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Microglia-Derived NLRP3 Activation Mediates the Pressor Effect of Prorenin in the Rostral Ventrolateral Medulla of Stress-Induced Hypertensive Rats

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Neuroscience Bulletin 2020年第5期36卷 475-492页

作者： Li Hu Shutian Zhang Kokwin Ooi Xuehai Wu Jiaxiang Wu Jian Cai Yinggang Sun Jijiang Wang Danian Zhu Fuxue Chen Chunmei Xia laboratory of neuropharmacology and Neurotoxicology Shanghai Key Laboratory of Bio-Energy CropsCollege of Life ScienceShanghai UniversityShanghai 200444China department of physiology and Pathophysiology Basic Medicine CollegeFudan UniversityShanghai 200032China department of Neurosurgery Huashan HospitalFudan UniversityShanghai 200040China department of Neurology Renji HospitalShanghai Jiaotong UniversityShanghai 200240China department of Cardiovascular Diseases Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

Increased microglial activation and neuroinflammation within autonomic brain regions such as the rostral ventrolateral medulla(RVLM)have been implicated in stress-induced hypertension(SIH).Prorenin,a member of the brain renin-angiotensin system(RAS),can directly activate microglia.The present study aimed to investigate the effects of prorenin on microglial activation in the RVLM of SIH rats.Rats were subjected to intermittent electric foot-shocks plus noise,this stress was administered for 2 h twice daily for 15 consecutive days,and mean arterial pressure(MAP)and renal sympathetic nerve activity(RSNA)were monitored.The results showed that MAP and RSNA were augmented,and this paralleled increased pro-inflammatory phenotype(M1)switching.Prorenin and its receptor(PRR)expression and the NLR family pyrin domain containing 3(NLRP3)activation were increased in RVLM of SIH rats.In addition,PLX5622(a microglial depletion agent),MCC950(a NLRP3 inhibitor),and/or PRO20(a(Pro)renin receptor antagonist)had antihypertensive effects in the rats.The NLRP3 expression in the RVLM was decreased in SIH rats treated with PLX5622.Mito-tracker staining showed translocation of NLRP3 from mitochondria to the cytoplasm in proreninstimulated microglia.Prorenin increased the ROS-triggering M1 phenotype-switching and NLRP3 activation,while MCC950 decreased the M1 polarization.In conclusion,upregulated prorenin in the RVLM may be involved in the pathogenesis of SIH,mediated by activation of the microglia-derived NLRP3 inflammasome.The link between prorenin and NLRP3 in microglia provides insights for the treatment of stress-related hypertension.

关键词： Stress NLRP3 Prorenin Microglia Hypertension

Effects of aqueous leaf extract of Tridax procumbens on contractile activity of corpus cavernosum in N-nitro-L-arginine methyl ester-induced hypertensive male rats

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Journal of Integrative Medicine 2018年第1期16卷 51-56页

作者： Shakiru Ademola Salami Hussein Mofomosara Salahdeen Evangelshane Chukwudubem Ugbebor Babatunde Adekunle Murtala Yinusa Raji department of physiology Lagos State University College of Medicine laboratory for Reproductive physiology and Developmental Programming Department of Physiology University of Ibadan

Objective： This study investigated the effects of aqueous leaf extract of Tridax procumbens （ALETP） on con- tractile activity of corpus cavernosum in N-nitro-L-arginine methyl ester （L-NAME）-induced hypertensive male rats. Methods： Twenty normal, adult male rats （130-150 g） were divided into four groups of five rats each. Group I （control） was given normal saline （0.6 mL/kg） and group II was given L-NAME （40 mg/kg） for 6 weeks. Groups Ill and IV also received L-NAME （40 mg/kg） for 6 weeks but were further co-treated with 100 and 200 mg/kg of ALETP, respectively, from week 4 to week 6. All treatments were given orally. Strips of corpus cavernosum from each of the four groups were exposed to increasing concentrations of acetyl~ choline （ACh） and sodium nitroprusside （SNP）（10^-9-10^-5 tool/L） after contraction with phenylephrine （10^-7 mol/L） to test for a dose-response effect, Response to potassium and calcium was also measured after cumulatively adding potassium and calcium （10-50 mmol/L） to potassium- and calcium-free organ chamber. Isometric contractions were recorded through an Ugo Basile data capsule acquisition system. Results： Mean arterial blood pressure was significantly reduced in the ALETP co-treated group compared to the control and L-NAME-only groups （P 〈 0.05）. Cavernosa strips from ALETP co-treated rats exhibited significant inhibition of contraction in response to phenylephrine, potassium chloride, and calcium chlo- ride （P 〈 0.05）. Relaxation in response to Ach and SNP was also significantly impaired in cavernosa strips from the L-NAME-only treated group （P 〈 0.05）, while ALETP co-treated groups showed enhanced per- centage relaxation. Conclusion： ALETP treatment of L-NAME-induced hypertensive rats promotes a relaxant effect on isolated cavernosa strips. ALETP shows potential in correcting erectile dysfunction in hypertension.

关键词： N-Nitro-L-arginine methyl ester Hypertensive Tridax procumbens Corpus cavernosum Relaxation Sodium nitroprusside Acetylcholine

Perspectives for the association between olfactory disturbances and depression in Parkinson's disease

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Neural Regeneration Research 2019年第4期14卷 591-592页

作者： Jessica L.Ilkiw Marcelo M.S.Lima Neurophysiology laboratory Department of PhysiologyFederal University of Paraná

Non-motor disturbances in Parkinson’s disease:Globally,population aged 60 or over is growing and considering the World Bank predictions for the next 20 years it is expected that the number of Parkinson’s disease(PD)cases will double at the end of this period thus,reaching an impressive 13–39 million patients worldwide.This scenario is potentially associated with a significant global negative impact on public health systems particularly in countries with increased ageing populations such as the European countries,Asia and Americas.The pathophysiology of PD involves the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta(SNpc)that triggers denervation of the nigrostriatal pathway and consequent significant reduction of dopamine in the dorsal striatum.Such process leads to a critical motor impairment scenario characterized by bradykinesia,rigidity,resting tremor,and postural instability(Emamzadeh and Surguchov,2018).However,several other non-motor disturbances develop earlier,thus,being considered as prodromal signs of the neurodegeneration.In this sense,the literature is increasingly emphasizing the importance of investigating mood and olfactory disruptions as high sensitive benchmarks of the early-phase disease.In fact,the need for innovative early-phase diagnostic tools,as well as the elucidation of the pathophysiological mechanisms of such disturbances,is essential priority in the field of investigation of PD.Remarkably,in the year of 2015,a woman was known for an intriguing ability of“smell PD”.Her husband had lived with the disease for twenty years and during this process she noticed that his odor slowly changed to a musky smell.Interestingly,this woman could associate this particular smell with PD after meeting different people with this distinct odor in a charity for PD patients.In fact,this clever observation is aligned with studies showing that hyposmia is found decades before the motor onset.Another type of anecdotal story,frequently reported by the patients,is the often

关键词： Parkinson olfactory disturbances association

Animal toxins： From molecules to physiology perspectives

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生理学报 2015年第3期67卷 237-238页

作者： TAO Jie JI Yong-Hua laboratory of neuropharmacology and Neurotoxicology Shanghai University Shanghai 200444 China department of Nephrology Putuo Hospital Shanghai University of Traditional Chinese Medicine Shanghai 200062 China department of Pharmacology School of Pharmacy Fudan University Shanghai 201203 China

As is known to all,venomous animals are really a threat to people's life a few decades ago.However,with the emergence of novel scientific discoveries,concepts and technologies,the consideration of these animals moved ... 详细信息

关键词：动物现代医学毒性医学研究

Enhancement of endogenous midbrain neurogenesis by microneurotrophin BNN-20 after neural progenitor grafting in a mouse model of nigral degeneration

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Neural Regeneration Research 2024年第6期19卷 1318-1324页

作者： Theodora Mourtzi Nasia Antoniou Christina Dimitriou Panagiotis Gkaravelas Georgia Athanasopoulou Panagiota Nti Kostantzo Olga Stathi Efthymia Theodorou Maria Anesti Rebecca Matsas Fevronia Angelatou Georgia Kouroupi Ilias Kazanis laboratory of Developmental Biology Department of Biology University of Patras laboratory of Cellular and Molecular Neurobiology-Stem Cells Hellenic Pasteur Institute 3. Department of Physiology School of Medicine University of Patras

We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the “weaver” mouse, a model of progressive nigrostriatal degeneration. Here, we extended our investigation in two clinically-relevant ways. First, we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors. Second, we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice, at late stages of degeneration. We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells, marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors. In agreement, we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice. However, the graft strongly induced an endogenous neurogenic response throughout the midbrain, which was significantly enhanced by the administration of microneurotrophin BNN-20. Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20. Interestingly, the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect.

关键词： adult neurogenesis BNN-20 brain-derived neurotrophic factor cell replacement induced pluripotent stem cells (iPSCs) neurotrophic factors Parkinson’s disease substantia

Exploring the obscure profiles of pharmacological binding sites on voltage-gated sodium channels by BmK neurotoxins

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Protein & Cell 2011年第6期2卷 437-444页

作者： Zhi-Rui Liu Pin Ye Yong-Hua Ji laboratory of neuropharmacology and Neurotoxicology Shanghai UniversityShanghai 200444China

Diverse subtypes of voltage-gated sodium channels(VGSCs)have been found throughout tissues of the brain,muscles and the heart.Neurotoxins extracted from the venom of the Asian scorpion Buthus martensi Karsch(BmK)act as sodium channel-specific modulators and have therefore been widely used to study VGSCs.α-type neurotoxins,named BmK I,BmKαIV and BmK abT,bind to receptor site-3 on VGSCs and can strongly prolong the inactivation phase of VGSCs.In contrast,β-type neurotoxins,named BmK AS,BmK AS-1,BmK IT and BmK IT2,occupy receptor site-4 on VGSCs and can suppress peak currents and hyperpolarize the activation kinetics of sodium channels.Accumulating evidence from binding assays of scorpion neurotoxins on VGSCs,however,indicate that pharmacological sensitivity of VGSC subtypes to different modulators is much more complex than that suggested by the simpleα-type and β-type neurotoxin distinction.Exploring the mechanisms of possible dynamic interactions between site 3-/4-specific modulators and region-and/or speciesspecific subtypes of VGSCs would therefore greatly expand our understanding of the physiological and pharmacological properties of diverse VGSCs.In this review,we discuss the pharmacological and structural diversity of VGSCs as revealed by studies exploring the binding properties and cross-competitive binding of site 3-or site 4-specific modulators in VGSC subtypes in synaptosomes from distinct tissues of diverse species.

关键词： voltage-gated sodium channel receptor sites scorpion neurotoxins

Correlation of Ferroptosis and Other Types of Cell Death in Neurodegenerative Diseases

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Neuroscience Bulletin 2022年第8期38卷 938-952页

作者： Xiaoting Dang Xuejie Huan Xixun Du Xi Chen Mingxia Bi Chunling Yan Qian Jiao Hong Jiang department of physiology Shandong Provincial Key Laboratory of PathogenesisPrevention of Neurological DisordersState Key Disciplines:PhysiologySchool of Basic MedicineQingdao UniversityQingdao266071China

Ferroptosis is defined as an iron-dependent,non-apoptotic cell death pathway,with specific morphological phenotypes and biochemical changes.There is a growing realization that ferroptosis has significant implications for several neurodegenerative diseases.Even though ferroptosis is different from other forms of programmed death such as apoptosis and autophagic death,they involve a number of common protein molecules.This review focuses on current research on ferroptosis and summarizes the cross-talk among ferroptosis,apoptosis,and autophagy that are implicated in neurodegenerative diseases.We hope that this information provides new ideas for understanding the mechanisms and searching for potential therapeutic approaches and prevention of neurodegenerative diseases.

关键词： Ferroptosis Apoptosis Autophagic death Neurodegenerative diseases

Crotonylation of PRKACA enhances PKA activity and promotes colorectal cancer development via the PKA-FAK-AKT pathway

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Genes & Diseases 2023年第2期10卷 332-335页

作者： Jia-Yi Hou Li-Juan Gao Jing Shen Lan Zhou Jian-Yun Shi Teng Sun Shu-Lan Hao De-Ping Wang Ji-Min Cao Key laboratory of Cellular physiology at Shanxi Medical University Ministry of EducationKey Laboratory of Cellular Physiology of Shanxi Provinceand the Department of PhysiologyShanxi Medical UniversityTaiyuanShanxi 030001China department of Clinical laboratory Shanxi Provincial Academy of Traditional Chinese MedicineTaiyuanShanxi 030012China Oncology department Shanxi Provincial Academy of Traditional Chinese MedicineTaiyuanShanxi 030012China

Colorectal cancer (CRC) is a common cancer with high morbidity and mortality.1 Post-translational modification (PTM) of protein plays an important role in the pathogenesis of CRC. Lysine crotonylation (Kcr) is an important type of PTM and has been proved evolutionarily conserved in eukaryotic cells from a wide range of species.2 However, the role of protein Kcr in the progression of CRC is unclear.

关键词： cancer mortality colorectal

Platinum nanoparticles promote breast cancer cell metastasis by disrupting endothelial barrier and inducing intravasation and extravasation

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Nano Research 2022年第8期15卷 7366-7377页

作者： De-Ping Wang Jing Shen Chuan-Yue Qin Yong-Mei Li Li-Juan Gao Jian Zheng Yan-Lin Feng Zi Yan Xin Zhou Ji-Min Cao Key laboratory of Cellular physiology at Shanxi Medical University Ministry of Educationand the Department of PhysiologyShanxi Medical UniversityTaiyuan 030001China department of Medical Imaging Shanxi Medical UniversityTaiyuan 030001China

Breast cancer is a common malignancy in women with disappointing prognosis especially the triple-negative subtype.Recently,nanomedicine becomes a promising therapeutic strategy for breast cancer,such as platinum nanoparticles(PtNPs).Despite the promising anticancer effects of PtNPs,the safety of PtNPs remains to be fully evaluated.Herein,a series of cell and animal experiments demonstrate that PtNPs facilitate breast cancer metastasis by damaging the vascular endothelial barrier.PtNPs disrupt endothelial cell proliferation,migration and tube-like structure formation,destruct endothelial adhesions junctions and induce endothelial barrier leakiness in vitro most likely by stimulating intracellular reactive oxygen species(ROS)generation and altering the expression and conformation of endothelial junctional proteins,thus promoting intravasation and extravasation of the implanted 4T1 breast cancer cells and leading to cancer metastasis in female BALB/c nude mice in vivo.In addition,smaller PtNPs(5 nm)are more potent than larger PtNPs(70 nm)in exerting the above effects.The study provides the first evidence that PtNPs can promote breast cancer metastasis by damaging endothelial barrier.The unexpected detrimental effects of PtNPs should be considered in future nanomedicine designs for the treatment of breast cancer.

关键词： platinum nanoparticle endothelium cell junction breast cancer metastasis