Metabolic dysfunction-associated steatohepatitis(MASH)is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses.Recent studies have indicated that...Metabolic dysfunction-associated steatohepatitis(MASH)is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses.Recent studies have indicated that the activation of the mammalian(or mechanistic)target of rapamycin(mTOR)signaling participates in MASH progression by facilitating lipogenesis and regulating the immune microenvironment.Although several molecular medicines have been demonstrated to inhibit the phosphorylation or activation of mTOR,their poor specificity and side effects limit their clinical application in MASH treatment.Phytic acid(PA),as an endogenous and natural antioxidant in the liver,presents significant anti-inflammatory and lipid metabolism-inhibiting functions to alleviate MASH.In this study,considering the unique phosphate-rich structure of PA,we developed a cerium-PA(CePA)nanocom-plex by combining PA with cerium ions possessing phosphodiesterase activity.CePA intervened in the S2448 phosphorylation of mTOR through the occupation effect of phosphate groups,thereby inhibiting the inflammatory response and mTOR-sterol regulatory element-binding protein 1(SREBP1)regulation axis.The in vivo experiments suggested that CePA alleviated MASH progression and fat accumulation in high-fat diet-fed mice.Mechanistic studies validated that CePA exerts a liver-targeted mTOR repressive function,making it a promising candidate for MASH and other mTOR-related disease treatments.展开更多
Background:Managing prolonged disorders of consciousness(pDoC)presents a significant clinical challenge despite numerous available therapies.While short-term spinal cord stimulation(st-SCS)for over 3 months has been r...Background:Managing prolonged disorders of consciousness(pDoC)presents a significant clinical challenge despite numerous available therapies.While short-term spinal cord stimulation(st-SCS)for over 3 months has been recognized as an effective treatment for pDoC,its efficacy within the first 3 months remains unclear.This study explores st-SCS's impact on patients with pDoC for less than 3 months.Material and methods:We enrolled 141 pDoC patients within 3 months of onset;104 received st-SCS,and 37 underwent conservative treatment.Consciousness levels were assessed using the Coma Recovery Scale-Revised(CRS-R)before treatment,2 weeks after,and at 3-month follow-up.Results:Comparing the data from the 3-month follow-up,we found that,the st-SCS group showed significantly greater improvement in CRS-R scores compared to the control group(p<0.01),with more patients showing symptom amelioration(51/104(49%)).Further analysis of the st-SCS treatment group showed significant improvement in CRS-R scores after 2 weeks(T1)and at the 3-month follow-up(T2)compared to baseline(T0).Both consciousness levels and specific CRS-R items improved notably posttreatment.Younger patients(<40 years)with traumatic brain injury and higher initial CRS-R scores were more likely to experience positive outcomes.Additionally,multivariate logistic regression identified etiology,time since injury,and initial CRS-R score as significant predictors of the 3-month outcome(p<0.05).Conclusions:st-SCS is an effective treatment for pDoC within 3 months of onset,particularly for younger patients and those with trauma-induced conditions,significantly improving consciousness and outcomes.展开更多
Sorafenib,as a first-line drug for advanced hepatocellular carcinoma(HCC),could trigger ferroptosis by inhibiting cystine/glutamate transporter.However,low-level intracellular iron and insufficient activation of adeno...Sorafenib,as a first-line drug for advanced hepatocellular carcinoma(HCC),could trigger ferroptosis by inhibiting cystine/glutamate transporter.However,low-level intracellular iron and insufficient activation of adenosine monophosphate(AMP)-activated protein kinase(AMPK)confer impaired response to sorafenib.In this study,a unique sorafenib nanocomposite dexterously modified with Fe-Material of Institut Lavoisier(sora@Fe-MIL)was synthesized to escalate intracellular iron level and activate AMPK,further potentiating the ferroptotic effect of sorafenib.Remarkably,this strategic deployment of sora@Fe-MIL triggered an extensive demise of cancer cells,while manifesting negligible deleterious impact on normal cells.Two prominent ferroptosis biomarkers,glutathione peroxidase 4(GPX4)and solute carrier family 7 member 11(SLC7A11),underwent pronounced downregulation,underscoring the efficacy of this strategy in inducing ferroptosis.Furthermore,the bioactivity of AMPK was considerably elevated,and its downstream targets were conspicuously inhibited by the treatment with sora@Fe-MIL.Using orthotopic HCC animal models,we observed a substantial suppression of primary in situ tumor growth,and ribonucleic acid(RNA)sequencing elucidated an elevated degree of ferroptosis and AMPK activation with the treatment of sora@Fe-MIL.In conclusion,we proposed that the meticulously designed strategy for secure and efficacious iron release and AMPK activation could significantly potentiate the ferroptotic impact of sorafenib,thus resuscitating its therapeutic response in HCC patients.展开更多
基金supported by the National Natural Science Foundation of China(82373409,82173143,and 82173082)the Top Young Talents Project of“Special Support Program for High Level Talents”in Shaanxi Province(TZ0422,2020−2025)+3 种基金the 2023 program for training talented pilots upon graduation(LHRCYB23009)support from the National Key Research and Development Program of China(2021YFB3500904)the Key Research and Development Program of Shaanxi(2024SF-YBXM-439)the support from the Fundamental Research Funds for the Central Universities(D5000210635 and D5000210829).
文摘Metabolic dysfunction-associated steatohepatitis(MASH)is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses.Recent studies have indicated that the activation of the mammalian(or mechanistic)target of rapamycin(mTOR)signaling participates in MASH progression by facilitating lipogenesis and regulating the immune microenvironment.Although several molecular medicines have been demonstrated to inhibit the phosphorylation or activation of mTOR,their poor specificity and side effects limit their clinical application in MASH treatment.Phytic acid(PA),as an endogenous and natural antioxidant in the liver,presents significant anti-inflammatory and lipid metabolism-inhibiting functions to alleviate MASH.In this study,considering the unique phosphate-rich structure of PA,we developed a cerium-PA(CePA)nanocom-plex by combining PA with cerium ions possessing phosphodiesterase activity.CePA intervened in the S2448 phosphorylation of mTOR through the occupation effect of phosphate groups,thereby inhibiting the inflammatory response and mTOR-sterol regulatory element-binding protein 1(SREBP1)regulation axis.The in vivo experiments suggested that CePA alleviated MASH progression and fat accumulation in high-fat diet-fed mice.Mechanistic studies validated that CePA exerts a liver-targeted mTOR repressive function,making it a promising candidate for MASH and other mTOR-related disease treatments.
基金the Jiangxi Provincial Health Technology Project,grant numbers[202311895]and[SKJP220228867]the Natural Science Foundation of Jiangxi Province,grant number[20224BAB206041].
文摘Background:Managing prolonged disorders of consciousness(pDoC)presents a significant clinical challenge despite numerous available therapies.While short-term spinal cord stimulation(st-SCS)for over 3 months has been recognized as an effective treatment for pDoC,its efficacy within the first 3 months remains unclear.This study explores st-SCS's impact on patients with pDoC for less than 3 months.Material and methods:We enrolled 141 pDoC patients within 3 months of onset;104 received st-SCS,and 37 underwent conservative treatment.Consciousness levels were assessed using the Coma Recovery Scale-Revised(CRS-R)before treatment,2 weeks after,and at 3-month follow-up.Results:Comparing the data from the 3-month follow-up,we found that,the st-SCS group showed significantly greater improvement in CRS-R scores compared to the control group(p<0.01),with more patients showing symptom amelioration(51/104(49%)).Further analysis of the st-SCS treatment group showed significant improvement in CRS-R scores after 2 weeks(T1)and at the 3-month follow-up(T2)compared to baseline(T0).Both consciousness levels and specific CRS-R items improved notably posttreatment.Younger patients(<40 years)with traumatic brain injury and higher initial CRS-R scores were more likely to experience positive outcomes.Additionally,multivariate logistic regression identified etiology,time since injury,and initial CRS-R score as significant predictors of the 3-month outcome(p<0.05).Conclusions:st-SCS is an effective treatment for pDoC within 3 months of onset,particularly for younger patients and those with trauma-induced conditions,significantly improving consciousness and outcomes.
基金supported by the National Natural Science Foundation of China(Nos.82173143 and 82373409)the Top Young Talents Project of the Special Support Program for High-Level Talents in Shaanxi Province(2020-2025)+1 种基金the Fundamental Research Funds for the Central Universities(Nos.D5000210635 and D5000210829)General Key R&D Projects in Shaanxi Province(No.2024SFYBXM-439).
文摘Sorafenib,as a first-line drug for advanced hepatocellular carcinoma(HCC),could trigger ferroptosis by inhibiting cystine/glutamate transporter.However,low-level intracellular iron and insufficient activation of adenosine monophosphate(AMP)-activated protein kinase(AMPK)confer impaired response to sorafenib.In this study,a unique sorafenib nanocomposite dexterously modified with Fe-Material of Institut Lavoisier(sora@Fe-MIL)was synthesized to escalate intracellular iron level and activate AMPK,further potentiating the ferroptotic effect of sorafenib.Remarkably,this strategic deployment of sora@Fe-MIL triggered an extensive demise of cancer cells,while manifesting negligible deleterious impact on normal cells.Two prominent ferroptosis biomarkers,glutathione peroxidase 4(GPX4)and solute carrier family 7 member 11(SLC7A11),underwent pronounced downregulation,underscoring the efficacy of this strategy in inducing ferroptosis.Furthermore,the bioactivity of AMPK was considerably elevated,and its downstream targets were conspicuously inhibited by the treatment with sora@Fe-MIL.Using orthotopic HCC animal models,we observed a substantial suppression of primary in situ tumor growth,and ribonucleic acid(RNA)sequencing elucidated an elevated degree of ferroptosis and AMPK activation with the treatment of sora@Fe-MIL.In conclusion,we proposed that the meticulously designed strategy for secure and efficacious iron release and AMPK activation could significantly potentiate the ferroptotic impact of sorafenib,thus resuscitating its therapeutic response in HCC patients.
