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Skin anti-aging potential of Launaea procumbens extract: Antioxidant and enzyme inhibition activities supported by ADMET and molecular docking studies Launaea procumbens 提取物的皮肤抗衰老潜力:ADMET 和分子对接研究支持的抗氧化和酶抑制活性
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-25 DOI: 10.1016/j.jsps.2024.102107
Hanan Khojah , Shaima R. Ahmed , Shahad Y. Alharbi , Kholood K. AlSabeelah , Hatham Y. Alrayyes , Kadi B. Almusayyab , Shahad R. Alrawiliy , Raghad M. Alshammari , Sumera Qasim

Aging is a natural process that occurs in all living organisms. Particularly, the skin embodies aging since it serves as a barrier between the body and its surroundings. Previously, we reported the wound healing effect of Launaea procumbens and identified compounds therein. The study aims to explore the skin anti-aging properties of the plant extract. To that effect, the antioxidant potential of L. procumbens methanolic extract (LPM) was assessed using two complementary DPPH and FRAP assays. The enzyme inhibitory effect of the extract on collagenase, elastase, hyaluronidase, and tyrosinase was evaluated to assess the direct skin anti-aging effects. Similarly, the anti-inflammatory activity was evaluated to explore the indirect anti-aging effects via the assessment of extract inhibitory effects on cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). In addition, ADMET and molecular docking studies were performed to explore the interaction mechanisms of identified compounds in LPM with target enzymes. LPM demonstrated significant antioxidant activity in DPPH (IC50 = 29.08 µg/mL) and FRAP (1214.67 µM FeSO4/g extract) assays. Plant extract showed significant inhibition of collagenase, elastase, hyaluronidase, and tyrosinase (IC50 = 52.68, 43.76, 31.031, and 37.13 µg/mL, respectively). The extract demonstrated significant COX-2 and 5-LOX inhibition capacity with IC50 values of 8.635 and 10.851 µg/mL, respectively. The molecular docking study revealed the high potential of the identified compounds to bind to the active sites of enzymes crucially involved in the skin aging process. ADMET analysis of the compounds revealed their good absorption, distribution, and metabolism profiles, and they were found to be safe as well. Study findings suggest L. procumbens as a promising source for the development of natural skin anti-aging and antioxidant compounds. This, in turn, may facilitate its incorporation into cosmetic formulations after further investigation.

衰老是所有生物都会经历的一个自然过程。尤其是皮肤,因为它是人体与周围环境之间的屏障,所以也体现了衰老。此前,我们曾报道过这种植物的伤口愈合效果,并确定了其中的化合物。本研究旨在探索该植物提取物的皮肤抗衰老特性。为此,我们使用两种互补的 DPPH 和 FRAP 试验评估了甲醇提取物(LPM)的抗氧化潜力。还评估了萃取物对胶原酶、弹性蛋白酶、透明质酸酶和酪氨酸酶的酶抑制作用,以评估其直接的皮肤抗衰老效果。同样,通过评估萃取物对环氧合酶-2(COX-2)和 5-脂氧合酶(5-LOX)的抑制作用,评估了抗炎活性,以探索间接抗衰老效果。此外,还进行了 ADMET 和分子对接研究,以探索 LPM 中已鉴定化合物与目标酶的相互作用机制。在 DPPH(IC = 29.08 µg/mL)和 FRAP(1214.67 µM FeSO4/g提取物)试验中,LPM表现出明显的抗氧化活性。植物提取物对胶原酶、弹性蛋白酶、透明质酸酶和酪氨酸酶有明显的抑制作用(IC 分别为 52.68、43.76、31.031 和 37.13 µg/mL)。该提取物具有明显的 COX-2 和 5-LOX 抑制能力,IC 值分别为 8.635 和 10.851 µg/mL。分子对接研究表明,所鉴定的化合物极有可能与皮肤老化过程中关键酶的活性位点结合。化合物的 ADMET 分析表明,它们具有良好的吸收、分布和代谢特征,而且是安全的。研究结果表明,这是开发天然皮肤抗衰老和抗氧化化合物的一个很有前景的来源。这反过来又有助于在进一步研究后将其纳入化妆品配方中。
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引用次数: 0
Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine 新型β-内酰胺类药物MC-100093和头孢曲松对暴露于吗啡递增剂量的C57BL/6小鼠星形胶质细胞谷氨酸转运体和神经炎症因子的影响
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-23 DOI: 10.1016/j.jsps.2024.102108
Youssef Sari , Ghadeer M.S. Swiss , Fatin A. Alrashedi , Kholoud A. Baeshen , Sultan A. Alshammari , Shakir D. Alsharari , Nemat Ali , Abdullah F. Alasmari , Ali Alhoshani , Alaa A. Alameen , Wayne E. Childers , Magid Abou-Gharbia , Fawaz Alasmari

Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-β) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and beta-lactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-β mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC-100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC-100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.

长期暴露于阿片类药物可导致星形胶质细胞谷氨酸转运体 1(GLT-1)的下调,该转运体调节大部分谷氨酸的摄取。我们实验室的研究发现,β-内酰胺类抗生素头孢曲松可减轻氢可酮诱导的 GLT-1 下调以及中枢奖赏脑区胱氨酸/谷氨酸抗转运体(xCT)的表达。在这项研究中,我们研究了吗啡剂量递增的影响,并测试了新型合成非抗生素药物 MC-100093 和头孢曲松在减轻吗啡暴露对脑核中 GLT-1、xCT 和神经炎症因子(IL-6 和 TGF-β)表达的影响方面的功效。由于阿片类药物对小鼠的运动敏感性有影响,本研究还调查了吗啡和β-内酰胺类药物对小鼠运动活动、自发交替率(SAP)和进入Y迷宫次数的影响。小鼠在第1、3、5、7天暴露于中等剂量的吗啡(20毫克/千克,静脉注射),在第9天暴露于较高剂量的吗啡(150毫克/千克,静脉注射),然后对这些小鼠进行行为测试,并在第10天安乐死。Western印迹分析表明,接触吗啡会降低NAc中GLT-1和xCT的表达,而MC-100093和头孢曲松均可减轻这些影响。此外,吗啡还增加了NAc中IL-6 mRNA和TGF-β mRNA的表达,而MC-100093和头孢曲松只减弱了对IL-6 mRNA表达的影响。此外,接触吗啡会导致行走距离增加,而MC-100093和头孢曲松会减弱这种效应。此外,暴露于吗啡会降低Y迷宫中的SAP并增加进入臂的次数,但MC-100093和头孢曲松均未显示出任何减弱作用。我们的研究结果首次证明,MC-100093和头孢曲松可减轻吗啡诱导的GLT-1和xCT表达下调、吗啡诱导的神经炎症因子IL-6增加以及过度活跃。这些发现揭示了MC-100093和头孢曲松对暴露于递增剂量吗啡的影响具有有益的治疗作用。
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引用次数: 0
Effect of eugenol on cytochrome P450 1A2, 2C9, 2D6, and 3A4 activity in human liver microsomes 丁香酚对人肝脏微粒体中细胞色素 P450 1A2、2C9、2D6 和 3A4 活性的影响
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-23 DOI: 10.1016/j.jsps.2024.102118
Naif Fahad M. Alharbi, Abdul Ahad, Yousef A. Bin Jardan, Fahad I. Al-Jenoobi

This study aimed to provide an understanding of the influence of eugenol on CYP1A2, 2C9, 2D6, and 3A4 in human liver microsomes (HLM). Specific substrate for CYP1A2, 2C9, 2D6, and 3A4 were incubated in HLM with or without eugenol. The formation of their respective metabolites was assessed with HPLC analytical methods. Eugenol at 1, 10 and 100 µM levels inhibited the activity of CYP1A2 and CYP2C9 by 23.38 %, 23.57 %, 39.80 % and 62.82 %, 63.27 %, 67.70 % respectively. While, CYP2D6 and CYP3A4 activity was decreased by 40.70 %, 45.88 %, 62.68 % and 37.41 %, 42.58 % and 67.86 % at 1, 10 and 100 µM eugenol level respectively. The IC50 value of eugenol for CYP2D6 and CYP3A4 was calculated as 11.09 ± 3.49 µM and 13.48 ± 3.86 µM respectively. Potential herb-drug interactions was noted when eugenol is administered simultaneously with medications metabolized by these enzymes, most notably CYP2C9, CYP2D6 and CYP3A4.

本研究旨在了解丁香酚对人肝脏微粒体(HLM)中 CYP1A2、2C9、2D6 和 3A4 的影响。将 CYP1A2、2C9、2D6 和 3A4 的特定底物与丁香酚或不与丁香酚一起在 HLM 中培养。采用 HPLC 分析方法评估其各自代谢物的形成。丁香酚在 1、10 和 100 µM 水平下分别抑制 CYP1A2 和 CYP2C9 的活性 23.38 %、23.57 %、39.80 % 和 62.82 %、63.27 %、67.70 %。而在 1、10 和 100 µM 丁香酚水平下,CYP2D6 和 CYP3A4 活性分别降低了 40.70 %、45.88 %、62.68 % 和 37.41 %、42.58 % 和 67.86 %。经计算,丁香酚对 CYP2D6 和 CYP3A4 的 IC50 值分别为 11.09 ± 3.49 µM 和 13.48 ± 3.86 µM。当丁香酚与由这些酶代谢的药物(尤其是 CYP2C9、CYP2D6 和 CYP3A4)同时服用时,可能会发生草药与药物之间的相互作用。
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引用次数: 0
Formulation, development and evaluation of hyaluronic acid-conjugated liposomal nanoparticles loaded with regorafenib and curcumin and their in vitro evaluation on colorectal cancer cell lines 载入瑞戈非尼和姜黄素的透明质酸共轭脂质体纳米颗粒的配制、开发和评估及其对结直肠癌细胞系的体外评估
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-18 DOI: 10.1016/j.jsps.2024.102099
Sewar G. Shnaikat , Ashok K. Shakya , Sanaa K. Bardaweel

Colorectal cancer is one of the major causes of global cancer, with chemotherapy and radiation therapy being effective but limited due to low specificity. Regorafenib, a multikinase inhibitor, provides hope to patients with metastatic colorectal cancer and was approved by the FDA in 2012. However, due to resistance issues and adverse events, its efficacy is compromised, necessitating further refinement. Meanwhile, curcumin, a compound of turmeric, exhibits anticancer effects through antioxidant and anti-inflammatory actions, induction of the apoptosis, arrest of cell cycle, inhibition of angiogenesis, and modulation of signaling pathways. Unfortunately, its clinical utility is limited by its poor bioavailability, pointing towards innovative drug delivery strategies for enhanced efficacy in colorectal cancer treatment.

Hyaluronic acid (HA)-decorated liposomes (LIPO) have been developed to target colorectal cells through an overexpressed CD44 receptor, increasing antitumor and antimetastasis efficacy. This study investigates the possibility of loading curcumin (CUR) or regorafenib (REGO) into a liposomal formulation for passive and HA-actively targeted treatment, evaluating its critical quality attributes (CQA) (size, zeta potential, polydispersity index) and cytotoxic activity in the HT29 colorectal cancer cell line. The average particle size of the plain liposomes and those decorated with HA was 144.00 ± 0.78 nm and 140.77 ± 1.64 nm, respectively. In contrast, curcumin-loaded plain liposomes and HA-decorated liposomes had 140 ± 2.46 nm and 164.53 ± 15.13 nm, respectively. The prepared liposomes had a spherical shape with a narrow size distribution and an acceptable zeta potential of less than −30 mV. The encapsulation efficiency was 99.2 % ± 0.3 and 99.9 ± 0.2 % for HA-decorated and bare regorafenib loaded. The % EE was 98.9 ± 0.2 % and 97.5 ± 0.2 % for bare liposomal nanoparticles loaded with curcumin and coated with curcumin. The IC50 of free REGO, CUR, REGO-LIPO, CUR-LIPO, REGO-LIPO-HA and CUR-LIPO-HA were 20.17 ± 0.78, 64.4 ± 0.33, 224.8 ± 0.06, 49.66 ± 0.22, 73.66 ± 0.6, and 27.86 ± 0.49 µM, respectively. The MTT assay in HT29 cells showed significant cytotoxic activity of the HA-decorated liposomal formulation compared to the base uncoated formulation, indicating that hyaluronic acid-targeted liposomes loaded with regorafenib or curcumin could be a promising targeted formulation against colorectal cancer cells.

结直肠癌是全球癌症的主要病因之一,化疗和放疗虽然有效,但由于特异性低而效果有限。瑞戈非尼是一种多激酶抑制剂,为转移性结直肠癌患者带来了希望,并于2012年获得美国食品药品管理局批准。然而,由于耐药性问题和不良反应,其疗效大打折扣,需要进一步改进。与此同时,姜黄中的一种化合物姜黄素通过抗氧化、抗炎、诱导细胞凋亡、抑制细胞周期、抑制血管生成和调节信号通路等作用发挥抗癌作用。透明质酸(HA)装饰脂质体(LIPO)已被开发出来,可通过过度表达的 CD44 受体靶向结直肠细胞,提高抗肿瘤和抗转移疗效。本研究探讨了将姜黄素(CUR)或瑞戈非尼(REGO)装入脂质体制剂进行被动和HA主动靶向治疗的可能性,评估了其关键质量属性(CQA)(粒度、ZETA电位、多分散指数)和在HT29结直肠癌细胞系中的细胞毒性活性。普通脂质体和用 HA 装饰的脂质体的平均粒径分别为 144.00 ± 0.78 nm 和 140.77 ± 1.64 nm。相比之下,负载姜黄素的普通脂质体和HA装饰脂质体的平均粒径分别为140 ± 2.46 nm和164.53 ± 15.13 nm。制备的脂质体呈球形,粒度分布较窄,zeta电位小于-30 mV。装载有 HA 装饰的瑞戈非尼和裸瑞戈非尼的封装效率分别为 99.2 % ± 0.3 % 和 99.9 ± 0.2 %。装载姜黄素的裸脂质体纳米颗粒和涂布姜黄素的裸脂质体纳米颗粒的EE%分别为98.9%±0.2%和97.5%±0.2%。游离 REGO、CUR、REGO-LIPO、CUR-LIPO、REGO-LIPO-HA 和 CUR-LIPO-HA 的 IC50 分别为 20.17 ± 0.78、64.4 ± 0.33、224.8 ± 0.06、49.66 ± 0.22、73.66 ± 0.6 和 27.86 ± 0.49 µM。在 HT29 细胞中进行的 MTT 试验表明,与未包被的基础制剂相比,HA 包被的脂质体制剂具有显著的细胞毒性活性,这表明载入瑞戈非尼或姜黄素的透明质酸靶向脂质体可能是一种很有前景的针对结直肠癌细胞的靶向制剂。
{"title":"Formulation, development and evaluation of hyaluronic acid-conjugated liposomal nanoparticles loaded with regorafenib and curcumin and their in vitro evaluation on colorectal cancer cell lines","authors":"Sewar G. Shnaikat ,&nbsp;Ashok K. Shakya ,&nbsp;Sanaa K. Bardaweel","doi":"10.1016/j.jsps.2024.102099","DOIUrl":"https://doi.org/10.1016/j.jsps.2024.102099","url":null,"abstract":"<div><p>Colorectal cancer is one of the major causes of global cancer, with chemotherapy and radiation therapy being effective but limited due to low specificity. Regorafenib, a multikinase inhibitor, provides hope to patients with metastatic colorectal cancer and was approved by the FDA in 2012. However, due to resistance issues and adverse events, its efficacy is compromised, necessitating further refinement. Meanwhile, curcumin, a compound of turmeric, exhibits anticancer effects through antioxidant and anti-inflammatory actions, induction of the apoptosis, arrest of cell cycle, inhibition of angiogenesis, and modulation of signaling pathways. Unfortunately, its clinical utility is limited by its poor bioavailability, pointing towards innovative drug delivery strategies for enhanced efficacy in colorectal cancer treatment.</p><p>Hyaluronic acid (HA)-decorated liposomes (LIPO) have been developed to target colorectal cells through an overexpressed CD44 receptor, increasing antitumor and antimetastasis efficacy. This study investigates the possibility of loading curcumin (CUR) or regorafenib (REGO) into a liposomal formulation for passive and HA-actively targeted treatment, evaluating its critical quality attributes (CQA) (size, zeta potential, polydispersity index) and cytotoxic activity in the HT29 colorectal cancer cell line. The average particle size of the plain liposomes and those decorated with HA was 144.00 ± 0.78 nm and 140.77 ± 1.64 nm, respectively. In contrast, curcumin-loaded plain liposomes and HA-decorated liposomes had 140 ± 2.46 nm and 164.53 ± 15.13 nm, respectively. The prepared liposomes had a spherical shape with a narrow size distribution and an acceptable zeta potential of less than −30 mV. The encapsulation efficiency was 99.2 % ± 0.3 and 99.9 ± 0.2 % for HA-decorated and bare regorafenib loaded. The % EE was 98.9 ± 0.2 % and 97.5 ± 0.2 % for bare liposomal nanoparticles loaded with curcumin and coated with curcumin. The IC<sub>50</sub> of free REGO, CUR, REGO-LIPO, CUR-LIPO, REGO-LIPO-HA and CUR-LIPO-HA were 20.17 ± 0.78, 64.4 ± 0.33, 224.8 ± 0.06, 49.66 ± 0.22, 73.66 ± 0.6, and 27.86 ± 0.49 µM, respectively. The MTT assay in HT29 cells showed significant cytotoxic activity of the HA-decorated liposomal formulation compared to the base uncoated formulation, indicating that hyaluronic acid-targeted liposomes loaded with regorafenib or curcumin could be a promising targeted formulation against colorectal cancer cells.</p></div>","PeriodicalId":49257,"journal":{"name":"Saudi Pharmaceutical Journal","volume":"32 7","pages":"Article 102099"},"PeriodicalIF":4.1,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S131901642400149X/pdfft?md5=5cd50216e308c94951791310c3d15aab&pid=1-s2.0-S131901642400149X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141072574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Role of KDM2B epigenetic factor in regulating calcium signaling in prostate cancer cells KDM2B 表观遗传因子在调控前列腺癌细胞钙信号转导中的作用
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-18 DOI: 10.1016/j.jsps.2024.102109
Evangelia Pantazaka , Saad Alkahtani , Saud Alarifi , Abdullah A. Alkahtane , Christos Stournaras , Galatea Kallergi

KDM2B, a histone lysine demethylase, is expressed in a plethora of cancers. Earlier studies from our group, have showcased that overexpression of KDM2B in the human prostate cancer cell line DU-145 is associated with cell adhesion, actin reorganization, and improved cancer cell migration. In addition, we have previously examined changes of cytosolic Ca2+, regulated by the pore-forming proteins ORAI and the Ca2+ sensing stromal interaction molecules (STIM), via store-operated Ca2+ entry (SOCE) in wild-type DU-145. This study sought to evaluate the impact of KDM2B overexpression on the expression of key molecules (SGK1, Nhe1, Orai1, Stim1) and SOCE. Furthermore, this is the first study to evaluate KDM2B expression in circulating tumor cells (CTCs) from patients with prostate cancer. mRNA levels for SGK1, Nhe1, Orai1, and Stim1 were quantified by RT-PCR. Calcium signals were measured in KDM2B-overexpressing DU-145 cells, loaded with Fura-2. Blood samples from 22 prostate cancer cases were scrutinized for KDM2B expression using immunofluorescence staining and the VyCAP system. KDM2B overexpression in DU-145 cells increased Orai1, Stim1, and Nhe1 mRNA levels and significantly decreased Ca2+ release. KDM2B expression was examined in 22 prostate cancer patients. CTCs were identified in 45 % of these patients. 80 % of the cytokeratin (CK)-positive patients and 63 % of the total examined CTCs exhibited the (CK + KDM2B + CD45−) phenotype. To conclude, this study is the first to report increased expression of KDM2B in CTCs from patients with prostate cancer, bridging in vitro and preclinical assessments on the potentially crucial role of KDM2B on migration, invasiveness, and ultimately metastasis in prostate cancer.

KDM2B 是一种组蛋白赖氨酸去甲基化酶,在多种癌症中都有表达。我们小组的早期研究表明,KDM2B 在人类前列腺癌细胞系 DU-145 中的过表达与细胞粘附、肌动蛋白重组和癌细胞迁移的改善有关。此外,我们之前还研究了野生型 DU-145 细胞中由孔道形成蛋白 ORAI 和 Ca2+ 传感基质相互作用分子(STIM)通过储存操作 Ca2+ 进入(SOCE)调控的细胞膜 Ca2+ 变化。本研究试图评估 KDM2B 过表达对关键分子(SGK1、Nhe1、Orai1、Stim1)和 SOCE 表达的影响。此外,这是首次评估前列腺癌患者循环肿瘤细胞(CTC)中 KDM2B 表达的研究。通过 RT-PCR 对 SGK1、Nhe1、Orai1 和 Stim1 的 mRNA 水平进行了量化。用 Fura-2 测量了 KDM2B 表达过高的 DU-145 细胞中的钙信号。利用免疫荧光染色法和 VyCAP 系统对 22 例前列腺癌患者的血样进行了 KDM2B 表达检测。在 DU-145 细胞中,KDM2B 的过表达增加了 Orai1、Stim1 和 Nhe1 的 mRNA 水平,并显著降低了 Ca2+ 的释放。在 22 名前列腺癌患者中检测了 KDM2B 的表达。这些患者中有 45% 发现了 CTC。80%的细胞角蛋白(CK)阳性患者和63%的受检 CTC 表现出(CK + KDM2B + CD45-)表型。总之,这项研究首次报告了前列腺癌患者的 CTCs 中 KDM2B 表达的增加,为体外和临床前评估 KDM2B 对前列腺癌的迁移、侵袭性和最终转移的潜在关键作用架起了桥梁。
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引用次数: 0
Baeckea frutescens L. Promotes wound healing by upregulating expression of TGF-β, IL-1 β, VEGF and MMP-2 通过上调 TGF-β、IL-1 β、VEGF 和 MMP-2 的表达促进伤口愈合
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-17 DOI: 10.1016/j.jsps.2024.102110
Ihsan Safwan Kamarazaman , Ling Sui Kiong , Mohd Kamal Nik Hasan , Norlia Basherudin , Nur Aini Mohd Kasim , Aida Azlina Ali , Salfarina Ramli , Sandra Maniam , Richard Johari James , Pornchai Rojsitthisak , Hasseri Halim

Baeckea frutescens L. has been traditionally used for treating snakebites and is known to possess antifebrile and hemostatic properties. These properties are closely related to wound healing. This study aimed to evaluate the wound healing properties of B. frutescens leaves extract (BFLE) in vitro and in vivo. The in vitro study focused on proliferation, migration, and expression of TGF-β, IL-1β, VEGF, and MMP-2 genes and proteins. The in vivo study included excisional wound healing, histology, and tensile strength studies. The ethanolic extract of B. frutescens (BFLE) was tested for its effects on proliferation and migration using keratinocytes (HaCaT) and fibroblasts (BJ) cells. Gene and protein expression related to wound healing were analyzed using real-time PCR and Western blot assays. The wound healing properties of BFLE were evaluated in vivo using Wistar albino rats, focusing on excisional wound healing, histology, and tensile strength studies. The BFLE displayed significant proliferative and migratory effects on keratinocytes and fibroblasts cells, while upregulating the expression of TGF-β, IL-1β, VEGF, and MMP-2 genes and proteins. BFLE also exhibited significant wound healing effects on Wistar albino rats’ excisional wounds and improved the overall tensile strength. The results suggest that BFLE has strong wound healing properties, as demonstrated by its ability to increase keratinocytes and fibroblasts proliferation and migration, upregulate genes and proteins involved in the wound healing process, and improve wound healing rates and tensile strength. The findings of this study provide important insights into the potential use of B. frutescens as a natural wound healing agent.

蛇麻草(Baeckea frutescens L.)传统上用于治疗蛇咬伤,具有止痛和止血的功效。这些特性与伤口愈合密切相关。本研究旨在评估 B. frutescens 叶提取物(BFLE)在体外和体内的伤口愈合特性。体外研究的重点是增殖、迁移以及 TGF-β、IL-1β、VEGF 和 MMP-2 基因和蛋白的表达。体内研究包括切除伤口愈合、组织学和拉伸强度研究。研究人员使用角质细胞(HaCaT)和成纤维细胞(BJ)测试了洋二仙草乙醇提取物(BFLE)对增殖和迁移的影响。使用实时 PCR 和 Western 印迹检测分析了与伤口愈合有关的基因和蛋白质表达。使用 Wistar 白化大鼠对 BFLE 的伤口愈合特性进行了体内评估,重点是切除伤口愈合、组织学和拉伸强度研究。BFLE 对角质形成细胞和成纤维细胞具有明显的增殖和迁移作用,同时还能上调 TGF-β、IL-1β、VEGF 和 MMP-2 基因和蛋白的表达。BFLE还对Wistar白化大鼠的切除伤口有明显的愈合作用,并能提高整体抗张强度。结果表明,BFLE 具有很强的伤口愈合能力,它能增加角质细胞和成纤维细胞的增殖和迁移,上调参与伤口愈合过程的基因和蛋白质,提高伤口愈合率和抗张强度。这项研究的结果为研究 B. frutescens 作为天然伤口愈合剂的潜在用途提供了重要启示。
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引用次数: 0
α-Glucosidase, butyrylcholinesterase and acetylcholinesterase inhibitory activities of phenolic compounds from Carthamus tinctorius L. flowers: In silico and in vitro studies 从洋蓟花中提取的酚类化合物对α-葡萄糖苷酶、丁酰胆碱酯酶和乙酰胆碱酯酶的抑制活性:硅学和体外研究
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-16 DOI: 10.1016/j.jsps.2024.102106
Jawaher A.M. Alotaibi , Alaa Sirwi , Ali M. El-Halawany , Ahmed Esmat , Gamal A. Mohamed , Sabrin R.M. Ibrahim , Abdulrahim A. Alzain , Taher F. Halawa , Martin Safo , Hossam M. Abdallah

Chemical investigation of Carthamus tinctorius L. flowers resulted in isolation of seven metabolites that were identified as; p-Hydroxybenzoic acid (1), trans hydroxy cinnamic acid (2), kaempferol-6-C-glucoside (3), astragalin (4), cartormin (5), kaempferol-3-O-rutinoside (6), and kaempferol–3-O-sophoroside (7). Virtual screening of the isolated compounds against human intestinal α-glucosidase, acetylcholinesterase, and butyrylcholinesterase was carried out. Additionally, the antioxidant activity of the bioactive compounds was assessed. Compounds 1 and 5 exhibited moderate binding affinities to acetylcholinesterase (binding energy −5.33 and −4.18 kcal/mol, respectively), compared to donepezil (-83.33kcal/mol). Compounds 17 demonstrated weak affinity to butyrylcholinesterase. Compounds 2 and 4 displayed moderate binding affinity to human intestinal α-glucosidase,compared to Acarbose (reference compound), meanwhile compound 2 exhibited lower affinity. Molecular dynamic studies revealed that compound 4 formed a stable complex with the binding site throughout a 100 ns simulation period. The in-vitro results were consistent with the virtual experimental results, as compounds 1 and 5 showed mild inhibitory effects on acetylcholinesterase (IC50s 150.6 and 168.7 µM, respectively). Compound 4 exhibited moderate α-glucosidase inhibition with an IC50 of 93.71 µM. The bioactive compounds also demonstrated notable antioxidant activity in ABTS [2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)], ORAC (oxygen radical-absorbance capacity), and metal chelation assays, suggesting their potential in improving dementia in Alzheimer’s disease (AD) and mitigating hyperglycemia.

通过对马齿苋花进行化学研究,分离出了七种代谢物,分别是:对羟基苯甲酸(1)、反式羟基肉桂酸(2)、山奈酚-6-C-葡萄糖苷(3)、黄芪苷(4)、软骨素(5)、山奈酚-3-O-芸香糖苷(6)和山奈酚-3-O-槐糖苷(7)。对分离出的化合物进行了针对人体肠道α-葡萄糖苷酶、乙酰胆碱酯酶和丁酰胆碱酯酶的虚拟筛选。此外,还评估了生物活性化合物的抗氧化活性。与多奈哌齐(-83.33 千卡/摩尔)相比,化合物 1 和 5 与乙酰胆碱酯酶的结合亲和力适中(结合能分别为-5.33 和-4.18 千卡/摩尔)。化合物 1-7 与丁酰胆碱酯酶的亲和力较弱。与阿卡波糖(参比化合物)相比,化合物 2 和 4 与人肠道 α-葡萄糖苷酶的结合亲和力适中,而化合物 2 的亲和力较低。分子动力学研究表明,在 100 毫微秒的模拟时间内,化合物 4 与结合位点形成了稳定的复合物。体外实验结果与虚拟实验结果一致,化合物 1 和 5 对乙酰胆碱酯酶有轻微的抑制作用(IC50 分别为 150.6 和 168.7 µM)。化合物 4 对α-葡萄糖苷酶有中度抑制作用,IC50 为 93.71 µM。这些生物活性化合物还在 ABTS [2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] 、ORAC(氧自由基吸收能力)和金属螯合试验中表现出显著的抗氧化活性,表明它们具有改善阿尔茨海默病(AD)痴呆症和缓解高血糖的潜力。
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引用次数: 0
Formulation and evaluation of Fluconazole Nanosuspensions: In vitro characterization and transcorneal permeability studies 氟康唑纳米悬浮剂的制备与评估:体外表征和经角膜渗透性研究
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-16 DOI: 10.1016/j.jsps.2024.102104
Basmah N. Aldosari, Mohamed Abbas Ibrahim, Yara Alqahtani, Amal El Sayeh F. Abou El Ela

The aim in this study was to develop and evaluate a nanofluconazole (FLZ) formulation with increased solubility and permeation rate using nanosuspensions. The FLZ nanosuspensions were stabilized using a variety of stabilizing agents and surfactants in various concentrations. The FLZ nanosuspension was characterized in vitro using particle size, zeta potential, X-ray powder diffraction (XRPD), and solubility. In addition, the ex vivo ocular permeation of FLZ through a goat cornea was analyzed. The results showed that the particle size of all nanosuspension formulations was in the nanometer range from 174.5 ± 1.9 to 720.2 ± 4.77 nm; that of the untreated drug was 18.34 μm. The zeta potential values were acceptable, which indicated suitable stability for formulations. The solubility of the nanosuspensions was up to 5.7-fold higher compared with that of the untreated drug. The results of the ex vivo ocular diffusion of the FLZ nanosuspensions showed the percentage of FLZ penetrating via the goat cornea increased after using Kollicoat to stabilize the nanosuspension formulation. Consequently, when using a nanosuspension formulation of Kollicoat, the antifungal activity of the drug strengthens.

本研究旨在利用纳米悬浮剂开发和评估一种可提高溶解度和渗透率的纳米氟康唑(FLZ)制剂。使用不同浓度的各种稳定剂和表面活性剂稳定了 FLZ 纳米悬浮液。利用粒度、ZETA电位、X射线粉末衍射(XRPD)和溶解度对FLZ纳米悬浮液进行了体外表征。此外,还分析了 FLZ 通过山羊角膜的体内渗透性。结果表明,所有纳米悬浮制剂的粒径都在 174.5 ± 1.9 至 720.2 ± 4.77 nm 的纳米范围内;未处理药物的粒径为 18.34 μm。zeta电位值是可接受的,这表明制剂具有适当的稳定性。纳米悬浮液的溶解度比未经处理的药物高出 5.7 倍。FLZ纳米悬浮剂的体外眼扩散结果表明,使用Kollicoat稳定纳米悬浮剂配方后,FLZ通过山羊角膜渗透的百分比增加了。因此,当使用 Kollicoat 纳米悬浮剂配方时,药物的抗真菌活性会增强。
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引用次数: 0
Diuretic effects of Hecogenin and Hecogenin acetate via aldosterone synthase inhibition 通过抑制醛固酮合成酶发挥海柯吉宁和醋酸海柯吉宁的利尿作用
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-16 DOI: 10.1016/j.jsps.2024.102105
Abdulmohsin J. Alamoudi , Maria Nazeer , Nabi Shah , Saif Ullah , Meshal Alshamrani , Waleed Y. Rizg , Osama M. Ashour , Ashraf B. Abdel-naim , Abdul Jabbar Shah

Hecogenin (HEC) is a steroidal saponin found in many plant species and serves as a precursor for steroidal drugs. The diuretic effects of HEC and its derivative, hecogenin acetate (HA), remain largely unexplored. The present study aimed to explore the potential diuretic effects of HEC and HA compared to furosemide (FUR) and spironolactone (SPIR). Additionally, the study aimed to explore the underlying mechanism particularly focusing on aldosterone synthase gene expression. Fifty-four Sprague-Dawley rats were allocated into nine groups (Group 1–9). Group 1 (control) received the vehicle, Groups 2 received FUR 10 mg/kg, Group 3, 4, and 5 were given HEC, while Groups 6, 7 and 8 received HA i.p at doses of 5, 10, and 25 mg/kg, respectively. Group 9 received SPIR i.p at the dose of 25 mg/kg. Urine volume, diuretic index and diuretic activity were monitored at 1, 2, 3, 4, 5, 6, and 24 h post-administration. Treatment was given daily for seven days. After that, rats were sacrificed and blood was collected for serum electrolytes determination. Adrenal glands were dissected out for gene expression studies. The results revealed that HEC and HA at the administered doses significantly and dose-dependently increased urine and electrolyte excretion. These results were primarily observed at 25 mg/kg of each compound. Gene expression studies demonstrated a dose-dependent reduction in aldosterone synthase gene expression, suggesting aldosterone synthesis inhibition as a potential mechanism for their diuretic activity. Notably, HA exhibited more pronounced diuretic effects surpassing those of HEC. This enhanced diuretic activity of HA can be attributed to its stronger impact on aldosterone synthase inhibition. These findings offer valuable insights into the diuretic effects of both HEC and HA along with their underlying molecular mechanisms.

橙皮苷(HEC)是一种甾体皂甙,存在于许多植物物种中,是甾体药物的前体。HEC 及其衍生物乙酸橙皮苷(HA)的利尿作用在很大程度上仍未得到研究。本研究旨在探讨 HEC 和 HA 与呋塞米(FUR)和螺内酯(SPIR)相比的潜在利尿作用。此外,本研究还旨在探索其潜在机制,特别是关注醛固酮合成酶基因的表达。54 只 Sprague-Dawley 大鼠被分为九组(1-9 组)。第 1 组(对照组)接受载体,第 2 组接受 10 毫克/千克的 FUR,第 3、4 和 5 组接受 HEC,而第 6、7 和 8 组接受 HA,剂量分别为 5、10 和 25 毫克/千克。第 9 组静脉注射 SPIR,剂量为 25 毫克/千克。在给药后 1、2、3、4、5、6 和 24 小时监测尿量、利尿指数和利尿活性。每天治疗一次,连续七天。之后,大鼠被处死,采血测定血清电解质。解剖肾上腺进行基因表达研究。研究结果表明,在给药剂量下,HEC 和 HA 能显著增加尿液和电解质的排泄量,且呈剂量依赖性。这些结果主要是在每种化合物的剂量为 25 毫克/千克时观察到的。基因表达研究表明,醛固酮合成酶基因表达的减少与剂量有关,这表明抑制醛固酮合成是这两种化合物具有利尿活性的潜在机制。值得注意的是,HA 的利尿作用比 HEC 更明显。HA 的这种增强的利尿活性可归因于其对醛固酮合成酶更强的抑制作用。这些发现为了解 HEC 和 HA 的利尿作用及其潜在的分子机制提供了宝贵的见解。
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引用次数: 0
Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling P2X7 受体拮抗剂 A740003 对急性心肌梗死引起的纤维重塑的抗纤维化作用
IF 4.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-16 DOI: 10.1016/j.jsps.2024.102102
Noura Almusallam , Asma Alonazi , Anfal Bin Dayel , Abdullah Almubarak , Rizwan Ali , Wajd Althakfi , Rehab Ali , Nouf Alrasheed

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-β (TGF-β). AMI is associated with a substantial increase in the levels of extracellular adenosine triphosphate (eATP), which acts on the purinergic P2X7-receptor (P2X7-R) and triggers an inflammatory response that contributes to myocardial fibrotic remodelling. P2X7-R has been implicated in several cardiovascular diseases; however, its role in the regulation of cardiac fibrosis remains unclear. Therefore, the current study aimed to determine the effect of the P2X7-R antagonist, A740003, on post-AMI fibrosis, via the profibrotic TGF-β1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3β. AMI was induced by surgical ligation of the left anterior descending coronary artery, Thereafter, animals were divided into groups: sham control, MI-untreated, MI-vehicle, and MI-A740003 (50 mg/kg/day) and treated for seven days accordingly. The heart weight/body weight ratio of untreated-ligated rats significantly increased by 15.1 %, creatine kinase‐MB (CK‐MB) significantly increased by 40 %, troponin‐I levels significantly increased by 25.4 %, and lactate dehydrogenase significantly increased by 47.2 %, indicating myocardial damage confirmed by morphological changes and massive cardiac fibrosis. The protein expression of cardiac fibronectin, TGF-β1, and p-Smad2 were also upregulated by 143 %, 40 %, and 8 %, respectively, indicating cardiac fibrosis. The treatment of ligated rats with A740003 led to improvement in all the above-mentioned parameters. Overall, A740003 exhibits potential cardio-protective effects on post-AMI fibrotic remodelling in the animal model of AMI through P2X7-R blockade, possibly by downregulating the profibrotic TGF-β1/Smad signalling pathway and restoring GSK-3β phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

急性心肌梗塞(AMI)后纤维化是一种病理生理过程,其特点是促纤维化介质转化生长因子-β(TGF-β)被激活。急性心肌梗死与细胞外三磷酸腺苷(eATP)水平的大幅上升有关,eATP 作用于嘌呤能 P2X7-受体(P2X7-R),引发炎症反应,导致心肌纤维重塑。P2X7-R 与多种心血管疾病有关,但它在心肌纤维化调控中的作用仍不清楚。因此,本研究旨在确定 P2X7-R 拮抗剂 A740003 通过促纤维化 TGF-β1/Smad 信号通路对 AMI 后纤维化的影响,并阐明其作用是否通过调节 GSK-3β 介导。通过手术结扎左前降支冠状动脉诱发急性心肌梗死,然后将动物分为假对照组、心肌梗死未处理组、心肌梗死车辆组和 MI-A740003(50 毫克/千克/天)组,并相应处理七天。结果显示,未经治疗的结扎大鼠的心脏重量/体重比显著增加了 15.1%,肌酸激酶-MB(CK-MB)显著增加了 40%,肌钙蛋白-I 水平显著增加了 25.4%,乳酸脱氢酶显著增加了 47.2%,形态学变化和大量心肌纤维化证实了心肌损伤。心脏纤连蛋白、TGF-β1 和 p-Smad2 蛋白表达也分别上调了 143%、40% 和 8%,表明心脏纤维化。用 A740003 治疗结扎大鼠可改善上述所有参数。总之,A740003 通过阻断 P2X7-R 对急性心肌梗死动物模型的急性心肌梗死后纤维重塑具有潜在的心脏保护作用,这可能是通过下调促纤维化 TGF-β1/Smad 信号通路和恢复 GSK-3β 磷酸化实现的。总之,使用 A740003 治疗可作为一种新的心脏保护策略,以减轻急性心肌梗死后的纤维重塑。
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Saudi Pharmaceutical Journal
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