Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanis...Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.展开更多
Background Hypoxia is a pervasive challenge in aquaculture that poses a significant threat to aquatic organisms.Since fish cannot synthesize vitamin A endogenously,it must be supplied through diet,and it plays a vital...Background Hypoxia is a pervasive challenge in aquaculture that poses a significant threat to aquatic organisms.Since fish cannot synthesize vitamin A endogenously,it must be supplied through diet,and it plays a vital role in supporting fish stress resistance.This study aimed to investigate the protective effects of VA on the gills of adult grass carp(Ctenopharyngodon idella)against hypoxia and to elucidate the underlying mechanisms.Methods Six experimental diets with graded VA levels(375,862,1,614,2,099,2,786,and 3,118 IU/kg)were fed to grass carp(initial weight:726±1.2 g)for 60 d.After the trial,24 fish per treatment were selected,divided equally into normoxic and hypoxic groups,fasted for 24 h,and then subjected to a 96-h acute hypoxic challenge.Results The results demonstrated that VA supplementation mitigated hypoxia-induced damage in gill tissue,as evidenced by histological examination.Furthermore,VA alleviated oxidative stress,as indicated by reduced levels of lactate(LD),lactate dehydrogenase(LDH),reactive oxygen species(ROS),protein carbonyl(PC),and malondialdehyde(MDA).Further investigations indicated that VA alleviated mitochondrial stress,potentially through suppressing the canonical UPR^(mt) axis while activating both the UPR^(mt) sirtuin axis and the UPRIMS/Erα axis.VA also modulated mitochondrial mass via multiple mechanisms,including the promotion of mitochondrial biogenesis,maintenance of dynamics by stimulating fusion and reducing fission,and inhibition of mitophagy.The suppression of mitophagy likely involved downregulating both the Pink1/Parkin-dependent pathway and the Hif1a-Bnip3 pathway.Taken together,these adaptations suggested an essential role for VA in preserving mitochondrial homeostasis.Based on the quadratic regression analysis of ROS and MDA levels from the hypoxic group,the estimated VA requirements for adult grass carp were 2,013 and 2,056 IU/kg diet,respectively.Conclusions In summary,this study provided the first evidence that VA conferred protective effects against hypoxiainduced gill damage in grass carp.展开更多
Background Environmental hypoxia is a common phenomenon in aquaculture,which causes gill tissue injury in fish.Glutathione(GSH)is a vital antioxidant in animal tissues,and its levels decrease under hypoxic conditions....Background Environmental hypoxia is a common phenomenon in aquaculture,which causes gill tissue injury in fish.Glutathione(GSH)is a vital antioxidant in animal tissues,and its levels decrease under hypoxic conditions.However,the effects of glutathione on fish under hypoxic stress remain poorly understood.This study aimed to investigate the impact of glutathione on gill tissue damage in fish under hypoxic stress and explore the underlying mechanisms.Methods Six experimental diets with varying glutathione concentrations.The actual glutathione levels in these diets,measured by high-performance liquid chromatography,were 0.00,145.95,291.90,437.85,583.80,and 729.75 mg/kg,respectively.Fish were fed these diets for 70 d,after which a 96-h hypoxic stress experiment was conducted.The experiment was set up with normoxic and hypoxic groups,in which the dissolved oxygen in the group was 6 mg/L,and that in the group was 1 mg/L.Results This research revealed that glutathione could enhance the growth performance and antioxidant capability of juvenile grass carp while mitigating the structural damage to gill tissues induced by hypoxia stress.Mechanistic investigations further indicated that glutathione mitigated hypoxia-induced oxidative injury in gill tissues and improved their antioxidant capacity.In addition,glutathione attenuated gill apoptosis induced by hypoxia stress.Glutathione also inhibited the initiation,nucleation,elongation,and degradation phases of autophagy,thereby attenuating hypoxia-induced gill autophagy.Moreover,glutathione was found to alleviate hypoxia-induced endoplasmic reticulum stress(ERS)in gills,a response potentially linked to the suppression of PERK,IRE1,and ATF6 signaling pathways.Finally,based on the ROS and PC contents in gill tissue,the optimum glutathione supplementation levels for juvenile grass carp under hypoxia stress were 437.10 and 495.00 mg/kg,respectively.Conclusions In conclusion,our experimental results demonstrated the effectiveness of glutathione in alleviating gill tissue damage caused by hypoxic stress.This study confirms the feasibility and effectiveness of dietary glutathione addition to alleviate hypoxic stress in fish.展开更多
Background As living standards improve,consumers are placing greater emphasis on the enhancement of fish flesh quality,making its improvement increasingly critical.Plant-derived polysaccharides positively affect the i...Background As living standards improve,consumers are placing greater emphasis on the enhancement of fish flesh quality,making its improvement increasingly critical.Plant-derived polysaccharides positively affect the improvement of animal flesh quality.Panax ginseng leaf polysaccharides(PGLP)have a similar composition and lower cost compared with Panax ginseng root polysaccharides.However,its function and application effects in grass carp(Ctenopharyngodon idella)are unclear.Methods A total of 540 sub-adult grass carp(679±1.29 g),one of the important economic fish species,were used as experimental models and fed diets supplemented with 0,100,200,300,400,or 500 mg/kg PGLP for 60 d.After 60 d,grass carp were weighed,and their muscles were collected to explore the effects of PGLP on the growth and development of myofibers and energy metabolism-related parameters.Results Our study found that PGLP increased the growth performance and muscle nutritional composition as well as improved muscle hardness,springiness,cohesiveness,chewiness,and hyperplasia of myofibers of sub-adult grass carp.Besides,PGLP promoted muscle energy metabolism by increasing creatine,glycogen,pyruvate,and acetyl-CoA contents and creatine kinase(CK),pyruvate kinase(PK),phosphofructokinase(PFK),and hexokinase(HK)activities,while decreasing lactate dehydrogenase(LDH)activity and lactate content in fish muscle.Finally,our study found that PGLP enhanced mitochondrial function by increasing the protein expression of mitochondrial complexes I–V,biogenesis,and fusion and decreasing autophagy and fission in fish muscle.Conclusions PGLP improved growth performance and flesh quality of sub-adult grass carp,which may be related to enhancing hyperplasia of myofibers by promoting energy metabolism.We concluded that the recommended amount of PGLP in sub-adult grass carp feed to optimize growth performance is 100–200 mg/kg.This study provides a theoretical basis for the application of PGLP in fish feed and for the analysis of the mechanism of nutrition and feed regulating fish flesh quality,which is of great significance.展开更多
基金supported by the Natural Science Foundation of Heilongjiang Province,No.YQ2021H011(to QL)China Postdoctoral Science Foundation,Nos.2020M670925,2022T150172(to QL)+2 种基金Postdoctoral Foundation of Heilongjiang Province,Nos.LBH‐Z19027,LBH‐TZ2019(to QL)Institute Cultivation Fund,No.PYMS2023-1(to QL)Natural Science Foundation of Jiangsu Province,No.BK20241233(to YL).
文摘Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke.Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis.However,the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA(dsDNA)-sensing cyclic GMP-AMP synthase(cGAS)signaling warrant further study.Using middle cerebral artery occlusion mice,we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation.Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release,as reflected byγH2AX staining,as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway,both of which were notably suppressed by melatonin treatment.Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3(NLRP3)inflammasome activation and nuclear factor(NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke,while exhibiting the capacity to attenuate the immune response to ischemia in mice.This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain.Specifically,melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-αby microglia.Regarding neurological outcomes,melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice.Notably,the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity.We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles(Mф-MLT@FNGs),which exhibited therapeutic properties in middle cerebral artery occlusion mice.Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway.By doing so,melatonin rescues damaged brain tissue and protects neurological function,highlighting its potential as a neuroprotective treatment for ischemic stroke.
基金funded by the Sichuan Science and Technology Program(2024YFNH0016)the earmarked fund for CARS(CARS-45)+1 种基金the National Science Fund for Distinguished Young Scholars of China(32425056)the National Key R&D Program of China(2023YFD2400600)。
文摘Background Hypoxia is a pervasive challenge in aquaculture that poses a significant threat to aquatic organisms.Since fish cannot synthesize vitamin A endogenously,it must be supplied through diet,and it plays a vital role in supporting fish stress resistance.This study aimed to investigate the protective effects of VA on the gills of adult grass carp(Ctenopharyngodon idella)against hypoxia and to elucidate the underlying mechanisms.Methods Six experimental diets with graded VA levels(375,862,1,614,2,099,2,786,and 3,118 IU/kg)were fed to grass carp(initial weight:726±1.2 g)for 60 d.After the trial,24 fish per treatment were selected,divided equally into normoxic and hypoxic groups,fasted for 24 h,and then subjected to a 96-h acute hypoxic challenge.Results The results demonstrated that VA supplementation mitigated hypoxia-induced damage in gill tissue,as evidenced by histological examination.Furthermore,VA alleviated oxidative stress,as indicated by reduced levels of lactate(LD),lactate dehydrogenase(LDH),reactive oxygen species(ROS),protein carbonyl(PC),and malondialdehyde(MDA).Further investigations indicated that VA alleviated mitochondrial stress,potentially through suppressing the canonical UPR^(mt) axis while activating both the UPR^(mt) sirtuin axis and the UPRIMS/Erα axis.VA also modulated mitochondrial mass via multiple mechanisms,including the promotion of mitochondrial biogenesis,maintenance of dynamics by stimulating fusion and reducing fission,and inhibition of mitophagy.The suppression of mitophagy likely involved downregulating both the Pink1/Parkin-dependent pathway and the Hif1a-Bnip3 pathway.Taken together,these adaptations suggested an essential role for VA in preserving mitochondrial homeostasis.Based on the quadratic regression analysis of ROS and MDA levels from the hypoxic group,the estimated VA requirements for adult grass carp were 2,013 and 2,056 IU/kg diet,respectively.Conclusions In summary,this study provided the first evidence that VA conferred protective effects against hypoxiainduced gill damage in grass carp.
基金financially supported by the Sichuan Science and Technology Program(2024YFNH0016,2024NSFSC2072)the earmarked fund for CARS(CARS-45)+2 种基金the National Science Fund for Distinguished Young Scholars of China(32425056)the National Key Research and Development Program of China(2023YFD2400600)Sichuan Innovation Team of National Modern Agricultural Industry Technology System(SCCXTD-2024-15)。
文摘Background Environmental hypoxia is a common phenomenon in aquaculture,which causes gill tissue injury in fish.Glutathione(GSH)is a vital antioxidant in animal tissues,and its levels decrease under hypoxic conditions.However,the effects of glutathione on fish under hypoxic stress remain poorly understood.This study aimed to investigate the impact of glutathione on gill tissue damage in fish under hypoxic stress and explore the underlying mechanisms.Methods Six experimental diets with varying glutathione concentrations.The actual glutathione levels in these diets,measured by high-performance liquid chromatography,were 0.00,145.95,291.90,437.85,583.80,and 729.75 mg/kg,respectively.Fish were fed these diets for 70 d,after which a 96-h hypoxic stress experiment was conducted.The experiment was set up with normoxic and hypoxic groups,in which the dissolved oxygen in the group was 6 mg/L,and that in the group was 1 mg/L.Results This research revealed that glutathione could enhance the growth performance and antioxidant capability of juvenile grass carp while mitigating the structural damage to gill tissues induced by hypoxia stress.Mechanistic investigations further indicated that glutathione mitigated hypoxia-induced oxidative injury in gill tissues and improved their antioxidant capacity.In addition,glutathione attenuated gill apoptosis induced by hypoxia stress.Glutathione also inhibited the initiation,nucleation,elongation,and degradation phases of autophagy,thereby attenuating hypoxia-induced gill autophagy.Moreover,glutathione was found to alleviate hypoxia-induced endoplasmic reticulum stress(ERS)in gills,a response potentially linked to the suppression of PERK,IRE1,and ATF6 signaling pathways.Finally,based on the ROS and PC contents in gill tissue,the optimum glutathione supplementation levels for juvenile grass carp under hypoxia stress were 437.10 and 495.00 mg/kg,respectively.Conclusions In conclusion,our experimental results demonstrated the effectiveness of glutathione in alleviating gill tissue damage caused by hypoxic stress.This study confirms the feasibility and effectiveness of dietary glutathione addition to alleviate hypoxic stress in fish.
基金supported by National Natural Science Foundation of China(U23A20250)the earmarked fund for CARS(CARS-45)+2 种基金the National Key R&D Program of China(2023YFD2400600)Sichuan Provincial Science and Technology Innovation Talent Project(2023JDRC0043)Sichuan Innovation Team of National Modern Agricultural Industry Technology System(SCCXTD-2024-15)。
文摘Background As living standards improve,consumers are placing greater emphasis on the enhancement of fish flesh quality,making its improvement increasingly critical.Plant-derived polysaccharides positively affect the improvement of animal flesh quality.Panax ginseng leaf polysaccharides(PGLP)have a similar composition and lower cost compared with Panax ginseng root polysaccharides.However,its function and application effects in grass carp(Ctenopharyngodon idella)are unclear.Methods A total of 540 sub-adult grass carp(679±1.29 g),one of the important economic fish species,were used as experimental models and fed diets supplemented with 0,100,200,300,400,or 500 mg/kg PGLP for 60 d.After 60 d,grass carp were weighed,and their muscles were collected to explore the effects of PGLP on the growth and development of myofibers and energy metabolism-related parameters.Results Our study found that PGLP increased the growth performance and muscle nutritional composition as well as improved muscle hardness,springiness,cohesiveness,chewiness,and hyperplasia of myofibers of sub-adult grass carp.Besides,PGLP promoted muscle energy metabolism by increasing creatine,glycogen,pyruvate,and acetyl-CoA contents and creatine kinase(CK),pyruvate kinase(PK),phosphofructokinase(PFK),and hexokinase(HK)activities,while decreasing lactate dehydrogenase(LDH)activity and lactate content in fish muscle.Finally,our study found that PGLP enhanced mitochondrial function by increasing the protein expression of mitochondrial complexes I–V,biogenesis,and fusion and decreasing autophagy and fission in fish muscle.Conclusions PGLP improved growth performance and flesh quality of sub-adult grass carp,which may be related to enhancing hyperplasia of myofibers by promoting energy metabolism.We concluded that the recommended amount of PGLP in sub-adult grass carp feed to optimize growth performance is 100–200 mg/kg.This study provides a theoretical basis for the application of PGLP in fish feed and for the analysis of the mechanism of nutrition and feed regulating fish flesh quality,which is of great significance.
