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Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

Neural Regeneration research 2025年第5期20卷 1258-1276页

作者： Qing Qiu Mengting Yang Danfeng Gong Haiying Liang Tingting Chen Department of Pharmacology School of PharmacyNantong UniversityNantongJiangsu ProvinceChina Jiangsu Province key laboratory of Inflammation and molecular drug Target NantongJiangsu ProvinceChina Department of pharmacy Longyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujian ProvinceChina

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be u

关键词： astrocytes calcium channels central nervous system extracellular ion concentration microglia neurological disorders neurons potassium channels

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Pathogenesis, diagnosis, and treatment of epilepsy: electromagnetic stimulation-mediated neuromodulation therapy and new technologies

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Neural Regeneration research 2025年第4期20卷 917-935页

作者： Dian Jiao Lai Xu Zhen Gu Hua Yan Dingding Shen Xiaosong Gu Academy of Medical Engineering and Translational Medicine Tianjin UniversityTianjinChina key laboratory of Advanced drug Delivery Systems of Zhejiang Province College of Pharmaceutical SciencesZhejiang UniversityHangzhouZhejiang ProvinceChina Affiliated Hospital of Nantong University NantongJiangsu ProvinceChina

Epilepsy is a severe,relapsing,and multifactorial neurological *** regarding the accurate diagnosis,prognosis,and in-depth pathogenesis are crucial for the precise and effective treatment of *** pathogenesis of epilepsy is complex and involves alterations in variables such as gene expression,protein expression,ion channel activity,energy metabolites,and gut microbiota *** results are lacking for conventional treatments for *** resection of lesions,drug therapy,and non-drug interventions are mainly used in clinical practice to treat pain associated with ***-pharmacological treatments,such as a ketogenic diet,gene therapy for nerve regeneration,and neural regulation,are currently areas of research *** review provides a comprehensive overview of the pathogenesis,diagnostic methods,and treatments of *** also elaborates on the theoretical basis,treatment modes,and effects of invasive nerve stimulation in neurotherapy,including percutaneous vagus nerve stimulation,deep brain electrical stimulation,repetitive nerve electrical stimulation,in addition to non-invasive transcranial magnetic stimulation and transcranial direct current *** studies have shown that electromagnetic stimulation-mediated neuromodulation therapy can markedly improve neurological function and reduce the frequency of epileptic ***,many new technologies for the diagnosis and treatment of epilepsy are being ***,current research is mainly focused on analyzing patients’clinical manifestations and exploring relevant diagnostic and treatment methods to study the pathogenesis at a molecular level,which has led to a lack of consensus regarding the mechanisms related to the disease.

关键词： diagnosis drug treatment electroencephalography epilepsy monitoring epilepsy nerve regeneration neurostimulation non-drug interventions pathogenesis prediction

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The dopaminergic system and Alzheimer's disease

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Neural Regeneration research 2025年第9期20卷 2495-2512页

作者： Yuhan Zhang Yuan Liang Yixue Gu International Medical college Chongqing Medical UniversityChongqingChina college of pharmacy Chongqing Medical UniversityChongqingChina Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of NeurologyChongqingChina

Alzheimer's disease is a common neurodegenerative disorder in older *** its prevalence,its pathogenesis remains unclea *** addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this *** is a crucial catecholaminergic neurotransmitter in the human ***-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical *** r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive *** review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related *** aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

关键词： adverse drug reaction Alzheimer's disease catecholamine dopamine receptor dopamine receptor heterodimers dopaminergic system neurodegenerative disease neurotransmitter signaling pathways traditional Chinese medicine treatment

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Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins

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Acta Pharmaceutica Sinica B 2019年第2期9卷 294-303页

作者： Yuan Zhang Zhihua Wang Xiaoyao Ma Shengnan Yang Xueyan Hu Jin Tao Yuanyuan Houn Gang Bai State key laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai University

Members of the RAS proto-oncogene superfamily are indispensable molecular switches that play critical roles in cell proliferation, differentiation, and cell survival. Recent studies have attempted to prevent the interaction of RAS/GTP with RAS guanine nucleotide exchange factors(GEFs), impair RASeffector interactions, and suppress RAS localization to prevent oncogenic signalling. The present study aimed to investigate the effect of the natural triterpenoic acid inhibitor glycyrrhetinic acid, which is isolated from the roots of Glycyrrhiza plant species, on RAS stability. We found that glycyrrhetinic acid may bind to the P-loop of RAS and alter its stability. Based on our biochemical tests and structural analysis results, glycyrrhetinic acid induced a conformational change in RAS. Meanwhile, glycyrrhetinic acid abolishes the function of RAS by interfering with the effector protein RAF kinase activation and RAS/MAPK signalling.

关键词： Glycyrrhetinic acid RAS Allosteric inhibitor RAS/MAPK signalling

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A temperature-regulated bioorthogonal reaction to target lysine:Hemiacetal pharmacophore in genipin irreversibly binds with UCP2,inhibiting mitochondrial thermogenesis

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Chinese Chemical Letters 2023年第10期34卷 191-196页

作者： Fukui Shen Wen Yang Kaixue Zhang Yanting Jiao Jing Cui Yuanyuan Hou Gang Bai State key laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300353China

Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegenerative diseases, and other disorders. Uncoupling protein 2(UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin(GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ?-amine of lysine on the UCP2 proton leakage channel through ringopening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ?-amine of lysine on proteins.

关键词： Bioorthogonal reaction Mitochondria Genipin UCP2 Irreversible binding

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Chemical proteomics combined with metabonomics reveals berberine targets NDUFV1 of complex Ⅰ in the respiratory chain to regulate energy metabolism

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Chinese Chemical Letters 2023年第3期34卷 419-423页

作者： Xiaoyao Ma Yiman Han Kaixin Liu Yongping Bai He Gao Yuanyuan Hou Gang Bai State key laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300381China

Berberine(BBR) is the primary alkaloid compound of the heat-clearing traditional Chinese medicine Huanglian(Coptis chinensis) and exerts regulatory effects on energy metabolism. However, the specific targets and molecular mechanisms are not clear. In this paper, the BBR-affected energy metabolism pathway was screened by nontargeted metabolomics, and a BBR-derived photoaffinity labeled(PAL) probe was designed to identify potential targets via a chemical proteomics approach. NDUFV1, a subunit of complex Ⅰ on mitochondria, was identified as a potential target of BBR. In the respiratory chain, BBR suppressed the activity of complex Ⅰ, reduced the electrochemical potential in the mitochondrial intermembrane and inhibited the generation of ATP and heat via competitive binding with NDUFV1. The results illustrated the underlying mechanism of BBR in the downregulation of energy metabolism.

关键词： Berberine Photoaffinity labeled Chemical proteomics NDUFV1 ComplexⅠ Energy metabolism

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Qingfei Xiaoyan Wan,a traditional Chinese medicine formula, ameliorates Pseudomonas aeruginosa–induced acute lung inflammation by regulation of PI3K/AKT and Ras/MAPK pathways

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Acta Pharmaceutica Sinica B 2016年第3期6卷 212-221页

作者： Yuanyuan Hou Yan Nie Binfeng Cheng Jin Tao Xiaoyao Ma Min Jiang Jie Gao Gang Bai State key laboratory of Medicinal Chemical Biology and college of pharmacy Nankai University tianjin key laboratory of molecular drug research Nankai University

Gram-negative pathogen–induced nosocomial infections and resistance are a most serious menace to global public health. Qingfei Xiaoyan Wan(QF), a traditional Chinese medicine(TCM)formula, has been used clinically in China for the treatment of upper respiratory tract infections, acute or chronic bronchitis and pulmonary infection. In this study, the effects of QF on Pseudomonas aeruginosa–induced acute pneumonia in mice were evaluated. The mechanisms by which four typical antiinflammatory ingredients from QF, arctigenin(ATG), cholic acid(CLA), chlorogenic acid(CGA) and sinapic acid(SPA), regulate anti-inflammatory signaling pathways and related targets were investigated using molecular biology and molecular docking techniques. The results showed that pretreatment with QF significantly inhibits the release of cytokines(TNF-α and IL-6) and chemokines(IL-8 and RANTES),reduces leukocytes recruitment into inflamed tissues and ameliorates pulmonary edema and necrosis. In addition, ATG was identified as the primary anti-inflammatory agent with action on the PI3K/AKT and Ras/MAPK pathways. CLA and CGA enhanced the actions of ATG and exhibited synergistic NF-κB inactivation effects possibly via the Ras/MAPK signaling pathway. Moreover, CLA is speculated to target FGFR and MEK firstly. Overall, QF regulated the PI3K/AKT and Ras/MAPK pathways to inhibit pathogenic bacterial infections effectively.

关键词： Anti-inflammatory Network pharmacology Pathogenic bacterial infection PI3K/AKT pathway Ras/MAPK pathway Lung Mouse

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SrCl_2 as an efficient cocatalyst for acidic hydrolysis of methyl glycosides

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Chinese Chemical Letters 2014年第4期25卷 561-566页

作者： Yong-Heng Ya-Fei Xie Yu-Qiang Liu Qun-Chao Wei Li-Da Tang Wei-Ren Xu Li-Da Tang Gui-Long Zhao School of pharmacy Tianjin Medical University tianjin key laboratory of molecular Design and drug Discovery Tianjin Institute of Pharmaceutical Research

SrCl2 was found to be the most efficient cocatalyst for the acidic hydrolysis of methyl glycosides after 26 kinds of most representative metal salts were screened. The SrCl2-cocatalyzed acidic hydrolysis of methyl glycosides is highlighted by short reaction times, less byproducts and high yields. A possible mechanism for the SrCl2-cocatalyzed hydrolysis is also proposed.

关键词： Cocatalyst Hydrolysis Lewis acid Methyl glycoside Strontium chloride

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Atractylenolide-I covalently binds to CYP11B2,selectively inhibits aldosterone synthesis, and improves hyperaldosteronism

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Acta Pharmaceutica Sinica B 2022年第1期12卷 135-148页

作者： Wenjuan Liu Zhenqiang Li Simeng Chu Xiaoyao Ma Xiaoying Wang Min Jiang Gang Bai State key laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300353China tianjin University of Traditional Chinese Medicine Tianjin 300193China

Hyperaldosteronism is a common disease that is closely related to endocrine hypertension and other cardiovascular diseases. Cytochrome P450 11 B2(CYP11 B2), an important enzyme in aldosterone(ALD) synthesis, is a promising target for the treatment of hyperaldosteronism. However, selective inhibitors targeting CYP11 B2 are still lacking due to the high similarity with CYP11 B1. In this study,atractylenolide-I(AT-I) was found to significantly reduce the production of ALD but had no effect on cortisol synthesis, which is catalyzed by CYP11 B1. Chemical biology studies revealed that due to the presence of Ala320, AT-I is selectively bound to the catalytic pocket of CYP11 B2, and the C8/C9 double bond of AT-I can be epoxidized, which then undergoes nucleophilic addition with the sulfhydryl group of Cys450 in CYP11 B2. The covalent binding of AT-I disrupts the interaction between heme and CYP11 B2 and inactivates CYP11 B2, leading to the suppression of ALD synthesis;AT-I shows a significant therapeutic effect for improving hyperaldosteronism.

关键词： Aldosterone CYP11B2 Hyperaldosteronism Atractylenolide-I Selective inhibitor

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A practical synthesis of β-carbolines by tetra-n-butylammonium bromide (TBAB)-mediated cycloaromatization reaction of aldehydes with tryptophan derivatives

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Chinese Chemical Letters 2019年第8期30卷 1541-1544页

作者： Zhen Wang Zhenzhen Yu Yao Yao Yakai Zhang Xuefeng Xiao Bin Wang college of pharmacy and tianjin key laboratory of molecular drug research Nankai UniversityTianjin 300353China tianjin University of Traditional Chinese Medicine Tianjin 300193China

A mild and efficient n Bu4 NBr-mediated oxidative cycloaromatization to prepareβ-carbolines from readily available tryptophans and aldehydes is *** reaction is practical and allows the synthesis ofβ-carbolines on *** of products crystallized from the reaction mixture and were easily removed by filtration,obviating the need for chromatographic separation.

关键词： Carbolines Tryptophan Cycloaromatization TBAB Tetra-n-butylammonium bromide

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