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Objective:To study the role of DDX3X/NF-κB pathway in early neuronal apoptosis in subarachnoid hemorrhage(SAH)mice.Methods:The mouse model of SAH was established by internal carotid artery puncture,and the neurological function score of the mice was evaluated.The DDX3X expression was knocked down using recombinant lentivirus expressing DDX3X targeted shRNA(Lv-shDDX3X),or the NF-κB pathway was inhibited by NF-κB-IN-1(IN-1).Western Blot was used to detect the expression of DDX3X and NF-κB(p65)in mouse cortex.TUNEL/NeuN staining was used to detect the apoptosis of cerebral cortex neurons.Results:Twenty-four hours after SAH operation,the neurological function of mice was significantly impaired(P＜0.05).While the expression of DDX3X was signifi-cantly increased and the expression of NF-κB(p65)was significantly decreased in the cortex(P＜0.05).When the DDX3X expression is knocked down firstly,then SAH surgery is performed.The neurological function of mice was sig-nificantly recovered,and the expression of NF-κB(p65)protein was significantly higher than that in SAH group(P＜0.05);If the NF-κB activity was inhibited by IN-1 while DDX3X knockdown,there is no significant recovery of neuro-logical function in SAH mice.TUNEL/NeuN staining showed that the number of TUNEL-positive neurons in the brain tissue after DDX3X knockdown was less than that in the SAH group(P＜0.05),while the number of TUNEL-positive neurons was not significantly reduced when IN-1 was used to inhibit NF-κB activity at the same time of DDX3X knock-down.Conclusion:DDX3X/NF-κB mediated cell death in mice with early brain injury after SAH.
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Objective:To investigate the effect of galectin-3 (gal-3) on microglia polarization after subarachnoid hemorrhage (SAH).Methods:C57BL/6 male adult mice were used to induce SAH or sham operation models. Gal-3 siRNA or negative control siRNA was injected into the lateral ventricle 48 h before the model was induced. After 24 h of model preparation, the SAH score, neurological function score, brain water content, and Evans blue exudate were measured. Western blot analysis was used to detect the expressions of M1 phenotypic markers (inducible nitric oxide synthase [iNOS], CD11b, tumor necrosis factor [TNF]-α) and M2 phenotype markers (CD206, YM1/2, arginase-1 [Arg1]).Results:After using Gal-3 siRNA to inhibit Gal-3, the neurological function score significantly increased, while the SAH score, brain water content, and Evans blue exudate significantly decreased ( P<0.001). Western blot analysis showed that the expressions of M1 phenotypic markers (iNOS, CD11b and TNF-α) in microglia were significantly decreased after Gal-3 inhibition, while the expressions of M2 phenotypic markers (CD206, YM1/2 and Arg1) were significantly increased ( P<0.001). Conclusion:Inhibition of Gal-3 expression can alleviate the early brain injury after SAH, and its mechanism may be associated with regulating the polarization of microglia from M1 to M2 phenotype.
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Objective:To investigate the effect of Sirtuin 1 (SIRT1) on subarachnoid hemorrhage (SAH) and its possible mechanism.Methods:A mouse model of SAH was constructed by internal carotid artery puncture. The protein and mRNA expression levels of SIRT1 at 0, 3, 6, 12, 24, 48, and 72 h were detected by Western Blot and qRT-PCR. A Western Blot assay was used to examine SIRT1 and the expression levels of endoplasmic reticulum stress-related markers GRP78, p-PERK/PERK, p-eIF2α/eIF2α, and CHOP after administration of a SIRT1 inhibitor or SIRT1 si-RNA. At 24 h after SAH, subarachnoid hemorrhage volume, neurological function score, brain water content, and blood-brain barrier integrity were measured.Results:The highest expression of SIRT1 protein and mRNA was observed at 24 h compared with other time points, and the differences were statistically significant (all P < 0.001). Inhibition of SIRT1 expression leads to increased expression of endoplasmic reticulum stress-related proteins GRP78, p-PERK/PERK, p-eIF2α/eIF2α, and CHOP, exacerbating hemorrhage and brain water content, disrupting blood-brain barrier integrity, and significantly reducing neurological function scores. Conclusions:Inhibition of SIRT1 expression significantly increased the endoplasmic reticulum response to excitation and exacerbated early brain injury after SAH.
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Objective:To conduct a bibliometric analysis of scientific publications on aneurysmal subarachnoid hemorrhage (aSAH) worldwide from 2012 to 2022 and to investigate the current research status and hotspots in this field.Methods:The Web of Science Core Collection was used as the data source. According to the set retrieval strategy, the CiteSpace bibliometric tools were used to analyze the published literature and explore the research hotspots and cutting-edge directions.Results:A total of 4 937 articles were included, and the number of publications increased year by year from 2012 to 2022. The United States is a leading country in this field, Harvard University is a leading institution in this field, and Rinkel Gabriel JE is the researcher with the most published articles in this field. The analysis of the keywords provided by the author showed that delayed cerebral ischemia, vasospasm, risk, intracranial aneurysms, endovascular treatment, risk factors, embolization, complications, Pipeline embolization device, coil embolization, hemodynamics, and wall shear stress were the main hotspots and cutting-edge directions of aSAH research.Conclusion:The results of bibliometric analysis help to grasp the current research status of aSAH and determine new directions for future research.
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Objective:To investigate the effects of naringin on early brain injury in rats with subarachnoid hemorrhage and its possible mechanism of action.Methods:Rats were randomly divided into the sham operation group, the model group, and the naringin group. Each group had 8 rats. The SAH model was established by intravascular perforation, and then rats in the model group and the naringin group were administered 0.9% NaCl or naringin 40 mg/kg by intraperitoneal injection after 0.5 h. SAH score, neurological function score, cerebral edema, and blood-brain barrier permeability were detected. The level of NAD + and nflammatory factors were detected by ELISA. The expression of poly(ADP-ribose) polymerase-1 (PARP-1), apoptosis inducing factor (AIF), and protease-activated receptor (PAR) proteins was detected by Western Blot. The expression of PARP-1 mRNA was detected by quantitative real-time fluorescence PCR (qRT-PCR). Neuronal apoptosis was detected by an immunofluorescence assay. Results:Compared with the model group, naringin treatment improved neurological function ( P<0.01), reduced cerebral edema and Evans blue exudation (all P<0.01), increased the content of NAD + ( P<0.001), reduced IL-1β, IL-6 and TNF-α levels (all P<0.001), and reduced the expression of PARP-1/AIF pathway-related proteins in vivo (all P<0.001). In addition, naringin could inhibit neuronal apoptosis in early brain injury after SAH. Conclusions:Naringin can improve the early brain injury after SAH, which may be achieved by inhibiting the PARP-1/AIF pathway.
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Objective:To investigate the effect of rutin on blood-brain barrier in early brain injury after subarachnoid hemorrhage (SAH) in rats.Methods:A rat model of SAH was induced by puncturing the internal carotid artery. The rats were divided into a sham operation group, a model group and a rutin (50 mg/kg) group. Twenty-four hours after modeling, SAH score and neurological deficit score were conducted, and brain water content and Evans blue extravasation rate were detected in each group. Western blot analysis was used to detect the expression of claudin-5, occludin and zonula occluden (ZO)-1. TUNEL staining was used to detect neuronal apoptosis.Results:Compared with the sham operation group, the SAH score increased, the neurological deficit score decreased, and the brain water content and Evans blue extravasation increased in the model group. Rutin could significantly reduce the SAH score, increase neurological deficit score, and reduce brain water content and Evans blue exudation (all P<0.01). Western blot analysis showed that the expression of claudin-5, occludin and ZO-1 protein decreased in the model group, and the expression of claudin-5, occludin and ZO-1 protein increased significantly in the rutin group ( P<0.01). In addition, the number of TUNEL positive cells induced by SAH in the rutin group decreased. Conclusion:Rutin can play a protective role in early brain injury after SAH, and its mechanism may be associated with protecting the integrity of blood-brain barrier.
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Objective:To investigate the effect of oleanolic acid (OA) on Sirtuin1 (SIRT1)-mediated high-mobility group box 1(HMGB1) deacetylation in the early brain injury after subarachnoid hemorrhage (SAH).Methods:A total of 176 male Sprague-Dawley rats were randomly divided into Sham operation (Sham group) ( n=48), SAH group ( n=48), OA group ( n=48) and Sirtinol group ( n=32). Rats in the SAH group, OA group and the Sirtinol group all adopted internal carotid artery puncture to construct SAH model, while rats in the sham group did not adopt puncture. One hour after modeling, the rats in the OA group were given intraperitoneal injection of OA (20 mg/kg), and the rats in the Sirtinol group were given intracerebroventricular injection of Sirtinol (2 mmol/L, 30 μL/kg). The rats in the sham group and SAH group were injected with equal volumes of sodium chloride injection. The SAH score and neurological score were performed 24 h after SAH, and the water content in the brain tissue and Evans blue exudation rate were measured. The expressions of HMGB1, SIRT1 and acetylated HMGB1 proteins in the brain tissue of rats were detected by Western Blot. The expression of HMGB1 mRNA in the brain of the rats was detected by quantitative real-time PCR. The distribution of HMGB1 protein in the brain of the rats was observed by immunofluorescence staining. TUNEL staining was used to observe the neuronal apoptosis in the brain tissue of the rats. Results:Compared with the SAH group, the SAH score of the OA group was significantly reduced ( P<0.001), the Garcia score was increased ( P<0.01), and the brain water content and Evans blue exudation rate were both reduced (all P<0.01). Compared with the OA group, the SAH score of the Sirtinol group was increased ( P<0.01), the Garcia score was significantly decreased ( P<0.001), and the brain water content and Evans blue exudation rate were both increased (all P<0.01). The results of Western Blot and real-time fluorescent quantitative PCR showed that, compared with the SAH group, the protein level ( P<0.01) and mRNA level ( P<0.05) of HMGB1 in the OA group were decreased, the expression of SIRT1 protein was significantly increased ( P<0.001), and the expression of acetylated HMGB1 protein was decreased ( P<0.01). Immunofluorescence staining showed that OA inhibited the migration of HMGB1 protein from the nucleus to the cytoplasm. TUNEL staining showed that OA could effectively reduce the number of TUNEL-positive cells. Compared with the OA group, Sirtinol significantly increased the number of TUNEL-positive cells. Conclusions:OA can reduce the release of HMGB1 through the SIRT1/HMGB1 pathway, thereby protecting the early brain injury after SAH.
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Objective:To discuss the antioxidant and anti-apoptosis effects of 3-hydroxy-olea- 12-en-28-oic acid (OA) on subarachnoid hemorrhage (SAH) and their mechanisms in rat models.Methods:In experiment one: 144 SD rats were divided into sham-operated group, SAH group and SAH+20 mg/kg OA group by random number table method ( n=48); SAH models were established by standard endovascular puncture method; rats in the SAH+20 mg/kg OA group received intraperitoneal injection of OA one h after modeling, while rats in the sham-operated group received the same operation without perforation; brain edema, destruction of blood-brain barrier, SAH severity degrees (Sugawa scale scores), neurological function scale scores and other early brain injury-related indicators were detected in rats from the three groups; the levels of malondialdehyde (MDA), superoxide dismutase (SOD) were investigated; the activation of nuclear factor related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis and neuronal apoptosis after SAH were detected. In experiment two: another 36 rats were divided into sham-operated group, SAH model group, sham operated+negative control siRNA group, SAH+negative control siRNA group, sham operated+Nrf siRNA group and SAH+Nrf siRNA group according to random number table method ( n=6); treatment methods in the sham-operated group and SAH modeling methods were the same as experiment one; negative control siRNA or Nrf siRNA were injected into the lateral ventricle of rats in the later 4 groups 24 h before SAH modeling; expressions of apoptosis-related factors in the downstream of Nrf2/HO-1 axis were detected in rats from the 6 groups. Results:In experiment one: (1) as compared with rats in the SAH group, rats in the SAH+20 mg/kg OA group had significantly decreased Sugawa scale scores, statistically increased neurological function scale scores and balance beam scale scores, significantly decreased brain moisture content and Evans blue exhalation rate ( P<0.05); (2) as compared with SAH group, SAH+20 mg/kg OA group had significantly decreased MDA level, and significantly increased SOD, glutathione peroxudase and catalase levels ( P<0.05); (3) the expressions of Nrf2, HO-1 and B-cell lymphoma-2(Bcl-2) were significantly increased, the expressions of apoptosis-related factors cytochrome-C, caspase-3 and activated caspase 3 were signficantly decreased, and the number of apoptotic neurons was significantly samller in the SAH+20 mg/kg OA group as compared with those in the SAH group ( P<0.05). In experiment two: as compared with those in the SAH+negative control siRNA group, the protein expressions of HO-1 and Bcl-2 in the SAH+Nrf siRNA group were significantly decreased, while the expression levels of cytochrome C, caspase-3 and activated caspase 3 were statistically increased ( P<0.05). Conclusion:OA can reduce the occurrence of oxidative stress and neuronal apoptosis by activating Nrf2/HO-1 axis.
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@#Nitric oxide(NO)is a vital signal messenger in human and generated by nitric oxide synthase including endothelial nitric oxide synthase(eNOS), inducible nitric oxide synthase(iNOS)and neuropathic nitric oxide synthase(nNOS). NO has important regulatory function on the immune system, nervous system and many other physiological systems. Endogenous NO can enhance the function of the vascular system and endothelial cell survival, and inhibit platelet accumulation and leukocyte infiltration. Excessive production of NO may damage tissues by cytotoxic and cytostatic effects. Thus, NO plays a dual role in physiology and pathology. This paper gives a brief review on regulatory effects of NOS-NO system by traditional Chinese medicine during the recent five years, so as to provide some clues or references for the treatment of related diseases and scientific evidene for reasonable and effective clinical application.
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@#The endoplasmic reticulum is an important organelle for eukaryotic cell protein synthesis, folding and secretion. Perturbation of endoplasmic reticulum homeostasis causes endoplasmic reticulum stress. It has been considered as one of important ways and new strategies to regulate endoplasmic reticulum stress in the treatment of multiple diseases. This paper mainly reviews the advances in the research on traditional Chinese medicines for modulating endoplasmic reticulum stress related to cancer, cardiovascular diseases, neurological diseases, diabetes and other complex diseases in recent years, aiming to provide some clues and references for exploring the characteristics and possible mechanism of traditional Chinese medicines treating related diseases.