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The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload. 磷酸二酯酶-5抑制剂或血管紧张素转换酶抑制剂对慢性容量超负荷导致的心力衰竭患者左右心室重塑的影响。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1172
Tereza Tykvartova, Matus Miklovic, Martin Kotrc, Petra Skaroupkova, Ludmila Kazdova, Jaroslava Trnovska, Vojtech Skop, Michal Kolar, Jiri Novotny, Vojtech Melenovsky

While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

虽然磷酸二酯酶-5抑制剂(PED5i)可在实验模型中预防压力过载心脏的肥大和衰竭,但PDE5i对容量过载(VO)诱导的肥大的影响尚不清楚。此外,肥厚的右心室(RV)和左心室(LV)对长期服用 PDE5i 的反应是否不同,以及这种疗法是否会影响肾功能,这些都还不清楚。本研究旨在阐明 PDE5i 治疗对主动脉腔瘘 (ACF) 引起的 VO 的影响,并将 PDE5i 治疗与使用血管紧张素转换酶抑制剂 (ACEi) 的标准心力衰竭 (HF) 治疗进行比较。ACF/sham 手术在 8 周龄的雄性 HanSD 大鼠身上进行。ACF 动物被随机分配接受 PDE5i 西地那非、ACEi 曲托普利或安慰剂治疗。20 周后,对 RV 和 LV 功能(超声心动图、压力-容积分析)、心肌基因表达和肾功能进行研究。对不同组别的大鼠进行了存活率分析。ACF 导致双心室偏心性肥厚(左心室:+68%,右心室:+145%)、搏出功增加(左心室:3.6 倍,右心室:6.7 倍)以及负荷无关收缩功能降低(PRSW,左心室:-54%,右心室:-51%)。两个 ACF 心室都表现出心肌应激和糖代谢基因的上调。ACEi 而非 PDE5i 可减轻肺充血、左心室重塑、白蛋白尿并提高存活率(ACF/ACEi 的中位存活时间为 41 周,ACF/安慰剂的中位存活时间为 35 周,P = .02)。PDE5i 可增加肺部的环鸟苷单磷酸水平,但不会增加左心室、左心室或肾脏的环鸟苷单磷酸水平。与 ACEi 相比,PDE5i 并未改善 ACF 大鼠的存活率以及心脏和肾脏功能。VO诱导的心房颤动对PDE5i疗法无反应。
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引用次数: 0
The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity. 阻断 TGF-β 通路可缓解脂肪营养不良而非肥胖症的葡萄糖和脂质代谢异常。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1160
Wen-Dong Xu, Shui-Zheng Lai, Jia Zhao, Shi-Jie Wei, Xue-Ying Fang, Yi-Yi Liu, Xiang-Lu Rong, Jiao Guo

TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.

TGF-β被认为参与早期器官发育的生理功能和实质性器官纤维化的病理变化,而围绕脂肪组织功能和系统性糖脂代谢紊乱的研究仍然很少。本研究采用了两种动物模型:aP2-SREBP-1c小鼠和ob/ob小鼠。在这两种动物模型的腹股沟白色脂肪组织(iWAT)中,TGF-β通路出现上调。TGF-β抑制剂SB431542成功地使腹股沟白色脂肪细胞体积增加了1.5倍以上,并使肝脏、脾脏和肾脏等外周器官的重量分别减少至给药前的73.05%、62.18%和73.23%。iWAT 显示,aP2-SREBP-1c 小鼠的 GLUTs 和脂肪酶表达升高,随后循环中的 GLU、TG、NEFA 和 GLYCEROL 恢复到野生型水平。相反,抑制 TGF-β 对肥胖/ob 小鼠没有类似影响。在体外,经 TGF-β 阻断剂处理的成熟脂肪细胞的甘油和甘油三酯水平大大高于对照组,而 GLUTs 和脂肪酶的表达水平则没有变化。这些研究结果表明,抑制异常上调的 TGF-β 通路只能恢复 iWAT 的扩张,改善脂肪营养不良症而非肥胖症中糖和脂质的整体代谢失调。
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引用次数: 0
Decreased hepatic enzymes reflect the decreased vitamin B6 levels in Parkinson's disease patients. 肝酶的减少反映了帕金森病患者体内维生素 B6 水平的降低。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1174
Kensuke Ikenaka, Yuta Kajiyama, César Aguirre, Chi-Jing Choong, Seira Taniguchi, Junko Doi, Nan Wang, Takahiro Ajiki, Kotaro Ogawa, Keita Kakuda, Yasuyoshi Kimura, Hideki Mochizuki

The study aims to investigate the vitamin B6 levels in Parkinson's disease (PD) patients and their association with liver enzymes and evaluate how much dysregulation is associated with levodopa dose. Furthermore, to evaluate the effect of Opicapone, a catechol-o-methyl-transferase inhibitor, on vitamin B6 levels by monitoring the AST and ALT levels in patients treated with Levodopa-Carbidopa Intestinal Gel Infusion (LCIG). For these aims, serum vitamin B6 levels were measured (PD, n = 72 and controls, n = 31). The vitamin B6 level was compared with the total levodopa dose, clinical parameters, and blood homocysteine, albumin, and hemoglobin levels in PD patients. Correlations between vitamin B6 levels and AST and ALT levels, as well as the ratio ALT/AST, were analyzed. Changes in the AST and ALT levels and ALT/AST were analyzed in the patients treated with LCIG before and after the therapy (n = 24) and in the patients treated with LCIG + Opicapone before and after Opicapone treatment (n = 12). We found vitamin B6 levels were significantly lower in PD patients. Total levodopa dose and albumin levels were independently associated with vitamin B6 levels. Decreased vitamin B6 levels appeared as lower AST and ALT levels and ALT/AS. Treatment with LCIG decreased the AST and ALT levels and ALT/AST. Adjunctive therapy with Opicapone to LCIG ameliorated the decreased ALT and ALT/AST. We conclude that the ALT and ALT/AST can be useful parameters for monitoring vitamin B6 levels and Opicapone can ameliorate the dysregulated vitamin B6 in PD patients.

该研究旨在调查帕金森病(PD)患者的维生素 B6 水平及其与肝酶的关系,并评估维生素 B6 水平失调与左旋多巴剂量的关系。此外,通过监测左旋多巴-卡比多巴肠溶胶体注射液(LCIG)患者的谷草转氨酶(AST)和谷丙转氨酶(ALT)水平,评估儿茶酚-邻甲基转移酶抑制剂 Opicapone 对维生素 B6 水平的影响。为达到上述目的,对血清维生素 B6 水平进行了测量(PD 72 人,对照组 31 人)。将维生素 B6 水平与左旋多巴总剂量、临床参数以及帕金森病患者血液中的同型半胱氨酸、白蛋白和血红蛋白水平进行了比较。分析了维生素 B6 水平与谷草转氨酶和谷丙转氨酶水平以及谷丙转氨酶/谷丙转氨酶比值之间的相关性。我们分析了接受 LCIG 治疗前后(24 人)以及接受 LCIG + Opicapone 治疗前后(12 人)患者的 AST 和 ALT 水平以及 ALT/AST 的变化。我们发现帕金森病患者的维生素 B6 水平明显较低。左旋多巴总剂量和白蛋白水平与维生素 B6 水平有独立关联。维生素 B6 水平的降低表现为谷草转氨酶(AST)和谷丙转氨酶(ALT)水平以及谷丙转氨酶/谷草转氨酶(ALT/AS)水平的降低。使用 LCIG 治疗可降低谷草转氨酶和谷丙转氨酶水平以及谷丙转氨酶/谷草转氨酶。在使用 LCIG 的同时使用 Opicapone 可改善 ALT 和 ALT/AST 的下降。我们的结论是,ALT和ALT/AST可作为监测维生素B6水平的有用参数,而Opicapone可改善帕金森病患者维生素B6失调的情况。
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引用次数: 0
Scopolamine regulates the osteogenic differentiation of human periodontal ligament stem cells through lactylation modification of RUNX2 protein. 东莨菪碱通过乳化修饰RUNX2蛋白调节人牙周韧带干细胞的成骨分化
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1169
Ying Wu, Pan Gong

Periodontal ligament stem cells (PDLSCs) are important mesenchymal stem cells contributing to regenerating lost periodontal tissues and repairing bone defects. Studies on the molecular mechanism affecting the osteogenic differentiation of PDLSCs are necessary. Scopolamine (SCO) is known as a regulator of neural cell damage. The focus of the current study is on unveiling the role of SCO-mediated molecular mechanism in the osteogenic differentiation of PDLSCs. Through CCK-8 assay and LDH detection, we confirmed that SCO enhanced the viability of PDLSCs. Moreover, we determined that SCO induced the PDLSCs osteogenic differentiation, according to data of ALP activity measurement and ARS staining. Mechanistically, we performed western blot and identified that SCO could promote the lactylation of runt-related transcription factor 2 (RUNX2). We also found through rescue assays that knockdown of RUNX2 could reverse the effect of SCO treatment on the osteogenic differentiation of PDLSCs. Further mechanism investigation revealed that lactylation of RUNX2 at K176 site enhances the protein stability of RUNX2 through deubiquitination. Collectively, our present study unveils that SCO stabilizes RUNX2 to promote the osteogenic differentiation of PDLSCs through the lactylation modification of RUNX2.

牙周韧带干细胞(PDLSCs)是重要的间充质干细胞,有助于牙周组织的再生和骨缺损的修复。有必要对影响牙周韧带干细胞成骨分化的分子机制进行研究。东莨菪碱(SCO)是众所周知的神经细胞损伤调节剂。本研究的重点是揭示 SCO 介导的分子机制在 PDLSCs 成骨分化中的作用。通过 CCK-8 试验和 LDH 检测,我们证实 SCO 能增强 PDLSCs 的活力。此外,根据ALP活性测定和ARS染色数据,我们确定SCO诱导了PDLSCs的成骨分化。从机理上讲,我们进行了 Western 印迹分析,发现 SCO 可促进 RUNT 相关转录因子 2(RUNX2)的乳化。我们还通过挽救实验发现,敲除 RUNX2 可以逆转 SCO 对 PDLSCs 成骨分化的影响。进一步的机制研究发现,RUNX2在K176位点的乳酰化可通过去泛素化增强RUNX2的蛋白稳定性。综上所述,本研究揭示了SCO通过对RUNX2的乳化修饰稳定RUNX2,从而促进PDLSCs的成骨分化。
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引用次数: 0
Clinical considerations on monkeypox antiviral medications: An overview. 猴痘抗病毒药物的临床考虑因素:概述。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1164
Fariba Pourkarim, Taher Entezari-Maleki

Monkeypox (mpox), a virus belonging to the orthopoxvirus family, can cause a zoonotic infectious disease with morbidity and cosmetic complications. Therefore, effective antiviral drugs with appropriate safety profiles are important for the treatment of patients with mpox. To date, there is no FDA-approved drug for the treatment of mpox. However, tecovirimat, brincidofovir, and cidofovir are the candidate therapies for the management of mpox. Given the safety concerns following the use of these medications, we aimed to review evidence on the clinical considerations of mpox antiviral medications that will be useful to guide clinicians in the treatment approach. Based on the current evidence, tecovirimat has favorable clinical efficacy, safety, and side effect profile and it can be considered as first-line treatment for mpox.

猴痘(mpox)是一种属于正痘病毒科的病毒,可引起人畜共患的传染病,并伴有发病率和外观并发症。因此,具有适当安全性的有效抗病毒药物对于治疗猴痘患者非常重要。迄今为止,美国食品和药物管理局尚未批准用于治疗麻腮风的药物。不过,替考韦利马特、布林昔多韦和西多福韦是治疗水痘的候选疗法。考虑到使用这些药物的安全性问题,我们旨在回顾有关水痘抗病毒药物临床注意事项的证据,以便为临床医生的治疗方法提供指导。根据目前的证据,替考韦瑞(tecovirimat)具有良好的临床疗效、安全性和副作用,可作为水痘的一线治疗药物。
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引用次数: 0
Role of G protein-coupled receptor kinases (GRKs) in β2 -adrenoceptor-mediated glucose uptake. G 蛋白偶联受体激酶(GRKs)在β2 -肾上腺素受体介导的葡萄糖摄取中的作用。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-02-01 DOI: 10.1002/prp2.1176
Seungmin Ham, Saori Mukaida, Masaaki Sato, Peter Keov, Tore Bengtsson, Sebastian Furness, Nicholas D Holliday, Bronwyn A Evans, Roger J Summers, Dana S Hutchinson

Truncation of the C-terminal tail of the β2 -AR, transfection of βARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the β2 -AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant β2 -ARs were generated and receptor affinity for [3 H]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by β2 -AR agonists, cAMP accumulation, GLUT4 translocation, [3 H]-2-deoxyglucose uptake, and β2 -AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between β2 -AR and β-arrestin2 or between β2 -AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to β2 -AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to β2 -AR agonists occurred in CHO-GLUT4myc cells expressing β2 -ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type β2 -AR. However, β2 -ARs lacking phosphorylation sites failed to recruit β-arrestin2 and did not internalize. GRK2 knock-down or GRK2 inhibitors decreased isoprenaline-stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the β2 -AR is not associated with isoprenaline- or BRL37344-stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock-down or GRK2 inhibition reduces isoprenaline-stimulated glucose uptake.

截短β2 -AR的C端尾巴、转染βARKct或过度表达激酶死亡的GRK突变体都会降低异丙肾上腺素刺激的葡萄糖摄取,这表明GRK对这种反应很重要。我们探讨了 GRK2 对 β2 -AR 的磷酸化是否在葡萄糖摄取中发挥作用,或者这种反应是否与 GRK2 作为支架蛋白的作用有关。生成了表达野生型和突变型 β2 -AR 的 CHO-GLUT4myc 细胞,并测定了受体对 [3 H]-CGP12177A 的亲和力、结合位点的密度以及异丙肾上腺素和 BRL37344 的亲和力。β2-AR激动剂激活受体后,cAMP积累、GLUT4转位、[3 H]-2-deoxyglucose 摄取和β2-AR内化均得到测定。生物发光共振能量转移用于研究 β2 -AR 与 β-restin2 之间或 β2 -AR 与 GRK2 之间的相互作用。测量了 siRNA 敲除或 GRK 抑制剂对 β2 -AR 激动剂反应后的葡萄糖摄取量。BRL37344 在产生 cAMP 方面是一种较差的部分激动剂,但在葡萄糖摄取和 GLUT4 转位方面显示出与异丙肾上腺素相似的效力和功效。这些对 β2 -AR 激动剂的反应发生在表达缺乏 GRK 或 GRK/PKA 磷酸化位点的 β2 -AR 的 CHO-GLUT4myc 细胞以及表达野生型 β2 -AR 的细胞中。然而,缺乏磷酸化位点的β2 -AR不能招募β-arrestin2,也不会内化。GRK2 基因敲除或 GRK2 抑制剂降低了大鼠 L6 骨骼肌细胞中异丙肾上腺素刺激的葡萄糖摄取。因此,β2 -AR的GRK磷酸化与异丙肾上腺素或BRL37344刺激的葡萄糖摄取无关。然而,作为支架蛋白的GRK对葡萄糖摄取很重要,因为GRK2敲除或GRK2抑制降低了异丙肾上腺素刺激的葡萄糖摄取。
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引用次数: 0
Investigation of the cytotoxicity induced by cannabinoids on human ovarian carcinoma cells 大麻素对人类卵巢癌细胞诱导的细胞毒性研究
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-15 DOI: 10.1002/prp2.1152
Kartheek Sooda, Simon J. Allison, Farideh A. Javid
Cannabinoids have been shown to induce anti-tumor activity in a variety of carcinoma cells such as breast, prostate, and brain. The aim of the present study is to investigate the anti-tumor activity of cannabinoids, CBD (cannbidiol), and CBG (cannabigerol) in ovarian carcinoma cells sensitive and resistant to chemotherapeutic drugs. Sensitive A2780 cells and resistant A2780/CP70 carcinoma cells and non-carcinoma cells were exposed to varying concentrations of CBD, CBG, carboplatin or CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, alone or in combination, at different exposure times and cytotoxicity was measured by MTT assay. The mechanism of action of CBD and CB in inducing cytotoxicity was investigated involving a variety of apoptotic and cell cycle assays. Treatment with CBD and CBG selectively, dose and time dependently reduced cell viability and induced apoptosis. The effect of CBD was stronger than CBG in all cell lines tested. Both CBD and CBG induced stronger cytotoxicity than afforded by carboplatin in resistant cells. The cytotoxicity induced by CBD was not CB1 or CB2 receptor dependent in both carcinoma cells, however, CBG-induced cytotoxicity may involve CB1 receptor activity in cisplatin-resistant carcinoma cells. A synergistic effect was observed when cannabinoids at sublethal doses were combined with carboplatin in both carcinoma cells. The apoptotic event may involve loss of mitochondrial membrane potential, Annexin V, caspase 3/7, ROS activities, and cell cycle arrest. Further studies are required to investigate whether these results are translatable in the clinic. Combination therapies with conventional cancer treatments using cannabinoids are suggested.
研究表明,大麻素能诱导乳腺癌、前列腺癌和脑癌等多种癌细胞产生抗肿瘤活性。本研究旨在探讨大麻素、CBD(大麻二酚)和 CBG(大麻酚)在对化疗药物敏感和耐药的卵巢癌细胞中的抗肿瘤活性。敏感的 A2780 细胞和耐药的 A2780/CP70 癌细胞以及非癌细胞在不同的暴露时间内分别单独或联合暴露于不同浓度的 CBD、CBG、卡铂或 CB1 和 CB2 受体拮抗剂 AM251 和 AM630,并通过 MTT 试验测定细胞毒性。CBD 和 CB 诱导细胞毒性的作用机制通过多种细胞凋亡和细胞周期检测方法进行了研究。CBD 和 CBG 可选择性地、按剂量和时间降低细胞活力并诱导细胞凋亡。在所有测试的细胞系中,CBD 的作用都强于 CBG。在耐药细胞中,CBD 和 CBG 诱导的细胞毒性均强于卡铂。在两种癌细胞中,CBD 诱导的细胞毒性都不依赖于 CB1 或 CB2 受体,但在顺铂耐药癌细胞中,CBG 诱导的细胞毒性可能涉及 CB1 受体的活性。当亚致死剂量的大麻素与卡铂结合使用时,在这两种癌细胞中都观察到了协同效应。凋亡事件可能涉及线粒体膜电位丧失、Annexin V、caspase 3/7、ROS 活性和细胞周期停滞。这些结果能否应用于临床还需要进一步研究。建议使用大麻素与传统癌症治疗方法相结合。
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引用次数: 0
Co-created in vivo pharmacology practical classes using the novel organism Lumbriculus variegatus 利用新型生物 Lumbriculus variegatus 共同创建体内药理学实践课程
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-08 DOI: 10.1002/prp2.1158
Julanta J. Carriere, Nia A. Davies, Margaret R. Cunningham, Melisa J. Wallace, Aidan Seeley
Co-creation within higher education emphasizes learner empowerment to promote collaboration between the students and staff, enabling students to become active participants in their learning process and the construction of resources with academic staff. Concurrently, a diminishing number of higher education institutions offer in vivo practical classes, resulting in an in vivo skills shortage. To address this, and to actively engage students in their own learning, we describe the co-creation of a student-led drug trial using Lumbriculus variegatus. Under blinded conditions, final-year undergraduate biomedical science students, under the tutelage of academic staff and fellow students, were involved in the co-creation of an in vivo practical class to determine the effects of histamine and histamine receptor inverse agonists mepyramine and loratadine. Throughout this process, undergraduate- and masters-level students played key roles in every aspect of practical delivery and data analysis. Herein, students demonstrated the test compounds, both in isolation and in combination, resulted in reduced stereotypical movements of L. variegatus (p < .05, n ≥ 6). 15% of students in the class responded to a feedback survey (n = 8) after the class. Students reported the class provided “real life” insights into in vivo research and enabled the development of hands-on skills which would be useful in applying in their future careers. All students reported that they enjoyed the class with 25% (n = 2) reporting concerns about animal use in research, enabling useful discussions about animals in research. Moreover, these student-led in vivo trials add to the pharmacological knowledge of L. variegatus promoting education-led research.
高等教育中的 "共同创造 "强调赋予学习者权力,促进学生与教职员工之间的合作,使学生成为学习过程的积极参与者,并与教职员工共同建设资源。与此同时,越来越多的高等教育机构开设了活体实践课程,导致活体技能短缺。为了解决这个问题,并让学生积极参与到自己的学习中,我们介绍了如何利用变色龙(Lumbriculus variegatus)共同创建一个由学生主导的药物试验。在盲法条件下,生物医学科学专业的应届本科生在学术人员和同学的指导下,参与了共同创建的体内实践课,以确定组胺和组胺受体反向激动剂甲吡胺和氯雷他定的作用。在整个过程中,本科生和硕士生在实践教学和数据分析的各个方面都发挥了关键作用。在此,学生们证明了试验化合物单独使用和混合使用都能减少变尾蜥的刻板动作(p < .05, n ≥ 6)。15%的学生在课后回复了反馈调查(n = 8)。学生们表示,这堂课让他们对体内研究有了 "真实 "的了解,并培养了他们的动手能力,这对他们未来的职业生涯很有帮助。所有学生都表示很喜欢这门课,只有 25% 的学生(n = 2)表示对研究中使用动物的问题感到担忧,从而对研究中的动物问题进行了有益的讨论。此外,这些由学生主导的体内试验增加了对变种枸橘的药理学知识,促进了以教育为主导的研究。
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引用次数: 0
Evaluating signaling bias for synthetic cannabinoid receptor agonists at the cannabinoid CB2 receptor. 评估合成大麻素受体激动剂对大麻素CB2受体的信号偏倚。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-01 DOI: 10.1002/prp2.1157
Monica Patel, Natasha L Grimsey, Samuel D Banister, David B Finlay, Michelle Glass

The rapid structural evolution and emergence of novel synthetic cannabinoid receptor agonists (SCRAs) in the recreational market remains a key public health concern. Despite representing one of the largest classes of new psychoactive substances, pharmacological data on new SCRAs is limited, particularly at the cannabinoid CB2 receptor (CB2 ). Hence, the current study aimed to characterize the molecular pharmacology of a structurally diverse panel of SCRAs at CB2 , including 4-cyano MPP-BUT7AICA, 4F-MDMB-BUTINACA, AMB-FUBINACA, JWH-018, MDMB-4en-PINACA, and XLR-11. The activity of SCRAs was assessed in a battery of in vitro assays in CB2 -expressing HEK 293 cells: G protein activation (Gαi3 and GαoB ), phosphorylation of ERK1/2, and β-arrestin 1/2 translocation. The activity profiles of the ligands were further evaluated using the operational analysis to identify ligand bias. All SCRAs activated the CB2 signaling pathways in a concentration-dependent manner, although with varying potencies and efficacies. Despite the detection of numerous instances of statistically significant bias, compound activities generally appeared only subtly distinct in comparison with the reference ligand, CP55940. In contrast, the phytocannabinoid THC exhibited an activity profile distinct from the SCRAs; most notably in the translocation of β-arrestins. These findings demonstrate that CB2 is able to accommodate a structurally diverse array of SCRAs to generate canonical agonist activity. Further research is required to elucidate whether the activation of CB2 contributes to the toxicity of these compounds.

在娱乐市场上,新型合成大麻素受体激动剂(SCRAs)的快速结构演变和出现仍然是一个关键的公共卫生问题。尽管代表了新精神活性物质的最大类别之一,但新scra的药理学数据有限,特别是大麻素CB2受体(CB2)。因此,目前的研究旨在表征CB2上结构不同的scas组的分子药理学,包括4-氰基MPP-BUT7AICA, 4F-MDMB-BUTINACA, AMB-FUBINACA, JWH-018, MDMB-4en-PINACA和XLR-11。在表达CB2的HEK 293细胞中,通过一系列体外实验评估SCRAs的活性:G蛋白激活(Gαi3和Gα ob)、ERK1/2磷酸化和β-阻滞蛋白1/2易位。利用操作分析进一步评价了配体的活性分布,以确定配体的偏倚。所有SCRAs都以浓度依赖的方式激活CB2信号通路,尽管其效力和效果不同。尽管检测到许多统计上显著偏差的实例,但与参考配体CP55940相比,化合物活性通常只表现出细微的差异。相比之下,植物大麻素THC表现出与scra不同的活性谱;最明显的是β-阻滞蛋白的易位。这些发现表明,CB2能够容纳结构多样化的scas阵列,以产生典型激动剂活性。需要进一步的研究来阐明CB2的激活是否有助于这些化合物的毒性。
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引用次数: 0
Experimental pharmacology in precision medicine. 精准医学中的实验药理学。
IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-12-01 DOI: 10.1002/prp2.1147
Alicja Urbaniak, Kenneth E Thummel, Ayoade N Alade, Allan E Rettie, Bhagwat Prasad, Amedeo De Nicolò, Jennifer H Martin, David N Sheppard, Michael F Jarvis
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引用次数: 0
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Pharmacology Research & Perspectives
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