Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (Mpro), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.

Flavonoids from the roots and rhizomes of Sophoratonkinensis and their in vitro anti-SARS-CoV-2 activity.

Acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused a global pandemic since 2019, and posed a serious threat to global health security. Traditional Chinese medicine (TCM) has played an indispensable role in the battle against the epidemic. Many components originated from TCMs were found to inhibit the production of SARS-CoV-2 3C-like protease (3CLpro) and papain-like protease (PLpro), which are two promising therapeutic targets to inhibit SARS-CoV-2. This study describes a systematic investigation of the roots and rhizomes of Sophora tonkinensis, which results in the characterization of 12 new flavonoids, including seven prenylated flavanones (1-7), one prenylated flavonol (8), two prenylated chalcones (9-10), one isoflavanone (11), and one isoflavan dimer (12), together with 43 known compounds (13-55). Their structures including the absolute configurations were elucidated by comprehensive analysis of MS, 1D and 2D NMR data, and time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculations. Compounds 12 and 51 exhibited inhibitory effects against SARS-CoV-2 3CLpro with IC50 values of 34.89 and 19.88 µmol·L-1, repectively while compounds 9, 43 and 47 exhibited inhibitory effects against PLpro with IC50 values of 32.67, 79.38, and 16.74 µmol·L-1, respectively.

Analyst Site Visits and Corporate Environmental Information Disclosure: Evidence from China.

Compared with developed countries, emerging economy countries are facing more severe environmental challenges. Therefore, effective disclosure of corporate environmental information is an important concern for emerging economies to cope with environmental issues. There is a growing volume of literature documenting that analyst site visits can urge corporations to provide high-quality financial information to investors. However, whether analyst site visits can also improve the quality of environmental information is still unclear. In the Chinese setting, where environmental information has attracted much attention, we explore the interaction between analyst site visits and environmental information disclosure. With three regression methods of the ordinary least squares model, two-stage least square model, and difference-in-difference model, we establish regressions to verify the relationships between them by using empirical data from 2012 to 2019 in China. The results show that analyst site visits are significantly positively correlated with corporate environmental information disclosure. This positive relation is more pronounced when corporations are in economically developed and highly market-oriented areas, in poor air quality areas, and for corporations with good, reasonable internal governance. In addition, we find that analyst site visits affect the quality of environmental information disclosure through the intermediary effect of media attention. In the robustness test, further evidence also indicates that the interaction between analyst site visits and corporate environmental information disclosure was more significant before the COVID-19 lockdown policy was implemented in Wuhan. Our findings suggest that governments should provide support for analysts to conduct site visits and formulate regulations on mandatory disclosure of environmental information by different regions as soon as possible.

Maternal psychological distress in the early postpartum period during COVID-19 pandemic: a pilot study.

BACKGROUND: The coronavirus disease 2019 infection (COVID-19) pandemic is a new global outbreak disease. According to the Taiwan Centers for Diseases Control statement, hospitals had to change their corresponding measures to prevent the spread of COVID-19. The frequency of parental visits to the special care nursery was reduced from three times to once daily. Visiting was not permitted from April 4 to May 10, 2020, and rooming-in with healthy neonates was discontinued, which could increase maternal postpartum distress. Therefore, this study was conducted to determine whether COVID-19 prevention increased maternal psychological distress. METHODS: This prospective study used convenience sampling to enroll healthy mothers who had just delivered via normal spontaneous delivery. Based on the neonates' status and visiting times, mothers were grouped into no-rooming-in, rooming-in, no-visiting, and one-visit/day groups. Mothers' baseline characteristics were compared using the Chi-square or Fisher's exact test and t-test. Salivary cortisol levels and scores of Chinese versions of the Perceived Stress Scale (PSS) and State-Trait Anxiety Inventory were evaluated on postpartum days 1 and 3 and analyzed by one-way analysis of variance and a paired t-test. RESULTS: There were 16, 58, 28, and 47 women categorized as no-rooming-in, rooming-in, no-visit, and one-visit/day groups, respectively. No significant differences were found between groups in mothers' baseline characteristics and postpartum salivary cortisol levels. The PSS on day 3 was significantly higher than on day 1 in every group (p < 0.001). The PSS increasing trend in the no-rooming-in group was significantly greater than that in the no-visit group (p = 0.02) and significantly greater in the rooming-in group than that in the one-visit/day group (p = 0.001). CONCLUSION: Postpartum stress increased for all mothers and was an even more significant response to the COVID-19 pandemic than the stress associated with neonates' hospitalization.

An IgM-like Inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 (preprint)

Many of the currently available COVID-19 vaccines and therapeutics are not effective against newly emerged SARS-CoV-2 variants. Here, we developed the metallo-enzyme domain of angiotensin converting enzyme 2 (ACE2)—the cellular receptor of SARS-CoV-2—into an IgM-like inhalable molecule (HH-120). HH-120 binds to the SARS-CoV-2 Spike (S) protein with exceptionally high avidity and confers potent and broad-spectrum neutralization activity against all known SARS-CoV-2 variants of concern. HH-120 was successfully developed as an inhaled formulation that achieves appropriate aerodynamic properties for respiratory system delivery, and we found that aerosol inhalation of HH-120 significantly reduced viral loads and lung pathology scores in golden Syrian hamsters infected by the SARS-CoV-2 wild-type strain and the Delta variant. Our study presents a breakthrough for the inhalation delivery of large biologics like HH-120 (molecular weight ~ 1000kDa) and demonstrates that HH-120 can serve as a highly efficacious, safe, and convenient agent against all SARS-CoV-2 variants. Finally, given the known role of ACE2 in viral reception, it is conceivable that HH-120 will be efficacious against additional emergent coronaviruses.

Tolerability, Safety, Pharmacokinetics, and Immunogenicity of a Novel SARS-CoV-2 Neutralizing Antibody, Etesevimab, in Chinese Healthy Adults: a Randomized, Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly worldwide. This study is the first to report the tolerability, safety, pharmacokinetics (PK), and immunogenicity of a recombinant human anti-SARS-CoV-2 monoclonal antibody, etesevimab (CB6, JS016, LY3832479, or LY-CoV016), in healthy adults. This paper describes a randomized, double-blind, placebo-controlled, phase 1 study. A total of 40 participants were enrolled to receive a single intravenous dose of either etesevimab or placebo in one of four sequential ascending intravenous dose cohorts. All 40 participants completed the study. Seventeen (42.5%) participants experienced 22 treatment emergent adverse events (TEAEs) that were drug-related, and the rates of these TEAEs among different dose cohorts were numerically comparable. No difference was observed between the combined etesevimab group and the placebo group. The exposure after etesevimab infusion increased in an approximately proportional manner as the dose increased from 2.5 to 50 mg/kg. The elimination half-life (t1/2) value did not differ among different dose cohorts and was estimated to be around 4 weeks. Etesevimab was well tolerated after administration of a single dose at a range of 2.5 mg/kg to 50 mg/kg in healthy Chinese adults. The PK profiles of etesevimab in healthy volunteers showed typical monoclonal antibody distribution and elimination characteristics. (This study has been registered at ClinicalTrials.gov under identifier NCT04441918.).

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.

Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.

Management of acute coronary syndrome in the context of coronavirus disease 2019.

ABSTRACT: Coronavirus disease 2019 (COVID-19) is still developing worldwide. The prognosis of the disease will become worse and mortality will be even higher when it is combined with cardiovascular disease. Furthermore, COVID-19 is highly infectious and requires strict isolation measures. For acute coronary syndromes (ACS), a common cardiovascular disease, infection may aggravate the occurrence and development of ACS, making the management of more difficult. It will be an enormous challenge for clinical practice to deal with ACS in this setting of COVID-19.Aim to reduce the mortality of ACS patients during the epidemic of COVID-19 by standardizing procedures as much as possible.Pubmed and other relevant databases were searched to retrieve articles on COVID-19 and articles on ACS management strategies during previous influenza epidemics. The data was described and synthesized to summarize the diagnosis and management strategy of ACS, the preparation of catheter laboratory, and the protection of the medical staff in the context of COVID-19. Ethical approval is not required in this study, because it is a review with no recourse to patient identifiable information.Standardized diagnosis and treatment advice can help reduce the mortality of COVID-19 patients with ACS. In the absence of contraindications, the third generation of thrombolytic drugs should be the first choice for thrombolytic treatment in the isolation ward. For patients who have to receive PCI, this article provides detailed protective measures to avoid nosocomial infection.

Effect of a Previous History of Antiretroviral Treatment on Clinical Picture of Patients with Co-infection of SARS-CoV-2 and HIV: A Preliminary Study.

OBJECTIVES: We aimed to explore the effect of antiretroviral treatment (ART) history on clinical characteristics of patients with co-infection of SARS-CoV-2 and HIV. METHODS: We retrospectively reviewed 20 patients with laboratory-confirmed co-infection of SARS-CoV-2 and HIV in a designated hospital. Patients were divided into medicine group (n = 12) and non-medicine group (n = 8) according to previous ART history before SARS-CoV-2 infection. RESULTS: The median age was 46.5 years and 15 (75%) were female. Ten patients had initial negative RT-PCR on admission, 5 of which had normal CT appearance and 4 were asymptomatic. Lymphocytes were low in 9 patients (45%), CD4 cell count and CD4/CD8 were low in all patients. The predominant CT features in 19 patients were multiple (42%) ground-glass opacities (58%) and consolidations (32%). Erythrocyte sedimentation rate (ESR) in the medicine group was significantly lower than that in the non-medicine group [median (interquartile range, IQR):14.0 (10.0-34.0) vs. 51.0 (35.8-62.0), P = 0.005]. Nineteen patients (95%) were discharged with a median hospital stay of 30 days (IQR, 26-30). CONCLUSIONS: Most patients with SARS-CoV-2 and HIV co-infection exhibited mild to moderate symptoms. The milder extent of inflammatory response to SARS-CoV-2 infection might be associated with a previous history of ART in HIV-infected patients.

Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients.

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.

Guideline for diagnosis and treatment of spine trauma in the epidemic of COVID-19.

Outbreak of COVID-19 is ongoing all over the world. Spine trauma is one of the most common types of trauma and will probably be encountered during the fight against COVID-19 and resumption of work and production. Patients with unstable spine fractures or continuous deterioration of neurological function require emergency surgery. The COVID-19 epidemic has brought tremendous challenges to the diagnosis and treatment of such patients. To coordinate the diagnosis and treatment of infectious disease prevention and spine trauma so as to formulate a rigorous diagnosis and treatment plan and to reduce the disability and mortality of the disease, multidisciplinary collaboration is needed. This expert consensus is formulated in order to (1) prevent and control the epidemic, (2) diagnose and treat patients with spine trauma reasonably, and (3) reduce the risk of cross-infection between patients and medical personnel during the treatment.

Recommendations of protective measures for orthopedic surgeons during COVID-19 pandemic.

PURPOSE: It was the primary purpose of the present systematic review to identify the optimal protection measures during COVID-19 pandemic and provide guidance of protective measures for orthopedic surgeons. The secondary purpose was to report the protection experience of an orthopedic trauma center in Wuhan, China during the pandemic. METHODS: A systematic search of the PubMed, Cochrane, Web of Science, Google Scholar was performed for studies about COVID-19, fracture, trauma, orthopedic, healthcare workers, protection, telemedicine. The appropriate protective measures for orthopedic surgeons and patients were reviewed (on-site first aid, emergency room, operating room, isolation wards, general ward, etc.) during the entire diagnosis and treatment process of traumatic patients. RESULTS: Eighteen studies were included, and most studies (13/18) emphasized that orthopedic surgeons should pay attention to prevent cross-infection. Only four studies have reported in detail how orthopedic surgeons should be protected during surgery in the operating room. No detailed studies on multidisciplinary cooperation, strict protection, protection training, indications of emergency surgery, first aid on-site and protection in orthopedic wards were found. CONCLUSION: Strict protection at every step in the patient pathway is important to reduce the risk of cross-infection. Lessons learnt from our experience provide some recommendations of protective measures during the entire diagnosis and treatment process of traumatic patients and help others to manage orthopedic patients with COVID-19, to reduce the risk of cross-infection between patients and to protect healthcare workers during work. LEVEL OF EVIDENCE: IV.