OBJECTIVES: To investigate the protective effects of dexmedetomidine (DEX) against heat stress (HS)-induced oncosis in human skeletal muscle cells (HSKMCs) and its underlying mechanisms. METHODS: A HSKMC model of HS-induced oncosis were established by 43 ℃ water bath for 4 h, and the effects of treatments with 30 μmol/L DEX, ML385 (a Nrf2 inhibitor) +DEX, si-Nrf2+HS, and si-Nrf2+DEX prior to modeling on cell viability was assessed using CCK-8 assay. Oncosis characteristics were evaluated using transmission electron microscopy and Annexin V-FITC/PI flow cytometry. The oxidative stress markers (GSH, GSH-Px, MDA, SOD and ROS), mitochondrial membrane potential, energy metabolism, and inflammatory cytokines (TNF-α, IL-6 and IL-1β) in the cells were quantified using standard kits, and the expressions of porimin, caspase-3 and Nrf2 pathway proteins were analyzed using Western blotting and qRT-PCR. RESULTS: HS induced typical oncotic features in HSKMCs including organelle swelling and cytoplasmic vacuolization. DEX pretreatment significantly attenuated these changes, reduced Annexin V⁺/PI⁺ cell ratio and cellular porimin expression, and lowered the levels of ROS and MDA while restoring GSH and SOD levels. DEX pretreatment also significantly increased the mitochondrial membrane potential and ATP level, upregulated the expressions of Nrf2, p-Nrf2, HO-1 and NQO1, and suppressed the expressions of TNF-α, IL-6 and IL-1β. The protective effects of DEX were obviously attenuated by interventions with ML385 or si-Nrf2. CONCLUSIONS DEX mitigates HS-induced HSKMC oncosis by activating the Nrf2/HO-1 pathway to relieve oxidative stress, mitochondrial dysfunction, and inflammatory responses.
Humans ; Dexmedetomidine/pharmacology* ; NF-E2-Related Factor 2/metabolism* ; Oxidative Stress/drug effects* ; Heat-Shock Response/drug effects* ; Signal Transduction/drug effects* ; Membrane Potential, Mitochondrial ; Muscle, Skeletal/cytology* ; Heme Oxygenase-1/metabolism* ; Apoptosis/drug effects*

Methods To investigate how the timing of cooling therapy affects organ injuries in rats with exertional heat stroke(EHS)and explore the possible mechanisms.Methods A total of 60 adult male Wistar rat models of EHS were randomized into model group without active cooling after modeling,immediate cooling group with cold water bath immediately after modeling,delayed cooling groups with cold water bath at 5,15 and 30 min after modeling,with another 12 mice without EHS as the normal control group.The changes in core body temperature of the mice were recorded and the cooling rate was calculated.After observation for 24 h,the mice were euthanized and blood samples were collected for detection of interleukin-1β(IL-1β),IL-2,IL-4,IL-6,IL-10,and interferon-γ,followed by pathological examination of the vital organs.The rats that died within 24 h were immediately dissected for examination.Results The number of deaths of the model rats within 24 h increased significantly with the time of delay of cooling treatment.The delay of cooling was positively correlated(r=0.996,P=0.004)while the cooling rate negatively correlated with the mortality rate(r=-0.961,P=0.009).The inflammatory cytokine levels presented with different patterns of variations among the cooling intervention groups.All the rat models of EHS had significant organ damages characterized mainly by epithelial shedding,edema,effusion,and inflammatory cell infiltration,and brain and renal injuries reached the peak level at 24 h after EHS.Conclusion EHS causes significant nonspecific pathologies of varying severities in the vital organs of rats,and the injuries worsen progressively with the delay of cooling.There is a significant heterogeneity in changes of serum inflammatory cytokines in rats with different timing of cooling intervention following EHS.

Methods To investigate how the timing of cooling therapy affects organ injuries in rats with exertional heat stroke(EHS)and explore the possible mechanisms.Methods A total of 60 adult male Wistar rat models of EHS were randomized into model group without active cooling after modeling,immediate cooling group with cold water bath immediately after modeling,delayed cooling groups with cold water bath at 5,15 and 30 min after modeling,with another 12 mice without EHS as the normal control group.The changes in core body temperature of the mice were recorded and the cooling rate was calculated.After observation for 24 h,the mice were euthanized and blood samples were collected for detection of interleukin-1β(IL-1β),IL-2,IL-4,IL-6,IL-10,and interferon-γ,followed by pathological examination of the vital organs.The rats that died within 24 h were immediately dissected for examination.Results The number of deaths of the model rats within 24 h increased significantly with the time of delay of cooling treatment.The delay of cooling was positively correlated(r=0.996,P=0.004)while the cooling rate negatively correlated with the mortality rate(r=-0.961,P=0.009).The inflammatory cytokine levels presented with different patterns of variations among the cooling intervention groups.All the rat models of EHS had significant organ damages characterized mainly by epithelial shedding,edema,effusion,and inflammatory cell infiltration,and brain and renal injuries reached the peak level at 24 h after EHS.Conclusion EHS causes significant nonspecific pathologies of varying severities in the vital organs of rats,and the injuries worsen progressively with the delay of cooling.There is a significant heterogeneity in changes of serum inflammatory cytokines in rats with different timing of cooling intervention following EHS.

Objective:To investigate the early changes of serum biomarkers in rats with mild blast-induced traumatic brain injury (bTBI) in cabin.Methods:Explosion source in the simulated cabin was detonated by initiator. The bTBI rat models caused by explosion shock wave in cabin were established. A total of 24 adult male Sprague-Dawley rats were divided into normal control group ( n=6) and bTBI group ( n=18), according to the random number table. Rats in bTBI group were subdivided at 3, 24, and 72 h post-blast, with 6 rats at each time point. Shock wave pressure at the rat head was measured during the explosion. At 3, 24, and 72 h post-blast, the general condition of rats was observed. Rat blood was collected by cardiac puncture. Then brains were taken completely and quickly for pathological observation. HE staining was used to observe the changes of neurons in hippocampal CA1 area. The collected serum was tested for levels of biomarkers, including interleukin- 6 (IL-6), neuron specific enolase(NSE), S100-β, alpha Ⅱ-spectrin breakdown product-145 (SBDP-145) and Tau. Results:The maximum peak value of the shock wave pressure curve at the rat head was (818.2±33.3)kPa, and the duration was about 1 000 μs. After the explosion, the activity of the rats decreased significantly, the hair was dull, and the appetite decreased. General observation showed that the brain tissue was obviously swollen, the blood vessels on the brain surface were thickened, and there was a little patchy bleeding, but no obvious brain contusion was seen. HE staining showed that some neurons in the hippocampus CA1 area had apoptosis or necrosis. At 3, 24, and 72 hours post-blast, the levels of IL-6 were (155.3±10.7)pg/ml, (171.3±25.3)pg/ml and (155.6±18.2)pg/ml, all of which were significantly higher than that in normal control group [(116.3±7.3)pg/ml]( P<0.05); the levels of NSE were (12.0±1.0)ng/ml, (11.0±1.0)ng/ml and (11.0±1.2)ng/ml, all of which were significantly higher than that in normal control group [(8.1±0.5)ng/ml]( P<0.05); the levels of S100-β were (71.9±10.7)pg/ml, (58.0±11.5)pg/ml and (56.5±12.2)pg/ml, all of which were significantly higher than that in normal control group [(35.2±2.5)pg/ml] ( P<0.05); the levels of SBDP-145 were (29.4±2.8)ng/ml, (24.5±4.8)ng/ml and (20.7±2.1)ng/ml, and only the level at 3 h post-blast was significantly higher than that in normal control group [(20.9±1.2)ng/ml]( P<0.05); the levels of Tau were (141.4±11.7)pg/ml, (189.5±28.2)pg/ml and (179.1±32.5)pg/ml, all of which were significantly higher than that in normal control group [(97.8±5.9)pg/ml]( P<0.05). Conclusion:The serum levels of IL-6, NSE, S100-β, SBDP-145 and Tau in mild bTBI rats increase in various degrees at early time, which provides a theoretical basis for use of serum markers in the early diagnosis of mild bTBI.