AIM:To investigate if and how programmed death type-1(PD-1)expression affects the natural course of hepatitis B virus(HBV)infection. METHODS:Sixty-four patients in different natural stages of chronic HBV infection wer...AIM:To investigate if and how programmed death type-1(PD-1)expression affects the natural course of hepatitis B virus(HBV)infection. METHODS:Sixty-four patients in different natural stages of chronic HBV infection were enrolled in this study.PD-1 expression in total T cells was detected by flow cytometry.Levels of total CD8+T cell responses and proliferation in relation to PD-1 expression levels were analyzed with intracellular staining and PD-1/ PD-L1 blockage. RESULTS:The PD-1 expression in T cells was dynamically changed during the natural course of chronic HBV infection,did not significantly increase in the immune tolerance phase,and returned to normal in the inactive virus carrier stage.Blockage of the PD-1/PD-L1 pathway could not affect the T-cell response in the immune tolerance and inactive virus carrier stages of chronic HBV infection.However,it could significantly restore the T-cell response in the immune clearance stage of chronic HBV infection.Furthermore,the PD-1 expression level in T cells was associated with the alanine aminotransferase level during the immune clearance stage of chronic HBV infection. CONCLUSION:The PD-l/PD-L1 pathway plays a different role in T-cell response during the natural course of chronic HBV infection.展开更多
Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analges...Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.展开更多
Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the pos...Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the possi-ble mechanism.Methods.Human umbilical vein endothelial ce lls(HUVECs )were obtained from normal fetus,and cul-tured conventionally.Then the HUVECs were exposed to test agents(linolenic acid,linoleic acid,oleic acid,stearic acid and prostaglandin J 2 respectively)in varying concentrations with fresh media.RT -PCR and ELISA were applied to determine the expression of PPARs and PAI-1in HUVECs.Results.PPARα,PPARδand PPARγmRNA were detected by using RT-PCR in HUVECs.Treatment of HUVECs with PPARαand PPARγactivators---linolenic acid,linoleic acid,oleic acid and prostaglandin J 2 respectively,but not with stearic a cid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner.However,the mRNA expressions of 3subclasses of PPAR with their activators in HUVECs were not changed compared w ith controls.Conclusion.HUVECs express PPARs.PPARs activators may increase PAI-1expression in ECs,but the underlying mechanism remains uncle ar.Although PPARs expression was not enhanced after stimulated by their activators in ECs,the role of functionally active PPARs in regulating PA I-1expression in ECs needs to be further investigated by using transient gen e transfection assay.展开更多
The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regul...The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor(CB1R),which is strongly expressed in the amygdala of non-human primates(NHPs).However,it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases.Here,we investigated the role of CB1R by knocking down the cannabinoid receptor 1(CNR1)gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA.We found that CB1R knockdown in the amygdala induced anxiety-like behaviors,including disrupted night sleep,agitated psychomotor activity in new environments,and reduced social desire.Moreover,marmosets with CB1R-knockdown had up-regulated plasma cortisol levels.These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets,and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.展开更多
Aim: We demonstrated the risk of developing islet autoantibodies-Insulin Autoanti-bodies (IAAs) and Islets cell Autoantibodies (ICAs)-in type-1 diabetic relatives and newly diagnosed type-1 patients compared to non-di...Aim: We demonstrated the risk of developing islet autoantibodies-Insulin Autoanti-bodies (IAAs) and Islets cell Autoantibodies (ICAs)-in type-1 diabetic relatives and newly diagnosed type-1 patients compared to non-diabetic controls. We also aimed to determine the predictive strengths of both autoantibodies in the development of type-1 diabetes mellitus, and which of the two autoantibodies is a better predictive marker of type-1 diabetes mellitus among Nigerian adults. Methodology: A total number of four hundred and fifty five (455) subjects (211 (46%) males, and 244 (54%) females) aged between 35 - 76 years were recruited for the study. IAA and ICA levels were estimated using ELISA reagents from Biomerica Inc. Other parameters such as fasting blood sugar, urine glucose, and urine protein were assessed using standard biochemical techniques. Results: Relatives of type-1 diabetic patients and newly diagnosed type-1 diabetic patients were at greater risk (p < 0.05) of testing positive for more than one autoantibody (ICA and IAA) compared to non-diabetic controls. In addition, IAAs appeared to be better predictors or markers of type-1 diabetes mellitus compared to ICAs. Conclusion: The present study indicated a greater risk of autoim-mune destruction of the insulin producing beta cells of the pancrease of the type-1 relatives and newly diagnosed type-1 patients and suggests the need for periodic re-cruitment of individuals in the general population, siblings and relatives of type-1 diabetic patients for planned intervention trials. In addition, IAAs appeared to be better autoimmune markers of type-1 diabetes compared to ICAs.展开更多
Electricity price forecasting is a subset of energy and power forecasting that focuses on projecting commercial electricity market present and future prices.Electricity price forecasting have been a critical input to ...Electricity price forecasting is a subset of energy and power forecasting that focuses on projecting commercial electricity market present and future prices.Electricity price forecasting have been a critical input to energy corporations’strategic decision-making systems over the last 15 years.Many strategies have been utilized for price forecasting in the past,however Artificial Intelligence Techniques(Fuzzy Logic and ANN)have proven to be more efficient than traditional techniques(Regression and Time Series).Fuzzy logic is an approach that uses membership functions(MF)and fuzzy inference model to forecast future electricity prices.Fuzzy c-means(FCM)is one of the popular clustering approach for generating fuzzy membership functions.However,the fuzzy c-means algorithm is limited to producing only one type of MFs,Gaussian MF.The generation of various fuzzy membership functions is critical since it allows for more efficient and optimal problem solutions.As a result,for the best and most improved results for electricity price forecasting,an approach to generate multiple type-1 fuzzy MFs using FCM algorithm is required.Therefore,the objective of this paper is to propose an approach for generating type-1 fuzzy triangular and trapezoidal MFs using FCM algorithm to overcome the limitations of the FCM algorithm.The approach is used to compute and improve forecasting accuracy for electricity prices,where Australian Energy Market Operator(AEMO)data is used.The results show that the proposed approach of using FCM to generate type-1 fuzzy MFs is effective and can be adopted.展开更多
Ethno-pharmaceutical products have received a lot of international attention in the scientific community in the management of diabetes mellitus (DM). In this study we determined the anti-diabetic and high dosage effec...Ethno-pharmaceutical products have received a lot of international attention in the scientific community in the management of diabetes mellitus (DM). In this study we determined the anti-diabetic and high dosage effects of Bidens pliosa in type 1 DM (T1DM). Methodology: Thirty rats were divided into six groups and subgrouped into the extract and non extract treatment groups. The extract treated group was subdivided into three groups which received 200 mg/kg, 400 mg/ kg and 800 mg/kg dosage treatments respectively. The blood glucose levels were monitored using a standard glucometer for one month, and biochemical analysis of the two liver function enzymes;Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) were carried out at the Institute of Biomedical Research (IBR-KIU-WC) at the end of week IV. The study revealed that Bidens pilosa maintained hypoglycemia for a period of two weeks and this status was lost in subsequent weeks. T1DM rats treated with a dosage of 200 mg/kg showed a better recovery (355.25 - 164.5 mg/dl) of the glucose levels, followed by those that were being treated at 400 mg/kg. The AST and ALT enzymes in blood varied with a mean ± SEM (33.72 ± 32.32 to -7.23 ± 12.61 IU and 22.98 ± 11.12 to 42 ± 38.2 IU, respectively) in both the glibencimide? and in the 800 mg/ kg treatment groups in the study. High dosages of extract were associated (P = 0.049) with increased systemic enzyme leakage. In conclusion, tissue degeneration caused by high levels of the extract was accompanied by leakage of various enzymes (AST and ALT) into the blood, which could be a major etiological factor for the development of secondary systemic pathologies, thus potentially worsening the effects of an existing T1DM prognosis in human patients. The preliminary results indicate that a dose of Bidens pilosa has an anti-diabetic effect for a limited initial duration before starting to cause systemic toxicological effects. It is highly recommended that further investigation into the cellular mechanisms and consequences of any therapy involving Bidens pilosa be carried out.展开更多
Background and Objectives: The cornerstone of the regulation fibrinolytic system is plasminogen activator inhibitor type-1. The 4G/5G polymorphism in the PAI-1 gene is a key genetic predictor of increased plasma level...Background and Objectives: The cornerstone of the regulation fibrinolytic system is plasminogen activator inhibitor type-1. The 4G/5G polymorphism in the PAI-1 gene is a key genetic predictor of increased plasma levels which is the most polymorphism associated with cardiovascular complications. The 4G carriers have six times higher PAI-1 levels than 5G carriers leading to an increase in the level of plasma inhibitor by about 25% more than 5G allele (wide type). Type 2 diabetes presents symptoms of hypercoagulability and hypofibrinolytic system that lead to contribute in the atherothrombosis and then the myocardial infarction (MI). These findings supported the hypothesis that there is a link between diabetes patients and this SNP. There is no data about the prevalence of this allele in Sudanese diabetic patients with type 2 and the allele differs in prevalence according to ethnicity, for these reasons, the aim of this study was to determine the allele and genotype frequency of the rs1799889 among Sudanese T2DM patients. Methods: A case-control study was conducted using 70 diagnosed diabetes type 2 patients and 50 healthy individuals as the control group. AS-PCR technique was used to genotype the rs1799889, and the allelic frequency was calculated according to Hardy-Weinberg equilibrium. Allelic frequencies were assessed using gene counting (SNP-STAT software V. Release 3.13), and genotypes were scored. Results: The result showed that 4G allele frequency was 28% among Sudanese diabetic patients without statistical difference when compared with control group (P-value = 0.998) but, high when compared with other studies in African population 13% and very low when compared with white and Indian populations studies. Conclusion: By this study, the allele frequency was higher in Sudanese diabetic patients with type 2, and also we need another study to evaluate the effect of this polymorphism in thrombophilic complications in Sudanese diabetic patients with type 2.展开更多
Objective To investigate the mechanism of prolonged uterine hemorrhage after terminating early pregnancy by mifepristone plus misoprostol.Methods Forty-five decidua specimens were obtained from 45 pregnant women wit...Objective To investigate the mechanism of prolonged uterine hemorrhage after terminating early pregnancy by mifepristone plus misoprostol.Methods Forty-five decidua specimens were obtained from 45 pregnant women with amenorrhea of 6-7 week duration. Fifteen women were treated with mifepristone and 15 were treated with mifepristone plus misoprostol. The remaining 15 served as controls. The tPA and PAI-1 mRNA levels were estimated by reverse transcription-polymerase chain reaction. Chromogenic assay and enzyme-linked immunosorbent assay were used to detect tPA activity and PAI-1 protein level in decidua. Results The activities of tPA in the mifepristone plus misoprostol group and in the mifepristone group were 46.91±20.74?IU/mg*protein and 64.25±35.81?IU/mg*protein respectively, lower than those in the normal decidua group (99.76±58.61?IU/mg*protein, P<0.05). tPA mRNA levels in the mifepristone plus misoprostol group were the highest (1.43±0.39) among the groups. In the mifepristone group, tPA mRNA level (0.90±0.16) was not significantly different from that in the normal decidua group (0.94±0.17). The protein and mRNA expression levels of PAI-1 were not significantly different among the three groups (P>0.05).Conclusions Mifepristone plus misoprostol decreased tPA activity in human early decidua by post-transcription pathways, which may influence decidua shedding, endometrial angiogenesis, endometrial remodeling, and cause prolonged uterine hemorrhage after drug abortion.展开更多
目的为受体相互作用蛋白激酶1(RIPK1)抑制剂的开发及作用机制研究提供参考。方法采用计算机检索2005年至2024年PubMed、Web of Science、中国知网等数据库中RIPK1抑制剂的相关研究文献,总结RIPK1的结构、生物学功能与影响疾病,以及其抑...目的为受体相互作用蛋白激酶1(RIPK1)抑制剂的开发及作用机制研究提供参考。方法采用计算机检索2005年至2024年PubMed、Web of Science、中国知网等数据库中RIPK1抑制剂的相关研究文献,总结RIPK1的结构、生物学功能与影响疾病,以及其抑制剂的分类。结果RIPK1为包含671个氨基酸的多功能蛋白,通过其激酶结构域、调节区域、死亡结构域、受体相互作用蛋白同型相互作用基序(RHIM)结构域在细胞死亡、炎性反应、肿瘤免疫反应中发挥重要作用。RIPK1与多发性硬化症、肌萎缩性侧索硬化症等慢性神经退行性疾病,炎症性肠病、银屑病等免疫和自身炎症性疾病,胶质母细胞瘤、黑色素瘤等肿瘤的发生与发展密切相关。基于作用构象和结合位点,RIPK1可分为Ⅰ型、Ⅱ型、Ⅲ型三磷酸腺苷竞争性抑制剂;基于化学结构,RIPK1可分为Necrostatin-1(Nec-1)及其衍生物类、苯并氧氮杂酮类、二氢吡唑类、苯并噻唑类、天然产物类及其衍生物类RIPK1抑制剂。结论RIPK1抑制剂研究在分子机制、构效关系及药物设计方面取得了显著进展,在基础研究与临床应用中有广阔前景。随着对RIPK1生物学功能的深入理解及新一代抑制剂的研发,RIPK1抑制剂有望为多种疾病提供新的治疗策略。展开更多
We present some known-key distinguishers for a type-1 Feistel scheme with a permutation as the round function. To be more specific, the 29-round known-key truncated differential distinguishers are given for the 256-bi...We present some known-key distinguishers for a type-1 Feistel scheme with a permutation as the round function. To be more specific, the 29-round known-key truncated differential distinguishers are given for the 256-bit type-1 Feistel scheme with an SP （substitution-permutation） round function by using the rebound attack, where the S-boxes have perfect differential and linear properties and the linear diffusion layer has a maximum branch number. For two 128-bit versions, the distinguishers can be applied on 25- round structures. Based on these distinguishers, we construct near-collision attacks on these schemes with MMO （Matyas- Meyer-Oseas） and MP （Miyaguchi-Preneel） hashing modes, and propose the 26-round and 22-round near-collision attacks for two 256-bit schemes and two 128-bit schemes, respectively. We apply the near-collision attack on MAME and obtain a 26-round near-collision attack. Using the algebraic degree and some integral properties, we prove the correctness of the 31-round known-key integral distinguisher proposed by Sasaki et al. We show that if the round function is a permutation, the integral distinguisher is suitable for a type-1 Feistel scheme of any size.展开更多
New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (bu...New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (but not uPA) and PAI-1 secretion in the culture are modified by FSH, forskolin, dbcAMP, GnRH, PMA and growth factors (EGF and FGF), but not by hCG and androstenedione (△4); (iii) in vitro secretion of tPA and PA-PAI-1 complexes of Sertoli cells are greatly enhanced by presence of Leydig cells which produce negligible tPA but measurable PAI-1 activity;(iv) combination culture of Sertoli and Leydig cells remarkably increases FSH-induced PAI-1 activity and decreases hCG- and forskolin-induced inhibitor activity as compared with that of two cell types cultured alone. These data suggest that rat Sertoli cells, similar to ovarian granulosa cells, are capable of secreting both tPA and uPA, as well as PAI-1. The interaction of Sertoli cells and Leydig cells is essential for the cells to response to hormone stimulation for tPA and PAI-1 secretion.展开更多
Background This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 （HIV-1） subtype B and to compare the concordance between the phenotypic resistance and genotyp...Background This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 （HIV-1） subtype B and to compare the concordance between the phenotypic resistance and genotypic resistance. Methods The genotypic resistance assay for the HIV-1 clinical isolates was performed. One isolate without resistance mutation was chosen as a drug-sensitive reference strain and seven subtype B isolates with resistance mutations were phenotypically tested. Fifty percent inhibitory concentrations （IC50） between resistant and sensitive viruses were compared. The resistance extent was determined by the folds of the increased IC50. The concordance between the phenotypic resistance and genotypic resistance was also analyzed. Results IC50 of resistant isolates were 0.0006--0.1300 μmol/L for zidovudine （AZT）, 0.0016--0.0390 μmol/L for lamivudine （3TC）, 0.0104--0.4234 μmol/L for nevirapine （NVP）, and 0.0163--0.1142 μmol/L for indinavir （IDV）, respectively. Genotypic and phenotypic resistance assays indicated that the resistant strains were intermediately and highly resistant to nucleotide analog reverse transcriptase inhibitors and non-nucleotide analog reverse transcriptase inhibitors. The phenotypic assay was consistent with the genotypic assay. For measuring the potential resistance, the genotypic assay was more sensitive than the phenotypic. In evaluating the resistance to protease inhibitors, these two assays were discrepant. Conclusions Both the phenotypic and genotypic assays indicate that the resistant viruses exist in HIV-infected patients in China who have received treatment. Phenotypic and genotypic assays have high concordance, and the genotypic assay could replace the phenotypic assay to predict the HIV- 1 resistance.展开更多
INCREASING evidence has demonstrated that the locally controlled proteolytic activity generatedby coordinated expression of tPA and PAI-1 in different tissues may play an important role inmany reproductive events. The...INCREASING evidence has demonstrated that the locally controlled proteolytic activity generatedby coordinated expression of tPA and PAI-1 in different tissues may play an important role inmany reproductive events. These are largely related to fibrinolytic activity. They include folli-cle rupture, luteolysis, spermatogenesis and trophoblast implantation. Parturition, whichis a complex process, may also be associated with tissue destruction. Detachment of placentaldecidua and partial breakdown of fetal membranes are possible examples. It has been展开更多
基金Supported by Grants from the"Yucai"Research Program of Changhai Hospital
文摘AIM:To investigate if and how programmed death type-1(PD-1)expression affects the natural course of hepatitis B virus(HBV)infection. METHODS:Sixty-four patients in different natural stages of chronic HBV infection were enrolled in this study.PD-1 expression in total T cells was detected by flow cytometry.Levels of total CD8+T cell responses and proliferation in relation to PD-1 expression levels were analyzed with intracellular staining and PD-1/ PD-L1 blockage. RESULTS:The PD-1 expression in T cells was dynamically changed during the natural course of chronic HBV infection,did not significantly increase in the immune tolerance phase,and returned to normal in the inactive virus carrier stage.Blockage of the PD-1/PD-L1 pathway could not affect the T-cell response in the immune tolerance and inactive virus carrier stages of chronic HBV infection.However,it could significantly restore the T-cell response in the immune clearance stage of chronic HBV infection.Furthermore,the PD-1 expression level in T cells was associated with the alanine aminotransferase level during the immune clearance stage of chronic HBV infection. CONCLUSION:The PD-l/PD-L1 pathway plays a different role in T-cell response during the natural course of chronic HBV infection.
基金This work was supported by the National Natural Science Foundation of China(Grant No.82071251)National Key Research and Development Program of China(Grant No.2018YFC2001802)Hubei Province Key Research and Development Program(Grant No.2021BCA145).
文摘Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.
文摘Objective.To investigate the effect of peroxis ome proliferator-activated recept ors(PPARs )activators on plasminogen activator inhibitor ty pe-1(PAI-1)expression in human umbilical vein e ndothelial cells and the possi-ble mechanism.Methods.Human umbilical vein endothelial ce lls(HUVECs )were obtained from normal fetus,and cul-tured conventionally.Then the HUVECs were exposed to test agents(linolenic acid,linoleic acid,oleic acid,stearic acid and prostaglandin J 2 respectively)in varying concentrations with fresh media.RT -PCR and ELISA were applied to determine the expression of PPARs and PAI-1in HUVECs.Results.PPARα,PPARδand PPARγmRNA were detected by using RT-PCR in HUVECs.Treatment of HUVECs with PPARαand PPARγactivators---linolenic acid,linoleic acid,oleic acid and prostaglandin J 2 respectively,but not with stearic a cid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner.However,the mRNA expressions of 3subclasses of PPAR with their activators in HUVECs were not changed compared w ith controls.Conclusion.HUVECs express PPARs.PPARs activators may increase PAI-1expression in ECs,but the underlying mechanism remains uncle ar.Although PPARs expression was not enhanced after stimulated by their activators in ECs,the role of functionally active PPARs in regulating PA I-1expression in ECs needs to be further investigated by using transient gen e transfection assay.
基金supported by the Zhejiang Province Natural Science Foundation of China(LD22H090003)Key-Area Research and Development Program of Guangdong Province(2019B030335001 and 2018B030334001)+3 种基金the National Natural Science Foundation of China(31871070,82090031,32071097,31871056,and 32170991)the Key R&D Program of Zhejiang Province(2020C03009)Fundamental Research Funds for the Central Universities(2021FZZX001-37)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057).
文摘The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor(CB1R),which is strongly expressed in the amygdala of non-human primates(NHPs).However,it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases.Here,we investigated the role of CB1R by knocking down the cannabinoid receptor 1(CNR1)gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA.We found that CB1R knockdown in the amygdala induced anxiety-like behaviors,including disrupted night sleep,agitated psychomotor activity in new environments,and reduced social desire.Moreover,marmosets with CB1R-knockdown had up-regulated plasma cortisol levels.These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets,and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.
文摘Aim: We demonstrated the risk of developing islet autoantibodies-Insulin Autoanti-bodies (IAAs) and Islets cell Autoantibodies (ICAs)-in type-1 diabetic relatives and newly diagnosed type-1 patients compared to non-diabetic controls. We also aimed to determine the predictive strengths of both autoantibodies in the development of type-1 diabetes mellitus, and which of the two autoantibodies is a better predictive marker of type-1 diabetes mellitus among Nigerian adults. Methodology: A total number of four hundred and fifty five (455) subjects (211 (46%) males, and 244 (54%) females) aged between 35 - 76 years were recruited for the study. IAA and ICA levels were estimated using ELISA reagents from Biomerica Inc. Other parameters such as fasting blood sugar, urine glucose, and urine protein were assessed using standard biochemical techniques. Results: Relatives of type-1 diabetic patients and newly diagnosed type-1 diabetic patients were at greater risk (p < 0.05) of testing positive for more than one autoantibody (ICA and IAA) compared to non-diabetic controls. In addition, IAAs appeared to be better predictors or markers of type-1 diabetes mellitus compared to ICAs. Conclusion: The present study indicated a greater risk of autoim-mune destruction of the insulin producing beta cells of the pancrease of the type-1 relatives and newly diagnosed type-1 patients and suggests the need for periodic re-cruitment of individuals in the general population, siblings and relatives of type-1 diabetic patients for planned intervention trials. In addition, IAAs appeared to be better autoimmune markers of type-1 diabetes compared to ICAs.
基金This research is an ongoing research supported by Yayasan UTP Grant(015LC0-321&015LC0-311)Fundamental Research Grant Scheme(FRGS/1/2018/ICT02/UTP/02/1)a grant funded by the Ministry of Higher Education,Malaysia.
文摘Electricity price forecasting is a subset of energy and power forecasting that focuses on projecting commercial electricity market present and future prices.Electricity price forecasting have been a critical input to energy corporations’strategic decision-making systems over the last 15 years.Many strategies have been utilized for price forecasting in the past,however Artificial Intelligence Techniques(Fuzzy Logic and ANN)have proven to be more efficient than traditional techniques(Regression and Time Series).Fuzzy logic is an approach that uses membership functions(MF)and fuzzy inference model to forecast future electricity prices.Fuzzy c-means(FCM)is one of the popular clustering approach for generating fuzzy membership functions.However,the fuzzy c-means algorithm is limited to producing only one type of MFs,Gaussian MF.The generation of various fuzzy membership functions is critical since it allows for more efficient and optimal problem solutions.As a result,for the best and most improved results for electricity price forecasting,an approach to generate multiple type-1 fuzzy MFs using FCM algorithm is required.Therefore,the objective of this paper is to propose an approach for generating type-1 fuzzy triangular and trapezoidal MFs using FCM algorithm to overcome the limitations of the FCM algorithm.The approach is used to compute and improve forecasting accuracy for electricity prices,where Australian Energy Market Operator(AEMO)data is used.The results show that the proposed approach of using FCM to generate type-1 fuzzy MFs is effective and can be adopted.
文摘Ethno-pharmaceutical products have received a lot of international attention in the scientific community in the management of diabetes mellitus (DM). In this study we determined the anti-diabetic and high dosage effects of Bidens pliosa in type 1 DM (T1DM). Methodology: Thirty rats were divided into six groups and subgrouped into the extract and non extract treatment groups. The extract treated group was subdivided into three groups which received 200 mg/kg, 400 mg/ kg and 800 mg/kg dosage treatments respectively. The blood glucose levels were monitored using a standard glucometer for one month, and biochemical analysis of the two liver function enzymes;Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) were carried out at the Institute of Biomedical Research (IBR-KIU-WC) at the end of week IV. The study revealed that Bidens pilosa maintained hypoglycemia for a period of two weeks and this status was lost in subsequent weeks. T1DM rats treated with a dosage of 200 mg/kg showed a better recovery (355.25 - 164.5 mg/dl) of the glucose levels, followed by those that were being treated at 400 mg/kg. The AST and ALT enzymes in blood varied with a mean ± SEM (33.72 ± 32.32 to -7.23 ± 12.61 IU and 22.98 ± 11.12 to 42 ± 38.2 IU, respectively) in both the glibencimide? and in the 800 mg/ kg treatment groups in the study. High dosages of extract were associated (P = 0.049) with increased systemic enzyme leakage. In conclusion, tissue degeneration caused by high levels of the extract was accompanied by leakage of various enzymes (AST and ALT) into the blood, which could be a major etiological factor for the development of secondary systemic pathologies, thus potentially worsening the effects of an existing T1DM prognosis in human patients. The preliminary results indicate that a dose of Bidens pilosa has an anti-diabetic effect for a limited initial duration before starting to cause systemic toxicological effects. It is highly recommended that further investigation into the cellular mechanisms and consequences of any therapy involving Bidens pilosa be carried out.
文摘Background and Objectives: The cornerstone of the regulation fibrinolytic system is plasminogen activator inhibitor type-1. The 4G/5G polymorphism in the PAI-1 gene is a key genetic predictor of increased plasma levels which is the most polymorphism associated with cardiovascular complications. The 4G carriers have six times higher PAI-1 levels than 5G carriers leading to an increase in the level of plasma inhibitor by about 25% more than 5G allele (wide type). Type 2 diabetes presents symptoms of hypercoagulability and hypofibrinolytic system that lead to contribute in the atherothrombosis and then the myocardial infarction (MI). These findings supported the hypothesis that there is a link between diabetes patients and this SNP. There is no data about the prevalence of this allele in Sudanese diabetic patients with type 2 and the allele differs in prevalence according to ethnicity, for these reasons, the aim of this study was to determine the allele and genotype frequency of the rs1799889 among Sudanese T2DM patients. Methods: A case-control study was conducted using 70 diagnosed diabetes type 2 patients and 50 healthy individuals as the control group. AS-PCR technique was used to genotype the rs1799889, and the allelic frequency was calculated according to Hardy-Weinberg equilibrium. Allelic frequencies were assessed using gene counting (SNP-STAT software V. Release 3.13), and genotypes were scored. Results: The result showed that 4G allele frequency was 28% among Sudanese diabetic patients without statistical difference when compared with control group (P-value = 0.998) but, high when compared with other studies in African population 13% and very low when compared with white and Indian populations studies. Conclusion: By this study, the allele frequency was higher in Sudanese diabetic patients with type 2, and also we need another study to evaluate the effect of this polymorphism in thrombophilic complications in Sudanese diabetic patients with type 2.
文摘Objective To investigate the mechanism of prolonged uterine hemorrhage after terminating early pregnancy by mifepristone plus misoprostol.Methods Forty-five decidua specimens were obtained from 45 pregnant women with amenorrhea of 6-7 week duration. Fifteen women were treated with mifepristone and 15 were treated with mifepristone plus misoprostol. The remaining 15 served as controls. The tPA and PAI-1 mRNA levels were estimated by reverse transcription-polymerase chain reaction. Chromogenic assay and enzyme-linked immunosorbent assay were used to detect tPA activity and PAI-1 protein level in decidua. Results The activities of tPA in the mifepristone plus misoprostol group and in the mifepristone group were 46.91±20.74?IU/mg*protein and 64.25±35.81?IU/mg*protein respectively, lower than those in the normal decidua group (99.76±58.61?IU/mg*protein, P<0.05). tPA mRNA levels in the mifepristone plus misoprostol group were the highest (1.43±0.39) among the groups. In the mifepristone group, tPA mRNA level (0.90±0.16) was not significantly different from that in the normal decidua group (0.94±0.17). The protein and mRNA expression levels of PAI-1 were not significantly different among the three groups (P>0.05).Conclusions Mifepristone plus misoprostol decreased tPA activity in human early decidua by post-transcription pathways, which may influence decidua shedding, endometrial angiogenesis, endometrial remodeling, and cause prolonged uterine hemorrhage after drug abortion.
文摘目的为受体相互作用蛋白激酶1(RIPK1)抑制剂的开发及作用机制研究提供参考。方法采用计算机检索2005年至2024年PubMed、Web of Science、中国知网等数据库中RIPK1抑制剂的相关研究文献,总结RIPK1的结构、生物学功能与影响疾病,以及其抑制剂的分类。结果RIPK1为包含671个氨基酸的多功能蛋白,通过其激酶结构域、调节区域、死亡结构域、受体相互作用蛋白同型相互作用基序(RHIM)结构域在细胞死亡、炎性反应、肿瘤免疫反应中发挥重要作用。RIPK1与多发性硬化症、肌萎缩性侧索硬化症等慢性神经退行性疾病,炎症性肠病、银屑病等免疫和自身炎症性疾病,胶质母细胞瘤、黑色素瘤等肿瘤的发生与发展密切相关。基于作用构象和结合位点,RIPK1可分为Ⅰ型、Ⅱ型、Ⅲ型三磷酸腺苷竞争性抑制剂;基于化学结构,RIPK1可分为Necrostatin-1(Nec-1)及其衍生物类、苯并氧氮杂酮类、二氢吡唑类、苯并噻唑类、天然产物类及其衍生物类RIPK1抑制剂。结论RIPK1抑制剂研究在分子机制、构效关系及药物设计方面取得了显著进展,在基础研究与临床应用中有广阔前景。随着对RIPK1生物学功能的深入理解及新一代抑制剂的研发,RIPK1抑制剂有望为多种疾病提供新的治疗策略。
基金Acknowledgements This research project was promoted by the Scientific Research Foundation for High Level Talents of Henan Normal University （01016500148） and the National Natural Science Foundation of China （Grant Nos. 61272476, 61232009）.
文摘We present some known-key distinguishers for a type-1 Feistel scheme with a permutation as the round function. To be more specific, the 29-round known-key truncated differential distinguishers are given for the 256-bit type-1 Feistel scheme with an SP （substitution-permutation） round function by using the rebound attack, where the S-boxes have perfect differential and linear properties and the linear diffusion layer has a maximum branch number. For two 128-bit versions, the distinguishers can be applied on 25- round structures. Based on these distinguishers, we construct near-collision attacks on these schemes with MMO （Matyas- Meyer-Oseas） and MP （Miyaguchi-Preneel） hashing modes, and propose the 26-round and 22-round near-collision attacks for two 256-bit schemes and two 128-bit schemes, respectively. We apply the near-collision attack on MAME and obtain a 26-round near-collision attack. Using the algebraic degree and some integral properties, we prove the correctness of the 31-round known-key integral distinguisher proposed by Sasaki et al. We show that if the round function is a permutation, the integral distinguisher is suitable for a type-1 Feistel scheme of any size.
基金Project supported by the National Natural Science Foundation of China and State Family Planning Commission.
文摘New data are provided to show that (i) rat Sertoli cells produce two types of plasminogen activators, tissue type (tPA) and urokinase type (uPA), and a plasminogen activator inhibitor type-1 (PAI-1); (ii) both tPA (but not uPA) and PAI-1 secretion in the culture are modified by FSH, forskolin, dbcAMP, GnRH, PMA and growth factors (EGF and FGF), but not by hCG and androstenedione (△4); (iii) in vitro secretion of tPA and PA-PAI-1 complexes of Sertoli cells are greatly enhanced by presence of Leydig cells which produce negligible tPA but measurable PAI-1 activity;(iv) combination culture of Sertoli and Leydig cells remarkably increases FSH-induced PAI-1 activity and decreases hCG- and forskolin-induced inhibitor activity as compared with that of two cell types cultured alone. These data suggest that rat Sertoli cells, similar to ovarian granulosa cells, are capable of secreting both tPA and uPA, as well as PAI-1. The interaction of Sertoli cells and Leydig cells is essential for the cells to response to hormone stimulation for tPA and PAI-1 secretion.
基金This study was supported by a grant from the "Tenth Five-Year" Key Project (No. 2004-BA-719A-05).
文摘Background This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 （HIV-1） subtype B and to compare the concordance between the phenotypic resistance and genotypic resistance. Methods The genotypic resistance assay for the HIV-1 clinical isolates was performed. One isolate without resistance mutation was chosen as a drug-sensitive reference strain and seven subtype B isolates with resistance mutations were phenotypically tested. Fifty percent inhibitory concentrations （IC50） between resistant and sensitive viruses were compared. The resistance extent was determined by the folds of the increased IC50. The concordance between the phenotypic resistance and genotypic resistance was also analyzed. Results IC50 of resistant isolates were 0.0006--0.1300 μmol/L for zidovudine （AZT）, 0.0016--0.0390 μmol/L for lamivudine （3TC）, 0.0104--0.4234 μmol/L for nevirapine （NVP）, and 0.0163--0.1142 μmol/L for indinavir （IDV）, respectively. Genotypic and phenotypic resistance assays indicated that the resistant strains were intermediately and highly resistant to nucleotide analog reverse transcriptase inhibitors and non-nucleotide analog reverse transcriptase inhibitors. The phenotypic assay was consistent with the genotypic assay. For measuring the potential resistance, the genotypic assay was more sensitive than the phenotypic. In evaluating the resistance to protease inhibitors, these two assays were discrepant. Conclusions Both the phenotypic and genotypic assays indicate that the resistant viruses exist in HIV-infected patients in China who have received treatment. Phenotypic and genotypic assays have high concordance, and the genotypic assay could replace the phenotypic assay to predict the HIV- 1 resistance.
文摘INCREASING evidence has demonstrated that the locally controlled proteolytic activity generatedby coordinated expression of tPA and PAI-1 in different tissues may play an important role inmany reproductive events. These are largely related to fibrinolytic activity. They include folli-cle rupture, luteolysis, spermatogenesis and trophoblast implantation. Parturition, whichis a complex process, may also be associated with tissue destruction. Detachment of placentaldecidua and partial breakdown of fetal membranes are possible examples. It has been
