Fundamental & Clinical Pharmacology最新文献_第6页

Anticancer effect of propranolol on diethylnitrosamine-induced hepatocellular carcinoma rat model 普萘洛尔对二乙基亚硝胺诱导的肝细胞癌大鼠模型的抗癌作用

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-07 DOI: 10.1111/fcp.12990

Yomna M. Tamim, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail

Background

Hepatocellular carcinoma (HCC) is the most widespread type of primary liver cancer. Diethylnitrosamine (DEN), a hepatotoxic hepatocarcinogenic compound, is used to induce HCC in animal models. The non-selective β-blocker propranolol demonstrated antiproliferative activity in many cancer types.

Objective

This investigation aimed to evaluate the anticancer effect of propranolol against DEN-induced HCC in rats.

Methods

Thirty adult male rats were divided into the following groups: Group I (C, control), Group II (HCC); received DEN, 70 mg/kg body weight (b.wt.) once a week for 10 weeks, to induce HCC, and Group III (HCC/Prop); received DEN for 10 weeks for HCC induction, then received 20 mg/kg b.wt. propranolol, intraperitoneally for four successive weeks.

Results

HCC was developed in rats' livers and confirmed via significant liver architecture changes, significantly elevated activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), α-fetoprotein (AFP), total- and direct-bilirubin (Bil), and a decline in albumin (ALB) level in serum. HCC group demonstrated elevated levels of malondialdehyde (MDA), nitric oxide (NO), HIF-1α, IL-8, NF-κB, PGE2, TGF-β1, VEGF, and CD8, but significant decline of GSH, and IL-10 level, with suppression of the antioxidant enzymes' activities. In addition, the gene expression of the hepatic inducible nitric oxide synthase (iNOS), and LAG-3 were up-regulated. Moreover, the protein expression of p-PKC was up-regulated, while that of PD-1 and PD-L1 were down-regulated in the liver tissues of the HCC group. However, propranolol ameliorated the investigated parameters in the HCC/Prop group.

Conclusion

Propranolol exhibited an anticancer effect and thus can be considered as a promising treatment for HCC. Blocking of PD-1/PD-L1 and LAG-3 signals participated in the anti-tumor effect of propranolol on HCC.

背景：肝细胞癌（HCC）是最常见的原发性肝癌类型。二乙基亚硝胺（DEN）是一种具有肝毒性的致肝癌化合物，可用于诱导动物模型中的 HCC。非选择性β-受体阻滞剂普萘洛尔在许多癌症类型中都具有抗增殖活性：本研究旨在评估普萘洛尔对 DEN 诱导的大鼠 HCC 的抗癌作用：方法：将 30 只成年雄性大鼠分为以下几组：方法：将30只成年雄性大鼠分为以下几组：I组（C，对照组）；II组（HCC组）；接受DEN诱导HCC，每周一次，每次70 mg/kg体重，共10周；III组（HCC/普萘洛尔组）；接受DEN诱导HCC，共10周，然后腹腔注射20 mg/kg体重的普萘洛尔，连续4周：结果：大鼠肝脏发生了 HCC，并通过肝脏结构的显著变化、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、α-胎儿蛋白（AFP）、总胆红素和直接胆红素（Bil）活性的显著升高以及血清中白蛋白（ALB）水平的下降证实了这一点。HCC 组的丙二醛（MDA）、一氧化氮（NO）、HIF-1α、IL-8、NF-κB、PGE2、TGF-β1、VEGF 和 CD8 水平升高，但 GSH 和 IL-10 水平显著下降，抗氧化酶活性受到抑制。此外，肝脏诱导型一氧化氮合酶（iNOS）和 LAG-3 的基因表达上调。此外，HCC 组肝脏组织中 p-PKC 蛋白表达上调，而 PD-1 和 PD-L1 蛋白表达下调。然而，普萘洛尔能改善HCC/Prop组的相关指标：结论：普萘洛尔具有抗癌作用，因此可被视为一种治疗 HCC 的有效方法。阻断 PD-1/PD-L1 和 LAG-3 信号参与了普萘洛尔对 HCC 的抗肿瘤作用。

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引用次数: 0

Angiotensin 1–7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart—The signaling mechanism 血管紧张素 1-7 增加心脏对缺血/再灌注的耐受性并减轻心脏的不良重塑--信号机制

IF 2.9 4区医学 Q2 Medicine

Fundamental & Clinical Pharmacology

Pub Date : 2024-02-04 DOI: 10.1111/fcp.12983

Ivan A. Derkachev, Sergey V. Popov, Leonid N. Maslov, Alexandr V. Mukhomedzyanov, Natalia V. Naryzhnaya, Alexander S. Gorbunov, Artur Kan, Andrey V. Krylatov, Yuri K. Podoksenov, Ivan V. Stepanov, Svetlana V. Gusakova, Feng Fu, Jian-Ming Pei

Background

The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1–7 has some promise in this regard.

Objective

The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1–7.

Methods

PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study.

Results

Angiotensin 1–7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1–7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1–7. Angiotensin 1–7 alleviates Ca²⁺ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1–7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1–7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1–7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1–7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1–7. However, the specific end-effector of the cardioprotective impact of angiotensin 1–7 remains unknown.

Conclusion

The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1–7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal K_ATP channel or the mitochondrial K_ATP channel.

急性心肌梗死（AMI）患者的高死亡率仍然是现代心脏病学最紧迫的问题。在过去 10 年中，急性心肌梗死患者的死亡率一直没有显著下降。显而易见，治疗急性心肌梗死急需开发全新的药物。在这方面，血管紧张素 1-7 具有一定的前景。

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引用次数: 0

Effect of spermidine on long non-coding RNAs MALAT1 in a rotenone induced-rat model of Parkinson's disease 在鱼藤酮诱导的帕金森病大鼠模型中，亚精胺对长非编码 RNA MALAT1 的影响

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-26 DOI: 10.1111/fcp.12986

Noha Mohamed Badae, Doaa A. Abdelmonsif, Rania Gaber Aly, Amira M. Omar, Mai S. Shoela, Eman M. Omar

Background

Spermidine is a natural biologically active substance that has widespread influences on the body.

Objective

This study aims to enhance our understanding of the potential effect of spermidine on long non-coding RNA MALAT1 and explore the underlying mechanism in the rotenone-induced rat model of Parkinson's disease.

Methods

Rats were sacrificed after locomotor behavioral testing. Striatal tissues were used to assess the expression of MALAT1, oxidative stress markers, and autophagy markers.

Results

Our study found that treatment with spermidine for 2 weeks during the induction of the model significantly improved behavioral assessment, dopamine levels, and attenuated the histopathological changes that occurred in PD in comparison to the non-treated group.

Conclusion

Our preliminary study supports the protective effect of spermidine on the activation of autophagy and its antioxidant properties. Part of the antioxidant activity is due to the inhibition of MALAT1. However, MALAT1 does not correlate with the spermidine-induced autophagy pathway.

背景：精胺是一种天然生物活性物质，对人体具有广泛的影响：本研究旨在进一步了解亚精胺对长非编码 RNA MALAT1 的潜在影响，并探讨其在鱼藤酮诱导的帕金森病大鼠模型中的作用机制：方法：大鼠在运动行为测试后被处死。方法：大鼠在运动行为测试后被处死，纹状体组织用于评估 MALAT1、氧化应激标记物和自噬标记物的表达：我们的研究发现，在诱导模型期间使用亚精胺治疗 2 周，与未治疗组相比，可显著改善行为评估和多巴胺水平，并减轻帕金森病的组织病理学变化：我们的初步研究证实了亚精胺对自噬激活的保护作用及其抗氧化特性。部分抗氧化活性是由于抑制了 MALAT1。然而，MALAT1与亚精胺诱导的自噬途径并不相关。

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引用次数: 0

Role of biomarkers and molecular signaling pathways in acute lung injury 生物标志物和分子信号通路在急性肺损伤中的作用。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-26 DOI: 10.1111/fcp.12987

Pakter Niri, Achintya Saha, Subramanyam Polopalli, Mohit Kumar, Sanghita Das, Pronobesh Chattopadhyay

Background

Acute lung injury (ALI) is caused by bacterial, fungal, and viral infections. When pathogens invade the lungs, the immune system responds by producing cytokines, chemokines, and interferons to promote the infiltration of phagocytic cells, which are essential for pathogen clearance. Their excess production causes an overactive immune response and a pathological hyper-inflammatory state, which leads to ALI. Until now, there is no particular pharmaceutical treatment available for ALI despite known inflammatory mediators like neutrophil extracellular traps (NETs) and reactive oxygen species (ROS).

Objectives

Therefore, the primary objective of this review is to provide the clear overview on the mechanisms controlling NETs, ROS formation, and other relevant processes during the pathogenesis of ALI. In addition, we have discussed the significance of epithelial and endothelial damage indicators and several molecular signaling pathways associated with ALI.

Methods

The literature review was done from Web of Science, Scopus, PubMed, and Google Scholar for ALI, NETs, ROS, inflammation, biomarkers, Toll- and nucleotide-binding oligomerization domain (NOD)-like receptors, alveolar damage, pro-inflammatory cytokines, and epithelial/endothelial damage alone or in combination.

Results

This review summarized the main clinical signs of ALI, including the regulation and distinct function of epithelial and endothelial biomarkers, NETs, ROS, and pattern recognition receptors (PRRs).

Conclusion

However, no particular drugs including vaccine for ALI has been established. Furthermore, there is a lack of validated diagnostic tools and a poor predictive rationality of current therapeutic biomarkers. Hence, extensive and precise research is required to speed up the process of drug testing and development by the application of artificial intelligence technologies, structure-based drug design, in-silico approaches, and drug repurposing.

背景：急性肺损伤（ALI）是由细菌、真菌和病毒感染引起的。当病原体侵入肺部时，免疫系统会产生细胞因子、趋化因子和干扰素，以促进吞噬细胞的浸润。细胞因子、趋化因子和干扰素的过量产生会导致过度活跃的免疫反应和病理性高炎症状态，从而引发 ALI。迄今为止，尽管已知有中性粒细胞胞外捕获物（NETs）和活性氧（ROS）等炎症介质，但仍没有治疗 ALI 的特效药物：因此，本综述的主要目的是提供关于控制中性粒细胞胞外捕获物（NETs）、活性氧（ROS）形成的机制以及 ALI 发病过程中其他相关过程的清晰概述。此外，我们还讨论了上皮和内皮损伤指标的重要性以及与 ALI 相关的几种分子信号通路：方法：我们从 Web of Science、Scopus、PubMed 和 Google Scholar 上查阅了有关 ALI、NETs、ROS、炎症、生物标志物、Toll 和核苷酸结合寡聚域（NOD）样受体、肺泡损伤、促炎细胞因子以及上皮/内皮损伤的单独或组合的文献：本综述总结了 ALI 的主要临床表现，包括上皮和内皮生物标志物、NETs、ROS 和模式识别受体（PRRs）的调节和不同功能：然而，目前还没有针对 ALI 的特定药物（包括疫苗）。此外，目前还缺乏有效的诊断工具，现有治疗生物标志物的预测合理性也很差。因此，需要开展广泛而精确的研究，通过应用人工智能技术、基于结构的药物设计、硅内方法和药物再利用，加快药物测试和开发进程。

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引用次数: 0

Arterial hypertension associated with PARPi: A meta-analysis of 41 placebo randomized controlled trials combined with a World Health Organization's pharmacovigilance study 与 PARPi 相关的动脉高血压：41 项安慰剂随机对照试验与世界卫生组织药物警戒研究的荟萃分析。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-25 DOI: 10.1111/fcp.12984

Clémence Blaize, Ellina Surtouque, Jonaz Font, Charles Dolladille, Sophie Postel-Vinay, Angélique Da Silva, Joachim Alexandre, Pierre-Marie Morice

Background

Arterial hypertension has been recently reported from randomized controlled trials (RCTs) assessing poly (ADP-ribose) polymerase inhibitor (PARPi).

Objective

In a context of increasing use of PARPi, it is crucial to properly assess risk and incidence of this adverse event for clinical practice.

Methods

We performed a systematic review and meta-analysis in MEDLINE, Cochrane CENTRAL and ClinicalTrials.gov up to January 4, 2023 with an ongoing surveillance up to June 7, 2023. RCTs comparing PARPi to placebo in adult patients with solid tumors were included if hypertension was reported. The primary outcome was the summary risk ratio (RR, with 95% CIs) of any hypertension of PARPi class in placebo RCTs. Secondary outcomes were the summary risk and incidence of hypertension of each individual PARPi. To provide clinical features of PARPi-associated hypertension, we independently queried the WHO's pharmacovigilance database, up to September 1, 2022.

Results

In total, 41 placebo RCTs (n = 15 264 adult patients) were included. PARPi class was not associated with an increased risk of hypertension compared with placebo. In individual analyses, the risk of hypertension was lower with olaparib than placebo (RR 0.77 [95% CI: 0.68–0.86], P < 0.01; I² = 19%, χ² P = 0.26). Niraparib monotherapy increased the risk of any (RR 2.84 [95% CI: 1.76–4.57], P < 0.01; I² = 66%, χ² P = 0.01) hypertension with a summary incidence of 19.87% (95% CI: 15.23–25.50). In real-life setting, niraparib-associated hypertension occurs within 20 days and was serious in 66%. Co-prescription of at least one antihypertensive or therapy-induced hypertension was reported in 20.5% or 14.4% of cases, respectively.

Conclusions

In a context of extensive assessment of niraparib in combination, these data reinforce the need of a close monitoring of this adverse event to preserve its clinical benefit on patients' survival.

背景：最近，评估聚（ADP-核糖）聚合酶抑制剂（PARPi）的随机对照试验（RCT）报告了动脉高血压：在越来越多地使用 PARPi 的情况下，正确评估这一不良事件的风险和发生率对于临床实践至关重要：截至 2023 年 1 月 4 日，我们在 MEDLINE、Cochrane CENTRAL 和 ClinicalTrials.gov 上进行了系统回顾和荟萃分析，并持续监测至 2023 年 6 月 7 日。如果报告了高血压，则纳入在实体瘤成年患者中比较 PARPi 和安慰剂的 RCT。主要结果是安慰剂 RCT 中 PARPi 类任何高血压的总风险比 (RR，含 95% CIs)。次要结果是每种 PARPi 的高血压总风险和发病率。为了提供 PARPi 相关高血压的临床特征，我们独立查询了世界卫生组织的药物警戒数据库（截至 2022 年 9 月 1 日）：结果：共纳入 41 项安慰剂 RCT（n = 15 264 名成年患者）。与安慰剂相比，PARPi 类药物与高血压风险增加无关。在单项分析中，奥拉帕利的高血压风险低于安慰剂（RR 0.77 [95% CI：0.68-0.86]，P 2 = 19%，χ2 P = 0.26）。尼拉帕利单药治疗会增加任何高血压的风险（RR 2.84 [95% CI：1.76-4.57]，P 2 = 66%，χ2 P = 0.01），总发生率为 19.87%（95% CI：15.23-25.50）。在现实生活中，尼拉帕利相关高血压发生在 20 天内，66% 的患者病情严重。据报道，20.5%或14.4%的病例同时服用了至少一种降压药或治疗引起的高血压：结论：在对尼拉帕利联合用药进行广泛评估的背景下，这些数据强化了密切监测这一不良事件的必要性，以保持其对患者生存的临床益处。

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引用次数: 0

Sodium hypochlorite accident diagnosis and management: Analysis from the literature and the French pharmacovigilance database 次氯酸钠事故的诊断和处理：文献和法国药物警戒数据库分析。

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-24 DOI: 10.1111/fcp.12985

Zahoua Kartit, Céline Delacroix, Céline Clement, Mathilde Beurrier, Claudie Mouton-Faivre, Nadine Petitpain

Purpose

Sodium hypochlorite (NaOCl) is considered as the reference irrigation solution in endodontics. However, NaOCl-related accidents may occur, and non-dentist health professionals might under-recognize this rare adverse effect although it is potentially severe, with possible medical and aesthetic sequelae. We performed a literature review to provide to non-dentist healthcare professionals a large picture of symptoms, management and potential consequences of NaOCl accidents.

Methods

We queried PubMed and the French Pharmacovigilance database and retrieved 76 cases for analysis (70 from 57 published articles, and six from the database).

Results

The analysis showed that patients were mostly women (79%), aged around of 42 years, undergoing upper jawbone (74%) endodontic procedure. NaOCl concentration ranged from 1% to 10%, with 0.5 to 30 mL injected. Most cases (86%) corresponded to an accidental extrusion beyond the root apex to the periapical tissues, followed by tissular injection by error (8%) and extrusion into the maxillary sinus (3%). Local symptoms always occurred within 24 h, mostly pain (99%), edema (89%) and/or ecchymosis (61%). Complications were mainly neurological (29%), necrotic (22%) and cutaneous (9%). Most of patients (76%) fully recovered after medical management but 18 (24%) required surgical management.

Conclusion

Any healthcare professional should be aware of the classical symptomatic triad of NaOCl accident with sudden pain, haemorrhage/ecchymosis and swelling, to start or recommend adequate management. Patients should be reassured, but a close follow-up is necessary to avoid delayed complication.

目的：次氯酸钠（NaOCl）被认为是牙髓病学的参考灌洗溶液。然而，与次氯酸钠相关的事故可能会发生，非牙科医生保健专业人员可能对这种罕见的不良反应认识不足，尽管这种不良反应可能很严重，并可能带来医疗和美学后遗症。我们进行了一次文献综述，旨在为非牙科医生的医疗保健专业人员提供有关 NaOCl 事故的症状、处理方法和潜在后果的全面信息：我们查询了 PubMed 和法国药物警戒数据库，并检索了 76 个病例进行分析（其中 70 例来自 57 篇发表的文章，6 例来自数据库）：分析结果显示，患者多为女性（79%），年龄在 42 岁左右，正在接受上颌骨牙髓治疗（74%）。NaOCl 浓度从 1%到 10%不等，注射量从 0.5 毫升到 30 毫升不等。大多数病例（86%）是由于意外挤出根尖至根尖周围组织，其次是组织注射错误（8%）和挤入上颌窦（3%）。局部症状总是在 24 小时内出现，主要是疼痛（99%）、水肿（89%）和/或瘀斑（61%）。并发症主要是神经系统（29%）、坏死（22%）和皮肤（9%）。大多数患者（76%）在接受内科治疗后完全康复，但有18名患者（24%）需要接受外科治疗：任何医护人员都应了解 NaOCl 事故的典型症状三联征，即突然疼痛、出血/瘀斑和肿胀，以便开始或建议适当的治疗。患者应得到安抚，但有必要进行密切随访，以避免延误并发症的发生。

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引用次数: 0

Repurposing of atorvastatin and metformin denotes their individual and combined antiproliferative effects in non-small cell lung cancer 阿托伐他汀和二甲双胍的再利用表明了它们在非小细胞肺癌中的单独和联合抗增殖作用。

IF 2.9 4区医学 Q2 Medicine

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-23 DOI: 10.1111/fcp.12981

Elsayed I. Salim, Safaa Elsebakhy, Mohamed Hessien

Background

Due to the limited success in the treatment of lung adenocarcinomas, new treatment protocols are urgently needed to increase the curability rate and the survival of lung cancer patients.

Objectives

Although statins, like atorvastatin (Ator), and metformin (Met) are widely accepted as hypolipidemic and hypoglycemic drugs, respectively, there are many predictions about their enhancing antitumor effect when they are combined with traditional chemotherapeutics.

Methods

The individual and combined antiproliferative potential of Ator and Met was tested by MTT-assay in non-small cell lung cancer (NSCLC) A549 cell line, compared to the corresponding effect of Gemcitabine (Gem) with implication on the mechanisms of action.

Results

Initially, both drugs demonstrated concentration-dependent cytotoxicity in A549 cells. Also, their combination index (CI) indicated their synergistic effect at equi-IC50 concentration (CI = 0.00984). Moreover, Ator and/or Met-treated cells revealed disrupted patterns of SOD, CAT, GSH, MDA, and TAC, developed apoptosis, and larger fractions of the cell population were arrested in G0/G1 phase, particularly in cells dually-treated both Ator and Met. These observations were accompanied by downregulation in the expression of iNOS, HO-1, and the angiogenic marker VEGF, meanwhile, an altered expression of MAPK and AMPK was observed.

Conclusion

Conclusively, these data suggest that repurposing of Ator and Met demonstrates their individual and combined antiproliferative effect in non-small cell lung cancer and they may adopt a similar mechanism of action.

背景：由于肺腺癌的治疗效果有限，迫切需要新的治疗方案来提高肺腺癌患者的治愈率和生存率：由于肺腺癌的治疗效果有限，因此迫切需要新的治疗方案来提高肺腺癌患者的治愈率和生存率：尽管他汀类药物（如阿托伐他汀（Atorvastatin，Ator））和二甲双胍（Met）分别作为降脂药和降糖药被广泛接受，但有很多人预测它们与传统化疗药联合使用会增强抗肿瘤效果：方法：在非小细胞肺癌（NSCLC）A549 细胞系中用 MTT 分析法检测了 Ator 和 Met 的单独和联合抗增殖潜力，并与吉西他滨（Gem）的相应作用进行了比较，同时对其作用机制进行了探讨：结果：最初，这两种药物在A549细胞中都表现出浓度依赖性细胞毒性。此外，它们的联合指数（CI）表明，在等效 IC50 浓度下，它们具有协同效应（CI = 0.00984）。此外，Ator 和/或 Met 处理过的细胞显示出 SOD、CAT、GSH、MDA 和 TAC 的紊乱模式，出现细胞凋亡，更多的细胞群停滞在 G0/G1 期，尤其是在同时使用 Ator 和 Met 的细胞中。这些观察结果伴随着 iNOS、HO-1 和血管生成标志物 VEGF 表达的下调，同时还观察到 MAPK 和 AMPK 表达的改变：总之，这些数据表明，Ator 和 Met 的再利用显示了它们在非小细胞肺癌中的单独和联合抗增殖作用，而且它们可能采用类似的作用机制。

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引用次数: 0

Probing polypharmacy, ageing and sex effects on physical function using different tests 使用不同的测试探究多种药物、老龄化和性别对身体功能的影响。

IF 2.9 4区医学 Q2 Medicine

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-21 DOI: 10.1111/fcp.12978

Gizem Gemikonakli, John Mach, Trang Tran, Harry Wu, Sarah N. Hilmer

Background

Ageing, sex and polypharmacy affect physical function.

Objectives

This mouse study investigates how ageing, sex and polypharmacy interact and affect grip strength, balance beam and wire hang, correlating and comparing the different test results between and within subgroups.

Methods

Young (2.5 months) and old (21.5 months) C57BL/6 J male and female mice (n = 10–6/group) were assessed for physical function at baseline on grip strength, balance beam and wire hang with three trials of 60 s (WH60s) and one trial of 300 s (WH300s). Mice were randomised to control or diet containing a high Drug Burden Index (DBI, total anticholinergic and sedative drug exposure) polypharmacy regimen (metoprolol, simvastatin, citalopram, oxycodone and oxybutynin at therapeutic oral doses). Following 6–8 weeks of treatment, mice were reassessed.

Results

High DBI polypharmacy and control mice both showed age group differences on all tests (p < 0.05). Only control mice showed sex differences, with females outperforming males on the WH60s and balance beam for old mice, WH300s for young mice (p < 0.05). Polypharmacy reduced grip strength in all subgroups (p < 0.05) and only in old females reduced wire hang time and cumulative behaviour and balance beam time and %walked (p < 0.05). Physical function assessments were all correlated with each other, with differences between subgroups (p < 0.05), and mice within subgroups showed interindividual variability in performance.

Conclusion

Age, sex and polypharmacy have variable effects on different tests, and behavioural measures are useful adjuvants to assessing performance. There was considerable within-group variability in change in measures over time. These findings can inform design and sample size of future studies.

背景老龄化、性别和多种药物影响身体功能：这项小鼠研究探讨了老龄化、性别和多种药物如何相互作用并影响握力、平衡木和吊线，并对亚组之间和亚组内的不同测试结果进行了关联和比较：方法：年轻（2.5 个月）和年老（21.5 个月）的 C57BL/6 J 雄性和雌性小鼠（n = 10-6/组）在基线时接受握力、平衡木和吊线的身体功能评估，其中包括三次 60 秒（WH60s）和一次 300 秒（WH300s）的测试。小鼠被随机分配到对照组或含有高药物负担指数（DBI，抗胆碱能和镇静药物总暴露量）的多药方案（治疗口服剂量的美托洛尔、辛伐他汀、西酞普兰、羟考酮和羟丁宁）的饮食中。治疗 6-8 周后，对小鼠进行重新评估：结果：高 DBI 多药小鼠和对照组小鼠在所有测试中均显示出年龄组差异（p 结论：高 DBI 多药小鼠和对照组小鼠在所有测试中均显示出年龄组差异：年龄、性别和多药性对不同测试的影响各不相同，行为测量是评估成绩的有用辅助手段。随着时间的推移，行为指标的变化在组内存在相当大的差异。这些发现可为今后研究的设计和样本大小提供参考。

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引用次数: 0

Update on monkeypox virus infection: Focusing current treatment and prevention approaches 猴痘病毒感染的最新情况：聚焦当前的治疗和预防方法。

IF 2.9 4区医学 Q2 Medicine

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-16 DOI: 10.1111/fcp.12980

Rishika Dhapola, Sneha Kumari, Prajjwal Sharma, Pramod KumarKushawaha, Dibbanti HariKrishnaReddy

Background

While the world is still facing the global pandemic COVID-19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the pathogenesis, symptoms, and management strategies will aid in the development of potent therapeutics for the treatment of monkeypox virus infection.

Objectives

To get insight into the current treatment and prevention strategies will aid in effectively coping with the disease.

Methods

For obtaining information regarding the ongoing treatment and prevention strategies and the drugs under pipeline, we referred to Google Scholar, Pub Med, Pub Chem, and WHO official site.

Results

There are a few drugs that came out to be effective for the treatment of Mpox. Tecovirimat acts by inhibiting viral replication and viral wrapping. Another drug is cidofovir, which hinders the activity of viral DNA polymerase but has the drawback of nephrotoxicity. To overcome this, a conjugate of cidofovir is being used—known as brincidofovir—which has a similar mechanism as cidofovir but lesser toxicity. Ribavirin acts via inhibiting inosine monophosphate dehydrogenase (IMPDPH) thus disrupting viral translation. It also interferes with helicase activity. Tiazofurin, Adenosine N1 oxide, and HPMPA have shown efficacy in in-vitro studies by inhibiting IMPDH, DNA polymerase, and viral mRNA translation respectively. In-silico studies have proven the effect of nilotinib, simeprevir, and dihydroergotamine for Mpox treatment. They have shown binding affinity for proteins required for the growth and release of MPXV. Vaccines have also been employed for the prevention of Mpox, which includes JYNNEOS, ACAM2000, and VIGIV.

Conclusion

This review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.

背景：当全球仍在面对COVID-19大流行病时，另一种人畜共患病猴痘（Mpox）也已出现，对社会构成了巨大威胁。对猴痘的发病机理、症状和治疗策略的深入了解将有助于开发治疗猴痘病毒感染的有效疗法：深入了解当前的治疗和预防策略将有助于有效应对该疾病：方法：为了获取有关当前治疗和预防策略以及正在研发的药物的信息，我们参考了谷歌学术、Pub Med、Pub Chem和世界卫生组织官方网站：结果：有几种药物对治疗麻风腮有效。Tecovirimat 通过抑制病毒复制和病毒包裹发挥作用。另一种药物是西多福韦，它能阻碍病毒 DNA 聚合酶的活性，但有肾毒性的缺点。为了克服这一缺点，目前正在使用一种西多福韦的共轭物，即布林昔多福韦，其作用机制与西多福韦相似，但毒性较小。利巴韦林通过抑制单磷酸肌苷脱氢酶（IMPDPH）发挥作用，从而破坏病毒的翻译。它还能干扰螺旋酶的活性。噻唑呋林、氧化腺苷 N1 和 HPMPA 分别通过抑制 IMPDH、DNA 聚合酶和病毒 mRNA 翻译，在体外研究中显示出疗效。室内研究证明了尼罗替尼、西美普韦和双氢麦角胺治疗 Mpox 的效果。它们显示出与 MPXV 生长和释放所需的蛋白质的结合亲和力。疫苗也被用于预防 Mpox，包括 JYNNEOS、ACAM2000 和 VIGIV：本综述重点介绍了病毒的致病机理、疾病表现、药物以及用于治疗和预防麻腮风的疫苗。

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引用次数: 0

Cell–cell communication in stem cells and cancer: Alone but in touch 干细胞和癌症中的细胞间通讯：孤军奋战却又亲密无间

IF 2.9 4区医学 Q2 Medicine

Fundamental & Clinical Pharmacology

Pub Date : 2024-01-16 DOI: 10.1111/fcp.12982

Mehran Radak, Hossein Fallahi

Background

Cellular communication and signaling pathways are fundamental regulators of stem cell and cancer cell behaviors. This review explores the intricate interplay of these pathways in governing cellular behaviors, focusing on their implications for diseases, particularly cancer.

Objectives

This comprehensive review aims to elucidate the significance of cellular signaling pathways in regulating the behavior of stem cells and cancer cells. It delves into the alterations in these pathways, their impact on cell fate, and their implications for developing diseases, notably cancer. The objective is to underscore the importance of understanding these signaling pathways for developing targeted therapeutic strategies.

Methods

The review critically analyzes existing literature and research findings concerning the roles of signaling pathways in stem cell behavior regulation, emphasizing their parallels and disparities in cancer cells. It synthesizes information on both direct and indirect modes of cell communication to delineate the complexity of signaling networks.

Results

Direct and indirect modes of cell communication intricately regulate the complex signaling pathways governing stem cell behaviors, influencing differentiation potential and tissue regeneration. Alterations in these pathways significantly impact stem cell fate, contributing to disease pathogenesis, including cancer. Understanding these signaling cascades offers insights into developing targeted therapies, particularly cancer treatment.

Conclusion

Understanding the regulation of signaling pathways in stem cells and the specialized subset of cancer stem cells holds promise for innovative therapeutic approaches. By targeting aberrant signaling pathways, tailored interventions may improve treatment outcomes. This review underscores the critical role of signaling pathways in cellular behaviors, offering a pathway toward developing novel, more effective therapies for diverse diseases and disorders.

细胞通讯和信号通路是干细胞和癌细胞行为的基本调节器。这篇综述探讨了这些途径在调控细胞行为方面错综复杂的相互作用，重点关注它们对疾病（尤其是癌症）的影响。

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引用次数: 0