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Targeting Epac2 and GluA3-containing AMPARs:a novel therapeutic strategy for Alzheimer's disease

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Neural Regeneration Research 2025年第11期20卷 3223-3224页

作者： Tong Zhang Martina Schmidt Department of molecular pharmacology Groningen Research Institute of PharmacyUniversity of GroningenGroningenThe Netherlands School of Pharmacy Tianjin Medical UniversityTianjinChina

Alzheimer's disease(AD)is a neurodegenerative disease that manifests progressive decline in memory and *** the early stage of AD,memory retrieval is impaired preceding memory acquisition and consolidation(Roy et al.,2016).Prior to the onset of symptoms,pathological amyloid-β(Aβ)plagues and tau protein tangles accumulate in extracellular and intracellular spaces,respectively,leading to *** these hallmark pathologies,Aβ is proposed to be the primary etiology by triggering a cascade of pathogenic events,including neuroinflammation,oxidative stress,tau hyperphosphorylation,synaptic/neuronal dysfunction,and neuronal death(Zhang et al.,2023b).

关键词： Alzheimer impaired Aβ

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

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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

A Network pharmacology Study to Uncover the Multiple molecular Mechanism of the Chinese Patent Medicine Toujiequwen Granules in the Treatment of Corona Virus Disease 2019(COVID-19)

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Current Medical Science 2021年第2期41卷 297-305页

作者： Bao-yu YANG Hao-zhen WANG Zhen zhong MA Chen LU Yang LI Zi-yin LU Xiu-li LU Bing GAO Department of Biochemistry and molecular biology Life Science SchoolLiaoning UniversityShenyang 110036China Department of Cell biology and Genetics Shenyang Medical CollegeShenyang 110034China

Since the outbreak of the novel corona virus disease 2019(COVID-19)at the end of 2019,specific antiviral drugs have been lacking.A Chinese patent medicine Toujiequwen granules has been promoted in the treatment of *** present study was designed to reveal the molecular mechanism of Toujiequwen granules against COVID-19.A network pharmacological method was applied to screen the main active ingredients of Toujiequwen *** analysis of 149 active ingredients and 330 drug targets showed the most active ingredient interacting with many drug targets is *** targets most ffected by the active ingredients were PTGS2,PTGS1,and *** target disease enrichment analysis showed drug targets were significantly enriched in cardiovascular diseases and digestive tract ***"active ingredient-target-disease"network showed that 57 active ingredients from Toujiequwen granules interacted with 15 key targets of *** were 53 ingredients that could act on DPP4,suggesting that DPP4 may become a potential new key target for the treatment of *** analysis results showed that key targets were mainly enriched in the cellular response to lipopolysaccharide,cytokine activity and other *** analysis showed they were mainly concentrated in viral protein interaction with cytokine and cytokine receptors and endocrine resistance *** evidence suggests that Toujiequwen granules might play an effective role by improving the symptoms of underlying diseases in patients with COVID-19 and multi-target interventions against mutiple signaling pathways related to the pathogenesis of COVID-19.

关键词： Toujiequwen granules COVID-19 network pharmacology target molecular mechanism

Effect of herpesvirus infection on pancreatic duct cell secretion

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World Journal of Gastroenterology 2005年第38期11卷 5997-6002页

作者： Péter Hegyi Balázs rdg Zoltán Rakonczai Jr Tamás Takács János Lonovics Annamária Szabolcs Réka Sári András Tóth Julius G Papp András Varró Mária K Kovács Mike A Gray Barry E Argent Zsolt Boldogki First Department of Medicine Department of biology Division of Cardiovascular pharmacology School of Cell and molecular Biosciences

AIM： To examine the effect of acute infection caused by herpesvirus （pseudorabies virus, PRV） on pancreatic ductal secretion. METHODS： The virulent Ba-DupGreen （BDG） and non- virulent Ka-RREp01acgfp （KEG） genetically modified strains of PRV were used in this study and both of them contain the gene for green fluorescent protein （GFP）. Small intra/ interlobular ducts were infected with BDG virus （10^7 PFU/mL for 6 h） or with KEG virus （10^10 PFU/mL for 6 h）, while non-infected ducts were incubated only with the culture media. The ducts were then cultured for a further 18 h. The rate of HCO3 secretion [base efflux -λ（B）] was determined from the buffering capacity of the cells and the initial rate of intracellular acidification （1） after sudden blockage of basolateral base loaders with dihydro-4,4,- diisothiocyanatostilbene-2,2,-disulfonic acid （500 μmol/L） and amiloride （200 μmol/L）, and （2） after alkali loading the ducts by exposure to NH4Cl. All the experiments were performed in HCO3-buffered Ringer solution at 37 ℃ （n = 5 ducts for each experimental condition）. Viral structural proteins were visualized by immunohistochemistry. Virallyencoded GFP and immunofluorescence signals were recorded by a confocal laser scanning microscope.RESULTS： The BDG virus infected the majority of accessible cells of the duct as judged by the appearance of GFP and viral anUgens in the ductal cells. KEG virus caused a similarly high efficiency of infection. After blockage of basolateral base loaders, BDG infection significantly elevated -λB-） 24 h after the infection, compared to the non-infected group. However, KEG infection did not modify -λB-）. After alkali loading the ducts, -λB-） was significantly elevated in the BDG group compared to the control group 24 h after the infection. As we found with the inhibitor stop method, no change was observed in the group KEG compared to the non-infected group. CONCLUSION： Incubation with the BDG or KEG strains of PRV results in an effective i

关键词： Pancreas Hypersecretion Ductal cells Infection Pseudorabies virus

Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis

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World Journal of Gastroenterology 2015年第30期21卷 9021-9037页

作者： Juliana Carvalho Santos Marcelo Lima Ribeiro Sao Francisco University Medical School Clinical pharmacology and Gastroenterology Unit Laboratory of Microbiology and molecular biology UNICAMP Universidade Estadual de CampinasGenetics and Molecular Biology

Although thousands of DNA damaging events occur in each cell every day,efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoiding the maintenance of mutations. The DNA repair enzymes continuously monitor the chromosomes to correct any damage that is caused by exogenous and endogenous mutagens. If DNA damage in proliferating cells is not repaired because of an inadequate expression of DNA repair genes,it might increase the risk of cancer. In addition to mutations,which can be either inherited or somatically acquired,epigenetic silencing of DNA repair genes has been associated with carcinogenesis. Gastric cancer represents the second highest cause of cancer mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes during the lifetime. Among the risk factors,Helicobacter pylori(H. pylori) infection is considered the main driving factor to gastric cancer development. Thus,in this review,we summarize the current knowledge of the role of H. pylori infection on the epigenetic regulation of DNA repair machinery in gastric carcinogenesis.

关键词： Helicobacter pylori DNA repair Epigenetic DNA methylation Gastric cancer Histone modification

Can leukocyte telomere shortening be a possible biomarker to track Huntington’s disease progression?

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Neural Regeneration Research 2019年第10期14卷 1709-1710页

作者： Elide Mantuano Martina Peconi Daniela Scarabino CNR Institute of Translational pharmacology RomeItaly CNR Institute of molecular biology and Pathology Rome Italy

Huntington's disease (HD): HD is an autosomal dominant neurodegenerative disease, caused by a CAG trinucleotide repeat expansion in the first exon of the HTT gene encoding the huntingtin protein. The mutant protein contains an expanded polyglutamine sequence that confers a toxic gain-of-function and causes neurodegeneration. Moreover, several studies indicate that loss of the normal protein beneficial functions, contribute to the pathology (Schulte and Littleton 2011). Triplet expansion over 40 repeats are fully penetrant and invariably lead to manifest HD in the fourth or fifth decade of life.

关键词： Huntington's disease(HD) neurodegenerative disease fifth decade of life

Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis,learning,and memory in a mouse model of Alzheimer’s disease

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Neural Regeneration Research 2025年第10期20卷 2969-2981页

作者： Mackenzie M.Spicer Jianqi Yang Daniel Fu Alison N.DeVore Marisol Lauffer Nilufer S.Atasoy Deniz Atasoy Rory A.Fisher Department of Neuroscience and pharmacology University of Iowa Carver College of MedicineIowa CityIAUSA Iowa Neuroscience Institute University of Iowa Carver College of MedicineIowa CityIAUSA Interdisciplinary Graduate Program in molecular Medicine University of Iowa Carver College of MedicineIowa CityIAUSA Neural Circuits and Behavior Core University of Iowa Carver College of MedicineIowa CityIAUSA

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s *** hippocampal neurogenesis is reduced in patients with Alzheimer’s *** stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s ***,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly ***,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in ***,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse *** found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control *** cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal *** hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor ***6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing ***,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

关键词： adult hippocampal neurogenesis Alzheimer’s disease dentate gyrus exercise learning/memory neural precursor cells regulator of G protein signaling 6(RGS6)

Hyperglycemia in acute ischemic stroke: physiopathological and therapeutic complexity

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Neural Regeneration Research 2022年第2期17卷 292-299页

作者： Federica Ferrari Antonio Moretti Roberto Federico Villa Department of biology and Biotechnology Laboratory of Pharmacology and Molecular Medicine of Central Nervous SystemUniversity of PaviaVia FerrataPaviaItaly

Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in these conditions and after the administration of the currently approved pharmacological treatment, i.e. insulin. The disappointing results of the clinical trials on insulin(including the hypoglycemic events) demand a change of strategy based on more focused therapies. Starting from the comprehensive evaluation of the physiopathological alterations occurring in the ischemic brain during hyperglycemic conditions, the effects of various classes of glucose-lowering drugs are reviewed, such as glucose-like peptide-1 receptor agonists, DPP-4 inhibitors and sodium glucose cotransporter 2 inhibitors, in the perspective of overcoming the up-to-date limitations and of evaluating the effectiveness of new potential therapeutic strategies.

关键词： acute ischemic stroke diabetes mellitus DPP-4 inhibitor glucose-like peptide-1 receptor agonist hyperglycemia hypoglycemia insulin physiopathology sodium glucose cotransporter 2 inhibitor

In vitro antihistamine-releasing activity of a peptide derived from wasp venom of Vespa orientalis

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Asian Pacific Journal of Tropical Biomedicine 2016年第3期6卷 259-264页

作者： Jafar Jalaei Mehdi Fazeli Hamid Rajaian Somayeh Layeghi Ghalehsoukhteh Alireza Dehghani Dominic Winter Department of pharmacology and Toxicology School of Veterinary Medicine Shiraz University Institute of Biochemistry and molecular biology University of Bonn

Objective: To investigate the antihistamine-releasing effect of a peptide isolated from wasp venom of Vespa ***: This peptide was separated from crude venom by chromatography methods and mass spectrometry. Then various concentrations(2, 4, 8, 16, 32, 64, 128 and256 mmol/L) of the peptide were incubated with mast cells and lactate dehydrogenase assay was ***: No significant effect was observed in lactate dehydrogenase absorbance under128 mmol/L concentration. This implied that the peptide did not cause cell death in mast cells and consequently, histamine release did not happen. Moreover, the results showed the IC50 of mast cells degranulation at 126 mmol/L, which was approximately high implying that this peptide had high selectivity for normal cells and did not cause histamine release from these ***: This would be a great aim in new drug development, in which an agent acts potentially on its target tissue without activating the immune system.

关键词： Vespa orientalis Antihistamine release Lactate dehydrogenase assay Peptide