The glucuronide metabolites of benproperine were synthesized from mono-hydroxylate metabolites of benproperine that were treated with methyl （2,3,4-tri-O-acetyl-1-O-tfichloroacetimidoyl ） -α-D-glucopyranuronate wit...The glucuronide metabolites of benproperine were synthesized from mono-hydroxylate metabolites of benproperine that were treated with methyl （2,3,4-tri-O-acetyl-1-O-tfichloroacetimidoyl ） -α-D-glucopyranuronate with BF3 · Eh O as the promoter followed by basic hydrolyzation with Na2 CO3. The form of basic acceptors, the order of addition, and the promoter are all important variables in this glucuronidation. The salt form of the basic acceptor was found to be better than its free form for glucuronidation with a Lewis acid as the promoter. Two mono-hydroxylated benproperines were synthesized from 2-benzylphenol in three steps.展开更多
BACKGROUND Lower respiratory tract viral infections are a major cause of mortality in children under five years old,leading to hundreds of thousands of fatalities annually.The highest risk is observed in infants under...BACKGROUND Lower respiratory tract viral infections are a major cause of mortality in children under five years old,leading to hundreds of thousands of fatalities annually.The highest risk is observed in infants under one year old,underscoring the critical need for safe and effective antiviral protocols.CASE SUMMARY A 9-month-old infant suffered from severe bronchiolitis as manifested by high fever(39°C),decreased appetite,tachypnea,wheezing,and oxygen desaturation(SpO284%on room air)and was effectively managed at home using Kelleni’s protocol,which includes age-adjusted dose of nitazoxanide(60 mg twice daily),ibuprofen and azithromycin,complemented by selective antihistaminic,antitussive and mucolytic immunomodulatory treatment.The fever resolved,wheezing became more prominent but without respiratory distress,and oxygen saturation gradually increased to 92%by day 10.Nitazoxanide exerts broad antiviral and immunomodulatory effects by enhancing host interferon responses and inhibiting viral replication,potentially attenuating airway inflammation and accelerating resolution of bronchiolitis.The nitazoxanide dose(60 mg twice daily for five days)was carefully adjusted based on the developmental expression and activity of the uridine diphosphate-glucuronosyltransferase 1A1 enzyme,responsible for its metabolism,ensuring safe age-appropriate administration.The infant’s clinical status steadily improved,and by day 14 the infant achieved full recovery with normalization of oxygen saturation(96%on room air).No adverse events occurred,and follow-up at day 28 confirmed sustained recovery.CONCLUSION To the best of my knowledge,this report presents,for the first time globally,a potential of nitazoxanide within Kelleni’s protocol to early manage infants younger than one year suffering from severe lower respiratory tract viral infection at home.Selective antitussive treatment,using agents such as low dose benproperine,was employed to mitigate troublesome cough and improve patient comfort without compromising respiratory function.Additionally,alpha amylase was used to facilitate pulmonary secretion clearance.The protocol aims to reduce morbidity and mortality from viral lower respiratory tract infections in this vulnerable population.展开更多
Background:The rapid turnover of the intestinal epithelium is driven by the proliferation and differentiation of intestinal stem cells(ISCs).The dynamics of the F-actin cytoskeleton are critical for maintaining interc...Background:The rapid turnover of the intestinal epithelium is driven by the proliferation and differentiation of intestinal stem cells(ISCs).The dynamics of the F-actin cytoskeleton are critical for maintaining intercellular force and the signal transduction network.However,it remains unclear how direct interference with actin polymerization impacts ISC homeostasis.This study aims to reveal the regulatory effects of the F-actin cytoskeleton on the homeostasis of intestinal epithelium,as well as the potential risks of benproperine(BPP)as an anti-tumor drug.Methods:Phalloidin fluorescence staining was utilized to test F-actin polymerization.Flow cytom-etry and IHC staining were employed to discriminate different types of intestinal epithelial cells.Cell proliferation was assessed through bromo-deoxyuridine(BrdU)and 5-ethynyl-2-deoxyuridine(EdU)incorporation assays.The proliferation and differentiation of intestinal stem cells were replicated in vitro through organoid culture.Epithelial migrationwas evaluated through BrdU pulse labeling and chasing in mice.Results:The F-actin content was observed to significantly increase as crypt cells migrated into the villus region.Additionally,actin polymerization in secretory cells,especially in Paneth cells(PCs),was much higher than that in neighboring ISCs.Treatment with the newly identified actin-related protein 2/3 complex subunit 2(ARPC2)inhibitor BPP led to a dose-dependent increase or inhibition of intestinal organoid growth in vitro and crypt cell proliferation in vivo.Compared with the vehicle group,BPP treatment decreased the expression of Lgr5 ISC feature genes in vivo and in organoid culture.Meanwhile,PC differentiation derived from ISCs and progenitors was decreased by inhibition of F-actin polymerization.Mechanistically,BPP-induced actin polymerization inhibition may activate the Yes1-associated transcriptional regulator pathway,which affects ISC proliferation and differentiation.Accordingly,BPP treatment affected intestinal epithelial cell migration in a dose-dependent manner.Conclusion:Our findings indicate that the regulation of cytoskeleton reorganization can affect ISC homeostasis.In addition,inhibiting ARPC2 with the Food and Drug Administration-approved drug BPP represents a novel approach to influencing the turnover of intestinal epithelial cells.展开更多
基金Supported by the National Natural Science Foundation of China(No. 39930180)
文摘The glucuronide metabolites of benproperine were synthesized from mono-hydroxylate metabolites of benproperine that were treated with methyl （2,3,4-tri-O-acetyl-1-O-tfichloroacetimidoyl ） -α-D-glucopyranuronate with BF3 · Eh O as the promoter followed by basic hydrolyzation with Na2 CO3. The form of basic acceptors, the order of addition, and the promoter are all important variables in this glucuronidation. The salt form of the basic acceptor was found to be better than its free form for glucuronidation with a Lewis acid as the promoter. Two mono-hydroxylated benproperines were synthesized from 2-benzylphenol in three steps.
文摘BACKGROUND Lower respiratory tract viral infections are a major cause of mortality in children under five years old,leading to hundreds of thousands of fatalities annually.The highest risk is observed in infants under one year old,underscoring the critical need for safe and effective antiviral protocols.CASE SUMMARY A 9-month-old infant suffered from severe bronchiolitis as manifested by high fever(39°C),decreased appetite,tachypnea,wheezing,and oxygen desaturation(SpO284%on room air)and was effectively managed at home using Kelleni’s protocol,which includes age-adjusted dose of nitazoxanide(60 mg twice daily),ibuprofen and azithromycin,complemented by selective antihistaminic,antitussive and mucolytic immunomodulatory treatment.The fever resolved,wheezing became more prominent but without respiratory distress,and oxygen saturation gradually increased to 92%by day 10.Nitazoxanide exerts broad antiviral and immunomodulatory effects by enhancing host interferon responses and inhibiting viral replication,potentially attenuating airway inflammation and accelerating resolution of bronchiolitis.The nitazoxanide dose(60 mg twice daily for five days)was carefully adjusted based on the developmental expression and activity of the uridine diphosphate-glucuronosyltransferase 1A1 enzyme,responsible for its metabolism,ensuring safe age-appropriate administration.The infant’s clinical status steadily improved,and by day 14 the infant achieved full recovery with normalization of oxygen saturation(96%on room air).No adverse events occurred,and follow-up at day 28 confirmed sustained recovery.CONCLUSION To the best of my knowledge,this report presents,for the first time globally,a potential of nitazoxanide within Kelleni’s protocol to early manage infants younger than one year suffering from severe lower respiratory tract viral infection at home.Selective antitussive treatment,using agents such as low dose benproperine,was employed to mitigate troublesome cough and improve patient comfort without compromising respiratory function.Additionally,alpha amylase was used to facilitate pulmonary secretion clearance.The protocol aims to reduce morbidity and mortality from viral lower respiratory tract infections in this vulnerable population.
基金supported by the National Natural Science Foundation of China(81872556)Chongqing Academician Program(Basic Research and Frontier Exploration)cstc2018jcyj-yszxX0004.
文摘Background:The rapid turnover of the intestinal epithelium is driven by the proliferation and differentiation of intestinal stem cells(ISCs).The dynamics of the F-actin cytoskeleton are critical for maintaining intercellular force and the signal transduction network.However,it remains unclear how direct interference with actin polymerization impacts ISC homeostasis.This study aims to reveal the regulatory effects of the F-actin cytoskeleton on the homeostasis of intestinal epithelium,as well as the potential risks of benproperine(BPP)as an anti-tumor drug.Methods:Phalloidin fluorescence staining was utilized to test F-actin polymerization.Flow cytom-etry and IHC staining were employed to discriminate different types of intestinal epithelial cells.Cell proliferation was assessed through bromo-deoxyuridine(BrdU)and 5-ethynyl-2-deoxyuridine(EdU)incorporation assays.The proliferation and differentiation of intestinal stem cells were replicated in vitro through organoid culture.Epithelial migrationwas evaluated through BrdU pulse labeling and chasing in mice.Results:The F-actin content was observed to significantly increase as crypt cells migrated into the villus region.Additionally,actin polymerization in secretory cells,especially in Paneth cells(PCs),was much higher than that in neighboring ISCs.Treatment with the newly identified actin-related protein 2/3 complex subunit 2(ARPC2)inhibitor BPP led to a dose-dependent increase or inhibition of intestinal organoid growth in vitro and crypt cell proliferation in vivo.Compared with the vehicle group,BPP treatment decreased the expression of Lgr5 ISC feature genes in vivo and in organoid culture.Meanwhile,PC differentiation derived from ISCs and progenitors was decreased by inhibition of F-actin polymerization.Mechanistically,BPP-induced actin polymerization inhibition may activate the Yes1-associated transcriptional regulator pathway,which affects ISC proliferation and differentiation.Accordingly,BPP treatment affected intestinal epithelial cell migration in a dose-dependent manner.Conclusion:Our findings indicate that the regulation of cytoskeleton reorganization can affect ISC homeostasis.In addition,inhibiting ARPC2 with the Food and Drug Administration-approved drug BPP represents a novel approach to influencing the turnover of intestinal epithelial cells.
