Journal of pharmacological sciences最新文献_第7页

Novel PDE9 inhibitors, KR39526 and KR39582, attenuate cardiac hypertrophy and fibrosis induced by pressure overload 新型PDE9抑制剂KR39526和KR39582可减轻压力过载引起的心脏肥大和纤维化

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-30 DOI: 10.1016/j.jphs.2025.05.015

Jeong Hyun Lee , Hyunjin Park , Seung Hyeong Lee , Su Ah Kim , Jun Young Choi , Chae Jo Lim , Ju-Young Shin , Byung Ho Lee , Kwang-Seok Oh

The natriuretic peptide and cyclic guanosine monophosphate (cGMP) cascade are promising therapeutic target for heart failure. This study evaluated the pharmacological properties and cardioprotective effects of novel phosphodiesterase 9 (PDE9) inhibitors, KR39526 and KR39582, in vitro and in vivo. The potency and selectivity of these compounds were assessed through PDE9 inhibitory activity and subfamily selectivity assays. Functional analyses in cardiomyocytes included calcium mobilization, cellular hypertrophy, and protein expression. The cardioprotective efficacy was investigated using a mouse model of pressure-overload-induced cardiac hypertrophy. KR39526 and KR39582 demonstrated potent PDE9A inhibitory activities (IC₅₀: 5 ± 2 nM and 0.4 ± 0.1 nM, respectively) with high selectivity. This inhibition led to concentration-dependent calcium influx through maintaining intracellular cGMP levels and significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy. Oral administration (50 mg·kg-1) of these compounds markedly attenuated cardiac hypertrophy and myocardial fibrosis induced by pressure overload. These results suggest that KR39526 and KR39582, as potent and selective PDE9A inhibitors, have strong potential for exerting anti-hypertrophic and anti-fibrotic effects in heart failure. These compounds can serve as valuable pharmacological tools to elucidate the roles of PDE9A signaling in heart failure pathophysiology and hold significant promise as potential therapeutic agents.

利钠肽和环鸟苷单磷酸（cGMP）级联是治疗心力衰竭的理想靶点。本研究评估了新型磷酸二酯酶9 （PDE9）抑制剂KR39526和KR39582的体外和体内药理特性和心脏保护作用。通过PDE9抑制活性和亚家族选择性测定来评估这些化合物的效价和选择性。心肌细胞的功能分析包括钙动员、细胞肥大和蛋白表达。采用压力过载致心肌肥厚小鼠模型研究其心脏保护作用。KR39526和KR39582表现出较强的PDE9A抑制活性（IC50分别为5±2 nM和0.4±0.1 nM），具有较高的选择性。这种抑制作用通过维持细胞内cGMP水平导致浓度依赖性钙内流，并显著抑制苯肾上腺素诱导的心肌细胞肥大。口服50 mg·kg-1可显著减轻压力过载引起的心肌肥厚和心肌纤维化。这些结果表明，KR39526和KR39582作为有效的、选择性的PDE9A抑制剂，在心力衰竭中具有很强的抗肥厚和抗纤维化作用。这些化合物可以作为有价值的药理学工具来阐明PDE9A信号在心力衰竭病理生理中的作用，并作为潜在的治疗药物具有重要的前景。

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引用次数: 0

Additive effects of mirabegron on muscarinic receptor binding and on relaxation of cholinergic detrusor muscle contraction by antimuscarinics mirabegron对毒蕈碱受体结合和抗毒蕈碱剂对胆碱能逼尿肌收缩松弛的加性作用

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-27 DOI: 10.1016/j.jphs.2025.05.018

Shizuo Yamada , Masae Mochizuki , Kana Maruyama-Fumoto , Satomi Kagota , Kazumasa Shinozuka

Mirabegron is the first selective β₃-adrenoceptor agonist, to be developed as an alternative to antimuscarinic therapy for patients with overactive bladder (OAB). This agent exerts off-target effects on muscarinic receptors. Its combination with solifenacin results in a higher incidence of anticholinergic effects, such as dry mouth, than solifenacin alone. The present study investigated whether the combination of mirabegron and antimuscarinics exerted additive effects on muscarinic receptors and cholinergic contraction in rat tissues. Muscarinic receptor binding activity and inhibitory effect on carbachol-induced contraction in rat tissues were evaluated by radioreceptor assays using [N-methyl-³H]scopolamine chloride (3HNMS) and the organ-bath procedure, respectively. The muscarinic receptor binding activities of solifenacin and imidafenacin in the rat brain increased when administered in combination with mirabegron. Moreover, the inhibitory effects of solifenacin and imidafenacin on carbachol-induced contractions in rat isolated bladder strips were increased by mirabegron, particularly at lower concentrations of solifenacin and imidafenacin. This is the first study to suggest that mirabegron in combination with antimuscarinics exerts additive effects for muscarinic receptor binding and inhibitory effects on cholinergic contractions in bladder strips. The results obtained also showed that these additive effects may contribute to enhanced therapeutic effects on OAB, but also cholinergic adverse effects.

Mirabegron是第一种选择性β3-肾上腺素能受体激动剂，作为抗uscarinic治疗膀胱过度活动症（OAB）的替代药物。这种药物对毒蕈碱受体产生脱靶效应。与索非那新联合使用会导致比单独使用索非那新更高的抗胆碱能作用发生率，如口干。本研究探讨美拉比龙与抗毒蕈素联用是否对毒蕈素受体和大鼠组织胆碱能收缩产生加性作用。采用[n-甲基- 3h]氯化东莨菪碱（3HNMS）和器官浴法分别测定毒毒碱受体结合活性和对大鼠组织中碳甾醇诱导的收缩的抑制作用。索利那新和咪他那新在大鼠脑内的毒蕈碱受体结合活性与mirabegron联合使用时增加。此外，索拉非那新和咪他那新对碳巴酚诱导的大鼠离体膀胱条收缩的抑制作用在米瑞比龙的作用下增强，尤其是在低浓度的索拉非那新和咪他那新下。本研究首次提示mirabegron联合抗毒蕈碱类药物对毒蕈碱受体结合具有加性作用，并对膀胱条胆碱能收缩具有抑制作用。结果还表明，这些加性效应可能有助于增强OAB的治疗效果，但也有胆碱能不良反应。

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引用次数: 0

HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4 破骨细胞中HIF-1α的稳定诱导了有氧糖酵解相关蛋白GLUT1、LDHA和MCT4的表达

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-26 DOI: 10.1016/j.jphs.2025.05.017

Tsuyoshi Nishioku, Sae Nakao, Rumi Anzai, Sami Hiramatsu, Akiko Momono, Miyu Moriyama, Mamiko Nakao, Ayaka Terazono

Hypoxia-inducible factor (HIF)-1α is a master transcription factor regulating hypoxic adaptation and activates the transcription of genes involved in various steps of energy metabolism. However, some subsets of cancer cells exhibit high HIF-1α levels regardless of the oxygen concentration. Even under normoxic and normoglycemic conditions, HIF-1α regulates basal expression of its target genes. Osteoclasts are giant multinucleated cells derived from the monocyte/macrophage lineage and are specialized in bone resorption. Excessive osteoclast resorbing activities is involved in destructive bone diseases. There are few data regarding how HIF-1α affects osteoclast differentiation. In this study, we investigated whether echinomycin, a HIF-1α inhibitor, reduced the expression of proteins of aerobic glycolysis, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), and whether HIF-1α stabilization is involved in osteoclast differentiation. HIF-1α was stabilized earlier than the upregulation of GLUT1, LDHA, and MCT4 expression during osteoclast differentiation. Echinomycin inhibited GLUT1, LDHA, and MCT4 expression. It also inhibited osteoclast differentiation and suppressed osteoclast bone-resorbing activity. We propose that HIF-1α inhibition suppresses excessive osteoclast differentiation and may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.

低氧诱导因子（Hypoxia-inducible factor， HIF）-1α是调控低氧适应的主转录因子，可激活参与能量代谢各环节的基因转录。然而，无论氧浓度如何，某些亚群的癌细胞都表现出高HIF-1α水平。即使在常氧和血糖正常的情况下，HIF-1α也能调节其靶基因的基础表达。破骨细胞是源自单核细胞/巨噬细胞谱系的巨大多核细胞，专门从事骨吸收。过度的破骨细胞吸收活动与破坏性骨疾病有关。关于HIF-1α如何影响破骨细胞分化的数据很少。在本研究中，我们研究了HIF-1α抑制剂echinomycin是否会降低葡萄糖转运蛋白1 （GLUT1）、乳酸脱氢酶a （LDHA）和单羧酸转运蛋白4 （MCT4）等有氧糖酵解蛋白的表达，以及HIF-1α的稳定是否参与破骨细胞的分化。在破骨细胞分化过程中，HIF-1α的稳定要早于GLUT1、LDHA和MCT4表达的上调。紫霉素抑制GLUT1、LDHA和MCT4的表达。它还能抑制破骨细胞分化，抑制破骨细胞骨吸收活性。我们提出HIF-1α抑制过度的破骨细胞分化，可能代表一种新的治疗策略来控制骨质疏松症和类风湿关节炎的过度骨吸收。

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引用次数: 0

Inhibitory effects of schisandrin A on contractions induced by spasmogenic candidates in porcine coronary arteries 五味子素A对猪冠状动脉痉挛候选物引起的收缩的抑制作用

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-24 DOI: 10.1016/j.jphs.2025.05.016

Qianghaodi Hong, Naho Takazakura, Hideaki Ozawa, Sakika Ichihara, Kento Yoshioka, Keisuke Obara, Yoshio Tanaka

The inhibitory effects and underlying mechanisms of schisandrin A (SA) on contractions induced by spasmogenic candidates and related chemicals were investigated in porcine coronary arteries (PCAs). SA (10⁻⁵–10⁻⁴ M) inhibited contractions induced by acetylcholine, histamine, serotonin, U46619 (thromboxane A₂ mimetic), prostaglandin F_2α, and endothelin-1 in a concentration-dependent manner. The inhibition of acetylcholine-induced contractions by SA was stronger than that by diltiazem, although both SA and diltiazem ultimately achieved similar levels of inhibition against other contractions. SA also inhibited high-KCl-induced contractions in PCAs and suppressed high-KCl-induced increases in intracellular Ca²⁺ concentrations in A7r5 cells. However, SA (10⁻⁴ M) did not inhibit SKF-96365-sensitive phenylephrine-induced contractions, despite potently inhibiting high-KCl-induced contraction in the guinea pig thoracic aorta. SA did not strongly inhibit NaF-induced contractions in Ca²⁺-free solution containing 0.2 mM EGTA. Furthermore, SA inhibited muscarinic receptor binding in mouse cerebral cortex and inhibited carbachol-induced increases in intracellular Ca²⁺ concentrations in 293T cells expressing muscarinic M₃ receptors. These findings indicate that SA inhibits coronary artery contractions induced by spasmogens primarily through the inhibition of L-type Ca²⁺ channels (LCCs) and exerts an anticholinergic and LCC inhibitory effect on acetylcholine-induced contractions.

本文研究了五味子素A （schisandrin A， SA）对猪冠状动脉（PCAs）痉挛候选物及相关化学物质引起的收缩的抑制作用及其机制。SA（10−5-10−4 M）以浓度依赖性方式抑制乙酰胆碱、组胺、5 -羟色胺、U46619（血栓素A2模拟物）、前列腺素F2α和内皮素1诱导的收缩。SA对乙酰胆碱诱导的收缩的抑制强于地尔硫卓，尽管SA和地尔硫卓最终对其他收缩的抑制水平相似。SA还抑制高kcl诱导的PCAs收缩，抑制高kcl诱导的A7r5细胞内Ca2+浓度的增加。然而，SA（10−4 M）不抑制skf -96365敏感的苯肾上腺素诱导的收缩，尽管它能有效抑制高kcl诱导的豚鼠胸主动脉收缩。在含有0.2 mM EGTA的无Ca2+溶液中，SA对naff诱导的收缩没有强烈的抑制作用。此外，SA抑制小鼠大脑皮质毒蕈碱受体结合，抑制碳水化合物诱导的表达毒蕈碱M3受体的293T细胞内Ca2+浓度升高。这些结果表明，SA主要通过抑制l型Ca2+通道（LCC）抑制痉挛原诱导的冠状动脉收缩，并对乙酰胆碱诱导的收缩发挥抗胆碱能和LCC抑制作用。

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引用次数: 0

Targeting CD38 to alleviate brain endothelial cell dysfunction and cognitive impairment in vascular dementia 靶向CD38缓解血管性痴呆患者脑内皮细胞功能障碍和认知障碍

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-21 DOI: 10.1016/j.jphs.2025.05.013

Mingjing Yu , Zhi Qi , Jiaxin Zhang , Ziyi Zhang , Jieli Chen , Tao Yan , Zhili Chen

Vascular dementia (VaD) is a leading cause of cognitive decline, closely associated with cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme implicated in neuroinflammation and cellular senescence, has emerged as a potential regulator of these pathological processes, yet its role in CEC dysfunction within the context of VaD remains unclear. In this study, we investigated the impact of CD38 on CEC dysfunction using a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Our results demonstrate that BCAS significantly reduces cerebral blood flow (CBF), increases BBB permeability, and induces cognitive deficits, all accompanied by elevated CD38 expression in CECs and heightened levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, treatment with the selective CD38 inhibitor 78c (10 mg/kg, twice daily for 1 month) effectively mitigated these effects, reducing white matter damage, improving CBF, enhancing the expression of CEC tight junction proteins, and decreasing neuroinflammation and BBB disruption. In vitro experiments further revealed that 78c attenuates TNF-α-induced CD38 expression and inflammatory responses in CECs, likely through the NOX4/eNOS aixs. These findings identify CD38 as a crucial mediator of CEC dysfunction in VaD, linking chronic cerebral hypoperfusion to neurovascular damage.

血管性痴呆（VaD）是认知能力下降的主要原因，与脑血管内皮细胞（CEC）功能障碍、血脑屏障（BBB）破坏和神经炎症密切相关。CD38是一种与神经炎症和细胞衰老有关的酶，已成为这些病理过程的潜在调节因子，但其在VaD背景下CEC功能障碍中的作用尚不清楚。在本研究中，我们通过双侧颈总动脉狭窄（BCAS）诱导的VaD小鼠模型研究了CD38对CEC功能障碍的影响。我们的研究结果表明，BCAS显著降低脑血流量（CBF），增加血脑屏障通透性，诱导认知缺陷，所有这些都伴随着CECs中CD38表达升高和促炎细胞因子（IL-1β, IL-6, TNF-α）水平升高。值得注意的是，使用选择性CD38抑制剂78c （10 mg/kg，每天两次，持续1个月）有效减轻了这些影响，减少了白质损伤，改善了CBF，增强了CEC紧密连接蛋白的表达，减少了神经炎症和血脑屏障的破坏。体外实验进一步表明，78c可能通过NOX4/eNOS通路，减弱了TNF-α-诱导的CECs中CD38的表达和炎症反应。这些发现表明CD38是VaD中CEC功能障碍的关键介质，将慢性脑灌注不足与神经血管损伤联系起来。

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引用次数: 0

Inhibition of CYP1B1 by miR-200b-3p increases the sensitivity of paclitaxel in hepatocellular carcinoma treatment miR-200b-3p抑制CYP1B1可增加紫杉醇治疗肝癌的敏感性

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-21 DOI: 10.1016/j.jphs.2025.05.014

Jiaqi Wang , Jiayi Wu , Haihong Hu , Lushan Yu , Xiaoli Zheng , Su Zeng

Liver cancer ranks as the third leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90 % of primary liver cancer cases. Elevated expression of drug-metabolizing enzyme CYP1B1 in HCC has been identified as a potential contributor to primary paclitaxel (PTX) resistance. This study demonstrated that miR-200b-3p suppresses CYP1B1 expression in HCC cells. Meanwhile, miR-200b-3p was significantly downregulated in HCC tissues compared to adjacent normal tissues and negatively correlated with CYP1B1 expression. In addition, miR-200b-3p sensitized HCC to PTX in vitro and in vivo patient-derived xenograft (PDX) models by inhibiting CYP1B1, promoting PTX-induced microtubule polymerization, and enhancing its cell cycle-blocking effects. These findings indicate that miR-200b-3p could serve as a promising therapeutic strategy by directly targeting CYP1B1 in HCC.

肝癌是全球癌症相关死亡的第三大原因，肝细胞癌（HCC）约占原发性肝癌病例的90%。HCC中药物代谢酶CYP1B1的表达升高已被确定为原发性紫杉醇（PTX）耐药的潜在因素。本研究证实miR-200b-3p抑制HCC细胞中CYP1B1的表达。同时，miR-200b-3p在HCC组织中较邻近正常组织显著下调，且与CYP1B1表达呈负相关。此外，在体外和体内患者源异种移植（PDX）模型中，miR-200b-3p通过抑制CYP1B1、促进PTX诱导的微管聚合和增强其细胞周期阻断作用，使HCC对PTX增敏。这些发现表明，miR-200b-3p可以通过直接靶向CYP1B1在HCC中作为一种有希望的治疗策略。

引用次数: 0

Tomatidine attenuates post-stroke cognitive impairment by reducing neuroinflammation through prevention of M1 microglial polarization via NF-κB signaling 番茄碱通过NF-κB信号传导预防M1小胶质细胞极化，减轻神经炎症，从而减轻脑卒中后认知障碍

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-15 DOI: 10.1016/j.jphs.2025.05.011

Ayami Kita, Yuka Kawade, Haruyoshi Murakami, Rei Ikeda, Ryota Araki, Takeshi Yabe

Post-stroke cognitive impairment (PSCI) is a clinical disorder that commonly occurs after a stroke and may persist long-term in most stroke survivors. Neuroinflammation involving proinflammatory M1 microglia, an activated microglial phenotype after stroke injury, is a major risk factor for PSCI. Tomatidine is a steroidal alkaloid of immature green tomatoes that has anti-inflammatory properties. To investigate the effects of tomatidine on cognitive impairment and microglial-associated neuroinflammation after stroke, we performed behavioral experiments and analyses on activated microglia in a transient bilateral common carotid arteries occlusion (tBCCAO) mouse model. Tomatidine attenuated cognitive impairment and neurodegeneration in the CA1 and CA3 hippocampal regions and reduced microglial activation and polarization into an M1 phenotype in the hippocampus in tBCCAO mice. The direct effect of tomatidine on polarization into the M1 phenotype was examined using LPS-stimulated BV2 microglia, as an M1 microglia model. Tomatidine reduced expression of M1 microglial markers and inflammatory mediators and inhibited nuclear translocation and phosphorylation of NF-κB in LPS-treated BV2 microglia. These results suggest that tomatidine suppresses microglial polarization into an M1 phenotype via modulation of NF-κB signaling, resulting in attenuation of neuroinflammation and reduction of PSCI.

脑卒中后认知障碍（PSCI）是一种临床障碍，通常发生在脑卒中后，并可能在大多数脑卒中幸存者中长期存在。神经炎症涉及促炎性M1小胶质细胞，这是卒中损伤后激活的小胶质细胞表型，是PSCI的主要危险因素。番茄碱是一种从未成熟的绿色番茄中提取的甾体生物碱，具有抗炎特性。为了研究番茄碱对脑卒中后认知功能障碍和小胶质细胞相关神经炎症的影响，我们在短暂性双侧颈总动脉闭塞（tBCCAO）小鼠模型中对激活的小胶质细胞进行了行为实验和分析。番茄碱减轻了tBCCAO小鼠海马CA1和CA3区的认知障碍和神经退行性变，并减少了海马小胶质细胞的激活和向M1表型的极化。利用lps刺激的BV2小胶质细胞作为M1小胶质细胞模型，研究了番茄碱对M1表型极化的直接影响。番茄碱降低lps处理的BV2小胶质细胞M1标记物和炎症介质的表达，抑制核易位和NF-κB的磷酸化。这些结果表明，番茄碱通过调节NF-κB信号传导抑制小胶质细胞极化为M1表型，导致神经炎症的衰减和PSCI的减少。

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引用次数: 0

Ferulic acid suppresses guinea pig ileal longitudinal smooth muscle contractions by inhibiting voltage-dependent Ca2+ channels 阿魏酸通过抑制电压依赖性Ca2+通道抑制豚鼠回肠纵向平滑肌收缩

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-14 DOI: 10.1016/j.jphs.2025.05.012

Keisuke Obara , Kento Yoshioka , Aya Shimada, Sakika Ichihara, Wakaba Kinami, Futaba Makino, Naho Takazakura, Miwa Enomoto, Yoshio Tanaka

We investigated the effects of ferulic acid (FA) on contractions in guinea pig ileal longitudinal smooth muscle (ILSM). FA (3 × 10⁻⁴–3 × 10⁻³ M) inhibited ILSM contractions induced by acetylcholine, histamine, prostaglandin F_2α, and serotonin concentration-dependently, reversibly, and noncompetitively with pD′₂ values of ∼3. FA also concentration-dependently and reversibly inhibited KCl-induced ILSM contractions. FA (10⁻³ M), which inhibited ILSM contractions by ∼50 %, also reduced verapamil-sensitive, KCl-induced intracellular Ca²⁺ increases in A7r5 cells by ∼35 %. These results suggest that FA inhibits ILSM contraction, primarily through the reversible inhibition of Ca²⁺ influx via voltage-dependent Ca²⁺ channels.

研究阿魏酸（FA）对豚鼠回肠纵向平滑肌（ILSM）收缩的影响。FA （3 × 10−4-3 × 10−3 M）对乙酰胆碱、组胺、前列腺素F2α和血清素诱导的ILSM收缩具有浓度依赖性、可逆性和非竞争性，pD′2值为~ 3。FA也具有浓度依赖性和可逆性地抑制kcl诱导的ILSM收缩。FA（10−3 M）抑制ILSM收缩约50%，也降低了维拉帕米敏感的，kcl诱导的A7r5细胞内Ca2+增加约35%。这些结果表明，FA抑制ILSM收缩，主要是通过电压依赖性Ca2+通道可逆抑制Ca2+内流。

引用次数: 0

Exposure of Zinc-induced Parkinson's disease-like non-motor and motor symptoms in relation to oxidative/nitrosative stress mediated neurodegeneration in the brain of Drosophila melanogaster 暴露于锌诱导的帕金森病样非运动和运动症状与氧化/亚硝化应激介导的黑腹果蝇大脑神经变性有关

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-14 DOI: 10.1016/j.jphs.2025.05.010

Abhishek P.R. Nadiga , K.L. Krishna , Afrasim Moin , Amr Selim Abu Lila , Syed Mohd Danish Rizvi , Sahyadri M. , Suman Pathak , Shahanawaz Syed , El-Sayed Khafagy

Parkinson's disease (PD) is the second most prevalent idiopathic neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to locomotor impairment. Despite extensive research, the etiology of PD remains unclear, and existing experimental models for pharmacological evaluation do not fully replicate the disease's hallmarks, necessitating the development of a cost-effective and reliable alternative. In recent past, Drosophila melanogaster has been utilized as a model organism for various neurodegenerative diseases, including PD. The present study was conceptualized to develop a reliable PD model in the Drosophila by Zinc (Zn⁺²).Chronic exposure to 20 mM Zn⁺² for 7 days exhibited non-motor and motor PD-like symptoms in adult Drosophila flies, with reduced locomotory activity, indicating motor function deficit and reduced olfactory function and courtship behavior, indicating a deficit in non-motor function. These behavioral symptoms were associated with decreased dopamine levels. Furthermore, chronic Zn⁺² exposure resulted in enhanced membrane lipid peroxidation and decreased endogenous antioxidants level in the Drosophila brain. These effects were primarily mediated by oxidative/nitrosative stress pathway. Thus, Zn²⁺-induced PD in Drosophila serves as a cost-effective model for drug discovery, facilitating the screening of potential therapeutic compounds. Additionally, this model offers a valuable platform to investigate the molecular mechanisms underlying PD pathophysiology.

帕金森病（PD）是第二常见的特发性神经退行性疾病，其特征是黑质致密部多巴胺能神经元的丧失，导致运动障碍。尽管进行了广泛的研究，但PD的病因仍不清楚，现有的药理学评估实验模型并不能完全复制该疾病的特征，因此需要开发一种具有成本效益且可靠的替代方法。近年来，黑腹果蝇已被用作多种神经退行性疾病的模式生物，包括帕金森病。本研究旨在建立一种可靠的锌（Zn+2）在果蝇体内的PD模型。长期暴露于20 mM Zn+2环境7天，成年果蝇表现出非运动和运动pd样症状，运动活动减少，表明运动功能缺陷，嗅觉功能和求偶行为减少，表明非运动功能缺陷。这些行为症状与多巴胺水平下降有关。此外，慢性Zn+2暴露导致果蝇脑膜脂过氧化增强和内源性抗氧化剂水平降低。这些作用主要通过氧化/亚硝化应激途径介导。因此，Zn2+诱导的果蝇PD可以作为一种具有成本效益的药物发现模型，促进潜在治疗化合物的筛选。此外，该模型为研究PD病理生理的分子机制提供了一个有价值的平台。

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引用次数: 0

Inhibitory effects of γ-linolenic acid on contractile responses in pig coronary arteries: Possible involvement of prostanoid TP receptor inhibition γ-亚麻酸对猪冠状动脉收缩反应的抑制作用：可能与前列腺素TP受体抑制有关

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences

Pub Date : 2025-05-12 DOI: 10.1016/j.jphs.2025.05.009

Keisuke Obara , Kento Yoshioka , Mikoto Ozawa, Haruki Kimura, Mayu Kiguchi, Yuri Nakao, Hinako Miyaji, Toma Yamashita, Noboru Saitoh, Yutaka Nakagome, Sakika Ichihara, Yoshio Tanaka

We examined whether γ-linolenic acid (GLA), an n−6 polyunsaturated fatty acid (PUFA) and a structural isomer of α-linolenic acid (an n−3 PUFA), inhibited contractions of isolated pig coronary arteries. GLA potently inhibited the contractions elicited by U46619/prostaglandin F_2α, while showing marginal effects against other contractions. Schild plot analysis of GLA versus U46619 showed a competitive antagonistic effect. GLA also inhibited the intracellular Ca²⁺ concentration increases caused by prostanoid TP but not by FP receptor stimulation. These results suggest that TP receptor antagonistic activity can be exhibited by non-n−3 PUFAs in coronary arteries.

我们研究了γ-亚麻酸（GLA），一种n - 6多不饱和脂肪酸（PUFA）和α-亚麻酸（n - 3 PUFA）的结构异构体是否能抑制离体猪冠状动脉的收缩。GLA能有效抑制U46619/前列腺素F2α引起的收缩，而对其他收缩作用微弱。GLA对U46619的Schild图分析显示出竞争性拮抗作用。GLA还抑制前列腺素TP引起的细胞内Ca2+浓度升高，而不抑制FP受体的刺激。这些结果表明，冠状动脉中的非n- 3 PUFAs可以表现出TP受体的拮抗活性。

引用次数: 0