Background:Repetitive mild traumatic brain injury(rmTBI)is a significant risk factor for neurodegeneration,characterized by pathological protein deposition and persistent neuroinflammation.Research has observed increa...Background:Repetitive mild traumatic brain injury(rmTBI)is a significant risk factor for neurodegeneration,characterized by pathological protein deposition and persistent neuroinflammation.Research has observed increased interleukin-33(IL-33)levels in the peripheral blood of patients with rmTBI,suggesting IL-33 may participate in regulating the pathological development of rmTBI.The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI,and to explore its potential as a therapeutic target to improve the neurological outcome.Methods:The study employed an rmTBI mouse model using the wild-type(WT)and IL-33 knockout mice.Cognitive function was assessed via the Y-maze and Barnes tests.The main cell type expressing IL-33 and its receptor,suppression of tumorigenicity 2(ST2),was then investigated in the mouse brain through immunofluorescence colocalization.As the primary neural cell responsible for ST2 expression,microglia were studied in vitro using the BV2 cell line.The effects of lipid droplets(LDs)accumulation and amyloid-beta(Aβ)phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells'phagocytosis.Additionally,HT22 neuronal apoptosis was assessed by flow cytometry.Finally,the cognitive effects of intranasal administration of IL-33 were evaluated in mice.Results:IL-33 KO mice exhibited pronounced cognitive impairment after rmTBI.In the mouse brain,astrocytes were identified as the primary source of IL-33 secretion,while microglia predominantly expressed ST2.Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function.IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβphagocytosis in vitro.In addition,the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage.Furthermore,intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.Conclusions:Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage.IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.展开更多
Loquat(Eriobotrya japonica)anthracnose,caused by Colletotrichum fructicola,affects multiple loquat tissues and leads to serious economic losses.In particular,foliar infections compromise not only fruit yield but also ...Loquat(Eriobotrya japonica)anthracnose,caused by Colletotrichum fructicola,affects multiple loquat tissues and leads to serious economic losses.In particular,foliar infections compromise not only fruit yield but also the medicinal value of loquat leaves.Despite this,no defence genes have been identified for effective disease management.In this study,an integrated analysis of symptom progression,cellular defence responses,and pathogen colonisation identified 72 h post-inoculation(hpi)as a critical time point.At this juncture,a significant difference in response to C.fructicola was observed between the resistant cultivar Peluches(Pell)and susceptible cultivar Donghuzao(DHZ).Comparative transcriptome analysis at 72 hpi revealed that Pell was enriched in activated key defence-related pathways,including‘plant—pathogen interactions'and‘sesquiterpene and triterpene biosynthesis',whereas DHZ was predominantly enriched in primary plant metabolism.We further identified Ej WRKY33,a transcription factor significantly up-regulated in response to C.fructicola,with higher expression levels in Pell compared to those in DHZ.Silencing Ej WRKY33 in loquat leaves resulted in larger lesions and increased pathogen colonisation,with down regulation of salicylic acid(SA)-related gene Ej NPR1,jasmonic acid(JA)/ethylene(ET)-related gene Ej PR4,the terpenoid biosynthetic gene Ej CYP71B37,and defensin gene Ej Def1.In contrast,overexpression of Ej WRKY33 in Arabidopsis thaliana exhibited enhanced resistance to C.fructicola.Furthermore,our investigation with exogenous hormone treatments revealed that while all three hormones(SA,Me JA,or ETH)induced Ej WRKY33 expression,the gene functions as a critical component of the SA-dependent pathway,with limited involvement in the JA/ET pathway.Collectively,these findings provide the molecular basis for developing anthracnose-resistant loquat cultivars and disease management applications.展开更多
BACKGROUND Patients with gallbladder carcinoma(GBC)often report abdominal pain,which is particularly severe,difficult to treat,and insufficiently relieved.Interleukin-33(IL-33)/suppression of tumorigenicity 2(ST2)sign...BACKGROUND Patients with gallbladder carcinoma(GBC)often report abdominal pain,which is particularly severe,difficult to treat,and insufficiently relieved.Interleukin-33(IL-33)/suppression of tumorigenicity 2(ST2)signaling plays a role in cancer and pain,but its role in GBC-induced chronic pain is still unknown.AIM To investigate the potential effects of IL-33/ST2 signaling on GBC-induced cancer pain.METHODS To establish a GBC-induced chronic pain model,the GBC cell line GBC-SD was implanted into the gallbladder of nude mice.Pain-related behavior was determined by evaluating withdrawal behavior in response to mechanical stimuation.Serum samples from patients were analyzed via enzyme-linked immunolsorbent assay.Spinal cord samples from the rodents were subjected to enzyme-linked immunosorbent assay,western blotting and quantitative real-time polymerase chain reaction.RESULTS Nude mice with GBC-induced chronic pain presented significant spontaneous visceral pain-related behavior and abdominal hypersensitivity to mechanical stimuli.We demonstrated a significant increase in IL-33 levels in patient serum and in the spinal cords of GBC-induced chronic pain model mice.IL-33/ST2 signaling activation in the spinal cord may promote GBC-induced chronic pain.Remarkable activation of astrocytes and microglia as well as increased levels of proinflammatory cytokines was observed in the spinal cords of the mice.A significant decrease in the activation of astrocytes and microglia and the levels proinflammatory cytokines was observed following the blockade of IL-33/ST2 signaling.CONCLUSION Blockade of spinal IL-33/ST2 signaling results in a significant reduction in GBC-induced pain-related behaviors.This study suggested that targeting IL-33/ST2 signaling may relieve chronic cancer pain due to GBC.展开更多
目的基于糖皮质激素诱导的小鼠股骨头坏死(osteonecrosis of the femoral head,ONFH)模型,探讨IL-33在ONFH发生发展中发挥的作用,重点关注其对骨重塑、炎症调控和纤维化的影响。方法(1)动物实验:将15只9周龄雄性C57BL/6J野生型小鼠,随...目的基于糖皮质激素诱导的小鼠股骨头坏死(osteonecrosis of the femoral head,ONFH)模型,探讨IL-33在ONFH发生发展中发挥的作用,重点关注其对骨重塑、炎症调控和纤维化的影响。方法(1)动物实验:将15只9周龄雄性C57BL/6J野生型小鼠,随机分为正常对照组、ONFH组及干预组,每组5只。ONFH组及干预组联合应用脂多糖和甲泼尼龙建立激素性ONFH模型,同时干预组造模早期连续4 d腹腔注射IL-33;正常对照组同时间点注射生理盐水。实验期间观察小鼠一般情况,取股骨标本通过免疫荧光染色、实时定量PCR及Western blot检测内源性IL-33、跨膜型ST2(ST2 ligand,ST2L)表达;HE与Masson染色评估骨坏死及纤维化程度;免疫组织化学染色检测成骨标志物[骨钙素(osteocalcin,OCN)、骨桥蛋白(osteopontin,OPN)、Runt相关转录因子2(Runt-related transcription factor 2,Runx2)]、破骨标志物[NF-κB受体活化因子配体(receptor activator of NF-κB ligand,RANKL)]表达水平;ELISA法检测血清炎症因子(TNF-α、IL-6、IL-1β、IL-4、IL-10)浓度。(2)细胞实验:取小鼠成骨细胞随机分为对照组(DMEM+PBS)、IL-33组(DMEM+10 ng/mL IL-33)、IL-33+ST2L阻断组(DMEM+10 ng/mL IL-33+1μg/mL ST2L抗体),对应处理后通过EdU掺入实验检测细胞增殖;另取成骨细胞在此基础上成骨诱导培养后,经ALP染色、茜素红染色及实时定量PCR技术,评估细胞成骨矿化水平及成骨相关基因(Runx2、Ⅰ型胶原、OCN和OPN)表达变化。结果(1)动物实验:各组动物均存活至实验完成,干预组及ONFH组小鼠出现活动受限。与正常对照组相比,ONFH组股骨头中IL-33及ST2L mRNA和蛋白表达均上调(P0.05)。结论IL-33通过损害成骨细胞活力和功能、抑制骨再生而加重小鼠ONFH,靶向IL-33/ST2L信号轴可能为ONFH治疗提供有前景的新策略。展开更多
Resolving the ignition issue of magnesium alloys is essential for broadening their application scope.This research investigates the EV33 magnesium alloy,delving into an innovative flame-retardant strategy,with a speci...Resolving the ignition issue of magnesium alloys is essential for broadening their application scope.This research investigates the EV33 magnesium alloy,delving into an innovative flame-retardant strategy,with a specific focus on the impact of the novel protective gas C3H2F6on the flame-retardant properties of the alloy.This paper unveils the morphological characteristics of the EV33 magnesium alloy surface in the absence of protective gas,while employing thermodynamic principles to establish the preferential reaction stages of the alloy,computing the residual stress of MgF2,and assessing the flame-retardant and antioxidative properties of C3H2F6.The study finds that under conditions without protective gas,the oxide film on the EV33 alloy surface is prone to cracking,which accelerates the ignition process of the alloy.Conversely,in an environment enriched with C3H2F6,the formation of a dense oxide film on the alloy surface significantly enhances its thermal stability and flame-retardant properties.This mechanism encompasses the formation of a secondary oxide film,where C3H2F6accelerates the rapid development of this film,effectively repairing damage to the primary oxide film and inhibiting further diffusion of the oxidation reaction.Furthermore,this study elucidates the origin of oxide film rupture,showing that under conditions without protective gas,the precipitated phases and grain boundaries on the surface of the alloy induce the rupture of the oxide film,attributed to stress concentration phenomena occurring around the grain boundaries.展开更多
基金supported by the National Natural Science Foundation of China(82271401,82071394)the Tianjin Health Research Project(TJWJ2024RC002)。
摘要Background:Repetitive mild traumatic brain injury(rmTBI)is a significant risk factor for neurodegeneration,characterized by pathological protein deposition and persistent neuroinflammation.Research has observed increased interleukin-33(IL-33)levels in the peripheral blood of patients with rmTBI,suggesting IL-33 may participate in regulating the pathological development of rmTBI.The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI,and to explore its potential as a therapeutic target to improve the neurological outcome.Methods:The study employed an rmTBI mouse model using the wild-type(WT)and IL-33 knockout mice.Cognitive function was assessed via the Y-maze and Barnes tests.The main cell type expressing IL-33 and its receptor,suppression of tumorigenicity 2(ST2),was then investigated in the mouse brain through immunofluorescence colocalization.As the primary neural cell responsible for ST2 expression,microglia were studied in vitro using the BV2 cell line.The effects of lipid droplets(LDs)accumulation and amyloid-beta(Aβ)phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells'phagocytosis.Additionally,HT22 neuronal apoptosis was assessed by flow cytometry.Finally,the cognitive effects of intranasal administration of IL-33 were evaluated in mice.Results:IL-33 KO mice exhibited pronounced cognitive impairment after rmTBI.In the mouse brain,astrocytes were identified as the primary source of IL-33 secretion,while microglia predominantly expressed ST2.Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function.IL-33 mitigated LDs accumulation in BV2 cells and enhanced Aβphagocytosis in vitro.In addition,the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage.Furthermore,intranasal administration of IL-33 was observed to be effective in alleviating neurodegeneration and cognitive outcome of rmTBI mice.Conclusions:Dysfunction of the IL-33/ST2 axis following rmTBI leads to cognitive dysfunction via impairing microglial phagocytosis capacity and promoting neuronal damage.IL-33 would be a promising therapeutic target for alleviating neurodegeneration following rmTBI.
基金financially supported by the National Natural Science Foundation of China(Grant No.31701876)the Chongqing Postgraduate Research and Innovation Programme,China(Grant No.CYB21114)+1 种基金the fundamental Research Funds for the Central Universities(Grant No.SWU-KQ22067)the National Key Research and Development Program of China(Grant No.2023YFD1600804-4)。
摘要Loquat(Eriobotrya japonica)anthracnose,caused by Colletotrichum fructicola,affects multiple loquat tissues and leads to serious economic losses.In particular,foliar infections compromise not only fruit yield but also the medicinal value of loquat leaves.Despite this,no defence genes have been identified for effective disease management.In this study,an integrated analysis of symptom progression,cellular defence responses,and pathogen colonisation identified 72 h post-inoculation(hpi)as a critical time point.At this juncture,a significant difference in response to C.fructicola was observed between the resistant cultivar Peluches(Pell)and susceptible cultivar Donghuzao(DHZ).Comparative transcriptome analysis at 72 hpi revealed that Pell was enriched in activated key defence-related pathways,including‘plant—pathogen interactions'and‘sesquiterpene and triterpene biosynthesis',whereas DHZ was predominantly enriched in primary plant metabolism.We further identified Ej WRKY33,a transcription factor significantly up-regulated in response to C.fructicola,with higher expression levels in Pell compared to those in DHZ.Silencing Ej WRKY33 in loquat leaves resulted in larger lesions and increased pathogen colonisation,with down regulation of salicylic acid(SA)-related gene Ej NPR1,jasmonic acid(JA)/ethylene(ET)-related gene Ej PR4,the terpenoid biosynthetic gene Ej CYP71B37,and defensin gene Ej Def1.In contrast,overexpression of Ej WRKY33 in Arabidopsis thaliana exhibited enhanced resistance to C.fructicola.Furthermore,our investigation with exogenous hormone treatments revealed that while all three hormones(SA,Me JA,or ETH)induced Ej WRKY33 expression,the gene functions as a critical component of the SA-dependent pathway,with limited involvement in the JA/ET pathway.Collectively,these findings provide the molecular basis for developing anthracnose-resistant loquat cultivars and disease management applications.
基金Supported by National Natural Science Foundation of China,No.82171222.
摘要BACKGROUND Patients with gallbladder carcinoma(GBC)often report abdominal pain,which is particularly severe,difficult to treat,and insufficiently relieved.Interleukin-33(IL-33)/suppression of tumorigenicity 2(ST2)signaling plays a role in cancer and pain,but its role in GBC-induced chronic pain is still unknown.AIM To investigate the potential effects of IL-33/ST2 signaling on GBC-induced cancer pain.METHODS To establish a GBC-induced chronic pain model,the GBC cell line GBC-SD was implanted into the gallbladder of nude mice.Pain-related behavior was determined by evaluating withdrawal behavior in response to mechanical stimuation.Serum samples from patients were analyzed via enzyme-linked immunolsorbent assay.Spinal cord samples from the rodents were subjected to enzyme-linked immunosorbent assay,western blotting and quantitative real-time polymerase chain reaction.RESULTS Nude mice with GBC-induced chronic pain presented significant spontaneous visceral pain-related behavior and abdominal hypersensitivity to mechanical stimuli.We demonstrated a significant increase in IL-33 levels in patient serum and in the spinal cords of GBC-induced chronic pain model mice.IL-33/ST2 signaling activation in the spinal cord may promote GBC-induced chronic pain.Remarkable activation of astrocytes and microglia as well as increased levels of proinflammatory cytokines was observed in the spinal cords of the mice.A significant decrease in the activation of astrocytes and microglia and the levels proinflammatory cytokines was observed following the blockade of IL-33/ST2 signaling.CONCLUSION Blockade of spinal IL-33/ST2 signaling results in a significant reduction in GBC-induced pain-related behaviors.This study suggested that targeting IL-33/ST2 signaling may relieve chronic cancer pain due to GBC.
基金supported by the National Key Laboratory for Precision Hot Processing of Metals(Nos.6142909220102).
摘要Resolving the ignition issue of magnesium alloys is essential for broadening their application scope.This research investigates the EV33 magnesium alloy,delving into an innovative flame-retardant strategy,with a specific focus on the impact of the novel protective gas C3H2F6on the flame-retardant properties of the alloy.This paper unveils the morphological characteristics of the EV33 magnesium alloy surface in the absence of protective gas,while employing thermodynamic principles to establish the preferential reaction stages of the alloy,computing the residual stress of MgF2,and assessing the flame-retardant and antioxidative properties of C3H2F6.The study finds that under conditions without protective gas,the oxide film on the EV33 alloy surface is prone to cracking,which accelerates the ignition process of the alloy.Conversely,in an environment enriched with C3H2F6,the formation of a dense oxide film on the alloy surface significantly enhances its thermal stability and flame-retardant properties.This mechanism encompasses the formation of a secondary oxide film,where C3H2F6accelerates the rapid development of this film,effectively repairing damage to the primary oxide film and inhibiting further diffusion of the oxidation reaction.Furthermore,this study elucidates the origin of oxide film rupture,showing that under conditions without protective gas,the precipitated phases and grain boundaries on the surface of the alloy induce the rupture of the oxide film,attributed to stress concentration phenomena occurring around the grain boundaries.