of underlying diseases in the death group was significantly higher than that in the survival group, such as dyspnea, sore throat, shiver, hypertension, diabetes, coronary heart disease, renal disease, and surgical history. There were no significant differences in other symptoms, signs and underlying diseases between the two group. (2) Laboratory test indexes of the two groups: in death group, white blood cell count [WBC (×109/L): 10.6 (4.0, 13.4) vs. 4.90 (3.92, 6.26)], neutrophils count [NEU (×109/L): 9.7 (3.4, 12.2) vs. 2.9 (2.1, 4.2)]; ratio of neutrophils to lymphocytes [NLR: 14.66 (5.19, 18.48) vs. 2.34 (1.47, 3.34)], CRP [mg/L: 130.21 (35.74, 210.86) vs. 17.90 (3.11, 50.23)], PCT [mg/L: 1.46 (0.45, 13.12) vs. 0.04 (0.02, 0.07)], lactate dehydrogenase [LDH (µmol×s-1×L-1): 4.80 (3.34, 7.37) vs. 3.77 (2.99, 5.12)], creatinine [Cr (µmol/L): 72.9 (69.6, 627.5) vs. 68.4 (55.5, 81.9)], D-dimer [mg/L: 0.86 (0.56, 3.32) vs. 0.39 (0.33, 0.58)], the area of ground glass opacity of chest CT scan [77.8% (7/9) vs. 35.0% (72/206)], the area of local patchy shadows [55.6% (5/9) vs. 17.5% (36/206)], the area of bilateral patchy shadows [100.0% (9/9) vs. 49.5% (102/206)] were significantly higher than those in survival group (all P < 0.01), lymphocyte count [LYM (×109/L): 0.6 (0.5, 0.8) vs. 1.3 (1.0, 1.6)], Na+ [mmol/L: 136.1 (131.0, 136.8) vs. 138.8 (136.5, 140.4)], Cl- [mmol/L: 97.7 (92.7, 100.9) vs. 102.7 (100.2, 104.3)], and carbon dioxide [CO2 (mmol/L): 23.0 (20.6, 28.5) vs. 29.2 (27.7, 30.9)] were significantly lower than those in survival group (all P < 0.05). (3) Laboratory test indicators in COVID-19 and control groups: in COVID-19 group, WBC, NEU, LYM, platelet count (PLT), coefficient of variation of red blood cell distribution width (RDW-CV), standard deviation of red blood cell distribution width (RDW-SD) and Cl- were significantly lower than those in control group, NLR, CRP, K+ and CO2 were significantly higher than those in control group. CONCLUSIONS: The major early symptoms of COVID-19 are fever, cough, chest tightness and fatigue. Age and underlying disease may be the risk factors which affect the prognosis of patients with COVID-19. The laboratory indexes such as WBC, NEU, LYM, CRP, PCT, LDH and Cr between death group and survival group were significantly abnormal in the early stages of COVID-19, which would have important implications for the prognosis of patients with COVID-19. Meanwhile, laboratory test indexes, including WBC, NEU, LYM, PLT, RDW-CV, RDW-SD, CRP, Cl-, K+ and CO2, also have important value in the differential diagnosis between COVID-19 and other viral pneumonia.

Massive migration promotes the early spread of COVID-19 in China: a study based on a scale-free network.

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic met coincidentally with massive migration before Lunar New Year in China in early 2020. This study is to investigate the relationship between the massive migration and the coronavirus disease 2019 (COVID-19) epidemic in China. METHODS: The epidemic data between January 25th and February 15th and migration data between Jan 1st and Jan 24th were collected from the official websites. Using the R package WGCNA, we established a scale-free network of the selected cities. Correlation analysis was applied to describe the correlation between the Spring Migration and COVID-19 epidemic. RESULTS: The epidemic seriousness in Hubei (except the city of Wuhan) was closely correlated with the migration from Wuhan between January 10 and January 24, 2020. The epidemic seriousness in the other provinces, municipalities and autonomous regions was largely affected by the immigration from Wuhan. By establishing a scale-free network of the regions, we divided the regions into two modules. The regions in the brown module consisted of three municipalities, nine provincial capitals and other 12 cities. The COVID-19 epidemics in these regions were more likely to be aggravated by migration. CONCLUSIONS: The migration from Wuhan could partly explain the epidemic seriousness in Hubei Province and other regions. The scale-free network we have established can better evaluate the epidemic. Three municipalities (Beijing, Shanghai and Tianjin), eight provincial capitals (including Nanjing, Changsha et al.) and 12 other cities (including Qingdao, Zhongshan, Shenzhen et al.) were hub cities in the spread of COVID-19 in China.

[Management and prevention of dental emergency during corona virus disease 2019 (COVID-19) epidemic]

The outbreak of corona virus disease 2019 (COVID-19) has developed rapidly and the situation of prevention and control is severe. During the epidemic period of COVID-19, due to the particularity of diagnosis and treatment of oral diseases, there is great challenges for how to deal with various types of dental emergency. In order to prevent and control the epidemic situation strictly, and to perform a scientific and orderly clinical diagnosis and treatment of dental emergency, this article provided suggestions on personnel management training, procedures and treatment, protection and disinfection of dental emergency during COVID-19 epidemic, and reference for dental institutions and medical staff.

[The risk and prevention of bio-aerosol transmission in dental clinics]

Corona virus disease 2019 (COVID-19) has become a Public Health Emergency of International Concern since its outbreak, and whether COVID-19 can transmit by aerosol remains controversial. The problem of bio-aerosol transmission in the relatively confined dental clinics has aroused wide attention in the field of dentistry. This review provided a most updated summary on the relation between bio-aerosols and dental clinics, which included the microorganisms in bio-aerosols, the bio-aerosol transmission and the sources testing methods, temporal and spatial distribution of dental bio-aerosols and summarized how to reduce the exposure to bio-aerosols in dental clinics.