Forensic Science Medicine and Pathology
·
2015
·Vol. 11
·期 4
·570-576
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IF 1.983
Zhang Lin,Ma Jinghong,Li Shangxun,Xue Rui,Jin Ming,Zhou Yiwu
Diphenidol hydrochloride (DPN), a nonphenothiazinic antiemetic agent used primarily in patients with Meniere disease and labyrinthopathies to treat vomiting and vertigo, is considered to be a relatively safe drug. Since it was first approved in the United States in 1967, this drug has been widely used in Latin America and Asia and has contributed to sporadic suicidal and accidental poisonings in mainland China and Taiwan. However, its toxic or lethal concentration ranges have not yet been determined. We report a case of a 23-year-old female who suffered from DPN poisoning that resulted in death. At autopsy, there were no typical pathological findings, except for cerebral edema with high acetylcholinesterase expression. Postmortem analysis of DPN revealed 45 µg/ml in heart blood, 39 µg/ml in femoral vein blood, 141 µg/g in the liver, and 53 mg in the gastric contents. These concentrations indicated that the cause of death was DPN poisoning. The circumstances indicated that the manner of death was suicide. We also present a retrospective study, in which we review and summarize the literature from 1998 to 2014 and describe 16 cases of poisoning, including information from autopsy reports and postmortem drug concentrations. In forensic practice, drug residues at the scene, patients with convulsions and disturbance of consciousness, and rapidly occurring deaths, should draw attention to the possibility of this drug. Toxicological analysis and the exclusion of other diseases may ultimately be used to confirm DPN poisoning.
研究领域:
法医学
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毒理学
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临床医学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2023
·
IF 3.5
Yizhou Zhong,Bingli Zhang,Yuji Huang,Jiaxin Du,Boxuan Liang,Zhiming Li,Rongyi Ye,Bo Wang,Hongyi Xian,Xifei Yang,Weifeng Rong,Xiang Guo,Xingfen Yang,Zhenlie Huang
1,2-Dichloroethane (1,2-DCE) is a pervasive environmental pollutant found in ambient and residential air, as well as ground and drinking water . Brain edema is the primary pathological consequence of 1,2-DCE overexposure. We found that microRNA (miRNA)-29b dysregulation after 1,2-DCE exposure can aggravate brain edema by suppressing aquaporin 4 (AQP4). Moreover, circular RNAs (circRNAs) can regulate the expression of downstream target genes through miRNA , and affect protein function. However, circRNAs’ role in 1,2-DCE-induced brain edema via miR-29b-3p/AQP4 axis remains unclear. To address the mechanism’s bottleneck, we explored the circRNA-miRNA-mRNA network underlying 1,2-DCE-driven astrocyte swelling in SVG p12 cells by circRNA sequencing, electron microscopy and isotope 3 H labeling combined with the 3-O-methylglucose uptake method. The results showed that 25 and 50 mM 1,2-DCE motivated astrocyte swelling, characterized by increased water content, enlarged cell vacuoles, and mitochondrial swelling. This was accompanied by miR-29b-3p downregulation and AQP4 upregulation. We verified that AQP4 were negatively regulated by miR-29b-3p in 1,2-DCE-induced astrocyte swelling. Also, circRNA sequencing highlighted that circBCL11B was upregulated by 1,2-DCE. This was manifested as circBCL11B overexpression playing an endogenous competitive role via upregulating AQP4 by binding to miR-29b-3p, thus leading to astrocyte swelling. Conversely, circBCL11B knockdown reversed the 1,2-DCE-motivated AQP4 upregulation and alleviated the cell swelling. Finally, we demonstrated that the circBCL11B was targeted to miR-29b-3p by fluorescence in situ hybridization and dual-luciferase reporter assay. In conclusion, our findings indicate that circBCL11B acts as a competing endogenous RNA to facilitate 1,2-DCE-caused astrocyte swelling via miR-29b-3p/AQP4 axis. These observations provide new insight into the epigenetic mechanisms underlying 1,2-DCE-induced brain edema.
研究领域:
毒理学
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神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2017
·
IF 5.012
Zhenzhou Lin,Hua Huang,Yong Gu,Kaibin Huang,Yafang Hu,Zhong Ji,Yongming Wu,Shengnan Wang,Tingting Yang,Suyue Pan
Glibenclamide (GBC), a sulfonylurea receptor 1 blocker, emerges recently as a promising neuron protectant in various neurological disorders . This study aimed to determine whether GBC improves survival and neurological outcome of status epilepticus (SE). Male Sprague-Dawley rats successfully undergoing SE for 2.5 h (n = 134) were randomly assigned to GBC or vehicle group. Rats in the GBC group received a loading dose of 10 μg/kg of GBC, followed by 1.2 μg/6 h for 3 days, while same dose of vehicle was used as control. The 28-day survival rate in the GBC group (11/23) was significantly higher than that in the vehicle group (8/36). In addition, the frequency and duration of spontaneous recurrent seizures in SE rats were profoundly reduced by GBC but not by vehicle treatment. Moreover, cognitive impairment was observed in the SE rats at day 28, which was reversed by GBC treatment. Meanwhile, cerebral edema , as well as neuronal loss, was decreased in several brain areas in the GBC group. Additionally, on the molecular basis, the subunits of sulfonylurea receptor 1/transient receptor potential M4 (SUR1-TRPM4) heterodimer were both strongly upregulated after SE but partly suppressed by GBC treatment. Furthermore, gene knockdown of Trpm4 in SE rats reduced BBB disruption and neuronal loss, similar to the inhibitory effects with GBC treatment. Taken together, GBC treatment markedly improved survival and neurologic outcomes after SE. The salutary effects of GBC were correlated to the alleviation of cerebral edema and reduction in neurological injury via down-regulation of SUR1-TRPM4 channel.
研究领域:
神经病学
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药理学
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神经科学
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DOI
PubMed
高影响因子
PATHOLOGY RESEARCH AND PRACTICE
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2024
·
IF 2.9
Haiping Zhang,Wei Li
Background Intracerebral hemorrhage (ICH) is one deadly subtype of stroke with high morbidity and mortality. Oxidative stress and inflammation are major factors contributing to blood-brain barrier (BBB) dysfunction, which induces perihematoma edema and exacerbates ICH-induced secondary brain injury. SYN1 is a crucial neuronal phosphoprotein that plays a pivotal role in neuronal development. Our study was devised to clarify the function of SYN1 in hemin-induced cell injury in PC12 cells and brain injury in ICH rat models. Methods For in vitro assay, PC12 cells were first stimulated by 150 µM hemin for 4 h and then transfected with si-SYN1 and pcDNA3.1-SP1. Cell viability was tested through lactate dehydrogenase (LDH) release and CCK-8 assays. Cell apoptosis was observed through TUNEL staining. Inflammatory factors (IL-1β, IL-6, and TNF-α) were evaluated through western blotting. Oxidative markers (GSH, MDA, and SOD) were detected by adopting commercial kits. The binding sites of SP1 on the SYN1 promoter were predicted by using the JASPAR database and were validated through performing CHIP and luciferase reporter assays. SP1 and SYN1 expression in PC12 cells was investigated by RT-qPCR. For in vivo assay, rats were administrated intracerebroventricularly with si-SYN1 at 72 h before ICH induction. SYN1 and SP1 expression in ICH rats was assessed by RT-qPCR. Neurological deficits, brain edema, and BBB disruption at 24 h following ICH were assessed by conducting neurobehavioral tests, brain water content examination, and Evans blue extravasation assay. Results In vitro, hemin stimulation elevated SYN1 expression, attenuated cell viability, enhanced apoptosis, and induced inflammation and oxidative stress in PC12 cells, which were offset by SYN1 knockdown. SP1 bound to the SYN1 promoter region and positively regulated SYN1 expression. Overexpressing SP1 antagonized the impacts of SYN1 downregulation on hemin-induced damage in PC12 cells. In vivo , SYN1 and SP1 expression was upregulated in ICH rat models. Administration of si-SYN1 effectually improved neurological function, attenuated brain edema, and ameliorated BBB disruption following ICH. Conclusion SP1-mediated SYN1 probably participates in the process of neuronal damage, BBB disruption, and brain injury following ICH.
研究领域:
神经科学
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细胞生物学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
Journal of Stroke & Cerebrovascular Diseases
·
2021
·
IF 2.136
Yue Shu,Juan Huang,Meng Gao,Shengwei Gan,Shujuan Zhu,Shiye Xu,Zhengyu Yang,Yuhui Liao,Weitian Lu
Dentin matrix protein 1 (DMP1) is an extracellular matrix phosphoprotein that is known to facilitate mineralization of collagen in bone and promote osteoblast/odontoblast differentiation. Blood-brain barrier (BBB) disruption is the major pathogenesis in secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to investigate the expression pattern of DMP1 in the mouse brain and explore the role of DMP1 in BBB disruption and brain injury in a mouse model of ICH. Mice were subjected to autologous blood injection-induced ICH. Immunofluorescence staining, western blot analysis , neurobehavioral tests, brain water content measurements, Evans blue permeability assay, and transmission electron microscopy were performed. Small interfering RNA targeting DMP1 (DMP1 siRNA) was administered at 72 h prior to ICH. Results showed that DMP1 is expressed extensively in the mouse brain, and is upregulated in the ICH model. Administration of DMP1 siRNA effectively ameliorated BBB disruption, attenuated brain edema , and improved neurological function after ICH. Moreover, the expression of zonula occludens-1 (ZO-1) and occludin were upregulated, and matrix metalloproteinase-9 (MMP-9) was downregulated in the ICH model. DMP1 siRNA administration reversed the expression of ZO-1, occludin, and MMP-9. These results demonstrated that DMP1 upregulation plays an essential role in inducing BBB disruption and brain injury after ICH. The inhibition of DMP1 could be a potential therapeutic strategy for ICH treatment .
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2019
·
IF 2.929
Linjie Wei,Jianbo Zhang,Bo Zhang,Junjun Geng,Qiang Tan,Ling Wang,Zhi Chen,Hua Feng,Gang Zhu
Background Traumatic brain injury (TBI) leads to severe mortality and disability, in which secondary injury induced by complement activation plays an important role. TBI tends to be associated with more severe cerebral edema and worse neurological functional recovery if it occurs in high-altitude areas than in low-altitude areas. However, the underlying mechanism of this difference is unknown. Thus, we used cobra venom factor (CVF) to deplete complement C3 in simulated high-altitude areas to explore whether the differences in outcome at different altitudes are related to secondary injury caused by complement C3. Methods The weight-drop model was adopted to induce TBI in rats. Rats were randomly divided into the following groups: sham + saline (sham), high altitude + TBI + saline (HAT), high altitude + TBI + CVF (H-CVF), low altitude + TBI + saline (LAT), and low altitude + TBI + CVF (L-CVF). Brain contusion and edema volumes, brain water content, myelin basic protein (MBP) expression, tumor necrosis factor alpha (TNF-a) expression, interleukin 1 beta (IL1B) expression, mortality rate, neurological function, and complement component 3 (C3) mRNA expression were measured by techniques such as Evans blue fluorescence, Perls staining, TUNEL staining, ELISA, immunohistochemistry and Western blotting to evaluate correlations between complement activation and secondary injury. Results The activation of complement after TBI was significantly higher at high altitude than at low altitude. High-altitude TBI resulted in a leakier blood-brain barrier, more severe cerebral edema and higher mortality than low-altitude TBI did. In addition, high-altitude TBI tended to be associated with more MBP degradation, ferric iron deposition, neuronal apoptosis, and inflammatory factor deposition than low-altitude TBI. All of these effects of TBI were partially reversed by inhibiting complement activation using CVF. Conclusion Our study provided evidence that TBI at high altitude leads to severe edema and high mortality and disability rates. Complement C3 activation is one of the important factors contributing to secondary brain injury.
研究领域:
神经科学
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免疫学
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病理生理学
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实验医学
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DOI
PubMed
高影响因子
JCI Insight
·
2021
·
IF 8.315
Kewei Liu,Juan Zhu,Yuan Chang,Zhenzhou Lin,Zhu Shi,Xing Li,Xing Chen,Chuman Lin,Suyue Pan,Kaibin Huang
Status epilepticus (SE) is a neurological emergency usually accompanied by acute cerebral edema and long-term cognitive impairment, and is characterized by neurodegeneration and aberrant hyperphosphorylated tau protein (p-tau) aggregation. The glia-lymphatic (glymphatic) system plays a central role in facilitating the clearance of metabolic waste from the brain, but its relationship with cerebral edema and cognitive dysfunction after SE is unclear. We hypothesized that cerebral edema after SE might impair glymphatic system function through compression, thus leading to impaired removal of metabolic waste, and ultimately affecting long-term cognitive function. Our results showed that glymphatic system function was temporarily impaired, as evidenced by 2-photon imaging, MRI enhancement, imaging of brain sections, and astrocytic water channel aquaporin 4 (AQP4) protein polarization. The severity of cerebral edema on MRI correlated well with glymphatic system dysfunction within 8 days following SE. Moreover, when cerebral edema was alleviated by glibenclamide treatment or genetic deletion of Trpm4 , post-SE glymphatic system function recovered earlier, along with fewer p-tau–deposited neurons and neuronal degeneration and better cognitive function. These findings suggest that SE-induced cerebral edema may cause glymphatic system dysfunction and render the post-SE brain vulnerable to p-tau aggregation and neurocognitive impairment.
研究领域:
神经科学
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神经病学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2022
·
IF 4.319
Xin-Yu Liao,Yang Lei,Song-Feng Chen,Jing Cheng,Dan Zhao,Zhi-Feng Zhang,Xin Han,Ya Zhang,Hua-Bao Liao,Yang Zhuang,Juan Chen,Hai-Bing Zhou,Qi Wan,Ying-Ying Zou
Background: The authors have recently designed a new compound bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and verified that bpV(pis) confers neuroprotection through suppressing PTEN and activating ERK1/2, respectively. Intracerebral hemorrhage (ICH) is the second most common cause of stroke and has severe clinical outcome. In this study, we investigate the effect of bpV(pis) in ICH model both in vivo and in vitro.Materials and methods: The novel drug bpV(pis) was synthesized in the Faculty of Pharmacy, Wuhan University School of Medicine. An ICH model was generated on both SD rats and cells. bpV(pis) was injected into intracerebroventricular or culture media. Western blotting was applied to test the signal pathway. To determine the effect of bpV(pis) on PTEN inhibition and ERK1/2 activation, we measured the phosphorylation level of AKT (a direct downstream target of PTEN that negatively regulates AKT) and ERK1/2. FJC, MTT, and LDH were applied to measure the cell viability. Neurobehavioral tests were performed to measure the effect of bpV(pis).Results: The in vivo results showed that intracerebroventricular administration of bpV(pis) significantly alleviates hematoma, the damage of brain–blood barrier and brain edema. The in vitro results demonstrated that bpV(pis) treatment reduces ICH-induced neuronal injury. Western blotting results identified that bpV(pis) exerts a neuroprotective effect by significantly increasing the phosphorylation level of AKT and ERK1/2 after experimental ICH. Neurobehavioral tests indicate that bpV(pis) promotes functional recovery in ICH animals.Conclusion: This study provides first and direct evidence for a potential role of bpV(pis) in ICH therapy.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2022
·
IF 6.058
Wei Wang,Qiu-Yuan Gong,Lin Cai,Yao Jing,Dian-Xu Yang,Fang Yuan,Hao Chen,Heng-Li Tian
Sirtuin 2 (SIRT2) inhibition or Sirt2 knockout in animal models protects against the development of neurodegenerative diseases and cerebral ischemia. However, the role of SIRT2 in traumatic brain injury (TBI) remains unclear. In this study, we found that knockout of Sirt2 in a mouse model of TBI reduced brain edema, attenuated disruption of the blood-brain barrier, decreased expression of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, reduced the activity of the effector caspase-1, reduced neuroinflammation and neuronal pyroptosis, and improved neurological function. Knockout of Sirt2 in a mechanical stretch injury cell model in vitro also decreased expression of the NLRP3 inflammasome and pyroptosis. Our findings suggest that knockout of Sirt2 is neuroprotective against TBI; therefore, Sirt2 could be a novel target for TBI treatment.
研究领域:
神经科学
·
分子生物学
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神经病学
·
炎症
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DOI
PubMed
高影响因子
Brain and Behavior
·
2022
·Vol. 12
·期 5
·e2558
·
IF 3.405
Jianjiang Wang,Jie Yin,Xi Zheng
Background and purpose Intracerebral hemorrhage (ICH) is a subtype of stroke and results in neurological deficits in patients without any effective treatments. Artemisinin (ART), a well-known antimalarial Chinese medicine, exerts multiple essential roles in the central and peripheral nervous system due to its antioxidative and anti-inflammation properties. Neural cell adhesion molecule L1 (L1CAM, L1) is considered to be implicated in neural development, functional maintenance, and neuroprotection during disease. However, whether these two essential molecules are neuroprotective in ICH remains unclear. Methods Therefore, the present study investigated the influence of ART on the recovery of neurological deficits in a mouse model of ICH induced by collagenase and the underlying mechanism. Results It was revealed that ART is capable of upregulating L1 expression to alleviate brain edema, reduce oxidative stress, and inhibit inflammation to alleviate ICH-induced brain injury to improve the neurological outcome in mice suffering from ICH. Conclusion These results may lay the foundation for ART to be a novel candidate treatment for ICH.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Shuang Zhou,Yuhua Li,Yi Hong,Zhitao Zhong,Min Zhao
Puerarin (Pue), an isoflavone compound extracted from Pueraria, has been shown to inhibit inflammation and reduce cerebral edema. The neuroprotective effect of puerarin has attracted much attention in recent years. Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that causes damage to the nervous system. This study aimed to investigate the effect of puerarin on SAE and elucidate the potential underlying mechanisms. A rat model of SAE was established by cecal ligation and puncture, and puerarin was injected intraperitoneally immediately after the operation. Puerarin was found to improve the survival rate and neurobehavioral score of SAE rats, alleviate symptoms, inhibit the level of brain injury markers NSE and S100β, and improve the pathological changes in rat brain tissue. Puerarin was also found to inhibit the level of factors related to the classical pathway of pyroptosis, such as NLRP3, Caspase-1, GSDMD, ASC, IL-1β, and IL-18. Puerarin also reduced the brain water content and penetration of Evan’s Blue dye in SAE rats, and reduced the expression of MMP-9. In the in vitro experiments, we further confirmed the inhibitory effect of puerarin on neuronal pyroptosis by establishing a pyroptosis model in HT22 cells. Our findings suggest that puerarin may improve SAE by inhibiting the classical pathway of NLRP3/Caspase-1/GSDMD-mediated pyroptosis and reducing blood-brain barrier damage, thus playing a role in brain protection. Our study may provide a novel therapeutic strategy for SAE.
研究领域:
神经科学
·
药理学
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免疫学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-16
·
IF 6.1
Lin Renbao,Luo Rui,Yu Xinyue,Zou Junjie,Huang Xiaowei,Guo Yanwu
Background Status epilepticus (SE) is a common severe neurological emergency. Cerebral edema caused by SE is unavoidable and may exacerbate epilepsy. Recent studies have identified cerebrospinal fluid (CSF) as a crucial fluid source of initial cerebral edema following ischemic stroke and cardiac arrest. Moreover, synchronized neuronal firings drive CSF influx into interstitial fluid (ISF). Parenchymal border macrophages (PBMs) have been found to play a role in regulating CSF flow dynamics. However, the involvement of CSF and PBMs in cerebral edema during SE remains unclear. Here, we investigated the fluid source of cerebral edema in the initial phase of SE with the role of PBMs involved.Methods Lithium chloride-pilocarpine was used to induce SE in C57BL/6 J mice. Electroencephalogram (EEG) was acquired to assess changes in relative EEG power pre- and post-seizure onset. Apparent diffusion coefficient (ADC) maps reconstructed from diffusion-weighted imaging (DWI) were utilized to evaluate cytotoxic edema. Blood–brain barrier (BBB) permeability was examined using sodium fluorescein (NaFl). CSF tracer influx into the brain was assessed by transcranial imaging and brain slices. PBMs were depleted using clodronate liposomes. Immunohistochemistry was used to evaluate PBM depletion, severity of vasogenic edema, inflammation, and neuronal damage.Results During the initial stage of SE, relative EEG power sharply increased and ADC values significantly decreased. Concurrently, CSF tracer influx into the cortex significantly elevated, though NaFl leakage from blood to brain parenchyma did not evidently alter. Following depletion of PBM, CSF influx declined but AQP4 expression and polarization remained unaffected. Post-PBM depletion, there was no significant alteration in relative EEG power, yet CSF influx decreased substantially during the initial stage of SE. The degree of ADC decline lessened, IgG extravasation after SE decreased, activated microglia and proliferating astrocytes count fell, and neuronal damage post-SE alleviated.Conclusion sCSF appeared to contribute to cerebral edema in SE. Depletion of PBM alleviated cytotoxic edema in the initial phase of SE, and subsequent vasogenic edema, inflammatory response and neurological damage were reduced. These findings may provide potential novel strategies for treating cerebral edema following SE.
研究领域:
神经科学
·
免疫学
·
神经影像学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）