Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection,leading to severe organ dysfunction and a high mortality rate.Reducing the incidence of sepsis is of paramount importance...Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection,leading to severe organ dysfunction and a high mortality rate.Reducing the incidence of sepsis is of paramount importance.Given that sepsis-associated drugs largely fail in clinical trials,in this project,we devised and validated a novel long-acting C5a-blocking cyclic peptide drug(Cp1)via phage screening technology to block the upstream“bottleneck molecule”C5a-mediated amplification cascade of the inflammatory response.In the early stage of infection,we utilized the efficient neutralization of Cp1 against C5a to effectively curb the“waterfall effect”of inflammatory factors and mitigate the progression to dysregulated systemic inflammation,thereby providing effective prevention and therapeutic intervention for sepsis.First,in vitro and in vivo studies collectively demonstrated the optimal binding affinity and blocking selectivity of Cp1.The excellent plasma stability of Cp1 further endows it with antibodylike systemic circulation.In the CLP-induced sepsis model,Cp1 significantly suppressed the expression of inflammatory factors and chemokines in both plasma and peritoneal lavage fluid(PLF).Additionally,Cp1 potently inhibited innate immune injury.Ultimately,after a single administration of Cp1,the CLP-induced septic mice presented a significant reduction in bacterial burden,evident amelioration of organ dysfunction,and notable prolongation of survival time.Overall,the novel cyclic peptide drug Cp1 developed in this study is a highly promising and cost-competitive therapeutic option for sepsis prophylaxis and therapy.展开更多
Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails ...Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.展开更多
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-076)the Shanghai Top Priority Research Center Project(2023ZZ02013)the Research Initiation Fund for High-caliber PhD Talent of the First Affiliated Hospital of Naval Medical University(2023).
文摘Sepsis is a life-threatening syndrome characterized by dysregulated host responses to infection,leading to severe organ dysfunction and a high mortality rate.Reducing the incidence of sepsis is of paramount importance.Given that sepsis-associated drugs largely fail in clinical trials,in this project,we devised and validated a novel long-acting C5a-blocking cyclic peptide drug(Cp1)via phage screening technology to block the upstream“bottleneck molecule”C5a-mediated amplification cascade of the inflammatory response.In the early stage of infection,we utilized the efficient neutralization of Cp1 against C5a to effectively curb the“waterfall effect”of inflammatory factors and mitigate the progression to dysregulated systemic inflammation,thereby providing effective prevention and therapeutic intervention for sepsis.First,in vitro and in vivo studies collectively demonstrated the optimal binding affinity and blocking selectivity of Cp1.The excellent plasma stability of Cp1 further endows it with antibodylike systemic circulation.In the CLP-induced sepsis model,Cp1 significantly suppressed the expression of inflammatory factors and chemokines in both plasma and peritoneal lavage fluid(PLF).Additionally,Cp1 potently inhibited innate immune injury.Ultimately,after a single administration of Cp1,the CLP-induced septic mice presented a significant reduction in bacterial burden,evident amelioration of organ dysfunction,and notable prolongation of survival time.Overall,the novel cyclic peptide drug Cp1 developed in this study is a highly promising and cost-competitive therapeutic option for sepsis prophylaxis and therapy.
基金CVB was funded by National Institutes of Health(NIH)R01NS071956,NIH R01NS090962,NIH R21NS089851,NIH R21NS094087Veterans Affairs Merit Review I01 BX001407
文摘Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.
