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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.
Subject(s)
Flavonoids/chemistry , SARS-CoV-2 , Rhizome , COVID-19 , Peptide Hydrolases , Antiviral Agents/chemistryABSTRACT
The papain-like protease (PLpro) in coronavirus is one of key cysteine proteases responsible for the proteolytic processing of viral polyproteins, and plays an important role in dysregulation of host immune response. PLpro is a promising therapeutic target with a major challenge in inhibitor design due to the restricted S1/S2 sites for two consecutive glycine of substrates. Here we reported the discovery of two activators of the SARS-CoV-2 PLpro from a biochemical screening, and the identification of the unique residue, C270, as an allosteric and covalent regulation site for the activators. This site was also specifically modified by glutathione oxidized, resulting in the S-glutathionylation and activation of the protease. Furthermore, one compound was found to allosterically inhibit the protease by covalent binding to this crucial site. Together, these results elucidated an unrevealed molecular mechanism for allosteric modulation of the proteases activity, and provided a new strategy for discovery of allosteric inhibitors of the SARS-CoV-2 PLpro.
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With the gradual aggravation of aging in China， the prevalence of osteoporosis is increasing year by year. Osteoporosis has become a major public health problem threatening the health of middle-aged and elderly people， especially middle-aged and elderly women. There are many predisposing factors and complex pathogenesis of osteoporosis. The interpretation of osteoporosis has been the focus of clinical research in recent years. How to prevent and treat osteoporosis more effectively has also become a major problem faced by researchers. In recent years， the balance and homeostasis of calcium and phosphorus regulated by intestinal absorption， renal excretion and bone have become one of the hot topics， and the balance and homeostasis of calcium and phosphorus in vivo are the key to normal bone homeostasis. At the same time， as a complex microbial community living in the gastrointestinal tract， intestinal flora can produce a variety of regulators affecting metabolism. It has been widely confirmed that it acts on the body indirectly or directly， in multiple ways and targets to prevent and treat osteoporosis. Therefore， further exploring the role and mechanism of intestine kidney bone axis in osteoporosis plays a far-reaching significance for the prevention and treatment of osteoporosis. In recent years， scholars have made a lot of exploration on the prevention and treatment of osteoporosis with traditional Chinese medicine （TCM）， and found that TCM can intervene the expression of intestinal flora and play the effect of prevention and treatment of osteoporosis. Based on the "intestine kidney bone axis"， this paper briefly discusses the integrated traditional Chinese and western medicine of kidney and osteoporosis， intestine and osteoporosis， intestine kidney axis， the treatment of kidney from intestine， intestine and osteoporosis， and the application of TCM in regulating intestinal flora in osteoporosis， in order to provide new ideas for the prevention and treatment of osteoporosis.
ABSTRACT
With the gradual aggravation of aging in China， the prevalence of osteoporosis is increasing year by year. Osteoporosis has become a major public health problem threatening the health of middle-aged and elderly people， especially middle-aged and elderly women. There are many predisposing factors and complex pathogenesis of osteoporosis. The interpretation of osteoporosis has been the focus of clinical research in recent years. How to prevent and treat osteoporosis more effectively has also become a major problem faced by researchers. In recent years， the balance and homeostasis of calcium and phosphorus regulated by intestinal absorption， renal excretion and bone have become one of the hot topics， and the balance and homeostasis of calcium and phosphorus in vivo are the key to normal bone homeostasis. At the same time， as a complex microbial community living in the gastrointestinal tract， intestinal flora can produce a variety of regulators affecting metabolism. It has been widely confirmed that it acts on the body indirectly or directly， in multiple ways and targets to prevent and treat osteoporosis. Therefore， further exploring the role and mechanism of intestine kidney bone axis in osteoporosis plays a far-reaching significance for the prevention and treatment of osteoporosis. In recent years， scholars have made a lot of exploration on the prevention and treatment of osteoporosis with traditional Chinese medicine （TCM）， and found that TCM can intervene the expression of intestinal flora and play the effect of prevention and treatment of osteoporosis. Based on the "intestine kidney bone axis"， this paper briefly discusses the integrated traditional Chinese and western medicine of kidney and osteoporosis， intestine and osteoporosis， intestine kidney axis， the treatment of kidney from intestine， intestine and osteoporosis， and the application of TCM in regulating intestinal flora in osteoporosis， in order to provide new ideas for the prevention and treatment of osteoporosis.
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Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic 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 is distinctly different from those of known inhibitors. Baicalein is perfectly 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 prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.
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The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a direct target of the antiviral drug, Remdesivir. Here we report the structure of the SARS-CoV-2 RdRp either in the apo form or in complex with a 50-base template-primer RNA and Remdesivir at a resolution range of 2.5-2.8 [A]. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is incorporated into the first replicated base pair and terminates the chain elongation. Our structures provide critical insights into the working mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.
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SARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 M and 0.04 M respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 M and 0.33 M, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 [A] resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.
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Objective@#To study the efficacy and safety of Cefpodoxime proxetil granules in the treatment of acute bronchitis in children.@*Methods@#One hundred and sixty children of the First People′s Hospital of Nanning from June to December 2018 with acute bronchitis were randomly divided into cefpodoxime group and cefaclor group, with 80 cases in each group.All patients received routine treatment.On this basis, 80 patients in the cefpodoxime group received oral Cefpodoxime proxetil granules 5 mg/kg (not more than 100 mg/time), twice a day; 80 patients in the cefaclor group received oral Cefaclor.The granules were 10 mg/kg (not more than 250 mg/time), 3 times a day, and the course of treatment was 5 days.The clinical efficacy and adverse reactions were observed.@*Results@#The cure rate and effective rate of Cefpodoxime group were 91.3% (73/80 cases) and 95.0% (76/80 cases), respectively, while the cure rate and effective rate of Cefaclor group were 66.3%(53/80 cases) and 81.3%(65/80 cases), respectively, and the differences between the 2 groups were statistically significant (χ2=14.94, 7.23, all P<0.05). Sixty-three strains of pathogenic bacteria and 66 strains of pathogenic bacteria were obtained in Cefpodoxine group and Cefaclor group, respectively, and the detection rates of bacteria in the 2 groups were 78.75% and 82.50%, respectively.There was no significant diffe-rence in the number of bacterial strains and strains detected in each group (χ2=0.36, P>0.05), but the total bacterial clearance rate in Cefpodoxine group was 88.9%(56/63 cases) while the bacterial Clearance rate in Cefaclor group was 74.2%(49/66 cases), and the difference between the 2 groups was statistically significant (χ2=4.57, P<0.05). In particular, the bacterial clearance rate in Cefpodoxine group to Streptococcus pneumoniae, Staphylococcus aureus and Klebsiella pneumoniae were significantly higher than those in Cefaclor group, while the bacterial Clearance rate of Proteus and Escherichia coli were lower than those in Cefaclor group.The incidence of adverse reactions in Cefpodoxine group and Cefaclor group were 5.0% and 3.8%, respectively, with no significant difference (P>0.05).@*Conclusions@#The clinical effect of Cefpodoxime pro-xetil granules in treating children with acute bronchitis is more significant than that of Cefaclor.It has high safety and no serious side effect.
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Objective To study the efficacy and safety of Cefpodoxime proxetil granules in the treatment of acute bronchitis in children.Methods One hundred and sixty children of the First People's Hospital of Nanning from June to December 2018 with acute bronchitis were randomly divided into cefpodoxime group and cefaclor group,with 80 cases in each group.All patients received routine treatment.On this basis,80 patients in the cefpodoxime group received oral Cefpodoxime proxetil granules 5 mg/kg (not more than 100 mg/time),twice a day;80 patients in the cefaclor group received oral Cefaclor.The granules were 10 mg/kg (not more than 250 mg/time),3 times a day,and the course of treatment was 5 days.The clinical efficacy and adverse reactions were observed.Results The cure rate and effective rate of Cefpodoxime group were 91.3％ (73/80 cases) and 95.0％ (76/80 cases),respectively,while the cure rate and effective rate of Cefaclor group were 66.3 ％ (53/80 cases) and 81.3％ (65/80 cases),respectively,and the differences between the 2 groups were statistically significant (x2 =14.94,7.23,all P ＜ 0.05).Sixty-three strains of pathogenic bacteria and 66 strains of pathogenic bacteria were obtained in Cefpodoxine group and Cefaclor group,respectively,and the detection rates of bacteria in the 2 groups were 78.75％ and 82.50％,respectively.There was no significant difference in the number of bacterial strains and strains detected in each group (x2 =0.36,P ＞ 0.05),but the total bacterial clearance rate in Cefpodoxine group was 88.9％ (56/63 cases) while the bacterial Clearance rate in Cefaclor group was 74.2％ (49/66 cases),and the difference between the 2 groups was statistically significant (x2 =4.57,P ＜ 0.05).In particular,the bacterial clearance rate in Cefpodoxine group to Streptococcus pneumoniae,Staphylococcus aureus and Klebsiella pneumoniae were significantly higher than those in Cefaclor group,while the bacterial Clearance rate of Proteus and Escherichia coli were lower than those in Cefaclor group.The incidence of adverse reactions in Cefpodoxine group and Cefaclor group were 5.0％ and 3.8％,respectively,with no significant difference (P ＞ 0.05).Conclusions The clinical effect of Cefpodoxime pro-xetil granules in treating children with acute bronchitis is more significant than that of Cefaclor.It has high safety and no serious side effect.
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Objective To explore the pathogenic bacterial distribution and drug sensitivity of cholangiitis in children who underwent hepatico-portoenterostomy for congenital biliary atresia in order to provide the guide for appropriate treatment. Methods The clinical data of 300 cases of congenital biliary atresia Kasai postoperative cholangitis in our hospital between 2007 and 2016 were included in the study to analyse the common pathogenic bacteria and antibiotics sensitivity according to its clinical types. Results(1)In the 300 children,cholangitis set on for 541 times,with blood culture positive in 128 cases.(2)The main pathogens of cholangitis after biliary atre-sia included escherichia coli,pseudomonas aeruginosa and enterococcus. Late cholangitis and frequent cholangitis contributed highly to enterococcus infections.(3)The sensitivity rates of escherichia coli and pseudomonas aerugi-nosa to cefoperazone sulbactam were 75% and 78%,respectively,and the rates to piperacillin tazobactam were 82% and 84%,respectively.The sensitivity rates to meropenem were 93% and 76%,respectively.The susceptibility of Enterococcus to vancomycin or linezolid was 100%.Conclusions Cefoperazone sulbactam and piperacillin tazo-bactam can be used as an option of antibiotics for biliary atresia Kasai postoperative cholangitis. In case of poor curative effect,timely replacement of meropenem is suggested.In case of late cholangitis and frequent cholangitis, enterococcus infection can be considered in its diagnosis.
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Objective To study the value of pre-surgery computed tomography(CT)scan on post-surgery pathological risk grades of gastrointestinal stromal tumor(GIST).Methods Forty-one patients of GIST were retrospectively evaluated and confirmed by histological diagnosis. Tumor size, density, margin, contour, location, growth pattern, degree and pattern of lesion enhancement was analyzed. Results Based on pathological results, the total diagnosis accuracy of location and character on CT is 95.1%(39/41)and 92.6%(38/41), respectively.Tumors size of low risk group was smaller than that in the other two groups(P>0.05).There was no significant difference in tumor size between moderate and high risk groups. Using Chi-test analysis, tumor density, margin, contour, growth pattern was statistically different among different pathological risk grades (P < 0.05). CT features of enhancement were not significantly different among the pathological risk groups (P > 0.05). Conclusions CT plays an important role not only in the detection and localizing GIST but also in the evaluation of the extension and characteristics of these tumors. CT imaging can predict the invasive behaviors through tumor density, size, shape, contour, growth pattern and enhanced pattern.
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Objective To investigate the effect and adverse reactions of intravenous cyclophosphamide (CTX) pulse therapy on refractory nephrotic syndrome (RNS) in children. Methods Retrospective study was carried on 102 patients with RNS treated with high dose CTX impact treatment in The First Hospital Affiliated to Guangxi Medical University from August 2006 to August 2016. Clinical data and follow-up records were analyzed. Results Biochemical indicators significantly improved after treatment ,and the difference was statistically signifi-cant(P < 0.05). Fifty-six patients achieved complete remission,and 21 patients achieved partial remission,with an effective percentage of 75.5%,and adverse drug reactions incidence rate of 19.6%. There was not significant difference in the remission rate of different clinical types. Conclusions High dose of CTX shock treatment on children refractory nephrotic syndrome is effective ,with low adverse reactions incidence.
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Objective To investigate the effect and adverse reactions of intravenous cyclophosphamide (CTX) pulse therapy on refractory nephrotic syndrome (RNS) in children. Methods Retrospective study was carried on 102 patients with RNS treated with high dose CTX impact treatment in The First Hospital Affiliated to Guangxi Medical University from August 2006 to August 2016. Clinical data and follow-up records were analyzed. Results Biochemical indicators significantly improved after treatment ,and the difference was statistically signifi-cant(P < 0.05). Fifty-six patients achieved complete remission,and 21 patients achieved partial remission,with an effective percentage of 75.5%,and adverse drug reactions incidence rate of 19.6%. There was not significant difference in the remission rate of different clinical types. Conclusions High dose of CTX shock treatment on children refractory nephrotic syndrome is effective ,with low adverse reactions incidence.
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Objective To perform a Meta-analysis on hepatitis B surface antigen (HBsAg)-positive rates among general Chinese population aged 1-59 years.Methods We systemically reviewed the related data (January 2007 to August 2016) published from Chinese National Knowledge Infrastructure (CNKI),VIP,and PubMed.We also assessed the HBsAg-positive rates among general Chinese populations aged 1-59 years,using a random effects regression model with the comprehensive Meta-analysis software 2.2.Results A total of 46 papers were finally included,with a total sample size of 625 053 individuals.Results from the Meta-analysis showed that the overall combined HBsAg-positive rate was 5.7％ (95％CI:4.8％-6.6％) among general Chinese populations aged 1-59 years.When comparing the HBsAg-positive rates in different regions,data showed that the HBsAg-positive rate of was higher in the mid-western areas (6.3％,95％CI:4.9％-8.0％)than in the eastern areas (5.5％,95％CI:4.4％-6.8％).Results showed that HBsAg-positive rates was higher in males (6.1％,95％CI:5.3％-7.0％) than in females (4.8％,95％CI:4.2％-5.5％).As for the HBsAg-positive rates in different time periods,data showed positive rate of 6.3％ (95％CI:5.5％-7.2％)in 2007-2009,5.9％ (95％CI:4.4％-8.0％) in 2010-2012 and 3.5％ (95％CI:2.0％-6.1％) in 2013-2016,respectively.Conclusion The prevalence of hepatitis B virus infection was decreasing between 2007 and 2016 in China,making the country an intermediate endemic area on HBV.
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Objective To perform a Meta-analysis on hepatitis B surface antigen (HBsAg)-positive rates among general Chinese population aged 1-59 years.Methods We systemically reviewed the related data (January 2007 to August 2016) published from Chinese National Knowledge Infrastructure (CNKI),VIP,and PubMed.We also assessed the HBsAg-positive rates among general Chinese populations aged 1-59 years,using a random effects regression model with the comprehensive Meta-analysis software 2.2.Results A total of 46 papers were finally included,with a total sample size of 625 053 individuals.Results from the Meta-analysis showed that the overall combined HBsAg-positive rate was 5.7％ (95％CI:4.8％-6.6％) among general Chinese populations aged 1-59 years.When comparing the HBsAg-positive rates in different regions,data showed that the HBsAg-positive rate of was higher in the mid-western areas (6.3％,95％CI:4.9％-8.0％)than in the eastern areas (5.5％,95％CI:4.4％-6.8％).Results showed that HBsAg-positive rates was higher in males (6.1％,95％CI:5.3％-7.0％) than in females (4.8％,95％CI:4.2％-5.5％).As for the HBsAg-positive rates in different time periods,data showed positive rate of 6.3％ (95％CI:5.5％-7.2％)in 2007-2009,5.9％ (95％CI:4.4％-8.0％) in 2010-2012 and 3.5％ (95％CI:2.0％-6.1％) in 2013-2016,respectively.Conclusion The prevalence of hepatitis B virus infection was decreasing between 2007 and 2016 in China,making the country an intermediate endemic area on HBV.
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Objective To evaluate the relationship between dyslipidemia and abdominal aortic aneurysm (AAA), with which as a theory base and proof we may further study about the mechanism of atherosclerosis (AS) leading to AAA. Methods Thirty abdominal aortic aneurysm patients in Guangdong General Hospital from 2013 to 2014 were enrolled into the experimental group and 26 healthy people into the control group. The serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), lipoprotein a (Lpa), nonestesterified fatty acid (NEFA), homocysteine (HCY), apolipoprotein A (ApoA) and apolipoprotein B(ApoB)were tested in the study. The statistical significance of the difference of them was examined by the independent two-sample t-test. Result The serum TG and HCY level in the experimental group were significantly higher than those in the control group (P 0.05). Conclusion The serum levels of TG and HCY are increased and the levels of Apo A and HDL are decreased in patients with AAA.
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Objective To detect the positively selected sites in the surface ( S) gene of hepatitis B viruses ( HBVs) from patients with occult HBV infection and to study the molecular mechanism of occult HBV infection.Methods The sequence of S gene from patients with occult HBV infection and reference strains of eight HBV genotypes ( A through H) were downloaded from GenBank and then alignment analysis were performed by using Clustal W software .Phylogenetic trees were constructed by using MEGA 5.05 soft-ware package.PAML4.7 was used to analyze positively selected sites .Results A total of 1286 HBV se-quences from patients with occult infection were searched in GenBank .One hundred and seventy-four com-plete gene sequences encoding surface S protein were screened after alignment analysis and confirmation , of which 13 sequences with nonsense mutation were removed .The likelihood ratio test showed that for both the 161 remained sequences and the 31 reference sequences , the selection models of M2, M3 and M8 were sig-nificantly better than the neutral models of M0, M1 and M7 (2△lnL<55.12, P<0.001).By using Bayes Empirical Bayes (BEB) analysis, 14 positively selected sites (including codon 3, 8, 40, 45, 46, 47, 49, 68, 126, 127, 164, 184, 207 and 210) were detected in the surface gene of HBVs from patients with occult HBV infection, eight of which were located at the immune epitope of HBsAg .However, only 2 positively se-lected sites were identified in reference sequences .Conclusion The long-lasting persistence of HBV in pa-tients with occult HBV infection might be caused by the adaptive evolution of their surface gene in a form of escape mutant under immune suppressive condition .
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Epidemiology,as a major subject in the field of public health science,plays a pivotal role in the construction and development of disease prevention and control system.It is also vital for the public health system to improve the emergency response ability and to cultivate high-quality talents.After analyzing current situation of graduate education of epidemiology,we found some problems.In our research,deepgoing dissection was carried out and possible solution was provided.
