Role of triggering receptor expressed on myeloid cells 1/2 in secondary injury after cerebral hemorrhage

Intracerebral hemorrhage(ICH)is a common severe emergency in neurosurgery,causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically,especially among patients with poor functional outcomes.ICH is often accompanied by decreased consciousness and limb dysfunction.This seriously affects patients’ability to live independently.Although rapid advances in neurosurgery have greatly improved patient survival,there remains insufficient evidence that surgical treatment significantly improves long-term outcomes.With in-depth pathophysiological studies after ICH,increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH.In basic and clinical studies of various systemic inflammatory diseases,triggering receptor expressed on myeloid cells 1/2(TREM-1/2),and the TREM receptor family is closely related to the inflammatory response.Various inflammatory diseases can be upregulated and downregulated through receptor intervention.How the TREM receptor functions after ICH,the types of results from intervention,and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown.An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response,significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage,and thus improve the ability of patients to live independently.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Preventive and therapeutic effect of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage

Objective:To investigate the preventive and therapeutic effect and mechanism of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage.Methods:Sixty SD rat aged 9-12 weeks were chosen and divided into the control group,model group and simvastatintreated group randomly with 20 rats in each group.Rats in the model group and simvastatintreated group were infused with autologous fresh uncoagulated blood to the right brain tissue of the basal ganglia to build the cerebral hemorrhage model,while rats in the control group were treated with the same amount of normal saline.Then,rats in the simvastatin-treated group were given a gavage of 3 mg/kg of simvastatin once a day after modeling.Rats in the three groups were given nerve dysfunction score(NDS) and wet-dry weighting method was used to detect the brain water content(BWC) of brain tissues around the lesion of the rats.Then Nissl staining was conducted and the undamaged neurons were counted.Immunohistochemical SP method was applied to count the number of NF-d the immuno fluorκB,TLR4 and IL-1escence method wasβ positive cells in brain tissues around the lesions,an employed to determine the expression levels of NF-κB,TLR4 and IL-1me points were aβ proteins.Results:The NDS results of the simvastatin-treated group at all till significantly higher than those of the model group(P < 0.05);the BWC values of the simvastatin-treated group at all time points were all significantly lower than those of the model group at the same periods(P < 0.05);the number of the undamaged neurons around the lesions of the simvastatin-treated group at all time points were all significantly higher than those of the model group(P < 0.05);seven days after treatment,the number of the NF-κB,TLR4 and IL-1β positive cells in brain tissues around the lesions of the simvastatin-treated group were all significantly lower than those of the model group(P < 0.05),and its expression levels of NF-ower than those of the model group(κB,TLR4 and IL-1P < 0.05).Conclusioβ protein were also significantly lns:Simvastatin can inhibit the expressions of NF-κB,TLR4 and IL-1β proteins in rats with cerebral hemorrhage,and protect neurons and reduce secondary inflammatory damages by down-regulating the above protein-mediated inflammatory responses.

Piezo1 as a potential player in intracranial hemorrhage:From perspectives on biomechanics and hematoma metabolism

Intracranial hemorrhage(ICH)causes numerous neurological deficits and deaths worldwide each year,leaving a significant health burden on the public.The pathophysiology of ICH is complicated and involves both primary and secondary injuries.Hematoma,as the primary pathology of ICH,undergoes metabolism and triggers biochemical and biomechanical alterations in the brain,leading to the secondary injury.Past endeavors mainly aimed at biochemical-initiated mechanisms for causing secondary injury,which have made limited progress in recent years,although ICH itself is also highly biomechanics-related.The discovery of the mechanically-activated cation channel Piezo1 provides a new avenue to further explore the mechanisms underlying the secondary injury.The current article reviews the structure and gating mechanisms of Piezo1,its roles in the physiology/pathophysiology of neurons,astrocytes,microglia,and bone-marrow-derived macrophages,and especially its roles in erythrocytic turnover and iron metabolism,revealing a potential interplay between the biomechanics and biochemistry of hematoma in ICH.Collectively,these advances provide deeper insights into the secondary injury of ICH and lay the foundations for future research.

Expression of yeast silencing information regulator 2 in secondary injury of intracerebral hemorrhage

Objective:to investigate the expression of yeast silencing information regulator 2(Sirt2)in the secondary injury of intracerebral hemorrhage(ICH).Methods:twelve Sprague Dawley(SD)rats were randomly divided into a sham group and an ICH group,with six rats in each group.A rat model of ICH was established by injecting collagenase type IV into the right striatum of the rats.The expression of Sirt2 was measured by Western blot and immunohistochemistry after ICH.Result:the behavioral score of the ICH rats was the lowest at 48 h after the operation;therefore the rats at 48 h after surgery were selected as the model rats.The expression of Sirt2 was significantly higher in the striatal tissue of the ICH rats compared with the sham group(P<0.05).Conclusion:the expression of Sirt2 around hematoma in ICH rats decreases,and Sirt2 is expected to become a new target for ICH treatment.

Perihematoma Damage at Different Time Points in Experimental Intracerebral Hemorrhage

The damage degree of neurons in perilesion at different time points was observed in order to explore the optimal operation occasion. Piglet lobar hematomas were produced by pressure-controlled infusions of 2.5 mL autonomous blood into the right frontal hemispheric white matter over 15 min, and the metabolic changes were ambulatorily detected with MRS at 3rd, 12th, 24th and 48th h after hematoma induction. Brain tissues of perihematoma were also obtained at different time points. The transcription level of Bax gene was detected by in situ hybridization and apoptosis by TUNEL technique, and the pathologic change of neurons was observed under an electron microscope. The results showed that the number of Bax positive cells reached the peak at 24 h （79.00± 4.243/5 fields）. There was no significant difference in A values between 3 h and 6 h, 12 h （P〉 0. 05）, but there significant difference between 24 h and 3 h, 6 h, 12 h （P〈0. 05）. The number of apoptotic cells reached the peak at 24 h （P〈0. 001）, and there was no significant difference between 3 h and 6 h （P=0. 999）. The area of the apoptotic cells showed no significant difference between 3 h and 6 h or among 3 h, 6 h and 6 h （P〉0.05）. Lac peak mainly occurred at 24 h and 48 h, while on the healthy side, no Lac peak was detectable. The ratio of NAA/Cr presented a descent tendency, but there was no significant difference among the groups before 12 h （P〉0. 05）, there was very significant difference between 3, 6 and 24, 48 h （P〈0. 01）. Under electronic microscopy, the neuronal damage surrounding hematoma in 3 to 6 h was milder than in 24 h to 48 h. It was concluded that the secondary apoptosis, damage and metabolic disturbance of the neurons surround- ing hematoma was milder in 3-6 h in acute intracerebral hemorrhage, while obviously aggravated in 24-48 h. An effective intervention is needed to reduce secondary damage as soon as possible.

Oxidized low-density lipoprotein receptor 1:a novel potential therapeutic target for intracerebral hemorrhage

Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.

Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage

Intracerebral hemorrhage is often accompanied by oxidative stress induced by reactive oxygen species,which causes abnormal mitochondrial function and secondary reactive oxygen species generation.This creates a vicious cycle leading to reactive oxygen species accumulation,resulting in progression of the pathological process.Therefore,breaking the cycle to inhibit reactive oxygen species accumulation is critical for reducing neuronal death after intracerebral hemorrhage.Our previous study found that increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4(NADPH oxidase 4,NOX4)led to neuronal apoptosis and damage to the blood-brain barrier after intracerebral hemorrhage.The purpose of this study was to investigate the role of NOX4 in the circle involving the neuronal tolerance to oxidative stress,mitochondrial reactive oxygen species and modes of neuronal death other than apoptosis after intracerebral hemorrhage.We found that NOX4 knockdown by adeno-associated virus(AAV-NOX4)in rats enhanced neuronal tolerance to oxidative stress,enabling them to better resist the oxidative stress caused by intracerebral hemorrhage.Knockdown of NOX4 also reduced the production of reactive oxygen species in the mitochondria,relieved mitochondrial damage,prevented secondary reactive oxygen species accumulation,reduced neuronal pyroptosis and contributed to relieving secondary brain injury after intracerebral hemorrhage in rats.Finally,we used a mitochondria-targeted superoxide dismutase mimetic to explore the relationship between reactive oxygen species and NOX4.The mitochondria-targeted superoxide dismutase mimetic inhibited the expression of NOX4 and neuronal pyroptosis,which is similar to the effect of AAV-NOX4.This indicates that NOX4 is likely to be an important target for inhibiting mitochondrial reactive oxygen species production,and NOX4 inhibitors can be used to alleviate oxidative stress response induced by intracerebral hemorrhage.

Incidence of Hemorrhage after ENT Procedures and Seasonal Variation: A Retrospective Study and Literature Review

Background: Ear, nose, throat procedures are the most performed procedures for adults and children per year. Doctors might have noticed that at certain times of the year, there would be an increase in admissions of post tonsillectomy bleeding or epistaxis after nasal surgeries. Objectives: To determine whether a correlation exists between season and the rate of hemorrhage presentation after ear, nose, throat procedures. Methods: A 12-year retrospective review from January of 2003 to June of 2015, involving 1032 patients who developed secondary hemorrhage following ear, nose, throat related surgeries. We analyzed the presentation of hemorrhage in relation to the month of admission. Meteorological data were obtained from the Meteorological directorate of Bahrain. Results: Post-Operative Hemorrhage occurred in (1032) patients. The season and air temperature had a significant influence on secondary post-tonsillectomy hemorrhage and post-septoplasty epistaxis according to the age with a significant increase in their rate during the summer months (p < 0.05). Conclusion: The incidence of hemorrhage showed monthly and seasonal variations. This is clearly a multi-factorial problem. However, in patients at high risk of bleeding, consideration should be given to performing surgeries at a time of year of lower rates.

Research progress on the mechanism of acupuncture in the treatment of secondary brain injury after intracerebral hemorrhage

Intracerebral hemorrhage is a major cause of death in humans,with high morbidity,mortality,and disability rates.Secondary brain injury after intracerebral hemorrhage is a consequence of brain edema and neurological dysfunction.Acupuncture is markedly effective against secondary brain injury,and various mechanisms are involved in its action,such as inhibition of inflammatory cascades,inhibition of oxidative stress,attenuation of brain edema,inhibition of nerve cell death,and regulation of neural plasticity.This paper summarizes the mechanism underlying the effects of acupuncture on secondary brain injury after intracerebral hemorrhage in recent years to provide new ideas for subsequent research.

靶向抑制铁死亡在脑出血后继发性脑损伤治疗中的作用研究进展

脑出血后继发性脑损伤(SBI-ICH)可导致神经元的不可逆损伤。研究表明,细胞铁死亡可以介导脑出血后神经元死亡的病理过程,而抑制铁死亡能够有效地减少SBI-ICH。作者综述了铁死亡参与SBI-ICH的发病机制及药物靶向抑制铁死亡在SBI-ICH防治方面应用的研究进展,以期为脑出血防治方法的探索提供帮助。

铁死亡的发生机制及其在脑出血中的作用与相关药物治疗研究进展

铁死亡是一种新发现的、铁依赖性的非凋亡性细胞死亡方式,参与多种疾病的病理过程。脑出血是一种高发病率、高死亡率、高致残率的疾病,是神经科常见的急危重症,预后不良,极大地威胁人类的健康。脑出血引起的脑组织原发性损伤与细胞毒性、神经炎症、氧化应激等相关的继发性损伤是导致其预后不良的主要原因,其中,脑出血后继发性脑损伤是目前临床治疗的难点。研究表明,铁死亡与脑出血后继发性脑损伤的过程密切相关。深入研究脑出血后铁死亡的发生机制及其药物治疗的前景,将为脑出血后继发性脑损伤的诊治提供新思路和新靶点。

凝血酶在脑出血继发性损伤中的研究进展

脑出血是出血性卒中的一种亚型,具有较高的发病率和病死率。脑出血后引起的继发性损伤,如氧化应激(OS)、炎症反应、血液内容物(Fe、凝血酶)引起毒性反应,最终导致神经细胞功能缺损,严重影响患者生存及预后。凝血酶在高血压脑出血患者的脑组织中以中度和高度阳性表达为主。脑出血后大量凝血酶通过多种机制发挥作用,使凝血酶成为脑出血治疗的潜在靶点。本文就凝血酶参与脑出血后继发性脑损伤的相关作用机制进行综述。

转录因子p53与脑出血铁死亡的研究进展

脑出血是死亡率最高的脑卒中亚型,占脑血管疾病的35%,具有高致残、致死率。铁死亡是一种铁依赖性非凋亡细胞死亡模式,近年来发现在脑卒中存在铁死亡现象。p53作为一种转录因子,p53表达不足的情况下可以促进铁死亡的发生;此外,通过各种代谢途径p53能够在存在铁死亡诱导剂(如谷胱甘肽过氧化酶4抑制剂或高水平的活性氧)的情况下抑制铁死亡。p53作为典型和非典型铁死亡途径的关键调节因子参与铁死亡的调节。本文就p53与脑出血后铁死亡脑损伤关系的研究进展进行综述。

Acrolein Aggravates Secondary Brain Injury After Intracerebral Hemorrhage Through Drp1-Mediated Mitochondrial Oxidative Damage in Mice

Clinical advances in the treatment of intracranial hemorrhage(ICH)are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury.Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases.Our results indicated a significant increase in the level of acrolein after ICH in mouse brain.In primary neurons,acrolein induced an increase in mitochondrial fragmentation,loss of mitochondrial membrane potential,generation of reactive oxidative species,and release of mitochondrial cytochrome c.Mechanistically,acrolein facilitated the translocation of dynaminrelated protein 1(Drpl)from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission.Further studies found that treatment with hydralazine(an acrolein scavenger)significantly reversed Drpl translocation and the morphological damage of mitochondria after ICH.In parallel,the neural apoptosis,brain edema,and neurological functional deficits induced by ICH were also remarkably alleviated.In conclusion,our results identify acrolein as an important contributor to the secondary brain injury following ICH.Meanwhile,we uncovered a novel mechanism by which Drpl-mediated mitochondrial oxidative damage is involved in acroleininduced brain injury.

自发性脑出血继发脑室出血预后相关危险因素的Meta分析

目的 了解中国自发性脑出血继发脑室出血人群预后相关的影响因素。方法 检索PubMed、Embase、Cochrane Library、万方、中国知网、维普数据库中有关自发性脑出血继发脑室出血病例预后分析的队列研究,检索时限为从1990年1月1日—2023年6月18日,最终共纳入11项非随机病例对照研究,共计944例自发性脑出血继发脑室出血患者,包括583例预后良好和361例预后不良的患者。采用Newcastle-Ottawa量表评估质量,RevMan 5.4.0软件进行Meta分析。结果 患者发病时意识障碍(OR=7.38,95%CI=4.91~11.09,P<0.00001)、年龄(OR=2.66,95%CI=1.57~4.51,P=0.0003)、出血量(OR=8.45,95%CI=4.95~14.41,P<0.00001)、出血部位(OR=10.18,95%CI=3.43~30.20,P<0.0001)、入院血糖(OR=5.76,95%CI=2.87~11.54,P<0.00001)、中线有无移位(OR=4.67,95%CI=2.50~8.72,P<0.00001)、破入脑室的部位(OR=3.80,95%CI=2.38~6.08,P<0.00001)、范围(OR=0.18,95%CI=0.08~0.40,P<0.0001)和程度(OR=9.34,95%CI=5.10~17.13,P<0.00001)、瞳孔改变(OR=191.67,95%CI=36.44~1008.04,P<0.00001)、脑膜刺激征(OR=9.76,95%CI=4.09~23.25,P<0.00001)、治疗方案(OR=0.31,95%CI=0.15~0.64,P=0.02)、脑室铸型(OR=8.01,95%CI=3.09~20.76,P<0.0001)是继发脑室出血患者预后不良的危险因素。结论 发病时意识障碍、年龄>70岁、出血量≥20 ml、脑干出血、入院时血糖值高、中线有移位、3、4脑室受累、破入脑室范围广、双瞳孔不等大、有脑膜刺激征、脑室铸型、采用内科治疗方案是发生SIVH预后不良的危险因素,能够为SIVH预防决策的制定提供循证依据。

脑出血后神经炎症反应相关生物标志物的研究进展

脑出血(ICH)是一种常见且严重的脑血管疾病,病死率和致残率均较高。ICH的病理、生理机制极其复杂,神经炎症反应在ICH的病理、生理变化过程中起重要作用,参与ICH后早期继发性脑损伤和脑损伤后续修复。ICH引起的神经炎症反应涉及多种炎症细胞激活、炎症细胞因子释放,在此过程中许多与ICH后神经炎症反应相关的生物标志物被广泛研究,动态监测炎症反应相关生物标志物水平有助于判断ICH的病情严重程度及预后评估,早期进行干预治疗可降低患者病死率和致残率。

Management of cerebral amyloid angiopathy and atrial fibrillation:We are still far from precision medicine

The use of anticoagulation therapy could prove to be controversial when trying to balance ischemic stroke and intracranial bleeding risks in patients with concurrent cerebral amyloid angiopathy(CAA)and atrial fibrillation(AF).In fact,CAA is an age-related cerebral vasculopathy that predisposes patients to intracerebral hemorrhage.Nevertheless,many AF patients require oral systemic dose-adjusted warfarin,direct oral anticoagulants(such as factor Xa inhibitors)or direct thrombin inhibitors to control often associated with cardioembolic stroke risk.The prevalence of both CAA and AF is expected to rise,due to the aging of the population.This clinical dilemma is becoming increasingly common.In patients with coexisting AF and CAA,the risks/benefits profile of anticoagulant therapy must be assessed for each patient individually due to the lack of a clear-cut consensus with regard to its risks in scientific literature.This review aims to provide an overview of the management of patients with concomitant AF and CAA and proposes the implementation of a risk-based decision-making algorithm.

带光源医用吸引器+扩张套管在高血压脑出血患者中的应用

目的探讨带光源医用吸引器+扩张套管在脑出血患者术中应用,对其脑脊液中细胞因子的影响。方法选择陕西省核工业二一五医院神经外科,于2019年1月至2024年1月收治有手术指征的基底节区高血压脑出血患者107例,随机分为治疗组与对照组,两组均进行常规去骨瓣减压血肿清除手术,治疗组:使用带光源医用吸引器+专用扩张套管,在管腔内操作清除血肿。对照组:采用脑压板牵开脑组织,无影灯照明下清除血肿,观察对比两组的血肿清除率、手术时间、住院时间、GOS评分、脑脊液IL-1β、TNF-α水平及患者日常生活活动能力评分(ADL)。结果治疗组与对照组,血肿清除率基本相同,前者比后者手术时间缩短43.88 min,住院时间缩短13.26 d,前者脑脊液中IL-1β、TNF-α含量明显低于后者,患者日常生活活动能力评分(ADL)高于后者,差异均有统计学意义(P<0.05)。结论带光源医用吸引器+扩张套管,可以在良好的照明下清除血肿,减少脑组织牵拉,防止医源性损伤发生,减少患者脑脊液中IL-1β、TNF-α因子含量,减少术中及术后继发性神经损害的发生,改善患者预后。

外泌体减轻出血性脑血管病后继发性损伤的研究进展

对于出血性脑血管病,目前临床上采用外科手术干预较多,但是患者在治疗后仍不可避免地出现不同程度的神经功能损伤。因此,寻求一种能够有效减轻患者继发性损伤的治疗手段至关重要。随着再生医学的发展,外泌体概念的引入为出血性脑血管病的诊疗提供了新的理念与方向。外泌体作为一种细胞外囊泡,能够携带细胞内物质,在细胞间发挥信息传递功能,更重要的是外泌体能自由穿过血脑屏障,在神经系统相关疾病中发挥调控作用。本综述主要介绍外泌体减轻出血性脑血管病后继发性损伤的4种病理生理机制——抑制炎症反应、减少细胞程序性死亡、保护血脑屏障以及减轻氧化应激损伤,并总结了其在临床诊断和治疗中的应用前景。