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Abstract Introduction: The endoparasite Dendrogaster argentinensis infects the intertidal brooder sea star Anasterias antarctica. This sea-star species is in the highest trophic level in the Beagle Channel. Objective: To study the effects of parasitism by D. argentinensis on the fitness and reproduction of A. antarctica. Methods: Adults from the brooder sea-star were collected from the rocky intertidal of Ensenada Zaratiegui bay (54°51' S & 68°29' W), Argentina. Eight seasonal samplings were performed (four seasons in two years) in the upper and low intertidal. During dissection, parasites were removed, and all organs were extracted and weighed separately. Results: Dendrogaster argentinensis prevalence was the highest for the region (20.4 %). Parasitized individuals were more frequent in the low intertidal in all seasons, with a higher difference in summer, where it is likely that the higher temperatures and strong winds could make the upper intertidal more challenging for a parasitized individual. Five parasitized individuals were castrated. Generally, the gonadal (GI) and somatic (pyloric caeca, PCI; stomach, SI; body wall, WI) indexes were lower in parasitized than non-parasitized individuals. Conclusions: Parasitism by D. argentinensis negatively affects A. antarctica condition. It affects reproduction because it reduces the GI, and can also produce castration. The parasite competes for the sea-stars' energetic resources, also decreasing the individual's capacity for feeding (reduced stomach) and growth (reduced body wall).
Resumen Introducción: El endoparásito Dendrogaster argentinensis infecta a la estrella de mar Anasterias antarctica, especie que se encuentra en el nivel trófico más alto del Canal Beagle. Objetivo: Estudiar los efectos del parasitismo de D. argentinensis en la condición fisiológica y reproducción de A. antarctica. Métodos: Adultos de la estrella de mar incubadora fueron recogidos del intermareal rocoso de la bahía Ensenada Zaratiegui (54°51' S & 68°29' W). Se realizaron ocho muestreos estacionales (cuatro temporadas en dos años) en el intermareal superior y bajo. Durante la disección, se removieron los parásitos, y todos los órganos, los cuales fueron pesados por separado. Resultados: La prevalencia de D. argentinensis fue la más alta de la región (20.4 %). Los individuos parasitados fueron más frecuentes en el intermareal bajo en todas las estaciones, siendo la mayor diferencia en verano, donde es probable que las temperaturas más altas y los fuertes vientos puedan hacer que el intermareal superior sea más desafiante para un individuo parasitado. Se observaron cinco individuos parasitados que estaban castrados. Generalmente, los índices gonadales (GI) y somáticos (ciego pilórico, estómago, y pared del cuerpo) fueron menores en los individuos parasitados que no parasitados. Conclusiones: El parasitismo de D. argentinensis afecta negativamente la condición fisiológica de A. antarctica. Afecta a la reproducción en términos de bajo GI y puede causar castración. El parásito compite por los recursos energéticos de las estrellas de mar, disminuyendo también la capacidad del individuo para alimentarse (reducción del estómago) y crecer (reducción de la pared del cuerpo).
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Animals , Parasites/microbiology , Starfish/parasitologyABSTRACT
@#Objective To investigate the effect of microparticles(MPs)derived from bone marrow mesenchymal stem cells(BMSCs) on myocardial hypertrophy and its mechanism.Methods The osteogenic differentiation and adipogenic differentiation of mesenchymal stem cells(MSCs) were induced. After isolation and purification,the morphological characteristics were observed by transmission electron microscope,and the MPs surface antigen was identified by flow cytometry. Myocardial hypertrophy model was induced by using isoprenaline(ISO)in rats,which were measured for the cardiac structure and function by echocardiography,and then detected for various indexes of the heart and isolated left ventricle. Single ventricular myocytes of rats were acutely isolated and divided into control group(Control group),cardiomyocyte hypertrophy group(ISO group),MPs group(MPs group),and MPs supernatant group(Supernatant group). The mRNA expressions of atrial natriuretic peptide(ANP)and B-type natriuretic peptide(BNP)were detected by qRTPCR. The expression levels of calmodulin-dependent protein kinaseⅡ（CaMKⅡ）and phosphorylated calmodulin-dependent protein kinaseⅡ（p-CaMKⅡ）were detected by ELISA. The L-type calcium current(LCa-L)in single ventricular myocyte of various groups was recorded by whole-cell patch clamp.Results The bone nodules of MSCs osteogenic differentiation turned red after alizarin red staining,and lipid droplets of adipogenic differentiation turned red after oil red O staining;Under transmission electron microscope,MPs membrane had a complete structure,a clear outline and a diameter of about200 nm;The positive rates of CD29 and CD90 on the surface of MPs were(98. 24 ± 0. 82)% and(97. 69 ± 1. 83)%,respectively. Compared with Control group,the left ventricular end diastolic dimension(LVEDD)reduced signifi-cantly(t =5. 065,P < 0. 05),while the interventricular septum end-diastolic dimension(IVSd),left ventricular posterior wall dimension(LVPWd),heart weight to body weight ratio(HW/BW),and heart weight to tibial length ratio(HW/Tibia)significantly increased in ISO group(t = 4. 013,2. 368,4. 392,5. 043 and 6. 120,respectively,each P < 0. 05),indicating that the hypertrophic model was successfully established. The expression levels of ANP and BNP mRNA in hypertrophic cardiomyocytes of rats in ISO group were significantly higher than those in Control group(t = 25. 120 and18. 261,respectively,each P < 0. 01);While the expression levels of ANP and BNP mRNA in MPs group significantly reduced after incubation with 48 μg/mL MPs for 48 h compared with ISO group(t = 12. 110 and 3. 526,respectively,each P < 0. 05);The expression levels of CaMK Ⅱand p-CaMKⅡ in ISO group were significantly higher than those in Control group(t = 3. 278 and 4. 181,respectively,each P < 0. 05),while the expression of p-CaMK Ⅱ in MPs group decreased significantly(t = 5. 420,P < 0. 05);The calcium current density in ISO group was significantly higher than that in Control group(t = 15. 261,P < 0. 01),while that in MPs group was significantly lower than that in ISO group(t =6. 216,P < 0. 05).Conclusion MSC-MPs can significantly inhibit ISO-induced cardiomyocyte hypertrophy in rats,which is related to its down-regulation of cardiomyocyte CaMKⅡ and inhibition of L-type calcium channel.
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Cold and heat belong to the eight-principal syndrome differentiation of traditional Chinese medicine， which can reflect the rise and fall of Yin and Yang in the body and the Yin and Yang nature of the disease. At present， traditional Chinese medicine has an inconsistent understanding of cold and heat in acute coronary syndrome. The emphasis on pathogenic factors of cold and heat is biased， and the elements of cold and heat syndrome are not fully reflected in the scale. Therefore， the literature has been reviewed from the perspectives of etiology， pathogenesis， symptom elements， and test signs with drugs. From the perspective of etiology， both cold evil and heat evil can increase the risk of acute coronary syndrome. It was previously believed that acute coronary syndrome occurs frequently in cold climates such as winter and spring. Based on this understanding， hot weather can also induce acute coronary syndrome， and different temperatures have different effects on patients of different ages and with different underlying diseases. In addition， artificial pathogenic factors such as excessive consumption of cold food and refrigeration air conditioners were added. From the perspective of pathogenesis， on the basis of the traditional ''asthenia in origin and asthenia in superficiality'' and ''phlegm stagnation''， it is found that Yin-cold and fire-heat can both cause paralysis of the heart chakra and pain induced by the blockage. The pathogenesis of acute coronary syndrome characterized by heat stagnation and coldness featuring heartburn should be distinguished from gastroesophageal reflux disease. Moreover， the pathogenesis of Yin cold coagulation and pulse stagnation and wind obstruction are different. The acute coronary syndrome is in line with the wind characteristics of frequent changes and can be treated with wind medicine. From the perspective of syndrome elements， the syndrome elements such as cold condensation， heat accumulation， and toxicity are analyzed， and the use of basic syndrome elements and their combination forms facilitates clinical and scientific research. In addition， according to the test sign with the drug， it can be seen that the attributes of cold and heat of traditional Chinese medicine prescriptions for acute coronary syndrome can be explained according to the temperature-sensitive transient receptor potential （TRP） ion channel， thus proving the pathogenesis of cold and heat of acute coronary syndrome.
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Transient receptor potential vanilloid receptor 4(TRPV4)is a non-selective cation channel responsible for sensing changes in cell swelling, temperature, mechanical stretch, shear stress and osmotic pressure by regulating transmembrane calcium signaling and thereby influencing gene expression, cell morphology, and cytoskeletal construction. TRPV4 is widely expressed throughout the body. Intraocularly, TRPV4 is functionally expressed in the cornea, lens, ciliary body, trabecular meshwork and retina. In this article, the expression and physiopathological functions of TRPV4 in various tissues of the eye were described. With the in-depth study of TRPV4 in ocular pathophysiological functions, TRPV4 may become a potential drug target in corneal injury repair, glaucoma and retinal angiogenesis, but further in-depth study is still needed.
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OBJECTIVE To provide reference for the smooth implementation of the “dual channel” management policy for China’s medical insurance negotiated drugs. METHODS Based on Smith policy implementation process model， the dilemmas for the implementation of “dual channel” policy for medical insurance negotiated drugs were analyzed from four aspects： implementation details and regulatory system， drug selection， drug provision and quality control， the situation of medical insurance funds and information technology capabilities. The corresponding promotion strategies were put forward. RESULTS & CONCLUSIONS The “dual channel” policy for medical insurance negotiated drugs in China might face implementation difficulties such as a lack of clear implementation rules and a full process supervision system， the suitability and operability of some medical insurance negotiated drugs need to be considered in the “dual channel” management， difficulties in drug allocation and quality control， differences in the management and operation of medical insurance funds in different regions， and insufficient informatization capability. In this regard， this study suggests that measures， such as improving the implementation rules of the “dual channel” policy， enhancing the rationality of the “dual channel” drug catalog， establishing a dynamic exit mechanism for “dual channel” pharmacies， promoting professional delivery services， and improving the electronic prescription circulation platform， which can be taken to enhance the implementation effect of the “dual channel” policy.
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ObjectiveTo explore the effect and mechanism of Zhishi Xiebai Guizhitang on the progression of atherosclerosis （AS） mice based on the regulation of cholesterol metabolism in foam cells by transient receptor potential channel ankyrin 1 （TRPA1）. MethodThe AS model was established on apolipoprotein E knockout （ApoE-/-） mice with a high-fat diet. The mice were randomly divided into low-dose， middle-dose， and high-dose groups of Zhishi Xiebai Guizhitang （2.97， 5.94， 11.88 g·kg-1） and simvastatin group （0.002 g·kg-1）， and the drug was administered along with a high-fat diet. C57BL/6J mice were fed an ordinary diet as a normal group. After the above process， the aorta and serum of mice were taken. The pathological changes of the aortic root were observed by hematoxylin-eosin （HE） staining. The lipid plaques in the aorta were observed by gross oil redness. Serum levels of total cholesterol （TC）， triglyceride （TG）， low density lipoprotein cholesterol （LDL-C）， and high density lipoprotein cholesterol （HDL-C） were detected， and the levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） were detected by enzyme-linked immunosorbent assay （ELISA）. Western blot and immunohistochemical method were used to analyze the expression of TRPA1， ATP-binding cassette transporter A1 （ABCA1）， ATP-binding cassette transporter G1 （ABCG1）， and mannose receptor （CD206）. ResultFrom the perspective of drug efficacy， compared with the normal group， pathological changes such as plaque， a large number of foam cells， and cholesterol crystals appeared in the aorta of the model group， and the serum levels of TC， LDL-C， IL-1β， and IL-18 were significantly increased （P<0.01）. The HDL-C level was significantly decreased （P<0.01）， and the CD206 level in aortic tissue was significantly decreased （P<0.01）. Compared with the model group， the lipid deposition in the aorta was alleviated in all drug administration groups. In addition， except for the high-dose group of Zhishi Xiebai Guizhitang， all drug administration groups could significantly decrease the levels of TC and LDL-C （P<0.01）. In terms of inflammation， except for the middle-dose group of Zhishi Xiebai Guizhitang， the levels of IL-1β and IL-18 were significantly decreased in all drug administration groups （P<0.05）. Moreover， Zhishi Xiebai Guizhitang could also up-regulate the levels of CD206， and the difference was significant in the middle-dose and high-dose groups （P<0.05）. From the perspective of mechanism， the expression levels of TRPA1， ABCA1， and ABCG1 in the aorta in the model group were lower than those in the normal group （P<0.05）. Compared with the model group， all drug administration groups significantly increased the expression of TRPA1 in the aorta （P<0.05）， and the expressions of ABCA1 and ABCG1 were increased. The differences in the middle-dose and high-dose groups and the simvastatin group were significant （P<0.05）， which was basically consistent with the trend of immunohistochemical results. ConclusionZhishi Xiebai Guizhitang can effectively reduce blood lipid and inflammation levels and inhibit the formation of aortic plaque. The mechanism may be explained as follows： the expressions of ABCA1 and ABCG1 downstream are increased through TRPA1， which promotes cholesterol outflow in foam cells， thereby regulating cholesterol metabolism， intervening in inflammation level to a certain extent， and finally treating AS.
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Ferroptosis is an iron-dependent cell death caused by phospholipid peroxidation damage of polyunsaturated fatty acids on cell membranes and involves several pathways, including the iron homeostasis regulatory pathway, the cystine glutamate reverse transporter (system Xc) pathway and the voltage-dependent anion channel (VDAC) pathway. Ferroptosis is involved in the development of several diseases (e. g. myocardial infarction, stroke, cancer and degenerative diseases). The ubiquitination is an important post-translational modification of various protein molecules in the organism. Studies have shown that regulating the ubiquitination of ferroptosis pathway-related molecules can control cellular ferroptosis. Targeting the ubiquitination of ferroptosis pathway-related molecules can effectively promote or inhibit ferroptosis, which is expected to be a new strategy for the treatment of cancer or cardiovascular diseases. In this paper we review the progress of the ferroptosis pathways and the ubiquitination modification of ferroptosis-related molecules.
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Objective To investigate the level of deltamethrin resistance and mutation sites in the sodium iron channel gene in Rhipicephalus microplus in Huaihua City, Hunan Province, and to examine the correlation between deltamethrin resistance and mutation sites in the sodium iron channel gene in Rh. microplus. Methods Rh. microplus was sampled from multiple yellow cattle farms in Huaihua City, Hunan Province from June to September 2022, and the level of resistance to deltamethrin was determined in ticks using the adult immersion test. The sodium iron channel domain III gene was amplified in deltamethrin-resistant and wild-type Rh. microplus using PCR assay. Following sequencing and sequence alignment, mutation sites were detected in bases. The sodium iron channel domain III gene in Rh. microplus was translated, and the signal peptide, transmembrane domain, and phosphorylation and glycosylation sites were detected in amino acid sequences. The tertiary structures of the sodium iron channel domain III protein of deltamethrin-resistant and wild-type Rh. microplus were deduced and compared, and the association be tween mutation sites in bases and resistance to deltamethrin was examined in Rh. microplus according the level of deltamethrin resistance, sequence alignment and protein tertiary structure. Results The median (LC50) and 95% lethal concentrations (LC95) of deltamethrin were 121.39 mg/L and 952.61 mg/L against Rh. microplus, with a resistance factor of 9.24 and level II resistance. The sequence of the sodium ion channel domain III gene was 1 010 bp in size, and mutation sites were detected in two neighboring bases in the sequence of the sodium ion channel domain III gene in deltamethrin-resistant Rh. microplus. Although no signal peptides were found in the sodium iron channel domain III protein of deltamethrin-resistant or wild-type Rh. microplus, 6 trans-membrane domains, 42 phosphorylation sites and 8 glycosylation sites were identified, with a significant difference in the tertiary structure of the sodium iron channel domain III protein between deltamethrin-resistant and wild-type Rh. microplus. Conclusions Level II resistance to deltamethrin is detected in Rh. microplus in Huaihua City, Hunan Province, and two mutation sites that correlate with the emergence of deltamethrin resistance are identified in the sequence of the sodium iron channel domain III gene in deltamethrin-resistant Rh. microplus.
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ObjectiveTo objectively analyze the effects of traditional Chinese Medicine （TCM） multi-channel intervention on the ovarian function，TCM syndromes and natural conception of poor ovarian responders（kidney-Yin deficiency，liver depression and blood stasis pattern） who planned to receive another in vitro fertilization embryo transfer（IVF-ET）antagonist regimen. MethodThe 128 low-prognosis patients （kidney Yin deficiency，liver depression and blood stasis pattern） who attended the West China Second University Hospital， Sichuan University and the Hospital of Chengdu University of Traditional Chinese Medicine from August 2020 to February 2023 and met the inclusion criteria were selected，and then divided into the treatment group and the control group according to the random number table，with 64 patients in each group. The control group was treated with oral dehydroepiandrosterone（DHEA），while the treatment group was treated with multi-channel TCM（oral TCM decoction + auricular point sticking + Bushen Huoxue prescription through retention enema）. After 3 menstrual cycles，the relevant indicators for ovarian function evaluation，TCM syndrome scores and natural conception were collected from both groups. ResultCompared with the situation before treatment，the basal follicle stimulating hormone（bFSH），bFSH/basal luteinizing hormone（bLH），basal estradiol（bE2），antral follicle count（AFC），the number of oocytes obtained，the number of normal fertilization，the number of superior embryos and TCM syndrome scores in the treatment group were improved after treatment（P<0.05，P<0.01）. For the control group， the bFSH/bLH and TCM syndrome scores were increased after treatment（P<0.05）， while the bFSH，bFSH/bLH，bE2，AFC，the number of oocytes obtained，the number of normal fertilization，and the number of superior embryos showed no significant difference after treatment. Compared with the control group after treatment，bFSH，bFSH/bLH，bE2，AFC，the number of normal fertilization，the number of superior embryos and TCM syndrome scores in the treatment group were better （P<0.05，P<0.01），while there was no significant difference in the number of oocytes obtained. After treatment，there were 3 cases of natural conception in the treatment group，while there were no natural conception in the control group. ConclusionFor patients with poor ovarian response and kidney Yin deficiency，liver depression and blood stasis pattern，multi-channel intervention of TCM plus the antagonist regimen can reduce bFSH，bFSH/bLH values，improve the levels of bE2，increase AFC，the number of oocytes obtained，the number of normal fertilization and the number of superior embryos，improve ovarian function，menstruation and TCM syndromes，improve their quality of life，and even enable some patients to get pregnant naturally before re-progression and improve their pregnancy outcome.
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OBJECTIVE@#To assess the effectiveness of the single Kocher-Langenbeck approach combined with anterograde channel screw technique for the treatment of acetabular transverse and posterior wall fractures.@*METHODS@#Between March 2020 and October 2022, 17 cases of acetabular transverse and posterior wall fractures were treated with the single Kocher-Langenbeck approach combined with anterograde channel screw technique. There were 11 males and 6 females, with an average age of 53.6 years (range, 42-64 years). Causes of injury included traffic accident in 12 cases, and falling from height in 5 cases. The time from injury to operation ranged from 4 to 16 days with an average of 8.8 days. The operation time, intraoperative blood loss, and fluoroscopy frequency were recorded; X-ray films were reviewed regularly after operation to observe the fracture healing, and postoperative complications were recorded. At last follow-up, Matta score was used to evaluate the reduction of fracture, Harris score and modified Merle D'Aubigné-Postel scores system were used to evaluate the hip joint function.@*RESULTS@#The operation time was 150-230 minutes (mean, 185.9 minutes), the intraoperative blood loss was 385-520 mL (mean, 446.2 mL), and the fluoroscopy frequency was 18-34 times (mean, 27.5 times). Postoperative fat liquefaction occurred in 1 case and the other incisions healed by first intention; 3 cases had limb numbness after operation, and the symptoms disappeared after active symptomatic treatment; no urogenital system and intestinal injury occurred. All patients were followed up 12-28 months (mean, 19.9 months). Bone union was achieved in all cases with an average healing time of 10.8 weeks (range, 8-14 weeks). There was no complication such as loosening and breakage of internal fixators. At last follow-up, according to Matta score, 12 cases achieved anatomic reduction, 3 satisfactory reduction, and 2 fair reduction, the satisfactory rate was 88.2%; according to Harris hip function score, 12 cases were excellent, 3 good, and 2 fair, the excellent and good rate was 88.2%; according to the modified Merle D'Aubign Aubigné-Postel scoring system, the results were excellent in 11 cases, good in 3 cases, and fair in 3 cases, with an excellent and good rate of 82.4%.@*CONCLUSION@#The single Kocher-Langenbeck approach combined with anterograde channel screw technique is a minimally invasive method for the treatment of acetabular transverse and posterior wall fractures with less complications, simple operation, and satisfactory effectiveness.
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Male , Female , Humans , Middle Aged , Blood Loss, Surgical , Fracture Fixation, Internal/methods , Treatment Outcome , Fractures, Bone/surgery , Acetabulum/injuries , Bone Screws , Hip Fractures/surgery , Retrospective StudiesABSTRACT
OBJECTIVES@#To isolate potassium ion channel Kv4.1 inhibitor from centipede venom, and to determine its primary and spatial structure.@*METHODS@#Ion-exchange chromatography and reversed-phase high-performance liquid chromatography were performed to separate and purify peptide components of centipede venom, and their inhibiting effect on Kv4.1 channel was determined by whole-cell patch clamp recording. The molecular weight of isolated peptide Kv4.1 channel inhibitor was identified with MALDI-TOF, its primary sequence was determined by Edman degradation sequencing and two-dimensional mass spectrometry, its patial structure was established based on iterative thread assembly refinement online analysis.@*RESULTS@#A peptide SsTx-P2 was separated from centipede venom with the molecular weight of 6122.8, and its primary sequence consists of 53 amino acid residues, showed as NH2-ELTWDFVRTCCKLFPDKSECTKACATEFTGGDESRLKDVWPRKLRSGDSRLKD-OH. Peptide SsTx-P2 potently inhibited the current of Kv4.1 channel transiently transfected in HEK293 cell, with 1.0 μmol/L SsTx-P2 suppressing 95% current of Kv4.1 channel. Its spatial structure showed that SsTx-P2 shared a conserved helical structure.@*CONCLUSIONS@#The study has isolated a novel peptide SsTx-P2 from centipede venom, which can potently inhibit the potassium ion channel Kv4.1, and its spatial structure displays a certain degree of conservation.
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Abstract Objective To assess the prevalence of GERD exclusively by means of multichannel intraluminal impedanciometry associated with pH monitoring (MIIpH) and compare it with respiratory symptoms in children with CF. To compare MIIpH with pHmetry alone to perform GERD diagnosis. Methods An analytical cross-sectional study was conducted with children diagnosed with CF who underwent MIIpH. Clinical and laboratory markers, including respiratory and digestive symptoms, were used for comparative analyses. High-resolution chest computed tomography was performed on patients with symptoms of chronic lung disease. Severity was classified according to the Bhalla score. Results A total of 29 children < 10 yo (18 girls) were evaluated; 19 of whom with physiological GER and 10 with GERD. Of the children with GERD, seven had predominantly acid GER, two acid+non-acid GER, and one non-acid GER. Three patients had GERD diagnosed only by MIIpH. Bhalla scores ranged from seven to 17.75 with no significant relationship with GERD. The number of pulmonary exacerbations was associated with a decrease in esophageal clearance regardless of the position in pHmetry and MIIpH. Conclusions The prevalence of GERD was 34% in children with CF. There was no association between respiratory disease severity and GER types. MIIpH detected 30% more patients with GERD than pHmetry.
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Purpose: To compare post?operative pain perception using bandage contact lens (BCL) stored at 2–8?C (Cold BCL, CL?BCL) or room temperature (23 – 25?C, RT?BCL) after photorefractive keratectomy (PRK) or corneal collagen?crosslinking (CXL) and determine status of nociception associated factors. Methods: In this prospective interventional study, 56 patients undergoing PRK for refractive correction and 100 keratoconus (KC) undergoing CXL were recruited following approval from the institutional ethics committee with informed consent. Patients undergoing bilateral PRK received RT?BCL on one eye and CL?BCL on the other. Pain was graded by Wong–Baker scoring on the first post?operative day (PoD1). Expression of transient receptor potential channels (TRPV1, TRPA1, TRPM8), calcitonin gene?related peptide (CGRP) and IL?6 was measured in cellular content from used BCLs collected on PoD1. Equal number of KC patients received RT?BCL or CL?BCL post?CXL. Pain was graded by Wong–Baker scoring on PoD1. Results: Pain scores on PoD1 were significantly (P < 0.0001) reduced in subjects receiving CL?BCL (Mean ± SD: 2.6 ± 2.1) compared to RT?BCL (6.0 ± 2.4) post?PRK. 80.4% of subjects reported reduced pain scores with CL?BCL. 19.6% reported no change or increased pain scores with CL?BCL. TRPM8 expression was significantly (P < 0.05) increased in BCL of subjects reporting reduced pain with CL?BCL compared to those who did not. Pain scores on PoD1 were significantly (P < 0.0001) reduced in subjects receiving CL?BCL (3.2 ± 2.1) compared to RT?BCL (7.2 ± 1.8) post?CXL. Conclusion: The simple approach of using a cold BCL post?operatively substantially reduced pain perception and could overcome post?operative pain?related limited acceptance of PRK/CXL.
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Doxorubicin (DOX) is widely used as an anticancer drug in humans' various solid and haematological tumours. Although many studies on the toxic effect of DOX are used in different organs, its impact on brain tissue has yet to be adequately studied. This study investigated the protective effect of selenium (Se) and the role of transient receptor potential melastatin?2 (TRPM2) channel activation against brain damage caused by DOX administration. Sixty rats were randomly divided into the sham, dimethyl sulfoxide (DMSO), DOX, DOX?+?Se, DOX?+?N-(p-amylcinnamoyl) anthranilic acid (ACA), and DOX?+?Se?+?ACA groups. The reactive oxygen species (ROS), poly [ADP-ribose] polymerase 1 (PARP1), and TRPM2 channel levels in brain tissues were measured by ELISA. In addition, a histopathological examination was performed in the cerebral cortex and hippocampal areas, and the TRPM2 channel, NF-?B, and caspase-3 expression were determined immunohistochemically. The levels of ROS, PARP1 and TRPM2 channel in the DOX group were higher than in the sham and DMSO groups (P <?0.05). However, these parameters were decreased in the in DOX+Se and DOX+ACA groups by the treatments of Se and ACA (P?<?0.05). Also, we determined that Se and ACA treatment decreased the NF-?B, caspase-3, and TRPM2 channel expression in the cerebral cortex and hippocampal areas in the DOX-induced rats. The data showed that Se and/or ACA administration together with DOX administration could be used as a protective agent against DOX-induced brain damage.
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This study aimed to investigate the relationship between prescription drugs and the slow-flow phenomenon after drug-coated balloon angioplasty. Of 30 patients, five (17%) presented with the slow-flow phenomenon. Patients with the slow-flow phenomenon were significantly less commonly prescribed calcium channel blockers than those without the slow-flow phenomenon (P ¼ 0.03). There was no intergroup difference in the prescription of angiotensin II receptor blockers and b-blockers. The clinical outcomes, including restenosis, thrombosis, target lesion revascularization, and death, did not differ between groups during the 10-month observation period.
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Aim: The aim of this study was to evaluate the anti-hypertensive efficacy of a fixed-dose combination (FDC) of Efonidipine 40 mg and Telmisartan 40 mg in Stage II hypertensive patients. Study Design: Multicentric, randomized, double-blind, parallel, comparative Phase III clinical trial. Methodology: This clinical trial was conducted at six geographically distributed sites across India and enrolled 240 Stage II hypertensive patients. They were randomized into two groups in a ratio of 1:1 using computer-generated block randomization to receive E+T (FDC of Efonidipine 40 mg + Telmisartan 40mg) or C+T (FDC of Cilnidipine 10 mg + Telmisartan 40 mg) group intervention once daily for a period of 90 days. The study site staff, investigator and patients were blinded to the treatment allocation. The primary endpoint of the study evaluated the mean reduction in sitting systolic BP (SBP) and diastolic BP (DBP) from baseline to day 90 whereas the secondary endpoints assessed were mean reduction in BP from baseline to day 30 & 60, patients achieving target BP (<140/90 mmHg) and the safety and tolerability of the investigational products based on the incidences of adverse events (AEs) reported. Results: A total of 118 subjects were randomized to the E+T group wherein the mean (±SD) SBP and DBP at baseline was 167.25 ± 4.68/107.26 ± 5.19 mmHg. After 30 days of treatment with the E+T group, the mean reduction in SBP/DBP of 29.37/18.06 mmHg was observed whereas at Day 60 reduction of 38.55/22.69 mmHg was seen from the baseline. At Day 90, SBP/DBP decreased to 119.41±14.99/81.67±4.29 mmHg with a mean reduction of 47.94/25.89 mmHg in the E+T group. During the study period, the difference in systolic blood pressure between the treatments with E+T and C+T was -0.48 mmHg, with the two-sided 95% confidence interval (CI) ranging from -4.54 to 3.58?mmHg. The corresponding difference in diastolic blood pressure was -0.77 (95% CI: -2.60 to 1.06) mm?Hg. The upper boundary of the 95% CI was below the margin of 10?mmHg, confirming the non-inferiority of E+T to C+T. A total of 92% of patients who had been assigned to E+T treatment achieved their target BP goal. Only one patient reported an adverse event with E+T treatment. No unexpected AEs were reported in the E+T group suggesting its good safety and tolerability. Overall, the E+T treatment was effective, safe and well-tolerated by the patients for 90 days. Conclusion: It was concluded that the FDC of Efonidipine 40 mg and Telmisartan 40 mg was efficacious in the management of Stage II hypertension.
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Objective:To study the therapeutic effect Tetrandrine (TET) on striatal injury caused by microwave radiation and underlying mechanism.Methods:C57BL/6N mice were randomly divided into blank control group (C), radiation control group (R), TET group (TET) and TET combined with radiation group (TET+ R). The mice of radiation group were exposed to 2.856 GHz 8 mW/cm2 microwave on whole-body for 15 min. TET (60 mg/kg) was injected intraperitoneally once a day for 3 consecutive days. The TET structure was verified by ultraviolet spectrophotometry. The open field experiment was used to detect the change of anxiety in mice. Histopathological and ultrastructural changes of the striatum were observed by light microscopy and transmission electron microscopy (TMT). Quantitative real-time PCR (qPCR) was used to detect gene expression changes of voltage-gated calcium channel (VGCC) subtype in the striatum.Results:The open field experiments showed that the time and distance of mice to explore the central region after microwave radiation were significantly lower than that before radiation ( t=4.60, 5.18, P<0.01), and the TET administration significantly improved these changes ( F=1.43, 4.37, P < 0.05). 7 d after microwave radiation, some neuronal nuclei in the striatum of mice contracted and could be stained deeply, which was more obvious in the globus pallidus area. The partial neuronal apoptosis, swelling and cavitation of glial cell mitochondria, blurring of synaptic gaps, and widening of perivascular gaps in the striatum were observed by TMT. The above lesions were significantly rescued after TET administration. But both microwave radiation and TET administration had no significant effect on the gene expressions of striatal VGCC ( P > 0.05). Conclusions:TET has a therapeutic effect on anxiety-like behavior and structural damage of striatum caused by microwave radiation, which is independent of the expression of striatal VGCC genes.
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OBJECTIVE Alzheimer disease(AD)is a neurodegenerative disease with clinical hallmarks of pro-gressive cognitive impairment.Synergistic effects of Aβ-tau cascade reaction are tightly implicated in AD patholo-gy,and microglial NLRP3 inflammasome activation drives neuronal tauopathy through microglia and neurons cross-talk.However,the underlying mechanism of how Aβ medi-ates NLRP3 inflammasome remains unclear.Shab related potassium channel member 1(Kv2.1)as a voltage gated po-tassium channel widely distributed in the central nervous system and plays an important role in regulating the out-ward potassium flow in neurons and glial cells.In current work,we aimed to explore the underlying mechanism of Kv2.1 in regulating Aβ/NLRP3 inflammasome/tau axis by using a determined Kv2.1 inhibitor drofenine(Dfe).METHODS Cell-based assays including Western blot-ting and immunofluorescence staining against primary microglia or neurons were carried out to expound the role of Kv2.1 channel in NLRP3 inflammasome activa-tion and subsequent neuronal tau hyperphosphorylation.For animal studies,new object recognition,Y-maze and Morris water maze were performed to evaluate the ame-lioration of Kv2.1 inhibition through either Kv2.1 inhibitor Dfe treatment or adeno-associated virus AAV-ePHP-si-Kv2.1injectionon5×FADADmodel mice.Assays of histol-ogy and immunostaining of tissue sections and Western blotting of brain tissues were performed to verify the con-clusion of cellular assays.RESULTS We reported that oligomeric Aβ(o-Aβ)bound to microglial Kv2.1 and pro-moted Kv2.1-dependent potassium leakage to activate NLRP3 inflammasome through JNK/NF-κB pathway sub-sequently resulting in neuronal tauopathy.Treatment of either Kv2.1 inhibitor Dfe or AAV-ePHP-si-Kv2.1 for brain-specific Kv2.1 knockdown deprived o-A β of its capability in inducing microglial NLRP3 inflammasome activation and neuronal tau hyperphosphorylation,while improved the cognitive impairment of 5×FAD AD model mice.CONCLUSION Our results have highly addressed that Kv2.1 channel is required for o-Aβ driving NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Kv2.1 inhibition is a prom-ising therapeutical strategy for AD and Dfe as a Kv2.1 inhibitor shows potential in the treatment of this disease.
ABSTRACT
Objective:To investigate the possible role and mechanism of purinergic ligand-gated ion channel 7(P2X7)/nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3) inflammasome pathway in cognitive impairment induced by sleep deprivation (SD)mice.Methods:SPF grade male C57BL / 6J mice aged 6-8 weeks were randomly divided into 3 groups according to the random number table method with 6 mice in each group.They were normal control group (CC group), SD group and SD+ P2X7 receptor antagonist brilliant blue G(BBG) group (SD+ BBG group). Modified multiple platform method was used to establish a 5-day SD model in mice.During the SD intervention period, the mice in SD+ BBG group were injected with BBG(50 mg/kg) intraperitoneally once a day, while the mice in CC group and SD group were injected with the same volume of 0.9% sodium chloride solution.Morris water maze was conducted to evaluate the cognitive function of mice.The protein expression levels of P2X7, NLRP3, caspase-1, apoptosis-associated proteins(ASC) and interleukin-1β(IL-1β) in hippocampus were detected by Western blot.RT-qPCR was used to detect the mRNA expression levels of tumor necrosis factor-α(TNF-α), IL-1β, interleukin-18(IL-18) and microglial polarization surface markers CD206 and CD86 in hippocampus.Graph pad Prism 8.0 software and SPSS 25.0 software were used for statistical analysis and mapping.Results:(1) The interaction effect between time and groups of escape latency in three groups of mice was significant ( F=15.76, P<0.001). From the 2nd to 5th day, the escape latencies of mice in SD group were higher than those of CC group, while the escape latencies of mice in SD+ BBG group were lower than those of SD group (all P<0.05). (2)The results of the space exploration experiment showed that there were statistically significant differences in target quadrant residence time and the times of crossing the platform( F=6.65, P=0.009; F=12.39, P<0.001). The target quadrant residence time ((23.42±0.55) s) and times of crossing the platform ((17.67±0.71) times) of the SD group were both lower than those of the CC group ((29.48±1.78) s, (23.33±0.95) times) (both P<0.05), while the target quadrant residence time ((28.62±1.19) s) and the times of crossing the platforms ((21.33±0.76) times) of the SD+ BBG group were both higher than those of the SD group (both P<0.05). (3)There were statistically significant differences in the protein levels of inflammatory related proteins such as P2X7, NLRP3, caspase-1, ASC and IL-1β in the hippocampus of mice among the 3 groups( F=8.23, 8.97, 8.45, 54.42, 8.12, all P<0.05). Compared with CC group, the protein levels of P2X7 ((0.93±0.02), (0.71±0.04)), NLRP3 ((0.97±0.04), (0.62±0.09)), caspase-1 ((1.00±0.03), (0.76±0.07)), ASC ((0.96±0.02), (0.77±0.04)) and IL-1β ((0.85±0.07), (0.54±0.04)) in SD group were all higher (all P<0.05). Compared with SD group, the protein levels of P2X7 (0.74±0.05), NLRP3 (0.78±0.02), caspase-1 (0.74±0.04), ASC (0.67±0.02), IL-1β (0.53±0.07) in SD+ BBG group were all lower (all P<0.05). (4)There were statistically significant differences in the mRNA levels of IL-18, IL-1β, TNF-α, CD86 and CD206 in hippocampus among the three groups ( F=12.80, 12.28, 105.80, 7.06, 30.19, all P<0.05). The mRNA levels of IL-18, IL-1β, TNF-α, CD86 in SD group were all higher than those in CC group(all P<0.05), while the mRNA level of CD206 in SD group was lower than that in CC group( P<0.05). Compared with SD group, the mRNA levels of IL-18, IL-1β, TNF-α, CD86 were lower in SD+ BBG group (all P<0.05), while the CD206 mRNA level of SD+ BBG group was higher than that in SD group( P<0.05). Conclusion:SD intervention can lead to cognitive impairment and increased expression of P2X7 in hippocampus of mice, which may be related to the activation of P2X7/ NLRP3 inflammasome signaling pathway, promoting the polarization of microglia into pro-inflammatory type and up-regulating the expression of pro-inflammatory cytokines.Inhibition of P2X7 can improve the cognitive function of mice.
ABSTRACT
One of the important causes of developmental epileptic encephalopathy (DEE) is the mutation of ion channel genes, including the mutation of the CACNA1E gene. CACNA1E-related DEE cases were first reported in 2018.The mutation types include new missense mutations, nonsense mutations and frameshift mutations, but the correlation between mutation sites and types with the phenotype of DEE is not clear.This review aims to summarize the reported CACNA1E-related DEE cases, and explore the correlation between the clinical phenotype of CACNA1E-related DEE and gene mutation sites and mutation types.Meanwhile, possible pathogenesis of CACNA1E-related DEE and the progress of drug intervention were reviewed to provide references for the diagnosis and precise treatment of DEE.