Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a ...Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.展开更多
BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory...BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory disease with specific clinical manifestations.Many patients with diabetes present with concurrent inflammatory symptoms.Diabetes exacerbates intestinal permeability and intestinal inflammation,thus leading to the progression to AP.Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.AIM To investigate the potential protective role of FGF21 against AP in diabetic mice.METHODS In the present study,a mouse model of AP was established in diabetic(db)/db diabetic mice through ceruletide injections.Thereafter,the protective effects of recombinant FGF21 protein against AP were evaluated,with an emphasis on examining serum amylase(AMS)levels and pancreatic and intestinal inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-alpha(TNF-),and intestinal IL-1β].Additionally,the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP.An antibiotic(Abx)cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, thePhylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformaticssoftware package, was used to predict different pathways between the groups and to explore the potentialmechanisms by which the gut microbiota influenced the protective effect of FGF21.RESULTSThe results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01)and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ±0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notablesigns of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation inthe small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantlyaltered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment withan Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ±0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinaltissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P <0.001). These findings underscored the superior protective effects of the combination therapy involving an Abxcocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota compositionacross different groups was further characterized, and a differential expression analysis of gene functions wasundertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confertherapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathwayof n-acetylceramide degradation in the gut microbiota.CONCLUSION This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing bloodglucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effectsof FGF21 are augmented when combined with the Abx cocktail.展开更多
目的探究血清摄食抑制因子(Nesfatin-1)、类胰岛素生长因子结合蛋白3(IGFBP-3)、成纤维细胞生长因子21(FGF-21)联合检测对特发性矮小症(ISS)的诊断价值。方法本研究选取2022年6月至2023年6月期间在本院诊治的85例ISS患儿记为ISS组,另选7...目的探究血清摄食抑制因子(Nesfatin-1)、类胰岛素生长因子结合蛋白3(IGFBP-3)、成纤维细胞生长因子21(FGF-21)联合检测对特发性矮小症(ISS)的诊断价值。方法本研究选取2022年6月至2023年6月期间在本院诊治的85例ISS患儿记为ISS组,另选74例在本院体检的儿童记为对照组,记录两组儿童一般资料并进行比较分析。酶联免疫吸附实验(ELISA)检测受试者血清Nesfatin-1、IGFBP-3、FGF-21;使用原子吸收光谱仪测定受试者血清营养元素钙(Ca)、镁(Mg)、铜(Cu)、铁(Fe)、锌(Zn)的水平。X线骨密度仪检查受试者骨龄(BA)。Pearson相关性分析ISS患儿血清Nesfatin-1、IGFBP-3、FGF-21水平的相关性;多因素Logistic回归分析影响儿童发生ISS的影响因素;受试者工作特征(ROC)曲线分析Nesfatin-1、IGFBP-3、FGF-21水平对ISS的诊断价值;通过Z检验比较曲线下面积(AUC)的差异。结果与对照组相比,ISS组BA、身高、体重、BMI以及IGFBP-3、FGF-21水平较低,Nesfatin-1水平、性发育状态I级人数较高(P<0.05);ISS组患儿Nesfatin-1与IGFBP-3、FGF-21水平呈负相关(r_(Nesfatin-1 vs IGFBP-3)=-0.469,r_(Nesfatin-1 vs FGF-21)=-0.483),IGFBP-3与FGF-21水平呈正相关(r_(IGFBP-3 vs FGF-21)=0.456)(P<0.05);BA、性发育状态、IGFBP-3、FGF-21是儿童发生ISS的独立保护因素,而Nesfatin-1是儿童发生ISS的独立危险因素(P<0.05);Nesfatin-1、IGFBP-3、FGF-21单独诊断ISS的AUC分别为0.831、0.836、0.823,3者联合诊断ISS的AUC为0.928,优于单独及两两联合诊断(P<0.05)。结论ISS患儿血清中Nesfatin-1水平较高,IGFBP-3、FGF-21水平较低,3者是儿童发生ISS的影响因素,联合诊断ISS具有较高价值。展开更多
基金supported by grants from Jiangsu Commission of Health,No.Z2021086(to XL)Science and Technology Program of Suzhou,Nos.SYSD2020008(to XL),SKYD2022012(to XL)+1 种基金Suzhou Municipal Health Commission,No.KJXW2020058(to XL)Science and Technology Program of Zhangjiagang,No.ZKS2018(to XL)。
文摘Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.
基金the 2022 Zhejiang Provincial Health Science and Technology Plan,No.2022KY1216.
文摘BACKGROUND Fibroblast growth factor 21(FGF21),primarily secreted by the pancreas,liver,and adipose tissues,plays a pivotal role in regulating glucose and lipid metabolism.Acute pancreatitis(AP)is a common inflammatory disease with specific clinical manifestations.Many patients with diabetes present with concurrent inflammatory symptoms.Diabetes exacerbates intestinal permeability and intestinal inflammation,thus leading to the progression to AP.Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice.AIM To investigate the potential protective role of FGF21 against AP in diabetic mice.METHODS In the present study,a mouse model of AP was established in diabetic(db)/db diabetic mice through ceruletide injections.Thereafter,the protective effects of recombinant FGF21 protein against AP were evaluated,with an emphasis on examining serum amylase(AMS)levels and pancreatic and intestinal inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-alpha(TNF-),and intestinal IL-1β].Additionally,the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP.An antibiotic(Abx)cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, thePhylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformaticssoftware package, was used to predict different pathways between the groups and to explore the potentialmechanisms by which the gut microbiota influenced the protective effect of FGF21.RESULTSThe results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01)and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ±0.051, P < 0.01), and IL-1β (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notablesigns of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation inthe small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantlyaltered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment withan Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ±0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinaltissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P <0.001). These findings underscored the superior protective effects of the combination therapy involving an Abxcocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota compositionacross different groups was further characterized, and a differential expression analysis of gene functions wasundertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confertherapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathwayof n-acetylceramide degradation in the gut microbiota.CONCLUSION This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing bloodglucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effectsof FGF21 are augmented when combined with the Abx cocktail.
文摘目的探究血清摄食抑制因子(Nesfatin-1)、类胰岛素生长因子结合蛋白3(IGFBP-3)、成纤维细胞生长因子21(FGF-21)联合检测对特发性矮小症(ISS)的诊断价值。方法本研究选取2022年6月至2023年6月期间在本院诊治的85例ISS患儿记为ISS组,另选74例在本院体检的儿童记为对照组,记录两组儿童一般资料并进行比较分析。酶联免疫吸附实验(ELISA)检测受试者血清Nesfatin-1、IGFBP-3、FGF-21;使用原子吸收光谱仪测定受试者血清营养元素钙(Ca)、镁(Mg)、铜(Cu)、铁(Fe)、锌(Zn)的水平。X线骨密度仪检查受试者骨龄(BA)。Pearson相关性分析ISS患儿血清Nesfatin-1、IGFBP-3、FGF-21水平的相关性;多因素Logistic回归分析影响儿童发生ISS的影响因素;受试者工作特征(ROC)曲线分析Nesfatin-1、IGFBP-3、FGF-21水平对ISS的诊断价值;通过Z检验比较曲线下面积(AUC)的差异。结果与对照组相比,ISS组BA、身高、体重、BMI以及IGFBP-3、FGF-21水平较低,Nesfatin-1水平、性发育状态I级人数较高(P<0.05);ISS组患儿Nesfatin-1与IGFBP-3、FGF-21水平呈负相关(r_(Nesfatin-1 vs IGFBP-3)=-0.469,r_(Nesfatin-1 vs FGF-21)=-0.483),IGFBP-3与FGF-21水平呈正相关(r_(IGFBP-3 vs FGF-21)=0.456)(P<0.05);BA、性发育状态、IGFBP-3、FGF-21是儿童发生ISS的独立保护因素,而Nesfatin-1是儿童发生ISS的独立危险因素(P<0.05);Nesfatin-1、IGFBP-3、FGF-21单独诊断ISS的AUC分别为0.831、0.836、0.823,3者联合诊断ISS的AUC为0.928,优于单独及两两联合诊断(P<0.05)。结论ISS患儿血清中Nesfatin-1水平较高,IGFBP-3、FGF-21水平较低,3者是儿童发生ISS的影响因素,联合诊断ISS具有较高价值。
