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Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing N-methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca2+-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury. TRPV3 expression is upregulated in mice subjected to cerebral I/R injury. Silencing of TRPV3 reduces intrinsic neuronal excitability, excitatory synaptic transmissions, and also attenuates cerebral I/R injury in mouse model of transient middle cerebral artery occlusion (tMCAO). Conversely, overexpressing or re-expressing TRPV3 increases neuronal excitability, excitatory synaptic transmissions and aggravates cerebral I/R injury. Furthermore, specific inhibition of TRPV3 by natural forsythoside B decreases neural excitability and attenuates cerebral I/R injury. Taken together, our findings for the first time reveal a causative role of neuronal TRPV3 channel in progressive cell death after stroke, and blocking overactive TRPV3 channel may provide therapeutic potential for ischemic brain injury.
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Genetic gain-of-function mutations of warm temperature-sensitive transient receptor potential vanilloid 3 (TRPV3) channel cause Olmsted syndrome characterized by severe itching and keratoderma, indicating that pharmacological inhibition of TRPV3 may hold promise for therapy of chronic pruritus and skin diseases. However, currently available TRPV3 tool inhibitors are either nonselective or less potent, thus impeding the validation of TRPV3 as therapeutic target. Using whole-cell patch-clamp and single-channel recordings, we report the identification of two natural dicaffeoylquinic acid isomers isochlorogenic acid A (IAA) and isochlorogenic acid B (IAB) that selectively inhibit TRPV3 currents with IC50 values of 2.7 ± 1.3 and 0.9 ± 0.3 μmol/L, respectively, and reduce the channel open probability to 3.7 ± 1.2% and 3.2 ± 1.1% from 26.9 ± 5.5%, respectively. In vivo evaluation confirms that both IAA and IAB significantly reverse the ear swelling of dermatitis and chronic pruritus. Furthermore, the isomer IAB is able to rescue the keratinocyte death induced by TRPV3 agonist carvacrol. Molecular docking combined with site-directed mutations reveals two residues T636 and F666 critical for the binding of the two isomers. Taken together, our identification of isochlorogenic acids A and B that act as specific TRPV3 channel inhibitors and gating modifiers not only provides an essential pharmacological tool for further investigation of the channel pharmacology and pathology, but also holds developmental potential for treatment of dermatitis and chronic pruritus.
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Arsenic is a carcinogenic metal-like poison that is widely present in the natural environment. Acute or long-term exposure to arsenic can cause a series of liver injury, such as hepatomegaly, liver fibrosis, cirrhosis, and even liver cancer. In recent years, new progress has been made in the study of the mechanism of arsenic exposure on liver injury. This article will systematically review the main pathogenesis of arsenic-induced liver injury, mainly covering DNA methylation, oxidative stress, inflammatory response, hepatocyte apoptosis, liver fibrosis and autophagy. It aims to provide a theoretical reference for the prevention and treatment of arsenic poisoning.
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Mycotoxin covers a large number and variety of secondary metabolites, which can induce toxicological effects in mammals. T-2 toxin and citreoviridin (CIT) are common mycotoxins. Many agricultural products are polluted to varying degrees during harvest or storage. Their toxin levels depend on environmental factors such as temperature and humidity of the soil, storage conditions and so on. These two mycotoxins pose potential health hazards to human beings. Among them, T-2 toxin causes degeneration and necrosis of epiphyseal plate cartilage in the development stage, which produces pathological changes similar to Kashin-Beck disease; CIT causes myocardial damage, which is associated with the outbreak of endemic Keshan disease. Therefore, the pathogenicity of T-2 toxin and CIT has been widely concerned. In this paper, the production, physicochemical properties, toxicological effects, pathogenesis and control measures of T-2 toxin and CIT are reviewed.
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Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound
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Arsenic is a pollutant widely distributed in the natural environment.The liver is one of the main target organs of arsenic toxicity.Arsenic causes liver damage and liver disease by affecting the imbalance of hepatocyte apoptosis.However,its specific mechanism is not very clear.In this paper,the research on pathways and influencing factors of arsenic-induced hepatocyte apoptosis in recent years is reviewed,which might provide a reference for the mechanism study and clinical prevention of liver injury in the future.
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With the development of tertiary treatment system,the higher quality of inter-hospital transport is the most critical factor for the prognosis of the critically ill pediatric patients,especially for pediatric patients whose condition is deteriorating rapidly.Improving the quality,creating the guideline,and establishing the network platform of inter-hospital will provide complete guarantee for inter-hospital transport of critically ill pediatric patients.With the development of information technology,the purpose of this study was to analyze the function of the network platform of inter-hospital transport in Hunan Children′s Hospital.
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The alpha-7 nicotinic acetylcholine receptor (7 nAChR), consisting of homomeric7 subunits, is a ligand-gated Ca-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of7 nAChR modulators used in clinical trials.
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To foster communication and interactions amongst international scholars and scientists in the field of ion channel research, the 6th International Ion Channel Conference (IICC-2017) was held between June 23-27, 2017 in the eastern coastal city of Qingdao, China. The meeting consisted of 450 attendees and 130 speakers and poster presenters. The program consisted of research progress, new findings and ongoing studies that were focused on (1) Ion channel structure and function; (2) Ion channel physiology and human diseases; (3) Ion channels as targets for drug discovery; (4) Technological advances in ion channel research. An insightful overview was presented on the structure and function of the mechanotransduction channelNOMPC (No mechanoreceptor potential C), a member of the transient receptor potential (TRP) channel family. Recent studies on Transmembrane protein 16 or Anoctamin-1 (TMEM16A, a member of the calcium-activated chloride channel [CaCC] family) were summarized as well. In addition, topics for ion channel regulation, homeostatic feedback and brain disorders were thoroughly discussed. The presentations at the IICC-2017 offer new insights into our understanding of ion channel structures and functions, and ion channels as targets for drug discovery.
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Objective To explore the effect of the autoregressive integrated moving average model?nonlinear auto?regressive neural network(ARIMA?NARNN)model on predicting schistosomiasis infection rates of population. Methods The ARIMA model,NARNN model and ARIMA?NARNN model were established based on monthly schistosomiasis infection rates from Janu?ary 2005 to February 2015 in Jiangsu Province,China. The fitting and prediction performances of the three models were com?pared. Results Compared to the ARIMA model and NARNN model,the mean square error(MSE),mean absolute error (MAE)and mean absolute percentage error(MAPE)of the ARIMA?NARNN model were the least with the values of 0.011 1, 0.090 0 and 0.282 4,respectively. Conclusion The ARIMA?NARNN model could effectively fit and predict schistosomiasis in?fection rates of population,which might have a great application value for the prevention and control of schistosomiasis.
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Stroke is a brain damage caused by a loss of blood supply to a portion of the brain, which requires prompt and effective treatment. The current pharmacotherapy for ischemic stroke primarily relies on thrombolysis using recombinant tissue plasminogen activators (rt-PAs) to breakdown blood clots. Neuroprotective agents that inhibit excitatory neurotransmitters are also used to treat ischemic stroke but have failed to translate into clinical benefits. This poses a major challenge in biomedical research to understand what causes the progressive brain cell death after stroke and how to develop an effective pharmacotherapy for stroke. This brief review analyzes the fate of about 430 potentially useful stroke medications over the period 1995-2015 and describes in detail those that successfully reached the market. Hopefully, the information from this analysis will shed light on how future stroke research can improve stroke drug discovery.
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In all six members of TRPV channel subfamily, there is an ankyrin repeat domain (ARD) in their intracellular N-termini. Ankyrin (ANK) repeat, a common motif with typically 33 residues in each repeat, is primarily involved in protein-protein interactions. Despite the sequence similarity among the ARDs of TRPV channels, the structure of TRPV3-ARD, however, remains unknown. Here, we report the crystal structure of TRPV3-ARD solved at 1.95 Å resolution, which reveals six-ankyrin repeats. While overall structure of TRPV3-ARD is similar to ARDs from other members of TRPV subfamily; it, however, features a noticeable finger 3 loop that bends over and is stabilized by a network of hydrogen bonds and hydrophobic packing, instead of being flexible as seen in known TRPV-ARD structures. Electrophysiological recordings demonstrated that mutating key residues R225, R226, Q255, and F249 of finger 3 loop altered the channel activities and pharmacology. Taken all together, our findings show that TRPV3-ARD with characteristic finger 3 loop likely plays an important role in channel function and pharmacology.
Subject(s)
Humans , Amino Acid Sequence , Ankyrin Repeat , Crystallography, X-Ray , HEK293 Cells , Models, Molecular , Molecular Sequence Data , Patch-Clamp Techniques , Protein Binding , Protein Conformation , Protein Structure, Tertiary , Sequence Homology, Amino Acid , TRPV Cation Channels , Chemistry , PhysiologyABSTRACT
Background and purpose:A pressing obstacle in clinical chemotherapy is drug resistance in breast cancer.A nano-delivery system,which has many advantages as a drug carrier,such as carrying anticancer drugs,can be used effectively to overcome drug resistance in tumors.This paper examined a new nano-delivery system,called calcium phosphate and glycerophosphocholine-mPEG(CAP/GPC-MPEG)composite nanoparticle and its influence on the cellular drug uptake of BCRP-over expressing mitoxantrone(MIT)-resistant breast cancer cell MCF-7/MIT.This paper will also examine its effect on overcoming drug resistance in the MCF-7/MIT cells.Methods:After the calcium phosphate and GPC-mPEG composite nanoparticles were designed and prepared,the entrapment efficiency and in vitro drug release of mitoxantrone-loaded nanoparticles were investigated.Quantitative comparisons were made between cellular uptake of drug-loaded nanoparticles and free drugs.Finally,a confocal laser scanning microscopy Was used to compare the subcellular distribution of drug-loaded nanoparticles and the free drugs.Results:Calcium phosphate and GPC-mPEG composite nanoparticles were nanoporous spherical particles with diameters between 50-100 mn.The MIT-loaded nanoparticles have an entrapment efficiency of(89.45±0.05)%.Although the drug-loaded nanoparticles showed an initial burst of drug release,it was followed by a more sustained release.The concentration of mitoxantrone was 1.89 times treated with MIT-loaded nanoparticles for 1 h compared to that treated with free mitoxantrone for 1 h in MCF-7/MIT cells.and which was 2.33 times in MCF-7 cells.Fluorescent red mitoxantrone appeared in the cytoplasm and nucleus of the MCF-7 and MCF-7,MIT cells treated with MlT-loaded nanoparticles whereas it is almost undetected in both cells treated with free mitoxantrone.Conclusion:Calcium phosphate and GPC-mPEG composite nanoparticles Can promote the cellular uptake and entering of mitoxantrone to the nucleus in MCF-7 and its corresponding BCRP-over expressing MIT-resistant MCF-7/MIT breast cancer cell lines.This nanoparticle is a potential nano-carrier for overcoming drug resistance in tumors.
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The study was made on 3H-leucine incorporation into brain of offsprings born by their mothers who were fed in severe iodine deficiency area. Control group received an iodine-supplemented diet (1.7mg KIO3/kg food). Disintegration per minute (dpm) was used as an index to assess the 3H-leu-cine incorporation rate in comparision of the two groups.The results of 3H-leucine incorporation into brain showed that the dpm/mg of brain cortex and cerebellum was significantly lower in experimental group than that of control group at the time of 1-14 hours after injection of the preparation on 11-day offsprings (p