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Treatment with β-sitosterol ameliorates the effects of cerebral ischemia/reperfusion injury by suppressing cholesterol overload, endoplasmic reticulum stress, and apoptosis

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Neural Regeneration research 2024年第3期19卷 642-649页

作者： Xiuling Tang Tao Yan Saiying Wang Qingqing Liu Qi Yang Yongqiang Zhang Yujiao Li Yumei Wu Shuibing Liu Yulong Ma Le Yang Precision Pharmacy&Drug Development Center Department of PharmacyTangdu HospitalAir Force Medical UniversityXi’anShaanxi ProvinceChina department of Clinical Pharmacy Jinling HospitalMedical School of Nanjing UniversityNanjingJiangsu ProvinceChina department of Pharmacology School of PharmacyAir Force Medical UniversityXi’anShaanxi ProvinceChina department of Anesthesiology The First Medical Center of Chinese PLA General HospitalBeijingChina department of anatomy Histology and Embryology and K.K.Leung Brain Research CentreAir Force Medical UniversityXi’anShaanxi ProvinceChina

β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.

关键词： apoptosis blood-brain barrier β-sitosterol cerebral ischemia/reperfusion injury cholesterol overload cholesterol transport endoplasmic reticulum stress ischemic stroke molecular docking NPC1L1

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Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain

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Science China(Life Sciences) 2024年第1期67卷 67-82页

作者： Chun-kui Zhang Pan Wang Yuan-Yuan Ji Jian-Shuai Zhao Jun-Xiang Gu Xian-Xia Yan Hong-Wei Fan Ming-Ming Zhang Yu Qiao Xiao-Die Liu Bao-Juan Li Ming-Hui Wang Hai-Long Dong Hao-Hong Li Peng-Cheng Huang Yun-Qing Li Wu-Gang Hou Jin-Lian Li Tao Chen department of anatomy and k.k.leung brain research centre Fourth Military Medical UniversityXi’an 710032China Beijing Institute of Basic Medical Sciences Beijing 100850China key Laboratory of Ministry of Public Health for Forensic Science Xi’an Jiaotong UniversityXi’an 710061China department of Anesthesiology Xijing HospitalFourth Military Medical UniversityXi’an 710032China department of Neurosurgery the Second Affiliated Hospital of Xian Jiaotong UniversityXi’an 710004China School of Biomedical Engineering Fourth Military Medical UniversityXi’an 710032China Affiliated Mental Health centre and Hangzhou Seventh People’s Hospital Zhejiang University School of MedicineHangzhou 310013China The MOE Frontier research Center of brain&brain-machine Integration Zhejiang University School of Brain Science and Brain MedicineHangzhou 310058China department of Neurology The First Affiliated Hospital of Nanchang UniversityNanchang 330006China department of anatomy School of MedicineNorthwest UniversityXi’an 710069China

Chronic pain often develops severe mood changes such as depression.However,how chronic pain leads to depression remains elusive and the mechanisms determining individuals’responses to depression are largely unexplored.Here we found that depression-like behaviors could only be observed in 67.9%of mice with chronic neuropathic pain,leaving 32.1%of mice with depression resilience.We determined that the spike discharges of the ventral tegmental area(VTA)-projecting lateral habenula(LHb)glutamatergic(Glu)neurons were sequentially increased in sham,resilient and susceptible mice,which consequently inhibited VTA dopaminergic(DA)neurons through a LHbGlu-VTAGABA-VTADA circuit.Furthermore,the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner.Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain.Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

关键词： chronic pain depression lateral habenula ventral tegmental area dopamine susceptibility

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Fos expression in tyrosine hydroxylase-containing neurons in rat brainstem after visceral noxious stimulation:an immunohistochemical study

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World Journal of Gastroenterology 2003年第5期9卷 1045-1050页

作者： Feng Han Yu-Fei Zhang Yun-Qing Li department of anatomy and k.k.leung brain research centre,the Fourth Military Medical University,Xi’an 710032,Shaanxi Province,China department of anatomy and k. k. leung brain research centre the Fourth Military Medical University Xi'an 710032 Shanxi Province China.

AIM: To prove that neurons in the different structures of the brainstem that express tyrosine hydroxylase (TH) are involved in the transmission and modulation of visceral or somatic nociceptive information in rat.METHODS: Immunohistochemical double-staining method was used to co-localize TH and Fos expression in neurons of the rat brainstem in visceral or subcutaneous noxious stimulation models.RESULTS: Neurons co-expressing TH/Fos were observed in lateral reticular nucleus (LRT), rostroventrolateral reticular nucleus (RVL), solitary tract nucleus (SOL), locus coeruleus (LC), A5, A7 neuronal groups and ventrolateral subdivision of the periaqueductal gray (vlPAG) in both models. But the proportion and number of the double-labeled neurons responding to the two noxious stimuli were significantly different in the LRT, RVL and LC nuclei. The proportion and number of the TH/Fos double-labeled neurons in the visceral pain model were smaller than that in the subcutaneous pain model. However, in the case of SOL, they were similar in the two models.CONCLUSION: Differences of Fos expression in TH immunoreactive neurons in animals after visceral and somatic noxious stimulation indicate that the mechanisms of the transmission and modulation of visceral nociceptive information in the brainstem may be different from that of somatic nociceptive information.

关键词：酪氨酸羟化酶链神经元脑干动物实验内脏损害免疫组织化学 Fos

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Unraveling the potential of acute intermittent hypoxia as a strategy for inducing robust repair in multiple sclerosis

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Neural Regeneration research 2024年第11期19卷 2339-2340页

作者： Valerie M.k.Verge Nataliya Tokarska Justin M.Naniong department of anatomy Physiology and PharmacologyUniversity of SaskatchewanSaskatoonSKCanada Cameco MS Neuroscience research Center University of SaskatchewanSaskatoonSKCanada

Multiple sclerosis(MS)is a debilitating inflammatory disease of the central nervous system characterized by immune-mediated segmental demyelination and variable degrees of axonal and neuronal degeneration that contribute to disability.Inducing efficient and effective repair programs following demyelination is a major goal and challenge in MS.Conventional MS therapies focus largely on modulating the immune aspects of the disease contributing to lesions.While this alleviates some symptoms and mitigates damage,it does not tackle the fundamental challenge of effective remyelination,which few MS patients experience,especially in the progressive phase of the disease.

关键词： sclerosis degeneration damage

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Migratory mode transition of astrocyte progenitors in the cerebral cortex: an intrinsic or extrinsic cell process?

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Neural Regeneration research 2024年第3期19卷 471-472页

作者： Michio Miyajima Hidenori Tabata kazunori Nakajima department of anatomy Keio University School of MedicineShinjuku-kuTokyoJapan department of Molecular Neurobiology Institute for Developmental ResearchAichi Developmental Disability CenterKasugaiAichiJapan

The cerebral cortex is comprised of properly localized cell types that exert their specific functions.In the developing brain,cells migrate from the germinal region to their functional locations(Silva et al.,2019;Cossart and Garel,2022).For example,neocortical excitatory neurons are generated in the cerebral ventricular and subventricular zones,move to the developing cortical plate via radial migration,and reside in a radial array of six neuronal layers(Oishi and Nakajima,2018).On the other hand,cortical interneurons are mainly generated in ganglionic eminences,migrate tangentially across the cerebral cortex,and reach their final destinations in the cortex(Lim et al.,2018).The failure of neuronal migration leads to defects in cortical layer formation.While the mechanisms of neuronal distribution have been well examined,how astrocytes are diffusely distributed in the cortex is still unclear.Astrocytes are glial cells in the cerebral cortex with several functions,including metabolic support and synapse formation(Abbott et al.,2006;Bosworth and Allen,2017;Allen and Lyons,2018).For example,astrocytes establish synaptic connectivity in the developing brain while they contact numerous synapses and maintain optimal neuronal activity in the adult brain.In the developing brain,astrocytes are primarily generated from radial glia after the neurogenic period.While a certain type of astrocyte called fibrous astrocytes populates the white matter,protoplasmic astrocytes migrate to the cortical plate during neural network formation.

关键词： cerebral migrate Abbott

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Inhibition of Ehrlich ascites carcinoma growth by melatonin:Studies with micro-CT

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Oncology research 2024年第1期32卷 175-185页

作者： SEHER YILMAZ ZÜLEYHA DOĞANYIĞIT MERT OCAk EVRIM SUNA ARIkAN SÖYLEMEZ ASLI OkAN OFLAMAZ SÜMEYYE UÇAR ŞÜkRÜATEŞ AMMAD AHMAD FAROOQI department of anatomy Faculty of MedicineYozgat Bozok UniversityYozgatTurkey department of Mechanical and Aerospace Engineering Case Western Reserve UniversityClevelandOhioUSA department of Histology and Embriology Faculty of MedicineYozgat Bozok UniversityYozgatTurkey department of anatomy Faculty of DentistryAnkara UniversityAnkaraTurkey department of Medical Biology Faculty of MedicineAfyonkarahisar Health Sciences UniversityAfyonTurkey department of anatomy Faculty of MedicineErciyes UniversityKayseriTurkey department of Molecular Oncology Institute of Biomedical and Genetic Engineering(IBGE)IslamabadPakistan

Melatonin is a versatile indolamine synthesized and secreted by the pineal gland in response to the photoperiodic information received by the retinohypothalamic signaling pathway.Melatonin has many benefits,such as organizing circadian rhythms and acting as a powerful hormone.We aimed to show the antitumor effects of melatonin in both in vivo and in vitro models through the mammalian target of rapamycin(mTOR)signaling pathway and the Argyrophilic Nucleolar Regulatory Region(AgNOR),using the Microcomputed Tomography(Micro CT).Ehrlich ascites carcinoma(EAC)cells were administered into the mice by subcutaneous injection.Animals with solid tumors were injected intraperitoneally with 50 and 100 mg/kg melatonin for 14 days.Volumetric measurements for the taken tumors were made with micro-CT imaging,immunohistochemistry(IHC),real-time polymerase chain reaction(PCR)and AgNOR.Statistically,the tumor tissue volume in the Tumor+100 mg/kg melatonin group was significantly lower than that in the other groups in the data obtained from micro-CT images.In the IHC analysis,the groups treated with Tumor+100 mg/kg melatonin were compared when the mTOR signaling pathway and factor 8(F8)expression were compared with the control group.It was determined that there was a significant decrease(pkinase(PI3k),AkT Serine/Threonine kinase(PkB/AkT)genes(p<0.05).Cell apoptosis was evaluated with Annexin V in an in vitro study with different doses of melatonin;It was observed that 100µg/mL melatonin dose caused an increase in the apoptotic cell death.In this study,we have reported anti-tumor effects of melatonin in cell culture studies as well as in mice models.Comprehensive characterization of the melatonin-mediated cancer inhibitory effects will be valuable in advancing our fundamental molecular understanding and

关键词： Signaling pathway Apoptosis Real-time PCR AgNOR

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Molecular typing of familial temporal lobe epilepsy

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World Journal of Psychiatry 2022年第1期12卷 98-107页

作者： Chao Liu Xiao-Zhi Qiao Zi-Han Wei Mi Cao Zhen-Yu Wu Yan-Chun Deng department of Neurology The First Affiliated Hospital of Air Force Medical UniversityXi'an 710032Shaanxi ProvinceChina department of anatomy Histology and Embryology and K.K.Leung Brain Research CentreSchool of Basic MedicineAir Force Medical UniversityXi'an 710032Shaanxi ProvinceChina

The pathogenesis of temporal lobe epilepsy(TLE)was originally considered to be acquired.However,some reports showed that TLE was clustered in some families,indicating a genetic etiology.With the popularity of genetic testing technology,eleven different types of familial TLE(FTLE),including ETL1-ETL11,have been reported,of which ETL9-ETL11 had not yet been included in the OMIM database.These types of FTLE were caused by different genes/Loci and had distinct characteristics.ETL1,ETL7 and ETL10 were characterized by auditory,visual and aphasia seizures,leading to the diagnosis of familial lateral TLE.ETL2,ETL3 and ETL6 showed prominent autonomic symptom and automatism with or without hippocampal abnormalities,indicating a mesial temporal origin.Febrile seizures were common in FTLEs such as ETL2,ETL5,ETL6 and ETL11.ETL4 was diagnosed as occipitotemporal lobe epilepsy with a high incidence of migraine and visual aura.Considering the diversity and complexity of the symptoms of TLE,neurologists enquiring about the family history of epilepsy should ask whether the relatives of the proband had experienced unnoticeable seizures and whether there is a family history of other neurological diseases carefully.Most FTLE patients had a good prognosis with or without anti-seizure medication treatment,with the exception of patients with heterozygous mutations of the CPA6 gene.The pathogenic mechanism was diverse among these genes and spans disturbances of neuron development,differentiation and synaptic signaling.In this article,we describe the research progress on eleven different types of FTLE.The precise molecular typing of FTLE would facilitate the diagnosis and treatment of FTLE and genetic counseling for this disorder.

关键词： Temporal lobe epilepsy Gene mutation Gene locus Phenotypes Prognosis

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Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats

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Neuroscience Bulletin 2022年第4期38卷 342-358页

作者： Dan Ren Jia-Ni Li Xin-Tong Qiu Fa-Ping Wan Zhen-Yu Wu Bo-Yuan Fan Ming-Ming Zhang Tao Chen Hui Li Yang Bai Yun-Qing Li department of anatomy Guangxi Medical UniversityNanning 510000China department of anatomy Histology and Embryology and K.K.Leung Brain Research CentreFourth Military Medical UniversityXi’an 710032China department of anatomy Xuzhou Medical UniversityXuzhou 221004China department of Cardiology The Second Affiliated Hospital of Xian Jiaotong UniversityXi’an 710004China department of Neurosurgery General Hospital of Northern Theater CommandShenyang 110016China key Laboratory of brain Science research and Transformation in Tropical Environment of Hainan Province Haikou 570216China department of Human anatomy College of Basic MedicineDali UniversityDali 671000China

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid(TNBS).TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats.Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii(NTS)and ACC,and some FOS-expressing neurons in the NTS projected to the ACC.In addition,a larger portion of ascending fibers from the NTS innervated pyramidal neurons,the neural subpopulation primarily expressing FOS under the condition of painful CP,rather than GABAergic neurons within the ACC.CP rats showed increased expression of vesicular glutamate transporter 1,and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor(NMDAR)subunit NR2B and theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunit GluR1 within the ACC.Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats,which was similar to the analgesic effect of endomorphins injected into the ACC.Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety,whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats.Taken together,these findings provide neurocircuit,biochemical,and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats,as well as novel insights into the cortical modulation of painful CP,and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

关键词： Chronic pancreatitis Anterior cingulate cortex Nucleus tractus solitaries Hyperalgesia Anxiety

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Star power: harnessing the reactive astrocyte response to promote remyelination in multiple sclerosis

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Neural Regeneration research 2024年第3期19卷 578-582页

作者： Markley Silva Oliveira Junior Laura Reiche Emerson Daniele Ines kortebi Maryam Faiz Patrick küry department of Neurology Neuroregeneration laboratoryMedical FacultyHeinrich-Heine-UniversityDüsseldorfGermany Institute of Medical Science University of TorontoTorontoCanada Division of anatomy Department of SurgeryUniversity of TorontoTorontoCanada

Astrocytes are indispensable for central nervous system development and homeostasis.In response to injury and disease,astrocytes are integral to the immunological-and the,albeit limited,repair response.In this review,we will examine some of the functions reactive astrocytes play in the context of multiple sclerosis and related animal models.We will consider the heterogeneity or plasticity of astrocytes and the mechanisms by which they promote or mitigate demyelination.Finally,we will discuss a set of biomedical strategies that can stimulate astrocytes in their promyelinating response.

关键词： astrocytes demyelination drug-based therapies myelin repair oligodendrocyte precursor cells reactive astrogliosis

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Co-existence of calcium-binding proteins and γ-aminobutyric acid or glycine in neurons of the rat medullary dorsal horn

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Chinese Medical Journal 2004年第3期117卷 430-433页

作者：王文武胜昔李云庆 department of anatomy and k.k. leung brain research centre Fourth Military Medical University

Background We investigated the co-expression of calb indin-D28k (CB), calretinin (CR) and parvalbumin (PV, a combination of the three is referred to as CaBPs) with γ-aminobutyric acid (GABA) or glycine in neurons of the rat medullary dorsal horn (MDH).Methods Immunofluorescence histochemical double-staining for CaBPs and GABA or glycine was performed on the sections from rat MDH. Results CB-, CR-, PV-, GABA- and glycine-like immunoreactive (LI) neurons were differentially observed in all layers of the MDH, but particularly in lamina Ⅱ. Neurons that exhibited immunoreactivity for both CaBPs and GABA or glycine were also observed mainly in lamina Ⅱ. A few of them were found in laminae I and III. The percentages of neurons which co-expressed CB/GABA or CB/glycine out of the total numbers of CB- and GABA-LI neurons or CB- and glycine-LI neurons were 5.3% and 12.1% or 4.1% and 10.0%, respectively. The ratios of CR/GABA or CR/glycine co-existing neurons out of the total numbers of CR- and GABA-LI neurons or CR- and glycine-LI neurons were 5.8% and 7.6% or 4.4% and 7.1%, respectively. The rates of PV/GABA or PV/glycine co-localized neurons out of the total numbers of PV- and GABA-LI neurons or PV- and glycine-LI neurons were 11.1% and 5.1% or 9.9% and 5.1%, respectively. Conclusion The results indicate that some neurons in the MDH contain both CaBPs and GABA or glycine.

关键词： aminobutyric acid glycine calcium-binding proteins rats

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