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GPNMB Ameliorates Neuroinflammation Via the Modulation of AMPK/NFκB Signaling Pathway After SAH in Mice. GPNMB通过调节小鼠SAH后AMPK/NFκB信号通路改善神经炎症。
IF 6.2 Pub Date : 2023-12-01 Epub Date: 2023-11-03 DOI: 10.1007/s11481-023-10087-6
Tao Li, Yuansheng Zhang, Qixiong Lu, Li Lei, Jingshu Du, Xiaoyang Lu

Glycoprotein non-metastatic melanoma protein B (GPNMB) got its name from the first discovery in a cell line of non-metastatic melanoma. Later studies found that GPNMB is widely expressed in various tissues and cells of the human body, most abundant in neural tissue, epithelial tissue, bone tissue, and monocyte-macrophage system. GPNMB has been shown to have anti-inflammatory effects in a variety of neurological diseases, however, it has not been reported in subarachnoid hemorrhage (SAH). Male CD-1 mice were used and intra-arterial puncture method was applied to establish the SAH model. Exogenous recombinant GPNMB (rGPNMB) was injected intracerebroventricularly 1 h after SAH. SAH grading, brain edema and blood-brain barrier (BBB) integrity were quantified, and neurobehavioral tests were performed to evaluate the effect of GPNMB on the outcome. Dorsomorphin, the selective inhibitor on AMPK was introduced to study the downstream signaling through which the GPNMB works. Furthermore, western blot, immunofluorescence staining and ELISA were utilized to confirm the signaling. After SAH, GPNMB expression increased significantly as a result of the inflammatory response. GPNMB was expressed extensively in mouse microglia, astrocytes and neurons. The administration of rGPNMB could alleviate brain edema, restore BBB integrity and improve the neurological outcome of mice with SAH. GPNMB treatment significantly magnified the expression of p-AMPK while p-NFκB, IL-1β, IL-6 and TNF-α were suppressed; in the meantime, the combined administration of GPNMB and AMPK inhibitor could decrease the intensity of p-AMPK and reverse the quantity of p-NFκB and the above inflammatory cytokines. GPNMB has the potential of ameliorating the brain edema and neuroinflammation, protecting the BBB and improving the neurological outcome, possibly via the AMPK/NFκB signaling pathway.

糖蛋白非转移性黑色素瘤蛋白B(GPNMB)因首次在非转移性黑素瘤细胞系中发现而得名。后来的研究发现,GPNMB在人体的各种组织和细胞中广泛表达,在神经组织、上皮组织、骨组织和单核巨噬细胞系统中最为丰富。GPNMB已被证明在多种神经系统疾病中具有抗炎作用,但在蛛网膜下腔出血(SAH)中尚未报道。选用雄性CD-1小鼠,采用动脉内穿刺法建立SAH模型。SAH后1h侧脑室注射外源性重组GPNMB(rGPNMB)。对SAH分级、脑水肿和血脑屏障(BBB)完整性进行量化,并进行神经行为测试以评估GPNMB对结果的影响。Dorsomorphin是AMPK的选择性抑制剂,用于研究GPNMB的下游信号传导。此外,利用蛋白质印迹、免疫荧光染色和ELISA来确认信号。SAH后,GPNMB的表达由于炎症反应而显著增加。GPNMB在小鼠小胶质细胞、星形胶质细胞和神经元中广泛表达。rGPNMB的给药可以减轻SAH小鼠的脑水肿,恢复血脑屏障的完整性,并改善其神经系统结果。GPNMB治疗显著增强p-AMPK的表达,而p-NFκB、IL-1β、IL-6和TNF-α的表达受到抑制;同时,GPNMB和AMPK抑制剂联合给药可降低p-AMPK的强度,逆转p-NFκB和上述炎性细胞因子的数量。GPNMB可能通过AMPK/NFκB信号通路,具有改善脑水肿和神经炎症、保护血脑屏障和改善神经系统结果的潜力。
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引用次数: 0
Sertraline Pre-Treatment Attenuates Hemorrhagic Transformation Induced in Rats after Cerebral Ischemia Reperfusion via Down Regulation of Neuronal CD163: Involvement of M1/M2 Polarization Interchange and Inhibiting Autophagy. 舍曲林预处理通过下调神经元CD163,参与M1/M2极化交换和抑制自噬,减轻大鼠脑缺血再灌注后出血转化。
IF 6.2 Pub Date : 2023-12-01 Epub Date: 2023-11-13 DOI: 10.1007/s11481-023-10093-8
Shimaa K Mohamed, Amany A E Ahmed, Abeer Elkhoely

Cerebral ischemia reperfusion (I/R) is one of the neurovascular diseases which leads to severe brain deterioration. Haemorrhagic transformation (HT) is the main complication of ischemic stroke. It exacerbates by reperfusion, causing a more deleterious effect on the brain and death. The current study explored the protective effect of sertraline (Sert) against cerebral I/R in rats by inhibiting HT, together with the molecular pathways involved in this effect. Forty-eight wister male rats were divided into 4 groups: Sham, Sert + Sham, I/R, and Sert + I/R. The ischemic model was induced by bilateral occlusion of the common carotid artery for 20 min, then reperfusion for 24 h. Sertraline (20 mg/kg, p.o.) was administrated for 14 days before exposure to ischemia. Pre-treatment with Sert led to a significant attenuation of oxidative stress and inflammation. In addition, Sert attenuated phosphorylation of extracellular regulated kinases and nuclear factor kappa-p65 expression, consequently modulating microglial polarisation to M2 phenotype. Moreover, Sert prevented the hemorrhagic transformation of ischemic stroke as indicated by the notable decrease in neuronal expression of CD163, activity of Heme oxygenase-2 and matrix metalloproteinase-2 and 9 levels. In the same context, Sert decreased levels of autophagy and apoptotic markers. Furthermore, histological examination, Toluidine blue, and Prussian blue stain aligned with the results. In conclusion, Sert protected against cerebral I/R damage by attenuating oxidative stress, inflammation, autophagy, and apoptotic process. It is worth mentioning that our study was the first to show that Sert inhibited hemorrhagic transformation. The protective effect of sertraline against injury induced by cerebral ischemia reperfusion via inhibiting Hemorrhagic transformation.

脑缺血再灌注(brain ischemia - reperfusion, I/R)是导致脑功能严重恶化的神经血管疾病之一。出血转化(HT)是缺血性脑卒中的主要并发症。它通过再灌注加剧,对大脑造成更有害的影响和死亡。本研究探讨舍曲林(Sert)通过抑制HT对大鼠大脑I/R的保护作用及其参与的分子途径。48只雄性雄性大鼠分为4组:Sham组、Sert + Sham组、I/R组、Sert + I/R组。双侧阻断颈总动脉20 min,再灌注24 h,给药舍曲林(20 mg/kg, p.o.) 14 d后缺血。Sert预处理导致氧化应激和炎症的显著衰减。此外,Sert减弱了细胞外调节激酶的磷酸化和核因子kappa-p65的表达,从而将小胶质细胞极化调节为M2表型。此外,Sert还能显著降低神经元CD163的表达、血红素加氧酶-2和基质金属蛋白酶-2和9的活性,从而阻止缺血性卒中的出血性转化。在相同的环境下,Sert降低了自噬和凋亡标志物的水平。此外,组织学检查,甲苯胺蓝和普鲁士蓝染色与结果一致。综上所述,Sert通过减轻氧化应激、炎症、自噬和凋亡过程来保护大脑I/R损伤。值得一提的是,我们的研究首次表明Sert抑制出血性转化。舍曲林通过抑制出血转化对脑缺血再灌注损伤的保护作用。
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引用次数: 0
Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen. HIV相关神经认知障碍患者脑脊液、肝脏和内膜中膜厚度生物标志物的变化随机接受低毒性治疗方案。
IF 6.2 Pub Date : 2023-12-01 Epub Date: 2023-10-31 DOI: 10.1007/s11481-023-10086-7
Giacomo Stroffolini, Alessandro Lazzaro, Ambra Barco, Veronica Pirriatore, Daniela Vai, Claudia Giaccone, Marco Nigra, Cristiana Atzori, Mattia Trunfio, Stefano Bonora, Giovanni Di Perri G, Andrea Calcagno

The prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, IMT and Fibroscan measurements were performed. After 1:1 randomization to a less neurotoxic regimen consisting of darunavir/cobicistat plus emtricitabine plus maraviroc, or mantaining actual care, tests were repeated after 24 weeks: CSF biomarkes (HIV RNA, tau, p-tau, Beta-amyloid1-42, S100Beta and neopterin) were included. Non-parametric tests (Mann-Whitney and Wilcoxon's) were used. 28 participants completed the study. Male and European ancestry were prevalent; median age was 55 years (51-60). All patients were virally suppressed; median CD4 + count was 626 cell/uL (469-772). Baseline characteristics were similar between the study arms. A significant decrease in CSF p-tau and an increase in CSF neopterin and NFL were observed. We observed a significant reduction in liver stiffness at W24. Despite a small sample size we observed changes in neuromarkers and in hepatic stiffness in patients randomized to the experimental arm. We observed changes in CSF biomarkers (lower phosphorylated-tau and higher neopterin and NFL) that need to be replicated in large cohorts. Subclinical neurotoxicity may be observed in patients with HAND and warrants prospective studies.

艾滋病毒感染者神经认知障碍的患病率估计在30%至50%之间。HIV相关神经认知障碍的发病机制是复杂和多因素的。本研究的目的是测量随机接受神经毒性较低方案的HAND或继续接受其治疗的PLWH的CSF生物标志物、Fibroscan和IMT测量的变化。如果没有主要耐药性相关突变、没有HIV病毒复制、没有服用依非韦伦或达芦那韦、携带R5型HIV且没有主要混淆病症,则对患有HAND的成年患者进行筛查和登记。进行腰椎穿刺、IMT和Fibroscan测量。在1:1随机化至由达芦那韦/柯比司他加恩曲他滨加马拉韦罗组成的神经毒性较低的方案后,或坚持实际护理,24周后重复测试:包括CSF生物标志物(HIV RNA、tau、p-tau、Beta-amyloid1-42、S100β和新蝶呤)。使用非参数检验(Mann-Whitney和Wilcoxon)。28名参与者完成了这项研究。男性和欧洲血统普遍存在;中位年龄55岁(51-60岁)。所有患者均受到病毒抑制;CD4中位数 + 计数为626细胞/uL(469-772)。研究组之间的基线特征相似。观察到CSF p-tau显著降低,CSF新蝶呤和NFL增加。我们观察到W24时肝硬度显著降低。尽管样本量较小,但我们观察到随机分配到实验组的患者的神经标记和肝硬度发生了变化。我们观察到CSF生物标志物的变化(较低的磷酸化tau和较高的新蝶呤和NFL),这些变化需要在大的队列中复制。HAND患者可观察到亚临床神经毒性,值得进行前瞻性研究。
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引用次数: 0
Prenatal SARS-CoV-2 Spike Protein Exposure Induces Autism-Like Neurobehavioral Changes in Male Neonatal Rats. 产前严重急性呼吸系统综合征冠状病毒2型刺突蛋白暴露诱导雄性新生大鼠自闭症样神经行为变化。
IF 6.2 Pub Date : 2023-12-01 Epub Date: 2023-10-27 DOI: 10.1007/s11481-023-10089-4
Mumin Alper Erdogan, Miray Turk, Gizem Dinler Doganay, Ibrahim Halil Sever, Bahattin Ozkul, Ibrahim Sogut, Ebru Eroglu, Yigit Uyanikgil, Oytun Erbas

Recent research on placental, embryo, and brain organoids suggests that the COVID-19 virus may potentially affect embryonic organs, including the brain. Given the established link between SARS-CoV-2 spike protein and neuroinflammation, we sought to investigate the effects of exposure to this protein during pregnancy. We divided pregnant rats into three groups: Group 1 received a 1 ml/kg saline solution, Group 2 received 150 μg/kg adjuvant aluminum hydroxide (AAH), and Group 3 received 40 μg/kg spike protein + 150 μg/kg AAH at 10 and 14 days of gestation. On postnatal day 21 (P21), we randomly separated 60 littermates (10 male-female) into control, AAH-exposed, and spike protein-exposed groups. At P50, we conducted behavioral analyses on these mature animals and performed MR spectroscopy. Subsequently, all animals were sacrificed, and their brains were subject to biochemical and histological analysis. Our findings indicate that male rats exposed to the spike protein displayed a higher rate of impaired performance on behavioral studies, including the three-chamber social test, passive avoidance learning analysis, open field test, rotarod test, and novelty-induced cultivation behavior, indicative of autistic symptoms. Exposure to the spike protein (male) induced gliosis and neuronal cell death in the CA1-CA3 regions of the hippocampus and cerebellum. The spike protein-exposed male rats exhibited significantly greater levels of malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and lactate and lower levels of brain-derived neurotrophic factor (BDNF) than the control group. Our study suggests a potential association between prenatal exposure to COVID-19 spike protein and neurodevelopmental problems, such as ASD. These findings highlight the importance of further research into the potential effects of the COVID-19 virus on embryonic and fetal development and the potential long-term consequences for neurodevelopment.

最近对胎盘、胚胎和大脑类器官的研究表明,新冠肺炎病毒可能会影响包括大脑在内的胚胎器官。鉴于严重急性呼吸系统综合征冠状病毒2型刺突蛋白与神经炎症之间的既定联系,我们试图研究妊娠期间接触该蛋白的影响。我们将怀孕大鼠分为三组:第一组接受1ml/kg盐水溶液,第二组接受150μg/kg佐剂氢氧化铝(AAH),第三组接受40μg/kg刺突蛋白 + 150μg/kg AAH。在出生后第21天(P21),我们将60只同窝出生的配偶(10只雄性雌性)随机分为对照组、AAH暴露组和刺突蛋白暴露组。在P50时,我们对这些成熟动物进行了行为分析,并进行了MR波谱分析。随后,处死所有动物,并对其大脑进行生化和组织学分析。我们的研究结果表明,暴露于刺突蛋白的雄性大鼠在行为研究中表现出更高的表现受损率,包括三室社交测试、被动回避学习分析、开放场地测试、旋转棒测试和新奇诱导的培养行为,这些都表明了自闭症症状。暴露于刺突蛋白(雄性)诱导海马和小脑CA1-CA3区域的胶质细胞增生和神经元细胞死亡。与对照组相比,暴露于刺突蛋白的雄性大鼠表现出显著更高的丙二醛(MDA)、肿瘤坏死因子α(TNF-α)、白细胞介素17(IL-17)、核因子κB(NF-κB)和乳酸水平,以及更低的脑源性神经营养因子(BDNF)水平。我们的研究表明,产前接触新冠肺炎刺突蛋白与ASD等神经发育问题之间存在潜在关联。这些发现强调了进一步研究新冠肺炎病毒对胚胎和胎儿发育的潜在影响以及对神经发育的潜在长期影响的重要性。
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引用次数: 0
Edaravone Confers Neuroprotective, Anti-inflammatory, and Antioxidant Effects on the Fetal Brain of a Placental-ischemia Mouse Model. 依达拉奉对胎盘缺血小鼠模型的胎脑具有神经保护、抗炎和抗氧化作用。
IF 6.2 Pub Date : 2023-12-01 Epub Date: 2023-11-04 DOI: 10.1007/s11481-023-10095-6
Marwa Atallah, Toru Yamashita, Xiao Hu, Xinran Hu, Koji Abe

Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, in addition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain. The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.

降低子宫灌注压(RUPP)是一种公认的模型,它模拟了先兆子痫(PE)的许多临床特征。依达拉奉是一种自由基清除剂,对不同的脑缺血模型具有神经保护、抗氧化和抗炎作用。因此,我们旨在使用我们之前建立的RUPP胎盘缺血小鼠模型来阐明PE影响胎儿大脑发育的不同潜在机制。此外,我们还研究了依达拉奉对RUPP诱导的胎儿大脑发育改变的神经保护作用。在妊娠第13天(GD),将妊娠小鼠分为四组;假手术(SV)、依达拉奉(SE)、RUPP(RV)和RUPP+依达拉奉。SV和SE组接受假手术,而RV和RE组通过双侧子宫结扎进行RUPP手术。依达拉奉(3mg/kg)从GD 14-18通过尾静脉注射进行注射。在GD18上收集来自不同组的胎儿大脑,并进行进一步的研究。结果表明,RUPP改变了胎儿大脑皮层的结构,诱导了神经退行性变,增加了所研究的促炎标志物的表达;TNF-α、IL-6、IL-1β和MMP-9。RUPP除了上调Hif-1α和iNOS外,还导致胎儿大脑中的小胶质细胞和星形胶质细胞活化。依达拉奉通过减轻炎症反应、恢复神经元结构和减少发育中的胎儿大脑中的氧化应激而具有神经保护作用。总之,RUPP胎盘缺血小鼠模型可能是进一步了解PE诱导的儿童神经元改变的潜在机制的有用工具。依达拉奉可能是PE期间保护发育中的胎儿大脑的一种潜在辅助疗法。目前的研究调查了使用降低子宫灌注压(RUPP)手术的胎盘诱导的缺血小鼠模型对胎儿大脑发育的影响以及药物依达拉奉的潜在神经保护作用。研究发现,RUPP模型在发育中的胎儿大脑中引起神经退行性变和促炎反应,以及缺氧和氧化应激。然而,母体注射依达拉奉显示出强大的能力来抵御这些有害影响,并靶向与神经元损伤相关的多种途径。目前的研究表明,RUPP模型可能有助于进一步研究先兆子痫对胎儿大脑发育的影响,依达拉奉可能有潜力作为一种预防这种损伤的治疗方法。
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引用次数: 0
PPARɑ Ligand Caudatin Improves Cognitive Functions and Mitigates Alzheimer's Disease Defects By Inducing Autophagy in Mice Models. PPARõ配体考达汀通过诱导小鼠自噬改善认知功能并减轻阿尔茨海默病缺陷。
IF 6.2 Pub Date : 2023-09-01 Epub Date: 2023-09-08 DOI: 10.1007/s11481-023-10083-w
Senthilkumar Krishnamoorthi, Ashok Iyaswamy, Sravan Gopalkrishnashetty Sreenivasmurthy, Abhimanyu Thakur, Karthick Vasudevan, Gaurav Kumar, Xin-Jie Guan, Kejia Lu, Isha Gaurav, Cheng-Fu Su, Zhou Zhu, Jia Liu, Yuxuan Kan, Selvaraj Jayaraman, Zhiqiang Deng, Ka Kit Chua, King-Ho Cheung, Zhijun Yang, Ju-Xian Song, Min Li

The autophagy-lysosomal pathway (ALP) is a major cellular machinery involved in the clearance of aggregated proteins in Alzheimer disease (AD). However, ALP is dramatically impaired during AD pathogenesis via accumulation of toxic amyloid beta (Aβ) and phosphorylated-Tau (phospho-Tau) proteins in the brain. Therefore, activation of ALP may prevent the increased production of Aβ and phospho-Tau in AD. Peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that can activate autophagy, and transcriptionally regulate transcription factor EB (TFEB) which is a key regulator of ALP. This suggests that targeting PPARα, to reduce ALP impairment, could be a viable strategy for AD therapy. In this study, we investigated the anti-AD activity of Caudatin, an active constituent of Cynanchum otophyllum (a traditional Chinese medicinal herb, Qing Yang Shen; QYS). We found that Caudatin can bind to PPARα as a ligand and augment the expression of ALP in microglial cells and in the brain of 3XTg-AD mice model. Moreover, Caudatin could activate PPARα and transcriptionally regulates TFEB-augmented lysosomal degradation of Aβ and phosphor-Tau aggregates in AD cell models. Oral administration of Caudatin decreased AD pathogenesis and ameliorated the cognitive dysfunction in 3XTg-AD mouse model. Conclusively, Caudatin can be a potential AD therapeutic agent via activation of PPARα-dependent ALP.

自噬-溶酶体途径(ALP)是阿尔茨海默病(AD)中参与聚集蛋白清除的主要细胞机制。然而,在AD发病过程中,ALP通过在大脑中积累有毒的淀粉样蛋白β(Aβ)和磷酸化Tau(磷酸Tau)蛋白而显著受损。因此,ALP的激活可能会阻止AD中Aβ和磷酸化Tau的产生增加。过氧化物酶体增殖物激活受体α(PPARα),一种可以激活自噬的转录因子,并转录调节转录因子EB(TFEB),转录因子EB是ALP的关键调节因子。这表明靶向PPARα以减少ALP损伤可能是AD治疗的可行策略。在本研究中,我们研究了牛心草(一种中草药,清阳神;QYS)的活性成分Caudatin的抗AD活性。我们发现Caudatin可以作为配体与PPARα结合,并增强小胶质细胞和3XTg AD小鼠模型大脑中ALP的表达。此外,在AD细胞模型中,Caudatin可以激活PPARα并转录调节TFEB增强的溶酶体对Aβ和磷酸Tau聚集体的降解。口服考达汀降低了3XTg AD小鼠模型的AD发病机制并改善了认知功能障碍。总之,考达汀可以通过激活PPARα依赖性ALP而成为一种潜在的AD治疗剂。
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引用次数: 0
Cyclophosphamide in the Treatment of Systemic Lupus Erythematosus-related Guillain-Barré Syndrome: A Systematic Review of Case Reports. 环磷酰胺治疗系统性红斑狼疮相关格林-巴利综合征:病例报告的系统回顾。
IF 6.2 Pub Date : 2023-09-01 Epub Date: 2023-06-30 DOI: 10.1007/s11481-023-10075-w
Anji Xiong, Hongxu Cui, Ruiting Deng, Xin Wei

A small category of Guillain-Barré syndrome (GBS) occurs in the presence of systemic lupus erythematosus (SLE). However, specific treatments for this condition have not been established. Cyclophosphamide (CYC) has been reported to benefit patients with SLE-related GBS in some isolated case reports. Consequently, our objective was to investigate the effectiveness of CYC in SLE-related GBS by means of a systematic literature review. Three online databases, PubMed, Embase and Web of Science, were searched for English articles describing the effectiveness of CYC treatment for SLE-related GBS. We extracted data on patient characteristics, disease course, and CYC efficacy and tolerance. Of 995 studies identified, 26 were included in this systematic review. The data for 28 patients (9 men and 19 women) with SLE-related GBS were reviewed, and the patient age at diagnosis varied from 9 to 72 years (mean: 31.5 years [median: 30.5 years]). Sixteen patients (57.1%) had SLE-related GBS before SLE diagnosis. With regard to CYC response, 24 patients (85.7%) showed resolution (46.4%) or improvement (39.3%) of neurological symptoms. Relapse occurred in one patient (3.6%). Four patients (14.3%) showed no improvement in neurological symptoms following CYC administration. With regard to CYC safety, infections developed in two patients (7.1%), and one death (3.6%) due to posterior reversible encephalopathy syndrome was reported. Lymphopenia developed in one patient (3.6%). Our preliminary data suggest that CYC appears to be an effective treatment for SLE-related GBS. However, it is important to differentiate patients with pure GBS concurrent with SLE, because CYC is ineffective for pure GBS.

一小类格林-巴利综合征(GBS)发生在系统性红斑狼疮(SLE)中。然而,这种情况的具体治疗方法尚未确定。在一些孤立的病例报告中,环磷酰胺(CYC)已被报道对SLE相关GBS患者有益。因此,我们的目的是通过系统的文献综述来研究CYC在SLE相关GBS中的有效性。检索PubMed、Embase和Web of Science三个在线数据库中描述CYC治疗SLE相关GBS有效性的英文文章。我们提取了有关患者特征、病程、CYC疗效和耐受性的数据。在已确定的995项研究中,26项被纳入本系统综述。回顾了28名SLE相关GBS患者(9名男性和19名女性)的数据,诊断时的患者年龄从9岁到72岁不等(平均:31.5岁[中位数:30.5岁])。16例(57.1%)患者在SLE诊断前有SLE相关GBS。关于CYC反应,24名患者(85.7%)的神经症状得到缓解(46.4%)或改善(39.3%)。1例患者(3.6%)复发。4例患者(14.3%)服用CYC后神经症状没有改善。关于CYC的安全性,报告了两名患者(7.1%)发生感染,一名患者(3.6%)死于后部可逆性脑病综合征。一名患者(3.6%)出现淋巴管减少。我们的初步数据表明,CYC似乎是治疗SLE相关GBS的有效方法。然而,区分单纯GBS并发SLE的患者很重要,因为CYC对单纯GBS无效。
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引用次数: 0
Ibrutinib Delays ALS Installation and Increases Survival of SOD1G93A Mice by Modulating PI3K/mTOR/Akt Signaling. 伊布替尼通过调节PI3K/mTOR/Akt信号传导延迟ALS的安装并增加SOD1G93A小鼠的存活率。
IF 6.2 Pub Date : 2023-09-01 Epub Date: 2023-06-16 DOI: 10.1007/s11481-023-10068-9
Chengyou Zheng, Weifen Li, Tahir Ali, Ziting Peng, Jieli Liu, Zhengying Pan, Jinxing Feng, Shupeng Li

Amyotrophic lateral sclerosis (ALS) is a fatal multisystem degenerative disorder with minimal available therapeutic. However, some recent studies showed promising results of immunological-based treatment. Here, we aimed to evaluate the efficacy of ibrutinib against ALS-associated abnormalities by targeting inflammation and muscular atrophy. Ibrutinib was administrated orally to SOD1 G93A mice from 6 to 19 weeks for prophylactic administration and 13 to 19 weeks for therapeutic administration. Our results demonstrated that ibrutinib treatment significantly delayed ALS-like symptom onset in the SOD1 G93A mice, as shown by improved survival time and reduced behavioral impairments. Ibrutinib treatment significantly reduced muscular atrophy by increasing muscle/body weight and decreasing muscular necrosis. The ibrutinib treatment also considerably reduced pro-inflammatory cytokine production, IBA-1, and GFAP expression, possibly mediated by mTOR/Akt/Pi3k signaling in the medulla, motor cortex and spinal cord of the ALS mice. In conclusion, our study demonstrated that ibrutinib could delay ALS onset, increase survival time, and reduce ALS progression by targeting inflammation and muscular atrophy via mTOR/Akt/PI3K modulation.

肌萎缩侧索硬化症(ALS)是一种致命的多系统退行性疾病,治疗方法很少。然而,最近的一些研究显示了基于免疫的治疗有希望的结果。在这里,我们旨在通过靶向炎症和肌肉萎缩来评估伊布替尼对ALS相关异常的疗效。对SOD1 G93A小鼠口服伊布替尼6至19周进行预防性给药,13至19周用于治疗性给药。我们的研究结果表明,伊布替尼治疗显著延迟了SOD1 G93A小鼠的ALS样症状发作,表现为生存时间的延长和行为障碍的减少。伊布替尼治疗通过增加肌肉/体重和减少肌肉坏死显著减少肌肉萎缩。伊布替尼治疗还显著降低了促炎细胞因子的产生、IBA-1和GFAP的表达,这可能是由ALS小鼠髓质、运动皮层和脊髓中的mTOR/Akt/Pi3k信号介导的。总之,我们的研究表明,伊布替尼可以通过mTOR/Akt/PI3K调节靶向炎症和肌萎缩,从而延缓ALS的发作,增加生存时间,并减少ALS的进展。
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引用次数: 0
Ginsenoside Re Mitigates Photooxidative Stress-Mediated Photoreceptor Degeneration and Retinal Inflammation. 人参皂苷Re减轻光氧化应激介导的光受体变性和视网膜炎症。
IF 6.2 Pub Date : 2023-09-01 Epub Date: 2023-06-16 DOI: 10.1007/s11481-023-10073-y
Jie Chang, Yujue Wang, Jing Xu, Xiaoye Du, Jingang Cui, Teng Zhang, Yu Chen

Loss of photoreceptors is the central pathology accountable for irreversible vision impairment in patients with photoreceptor degenerative disorders. Currently, mechanisms-based pharmacological therapies protecting photoreceptors from degenerative progression remain clinically unavailable. Photooxidative stress plays a pivotal role in initiating the degenerative cascade in photoreceptors. Meanwhile, photoreceptor degeneration interacts closely with neurotoxic inflammatory responses primarily mediated by aberrantly activated microglia in the retina. Thus, therapies with anti-oxidant and anti-inflammatory properties have been actively investigated for their pharmacological value in controlling photoreceptor degeneration. In the current study, we examined the pharmacological potentials of ginsenoside Re (Re), a naturally occurring antioxidant with anti-inflammatory activities, in photooxidative stress-mediated photoreceptor degeneration. Our results demonstrate that Re attenuates photooxidative stress and associated lipid peroxidation in the retina. Furthermore, Re treatment preserves the morphological and functional integrity of the retina, counteracts photooxidative stress-induced perturbation of the retinal gene expression profiles and mitigates photoreceptor degeneration-associated neuroinflammatory responses and microglia activation in the retina. Lastly, Re partially antagonizes the deleterious effects of photooxidative stress on müller cells, verifying its beneficial impact on retina homeostasis. In conclusion, the work here provides experimental evidence supporting novel pharmacological implications of Re in attenuating photooxidative stress-mediated photoreceptor degeneration and ensuing neuroinflammation.

光感受器丧失是光感受受器退行性疾病患者不可逆视力损伤的核心病理学。目前,基于机制的药物疗法保护光感受器免受退行性进展的影响在临床上仍然不可用。光氧化应激在启动光感受器的退行性级联反应中起着关键作用。同时,光感受器变性与主要由视网膜中异常激活的小胶质细胞介导的神经毒性炎症反应密切相互作用。因此,具有抗氧化和抗炎特性的疗法因其在控制光感受器变性方面的药理学价值而受到积极研究。在目前的研究中,我们检测了人参皂苷Re(Re)在光氧化应激介导的光感受器变性中的药理学潜力,Re是一种具有抗炎活性的天然抗氧化剂。我们的研究结果表明,Re可以减轻视网膜中的光氧化应激和相关的脂质过氧化。此外,再治疗保留了视网膜的形态和功能完整性,抵消了光氧化应激诱导的视网膜基因表达谱紊乱,并减轻了视网膜中与光感受器变性相关的神经炎症反应和小胶质细胞活化。最后,Re部分拮抗了光氧化应激对穆勒细胞的有害影响,验证了其对视网膜稳态的有益影响。总之,本文的工作提供了实验证据,支持Re在减轻光氧化应激介导的光感受器变性和随后的神经炎症方面的新药理学意义。
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引用次数: 0
Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide. 脂肪酸结合蛋白4是小胶质细胞对脂多糖的炎症和代谢反应所必需的。
IF 6.2 Pub Date : 2023-09-01 Epub Date: 2023-08-09 DOI: 10.1007/s11481-023-10079-6
Yoshiteru Kagawa, Yi Ling Low, Jae Pyun, Umberto Doglione, Jennifer L Short, Yijun Pan, Joseph A Nicolazzo

Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of 3H-oleic acid and microglial uptake of 3H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.

小胶质细胞的长期激活会导致促炎介质的过度释放,这对大脑健康有害。因此,在确定介导小胶质细胞活化的途径方面做出了重大努力。最近的研究表明,脂肪酸结合蛋白4(FABP4)是一种脂质结合蛋白,在巨噬细胞介导的炎症中起着关键作用。鉴于我们之前已经在小胶质细胞中鉴定了FABP4,本研究的目的是评估FABP4活性是否有助于永生小鼠小胶质细胞(BV-2细胞)的炎症、代谢和免疫功能(即免疫代谢),使用促炎刺激脂多糖(LPS)诱导小胶质细胞的普遍激活。暴露于LPS后,小胶质细胞FABP4的表达显著增加,这一结果与小胶质细胞增殖率的显著增加有关。LPS刺激的BV-2小胶质细胞表现出活性氧(ROS)和肿瘤坏死因子α(TNF-α)的产生、c-Jun N-末端激酶(JNK)的磷酸化、Toll样受体4(TLR4)的表达增加和解偶联蛋白2(UCP2)的表达减少的显著增加,在FABP4基因沉默和BMS309403化学抑制后,所有这些都被逆转。LPS激活调节3H-油酸的氧化速率和小胶质细胞对3H-2-脱氧-D-葡萄糖的摄取,FABP4的遗传和化学抑制恢复了这一过程。这是第一项报道FABP4在介导LPS对小胶质细胞免疫代谢的有害影响中的关键作用的研究,表明FABP4可能是一种新的治疗靶点,可以缓解小胶质细胞介导的神经炎症,这是多种神经退行性疾病中常见的因子。
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引用次数: 0
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Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
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