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The Impact of Atorvastatin on Cardiometabolic Risk Factors in Sisters of Women with Polycystic Ovary Syndrome. 阿托伐他汀对多囊卵巢综合征女性姐妹心脏代谢危险因素的影响。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2023-08-03 DOI: 10.1159/000531321
Robert Krysiak, Karolina Kowalcze, Bogusław Okopień

Introduction: Polycystic ovary syndrome (PCOS) is a frequent endocrinopathy in young women with significantly increased cardiometabolic risk. Siblings of women with this disorder are at increased risk of insulin resistance and androgen excess. The current study was aimed at investigating cardiometabolic effects of atorvastatin in sisters of women with PCOS.

Methods: This prospective observational study compared two age-, body mass index-, blood pressure-, and plasma lipid-matched groups of women with hypercholesterolemia: sisters of PCOS probands (group A) and unrelated control subjects (group B), receiving atorvastatin (40 mg daily). Plasma lipids, glucose homeostasis markers, concentrations of sex hormones, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen and uric acid, and the urinary albumin-to-creatinine ratio (UACR) were measured before entering the study and 6 months later.

Results: Both groups differed in the degree of insulin resistance, testosterone, free androgen index (FAI), circulating levels of hsCRP and homocysteine, and UACR. There were no between-group differences in the impact of atorvastatin on plasma lipids. Despite reducing hsCRP and homocysteine in both groups of women, the effect on these biomarkers was stronger in group B than in group A. Only in group B, atorvastatin did reduce fibrinogen, uric acid, and UACR. Only in group A, atorvastatin did worsen insulin sensitivity and tended to reduce testosterone and FAI. The impact of atorvastatin on hsCRP, homocysteine, fibrinogen, uric acid, and UACR inversely correlated with testosterone and FAI.

Conclusion: The obtained results suggest that sisters of women with PCOS may benefit to a lesser degree from atorvastatin treatment than other women.

引言:多囊卵巢综合征(PCOS)是年轻女性常见的内分泌疾病,心脏代谢风险显著增加。患有这种疾病的女性的兄弟姐妹患胰岛素抵抗和雄激素过量的风险增加。本研究旨在调查阿托伐他汀对多囊卵巢综合征女性姐妹的心脏代谢影响。在进入研究前和6个月后测量血脂、葡萄糖稳态标志物、性激素浓度、高敏C反应蛋白(hsCRP)、同型半胱氨酸、纤维蛋白原和尿酸,以及尿白蛋白与肌酐比值(UACR)。结果:两组患者的胰岛素抵抗程度、睾酮、游离雄激素指数(FAI)、循环hsCRP和同型半胱氨酸水平以及UACR均存在差异。阿托伐他汀对血脂的影响在组间没有差异。尽管两组女性的hsCRP和同型半胱氨酸都有所降低,但B组对这些生物标志物的影响比A组更强。只有在B组,阿托伐他汀确实降低了纤维蛋白原、尿酸和UACR。只有在A组,阿托伐他汀确实使胰岛素敏感性恶化,并倾向于降低睾酮和FAI。阿托伐他汀对hsCRP、同型半胱氨酸、纤维蛋白原、尿酸和UACR的影响与睾酮和FAI呈负相关。
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引用次数: 0
Matrine Protects Endothelial Progenitor Cells against Apoptosis and Promotes Their Migration, Invasion, and Tube Formation Abilities via Modulating miR-126b/FOXO4 Axis. 苦参碱通过调节miR-126b/FOXO4轴保护内皮祖细胞免受凋亡,促进其迁移、侵袭和成管能力。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1159/000527812
Xiqi Zhu, Jian Jiang, Jian Wang, Zhiyin Zhou, Xiaoming Ge

Introduction and objective: Endothelial progenitor cells (EPCs) have been proven to exhibit a therapeutic effect in deep vein thrombosis, but are susceptible to microenvironment. Besides, Matrine has promotive effects on EPCs, but its effects on microRNA (miR)-126 remain obscure, which are therefore discussed in the study.

Methods: The cultured EPCs were extracted from Sprague-Dawley rats and identified by immunofluorescence assay. After being treated with Matrine or transfected with miR-126b inhibitor and small interfering RNA targeting forkhead box (FOXO) 4, the viability and apoptosis of EPCs were determined by cell counting kit-8 assay and flow cytometry. The migration, invasion, and tube formation abilities were detected by scratch, Transwell, and tube formation assays. The target genes of miR-126b were predicted by TargetScan, and verified by dual-luciferase reporter assay. The expressions of miR-126b, FOXO4, matrix metalloproteinase (MMP) 2, MMP9, and vascular endothelial growth factor (VEGF) A were determined by quantitative real-time polymerase chain reaction and Western blot.

Results: The EPCs were successfully extracted and cultured, as evidenced by positive reaction cluster of differentiation (CD) 34 and CD133. Matrine promoted the viability, migration, invasion, and tube formation while inhibiting the apoptosis of EPCs, and upregulated the expression of miR-126b. Besides, miR-126b inhibitor reversed the effects of Matrine on EPCs and downregulated the expression levels of MMP2, MMP9, and VEGFA. MiR-126b targeted the FOXO4, and siFOXO4 reversed the abovementioned effects of miR-126b inhibitor on EPCs.

Conclusion: Matrine protects EPCs from apoptosis and promotes their migration, invasion, and tube formation abilities via regulating miR-126b/FOXO4 axis.

前言和目的:内皮祖细胞(EPCs)在深静脉血栓的治疗中已被证实具有一定的疗效,但其易受微环境的影响。此外,苦参碱对EPCs有促进作用,但其对microRNA (miR)-126的作用尚不清楚,因此在本研究中进行了讨论。方法:提取Sprague-Dawley大鼠体外培养的EPCs,采用免疫荧光法进行鉴定。经苦参碱处理或转染miR-126b抑制剂和小干扰RNA靶向叉头盒(FOXO) 4后,通过细胞计数试剂盒-8检测和流式细胞术检测EPCs的活力和凋亡情况。通过划痕、Transwell和管柱形成试验来检测运移、侵入和管柱形成能力。通过TargetScan预测miR-126b的靶基因,并通过双荧光素酶报告基因试验进行验证。采用实时定量聚合酶链反应和Western blot检测miR-126b、FOXO4、基质金属蛋白酶(MMP) 2、MMP9、血管内皮生长因子(VEGF) A的表达。结果:成功提取并培养EPCs, cd34和CD133阳性反应。苦参碱可促进EPCs的存活、迁移、侵袭和成管,同时抑制EPCs的凋亡,上调miR-126b的表达。此外,miR-126b抑制剂逆转了苦参碱对EPCs的作用,下调了MMP2、MMP9和VEGFA的表达水平。MiR-126b靶向FOXO4, siFOXO4逆转了MiR-126b抑制剂对EPCs的上述作用。结论:苦参碱通过调控miR-126b/FOXO4轴,促进EPCs的迁移、侵袭和成管能力。
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引用次数: 0
Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine. 胆汁淤积相关的肺部炎症、氧化应激和组织纤维化:生物胺胍的保护作用。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1159/000530307
Mohammad Mehdi Ommati, Hossein Niknahad, Asma Najibi, Abdollah Arjmand, Sepideh Alidaee, Sahra Mazloomi, Parinaz Ahmadi, Alireza Ghiasvand, Maral Javadi, Jamal Yazdani, Samira Sabouri, Heresh Rezaei, Negar Azarpira, Reza Heidari

Introduction: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties.

Methods: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL).

Results: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-β were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury.

Conclusion: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.

简介:胆汁淤积是胆汁流动的停止,导致潜在的细胞毒性胆汁成分在肝脏中的积累。这些细胞毒性分子影响许多器官。胆汁淤积引起的肺损伤是一种严重的并发症,可导致组织纤维化和呼吸窘迫。大量证据表明,氧化应激和炎症反应在胆汁淤积相关肺损伤的发病机制中的作用。胍基丁胺(AGM;1-氨基-4-胍丁烷)是人体内内源性合成的一种生物胺。这种胺具有有效的抗炎和抗氧化特性。方法:在本研究中,对一系列(6只C57BL/6J雄性小鼠/组)胆管结扎(BDL)动物(BDL手术后7、14和28天)进行定期监测,以确保肺组织的炎症反应(通过分析它们的支气管肺泡灌洗液[BALF])。结果发现,BDL术后第28天,BALF中炎症细胞、促炎细胞因子、IgG水平达到最高值。因此,选择其他研究组:1)假手术组(生理盐水2.5 mL/kg, ig,连续28天),2)BDL组,3)BDL + AGM组(1 mg/kg/d, ig,连续28天),4)BDL + AGM组(10 mg/kg/d, ig,连续28天)。然后,在预定的时间间隔(bdl后7、14和28天)监测BALF。结果:BDL小鼠BALF中促炎因子(TNF-α、IL-6、IL-1β)、胆汁酸、胆红素、炎症细胞(单核细胞、中性粒细胞、淋巴细胞)显著升高。此外,在胆汁淤积动物的肺组织中,氧化应激的生物标志物显著增加。肺组织病理改变,组织胶原沉积,TGF-β升高。发现AGM可显著改善胆汁淤积性肺损伤。结论:AGM对炎症指标、氧化应激生物标志物和组织纤维化的影响似乎在其保护特性中起关键作用。
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引用次数: 3
New Role of D-Cycloserine: Shorten Adaptation Process and Extend Maintenance Time of Motion Sickness. d -环丝氨酸的新作用:缩短运动病的适应过程和延长维持时间。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1159/000530575
Yilin Lu, Zehua Chen, Leilei Pan, Ling Zhang, Shuifeng Xiao, Ruirui Qi, Yiling Cai, Junqin Wang

Introduction: The aim of the study was to investigate the role of D-cycloserine (DCS) in the adaptation process and maintenance of motion sickness (MS).

Methods: In experiment 1, 120 SD rats were used to study the promoting effect of DCS on the adaptation process of MS in rats. They were randomly divided into four groups, DCS-rotation (DCS-Rot), DCS-static, saline-rotation (Sal-Rot), and saline-static, and further divided into three subgroups according to the adaptation time (4 days, 7 days, and 10 days) in each group. After being given DCS (0.5 mg/kg) or 0.9% saline, they were rotated or kept static according to the group. Their fecal granules, total distance, and total activity of spontaneous activity were recorded and analyzed. In experiment 2, other 120 rats were used. The experimental grouping and specific experimental method were the same as experiment 1. According to the grouping of the adaptive maintenance duration, the animals of 14 days, 17 days, and 21 days groups were measured on the corresponding date of the changes in the animals' exploratory behavior.

Results: In experiment 1, the fecal granules, total distance, and total activity of spontaneous activity of Sal-Rot returned to the control level on 9 days, and the DCS-Rot group returned to the control level on 6 days, indicating that DCS could shorten the adaptation time of MS rats from 9 days to 6 days. In experiment 2, the Sal-Rot could not maintain the adaptive state after 14 days' absence from the seasickness environment. The fecal granules of DCS-Rot increased significantly, and total distance and total activity of spontaneous activity of DCS-Rot decreased significantly from 17 days. These illustrate that DCS can prolong the adaptive maintenance time from within 14 days to 17 days in MS rats.

Conclusion: 0.5 mg/kg DCS injected intraperitoneally can shorten the MS adaptation process and extend the maintenance time of adaptation of SD rats.

前言:本研究旨在探讨d -环丝氨酸(DCS)在运动病(MS)的适应过程和维持中的作用。方法:实验1采用120只SD大鼠,研究DCS对大鼠MS适应过程的促进作用。随机分为dcs -轮作(DCS-Rot)、dcs -静态、盐-轮作(Sal-Rot)和盐-静态4组,并根据每组适应时间(4 d、7 d、10 d)再分为3个亚组。给予DCS (0.5 mg/kg)或0.9%生理盐水后,按组旋转或静止。记录和分析它们的粪便颗粒、总距离和自发活动的总活性。实验2另取大鼠120只。实验分组及具体实验方法与实验1相同。根据适应性维持时间的分组,在相应的日期测量14天、17天和21天组动物的探索行为变化。结果:实验1中,Sal-Rot的粪便颗粒、总距离、总自发活性在第9天恢复到对照水平,DCS- rot组在第6天恢复到对照水平,说明DCS可将MS大鼠的适应时间从9天缩短到6天。在实验2中,盐腐菌在离开晕船环境14天后仍不能保持适应状态。从17 d开始,粪便中DCS-Rot颗粒显著增加,总距离和总自发活性显著降低。说明DCS可将MS大鼠的适应性维持时间从14天延长至17天。结论:腹腔注射0.5 mg/kg DCS可缩短SD大鼠MS适应过程,延长适应维持时间。
{"title":"New Role of D-Cycloserine: Shorten Adaptation Process and Extend Maintenance Time of Motion Sickness.","authors":"Yilin Lu,&nbsp;Zehua Chen,&nbsp;Leilei Pan,&nbsp;Ling Zhang,&nbsp;Shuifeng Xiao,&nbsp;Ruirui Qi,&nbsp;Yiling Cai,&nbsp;Junqin Wang","doi":"10.1159/000530575","DOIUrl":"https://doi.org/10.1159/000530575","url":null,"abstract":"<p><strong>Introduction: </strong>The aim of the study was to investigate the role of D-cycloserine (DCS) in the adaptation process and maintenance of motion sickness (MS).</p><p><strong>Methods: </strong>In experiment 1, 120 SD rats were used to study the promoting effect of DCS on the adaptation process of MS in rats. They were randomly divided into four groups, DCS-rotation (DCS-Rot), DCS-static, saline-rotation (Sal-Rot), and saline-static, and further divided into three subgroups according to the adaptation time (4 days, 7 days, and 10 days) in each group. After being given DCS (0.5 mg/kg) or 0.9% saline, they were rotated or kept static according to the group. Their fecal granules, total distance, and total activity of spontaneous activity were recorded and analyzed. In experiment 2, other 120 rats were used. The experimental grouping and specific experimental method were the same as experiment 1. According to the grouping of the adaptive maintenance duration, the animals of 14 days, 17 days, and 21 days groups were measured on the corresponding date of the changes in the animals' exploratory behavior.</p><p><strong>Results: </strong>In experiment 1, the fecal granules, total distance, and total activity of spontaneous activity of Sal-Rot returned to the control level on 9 days, and the DCS-Rot group returned to the control level on 6 days, indicating that DCS could shorten the adaptation time of MS rats from 9 days to 6 days. In experiment 2, the Sal-Rot could not maintain the adaptive state after 14 days' absence from the seasickness environment. The fecal granules of DCS-Rot increased significantly, and total distance and total activity of spontaneous activity of DCS-Rot decreased significantly from 17 days. These illustrate that DCS can prolong the adaptive maintenance time from within 14 days to 17 days in MS rats.</p><p><strong>Conclusion: </strong>0.5 mg/kg DCS injected intraperitoneally can shorten the MS adaptation process and extend the maintenance time of adaptation of SD rats.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9805589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Factors Associated with Potentially Inappropriate Prescribing in Patients on Peritoneal Dialysis. 腹膜透析患者潜在不适当处方的相关因素。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.1159/000527263
Milorad Stojadinovic, Radica Zivkovic Zaric, Mirjana Lausevic, Tamara Jemcov, Ljiljana Komadina, Dejan Petrovic, Petar Djuric, Ana Bulatovic, Slobodan Jankovic

Introduction: Inappropriate prescribing is common in patients with end-stage kidney disease, especially in those over 65 years of age. Our study aimed to reveal potentially inappropriate drug prescribing in patients on peritoneal dialysis (PD) and explore factors associated with this phenomenon.

Methods: The research was designed as an observational, cross-sectional study on a convenient sample of 145 consecutive patients with PD who attended the four tertiary-care hospitals in Serbia. The main outcome was the extent of inappropriate prescribing, as assessed by the medication appropriateness index, and potential predictors were tested by multiple linear regression.

Results: Inappropriate prescribing was a widespread phenomenon among patients on PD. The main factors that promote inappropriate prescribing in this subgroup of patients on kidney replacement therapy are comorbidities (p = 0.000), increased body weight (p = 0.022), a number of prescribed drugs (p = 0.000), and arterial hypertension on examination (p = 0.030). On the other hand, drinking alcohol and higher systolic blood pressure were associated with a lower inappropriate prescribing.

Conclusion: In order to prevent the occurrence of inappropriate prescribing and its severe health or economic consequences, clinicians should pay special attention when prescribing new drugs to high-risk patients.

不恰当的处方在终末期肾病患者中很常见,尤其是在65岁以上的患者中。我们的研究旨在揭示腹膜透析(PD)患者可能不适当的药物处方,并探讨与此现象相关的因素。方法:该研究被设计为一项观察性横断面研究,以145名连续在塞尔维亚四家三级医院就诊的PD患者为方便样本。主要观察指标为处方不当程度,采用药物适宜性指数评估,并采用多元线性回归检验潜在预测因素。结果:处方不当在帕金森病患者中普遍存在。导致该亚组患者在接受肾脏替代治疗时处方不当的主要因素是合并症(p = 0.000)、体重增加(p = 0.022)、处方药物过多(p = 0.000)和检查时动脉高血压(p = 0.030)。另一方面,饮酒和较高的收缩压与较低的不当处方有关。结论:临床医生在给高危患者开新药处方时应特别注意,以防止不当处方的发生及其严重的健康或经济后果。
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引用次数: 0
Quercetin Alleviates Asthma-Induced Airway Inflammation and Remodeling through Downregulating Periostin via Blocking TGF-β1/Smad Pathway. 槲皮素通过阻断TGF-β1/Smad通路下调Periostin,减轻哮喘诱导的气道炎症和重塑。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2023-06-21 DOI: 10.1159/000530703
Yanni Fang, Wenwen Jin, Zhen Guo, Jumei Hao

Introduction: The aim of the study was to discuss whether the anti-asthmatic effect of quercetin is related to periostin and the downstream molecular pathway of quercetin's anti-asthmatic effect.

Methods: We constructed asthmatic mice, sensitized by ovalbumin, and administrated different treatments into mice according to the experimental design. In this study, we mainly observed the inflammatory response, airway fibrosis, and airway hyperresponsiveness in asthmatic mice. Pathological stains (H&E, PAS, and Masson) were performed. We also detected the inflammation factors and fibrosis-related cytokines by enzyme-linked immunosorbent serologic assay. In addition, we also explored the level of periostin by enzyme-linked immunosorbent serologic assay and Western blot. At the same time, TGF-β1/Smad pathway was also determined by Western blot.

Results: A high expression of periostin was found in asthmatic mice, and quercetin decreases periostin content in bronchoalveolar lavage fluid. Quercetin and OC-20 inhibit airway inflammation response, airway fibrosis, and airway hyperreactivity. Quercetin downregulated TGF-β1/Smad pathway in the lung tissues of asthmatic mice. Anti-asthma role of quercetin is related to periostin. Then deeper mechanical study revealed that inhibiting TGF-β1 could improve asthmatic symptoms, and quercetin exerted the protective effect on asthmatic mice through inhibition of TGF-β1/Smad pathway.

Conclusion: Quercetin provided a protective role against asthma via periostin, manifested by mild inflammatory infiltration, reduced goblet cell proliferation, and reduced airway fibrosis. TGF-β1/Smad pathway is an important transduction system, participating in the protective effect of quercetin on asthma.

引言:本研究旨在探讨槲皮素的平喘作用是否与紫苏素有关,以及槲皮素平喘作用的下游分子途径。方法:构建卵清蛋白致敏的哮喘小鼠,并根据实验设计对其进行不同的治疗。在本研究中,我们主要观察了哮喘小鼠的炎症反应、气道纤维化和气道高反应性。进行病理染色(H&;E、PAS和Masson)。我们还通过酶联免疫吸附血清学检测了炎症因子和纤维化相关细胞因子。此外,我们还通过酶联免疫吸附血清学分析和蛋白质印迹来探讨紫苏素的水平。同时,用蛋白质印迹法检测TGF-β1/Smad通路。结果:紫苏素在哮喘小鼠中高表达,槲皮素可降低支气管肺泡灌洗液中紫苏素的含量。槲皮素和OC-20抑制气道炎症反应、气道纤维化和气道高反应性。槲皮素下调哮喘小鼠肺组织中TGF-β1/Smad通路。槲皮素的平喘作用与紫苏素有关。进一步的力学研究表明,抑制TGF-β1可以改善哮喘症状,槲皮素通过抑制TGF-α1/Smad通路对哮喘小鼠产生保护作用。结论:槲皮素通过紫苏素对哮喘具有保护作用,表现为轻度炎症浸润,减少杯状细胞增殖,减少气道纤维化。TGF-β1/Smad通路是一个重要的转导系统,参与槲皮素对哮喘的保护作用。
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引用次数: 1
Glioblastoma Multiforme: The Latest Diagnostics and Treatment Techniques. 多型胶质母细胞瘤:最新诊断和治疗技术。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2023-07-17 DOI: 10.1159/000531319
Agata Czarnywojtek, Magdalena Borowska, Kamil Dyrka, Stefaan Van Gool, Nadia Sawicka-Gutaj, Jakub Moskal, Jeremi Kościński, Patryk Graczyk, Tomasz Hałas, Agnieszka Marta Lewandowska, Rafał Czepczyński, Marek Ruchała

Background: Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumour. Recently, there has been outstanding progress in the treatment of GBM. In addition to the newest form of GBM removal using fluorescence, three-dimensional (3D) imaging, tomoradiotherapy, moderate electro-hyperthermia, and adjuvant temozolomide (post-operative chemotherapy), new developments have been made in the fields of immunology, molecular biology, and virotherapy. An unusual and modern treatment has been created, especially for stage 4 GBM, using the latest therapeutic techniques, including immunotherapy and virotherapy. Modern oncological medicine is producing extraordinary and progressive therapeutic methods. Oncological therapy includes individual analysis of the properties of a tumour and targeted therapy using small-molecule inhibitors. Individualised medicine covers the entire patient (tumour and host) in the context of immunotherapy. An example is individualised multimodal immunotherapy (IMI), which relies on individual immunological tumour-host interactions. In addition, IMI is based on the concept of oncolytic virus-induced immunogenic tumour cell death.

Summary: In this review, we outline current knowledge of the various available treatment options used in the therapy of GBM including both traditional therapeutic strategy and modern therapies, such as tomotherapy, electro-hyperthermia, and oncolytic virotherapy, which are promising treatment strategies with the potential to improve prognosis in patients with GBM.

Key messages: This newest therapy, immunotherapy combined with virotherapy (oncolytic viruses and cancer vaccines), is displaying encouraging signs for combating GBM. Additionally, the latest 3D imaging is compared to conventional two-dimensional imaging.

背景:多形性胶质母细胞瘤(GBM)是世界卫生组织4级胶质瘤,也是最常见的恶性原发性脑肿瘤。近年来,GBM的治疗取得了突出进展。除了使用荧光、三维(3D)成像、断层放射治疗、中等电热疗和辅助替莫唑胺(术后化疗)的最新形式的GBM去除外,免疫学、分子生物学和病毒治疗领域也取得了新的进展。使用最新的治疗技术,包括免疫疗法和病毒疗法,已经创造了一种不同寻常的现代治疗方法,尤其是针对4期GBM。现代肿瘤学正在产生非凡而进步的治疗方法。肿瘤治疗包括对肿瘤特性的个体分析和使用小分子抑制剂的靶向治疗。在免疫疗法的背景下,个体化药物涵盖整个患者(肿瘤和宿主)。一个例子是个体化多模式免疫疗法(IMI),它依赖于个体免疫肿瘤-宿主的相互作用。此外,IMI是基于溶瘤病毒诱导的免疫原性肿瘤细胞死亡的概念。摘要:在这篇综述中,我们概述了GBM治疗中使用的各种可用治疗方案的最新知识,包括传统治疗策略和现代治疗,如断层治疗、电热疗和溶瘤病毒治疗,这些都是有前景的治疗策略,有可能改善GBM患者的预后,免疫疗法结合病毒疗法(溶瘤病毒和癌症疫苗)正在显示出对抗GBM的令人鼓舞的迹象。此外,将最新的3D成像与传统的二维成像进行比较。
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引用次数: 1
PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy. PG545通过调节PI3K/AKT/mTOR信号传导和激活软骨细胞自噬来预防骨关节炎的发展。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2023-10-11 DOI: 10.1159/000532078
Peiyu Guo, Hua Li, Xuming Wang, Xingguo Li, Xi Li

Introduction: Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1β (IL -1β).

Methods: Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo.

Results: PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1β-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545.

Conclusion: PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.

简介:骨关节炎(OA)是一种常见于老年人的退行性疾病,其特征是关节疼痛、肿胀和活动受限。近年来,乙酰肝素酶已被报道在骨关节炎软骨的发育中发挥重要作用。PG545是一种具有乙酰肝素酶抑制活性的硫酸乙酰肝素模拟物。本研究在白细胞介素-1β(IL-1β)诱导的软骨细胞损伤模型中研究了PG545的治疗作用和可能的机制。流式细胞仪检测软骨细胞凋亡率。通过免疫荧光标记监测轻链3和P62的表达。采用蛋白质印迹、红荧光蛋白和绿荧光蛋白感染慢病毒以及实时定量聚合酶链式反应测定软骨细胞标志物、凋亡相关因子、自噬蛋白和磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)/哺乳动物雷帕霉素靶点(mTOR)途径的关键蛋白的表达水平。研究了丙二醛、超氧化物歧化酶和过氧化氢酶(CAT)等应激特异性酶的表达和活性。使用ATG5敲低的软骨细胞来研究PG545的治疗效果与自噬之间的关系。PG545的治疗效果在体内得到了验证。结果:PG545对软骨细胞具有显著的保护作用,可降低软骨细胞的氧化应激、凋亡和降解,促进软骨细胞增殖。PG545在IL-1β处理的细胞中有效诱导自噬,而3-MA减弱了这种作用。PI3K/Akt/mTOR通路可能参与PG545促进自噬和OA治疗。结论:PG545能够通过PI3K/Akt/mTOR通路恢复受损的自噬和自噬流量,从而延缓OA的进展,表明PG545可能是一种新的OA治疗方法。
{"title":"PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy.","authors":"Peiyu Guo, Hua Li, Xuming Wang, Xingguo Li, Xi Li","doi":"10.1159/000532078","DOIUrl":"10.1159/000532078","url":null,"abstract":"<p><strong>Introduction: </strong>Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1β (IL -1β).</p><p><strong>Methods: </strong>Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo.</p><p><strong>Results: </strong>PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1β-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545.</p><p><strong>Conclusion: </strong>PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41210011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Can Nonsteroidal Anti-Inflammatory Drugs Lead to First-Time Heart Failure in Patients with Diabetes Mellitus Type-2: Is There a Link? 非甾体抗炎药会导致2型糖尿病患者首次心力衰竭吗?有联系吗?
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2023-07-27 DOI: 10.1159/000531604
Shehroze Tabassum, Aroma Naeem, Uzzam Ahmed Khawaja, Abdulqadir J Nashwan
Dear Editor, Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed drugs; however, they can lead to potential adverse effects [1]. The detrimental association between NSAIDs (apart from aspirin) usage and the peril to cardiac health has been documented profoundly in the literature [2–7]. The possible mechanism behind this adverse relationship can be due to an imbalance in the levels of prostaglandin E2 and vasodilatory prostacyclin compared to those of vasoconstrictive thromboxane A2, established due to NSAID usage targeting the endothelium and eventually leading to thrombus formation [8, 9]. Unlike other NSAIDs, aspirin irreversibly inhibits COX-1, leading to a reduction in thromboxane A2 and clot formation, while not significantly impacting vasodilatory prostaglandins and at low doses, this provides a cardioprotective effect [2]. NSAIDs are further known to exacerbate heart failure (HF) through increased salt and water retention [10–12]. A study conducted by Page and Henry [13] evaluated the hospitalization risk of HF for patients on NSAIDs. A relative risk of 2.1 was found in patients taking NSAIDs compared to nonusers. According to this study, NSAIDs use might contribute to 19% of newly diagnosed congestive HF cases. A study by Mamdani et al. [14] compared the hospitalization risk for congestive HF for patients being managed with nonselective NSAIDs, coxibs, and controls. Patients taking rofecoxib showed the most significant risk (RR = 1.8, 95% confidence interval [CI] = 1.5–2.2). While those taking nonselective NSAIDs showed a relative risk of 1.4 (95% CI = 1.0–1.9). These studies demonstrate that NSAIDs can cause as well as exacerbate preexisting HF. However, there is very limited data available that can relate to patients with first-time cardiac failure prescribed NSAIDs having T2DM. A study recently presented at the 2022 Congress of the European Society of Cardiology (ESC) revealed that short-term NSAID use could potentially augment the chance of first-time HF in patients having T2DM [15]. A greater than 40% increase in the likelihood of hospitalization for first-time HF in patients who took NSAIDs, including ibuprofen, the most widely used drug, was observed. According to the statement from ESC, lead investigator Anders Holt, MD, stated that almost 1 in 6 patients with T2DM in their study had usage of at least one NSAID for 1 year. Holt and a team of colleagues from institutions in Denmark and the United Kingdom designed this study as an observational one using data from Danish registers to find patients suffering with DM from 1998 to 2018. Investigators used a case-crossover method where the
{"title":"Can Nonsteroidal Anti-Inflammatory Drugs Lead to First-Time Heart Failure in Patients with Diabetes Mellitus Type-2: Is There a Link?","authors":"Shehroze Tabassum,&nbsp;Aroma Naeem,&nbsp;Uzzam Ahmed Khawaja,&nbsp;Abdulqadir J Nashwan","doi":"10.1159/000531604","DOIUrl":"10.1159/000531604","url":null,"abstract":"Dear Editor, Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed drugs; however, they can lead to potential adverse effects [1]. The detrimental association between NSAIDs (apart from aspirin) usage and the peril to cardiac health has been documented profoundly in the literature [2–7]. The possible mechanism behind this adverse relationship can be due to an imbalance in the levels of prostaglandin E2 and vasodilatory prostacyclin compared to those of vasoconstrictive thromboxane A2, established due to NSAID usage targeting the endothelium and eventually leading to thrombus formation [8, 9]. Unlike other NSAIDs, aspirin irreversibly inhibits COX-1, leading to a reduction in thromboxane A2 and clot formation, while not significantly impacting vasodilatory prostaglandins and at low doses, this provides a cardioprotective effect [2]. NSAIDs are further known to exacerbate heart failure (HF) through increased salt and water retention [10–12]. A study conducted by Page and Henry [13] evaluated the hospitalization risk of HF for patients on NSAIDs. A relative risk of 2.1 was found in patients taking NSAIDs compared to nonusers. According to this study, NSAIDs use might contribute to 19% of newly diagnosed congestive HF cases. A study by Mamdani et al. [14] compared the hospitalization risk for congestive HF for patients being managed with nonselective NSAIDs, coxibs, and controls. Patients taking rofecoxib showed the most significant risk (RR = 1.8, 95% confidence interval [CI] = 1.5–2.2). While those taking nonselective NSAIDs showed a relative risk of 1.4 (95% CI = 1.0–1.9). These studies demonstrate that NSAIDs can cause as well as exacerbate preexisting HF. However, there is very limited data available that can relate to patients with first-time cardiac failure prescribed NSAIDs having T2DM. A study recently presented at the 2022 Congress of the European Society of Cardiology (ESC) revealed that short-term NSAID use could potentially augment the chance of first-time HF in patients having T2DM [15]. A greater than 40% increase in the likelihood of hospitalization for first-time HF in patients who took NSAIDs, including ibuprofen, the most widely used drug, was observed. According to the statement from ESC, lead investigator Anders Holt, MD, stated that almost 1 in 6 patients with T2DM in their study had usage of at least one NSAID for 1 year. Holt and a team of colleagues from institutions in Denmark and the United Kingdom designed this study as an observational one using data from Danish registers to find patients suffering with DM from 1998 to 2018. Investigators used a case-crossover method where the","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9885634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study. 肝细胞癌患者乐伐替尼诱发高级别甲状腺功能减退的危险因素:一项回顾性研究。
IF 3.1 4区 医学 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 Epub Date: 2023-08-17 DOI: 10.1159/000531881
Shusuke Uekusa, Maho Nemoto, Yuki Hanai, Misaki Nakashin, Arisu Miyagawa, Sachiko Yanagino, Yoshiki Arita, Takahiro Matsumoto, Kenji Nishizawa, Hidenari Nagai, Koji Higai, Kazuhiro Matsuo

Introduction: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN.

Methods: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration.

Results: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively.

Conclusion: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

简介:甲磺酸乐伐替尼(LEN)是一种口服酪氨酸激酶抑制剂,用于治疗各种癌症,包括肝细胞癌(HCC)。LEN治疗HCC与非常高的不良事件发生率相关,尤其是甲状腺功能减退。本研究通过分析接受LEN治疗的HCC患者的临床实验室数据,调查了LEN引起的甲状腺功能减退的发病率以及甲状腺功能减退发病率与患者人口统计学之间的关系。观察期为LEN给药开始前1周至给药结束后1个月。结果:共有61例HCC患者入选。36.1%(22/61名患者)发现了高度甲状腺功能减退症(CTCAE 2-3级)。在高级别甲状腺功能减退症中,嗜酸性粒细胞(EOSINO)计数显著较低(p=0.029)。EOSINO计数的临界值估计约为150/µL。当前吸烟和EOSINO计数的高级甲状腺功能减退症的调整比值比<;150/µL分别为0.237(95%置信区间:0.063-0.893)和4.219(95%置信间隔:1.119-15.92)。结论:非持续吸烟和EOSINO计数<;150/µL是LEN诱导的高级别甲状腺功能减退的危险因素。
{"title":"Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study.","authors":"Shusuke Uekusa,&nbsp;Maho Nemoto,&nbsp;Yuki Hanai,&nbsp;Misaki Nakashin,&nbsp;Arisu Miyagawa,&nbsp;Sachiko Yanagino,&nbsp;Yoshiki Arita,&nbsp;Takahiro Matsumoto,&nbsp;Kenji Nishizawa,&nbsp;Hidenari Nagai,&nbsp;Koji Higai,&nbsp;Kazuhiro Matsuo","doi":"10.1159/000531881","DOIUrl":"10.1159/000531881","url":null,"abstract":"<p><strong>Introduction: </strong>Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN.</p><p><strong>Methods: </strong>This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration.</p><p><strong>Results: </strong>In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count &lt;150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively.</p><p><strong>Conclusion: </strong>The results showed that noncurrent smoking and EOSINO count &lt;150/µL are risk factors for LEN-induced high-grade hypothyroidism.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10396136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Pharmacology
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