The synergistic regulatory effect of PTP1B and PTK inhibitors on the development of Oedaleus decorus asiaticus Bei-Bienko

Tyrosine phosphorylation is crucial for controlling normal cell growth,survival,intercellular communication,gene transcription,immune responses,and other processes.protein tyrosine phosphatase(PTP)and protein tyrosine kinases(PTK)can achieve this goal by regulating multiple signaling pathways.Oedaleus decorus asiaticus is an important pest that infests the Mongolian Plateau grassland.We aimed to evaluate the survival rate,growth rate,overall performance,and ovarian developmental morphology of the 4th instar nymphs of O.decorus asiaticus while inhibiting the activity of protein tyrosine phosphatase-1B(PTP1B)and PTK.In addition,the expression and protein phosphorylation levels of key genes in the MAPK signaling pathway and antioxidant enzyme activity were assessed.The results showed no significant differences in survival rate,growth rate,or overall performance between PTP1B inhibitor treatment and control.However,after PTK inhibitor treatment,these indexes were significantly lower than those in the control.The ovarian size of female larvae after 15 days of treatment with PTK inhibitors showed significantly slower development,while female larvae treated with PTP1B exhibited faster ovarian growth than the control group.In comparison to controls and nymphs treated with PTK inhibitors,the expression and phosphorylation levels of key genes in the MAPK signaling pathway under PTP1B inhibitor treatments were significantly higher in 4th instar nymphs.However,reactiveoxygen(ROS)species levels and the activities of NADPH oxidase and other antioxidant enzymes were considerably reduced,although they were significantly greater in the PTK inhibitor treatment.The results suggest that PTP1B and PTK feedback inhibition in the mitogen-activated-protein kinases(MAPK)signal transfer can regulate the physiological metabolism of the insect as well as its developmental rate.These findings can facilitate future uses of PTP1B and PTK inhibitors in controlling insect development to help control pest populations.

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors

This editorial commented on an article in the World Journal of Gastroenterology titled“Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors:Case Report and Literature Analysis”by Colapietro et al.In this editorial,we focused on providing a more comprehensive exploration of hepatitis B virus reactivation(HBVr)associated with the usage of tyrosine kinase inhibitors(TKIs).It includes insights into the mechanisms underlying HBV reactivation,the temporal relationship between TKIs and HBV reactivation,and preventive measures.The aim is to understand the need for nucleos(t)ide analogs(NAT)and serial blood tests for early recognition of reactivation and acute liver injury,along with management strategies.TKIs are considered to be an intermediate(1%-10%)of HBVr.Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen,anti-hepatitis B core antigen(HBc),and anti-hepatitis B surface antibody.Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV.Nucleoside or nucleotide analogs(NAs)like entecavir(ETV),tenofovir disoproxil fumarate(TDF),and tenofovir alafenamide(TAF)form the basis of HBV reactivation prophylaxis and treatment during immunosuppression.Conversely,lamivudine,telbivudine,and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains.However,these less effective NAs may still be utilized in cases where ETV,TDF,and TAF are not feasible treatment options.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors

In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Three New Hydroxytetradecenals from Amomum tsao-ko with Protein Tyrosine Phosphatase 1B and Glycogen Phosphorylase Inhibitory Activity

The fruits of Amomum tsao-ko(Cao-Guo)were documented in Chinese Pharmacopoeia for the treatment of abdominal pain,vomiting,and plague.In our previous study,a series of diarylheptanes and flavonoids withα-glucosidase and protein tyrosine phosphatase 1B(PTP1B)inhibitory activity have been reported from the middle-polarity part of A.tsao-ko,whereas the antidiabetic potency of the low-polarity constituents is still unclear.In this study,three new hydroxytetradecenals,(2E,4E,8Z,11Z)-6R-hydroxytetradeca-2,4,8,11-tetraenal(1),(2E,4E,8Z)-6R-hydroxytetradeca-2,4,8-trienal(2)and(2E,4E)-6R-hydroxytetradeca-2,4-dienal(3)were obtained from the volatile oils of A.tsao-ko.The structures of compounds 1–3 were determined using spectroscopic data involving 1D and 2D nuclear magnetic resonance(NMR),high-resolution mass spectra(HRMS),and specific rotation([α]D).Their hypoglycemic activity was evaluated against glycogen phosphorylase(GPa)and PTP1B.Compounds 1 and 2 displayed moderate activity against PTP1B with inhibition rates of 33.8%−50.3%at 100 and 200μM.Moreover,compound 1 exhibited an obvious inhibitory effect on GPa(IC50=31.7μM),whereas compound 2 was inactive.This study demonstrates hydroxytetradecenals as the characteristic components of A.tsao-ko with therapeutic potential in diabetes.

Tissue inhibitor of metalloproteinase-3 expression affects clinicopathological features and prognosis of aflatoxin B1-related hepatocellular carcinoma

BACKGROUND The dysregulation of tissue inhibitor of metalloproteinase-3(TIMP3)was positively correlated with the progression of hepatocellular carcinoma(HCC).However,it is not clear whether TIMP3 expression is associated with the clinico-pathological features and prognosis of aflatoxin B1(AFB1)-related HCC(AHCC).A retrospective study,including 182 patients with AHCC,was conducted to explore the link between TIMP3 expression in cancerous tissues and the clinico-pathological characteristics and prognosis of AHCC.TIMP3 expression was detected by immunohistochemistry and its effects on the clinicopathological features and prognosis of AHCC were evaluated by Kaplan-Meier survival analysis and Cox regression survival analysis.Odds ratio,hazard ratio(HR),median overall survival time(MST),median tumor recurrence-free survival time(MRT),and corresponding 95%confidential interval(CI)was calculated to RESULTS Kaplan-Meier survival analysis showed that compared with high TIMP3 expression,low TIMP3 expression in tumor tissues significantly decreased the MST(36.00 mo vs 18.00 mo)and MRT(32.00 mo vs 16 mo)of patients with AHCC.Multivariate Cox regression survival analysis further proved that decreased expression of TIMP3 increased the risk of death(HR=2.85,95%CI:2.04-4.00)and tumor recurrence(HR=2.26,95%CI:1.57-3.26).Furthermore,decreased expression of TIMP3 protein in tissues with AHCC was significantly correlated with tumor clinicopatho-logical features,such as tumor size,tumor grade and stage,tumor microvessel density,and tumor blood invasion.Additionally,TIMP3 protein expression was also negatively associated with amount of AFB1-DNA adducts in tumor tissues.CONCLUSION These findings indicate that the dysregulation of TIMP3 expression is related to AHCC biological behaviors and affects tumor outcome,suggesting that TIMP3 may act as a prognostic biomarker for AHCC.

Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinson’s Disease: A Systematic Review and Meta-Analysis

Objective: In the manuscript titled Monoamine Oxidase-B Inhibitor Rasagiline Effects on Motor and Non-Motor Symptoms in Individuals with Parkinsons Disease: A Systematic Review and Meta-Analysis, the objective was to conduct a systematic review with meta-analysis to investigate the effects that Rasagiline has on motor and non-motor symptoms in individuals with PD. Introduction: Rasagiline is a second-generation monoamine oxidase-B (MAO-B) inhibitor used both as monotherapy and adjunctive therapy for Parkinsons Disease (PD). Methods: A systematic literature search and meta-analysis were performed with randomized control trials that investigated the effects of Rasagiline on motor and non-motor symptoms in individuals with PD. The systematic search was conducted in PubMed, Cochrane, and EBSCO databases. Methodological quality was assessed using the Cochrane Grading Recommendations Assessment, Development and Evaluation approach. Results: Fourteen studies were included in our review. There were trivial to small and statistically significant improvements in motor symptoms for individuals with PD treated with Rasagiline compared to placebo. Non-motor symptoms showed no significant improvement with Rasagiline compared to placebo in five of six meta-analyses. Results were based on very low to moderate certainty of evidence. Conclusion: 1 mg/day Rasagiline significantly improved Parkinsonian motor symptoms in individuals with PD compared with placebo. For all outcomes, the 1 mg/day Rasagiline group was favored over the placebo group.

大肠癌中Survivin、NF-κB、I-κB及Caspase-3的表达及意义

目的研究Survivin、NF-κB、I-κB及Caspase-3在大肠癌中的表达及临床病理。方法采用Max Vision免疫组织化学法分别检测大肠腺癌、大肠腺瘤及正常大肠黏膜组织中Survivin、NF-κB、I-κB及Caspase-3的表达,分析表达结果与患者的年龄、性别、肿瘤组织浸润程度、分化程度、Dukes分期及淋巴结转移之间的关系。结果大肠腺癌组织中Survivin和NF-κB阳性表达(100%,100%)高于大肠腺瘤(80%,90%)及大肠正常黏膜组织(25%,35%,P<0.01,P<0.05)。大肠腺癌中I-κB和Caspase-3的阳性表达(22%,24%)明显低于大肠腺瘤组织(80%,70%)及大肠正常黏膜组织(80%,85%,P<0.01)。大肠腺癌中NF-κB和I-κB的阳性表达与Dukes分期及淋巴结转移密切相关(P<0.05)。在大肠腺癌中Survivin的阳性表达与Caspase-3呈显著负相关(r=-0.697,P<0.01),与NF-κB呈显著正相关(r=0.639,P<0.01),与I-κB呈显著负相关(r=-0.613,P<0.01);Caspase-3的阳性表达与NF-κB呈显著负相关(r=-0.601,P<0.01),与I-κB呈显著正相关(r=0.616,P<0.01);NF-κB的表达与I-κB呈显著负相关(r=-0.822,P<0.01)。结论 Survivin、NF-κB高表达及I-κB与Caspase-3低表达是大肠腺癌发生的必然事件,联合检测上述指标有助于大肠腺癌的诊断。NF-κB及I-κB在大肠腺癌的浸润生长及远处转移过程中发挥着一定的作用。联合检测该四个因子不能用于全面评价大肠腺癌的预后。

艾灸对亚急性衰老大鼠胸腺CD4^+T细胞IL-2、IL-2Rα、NF-κB和I-κB蛋白表达的影响

目的:通过观察IL-2及相关受体蛋白水平的变化情况,探讨艾灸对亚急性衰老大鼠胸腺CD4+T细胞的影响。方法:采用D-半乳糖致亚急性衰老大鼠模型。24只清洁级雄性SD大鼠随机分为:正常组,模型组和艾灸组。艾灸组温和灸双侧肾俞穴5 min/次,共计40 d。采用免疫磁珠法分离胸腺CD4+T细胞,并再用Western Blot方法检测各组大鼠胸腺CD4+T细胞IL-2、IL-2Rα、NF-κB和I-κB的蛋白表达量。结果:模型组大鼠胸腺CD4+T细胞中IL-2、IL-2Rα、NF-κB、I-κB蛋白的表达量较正常组降低,差异有统计学意义(P<0.05);艾灸组大鼠胸腺CD4+T细胞中IL-2、IL-2Rα、NF-κB、I-κB蛋白表达量升高,与模型组比较差异有统计学意义(P<0.05)。结论:艾灸肾俞穴可上调胸腺CD4+T细胞IL-2、IL-2Rα、NF-κB、I-κB的表达。

NF-κB、I-κB、Bcl-2在宫颈癌组织中的表达及其与人乳头瘤病毒感染的关系

背景与目的:已表明核因子κB(nuclearfactorκB,NF-κB)及其抑制蛋白κB(inhibitorproteinκB,I-κB)对凋亡基因的调控起重要作用,NF-κB在某些肿瘤中高表达,与肿瘤的发生有关,但在宫颈癌中的表达以及与人乳头瘤病毒(humanpapillomavirus,HPV)感染的关系未见报道。本研究旨在探讨宫颈癌组织中NF-κB、I-κB、bcl-2的表达及其与HPV感染的关系。方法:采用免疫组织化学SP法对46例宫颈癌和26例正常宫颈组织进行NF-κB、I-κB、bcl-2蛋白检测,用PCR技术对组织标本的HPV-DNA进行检测。结果:NF-κB、bcl-2在宫颈癌组织中的表达率分别为60.9%(28/46)和52.2%(24/46),在正常对照组的表达率分别为23.1%(6/26)和0(0/26),宫颈癌组显著高于正常对照组(P<0.01);I-κB在宫颈癌组和正常对照组的表达率分别为30.4%(14/46)和57.7%(15/26),宫颈癌组显著低于正常对照组(P<0.05);NF-κB与bcl-2的表达呈显著性相关(P<0.05)。HPV-DNA阳性的宫颈癌组织中NF-κB的阳性率显著高于阴性组(P<0.05);I-κB、bcl-2的阳性率在HPV-DNA阳性和阴性组之间无显著性差异(P>0.05)。结论:NF-κB、bcl-2的高表达和I-κB的低表达与宫颈癌的发生过程可能有关;HPV感染可能与NF-κB表达有关。

NF-κB及其抑制蛋白I-κBα与大肠癌侵袭和转移的相关性

目的探讨NF-κB和I-κBα在大肠癌中的表达特点、相互关系及其与大肠癌进展的相关性。方法免疫组化和Western印迹方法检测48例大肠癌患者手术切除的癌组织以及配对的癌旁正常组织标本中NF-κB,I-κBα和p-IκBα的表达情况,分析这3种蛋白的表达与大肠癌侵袭和转移的相关性。结果大肠癌组织中NF-κB的表达水平明显高于正常组织(P<0.01),且随着肿瘤Dukes分期的进展,NF-κB的表达水平呈逐渐升高趋势。大肠癌组织中I-κBα的表达水平明显低于正常组织(P<0.01),且随着肿瘤Dukes分期的进展,I-κBα的表达水平呈逐渐降低趋势,同时,I-κBα的磷酸化(p-IκBα)水平逐渐升高。结论在大肠癌组织中I-κBα的磷酸化降解与NF-κB表达升高有助于肿瘤的进展和不良预后。

HMGB1对小鼠腹腔巨噬细胞吞噬和I-A/E表达的影响

目的：探讨HMGB1对巨噬细胞免疫功能的影响。方法：梯度浓度HMGB1处理小鼠腹腔巨噬细胞,或将小鼠随机分为生理盐水对照、24h和48h高与低剂量HMGB1注射组,腹腔注射0.2μg或20μg HMGB1,或生理盐水。检测巨噬细胞吞噬功能和I-A/E表达。结果：10μg/L HMGB1刺激6-12h,巨噬细胞吞噬功能较其他剂量组明显增强（P〈0.05或P〈0.01）。HMGB1对培养巨噬细胞I-A/-E表达无影响。高剂量HMGB1攻击小鼠24h,其腹腔巨噬细胞吞噬能力明显降低（P〈0.05）;低剂量HMGB1攻击48h,巨噬细胞I-A/-E表达明显上调（P〈0.05或P〈0.01）。结论：高剂量HMGB1抑制巨噬细胞吞噬功能,低剂量HMGB1增强巨噬细胞免疫功能。

Calpain inhIbitorⅠ对烧伤小鼠肝脏NF-κB转录及炎性细胞因子分泌的影响

探讨Calpain inhibitor I(CI-I)对严重烧伤小鼠肝脏IκBa表达,NF-κB转录及炎性细胞因子分泌的影响。将CI-Ⅰ腹腔给药预处理小鼠1 h后背部行20%全身体表面积(TBSA)Ⅲ度烧伤,收集肝组织,检测其IκBa表达,NF-κB转录和血清TNF-a、IL-1B、IL-6分泌水平。与烧伤对照组比较,CI-Ⅰ预处理后肝脏NF-κB转录活性和炎性细胞因子分泌有所降低。提示CI-Ⅰ预处理可有效抑制严重烧伤小鼠肝细胞NF-κB活化和血清炎性细胞因子分泌,从而有利于烧伤后的炎症调节。

大鼠脑出血后的细胞凋亡及其与NF-κB和I-κBα蛋白表达的关系

目的:探讨大鼠脑出血(ICH)后细胞凋亡及其与NF-κB和I-κBα蛋白表达的关系和演变规律,本实验用Ⅶ胶原酶联合肝素注入大鼠右侧脑纹状体制备脑出血模型。方法:TUNEL染色(末端脱氧核糖核苷转移酶介导的dUTP缺口末端标记法)观察细胞凋亡的变化;免疫组化SABC法检测NF-κB和I-κBα蛋白的表达;Western Blot技术检测NF-κB和I-κBα蛋白相对光密度值。结果:(1)ICH组TUNEL阳性细胞于出血后12h可检测到,3d达高峰,7d仍有较高表达(P<0.01);(2)ICH组I-κBα和NF-κB蛋白免疫阳性细胞分别于出血12h、3d达高峰,7d仍高于假手术组和正常对照组(P<0.01);(3)Western Blot结果显示NF-κB相对光密度比值在ICH3d出血侧达高峰,I-κBα蛋白相对光密度比值在ICH组ICH侧12h达高峰,7d时仍明显高于正常对照组(P<0.05)。结论:ICH后存在细胞凋亡;NF-κB和I-κBα参与了ICH所致的细胞凋亡。

CD20阳性B细胞NHL^(131)I-美罗华放射免疫治疗剂量个体化的临床初步研究

本研究旨在观察不同个体间131I-美罗华全身清除速率的差异,并拟定131I-美罗华放射免疫治疗个体化治疗剂量。选取CD20阳性B细胞NHL患者13例,于不同时相行全身平面显像,监测131I-美罗华的全身分布和清除情况,绘制时间-放射性曲线得到全身清除速率常数(λ),计算全身有效半清除时间Teff,采用医用内照射吸收剂量(Medical Internal Radiation Dosimetry,MIRD)法求得示踪剂量水平的全身辐射吸收剂量,并参照体重为70 kg的标准人体模型131I-美罗华全身最大耐受剂量为75 cGy,求得个体化的最大允许注射活度。结果显示:13例患者Teff为58.73~177.69 h(96.87±30.58 h),似呈正态分布;最大允许注射活度为1.14~2.95 GBq,其分布无明显规律。根据求得的最大允许注射活度试行治疗其中1例病人,其病情获得了部分缓解。

^(125)I-白蛋白融合干扰素α2b大鼠体内排泄研究

为研究125I-白蛋白融合干扰素α2b大鼠体内排泄行为,利用氯胺-T法制备了125I-白蛋白融合干扰素α2b,其标记率为82.72%,放化纯度为95.53%,放射性比活度为0.26MBq/μg。体外WISH/VSV系统抗病毒活性比较分析表明,白蛋白融合干扰素α2b和125I-白蛋白融合干扰素α2b具有相近的抗病毒活性。SD大鼠皮下注射125I-白蛋白融合干扰素α2b后,0～6、6～12、12～24、24～48、48～96、96～192和192～300h7个不同时段的尿、粪的放射性分析结果表明,125I-白蛋白融合干扰素α2b主要通过肾脏排泄,部分可通过粪便排泄,300h时尿、粪中平均累积排泄率分别为80.10%和16.00%;0～1、1～2、2～4、4～6、6～12、12～24和24～30h7个不同时段的胆汁的放射性分析结果表明,125I-白蛋白融合干扰素α2b也可通过肝脏代谢后经胆汁排泄,但这不是它的主要排泄途径,30h时,胆汁中的平均累积排泄率仅为1.61%。

胡黄连苷Ⅱ对大鼠脑缺血再灌注损伤后TLR4、NF-κB及I-κB表达的影响

目的观察胡黄连苷Ⅱ对大鼠脑缺血再灌注损伤后Toll样受体4(TLR4)、核因子-κB(NF-κB)及核因子-κB抑制剂(I-κB)表达的影响。方法选取成年雌性健康大鼠72只,从中随机选择12只为空白对照组,其余60只大鼠采用线栓法建立大脑中动脉脑缺血再灌注损伤的模型。选取建模成功的36只大鼠,采用随机数字表法分为胡黄连苷Ⅱ治疗组、阳性对照组以及阴性对照组,每组12只。胡黄连苷Ⅱ治疗组大鼠给予胡黄连苷Ⅱ注射干预,阳性对照组大鼠给予丹参素钠干预,空白对照组和阴性对照组给予磷酸盐缓冲液(PBS)干预。采用TUNEL染色方法检测3组大鼠的细胞凋亡情况;采用免疫组织化学染色方法检测各组大鼠脑内TLR4、NF-κB及I-κB表达的情况。结果空白对照组大鼠的TUNEL阳性细胞呈散在分布、数量较少,大鼠的海马组织、纹状体、大脑皮质中TLR4、NF-κB及I-κB的表达较微弱;阴性对照组大鼠的TUNEL阳性细胞比空白对照组大鼠的数量显著增加,海马组织、纹状体、大脑皮质中TLR4、NF-κB及I-κB的表达较空白对照组显著增加(P<0.05);胡黄连苷Ⅱ治疗组以及阳性对照组大鼠TUNEL阳性细胞数、不同脑组织中TLR4、NF-κB及I-κB的表达均较阴性对照组大鼠低(P<0.05),组间差异无统计学意义(P>0.05)。结论对脑缺血再灌注损伤大鼠来说,给予胡黄连苷Ⅱ治疗可以下调大鼠TLR4、NF-κB及I-κB的表达,显著的抑制大鼠的炎症反应,抑制神经细胞的凋亡。