Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Objective:To explore the impacts of thermotherapy combined with gemcitabine on the biological behavior of tongue squamous cell carcinoma cells.Methods:Human tongue squamous cell carcinoma Tca8113 cells were divided into the control group (blank control), gemcitabine group, thermotherapy group (heated in an incubator at 43℃ for 1 h and then incubated at 37℃ for 24 h) and thermotherapy + gemcitabine group. The proliferation ability of Tca8113 cells was assessed by EdU staining and CCK-8 assay. Cell apoptosis and cell cycle of Tca8113 cells were detected by flow cytometry. The invasion of Tca8113 cells was determined by Transwell chamber assay. The expression levels of cyclin D1 (CyclinD1), Bcl-2-associated X protein (Bax), matrix metalloproteinase (MMP)-9, phosphorylated histone H2AX (γH2AX) and Nijmegen breakage syndrome 1 (NBS1) proteins in Tca8113 cells were measured by Western blot. The changes of tumor mass and volume were detected by xenograft tumor in vivo test in nude mice. Multi-group comparison was performed by one-way ANOVA. Two group comparison was conducted by SNK- q test. Results:Compared with the control group, EdU positive cell percentage, OD 450 value, invasive cell number, CyclinD1, MMP-9 and NBS1 protein expression of Tca8113 cells were decreased, whereas the apoptosis rate, the expression of Bax and γH2AX proteins were increased in the gemcitabine, thermotherapy and thermotherapy + gemcitabine groups ( q=4.45-72.06, all P<0.001). Compared with the control group, the proportion of G 0/G 1 phase cells was decreased, whereas the proportion of S and G 2/M phase cells was increased in the gemcitabine and thermotherapy + gemcitabine groups, the proportion of G 0/G 1 phase cells was decreased and the proportion of G 2/M phase cells was increased in the hyperthermia group ( q=10.36-61.09, all P<0.001). Compared with the gemcitabine and thermotherapy groups, EdU positive cell percentage, OD 450 value, G 0/G 1 phase cell proportion, invasive cell number, CyclinD1, MMP-9 and NBS1 protein expression of Tca8113 cells were decreased, whereas apoptosis rate, S, G 2/M phase cell proportion, Bax and γH2AX protein expression were increased in the thermotherapy + gemcitabine group ( q=4.45-28.73, all P<0.001). Xenograft tumor in vivo test in nude mice showed that the tumor volume and mass of nude mice in the gemcitabine, thermotherapy, and thermotherapy + gemcitabine groups were decreased compared with those in the control group ( q=5.58-73.02, all P<0.001). Compared with the gemcitabine and thermotherapy groups, the tumor volume and mass in the thermotherapy + gemcitabine group were decreased ( q=5.58-21.45, all P<0.001). Conclusion:The combination of thermotherapy and gemcitabine can inhibit the proliferation and invasion, block the cell cycle, and induce cell apoptosis of Tca8113 cells.

Objective To observe the effect of buccal needle therapy on perioperative analgesia in patients undergoing laparoscopic radical colon cancer surgery.Methods Sixty patients underwent dective laparoscopic radical of colon cancer surgery were selected,32 males and 28 females,aged 45-74 years,BMI 18.5-25.0 kg/m2 and ASA physical status Ⅱ or Ⅲ.The patients were divided into two groups using the randomized numerical table method:buccal needle group and control group,30 patients in each group.Before the induction of anesthesia,the buccal needle group was given buccal needle therapy once,and buc-cal needle therapy was performed once a day at 9 a.m.in the postoperative period,leaving the needle in place for 30 minutes each time,for 3 consecutive days of treatment,and the control group was not treated with buccal needle therapy.The amount of intraoperative propofol,remifentanil,sufentanil used in the 48 hours postoperative period and recorded.VAS pain scores were recorded at 1 hour,4,24,and 48 hours postoperatively.Venous blood was collected at the time of admission to the hand room and at 1 day,2,and 3 days postoperatively,respectively,and the concentrations of plasma C-reactive protein(CRP),interleu-kin-6(IL-6),and tumor necrosis factor-alpha(TNF-α)were measured.The occurrence of adverse reactions within 48 hours after operation was recorded.Results Compared with the control group,intraop-erative propofol,remifentanil,the amount of sufentanil used and the number of analgesic pump presses with-in 48 hours after operation in the buccal needle group were significantly reduced in the buccal needle group(P＜0.05),VAS pain scores were significantly lower at 1 hour,4,24,and 48 hours postoperatively(P＜0.05),CRP,IL-6,and TNF-α concentrations were significantly lower at 1 day,2,and 3 days postopera-tively(P＜0.05),and nausea and vomiting,incidence of laryngospasm and laryngeal discomfort were sig-nificantly reduced(P＜0.05).Conclusion The perioperative use of buccal needle therapy in patients un-dergoing laparoscopic radical colon cancer surgery can effectively reduce pain,inhibit inflammatory respon-ses,and decrease the incidence of postoperative adverse reactions.

Objective:To apply digital analysis to quantify hyperechogenicity of substantia nigra, and explore its clinical value for diagnosis of Parkinson′s disease (PD).Methods:The cross-sectional study included 652 PD patients (PD group) and 99 healthy controls (healthy control group) from November 2017 to October 2020 in Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. All subjects underwent transcranial sonography. The diagnostic accuracy of substantia nigra hyperechogenicity using digital analysis was compared with that in a manual measurement in PD. Furthermore, the receiver operating characteristic (ROC) curve analysis was applied to explore its diagnosis value in PD.Results:There were 482 subjects including 400 in the PD group and 82 in the healthy control group, whose quantified results of substantia nigra hyperechogenicity could be used for analysis. The ROC analysis showed that the area under the curve of the quantified larger substantia nigra hyperechoic region detection for diagnosing PD was 0.858 (95% CI 0.805-0.910), the sensitivity was 87.8%, and the specificity was 73.2%, consistent with that of doctors (area under the curve: 0.884). Further more, among these PD patients, there was no correlation between larger substantia nigra hyperechogenicity and age, age of onset, course of disease, non-motor symptoms, and motor symptoms (all P>0.05). Conclusions:Digital analysis was used to quantify the changes in substantia nigra hyperechogenicity in this seudy. The results showed that diagnostic accuracy for PD based on digital analysis was consistent with that of experienced clinicians.

Humans ; Rectum/surgery* ; Liposarcoma/surgery* ; Biomarkers, Tumor

The data of a patient with carbamate pesticide poisoning were analyzed. Cardiac arrest, oliguria, acute renal injury and pulmonary infection occurred during treatment. After cardiopulmonary resuscitation, tracheal intubation, CRRT, anti-infection and other symptomatic support treatment, the patient recovered and discharged. The myocardial damage caused by carbamate pesticide poisoning is easy to be ignored, and it often causes cardiac manifestations such as arrhythmia and cardiac insufficiency, and the related markers of cardiac injury, electrocardiogram and echocardiogram are also changed. Therefore, the awareness of cardiac damage caused by carbamate pesticide poisoning should be improved.
Humans ; Pesticides ; Carbamates ; Heart Arrest ; Arrhythmias, Cardiac ; Poisoning/therapy* ; Organophosphate Poisoning

In this study, we explored the mechanism of Huganning tablet (HGNP) in the treatment of nonalcoholic fatty liver disease (NAFLD) based on network pharmacology and computer-aided drug design. Firstly, the potential ingredients and targets of HGNP were identified from TCMSP database, Swiss Target Prediction database, Chinese pharmacopoeia (2015) and literatures, and then the targets of HGNP intersected with NAFLD disease targets that obtained in GeneCards database to acquired potential targets. The bioconductor bioinformatics package of R software was used for gene ontology (GO) enrichment and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. The network of “potential ingredient-key target-pathway” was formed in Cytoscape software to study the interactions between potential ingredients of HGNP, key targets, pathways and NAFLD. Based on the results of network pharmacology, the molecular docking analysis of the key targets and potential active ingredients in HGNP tablets with top degree in the network was conducted using Discovery Studio 2020 software, followed by molecular dynamics simulations, binding free energy calculation, drug-likeness properties analysis and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties prediction. In vitro, HepG2 cells were used to establish steatosis model, and the effects of five key compounds on hepatocyte steatosis were analyzed by oil red O staining and triglyceride (TG) content determination. The results showed that 141 ingredients and 151 potential targets were obtained. A total of 2 526 items and 151 pathways were identified by GO and KEGG enrichment analysis. The molecular docking suggested that five components, isorhamnetin, salvianolic acid B, emodin, resveratrol and rhein, exhibited strong binding ability with key targets [retinoic acid receptor RXR-alpha (RXRA), tumor necrosis factor (TNF), glycogen synthase kinase-3 beta (GSK3B), serine/threonine-protein kinase 1 (AKT1)]. It was further verified that isorhamnetin and salvianolic acid B bind to key targets with good structural stability and binding affinity based on molecular dynamics simulations and binding free energy calculations. The drug-likeness properties, pharmacokinetic properties and toxicity of five key compounds were more comprehensively analyzed through drug-likeness properties analysis and ADMET properties prediction. In vitro, all five compounds, isorhamnetin, salvianolic acid B, emodin, resveratrol, and rhein, improved hepatocyte steatosis of HepG2 cells, confirming the reliability of the present study. In conclusion, based on network pharmacology, computer-aided drug design and in vitro validation, this study investigated the mechanism of HGNP for the treatment of NAFLD at multiple levels and provided a basis for its clinical application.

To clarify the content characteristics of the main active components and mineral elements of Cynomorium songaricum under different habitat conditions, and further explore the relationship between the quality of C. songaricum and habitats, this study took C. songaricum from 25 different habitats in China as the research object, and measured the contents of 8 main active components and 12 mineral elements separately. Diversity analysis, correlation analysis, principal component analysis and cluster analysis were carried out. The results showed that the genetic diversity of total flavonoids, ursolic acid, ether extract, potassium(K), phosphorus(P) and zinc(Zn) in C. songaricum was high. The coefficient of variation of crude polysaccharide, ether extract, gallic acid, protocatechuic aldehyde, catechin, epicatechin, calcium(Ca), sodium(Na), magnesium(Mg), sulfur(S), iron(Fe), manganese(Mn), selenium(Se) and nickel(Ni) were all over 36%, indicating that the quality of C. songaricum was significantly affected by habitats. There were strong synergistic and weak antagonistic effects among the contents of the 8 active components, and complex antagonistic and synergistic effects among the contents of the 12 mineral elements. Principal component analysis revealed that crude polysaccharide, ursolic acid, catechin, epicatechin and total flavonoids could be used as the characteristic components to evaluate the quality of C. songaricum, and Na, copper(Cu), Mn and Ni were the characteristic elements to evaluate the quality of C. songaricum. In cluster ana-lysis, the second group with the main active components as cluster center had better quality in terms of the content of active substances, and the second group with the mineral elements as cluster center had higher utilization potential in the exploitation of mineral elements. This study could provide a basis for resource evaluation and breeding of excellent varieties of C. songaricum in different habitats, and provide a reference for cultivation and identification of C. songaricum.
Cynomorium ; Catechin ; Plant Breeding ; Selenium ; Ethers ; Ethyl Ethers ; Flavonoids ; Plant Extracts

To realize the non-destructive and rapid origin discrimination of Poria cocos in batches, this study established the P. cocos origin recognition model based on hyperspectral imaging combined with machine learning. P. cocos samples from Anhui, Fujian, Guangxi, Hubei, Hunan, Henan and Yunnan were used as the research objects. Hyperspectral data were collected in the visible and near infrared band(V-band, 410-990 nm) and shortwave infrared band(S-band, 950-2 500 nm). The original spectral data were divided into S-band, V-band and full-band. With the original data(RD) of different bands, multiplicative scatter correction(MSC), standard normal variation(SNV), S-G smoothing(SGS), first derivative(FD), second derivative(SD) and other pretreatments were carried out. Then the data were classified according to three different types of producing areas: province, county and batch. The origin identification model was established by partial least squares discriminant analysis(PLS-DA) and linear support vector machine(LinearSVC). Finally, confusion matrix was employed to evaluate the optimal model, with F1 score as the evaluation standard. The results revealed that the origin identification model established by FD combined with LinearSVC had the highest prediction accuracy in full-band range classified by province, V-band range by county and full-band range by batch, which were 99.28%, 98.55% and 97.45%, respectively, and the overall F1 scores of these three models were 99.16%, 98.59% and 97.58%, respectively, indicating excellent performance of these models. Therefore, hyperspectral imaging combined with LinearSVC can realize the non-destructive, accurate and rapid identification of P. cocos from different producing areas in batches, which is conducive to the directional research and production of P. cocos.
Hyperspectral Imaging ; Wolfiporia ; China ; Least-Squares Analysis ; Support Vector Machine