Traumatic brain injury (TBI) is a major public health problem and a major cause of mortality and disability that imposes a substantial economic burden worldwide. Dexmedetomidine (DEX), a highly selective α-2-adrenergic receptor agonist that functions as a sedative and analgesic with minimal respiratory depression, has been reported to alleviate early brain injury (EBI) following traumatic brain injury by reducing reactive oxygen species (ROS) production, apoptosis and autophagy. Autophagy is a programmed cell death mechanism that serves a vital role in neuronal cell death following TBI. However, the precise role of autophagy in DEX-mediated neuroprotection following TBI has not been confirmed. The present study aimed to investigate the neuroprotective effects and potential molecular mechanisms of DEX in TBI-induced EBI by regulating neural autophagy in a C57BL/6 mouse model. Mortality, the neurological score, brain water content, neuroinflammatory cytokine levels, ROS production, malondialdehyde levels and neuronal death were evaluated by TUNEL staining, Evans blue extravasation, ELISA, analysis of ROS/lipid peroxidation and western blotting. The results showed that DEX treatment markedly increased the survival rate and neurological score, increased neuron survival, decreased the expression of the LC3, Beclin-1 and NF-κB proteins, as well as the cytokines IL-1β, IL-6 and TNF-α, which indicated that DEX-mediated inhibition of autophagy and neuroinflammation ameliorated neuronal death following TBI. The neuroprotective capacity of DEX is partly dependent on the ROS/nuclear factor erythroid 2-related factor 2 signaling pathway. Taken together, the results of the present study indicated that DEX improves neurological outcomes in mice and reduces neuronal death by protecting against neural autophagy and neuroinflammation.
Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease, and most of the SAH patients experience sleep deprivation during their hospital stay. It is well-known that sleep deprivation is one of the key components of developing several neurological disorders, but its effect on brain damage after SAH has not been determined. Therefore, this study was designed to evaluate the effect of sleep deprivation using an experimental SAH model in rats. Induction of sleep deprivation for 24 h aggravated the SAH-induced brain damage, as evidenced by brain edema, neuronal apoptosis and activation of caspase-3. Sleep deprivation also worsened the neurological impairment and cognitive deficits after SAH. The results of immunostaining and western blot showed that sleep deprivation increased the activation of microglial cells. In addition, sleep deprivation differently regulated the expression of anti-inflammatory and pro-inflammatory cytokines. The results of immunofluorescence staining and western blot showed that sleep deprivation markedly increased the activation of Toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88). Mechanically, treatment with the TLR4 inhibitor TAK-242 or the MyD88 inhibitor ST2825 significantly attenuated the brain damage and neuroinflammation induced by sleep deprivation after SAH. In conclusion, our results indicate that sleep deprivation aggravates brain damage and neurological dysfunction following experimental SAH in rats. These effects were mediated by the activation of the TLR4-MyD88 cascades and regulation of neuroinflammation.
The mechanisms by which inflammation affects the different emotional moods are only partially known. Previous works have pointed to stress hormones like glucocorticoids plus the vascular factor endothelin-1 as key factors evoking stressful states especially in relation to endothelial dysfunctions. With this work, it was our intention to establish the role of pro- and anti-inflammatory cytokine expression variations towards depression-like behaviors and consequently the development of neurodegeneration events caused by endothelial damages in the hamster (Mesocricetus auratus). Such a rodent, which is considered a valuable animal model to test depression and anxiety states, exhibited a variety of depression-like behaviors including reduction in sucrose consumption, locomotion, and exploration (p < 0.01) following exposure to unpredictable chronic mild stress. Contextually, a tight correlation between unpredictable chronic mild stress-induced depressive states and expression of the pro-inflammatory cytokines was detected as shown by marked expression levels (p < 0.01) of IL-1β and NF-kB in the hippocampus, amygdala, and prefrontal cortex. Even the anti-inflammatory cytokine IL-10 supplied notably significant (p < 0.001) expression levels in the same areas of resilient hamsters. Application of hemodynamic and endothelial functional studies pointed to altered arterial endothelial activities in depressed with respect to resilient animals. Moreover, evident damaged neuronal fields in the above areas of depressed hamsters allowed us to correlate such a behavioral phenomenon to the upregulation of IL-1β and NF-κB. Overall, the differing roles of pro- and anti-inflammatory cytokines on depressive states, especially in view of brain endothelial damages, may provide novel therapeutic measures against mood disorders linked to neurodegenerative diseases.
Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke associated with high mortality and morbidity due to the lack of effective therapy. Obstructive sleep apnea (OSA) has been reported to aggravate early brain injury (EBI) and worsen the overall outcome of patients with ICH. However, the precise role of OSA-mediated neuroinflammation and apoptosis following ICH has not been confirmed. The present study aimed to investigate the neuronal damage induced by OSA and the potential molecular mechanisms by which ICH-induced EBI regulates neural apoptosis in a C57BL/6 mouse ICH model. Mortality, neurological score, brain water content and neuronal death were evaluated by Evans blue extravasation, TUNEL staining, ELISA, analysis of reactive oxygen species/lipid peroxidation and western blotting. The results showed that OSA induction decreased survival rate, neurological score and neuron survival and upregulated the protein expression levels of Caspase-3, Bax, cytokines IL-1β, IL-6 and TNF-α and NF-κB, which indicated that OSA-mediated induction of apoptosis and neuroinflammation aggravated neuronal death following ICH. The molecular mechanism was partly dependent on the activating transcription factor/CHOP pathway. Taken together, the results demonstrated that OSA worsens neurological outcomes in mice and increases neuronal death by enhancing neural apoptosis and neuroinflammation.
Background: Although the importance of physical fitness for injury prevention is recognized in sports medicine and rehabilitation, few studies have investigated this factor among recreational alpine skiers. Objective: To determine the effect of lower extremity fitness on the risk and severity of injury among recreational alpine skiers. Method: This prospective cohort study involved 117 recreational skiers at two alpine resorts during the 2021–2022 winter season. Anthropometric characteristics, skiing skills, and lower extremity agility (hexagon test), balance (Y-Balance Test), and endurance (60-s squat test) were assessed before the winter season. All of the participants were divided into an injured group and an uninjured group, based on whether an injury was recorded throughout the season. Results: In binary logistic regression, the hexagon test duration and composite Y-Balance Test score were significant injury risk factors (p < 0.05). Ordinal polytomous logistic regression revealed no significant factors for injury severity (p > 0.05). Conclusions: Recreational alpine skiers with inferior lower extremity agility or balance may have a higher injury risk and this must be considered when assessing individual risk. In the context of injury prevention, regular neuromuscular training and testing, including agility and balance aspects should be recommended to skiers.
Purpose: Spontaneous intracerebral hemorrhage (ICH) is a major public health problem with a huge economic burden worldwide. Ulinastatin (UTI), a serine protease inhibitor, has been reported to be anti-inflammatory, immune regulation, and organ protection by reducing reactive oxygen species production, and inflammation. Necroptosis is a programmed cell death mechanism that plays a vital role in neuronal cell death after ICH. However, the neuroprotection of UTI in ICH has not been confirmed, and the potential mechanism is unclear. The present study aimed to investigate the neuroprotection and potential molecular mechanisms of UTI in ICH-induced EBI in a C57BL/6 mouse model. Methods: The neurological score, brain water content, neuroinflammatory cytokine levels, and neuronal damage were evaluated. The anti-inflammation effectiveness of UTI in ICH patients also was evaluated. Results: UTI treatment markedly increased the neurological score, alleviate the brain edema, decreased the inflammatory cytokine TNF-α, interleukin‑1β (IL‑1β), IL‑6, NF‑κB levels, and RIP1/RIP3, which indicated that UTI-mediated inhibition of neuroinflammation, and necroptosis alleviated neuronal damage after ICH. UTI also can decrease the inflammatory cytokine of ICH patients. The neuroprotective capacity of UTI is partly dependent on the MAPK/NF-κB signaling pathway. Conclusions: UTI improves neurological outcomes in mice and reduces neuronal death by protecting against neural neuroinflammation, and necroptosis.
Background Long non‐coding RNA potassium voltage‐gated channel subfamily Q member 1 opposite strand 1 (lnc‐KCNQ1OT1) represses inflammation and multiple organ dysfunction, whereas its clinical value in sepsis is unclear. Thus, this study aimed to explore this issue. Methods Lnc‐KCNQ1OT1 from peripheral blood mononuclear cells were detected by RT‐qPCR in 116 sepsis patients and 60 healthy controls (HCs). Moreover, sepsis patients were followed‐up until death or up to 28 days. Results Lnc‐KCNQ1OT1 decreased in patients with sepsis than in HCs (p < 0.001). In sepsis patients, lnc‐KCNQ1OT1 was negatively correlated with sequential organ failure assessment (SOFA) scores (r = −0.344, p < 0.001) and several SOFA subscale scores (including respiratory system, coagulation, liver, and renal systems) (all r < 0, p < 0.05). Furthermore, lnc‐KCNQ1OT1 was negatively correlated with CRP (r = −0.386, p < 0.001), TNF‐α (r = −0.332, p < 0.001), IL‐1β (r = −0.319, p < 0.001), and IL‐6 (r = −0.255, p = 0.006). Additionally, lnc‐KCNQ1OT1 levels were lower in sepsis deaths than in sepsis survivors (p < 0.001), and the receiver operating characteristic curve showed that lnc‐KCNQ1OT1 had an acceptable ability to predict 28‐day mortality (area under the curve: 0.780, 95% confidence interval: 0.678–0.882). Meanwhile, its ability to predict 28‐day mortality risk was higher than that of CRP, TNF‐α, IL‐1β, and IL‐6, but slightly lower than the SOFA score and acute physiology and chronic health evaluation II score. Conclusion Lnc‐KCNQ1OT1 serves as a potential biomarker for monitoring disease severity and prognosis in patients with sepsis.
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