Extreme heat events contribute to high mortality[1,2]and overwhelm emergency medical services through increased ambulance calls and overcrowded emergency departments.[3]Because morbidity and mortality are directly rel...Extreme heat events contribute to high mortality[1,2]and overwhelm emergency medical services through increased ambulance calls and overcrowded emergency departments.[3]Because morbidity and mortality are directly related to both the degree and duration of hyperthermia,timely recognition and management of heat exhaustion and heat stroke are critical for preventing death and reducing healthcare burdens.展开更多
Acute exposure to high altitude can cause acute altitude illnesses and is associated with impaired cognitive and physical performance.The most effective preventive strategies currently recommended include environmenta...Acute exposure to high altitude can cause acute altitude illnesses and is associated with impaired cognitive and physical performance.The most effective preventive strategies currently recommended include environmental acclimatization(slow ascent and/or pre-acclimatization)or pharmacological support of acclimatization using acetazolamide.However,these strategies are not practical for high-altitude exposures that require rapid and unplanned ascent,high physical and mental performance,such as rescue missions or military operations.Dexamethasone and other modulators of the glucocorticoid system take effect quickly and are effective alternatives for preventing acute altitude illnesses when rapidly ascending to high altitudes.As the efficacy of dexamethasone in preventing acute mountain illnesses remains controversial,a review of existing studies on the use of dexamethasone for the prevention of acute mountain sickness was conducted,aiming to determine the best strategy.Possible mechanisms of protection against acute altitude illnesses are discussed based on the results of clinical trials.The data indicate that dexamethasone is most effective at altitudes above 4000 m at doses of 8–16 mg/d.Appropriately designed and powered trials are needed to obtain more evidence-based results on the dosage and timing of dexamethasone administration,and to provide optimized recommendations for the application of this powerful pharmacological tool.展开更多
BACKGROUND:The central nervous system is a critical target of severe heatstroke,with oxidative stress and multi-organelle damage being the key pathogenic mechanisms.However,research on endogenous antioxidant defense r...BACKGROUND:The central nervous system is a critical target of severe heatstroke,with oxidative stress and multi-organelle damage being the key pathogenic mechanisms.However,research on endogenous antioxidant defense remains limited.In this study,we aimed to characterize neuronal oxidative damage as a key heatstroke pathological mechanism and assess the neuroprotective effects of nuclear factor E2-related factor 2(NRF2).METHODS:After developing in vivo and in vitro heatstroke models,we employed histological staining,cell viability and apoptosis assays,oxidative stress indicators determination,organelle ultrastructural observation,and molecular expression analysis to investigate the mechanisms of brain injury and changes in the NRF2 pathway following heatstroke.We pretreated mice and SH-SY5Y cells with tert-butylhydroquinone(TBHQ) to activate NRF2 expression.Furthermore,we utilized NRF2 knockout(KO) mice and NRF2 siRNA transfection to suppress NRF2 expression,thereby examining the effects of NRF2 both in vivo and in vitro.RESULTS:We found that heatstroke induced neuronal damage,elevated oxidative stress levels,and caused structural damage to both the mitochondria and the endoplasmic reticulum(ER).Notably,NRF2 activation was insufficient post-heatstroke.Pretreatment with TBHQ effectively activated the NRF2 signaling pathway and mitigated the resulting damage.In contrast,these injuries were exacerbated in NRF2 KO mice and SH-SY5Y cells transfected with NRF2 siRNA.CONCLUSION:This preliminary research shows that the NRF2 antioxidant signaling pathway exerts a protective effect against oxidative stress,mitigating both mitochondrial and ER structural damage in neuronal cells during heatstroke.Therefore,targeting the NRF2 pathway is a promising therapeutic strategy for heatstroke-induced neuronal injury.展开更多
文摘Extreme heat events contribute to high mortality[1,2]and overwhelm emergency medical services through increased ambulance calls and overcrowded emergency departments.[3]Because morbidity and mortality are directly related to both the degree and duration of hyperthermia,timely recognition and management of heat exhaustion and heat stroke are critical for preventing death and reducing healthcare burdens.
文摘Acute exposure to high altitude can cause acute altitude illnesses and is associated with impaired cognitive and physical performance.The most effective preventive strategies currently recommended include environmental acclimatization(slow ascent and/or pre-acclimatization)or pharmacological support of acclimatization using acetazolamide.However,these strategies are not practical for high-altitude exposures that require rapid and unplanned ascent,high physical and mental performance,such as rescue missions or military operations.Dexamethasone and other modulators of the glucocorticoid system take effect quickly and are effective alternatives for preventing acute altitude illnesses when rapidly ascending to high altitudes.As the efficacy of dexamethasone in preventing acute mountain illnesses remains controversial,a review of existing studies on the use of dexamethasone for the prevention of acute mountain sickness was conducted,aiming to determine the best strategy.Possible mechanisms of protection against acute altitude illnesses are discussed based on the results of clinical trials.The data indicate that dexamethasone is most effective at altitudes above 4000 m at doses of 8–16 mg/d.Appropriately designed and powered trials are needed to obtain more evidence-based results on the dosage and timing of dexamethasone administration,and to provide optimized recommendations for the application of this powerful pharmacological tool.
基金supported by the National Natural Science Foundation of China (No.82202432)the Guangzhou Science and Technology Plan Project (No.2023A04J2059,2024A03J0242)。
文摘BACKGROUND:The central nervous system is a critical target of severe heatstroke,with oxidative stress and multi-organelle damage being the key pathogenic mechanisms.However,research on endogenous antioxidant defense remains limited.In this study,we aimed to characterize neuronal oxidative damage as a key heatstroke pathological mechanism and assess the neuroprotective effects of nuclear factor E2-related factor 2(NRF2).METHODS:After developing in vivo and in vitro heatstroke models,we employed histological staining,cell viability and apoptosis assays,oxidative stress indicators determination,organelle ultrastructural observation,and molecular expression analysis to investigate the mechanisms of brain injury and changes in the NRF2 pathway following heatstroke.We pretreated mice and SH-SY5Y cells with tert-butylhydroquinone(TBHQ) to activate NRF2 expression.Furthermore,we utilized NRF2 knockout(KO) mice and NRF2 siRNA transfection to suppress NRF2 expression,thereby examining the effects of NRF2 both in vivo and in vitro.RESULTS:We found that heatstroke induced neuronal damage,elevated oxidative stress levels,and caused structural damage to both the mitochondria and the endoplasmic reticulum(ER).Notably,NRF2 activation was insufficient post-heatstroke.Pretreatment with TBHQ effectively activated the NRF2 signaling pathway and mitigated the resulting damage.In contrast,these injuries were exacerbated in NRF2 KO mice and SH-SY5Y cells transfected with NRF2 siRNA.CONCLUSION:This preliminary research shows that the NRF2 antioxidant signaling pathway exerts a protective effect against oxidative stress,mitigating both mitochondrial and ER structural damage in neuronal cells during heatstroke.Therefore,targeting the NRF2 pathway is a promising therapeutic strategy for heatstroke-induced neuronal injury.
