Fundamental & Clinical Pharmacology最新文献_第5页

Synergistic effects of epoxyazadiradione (EAD) and paclitaxel against triple-negative breast cancer cells 环氧偶氮二酮（EAD）和紫杉醇对三阴性乳腺癌细胞的协同作用。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-03-14 DOI: 10.1111/fcp.13000

Kunnathully Sudhan Sijisha, Rajitha Anusha, Sulochana Priya

Background

Triple-negative breast cancer (TNBC) is the most aggressive and chemo-resistant form of breast cancer subtype, and chemotherapy is a vital treatment option for that. Paclitaxel is an effective chemo drug for TNBC. However, in clinical settings, paclitaxel has adverse side effects. The synergistic combination is the most promising method for overcoming undesirable toxicity and achieving a beneficial therapeutic outcome. Previous reports, including our study, showed certain anticancer potential of epoxyazadiradione (EAD), the neem limonoid, in different types of cancer cells, including TNBC.

Objective

This study was designed to investigate the possible synergistic effects of EAD and paclitaxel against TNBC cells.

Methods

We examined the effects of EAD and paclitaxel alone and in combination in MDA-MB 231 cells, and the percentage cytotoxicity was used to calculate synergism. Characteristic apoptotic changes were observed by visualizing cellular morphology, nuclear fragmentation and membrane integrity. We further estimated anti-migratory potential of experimental compounds by wound healing assay. The reduction in inflammation during combinatorial treatment was evaluated by observing NF-κB translocation.

Results

The combined treatment with EAD (5 μM) and paclitaxel (5 nM), which were used at doses lower than their individual IC₅₀ concentrations, showed a synergistic effect in MDA-MB-231 cells. This combination effectively induced apoptosis and antimigration and reduced the inflammatory reactions induced by the higher dose of paclitaxel.

Conclusion

To conclude, EAD could be the drug of choice for combined treatment with paclitaxel in a chemotherapy regimen.

背景：三阴性乳腺癌（TNBC三阴性乳腺癌（TNBC）是乳腺癌亚型中最具侵袭性和化疗耐药性的一种，化疗是其重要的治疗手段。紫杉醇是治疗 TNBC 的有效化疗药物。然而，在临床应用中，紫杉醇存在不良副作用。协同联合用药是克服不良毒副作用、取得良好疗效的最有希望的方法。以往的报告（包括我们的研究）显示，楝树类柠檬素环氧氮二酮（EAD）在不同类型的癌细胞（包括 TNBC）中具有一定的抗癌潜力：本研究旨在探讨 EAD 和紫杉醇对 TNBC 细胞可能产生的协同作用：我们检测了 EAD 和紫杉醇单独或联合使用对 MDA-MB 231 细胞的作用，并使用细胞毒性百分比来计算协同作用。通过观察细胞形态、核破碎和膜完整性，我们发现了细胞凋亡的特征性变化。我们通过伤口愈合试验进一步评估了实验化合物的抗迁移潜力。通过观察 NF-κB 的转位，评估了联合治疗过程中炎症的减轻情况：结果：EAD（5 μM）和紫杉醇（5 nM）的联合治疗在 MDA-MB-231 细胞中显示出协同效应。这种组合能有效诱导细胞凋亡和抗迁移，并减少高剂量紫杉醇诱导的炎症反应：总之，EAD 可以作为化疗方案中与紫杉醇联合治疗的首选药物。

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引用次数: 0

Intradermal testing of iodinated contrast media: Should we test up to pure or with diluted compounds only? 碘化造影剂的皮内测试：我们应该检测纯碘还是仅检测稀释后的化合物？

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-03-14 DOI: 10.1111/fcp.12998

Adrian A. Schmid, Martin N. Hungerbühler, Paolo Lombardo, Ingrid B. Boehm

Background

Intradermal testing (IDT) with iodinated contrast media (ICMs) is an established diagnostic tool in patients with ICM hypersensitivity. Currently, it is unclear which test concentration is the more useful one, up to pure or up to 1:10 diluted ICMs.

Methods

We searched the literature database PubMed for eligible papers dealing with ICM allergy and their IDT results. We analyzed the data presented by the papers and compared the pooled groups tested with diluted and undiluted ICMs.

Results

We identified 29 eligible original papers, and extracted data of 1137 patients that formed the study population. Although in the cohort tested with diluted ICMs the number of tested ICMs was greater, the percentage of positive tests was significantly less (9.0% vs. 24.7%; P < 0.0001; OR 0.30 [0.26–0.34]). The frequency of positive tested culprit ICMs was also lesser in the group tested with diluted ICMs (31.0% vs. 72.5%; P < 0.0001; OR 0.17 [0.12–0.23]). The number of drug provocation tests (DPTs) was greater in patients with diluted IDTs (374 vs. 89; P < 0.0001; OR 2.54 [1.93–3.36]). We detected an increased sensitivity in patients with undiluted tests (0.774 vs. 0.282) and a nearly identical specificity in both groups (1 vs. 0.983).

Conclusions

For the first time, we show that IDT up to pure ICM concentrations is superior to using diluted ICMs only. Possibly, we can reduce the number of DPTs when performing IDTs with pure ICMs. In the undiluted group, there were no hints for skin irritations or unspecific test reactions.

背景：使用碘化造影剂（ICMs）进行皮内试验（IDT）是诊断 ICMs 过敏症患者的成熟工具。目前，还不清楚哪种浓度的碘化造影剂更有用，是纯碘化造影剂还是 1:10 稀释碘化造影剂：我们在文献数据库 PubMed 中搜索了有关 ICM 过敏及其 IDT 结果的合格论文。我们分析了论文中提供的数据，并对使用稀释和未稀释 ICMs 进行测试的汇总组进行了比较：结果：我们找到了 29 篇符合条件的原始论文，并提取了构成研究人群的 1137 名患者的数据。虽然在使用稀释 ICMs 检测的人群中，检测的 ICMs 数量更多，但检测结果呈阳性的比例却明显较低（9.0% 对 24.7%；P 结论：我们首次发现，在使用稀释 ICMs 检测的人群中，检测结果呈阳性的比例明显较低（9.0% 对 24.7%；P）：我们首次证明，IDT 达到纯 ICM 浓度要优于仅使用稀释 ICM。在使用纯 ICM 进行 IDT 时，我们有可能减少 DPT 的数量。在未稀释组中，没有提示皮肤刺激或非特异性试验反应。

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引用次数: 0

GW9508 ameliorates cognitive dysfunction via autophagy pathway in streptozotocin-induced mouse model of Alzheimer's disease GW9508通过自噬途径改善链脲佐菌素诱导的阿尔茨海默病小鼠模型的认知功能障碍。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-03-14 DOI: 10.1111/fcp.13002

Yanan Wang, Jingjing Chen, Chen Wang, Tong Chen, Ling He

Background

G protein-coupled receptor 40 (GPR40) is a potential drug target for Alzheimer's disease (AD), and its agonist GW9508 ameliorates cognitive impairment by intravenous administration.

Objectives

The present study was conducted to investigate the efficacy of GW9508 administered peripherally on cognitive dysfunction in streptozotocin (STZ)-induced AD mice.

Methods

Seventy male ICR mice were randomly divided into seven groups: vehicle sham group, model, Donepezil, GW9508-L, GW9508-M, GW9508-H, and GW1100 + GW9508-H groups, and administered either vehicle (artificial cerebrospinal fluid [aCSF]) or STZ (3 mg/kg in the vehicle) once a day (9:00 a.m.) by intracerebroventricular injection bilaterally on day 1 and day 3, respectively. After 2 weeks of recovery, all mice were given drug treatment. Behavioral experiments were applied to test the recognition and spatial memory of mice, while molecular biology experiments such as Western blot, ELISA, and Nissl staining were used to detect the corresponding changes of signaling pathways.

Results

Intraperitoneal administration of GW9508 prevented STZ-induced cognitive impairment as well as decreased the level of p-tau and Aβ_1–42 in plasma and brain. GW9508 upregulated the expression of gut-brain peptides like PYY, CCK, IGF-1, and GLP-1 both in blood circulation and brain and downregulated the expression level of autophagy-related proteins through activating Akt/mTOR signaling pathway. Meanwhile, the treatment effect of GW9508 was reversed by GPR40 antagonist GW1100 significantly.

Conclusion

Peripheral administration of GW9508 exhibits neuroprotective effects, and it could be a promising therapy for AD. The neuroprotective mechanism of GW9508 was based on promoting gut-brain peptide secretion, activating Akt/mTOR signal pathway, and regulating neuronal autophagy.

背景：G蛋白偶联受体40（GPR40）是阿尔茨海默病（AD）的潜在药物靶点，其激动剂GW9508通过静脉给药可改善认知障碍：本研究旨在探讨GW9508外周给药对链脲佐菌素（STZ）诱导的AD小鼠认知功能障碍的疗效：将70只雄性ICR小鼠随机分为7组：载体假组、模型组、多奈哌齐组、GW9508-L组、GW9508-M组、GW9508-H组和GW1100 + GW9508-H组，分别于第1天和第3天每天一次（上午9:00）双侧脑室内注射载体（人工脑脊液[aCSF]）或STZ（载体中含3 mg/kg）。恢复 2 周后，对所有小鼠进行药物治疗。行为实验用于检测小鼠的识别和空间记忆能力，分子生物学实验如 Western blot、ELISA 和 Nissl 染色则用于检测信号通路的相应变化：结果：腹腔注射GW9508可预防STZ诱导的认知障碍，并降低血浆和大脑中p-tau和Aβ1-42的水平。GW9508通过激活Akt/mTOR信号通路，上调PYY、CCK、IGF-1和GLP-1等肠脑多肽在血液循环和大脑中的表达，并下调自噬相关蛋白的表达水平。同时，GPR40拮抗剂GW1100能显著逆转GW9508的治疗效果：结论：外周给药 GW9508 具有神经保护作用，有望成为一种治疗 AD 的方法。GW9508的神经保护机制基于促进肠脑多肽分泌、激活Akt/mTOR信号通路和调节神经元自噬。

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引用次数: 0

Antimanic-like effect of dipyridamole in the methylphenidate-induced hyperlocomotion 双嘧达莫在哌醋甲酯诱导的过度运动中的抗躁狂样作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-03-12 DOI: 10.1111/fcp.13001

Anderson Gustavo Santos, Carlos Eduardo Kühl, Arisa Namie Higashijima, Luiz Kae Sales Kanazawa, Suzen Tortato Furtado de Souza, Roberto Andreatini

Background

Adenosinergic system has been implicated in the pathophysiology of bipolar disorder and drugs that affect adenosine neurotransmission have shown some efficacy as add-on therapy in manic patients.

Objective

Thus, the aim of the present study was to screen adenosinergic drugs for antimanic-like effect in methylphenidate (MPH)-induced hyperlocomotion in mice.

Methods

Male and female Swiss mice received a single allopurinol (50 and 200 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) administration before an acute MPH challenge (5 mg/kg, sc). In experiments with repeated treatment, male mice received a daily administration of allopurinol (25 and 50 mg/kg, ip), dipyridamole (20 mg/kg, ip), or inosine (50 mg/kg, ip) for 14 days. Finally, pretreatment with aminophylline (2 mg/kg, sc), an unspecific adenosine receptor antagonist, was used to evaluate a putative adenosinergic mediation. Locomotor activity was measured in the automated activity chamber for 20 min.

Results

Acute and repeated dipyridamole reduced the increase in locomotor activity induced by MPH, while allopurinol and inosine had no effect. Aminophylline blocked the effect of dipyridamole in MPH-induced hyperlocomotion.

Conclusion

The present results suggest that dipyridamole may have an antimanic-like effect through adenosine receptors and reinforce the proposal that the adenosine system may be an interesting target for new antimanic drugs.

背景：腺苷能系统与双相情感障碍的病理生理学有关，影响腺苷神经递质的药物作为躁狂症患者的附加疗法已显示出一定的疗效：因此，本研究旨在筛选腺苷能药物对哌醋甲酯（MPH）诱导的小鼠过度运动的抗躁狂样作用：雄性和雌性瑞士小鼠在接受急性 MPH 挑战（5 毫克/千克，sc）之前分别接受一次别嘌醇（50 和 200 毫克/千克，ip）、双嘧达莫（20 毫克/千克，ip）或肌苷（50 毫克/千克，ip）给药。在重复治疗的实验中，雄性小鼠每天接受别嘌醇（25 和 50 毫克/千克，静脉注射）、双嘧达莫（20 毫克/千克，静脉注射）或肌苷（50 毫克/千克，静脉注射），持续 14 天。最后，使用非特异性腺苷受体拮抗剂氨茶碱（2 毫克/千克，sc）进行预处理，以评估推定的腺苷能中介作用。在自动活动室中测量了20分钟的运动活动：结果：急性和反复使用双嘧达莫可减少 MPH 引起的运动活动增加，而别嘌呤醇和肌苷则没有影响。氨茶碱阻断了双嘧达莫对 MPH 诱导的过度运动的作用：本研究结果表明，双嘧达莫可能通过腺苷受体产生类似抗躁狂症的作用，并强化了腺苷系统可能是新型抗躁狂症药物的一个有趣靶点的观点。

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引用次数: 0

Challenges and opportunities of medicines for treating tendon inflammation and fibrosis: A comprehensive and mechanistic review 治疗肌腱炎症和纤维化药物的挑战与机遇：机理综述。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-03-11 DOI: 10.1111/fcp.12999

Zohreh Najafi, Pouria Rahmanian-Devin PharmD, PhD, Vafa Baradaran Rahimi PharmD, PhD, Ali Nokhodchi PharmD, PhD, Vahid Reza Askari PharmD, PhD

Background

Tendinopathy refers to conditions characterized by collagen degeneration within tendon tissue, accompanied by the proliferation of capillaries and arteries, resulting in reduced mechanical function, pain, and swelling. While inflammation in tendinopathy can play a role in preventing infection, uncontrolled inflammation can hinder tissue regeneration and lead to fibrosis and impaired movement.

Objectives

The inability to regulate inflammation poses a significant limitation in tendinopathy treatment. Therefore, an ideal treatment strategy should involve modulation of the inflammatory process while promoting tissue regeneration.

Methods

The current review article was prepared by searching PubMed, Scopus, Web of Science, and Google Scholar databases. Several treatment approaches based on biomaterials have been developed.

Results

This review examines various treatment methods utilizing small molecules, biological compounds, herbal medicine-inspired approaches, immunotherapy, gene therapy, cell-based therapy, tissue engineering, nanotechnology, and phototherapy.

Conclusion

These treatments work through mechanisms of action involving signaling pathways such as transforming growth factor-beta (TGF-β), mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), all of which contribute to the repair of injured tendons.

背景：肌腱病是指肌腱组织内胶原蛋白变性，同时伴有毛细血管和动脉增生，导致机械功能减退、疼痛和肿胀。虽然肌腱病中的炎症可以起到预防感染的作用，但不受控制的炎症会阻碍组织再生，导致纤维化和运动障碍：目标：无法控制炎症是治疗腱鞘炎的一大局限。因此，理想的治疗策略应包括调节炎症过程，同时促进组织再生：本综述文章是通过搜索 PubMed、Scopus、Web of Science 和 Google Scholar 数据库编写的。结果：这篇综述文章探讨了利用小分子材料进行治疗的各种方法：本综述探讨了利用小分子、生物化合物、草药启发疗法、免疫疗法、基因疗法、细胞疗法、组织工程、纳米技术和光疗法的各种治疗方法：这些疗法的作用机制涉及信号通路，如转化生长因子-β（TGF-β）、丝裂原活化蛋白激酶（MAPKs）和活化B细胞的核因子卡帕-轻链-增强因子（NF-κB），它们都有助于损伤肌腱的修复。

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引用次数: 0

The role of β-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do β-adrenergic receptor agonists and antagonists protect the heart? β-肾上腺素能受体在调节心脏对缺血/再灌注耐受性中的作用。为什么β肾上腺素能受体激动剂和拮抗剂能保护心脏？

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-29 DOI: 10.1111/fcp.12988

Leonid N. Maslov, Natalia V. Naryzhnaya, Nikita S. Voronkov, Boris K. Kurbatov, Ivan A. Derkachev, Vyacheslav V. Ryabov, Evgeny V. Vyshlov, Viktor V. Kolpakov, Eugenia A. Tomilova, Ekaterina V. Sapozhenkova, Nirmal Singh, Feng Fu, Jianming Pei

Background

Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of β-AR ligands.

Methods

We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of β-AR agonists and antagonists.

Results

The infarct-reducing effect of β-AR antagonists did not depend on a decrease in the heart rate. The target for β-blockers is not only cardiomyocytes but also neutrophils. β1-blockers (metoprolol, propranolol, timolol) and the selective β2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of β1- and β2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All β-AR ligands that reduced infarct size are the selective or nonselective β1-blockers. It was hypothesized that β1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of β1-AR, β2-AR, and β3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of β-AR agonists is mediated via the activation of kinases and reactive oxygen species production.

Conclusions

It is unclear why β-blockers with the similar receptor selectivity have the infarct-sparing effect while other β-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of β-blockers in reperfusion? Why did in early studies β-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies β-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective β-AR ligands depends on the answers to these questions.

背景：儿茶酚胺和β-肾上腺素能受体（β-ARs）在调节心脏对缺血和再灌注影响的耐受性方面发挥着重要作用。这篇系统性综述分析了β-AR配体心脏保护活性的分子机制：我们使用 PubMed 数据库对 1966 年至 2023 年的专题文章进行了电子检索。我们引用了记录 β-AR 激动剂和拮抗剂心脏保护特性的原始体外和体内研究以及综述文章：结果：β-AR 拮抗剂的梗死减轻作用并不依赖于心率的降低。β1-受体阻滞剂（美托洛尔、普萘洛尔、噻吗洛尔）和选择性β2-AR 激动剂阿福莫特罗对冠状动脉闭塞（CAO）动物具有减轻梗死的作用。β1-和β2-АR（美托洛尔、普萘洛尔、纳多洛尔、卡维地洛尔、比索洛尔、艾司洛尔）拮抗剂能够防止再灌注心脏损伤。所有能缩小梗死面积的β-AR配体都是选择性或非选择性β1-受体阻滞剂。据推测，β1-AR 受体阻断可促进心脏对 I/R 的耐受性增强。β1-AR、β2-AR 和 β3-AR 的激活可增加心脏对 I/R 的耐受性。β-AR激动剂的心脏保护作用是通过激活激酶和活性氧生成介导的：结论：目前尚不清楚为什么具有类似受体选择性的β受体阻滞剂具有保护心梗的作用，而具有相同选择性的其他β受体阻滞剂却不影响心梗的面积。β-受体阻滞剂在再灌注中减少梗死效应的分子机制是什么？为什么在早期研究中，β-受体阻滞剂能降低急性心肌梗死（AMI）且未进行再灌注患者的死亡率，而在最近的研究中，β-受体阻滞剂对急性心肌梗死且进行再灌注患者的死亡率没有影响？能否研制出更有效的 βAR 配体取决于这些问题的答案。

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引用次数: 0

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats 硼褪黑激素可限制卵巢切除大鼠的认知缺陷和神经元损失，同时增加前BDNF。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-29 DOI: 10.1111/fcp.12997

Mónica Barrón-González, Astrid M. Rivera-Antonio, Rosa A. Jarillo-Luna, José M. Santiago-Quintana, David Levaro-Loquio, Teresa Pérez-Capistran, Christian H. Guerra-Araiza, Marvin A. Soriano-Ursúa, Eunice D. Farfán-García

Background

Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays.

Objective

In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed.

Methods

Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro.

Results

Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time.

Conclusion

Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.

背景：硼褪黑激素是治疗阿尔茨海默病（AD）等神经元疾病的潜在药物。在雄性大鼠的行为测试和神经元免疫组化测定中，服用硼褪黑激素能产生与等摩尔剂量服用褪黑激素相同的改善效果：本研究以神经生物学和AD发病率的性别差异为动机，评估了硼褪黑激素诱导雌性大鼠发生变化的能力：方法：通过评估行为学和免疫组织病理学方法来衡量硼褪黑激素的作用；此外，还在体外测定了硼褪黑激素限制淀粉样蛋白毒性的能力：令人惊讶的是，行为变化与雄性大鼠的报告相似，但与免疫测定评估的神经元存活率不同；同时首次观察到前脑源性神经营养因子（BDNF）的免疫活性和淀粉样蛋白在体外的毒性限制：结论：服用硼那宁可诱导雌性大鼠发生变化。结论：服用硼褪黑激素或褪黑激素会引起雌性大鼠的变化，这可能与性依赖中类固醇激素分泌的差异有关。要弄清性腺切除术导致雌雄大鼠记忆力紊乱的可能机制和原因，还需要进一步的研究。

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引用次数: 0

Evaluation of potential antiviral activities of antimicrobial peptides in fish mucus 评估鱼类粘液中抗菌肽的潜在抗病毒活性。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-20 DOI: 10.1111/fcp.12996

Irmak Dik, Burak Dik, Öznur Tufan, Ayşe Er

Background

Fish skin mucus contains innate immune factors and acts as the first line of physical or chemical defense against pathogens.

Objective

The primary aim of this study was to determine the antiviral activity of sea bream (SBr), rainbow trout (RT), and sea bass (SBa) fish skin mucus against herpes simplex virus (HSV)-1. In addition, it was aimed to associate possible antiviral activity with antimicrobial peptides (AMPs) such as cathelicidin, hepcidin, galectin 2, and C10ORF99, whose levels were determined in the mucus.

Methods

The antiviral activity and oxidative/antioxidant status of mucus against HSV-1 virus was evaluated. In addition, AMPs, SOD, and CAT activities, and immunoglobulin M levels were also analyzed in mucus of fish.

Results

Antiviral activity mucus of SBr, RT, and SBa against HSV-1 were determined as 2⁻⁴, 2⁻⁵, and 2⁻², respectively. The higher antiviral activity of SBr and RT mucus compared to the mucus of SBa can be associated with higher AMP levels in them.

Conclusion

The skin mucus of SBr and RT may be nutritional supplement, adjuvant, and a new agent that can potentiate the effects of antimicrobial/antiviral agents.

背景：鱼皮粘液含有先天性免疫因子，是抵御病原体的第一道物理或化学防线：本研究的主要目的是确定鲷鱼（SBr）、虹鳟鱼（RT）和鲈鱼（SBa）鱼皮粘液对单纯疱疹病毒（HSV）-1 的抗病毒活性。此外，研究还旨在将可能的抗病毒活性与抗菌肽（AMPs）联系起来，如猫肝素、肝素、galectin 2 和 C10ORF99，这些抗菌肽在粘液中的含量已被测定：方法：评估粘液对 HSV-1 病毒的抗病毒活性和氧化/抗氧化状态。此外，还分析了鱼类粘液中的 AMPs、SOD 和 CAT 活性以及免疫球蛋白 M 水平：结果：SBr、RT 和 SBa 的粘液对 HSV-1 的抗病毒活性分别为 2-4、2-5 和 2-2。与 SBa 的粘液相比，SBr 和 RT 的粘液具有更高的抗病毒活性，这可能与它们体内较高的 AMP 水平有关：结论：SBr 和 RT 的皮肤粘液可能是营养补充剂、佐剂和一种能增强抗菌剂/抗病毒剂效果的新制剂。

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引用次数: 0

Patterns of ketamine use among people with substance use disorder in France: Multisource analysis of the data from the French Addictovigilance Network 法国药物使用障碍患者使用氯胺酮的模式：对法国毒瘾警戒网络数据的多源分析。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-19 DOI: 10.1111/fcp.12995

Pauline Gandolfo, Thomas Soeiro, Élisabeth Jouve, Bruno Revol, Amélie Daveluy, Célian Bertin, Céline Eiden, Valérie Gibaja, Leila Chaouachi, Marie-Christine Pérault-Pochat, Cécile Chevallier, Aurélie Aquizérate, Reynald Le Boisselier, Louise Carton, Maryse Lapeyre-Mestre, Élisabeth Frauger, Clémence Lacroix, Joëlle Micallef

Background

Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose.

Objectives

To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network.

Methods

First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them.

Results

There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms.

Conclusion

The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses.

背景由于氯胺酮具有精神活性作用，它已成为一种非医疗用途药物：评估氯胺酮在药物使用障碍患者中使用的最新趋势，并利用法国毒瘾警戒网络的补充健康数据来源描述其临床并发症的特征：首先，我们从OPPIDUM项目（即一项与数百家药物滥用治疗机构合作开展的多中心项目，收集药物滥用障碍患者使用药物的数据）的数据库中提取了2012年至2021年涉及氯胺酮的所有报告。我们从全球范围描述了这些报告以及 2012 年至 2021 年期间的变化。其次，我们从法国国家药物警戒数据库（BNPV）中提取了 2020 年 7 月至 2022 年 12 月期间涉及氯胺酮的所有病例。我们确定了在药物使用障碍患者中使用氯胺酮的相关病例，并对其进行了描述：结果：在OPPIDUM项目中，患有药物使用障碍的氯胺酮使用者人数增加了2.5倍，从2012年的35人（0.7%）增至2021年的89人（1.7%）。每天吸食、停药后感到痛苦以及出现成瘾症状的受试者比例有所增加。2020年7月至2022年12月期间，法国国家药物警戒数据库共收录了238例与药物使用障碍患者使用氯胺酮有关的病例。其中，94例（39.5%）涉及氯胺酮使用障碍，20例（8.4%）涉及尿路和肾脏症状，13例（5.5%）涉及肝胆症状：结论：10年来所观察到的趋势反映了氯胺酮使用在药物使用障碍患者中的增长情况，但并不能据此估算氯胺酮在普通人群中的非医疗使用率。有报告称，氯胺酮诱发的尿路感染和胆道病变发生在氯胺酮使用者中，尤其是在反复和/或长期使用大剂量氯胺酮的情况下。

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引用次数: 0

Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: Promising therapy against post-COVID-19 pulmonary fibrosis 唑来膦酸盐靶向甲羟戊酸途径可改善大鼠模型中的肺纤维化：COVID-19后肺纤维化有望治愈

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-15 DOI: 10.1111/fcp.12994

Reham Hussein Mohamed, Nesma Hussein Abdel hay, Nesma Mohamed Fawzy, Yomna M. Tamim, M. M. Doaa Karem, Dalia Ahmed Yousef Yehia, Omnia M. Abdel Maksoud, Dina S. Abdelrahim

Background

Rho kinase (ROCK) pathway plays a critical role in post-COVID-19 pulmonary fibrosis (PCPF) and its intervention with angiotensin-converting enzyme 2 (ACE2) and vascular endothelial growth factor (VEGF) will be a potential therapeutic target.

Objectives

The present study was conducted to investigate the efficacy of zoledronate (ZA) on carbon tetrachloride (CCl4) induced pulmonary fibrosis (PF) in rats through targeting ACE2, ROCK, and VEGF signaling pathways.

Methods

Fifty male Wistar rats were divided into five groups: control, vehicle-treated, PF, PF-ZA 50, and PF-ZA 100 groups. ZA was given in two different doses 100 and 50 μg/kg/week intraperitoneally. After anesthesia, mean arterial blood pressure (MBP) was measured. After scarification, lung coefficient was calculated. Lung levels of ACE 2, interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), VEGF, glutathione (GSH), and superoxide dismutase (SOD) were measured. Expression of ROCK, phosphorylated myosin phosphatase target subunit 1 (P-MYPT1), and matrix metalloproteinase (MMP-1), along with histopathological changes and immune-histochemical staining for lung α-smooth muscle actin (α-SMA), tumor necrosis factor-alpha (TNFα), and caspase-3, were evaluated.

Results

ZA significantly prevented the decrease in MBP. ZA significantly increased ACE2, GSH, and SOD and significantly decreased IL-1β, TGF-β, and VEGF in lung in comparison to PF group. ZA prevented the histopathological changes induced by CCl4. ZA inhibited lung expression of ROCK, P-MYPT1, MMP-1, α-SMA, TNFα, and caspase-3 with significant differences favoring the high dose intervention.

Conclusion

ZA in a dose-dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF.

背景：Rho激酶（ROCK）通路在COVID-19后肺纤维化（PCPF）中发挥关键作用，其与血管紧张素转换酶2（ACE2）和血管内皮生长因子（VEGF）的干预将成为潜在的治疗靶点：本研究旨在探讨唑来膦酸钠（ZA）通过靶向 ACE2、ROCK 和血管内皮生长因子信号通路对四氯化碳（CCl4）诱导的大鼠肺纤维化（PF）的疗效：将 50 只雄性 Wistar 大鼠分为五组：对照组、药物治疗组、PF 组、PF-ZA 50 组和 PF-ZA 100 组。腹腔注射 100 和 50 μg/kg/week 两种不同剂量的ZA。麻醉后，测量平均动脉血压（MBP）。结疤后，计算肺系数。测量了肺中 ACE 2、白细胞介素-1β（IL-1β）、转化生长因子-β（TGF-β）、血管内皮生长因子、谷胱甘肽（GSH）和超氧化物歧化酶（SOD）的水平。还评估了ROCK、磷酸化肌球蛋白磷酸酶靶亚基1（P-MYPT1）和基质金属蛋白酶（MMP-1）的表达，以及组织病理学变化和肺α-平滑肌肌动蛋白（α-SMA）、肿瘤坏死因子α（TNFα）和Caspase-3的免疫组织化学染色：结果：ZA明显阻止了MBP的下降。与 PF 组相比，ZA 能明显增加肺中的 ACE2、GSH 和 SOD，明显降低 IL-1β、TGF-β 和 VEGF。ZA能防止CCl4引起的组织病理学变化。ZA可抑制肺部ROCK、P-MYPT1、MMP-1、α-SMA、TNFα和caspase-3的表达，高剂量干预组与对照组有显著差异：结论：ZA通过靶向甲羟戊酸通路，以剂量依赖的方式阻止了CCl4对肺部的病理效应。结论：ZA通过靶向甲羟戊酸通路，以剂量依赖性的方式阻止了CCl4对肺部的病理效应，是一种很有前景的治疗方法。

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引用次数: 0