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Campothecin suppresses cell proliferation and migration in head and neck squamous cell carcinoma by blocking RAB27A-mediated phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway. 通过阻断RAB27A介导的磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)通路,喜树碱可抑制头颈部鳞状细胞癌细胞的增殖和迁移。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.09
Y Zhao, Y Wang, L Zhao, L Qu, J H Zheng

Camptothecin (CPT), a naturally occurring alkaloid derived from the Camptotheca acuminate plant, exerts anti-tumor properties. However, its specific impact on head and neck squamous cell carcinoma (HNSCC) remains uncertain. The study was to explore the action and mechanism of CPT on HNSCC cells. First, two HNSCC cell lines (FaDu and TU686) and a normal immortalized keratinocyte (HEK001) cell line, were exposed to a spectrum of CPT concentrations (ranging from 10 to 50 μM) for durations of 24 h and 48 h. Cell viability, proliferation, migration, and invasion were assessed by CCK-8 assay, EdU incorporation assay, wound healing assay and transwell assay. Subsequently, si-RAB27A or negative control (NC) was introduced into FaDu and TU686 cells through transfection, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was manipulated with L740Y-P, an activator of this pathway. The expression of proliferating cell nuclear antigen (PCNA), E-cadherin, PI3K/AKT signaling factors and RAB27A were determined by Western blot analysis. RAB27A was detected by immunofluorescence assay. It was found that CPT significantly hindered the viability, proliferation (p<0.01), migration (p<0.001), and invasion (p<0.001) of FaDu and TU686 cells. At the molecular level, administration of CPT caused a decline in the expression of PCNA, P-PI3K, P-AKT, and RAB27A, alongside an elevation in E-cadherin levels within HNSCC cells (p<0.05, p<0.01 and p<0.001). Reducing RAB27A expression enhanced the suppressive impacts of CPT on HNSCC cell viability (p<0.05 and p<0.01), migration (p<0.001) and invasion (p<0.01), these effects that were reversed upon treatment with L740Y-P in HNSCC cells (p<0.001). In summary, our study highlights the efficacy of CPT in HNSCC, demonstrating its influence on cell processes via the RAB27A-mediated PI3K/AKT pathway.

喜树碱(CPT)是一种天然生物碱,提取自喜树科植物,具有抗肿瘤特性。然而,它对头颈部鳞状细胞癌(HNSCC)的具体影响仍不确定。本研究旨在探索 CPT 对 HNSCC 细胞的作用和机制。首先,将两个 HNSCC 细胞系(FaDu 和 TU686)和一个正常的永生化角质形成细胞系(HEK001)暴露于不同浓度的 CPT(从 10 μM 到 50 μM)中,持续时间分别为 24 小时和 48 小时,通过 CCK-8 试验、EdU 结合试验、伤口愈合试验和透孔试验评估细胞的活力、增殖、迁移和侵袭。随后,通过转染将si-RAB27A或阴性对照(NC)导入FaDu和TU686细胞,并用L740Y-P(该通路的激活剂)操纵磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)信号通路。增殖细胞核抗原(PCNA)、E-cadherin、PI3K/AKT 信号转导因子和 RAB27A 的表达通过 Western 印迹分析进行测定。通过免疫荧光检测 RAB27A。结果发现,CPT 明显阻碍了细胞的活力、增殖(p
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引用次数: 0
Punicalagin attenuates isoproterenol-induced myocardial infarction through nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1-mediated inhibition of inflammation and cardiac stress markers in experimental animal models. 在实验动物模型中, Punicalagin 通过核因子红细胞 2 相关因子 2/沉默信息调节器转录本-1介导的炎症和心脏应激标记物抑制作用,减轻异丙肾上腺素诱发的心肌梗死。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.02
X Y Liao, P Liu, T F Luo, Y Li, Y Gao, F Y Pan, K C Wang

Myocardial infarction (MI) is a significant global health issue and the leading cause of death. Myocardial infarction (MI) is characterized by events such as damage to heart cells and stress generated by inflammation. Punicalagin (PCN), a naturally occurring bioactive compound found in pomegranates, exhibits a diverse array of pharmacological effects against many disorders. This study aimed to assess the preventive impact of PCN, with its potential anti-inflammatory and antioxidant properties, on myocardial injury caused by isoproterenol (ISO) in rats and elucidate the possible underlying mechanisms. Experimental rats were randomly categorized into four groups: control group (fed a regular diet for 15 days), PCN group (orally administered PCN at 50 mg/kg body weight (b.w.) for 15 days), ISO group (subcutaneously administered ISO (85 mg/kg b.w.) on days 14 and 15 to induce MI), and PCN+ISO group (orally preadministered PCN (50 mg/kg b.w.) for 15 days and administered ISO (85 mg/kg b.w.) on days 14 and 15). The rat cardiac tissue was then investigated for cardiac marker, oxidative stress marker, and inflammatory marker expression levels. PCN prevented ISO-induced myocardial injury, suppressing the levels of creatine kinase-myocardial band, C-reactive protein, homocysteine, cardiac troponin T, and cardiac troponin I in the rats. Moreover, PCN treatment reversed (P<0.01) the ISO-induced increase in blood pressure, attenuated lipid peroxidation markers, and depleted both enzymatic and nonenzymatic markers in the rats. Additionally, PCN inhibited (P<0.01) ISO-induced overexpression of oxidative stress markers (p-38, p-c-Jun N-terminal kinase, and p-extracellular signal-regulated kinase 1), inflammatory markers (nuclear factor-kappa B, tumor necrosis factor-alpha, and interleukin-6), and matrix metalloproteinases and decreased the levels (P<0.01) of apoptosis proteins in the rats. Nuclear factor erythroid 2-related factor 2/silent information regulator transcript-1 (Nrf2/Sirt1) is a major cellular defense protein that regulates and scavenges oxidative toxic substances through apoptosis. Therefore, overexpression of Nrf2/Sirt1 to inhibit inflammation and oxidative stress is considered a novel target for preventing MI. PCN also significantly enhanced the expression of Nrf2/Sirt1 in ISO-induced rats. Histopathological analyses of cardiac tissue revealed that PCN treatment exhibited a protective effect on the heart tissue, mitigating damage. These findings show that by activating the Nrf2/Sirt1 pathway, PCN regulates oxidative stress, inflammation, and apoptosis, hence providing protection against ISO-induced myocardial ischemia.

心肌梗塞(MI)是一个重大的全球性健康问题,也是导致死亡的主要原因。心肌梗塞(MI)的特点是心脏细胞受损和炎症产生应激反应。Punicalagin(PCN)是一种存在于石榴中的天然生物活性化合物,对多种疾病具有不同的药理作用。本研究旨在评估 PCN(具有潜在的抗炎和抗氧化特性)对异丙肾上腺素(ISO)引起的大鼠心肌损伤的预防作用,并阐明其可能的内在机制。实验大鼠被随机分为四组:对照组(喂食普通食物 15 天)、PCN 组(口服 PCN(50 毫克/千克体重)15 天)、ISO 组(第 14 天和第 15 天皮下注射 ISO(85 毫克/千克体重)诱导心肌梗死)和 PCN+ISO 组(口服 PCN(50 毫克/千克体重)15 天,第 14 天和第 15 天注射 ISO(85 毫克/千克体重))。然后对大鼠心脏组织进行心脏标志物、氧化应激标志物和炎症标志物表达水平的检测。PCN 可预防 ISO 引起的心肌损伤,抑制大鼠体内肌酸激酶-心肌带、C 反应蛋白、同型半胱氨酸、心肌钙蛋白 T 和心肌钙蛋白 I 的水平。此外,PCN 还能逆转(P
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引用次数: 0
Towards optimizing the protocol for untargeted profiling of urine volatiles via gas chromatography-ion mobility spectrometry. A pilot study. 通过气相色谱-离子迁移谱法优化尿液挥发性物质非靶标分析方案。试点研究。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.10
S Novakova, B Czippelova, E Baranovicova, M Sarlinova, A Urbanova, Z Hatokova, A Dzian, P Banovcin, J Strnadel, P Novak, G Horvath, E Halasova, H Skovierova

The analysis of volatile organic compounds (VOCs) present in various biological samples holds immense potential for non-invasive disease diagnostics and metabolic profiling. One of the biological fluids that are suitable for use in clinical practice is urine. Given the limited quantity of VOCs in the urine headspace, it's imperative to enhance their extraction into the gaseous phase and prevent any degradation of VOCs during the thawing process. The study aimed to test several key parameters (incubation time, temperature, and thawing) that can influence urine volatilome and monitor selected VOCs for their stability. The analysis in this study was performed using a BreathSpec® (G.A.S., Dortmund, Germany) device consisting of a gas chromatograph (GC) coupled with an ion mobility spectrometer (IMS). Testing three different temperatures and incubation times yielded a low number of VOCs (9 out of 34) that exhibited statistically significant differences. However, examining three thawing conditions revealed no VOCs with statistically significant changes. Thus, we conclude that urine composition remains relatively stable despite exposure to various thermal stresses.

对各种生物样本中的挥发性有机化合物(VOC)进行分析,在无创疾病诊断和新陈代谢分析方面具有巨大的潜力。尿液是适用于临床实践的生物液体之一。由于尿液顶空气体中的挥发性有机化合物数量有限,因此必须加强对气相中挥发性有机化合物的提取,并防止挥发性有机化合物在解冻过程中发生降解。本研究旨在测试可能影响尿液挥发性的几个关键参数(培养时间、温度和解冻),并监测所选挥发性有机化合物的稳定性。本研究使用 BreathSpec® (G.A.S.,德国多特蒙德)装置进行分析,该装置由气相色谱仪 (GC) 和离子迁移谱仪 (IMS) 组成。通过测试三种不同的温度和培养时间,只有少数挥发性有机化合物(34 种中的 9 种)显示出显著的统计学差异。然而,对三种解冻条件进行检测后发现,没有任何挥发性有机化合物在统计学上有显著变化。因此,我们得出结论,尽管暴露在各种热应力下,尿液成分仍然保持相对稳定。
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引用次数: 0
Changes and significance of the fibrinolytic system following two pulmonary thromboembolisms in a rabbit model. 兔模型两次肺血栓栓塞后纤维蛋白溶解系统的变化及其意义。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.03
D-C Liu, B Duan, M-N Zhao, L Wu, Y-Z Cao, N-B Liu, Z Xue, Z-H He, J Mi

In this study, we examined the changes in the fibrinolytic system in a rabbit model of two acute pulmonary thromboembolisms (PTE). Fourteen healthy adult New Zealand white rabbits were divided into three groups: the single PTE group (five rabbits), the double PTE group (five rabbits), and the control group (four rabbits). A rabbit model of acute pulmonary embolism was established, and immunohistochemistry and polymerase chain reaction (PCR) were performed on tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) in plasma, and pulmonary embolism tissue. Plasma results: 1) t-PA levels: one hour following the initial modeling, the levels of t-PA in the modeling groups were significantly lower than those in the control group (P<0.05). In addition, the t-PA levels in the double PTE group were found to be lower after the modeling, as compared to the pre-modeling period (P<0.05). One hour after the second modeling, the double PTE group had lower t-PA levels compared to the control group (P<0.05). However, t-PA rebounded two hours after modeling in the double PTE group. One week after the second modeling, the double PTE group had higher t-PA levels compared to the other two groups (P<0.05). 2) PAI-1 results: one hour after the initial modeling, PAI-1 levels in the two modeling groups were lower compared to the pre-modeling period and control groups (P<0.05). Two hours following modeling, PAI-1 levels in both modeling groups were lower compared to the control group (P<0.05). PAI-1 levels were lower in the double PTE group one and two hours after the second modeling compared to the other two groups and pre-modeling period (P<0.05). 3) The immunohistochemistry results: the expression of PAI-1 decreased in the two modeling groups, while t-PA expression increased compared to the control group. 4) PCR results: t-PA mRNA expression did not differ among the three groups. The PAI-1 mRNA expression was lower in the two PTE groups compared to the control group. We conclude that in the early stages of PTE, the local fibrinolytic activity of the thrombus is increased, which is favorable for thrombolysis. However, as the thrombus persists, the activity of the fibrinolytic system is inhibited, contributing to the development of chronic thromboembolic pulmonary hypertension.

在这项研究中,我们研究了两次急性肺血栓栓塞症(PTE)兔模型中纤维蛋白溶解系统的变化。我们将 14 只健康的成年新西兰白兔分为三组:单 PTE 组(5 只)、双 PTE 组(5 只)和对照组(4 只)。建立急性肺栓塞兔模型,对血浆中的组织纤溶酶原激活剂(t-PA)、纤溶酶原激活剂抑制剂-1(PAI-1)和肺栓塞组织进行免疫组化和聚合酶链反应(PCR)检测。血浆结果1) t-PA 水平:初始建模一小时后,建模组的 t-PA 水平明显低于对照组(P
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引用次数: 0
Modulation of the microRNA-6089/E2F transcription factor2 axis by querceting: implications for osteoblast viability, proliferation, migration, and osteogenic differentiation in fracture healing. 槲皮素对microRNA-6089/E2F转录因子2轴的调节:对骨折愈合中成骨细胞活力、增殖、迁移和成骨分化的影响
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.06
R Dong, M Y Liu, G B Zhu, K M Tan, Y Q Wang, L Li

Quercetin is widely distributed in plants as a flavonol compound with multiple biological activities. It has been found that quercetin can regulate bone homeostasis through multiple pathways and targets. This study investigated the role and specific molecular mechanisms of quercetin in regulating osteoblast viability, proliferation, migration and osteogenic differentiation. A mouse model of traumatic fracture was established and then 100 mg/kg quercetin corn oil suspension was gavaged at the same time every day for 28 days. miR-6089 and E2F transcription factor 2 (E2F2) expression levels in mice were measured. Fracture healing in mice was observed. MC3T3-E1 cells were transfected with plasmids targeting miR-6089 and E2F2, and cell viability, proliferation, migration, apoptosis, and osteogenic differentiation were determined. The targeting relationship between miR-6089 and E2F2 was verified. In vivo experiments showed that quercetin significantly increased osteocalcin (OCN) expression (P<0.05) and promoted fracture healing in traumatic fracture (TF) mice. miR-6089 expression was down-regulated (P<0.05) and E2F2 expression was up-regulated (P<0.05) in TF mice. Quercetin promoted miR-6089 expression and inhibited E2F2 expression (both P<0.05). In vitro results showed that quercetin promoted miR-6089 expression and inhibited E2F2 expression in a dose-dependent manner (both P<0.05). Quercetin dose-dependently promoted MC3T3-E1 cell viability, proliferation, migration, and osteogenic differentiation, and inhibited MC3T3-E1 cell apoptosis (all P<0.05). Up-regulating miR-6089 further promoted MC3T3-E1 cell viability, proliferation, migration and osteogenic differentiation, and inhibited MC3T3-E1 cell apoptosis (all P<0.05). miR-6089 targeted and regulated E2F2 expression. Up-regulating E2F2 attenuated the promoting effect of up-regulated miR-6089 on MC3T3-E1 cell viability, proliferation, migration, osteogenic differentiation, and inhibition of apoptosis (all P<0.05). We conclude that quercetin enhances osteoblast viability, proliferation, migration, and osteogenic differentiation by modulating the miR-6089/E2F2 axis, thereby promoting fracture healing.

槲皮素作为一种黄酮醇化合物广泛分布于植物中,具有多种生物活性。研究发现,槲皮素可通过多种途径和靶点调节骨稳态。本研究探讨了槲皮素在调节成骨细胞活力、增殖、迁移和成骨分化中的作用和具体分子机制。研究建立了创伤性骨折小鼠模型,然后每天同一时间灌胃 100 毫克/千克槲皮素玉米油混悬液,连续 28 天,测定小鼠体内 miR-6089 和 E2F 转录因子 2(E2F2)的表达水平。观察小鼠骨折愈合情况。用靶向 miR-6089 和 E2F2 的质粒转染 MC3T3-E1 细胞,测定细胞活力、增殖、迁移、凋亡和成骨分化。实验验证了 miR-6089 和 E2F2 之间的靶向关系。体内实验表明,槲皮素能显著增加骨钙素(OCN)的表达(P
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引用次数: 0
The multidirectional assessment of moderate caloric restriction and metformin treatment in obese patients. 对肥胖患者进行适度热量限制和二甲双胍治疗的多方位评估。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.05
A Kanikowska, D Kanikowska, E Swora-Cwynar, M Sato, A Krawczyk, K Bieganski, A Grzymislawski, A Breborowicz, J Witowski, K Korybalska

Obesity treatment is often burdensome for patients. We used the combination of moderate caloric restriction (CR) with hypoglycemic metformin to assess their multidirectional effect in obese patients. One group was treated only with moderate CR (n=21) the second was treated with moderate CR and 800 mg metformin twice daily (n=23). Serum was drawn before and after treatment. The following parameters were monitored: anthropometric, cardiovascular, inflammatory, metabolic, and markers characteristic for thyroid, liver, pancreas, and kidney functions. Both tested groups did not significantly differ in most tested parameters after the treatment. Two groups reduced anthropometric parameters (body mass, body mass index (BMI), waist circumference) and fat mass but also muscle and fat-free mass, improving systolic blood pressure, insulin and leptin concentration, insulin sensitivity, leptin to adiponectin ratio, and inflammatory markers. Unfortunately, there was little impact on improving dyslipidemia and the thyroid and liver parameters. Free triiodothyronine (fT3) and gamma glutamyl transferase (GGT) activity were decreased in both groups, but triglycerides were reduced only in patients treated with moderate CR. Metformin with CR treatment decreases uric acid and aspartate aminotransferase (AspAT) activity. Metformin treatment with moderate CR in obese patients mainly improved insulin sensitivity, resulting in a reduction of patients with glucose intolerance, improved anthropometric, cardiovascular, and inflammatory mediators, and only slightly enhanced liver and thyroid function. No changes in kidney and pancreas function were observed during the treatment. In conclusion, eight weeks of CR alone and CR with metformin in obese adults improved anthropometric and metabolic markers, reduced muscle mass, fT3, GGT, proinflammatory, and CV parameters, and displayed no changes in kidney and pancreas function. The group treated with metformin after the treatment was still more obese and had higher C-reactive protein (CRP) and homeostasis model assessment-an index of insulin resistance (HOMA-IR), but despite this, considerably reduced the number of patients with glucose intolerance.

肥胖症治疗往往给患者带来沉重负担。我们将适度热量限制(CR)与降糖二甲双胍结合使用,以评估它们对肥胖患者的多向作用。一组只接受适度热量限制治疗(21 人),另一组接受适度热量限制和 800 毫克二甲双胍治疗,每天两次(23 人)。治疗前后均抽取血清。对以下参数进行了监测:人体测量、心血管、炎症、代谢以及甲状腺、肝脏、胰腺和肾脏功能的特征性指标。治疗后,两个受测组在大多数受测参数上没有明显差异。两组均降低了人体测量参数(体重、体重指数(BMI)、腰围)和脂肪量,还降低了肌肉和无脂肪量,改善了收缩压、胰岛素和瘦素浓度、胰岛素敏感性、瘦素与脂肪连通素的比率以及炎症指标。遗憾的是,对改善血脂异常以及甲状腺和肝脏指标的影响甚微。两组患者的游离三碘甲状腺原氨酸(fT3)和γ-谷氨酰转移酶(GGT)活性都有所下降,但只有接受中度 CR 治疗的患者甘油三酯有所下降。二甲双胍联合 CR 治疗可降低尿酸和天冬氨酸氨基转移酶(AspAT)活性。肥胖患者接受二甲双胍联合中度 CR 治疗后,主要改善了胰岛素敏感性,从而减少了葡萄糖不耐受患者,改善了人体测量、心血管和炎症介质,仅轻微增强了肝脏和甲状腺功能。治疗期间未观察到肾脏和胰腺功能的变化。总之,对肥胖成人进行为期八周的单纯 CR 和 CR 联合二甲双胍治疗可改善人体测量指标和代谢指标,降低肌肉质量、fT3、谷氨酰转肽酶、促炎症和心血管参数,但肾脏和胰腺功能没有变化。治疗后使用二甲双胍治疗的一组肥胖程度仍然较高,C反应蛋白(CRP)和胰岛素抵抗指数(HOMA-IR)也较高,但尽管如此,糖耐量减低的患者人数却大大减少。
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引用次数: 0
Mechanism of microRNA regulating apoptosis after reperfusion in patients with mechanical thrombectomy. 微RNA调控机械血栓切除术患者再灌注后细胞凋亡的机制
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.04
Z J Chen, J Han

Stroke is the second leading cause of death worldwide. Understanding of gene expression dynamics could bring new approaches in diagnostics and therapy of stroke. Small noncoding molecules termed 'microRNA' represent the most flexible network of gene expression regulators. To screen out miRNAs that are mainly regulated during reperfusion in mechanically embolized patients, and study their mechanisms of action in reperfusion injury after thrombectomy, in order to find new therapeutic targets for mechanically embolized patients. Serums from 30 patients with moderate to severe stroke after mechanical thrombectomy (MT) were collected to measure miRNA expressions. Clinical information of patients was analyze, and patients were divided into poor prognosis and good prognosis. Factors affecting prognosis was classified, and independent risk factors for poor prognosis were determined. Prognostic value of National Institutes of Health Stroke Scale (NIHSS) score on admission to patients with MT was assessed. ROC (receiver operating characteristic) curves were drawn, and Kaplan-Merier method determined whether different NIHSS scores at admission had any difference in the in-hospital survival rate of consistency index/random consistency index (CI/RI) patients treated with MT. An oxygen-glucose deprivation/reperfusion (OGD/R) cell model and an middle cerebral artery occlusion (MCAO)/reperfusion mouse model were established, in which miR-298 expression was tested. In OGD/R cells, proliferation, apoptosis, and autophagy were assessed after intervention with miR-298 and/or autophagy related gene 5 (ATG5). In MCAO mice, the infarct area was calculated, and neurological function was assessed. The relationship between miR-298 and ATG5 was explored and validated. Age, diabetes, hypertension, hemorrhage transformation, NIHSS score at admission, leukocyte, neutrophil count and neutrophil to lymphocyte ratio (NLR) level were associated with patient's prognosis. Diabetes, NIHSS score at admission, and hemorrhagic transformation were independent risk factors for predicting poor prognosis in patients treated with MT. NIHSS score on admission had a predictive value on patient's prognosis. miR-298 was upregulated in acute cerebral ischemia patients with MT (p<0.05), especially in those with poor prognosis. miR-298 was elevated in both cell and mouse models (p<0.05). Apoptosis and autophagy of cells were weakened after miR-298 knockdown, and infarction in the mouse brain tissues was reduced. ATG5 was a target of miR-298. Overexpressing ATG5 rescued miR-298-induced apoptosis and autophagy. In conclusion: regulation of miR-298 and ATG5 attenuates neuronal apoptosis and autophagy, providing a new strategy for brain injury after reperfusion in patients with MT.

中风是全球第二大死亡原因。了解基因表达动态可为中风的诊断和治疗带来新方法。被称为 "microRNA "的非编码小分子代表了最灵活的基因表达调控网络。筛选出机械性栓塞患者再灌注过程中主要受调控的 miRNA,并研究其在血栓切除术后再灌注损伤中的作用机制,从而为机械性栓塞患者找到新的治疗靶点。研究人员收集了30名机械取栓术(MT)后中重度脑卒中患者的血清,以测定miRNA的表达。分析患者的临床信息,将患者分为预后差和预后好两种。对影响预后的因素进行了分类,并确定了预后不良的独立危险因素。评估了 MT 患者入院时美国国立卫生研究院卒中量表(NIHSS)评分的预后价值。绘制了ROC(接收器操作特征)曲线,并用Kaplan-Merier法测定了入院时不同的NIHSS评分对接受MT治疗的一致性指数/随机一致性指数(CI/RI)患者的院内存活率是否有影响。建立了氧-葡萄糖剥夺/再灌注(OGD/R)细胞模型和大脑中动脉闭塞(MCAO)/再灌注小鼠模型,并在其中检测了miR-298的表达。用 miR-298 和/或自噬相关基因 5(ATG5)干预 OGD/R 细胞后,对细胞的增殖、凋亡和自噬进行了评估。在 MCAO 小鼠中,计算梗死面积并评估神经功能。研究还探讨并验证了 miR-298 和 ATG5 之间的关系。年龄、糖尿病、高血压、出血转化、入院时的 NIHSS 评分、白细胞、中性粒细胞计数和中性粒细胞与淋巴细胞比值(NLR)水平与患者的预后有关。糖尿病、入院时的 NIHSS 评分和出血转化是预测 MT 患者预后不良的独立风险因素。入院时的 NIHSS 评分对患者的预后有预测价值。
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引用次数: 0
Local aldosterone release and CYP11B2 expression in response to angiotensin peptides, glucose, and potassium - an ex vivo study on murine colon. 局部醛固酮释放和 CYP11B2 表达对血管紧张素肽、葡萄糖和钾的反应--对小鼠结肠的体外研究。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.07
Z Pang, R Korpela, H Vapaatalo

We have previously described local aldosterone synthesis in mouse colon. In the renin-angiotensin-aldosterone system (RAAS), angiotensin II (Ang II) peptide is the physiological factor which stimulates aldosterone synthesis in the adrenal glands. We have recently demonstrated that Ang II stimulates aldosterone synthesis also in mouse colon. Here, we conducted a 75-min ex vivo incubation of murine colonic tissue and evaluated the effects of three other Ang peptides, Ang I (1 μM), Ang III (0.1 μM) and Ang (1-7) (0.1 μM) on aldosterone synthesis. As a possible mechanism, their effects on tissue levels of the rate-limiting enzyme, aldosterone synthase (CYP11B2) were measured by ELISA and Western blot. Ang III significantly elevated the amount of tissue CYP11B2 protein in colon. The values of released aldosterone in colon tissue incubation were increased over the control in the presence of Ang I, II or III, however, being statistically non-significant. In Western blot analysis, the values of tissue CYP11B2 protein content were elevated by Ang I and II. Ang (1-7) alone in colon did not influence CYP11B2 protein levels in the incubation experiment but showed higher aldosterone release without statistical significance. Ang (1-7) showed an antagonistic effect towards Ang II in release of aldosterone in adrenal gland. An overall estimation of a single peptide (three measured variables), the results were always in an increasing direction. The responses of aldosterone synthesis to high levels of glucose (44 mM) and potassium (18.8 mM) as physiological stimulators in vivo were investigated in the colon incubation. Glucose, equal to four times the concentration of the control buffer in the incubation, showed higher values of aldosterone release in colon than control without statistical significance similarly to the effect seen in adrenal glands. Increasing the concentration of potassium in the incubation buffer exerted no effect on colonic aldosterone production. Intriguingly, no correlation was found between aldosterone release and the tissue CYP11B2 protein content in colon. In summary, the response of colonic aldosterone synthesis to different Ang peptides resembles, but is not identical to, the situation in the adrenal glands.

我们曾描述过小鼠结肠中醛固酮的局部合成。在肾素-血管紧张素-醛固酮系统(RAAS)中,血管紧张素 II(Ang II)肽是刺激肾上腺合成醛固酮的生理因素。最近,我们证实 Ang II 也能刺激小鼠结肠中醛固酮的合成。在此,我们对小鼠结肠组织进行了 75 分钟的体外培养,并评估了另外三种 Ang 肽(Ang I(1 μM)、Ang III(0.1 μM)和 Ang (1-7)(0.1 μM))对醛固酮合成的影响。作为一种可能的机制,我们通过 ELISA 和 Western 印迹法测定了它们对组织中限速酶醛固酮合成酶(CYP11B2)水平的影响。Ang III 能明显增加结肠组织中 CYP11B2 蛋白的含量。在 Ang I、II 或 III 的作用下,结肠组织培养释放的醛固酮值比对照组有所增加,但在统计学上并不显著。在 Western 印迹分析中,组织中 CYP11B2 蛋白含量的数值因 Ang I 和 Ang II 而升高。在培养实验中,结肠中单独使用 Ang (1-7) 不会影响 CYP11B2 蛋白水平,但醛固酮释放量增加,但无统计学意义。在肾上腺释放醛固酮的过程中,Ang (1-7) 对 Ang II 有拮抗作用。对单一肽(三个测量变量)的总体估计结果始终呈上升趋势。在结肠培养中,研究了醛固酮合成对高浓度葡萄糖(44 毫摩尔)和钾(18.8 毫摩尔)作为体内生理刺激物的反应。葡萄糖(相当于培养液中对照缓冲液浓度的四倍)在结肠中显示出比对照组更高的醛固酮释放值,但无统计学意义,这与在肾上腺中看到的效果类似。提高孵育缓冲液中钾的浓度对结肠醛固酮的产生没有影响。耐人寻味的是,醛固酮的释放与结肠组织中 CYP11B2 蛋白含量之间没有相关性。总之,结肠醛固酮合成对不同 Ang 肽的反应与肾上腺的情况相似,但并不完全相同。
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引用次数: 0
Exploring the role of histone deacetylase inhibitors in cancer development and therapeutic potential. 探索组蛋白去乙酰化酶抑制剂在癌症发展中的作用和治疗潜力。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.01
C Zhang, H X Li, Y Man, Z H Jiang, P Yin, K Yu

The process of acetylation and deacetylation of histones within the nucleus operates within a dynamic equilibrium. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) collaboratively and precisely regulate normal gene transcription and expression. Any disorder in the activity of HATs/HDACs can lead to uncontrolled gene expression, consequently resulting in tumorigenesis. Histone deacetylase inhibitors (HDACIs) have the capacity to block the cell cycle, thereby restraining tumor cell proliferation and tumor growth. Also, HDACIs exhibit a significant capability to diminish the expression of apoptosis protein inhibitors such as Bcl-2 and B-cell lymphoma-extra-large (Bcl-xL), while concurrently up-regulating pro-apoptotic proteins such as Bax, Bad, and Bim. Also, HDACIs demonstrate the ability to inhibit tumor cell angiogenesis. Representing a new category of targeted anti-cancer therapeutics, HDACIs possess the capability to restore the expression of tumor suppressor genes, induce apoptosis, and stimulate cell differentiation. Additionally, they exert anti-cancer effects through diverse pathways both in vivo and in vitro, thereby presenting promising prospects in tumor therapy. This review delves into the involvement of HDACs in cancer pathology and the therapeutic potential of HDACIs as emerging drugs in cancer treatment.

组蛋白在细胞核内的乙酰化和去乙酰化过程处于动态平衡状态。组蛋白乙酰转移酶(HATs)和组蛋白去乙酰化酶(HDACs)相互协作,精确调控正常的基因转录和表达。组蛋白乙酰转移酶/组蛋白去乙酰化酶的任何活性失调都会导致基因表达失控,进而导致肿瘤发生。组蛋白去乙酰化酶抑制剂(HDACIs)能够阻断细胞周期,从而抑制肿瘤细胞增殖和肿瘤生长。此外,HDACIs 还能显著降低 Bcl-2 和 B 细胞淋巴瘤超大型(Bcl-xL)等凋亡蛋白抑制剂的表达,同时上调 Bax、Bad 和 Bim 等促凋亡蛋白。此外,HDACIs 还能抑制肿瘤细胞的血管生成。作为一种新型靶向抗癌疗法,HDACIs 具有恢复肿瘤抑制基因表达、诱导细胞凋亡和刺激细胞分化的能力。此外,它们通过体内和体外的不同途径发挥抗癌作用,因此在肿瘤治疗方面前景广阔。本综述将深入探讨 HDACs 在癌症病理学中的参与作用,以及 HDACIs 作为新兴药物在癌症治疗中的治疗潜力。
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引用次数: 0
3-carene supresses inflammatory cytokine interleukin-4, interleukin-5 and interleukin-13 in a murine model of asthma. 3-carene 能抑制小鼠哮喘模型中的炎性细胞因子白细胞介素-4、白细胞介素-5 和白细胞介素-13。
IF 2.2 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-04-01 Epub Date: 2024-05-06 DOI: 10.26402/jpp.2024.2.08
K Kim, Y Kim, J Lee, M Lee, C Ahn, M-J Park, H Na, E-B Jeung

Asthma is a common airway disease associated with allergic inflammation. Environmental factors, such as pollens, pollution, insect-borne antigens, or commercial chemicals, cause this disease. The common symptoms of this airway allergic reaction are increasing mucus, narrowing of the airway wall, coughing, and chest tightness. Medications, such as steroids, alleviate the disease but with severe side effects. Several studies have reported the anti-inflammatory effects of tree-based essential oil components, particularly 3-carene. Therefore, this study used 3-carene to determine if it alleviates asthmatic symptoms in the murine model. First, BALB/c mice were sensitized to an ovalbumin and aluminium hydroxide mixture on day 7th and 14th. From days 21st to 23rd, the mice were challenged with 3-carene and budesonide. The lung trachea, plasma, and bronchiolar lavage fluid (BAL fluid) were collected on day 24. The 3-carene treatment suppressed the cytokine gene expression, such as interleukin-4 (IL-4), IL-5, and IL-13, reducing the lung epithelial cell thickness in the asthmatic model. These results suggest that essential oil 3-carene has an anti-asthmatic effect.

哮喘是一种常见的气道疾病,与过敏性炎症有关。花粉、污染、昆虫传播的抗原或商业化学品等环境因素会导致这种疾病。这种气道过敏反应的常见症状是粘液增多、气道壁变窄、咳嗽和胸闷。类固醇等药物可以缓解病情,但副作用很大。有几项研究报道了树基精油成分的抗炎作用,尤其是 3-蒈烯。因此,本研究使用 3-蒈烯来确定它是否能缓解小鼠模型中的哮喘症状。首先,BALB/c 小鼠在第 7 天和第 14 天对卵清蛋白和氢氧化铝混合物过敏。第 21 至 23 天,小鼠接受 3-卡林和布地奈德的挑战。第 24 天收集肺气管、血浆和支气管灌洗液(BAL 液)。结果表明,3-蒈烯能抑制细胞因子基因的表达,如白细胞介素-4(IL-4)、IL-5 和 IL-13,减少哮喘模型肺上皮细胞的厚度。这些结果表明,3-蒈烯精油具有抗哮喘的作用。
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引用次数: 0
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