During liver injury,intrahepatic macrophage compartment is augmented by circulating monocytes that infiltrate the liver driven by C-C motif chemokine ligand/C-C motif chemokine receptor(CCL/CCR)axis including CCL1‒CCR...During liver injury,intrahepatic macrophage compartment is augmented by circulating monocytes that infiltrate the liver driven by C-C motif chemokine ligand/C-C motif chemokine receptor(CCL/CCR)axis including CCL1‒CCR8 axis,thereby contributing to liver inflammation.Numerous small molecular receptor antagonists,including R243,have been developed for targeting CCR8;however,these agents face challenges in clinical translation,potentially attributed to their poor pharmacokinetic profiles,lack of target specificity,and potential adverse effects.In this study,we designed four CCR8 antagonizing peptides(AP8i-AP8iv)and performed molecular characterization in silico and therapeutic investigation in vitro and in vivo.Based on in silico docking,molecular dynamic simulation using homology build model and in-vitro(competitive)binding studies,AP8ii(YEWRFYHG)evidenced highly favorable and selective interactions at the CCR8-active site.AP8ii inhibited CCL1-driven chemotaxis and LPS/IFNg-induced pro-inflammatory activation of monocytes-macrophages in vitro.In a CCl4-induced acute liver injury mouse model,AP8ii treatment decreased intrahepatic infiltration of circulating monocytes.Moreover,AP8ii reduced liver inflammation,as indicated by decreased F4/80,IL6 and iNOS expression,diminished ALT levels,and attenuated fibrosis,as indicated by reduced collagen-I expression.In conclusion,we report a novel CCR8-antagonizing peptide that inhibited CCL1-driven intrahepatic monocytes infiltration and differentiation into pro-inflammatory phenotype,consequently ameliorating liver inflammation and fibrogenesis in an acute liver injury mouse model.展开更多
Purpose:Subtrochanteric fractures of the femur are being managed successfully with various intramedullary and extramedulary implants with reasonable success.However,these implants require precise placement under image...Purpose:Subtrochanteric fractures of the femur are being managed successfully with various intramedullary and extramedulary implants with reasonable success.However,these implants require precise placement under image intensifier guidance,which exposes the surgeon to substantial amount of radiation.It also restricts the management of these fractures at peripheral centers where facility of image intensifiers is not available.Keeping this in mind we designed this study to identify if contralateral reversed distal femoral locking plate can be used successfully without the use of image intensifier.Methods:Twenty-four consecutive patients(18 men and 6 women)with a mean age of 28 years(range 19-47 years)suffering subtrochanteric fractures of the femur underwent open reduction and internal fixation with reversed contralateral distal femoral locking plate.The outcome was assessed at the mean follow-up period of 3.2 years(range 2-4.6 years)using the Harris hip score.Results:Twenty-one fractures united with the primary procedure,with a mean time of consolidation being 11 weeks(range,9-16 weeks).One patient developed superficial suture line infection,which resolved with oral antibiotics.Another patient had a fall 3 weeks after surgery and broke the plate.Repeat surgery with reversed distal femoral locking compression plate was performed along with bone grafting and the fracture united.Two cases had nonunion,which went in for union after bone grafting.The mean Harris hip score at the time of final follow-up was 90.63(range 82-97).Conclusion:The reversed contralateral distal femoral plate is a biomechanically sound implant,which when used for fixation of the subtrochanteric fractures with minimal soft tissue stripping shows results comparable to those achieved by using other extramedullary implants as well as intramedullary devices.The added advantage of this implant is its usability in the absence of an image intensifier.展开更多
文摘During liver injury,intrahepatic macrophage compartment is augmented by circulating monocytes that infiltrate the liver driven by C-C motif chemokine ligand/C-C motif chemokine receptor(CCL/CCR)axis including CCL1‒CCR8 axis,thereby contributing to liver inflammation.Numerous small molecular receptor antagonists,including R243,have been developed for targeting CCR8;however,these agents face challenges in clinical translation,potentially attributed to their poor pharmacokinetic profiles,lack of target specificity,and potential adverse effects.In this study,we designed four CCR8 antagonizing peptides(AP8i-AP8iv)and performed molecular characterization in silico and therapeutic investigation in vitro and in vivo.Based on in silico docking,molecular dynamic simulation using homology build model and in-vitro(competitive)binding studies,AP8ii(YEWRFYHG)evidenced highly favorable and selective interactions at the CCR8-active site.AP8ii inhibited CCL1-driven chemotaxis and LPS/IFNg-induced pro-inflammatory activation of monocytes-macrophages in vitro.In a CCl4-induced acute liver injury mouse model,AP8ii treatment decreased intrahepatic infiltration of circulating monocytes.Moreover,AP8ii reduced liver inflammation,as indicated by decreased F4/80,IL6 and iNOS expression,diminished ALT levels,and attenuated fibrosis,as indicated by reduced collagen-I expression.In conclusion,we report a novel CCR8-antagonizing peptide that inhibited CCL1-driven intrahepatic monocytes infiltration and differentiation into pro-inflammatory phenotype,consequently ameliorating liver inflammation and fibrogenesis in an acute liver injury mouse model.
文摘Purpose:Subtrochanteric fractures of the femur are being managed successfully with various intramedullary and extramedulary implants with reasonable success.However,these implants require precise placement under image intensifier guidance,which exposes the surgeon to substantial amount of radiation.It also restricts the management of these fractures at peripheral centers where facility of image intensifiers is not available.Keeping this in mind we designed this study to identify if contralateral reversed distal femoral locking plate can be used successfully without the use of image intensifier.Methods:Twenty-four consecutive patients(18 men and 6 women)with a mean age of 28 years(range 19-47 years)suffering subtrochanteric fractures of the femur underwent open reduction and internal fixation with reversed contralateral distal femoral locking plate.The outcome was assessed at the mean follow-up period of 3.2 years(range 2-4.6 years)using the Harris hip score.Results:Twenty-one fractures united with the primary procedure,with a mean time of consolidation being 11 weeks(range,9-16 weeks).One patient developed superficial suture line infection,which resolved with oral antibiotics.Another patient had a fall 3 weeks after surgery and broke the plate.Repeat surgery with reversed distal femoral locking compression plate was performed along with bone grafting and the fracture united.Two cases had nonunion,which went in for union after bone grafting.The mean Harris hip score at the time of final follow-up was 90.63(range 82-97).Conclusion:The reversed contralateral distal femoral plate is a biomechanically sound implant,which when used for fixation of the subtrochanteric fractures with minimal soft tissue stripping shows results comparable to those achieved by using other extramedullary implants as well as intramedullary devices.The added advantage of this implant is its usability in the absence of an image intensifier.
