Objective: To access the toxicity of forsythin from Forsythia suspensa leaves and evaluate its safety,Methods: Acute toxicity was determined by oral administration of a single dose of 18 100 mg/kg forsythin in NIH mic...Objective: To access the toxicity of forsythin from Forsythia suspensa leaves and evaluate its safety,Methods: Acute toxicity was determined by oral administration of a single dose of 18 100 mg/kg forsythin in NIH mice,Sub-chronic toxicity was evaluated by oral administration of several doses of forsythin for 30 days at does of 0,540,1 620,and 6 480 mg/kg in SD rats.Results: In the acute toxicity study,mortality was not observed after 14 days,In addition,clinically relevant adverse effects,or variations in body weight or food consumption were not observed,Similarly,after 30 days in the sub-chronic toxicity study,no mortality or significant toxicological effects such as decreased food consumption,body weight,biochemical parameters and vital organs etc,were noticed,Conclusion: The results revealed that the forsythin from Forsythia suspensa leaves has low or no toxicity via oral administration,and therefore is suitable for further development and applications.展开更多
SARS-CoV-2,the culprit pathogen of COVID-19,elicits prominent immune responses and cytokine storms.Intracellular Cl^(−)is a crucial regulator of host defense,whereas the role of Cl^(−)signaling pathway in modulating p...SARS-CoV-2,the culprit pathogen of COVID-19,elicits prominent immune responses and cytokine storms.Intracellular Cl^(−)is a crucial regulator of host defense,whereas the role of Cl^(−)signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear.By using human respiratory epithelial cell lines,primary cultured human airway epithelial cells,and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge,we demonstrated that SARS-CoV-2 nucleocapsid(N)protein could interact with Smad3,which downregulated cystic fibrosis transmembrane conductance regulator(CFTR)expression via microRNA-145.The intracellular Cl^(−)concentration([Cl^(−)]i)was raised,resulting in phosphorylation of serum glucocorticoid regulated kinase 1(SGK1)and robust inflammatory responses.Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation.Moreover,N protein promoted a sustained elevation of[Cl^(−)]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4(PDE4).Rolipram,a selective PDE4 inhibitor,countered airway inflammation by reducing[Cl^(−)]i.Our findings suggested that Cl^(−)acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection.Targeting the Cl^(−)signaling pathway might be a novel therapeutic strategy for COVID-19.展开更多
基金supported by the Basic Science Research Program of Guangdong Province Science and Technology Plan Projects Fund[grant numbers:2016A010119136]the High-level Leading Talent Introduction Program of GDAS[grant numbers:2016GDASRC-0104]
文摘Objective: To access the toxicity of forsythin from Forsythia suspensa leaves and evaluate its safety,Methods: Acute toxicity was determined by oral administration of a single dose of 18 100 mg/kg forsythin in NIH mice,Sub-chronic toxicity was evaluated by oral administration of several doses of forsythin for 30 days at does of 0,540,1 620,and 6 480 mg/kg in SD rats.Results: In the acute toxicity study,mortality was not observed after 14 days,In addition,clinically relevant adverse effects,or variations in body weight or food consumption were not observed,Similarly,after 30 days in the sub-chronic toxicity study,no mortality or significant toxicological effects such as decreased food consumption,body weight,biochemical parameters and vital organs etc,were noticed,Conclusion: The results revealed that the forsythin from Forsythia suspensa leaves has low or no toxicity via oral administration,and therefore is suitable for further development and applications.
基金supported by the Guangzhou Institute of Respiratory Health Open Project(Funds provided by China Evergrande Group)-Project No.2020GIRHHMS13,2020GIRHHMS24,Zhongnanshan Medical Foundation of Guangdong Province(ZNSA-2020012)the National Natural Science Foundation of China(No.81802031 and 31771286)。
文摘SARS-CoV-2,the culprit pathogen of COVID-19,elicits prominent immune responses and cytokine storms.Intracellular Cl^(−)is a crucial regulator of host defense,whereas the role of Cl^(−)signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear.By using human respiratory epithelial cell lines,primary cultured human airway epithelial cells,and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge,we demonstrated that SARS-CoV-2 nucleocapsid(N)protein could interact with Smad3,which downregulated cystic fibrosis transmembrane conductance regulator(CFTR)expression via microRNA-145.The intracellular Cl^(−)concentration([Cl^(−)]i)was raised,resulting in phosphorylation of serum glucocorticoid regulated kinase 1(SGK1)and robust inflammatory responses.Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation.Moreover,N protein promoted a sustained elevation of[Cl^(−)]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4(PDE4).Rolipram,a selective PDE4 inhibitor,countered airway inflammation by reducing[Cl^(−)]i.Our findings suggested that Cl^(−)acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection.Targeting the Cl^(−)signaling pathway might be a novel therapeutic strategy for COVID-19.
