ADVANCED FUNCTIONAL MATERIALS
·
2021
·Vol. 31
·期 19
·2010757
·
IF 18.808
Boying Li,Yiying Wang,Dong Gao,Shuxi Ren,Li Li,Ning Li,Hailong An,Tiantian Zhu,Yakun Yang,Hailin Zhang,Chengfen Xing
Considering recent breakthroughs in the field of optogenetics, a powerful tool is established in the present study to modulate the activities of target neurons through the application of light-based methods. Near-infrared (NIR) light enables the penetration of deep-tissue. As a result, it can be used to modulate the functions of proteins/cells. Herein, it is aimed to develop a NIR light-sensitive drug delivery system to spatially and temporally control the activation of the loaded drug at the stimulation sites through its release from a nanoparticle sensitive to NIR. Owing to their excellent photothermal effect under NIR irradiation, the nanoparticles are found to penetrate the blood-brain barrier effectively, ultimately reaching neurons. Furthermore, by loading fasudil, a selective activator of the Kv7.4 potassium channel, into the precisely designed and synthesized NIR light-sensitive nanoparticles, the firing frequency of dopaminergic neurons in the ventral tegmental area is found to be remarkably reduced upon NIR light irradiation. Such findings shed light on a new concept that can be used for developing more selective drug therapies for the treatment of diseases, such as major depression.
研究领域:
神经科学
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药理学
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生物医学工程
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DOI
高影响因子
ANALYTICA CHIMICA ACTA
·
2021
·
IF 6.558
Qi Liu,Shushu Ding,Rui Gao,Guoyue Shi,Anwei Zhu
ATP-sensitive potassium (K ATP ) channels couple intracellular metabolism to the electrical activity by regulating K + flux across the plasma membrane, thus playing an important role in both normal and pathophysiology. To understand the mechanism of ATP regulating biological ion channels, developing an ATP-responsive artificial nanochannel is an appealing but challenging topic because K ATP channel is a heteromultimer of two subunits (potassium channel subunit (Kir6.x) and sulfonylurea receptor (SUR)) and exhibit dynamic functions with adjustability and reversibility. Inspired by the structure of K ATP channels, we designed a smart copolymer modified nanochannel that may address the challenge. In the tricomponent poly( N -isopropylacrylamide) (PNIPAAm, PNI)-based copolymer system, phenylthiourea was used to bind the phosphate units of nucleotides and phenylboronic acid was introduced to combine the pentose ring of the nucleoside unit. Besides, a –COOH group with electron-withdrawing property was added into the phenylthiourea units, which may promote the hydrogen-bond-donating ability of thiourea . Specially, the smart copolymer not only provided static binding sites for recognition but also translated the recognition of ATP into their dynamic conformational transitions by changing the hydrogen-bonding environments surrounding PNIPAAm chains, thus achieving the gating function of nanochannel, which resembled the integration and coordination of Kir6.x and SUR units in active K ATP . The ATP-regulated ion channel exhibited excellent stability and reversibility. This study is the first example showing how to learn from nature to assemble the ATP-responsive artificial nanochannel and demonstrate the possible mechanism of ATP gating.
研究领域:
生物化学
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材料科学
·
分子生物学
✓ 已验证
DOI
高影响因子
Oxidative Medicine and Cellular Longevity
·
2016
·
IF 4.492
Zhuo Fan,Ting Wen,Yaoxu Chen,Lijie Huang,Wei Lin,Chunxia Yin,Wen Tan
channel is an important mediator or factor in physiological and pathological metabolic pathway. Activation of channel has been identified to be a critical step in the cardioprotective mechanism against IR injury. On the other hand, desensitization of the channel to its opener or the metabolic ligand ATP in pathological conditions, like cardiac hypertrophy, would decrease the adaption of myocardium to metabolic stress and is a disadvantage for drug therapy. Isosteviol, obtained by acid hydrolysis of stevioside, has been demonstrated to play a cardioprotective role against diseases of cardiovascular system, like anti-IR injury, antihypertension, antihyperglycemia, and so forth. The present study investigated the effect of isosteviol (STV) on sarc channel current induced by pinacidil and mitochondrial flavoprotein oxidation induced by diazoxide. Our results showed that preincubating cells with STV not only increased the current amplitude and activating rate of sarc channels induced by pinacidil but also potentiated diazoxide-elicited oxidation of flavoprotein in mitochondria.
研究领域:
药理学
·
心血管生理学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2022
·
IF 8.008
Yuxian Liao,Ting Jing,Fan Zhang,Pingang He
The expression of potassium channels can be related to the occurrence and development of tumors. Their change would affect K+ outflow. Thus, in situ monitoring of extracellular K+ shows a great significance. Herein, the dual-functional K+ ion-selective electrode as the scanning electrochemical microscopy (SECM) tip (K+-ISE SECM tip) has been developed for in situ monitoring of the extracellular K+. Based on multi-wall carbon nanotubes as a transduction layer, the K+-ISE SECM tip realizes both the plotting of approach curves to position the tip for in situ detection and the recording of potential responses. It shows a near Nernstian response, good selectivity, and excellent stability. Based on these characteristics, it was used to in situ monitor K+ concentrations ([K+]o) of three breast cancer cell lines (MCF-7, MDA-MB-231, and SK-BR-3 cells) at 3 μm above the cell, and [K+]o of MDA-MB-231 cells show the highest value, followed by MCF-7 cells and SK-BR-3 cells. K+ outflow induced by electrical stimulation or pH changes of the culture environment (Δ[K+]o) was further determined, and the possible mechanism of K+ outflow was investigated with 4-aminopyridin (4-AP). MCF-7 cells present the largest value of Δ[K+]o, followed by MDA-MB-231 cells and SK-BR-3 cells at all the stimulation potentials, and pH 6.50 shows the greatest impact on K+ outflow of the three cell lines. The pretreatment of 4-AP changed K+ outflow, probably due to the regulation of voltage-gated channels. These findings provide insight into a deep understanding of the microenvironment influence on K+ outflow, thereby reflecting the possible mechanism of potassium channels.
研究领域:
生物化学
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医学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Toxins
·
2020
·Vol. 12
·期 11
·733
·
IF 3.531
Hui-Hui Zhang,Xin-Kai Zhang,Ran-Ran Si,Si-Cheng Shen,Ting-Ting Liang,Ting-Ting Fan,Wei Chen,Lian-Hua Xu,Bing-Nan Han
Since 1970s, aplysiatoxins (ATXs), a class of biologically active dermatoxins, were identified from the marine molluskStylocheilus longicauda, whilst further research indicated that ATXs were originally metabolized by cyanobacteria. So far, there have been 45 aplysiatoxin derivatives discovered from marine cyanobacteria with various geographies. Recently, we isolated two neo-debromoaplysiatoxins, neo-debromoaplysiatoxin G (1) and neo-debromoaplysiatoxin H (2) from the cyanobacteriumLyngbyasp. collected from the South China Sea. The freeze-dried cyanobacterium was extracted with liquid–liquid extraction of organic solvents, and then was subjected to multiple chromatographies to yield neo-debromoaplysiatoxin G (1) (3.6 mg) and neo-debromoaplysiatoxin H (2) (4.3 mg). They were elucidated with spectroscopic methods. Moreover, the brine shrimp toxicity of the aplysiatoxin derivatives representing differential structural classifications indicated that the debromoaplysiatoxin was the most toxic compound (half inhibitory concentration (IC50) value = 0.34 ± 0.036 µM). While neo-aplysiatoxins (neo-ATXs) did not exhibit apparent brine shrimp toxicity, but showed potent blocking action against potassium channel Kv1.5, likewise, compounds1and2with IC50values of 1.79 ± 0.22 µM and 1.46 ± 0.14 µM, respectively. Therefore, much of the current knowledge suggests the ATXs with different structure modifications may modulate multiple cellular signaling processes in animal systems leading to the harmful effects on public health.Keywords:marine cyanobacterium;Lyngbyasp.;aplysiatoxin;Kv1.5 inhibitory activity;brine shrimp toxicityKey Contribution:Two novel aplysiatoxin derivatives were isolated from the marine cyanobacteriumLyngbyasp. Neo-debromoaplysiatoxin G (1) and neo-debromoaplysiatoxin H (2) featuring novel structural skeletons characterized by a bicyclo[2.1.1]tetrahydropyran and unique 5/6 fused-ring systems, respectively. Compounds1and2showed potent blocking action against potassium channel Kv1.5.
研究领域:
海洋生物学
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药理学
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毒理学
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产品关联
DOI
PubMed
高影响因子
PLANTA MEDICA
·
2016
·Vol. 83
·期 07
·624-630
·
IF 1.99
Yi-Lin Zhang,Jia-Wen Xu,Xiong-Hao Wu,Peng-Xiao Chen,Fang Wei,Dong-Dong Gao,Xiao-Wen Chen,Yu-Li Luo,Yun-Xin Zhu,Jiehong Huang,Ya-Xia Tan,Lei Zhao,Wen-Liang Zhou
Sodium tanshinone IIA sulphonate, a water-soluble derivative of tanshinone IIA, has been proven to possess versatile biological properties, but its pharmacological effect on tracheal smooth muscle remains elusive. This paper presents a study on the relaxant effect and underlying mechanisms of sodium tanshinone IIA sulphonate on mouse tracheal smooth muscle. The relaxant effect of sodium tanshinone IIA sulphonate was evaluated in mouse tracheal rings using a mechanical recording system. Intracellular Ca2+ concentration was measured in primary cultured tracheal smooth muscle cells using confocal imaging system. The results showed that sodium tanshinone IIA sulphonate induced dose-dependent relaxation of mouse tracheal rings in a β-adrenoceptor- and epithelium-independent manner. Pretreatment with the ATP-sensitive K+ channel blocker glibenclamide partly attenuated the relaxation response. Administration of sodium tanshinone IIA sulphonate notably inhibited the extracellular Ca2+-induced contraction. High KCl or carbachol-evoked elevation in the intracellular Ca2+ concentration was also abrogated by sodium tanshinone IIA sulphonate in tracheal smooth muscle cells. In conclusion, the tracheal relaxant effect of sodium tanshinone IIA sulphonate was independent of β-adrenoceptor and airway epithelium, mediated primarily by inhibition of extracellular Ca2+ influx via L-type voltage-dependent Ca2+ channels and partially by activation of the ATP-sensitive K+ channel. These results indicate the potential therapeutic value of sodium tanshinone IIA sulphonate for asthma treatment.
研究领域:
药理学
·
呼吸系统研究
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产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2014
·Vol. 387
·期 11
·1079-1089
·
IF 2.36
Zhao Xin,Zhang Kai-ping,Huang Ting,Yan Cai-Chuan,Liu Li-Rong,Zhu Qi-Lei,Guo Feng-Feng,Liu Chen,Li Bao-Xin
Arsenic trioxide (As 2 O 3 ) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As 2 O 3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As 2 O 3 -insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As 2 O 3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As 2 O 3 -caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As 2 O 3 on cardiotoxicity.
研究领域:
药理学
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毒理学
·
心脏病学
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产品关联
DOI
PubMed
高影响因子
Pharmacognosy Magazine
·
2024
·
IF 0.6
Huijuan Yang,Hailong Li,Yuxin Liu,Jinrui Jiang,Mei Hai,Cong Li,Zhiqiang Hu,Ru Zhou
Background: The purpose of this study was to evaluate the effect of 18β-glycyrrhetinic acid (18β-GA) on isolated rat pulmonary artery vascular rings as well as the mechanism that lies behind the diastolic effects of this compound.Methods: To examine the effects of various doses of 18β-GA on resting normal vascular rings, we used isolated rat pulmonary artery vascular rings. The isolated rat pulmonary artery vascular ring was precontracted with phenylephrine (PE) and potassium chloride solution (KCl), which allowed for the observation of the diastolic effects of 18β-GA, as well as the effects of various concentrations of 18β-GA on blocking the four potassium channels of glibenclamide, barium chloride (BaCl2), tetraethylamine (TEA), or 4-aminopyridine; the impact of various 18β-GA concentrations on the pulmonary artery vasodilation effect pre-use of the nitric oxide synthase inhibitors l-nitroarginine methyl ester and indomethacin.Results: It was shown that 18β-GA has concentration-dependent diastolic effects on isolated rat pulmonary vascular rings that have been precontracted with PE and KCl but it has no effect on resting isolated thoracic aortic vascular rings.Conclusion: The two Kir and Kv channels may be connected to the endothelium-dependent vasodilation mechanism of 18β-GA.
研究领域:
药理学
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心血管研究
·
分子生物学
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产品关联
DOI
高影响因子
HIPPOCAMPUS
·
2023
·
IF 3.5
Shicheng Jiang,Bei Liu,Kaiwen Lin,Lianjun Li,Rongrong Li,Shuo Tan,Xinyu Zhang,Lei Jiang,Hong Ni,Yuanyuan Wang,Haihu Ding,Jing Hu,Hao Qian,Rongjing Ge
Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.
研究领域:
神经科学
·
药理学
·
分子生物学
·
遗传学
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2023
·
IF 10
Chaoqun Li,Dong Gao,Yijian Gao,Ran Zhang,Xiongwei Qu,Shengliang Li,Chengfen Xing
Cell fate can be efficiently modulated by switching ion channels. However, the precise regulation of ion channels in cells, especially in specific organelles, remains challenging. Herein, biomimetic second near-infrared (NIR-II) responsive conjugated oligomer nanoparticles with dual-targeted properties are designed and prepared to modulate the ion channels of mitochondria to selectively kill malignant cells in vivo. Upon 1060 nm laser irradiation, the mitochondria-located nanoparticles photothermally release a specific ion inhibitor of the potassium channel via a temperature-sensitive liposome, thus altering the redox balance and pathways of mitochondria. NIR-II responsive nanoparticles can effectively regulate the potassium channels of mitochondria and fully suppress tumor growth. This work provides a new modality based on the NIR-II nanoplatform to regulate ion channels in specific organelles and proposes an effective therapeutic mechanism for malignant tumors.
研究领域:
纳米技术
·
癌症生物学
·
诊疗学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Research
·
2023
·
IF 11
Chu Tong,Peng-Xiang Min,Qian Zhang,Ru-Xin Gu,Yao-Hai Wen,Yi Shi,Yu-Huan Bao,Xiang Chen,Yi-Xuan Zhang,Xing-Feng Mao,Hao-Yang Yuan,Xiu-Xiu Liu,Takuya Sasaki,Li Zhang,Feng Han,Ying-Mei Lu
Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors. However, the molecular mechanisms underlying this disturbance remain elusive. Here, we showed that cyclin-dependent kinase 5 (Cdk5) was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis. Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms. Moreover, Cdk5 deficiency in cholinergic neurons triggered paw tremors, abnormal motor coordination, and motor balance deficits in mice. These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+ channels (BK channels). Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice. Furthermore, CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908. Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice. Together, these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuron-mediated motor function, providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.
研究领域:
神经科学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
·
2016
·Vol. 43
·期 5
·562-568
·
IF 2.004
Ailin Xiao,Jing Li,Tianjian Liu,Zhuxi Liu,Chuanfei Wei,Xiaomeng Xu,Qin Li,Jingxin Li
Summary Hydrogen sulphide (H 2 S) is generated endogenously from l -cysteine ( l -Cys) by the enzymes cystathionine- β -synthase (CBS) and cystathionine- γ -lyase (CSE). In addition, l -Cys is commonly used as a precursor in the food and pharmaceutical industries. The aim of the present study is to determine whether l -Cys regulates intestinal nutrient transport. To that end, the presence of CBS and CSE in the jejunum epithelium was assessed by immunohistochemistry, Western blotting and the methylene blue assay. In addition, in vivo l -Cys (100 mg/kg, administered immediately after the glucose load) significantly increased blood glucose levels 30 min after the oral administration of glucose to mice. This effect of l -Cys was completely blocked by amino-oxyacetic acid (AOA; 50 mg/kg; administered at the same time as l -Cys) an inhibitor of CBS. Measurements of the short-circuit current ( I sc ) in the rat jejunum epithelium revealed that l -Cys (1 mmol/L; 6 min before the administration of l -alanine) enhances Na + -coupled l -alanine or glucose transport, and that this effect is inhibited by AOA (1 mmol/L;10 min before the administration of l -Cys), but not d , l -propargylglycine (PAG;1 mmol/L; 10 min before the administration of l -Cys), a CSE inhibitor. Notably, l -Cys-evoked enhancement of nutrient transport was alleviated by glibenclamide (Gli;0.1 mmol/L; 10 min before the administration of l -Cys), a K + channel blocker. Together, the data indicate that l -Cys enhances jejunal nutrient transport, suggesting a new approach to future treatment of nutrition-related maladies, including a range of serious health consequences linked to undernutrition.
研究领域:
营养学
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药理学
·
生理学
·
胃肠病学
✓ 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）