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Antibody drug conjugates as targeted cancer therapy: past development, present challenges and future opportunities 抗体药物偶联物作为靶向癌症治疗:过去的发展,目前的挑战和未来的机遇
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-04-18 DOI: 10.1007/s12272-023-01447-0
Ritwik Maiti, Bhumika Patel, Nrupesh Patel, Mehul Patel, Alkesh Patel, Nirav Dhanesha

Antibody drug conjugates (ADCs) are promising cancer therapeutics with minimal toxicity as compared to small cytotoxic molecules alone and have shown the evidence to overcome resistance against tumor and prevent relapse of cancer. The ADC has a potential to change the paradigm of cancer chemotherapeutic treatment. At present, 13 ADCs have been approved by USFDA for the treatment of various types of solid tumor and haematological malignancies. This review covers the three structural components of an ADC—antibody, linker, and cytotoxic payload—along with their respective structure, chemistry, mechanism of action, and influence on the activity of ADCs. It covers comprehensive insight on structural role of linker towards efficacy, stability & toxicity of ADCs, different types of linkers & various conjugation techniques. A brief overview of various analytical techniques used for the qualitative and quantitative analysis of ADC is summarized. The current challenges of ADCs, such as heterogeneity, bystander effect, protein aggregation, inefficient internalization or poor penetration into tumor cells, narrow therapeutic index, emergence of resistance, etc., are outlined along with recent advances and future opportunities for the development of more promising next-generation ADCs.

抗体药物偶联物(adc)是一种很有前景的癌症治疗药物,与单独的小细胞毒性分子相比,它的毒性很小,并且已经显示出克服肿瘤耐药性和防止癌症复发的证据。ADC有可能改变癌症化疗治疗的模式。目前,已有13种adc被美国fda批准用于治疗各种类型的实体瘤和血液系统恶性肿瘤。本文综述了adc的三种结构成分——抗体、连接体和细胞毒性有效载荷,以及它们各自的结构、化学、作用机制和对adc活性的影响。它涵盖了对连接器在功效,稳定性和amp方面的结构作用的全面见解;adc、不同类型连接器的毒性;各种共轭技术。简要概述了用于ADC定性和定量分析的各种分析技术。本文概述了adc目前面临的挑战,如异质性、旁观者效应、蛋白质聚集、肿瘤细胞内化效率低或渗透能力差、治疗指数窄、耐药性的出现等,以及更有前景的下一代adc的最新进展和未来发展机遇。
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引用次数: 2
Phytochemistry and pharmacology of natural prenylated flavonoids 天然烯丙基黄酮的植物化学和药理学研究
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-04-14 DOI: 10.1007/s12272-023-01443-4
Hua-Wei Lv, Qiao-Liang Wang, Meng Luo, Meng-Di Zhu, Hui-Min Liang, Wen-Jing Li, Hai Cai, Zhong-Bo Zhou, Hong Wang, Sheng-Qiang Tong, Xing-Nuo Li

Prenylated flavonoids are a special kind of flavonoid derivative possessing one or more prenyl groups in the parent nucleus of the flavonoid. The presence of the prenyl side chain enriched the structural diversity of flavonoids and increased their bioactivity and bioavailability. Prenylated flavonoids show a wide range of biological activities, such as anti-cancer, anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, cardioprotective effects, and anti-osteoclastogenic activities. In recent years, many compounds with significant activity have been discovered with the continuous excavation of the medicinal value of prenylated flavonoids, and have attracted the extensive attention of pharmacologists. This review summarizes recent progress on research into natural active prenylated flavonoids to promote new discoveries of their medicinal value.

烯丙基化类黄酮是一类特殊的类黄酮衍生物,在类黄酮的母核中含有一个或多个烯丙基。烯丙基侧链的存在丰富了黄酮类化合物的结构多样性,提高了其生物活性和生物利用度。烯丙基黄酮类化合物具有广泛的生物活性,如抗癌、抗炎、神经保护、抗糖尿病、抗肥胖、心脏保护和抗破骨细胞活性等。近年来,随着对烯酰化类黄酮药用价值的不断挖掘,发现了许多具有显著活性的化合物,引起了药理学家的广泛关注。本文综述了近年来天然活性戊烯酸类黄酮的研究进展,以期促进其药用价值的新发现。
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引用次数: 5
Aspergillus co-cultures: A recent insight into their secondary metabolites and microbial interactions 曲霉共培养:对其次生代谢物和微生物相互作用的最新见解
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-04-10 DOI: 10.1007/s12272-023-01442-5
Abdullah Alanzi, Esraa A. Elhawary, Mohamed L. Ashour, Ashaimaa Y. Moussa

There is an urgent need for novel antibiotics to combat emerging resistant microbial strains. One of the most pressing resources is Aspergillus microbial cocultures. The genome of Aspergillus species comprises a far larger number of novel gene clusters than previously expected, and novel strategies and approaches are essential to exploit this potential source of new drugs and pharmacological agents. This is the first review consulting recent developments and chemical diversity of Aspergillus cocultures and highlighting its untapped richness. The analyzed data revealed that cocultivation of several Aspergillus species with other microorganisms, including bacteria, plants, and fungi, is a source of novel bioactive natural products. Various vital chemical skeleton leads were newly produced or augmented in Aspergillus cocultures, among which were taxol, cytochalasans, notamides, pentapeptides, silibinin, and allianthrones. The possibility of mycotoxin production or complete elimination in cocultivations was detected, which pave the way for better decontamination strategies. Most cocultures revealed a remarkable improvement in their antimicrobial or cytotoxic behavior due to their produced chemical patterns; for instance, weldone and asperterrin whose antitumor and antibacterial activities, respectively, were superior. Microbial cocultivation elicited the upregulation or production of specific metabolites whose importance and significance are yet to be revealed. With more than 155 compounds isolated from Aspergillus cocultures in the last 10 years, showing overproduction, reduction, or complete suppression under the optimized coculture circumstances, this study filled a gap for medicinal chemists searching for new lead sources or bioactive molecules as anticancer agents or antimicrobials.

迫切需要新的抗生素来对抗新出现的耐药微生物菌株。其中最紧迫的资源是曲霉微生物共培养。曲霉物种的基因组包含的新基因簇的数量比以前预期的要多得多,新的策略和方法对于开发这一潜在的新药和药理学制剂至关重要。这是第一次回顾了曲霉共培养物的最新发展和化学多样性,并强调了其未开发的丰富性。分析数据表明,几种曲霉与其他微生物(包括细菌、植物和真菌)共培养是新型生物活性天然产物的来源。在曲霉共培养过程中新产生或增加了多种重要的化学骨架引线,其中包括紫杉醇、细胞chalasans、notamides、五肽、水飞蓟宾和联胺。在共培养中检测到霉菌毒素产生或完全消除的可能性,这为更好的去污染策略铺平了道路。大多数共培养由于其产生的化学模式而显示出其抗菌或细胞毒性行为的显著改善;例如,weldone和asperterrin分别具有较好的抗肿瘤和抗菌活性。微生物共培养引起了特定代谢物的上调或产生,其重要性和意义尚未揭示。近10年来,从曲霉共培养中分离出的化合物超过155种,在优化的共培养环境下表现出过量生产、减少或完全抑制,填补了药物化学家寻找新的铅源或生物活性分子作为抗癌剂或抗菌剂的空白。
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引用次数: 1
Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway 二甲双胍通过激活AMPK/PPARα通路减轻肥胖胰岛素抵抗大鼠的肾功能障碍
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-26 DOI: 10.1007/s12272-023-01439-0
Laongdao Thongnak, Nattavadee Pengrattanachot, Sasivimon Promsan, Nichakorn Phengpol, Prempree Sutthasupha, Krit Jaikumkao, Anusorn Lungkaphin

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

胰岛素信号和脂质代谢被长期高脂肪饮食(HFD)所破坏。由于amp活化的蛋白激酶(AMPK)和过氧化物酶体增殖物活化受体-α (PPARα)或AMPK/PPARα途径失活,这种破坏可导致胰岛素抵抗、血脂异常和随后的肾功能障碍。在HFD诱导的胰岛素抵抗大鼠中,我们研究了二甲双胍通过调节ampk调节的ppar α依赖通路来预防肾功能障碍的影响。雄性Wistar大鼠喂HFD 16周诱导胰岛素抵抗。确诊胰岛素抵抗后,给予二甲双胍(30mg /kg)或吉非齐尔(50mg /kg)口服8周。在HF大鼠中观察到胰岛素抵抗、血脂异常、脂质积累和肾损伤的证据。心衰大鼠的脂质氧化、能量代谢和肾有机阴离子转运蛋白3 (Oat3)的表达和功能受到损害。二甲双胍可以刺激AMPK/PPARα通路,抑制甾醇调节元件结合转录因子1 (SREBP1)和脂肪酸合成酶(FAS)信号通路(SREBP1/FAS),从而调控脂质代谢。二甲双胍治疗比吉非齐治疗更有效地降低了HFD诱导的肾脏炎症标志物和肾纤维化表达。有趣的是,在二甲双胍和吉非齐治疗后,肾脏Oat3功能和表达以及肾损伤得到改善。在二甲双胍或吉非齐治疗后,肾分化簇36 (CD36)或葡萄糖钠共转运蛋白2型(SGLT2)的表达没有差异。二甲双胍和吉非齐尔可以通过AMPK/ ppar α依赖途径减轻HFD诱导的肥胖肾损伤的损害。有趣的是,通过ampk调控的SREBP1/FAS信号通路,二甲双胍在减轻肾脂毒性方面比吉非罗吉更有效。
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引用次数: 0
The function, mechanisms, and clinical applications of metformin: potential drug, unlimited potentials 二甲双胍的作用、作用机制及临床应用:潜力药物,潜力无限
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-24 DOI: 10.1007/s12272-023-01445-2
Jianhong Liu, Ming Zhang, Dan Deng, Xiao Zhu

Metformin has been used clinically for more than 60 years. As time goes by, more and more miraculous effects of metformin beyond the clinic have been discovered and discussed. In addition to the clinically approved hypoglycemic effect, it also has a positive metabolic regulation effect on the human body that cannot be ignored. Such as anti-cancer, anti-aging, brain repair, cardiovascular protection, gastrointestinal regulation, hair growth and inhibition of thyroid nodules, and other nonclinical effects. Metformin affects almost the entire body in the situation taking it over a long period, and the preventive effects of metformin in addition to treating diabetes are also beginning to be recommended in some guidelines. This review is mainly composed of four parts: the development history of metformin, the progress of clinical efficacy, the nonclinical efficacy of metformin, and the consideration and prospect of its application.

二甲双胍在临床上已经使用了60多年。随着时间的推移,越来越多的二甲双胍在临床之外的奇效被发现和讨论。除了临床认可的降糖作用外,它对人体还有不可忽视的正向代谢调节作用。如抗癌、抗衰老、脑修复、心血管保护、胃肠调节、毛发生长和抑制甲状腺结节等非临床作用。在长期服用二甲双胍的情况下,二甲双胍几乎影响到整个身体,并且除了治疗糖尿病外,二甲双胍的预防作用也开始在一些指南中被推荐。本文主要由四部分组成:二甲双胍的发展历史、临床疗效进展、二甲双胍的非临床疗效、二甲双胍应用的思考与展望。
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引用次数: 2
Regulation of NOX/p38 MAPK/PPARα pathways and miR-155 expression by boswellic acids reduces hepatic injury in experimentally-induced alcoholic liver disease mouse model: novel mechanistic insight 乳香酸调节NOX/p38 MAPK/PPARα通路和miR-155表达减轻实验性酒精性肝病小鼠模型中的肝损伤:新的机制见解
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-23 DOI: 10.1007/s12272-023-01441-6
Rania M. Salama, Samah S. Abbas, Samar F. Darwish, Al Aliaa Sallam, Noura F. Elmongy, Sara A. El Wakeel

Alcoholic liver disease (ALD) refers to hepatic ailments induced by excessive alcohol intake. The pathogenesis of ALD comprises a complex interplay between various mechanistic pathways, among which inflammation and oxidative stress are key players. Boswellic acids (BAs), found in Boswellia serrata, have shown hepatoprotective effects owing to their antioxidant and anti-inflammatory activities, nevertheless, their therapeutic potential against ALD has not been previously investigated. Hence, this study was performed to depict the possible protective effect of BAs and detect their underlying mechanism of action in an experimentally-induced ALD mouse model. Male BALB/c mice were equally categorized into six groups: control, BAs-treated, ALD, and ALD that received BAs at three-dose levels (125, 250, and 500 mg/kg) by oral gavage for 14 days. Results showed that the high dose of BAs had the most protective impact against ALD according to histopathology examination, blood alcohol concentration (BAC), and liver function enzymes. Mechanistic investigations revealed that BAs (500 mg/kg) caused a significant decrease in cytochrome P450 2E1(CYP2E1), nicotine adenine dinucleotide phosphate oxidase (NOX) 1/2/4, p38 mitogen-activated protein kinase (MAPK), and sterol regulatory element-binding protein-1c (SREBP-1c) levels, and the expression of miR-155, yet increased peroxisome proliferator-activated receptor alpha (PPARα) levels. This led to an improvement in lipid profile and reduced hepatic inflammation, oxidative stress, and apoptosis indices. In summary, our study concludes that BAs can protect against ethanol-induced hepatic injury, via modulating NOX/p38 MAPK/PPARα pathways and miR-155 expression.

酒精性肝病(ALD)是指由过量饮酒引起的肝脏疾病。ALD的发病机制包括各种机制途径之间的复杂相互作用,其中炎症和氧化应激是关键因素。在锯状Boswellia serrata中发现的Boswellic acids(BA)由于其抗氧化和抗炎活性而显示出保肝作用,然而,它们对ALD的治疗潜力此前尚未得到研究。因此,本研究旨在描述BA可能的保护作用,并在实验诱导的ALD小鼠模型中检测其潜在的作用机制。雄性BALB/c小鼠被平等地分为六组:对照组、BA治疗组、ALD组和ALD组,它们通过经口灌胃接受三个剂量水平(125、250和500 mg/kg)的BA,持续14天。结果显示,从组织病理学检查、血液酒精浓度(BAC)和肝功能酶来看,高剂量BA对ALD的保护作用最大。机制研究显示,BA(500 mg/kg)导致细胞色素P450 2E1(CYP2E1)、尼古丁腺嘌呤二核苷酸磷酸氧化酶(NOX)1/2/4、p38丝裂原活化蛋白激酶(MAPK)和固醇调节元件结合蛋白-1c(SREBP-1c)水平显著降低,但过氧化物酶体增殖物激活受体α(PPARα)水平增加。这导致了脂质状况的改善,并减少了肝脏炎症、氧化应激和细胞凋亡指数。总之,我们的研究得出结论,BA可以通过调节NOX/p38 MAPK/PPARα通路和miR-155的表达来预防乙醇诱导的肝损伤。
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引用次数: 5
Low-dose curcumin enhances hippocampal neurogenesis and memory retention in young mice 低剂量姜黄素增强幼鼠海马神经发生和记忆保留
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-22 DOI: 10.1007/s12272-023-01440-7
Yujeong Lee, Hee Ra Park, Joo Yeon Lee, Jaehoon Kim, Seonguk Yang, Chany Lee, Kipom Kim, Hyung Sik Kim, Seung-Cheol Chang, Jaewon Lee

Adult neurogenesis generates new functional neurons from adult neural stem cells in various regions, including the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) of hippocampal dentate gyrus (DG). Available evidence shows hippocampal neurogenesis can be negatively or positively regulated by dietary components. In a previous study, we reported that curcumin (diferuloylmethane; a polyphenolic found in curry spice) stimulates the proliferation of embryonic neural stem cells (NSCs) by activating adaptive cellular stress responses. Here, we investigated whether subchronic administration of curcumin (once daily at 0.4, 2, or 10 mg/kg for 14 days) promotes hippocampal neurogenesis and neurocognitive function in young (5-week-old) mice. Oral administration of low-dose curcumin (0.4 mg/kg) increased the proliferation and survival of newly generated cells in hippocampus, but surprisingly, high-dose curcumin (10 mg/kg) did not effectively upregulate the proliferation or survival of newborn cells. Furthermore, hippocampal BDNF levels and phosphorylated CREB activity were elevated in only low-dose curcumin-treated mice. Passive avoidance testing revealed that low-dose curcumin increased cross-over latency times, indicating enhanced memory retention, and an in vitro study showed that low-concentration curcumin increased the proliferative activity of neural progenitor cells (NPCs) by upregulating NF1X levels. Collectively, our findings suggest that low-dose curcumin has neurogenic effects and that it may prevent age and neurodegenerative disease-related cognitive deficits.

成体神经发生由不同区域的成体神经干细胞产生新的功能神经元,包括侧脑室室下区(SVZ)和海马齿状回(DG)的亚颗粒区(SGZ)。现有证据表明,饮食成分可负或正调节海马神经发生。在之前的研究中,我们报道了姜黄素(异丙基甲烷;一种在咖喱香料中发现的多酚)通过激活适应性细胞应激反应来刺激胚胎神经干细胞(NSCs)的增殖。在这里,我们研究了亚慢性给药姜黄素(每天一次,剂量为0.4、2或10 mg/kg,持续14天)是否能促进幼龄(5周龄)小鼠的海马神经发生和神经认知功能。口服低剂量姜黄素(0.4 mg/kg)可增加海马新生细胞的增殖和存活,但令人惊讶的是,高剂量姜黄素(10 mg/kg)并没有有效上调新生细胞的增殖和存活。此外,仅在低剂量姜黄素处理的小鼠中,海马BDNF水平和磷酸化CREB活性升高。被动回避测试显示,低剂量姜黄素增加了交叉潜伏期,表明记忆保留能力增强,一项体外研究表明,低浓度姜黄素通过上调NF1X水平增加神经祖细胞(npc)的增殖活性。总的来说,我们的研究结果表明,低剂量姜黄素具有神经原性作用,它可能预防年龄和神经退行性疾病相关的认知缺陷。
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引用次数: 0
EGF, a veteran of wound healing: highlights on its mode of action, clinical applications with focus on wound treatment, and recent drug delivery strategies EGF,伤口愈合的老手:重点介绍其作用方式,临床应用,重点是伤口治疗,以及最近的给药策略
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-16 DOI: 10.1007/s12272-023-01444-3
Kanchan Shakhakarmi, Jo-Eun Seo, Shrawani Lamichhane, Chhitij Thapa, Sangkil Lee

Epidermal growth factor (EGF) has been used in wound management and regenerative medicine since the late 1980s. It has been widely utilized for a long time and still is because of its excellent tolerability and efficacy. EGF has many applications in tissue engineering, cancer therapy, lung diseases, gastric ulcers, and wound healing. Nevertheless, its in vivo and during storage stability is a primary concern. This review focuses on the topical use of EGF, especially in chronic wound healing, the emerging use of biomaterials to deliver it, and future research possibilities. To successfully deliver EGF to wounds, a delivery system that is proteolytically resistant and stable over the long term is required. Biomaterials are an area of interest for the development of such systems. These systems may be used in non-healing wounds such as diabetic foot ulcers, pressure ulcers, and burns. In these pathologies, EGF can reduce the risk of amputation of the lower extremities, as it accelerates the wound healing process. Furthermore, appropriate delivery system would also stabilize and control the EGF release profile in a wound. Several in vitro and in vivo studies have already proven the efficacy of such systems in the above-mentioned types of wounds. Moreover, several formulations such as ointments and intralesional injections are already available on the market. However, these products are still problematic in terms of inadequate diffusion of EGF, low bioavailability storage conditions, and shelf-life. This review discusses the nano formulations comprising biomaterials infused with EGF which could be a promising delivery system for chronic wound healing in the future.

表皮生长因子(EGF)自20世纪80年代末以来一直用于伤口管理和再生医学。由于其良好的耐受性和疗效,它已经被广泛应用了很长时间,现在仍然是。EGF在组织工程、癌症治疗、肺部疾病、胃溃疡和伤口愈合等方面有广泛的应用。然而,其在体内和贮存期间的稳定性是一个主要问题。这篇综述的重点是EGF的局部应用,特别是在慢性伤口愈合中的应用,新兴的生物材料的应用,以及未来的研究可能性。为了成功地将EGF输送到伤口,需要一种具有蛋白水解抗性和长期稳定的输送系统。生物材料是开发此类系统的一个感兴趣的领域。这些系统可用于不愈合的伤口,如糖尿病足溃疡、压疮和烧伤。在这些疾病中,EGF可以降低下肢截肢的风险,因为它加速了伤口愈合过程。此外,适当的给药系统也可以稳定和控制EGF在伤口中的释放。一些体外和体内研究已经证明了这种系统在上述类型伤口中的功效。此外,市场上已经有一些配方,如软膏和局部注射。然而,这些产品在表皮生长因子扩散不足、生物利用度低、储存条件和保质期方面仍然存在问题。这篇综述讨论了由生物材料注入EGF组成的纳米配方,它可能是未来慢性伤口愈合的一种有前途的递送系统。
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引用次数: 4
Apocynin abrogates methotrexate-induced nephrotoxicity: role of TLR4/NF-κB-p65/p38-MAPK, IL-6/STAT-3, PPAR-γ, and SIRT1/FOXO3 signaling pathways 罗布麻苷消除甲氨蝶呤诱导的肾毒性:TLR4/NF-κB-p65/p38-MAPK、IL-6/STAT-3、PPAR-γ和SIRT1/FOXO3信号通路的作用
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-13 DOI: 10.1007/s12272-023-01436-3
Emad H. M. Hassanein, Ahmed M. Sayed, Omnia A. M. Abd El-Ghafar, Zainab M. M. Omar, Eman K. Rashwan, Zuhair M. Mohammedsaleh, So Young Kyung, Jae Hyeon Park, Hyung Sik Kim, Fares E. M. Ali

The present study was designed to evaluate the potential renoprotective impacts of apocynin (APC) against nephrotoxicity induced by methotrexate (MTX) administration. To fulfill this aim, rats were allocated into four groups: control; APC (100 mg/kg/day; orally); MTX (20 mg/kg; single intraperitoneal dose at the end of the 5th day of the experiment); and APC +MTX (APC was given orally for 5 days before and 5 days after induction of renal toxicity by MTX). On the 11th day, samples were collected to estimate kidney function biomarkers, oxidative stress, pro-inflammatory cytokines, and other molecular targets. Compared to the MTX control group, treatment with APC significantly decreased urea, creatinine, and KIM-1 levels and improved kidney histological alterations. Furthermore, APC restored oxidant/antioxidant balance, as evidenced by a remarkable alleviation of MDA, GSH, SOD, and MPO levels. Additionally, the iNOS, NO, p-NF-κB-p65, Ace-NF-κB-p65, TLR4, p-p38-MAPK, p-JAK1, and p-STAT-3 expressions were reduced, while the IκBα, PPAR-γ, SIRT1, and FOXO3 expressions were significantly increased. In NRK-52E cells, MTX-induced cytotoxicity was protected by APC in a concentration-dependent manner. In addition, increased expression of p-STAT-3 and p-JAK1/2 levels were reduced in MTX-treated NRK-52E cells by APC. The in vitro experiments revealed that APC-protected MTX-mediated renal tubular epithelial cells were damaged by inhibiting the JAK/STAT3 pathway. Besides, our in vivo and in vitro results were confirmed by predicting computational pharmacology results using molecular docking and network pharmacology analysis. In conclusion, our findings proved that APC could be a good candidate for MTX-induced renal damage due to its strong antioxidative and anti-inflammatory bioactivities.

本研究旨在评估罗布麻苷(APC)对甲氨蝶呤(MTX)引起的肾毒性的潜在保护作用。为了实现这一目标,大鼠被分为四组:对照组;APC (100 mg/kg/天;口头);甲氨蝶呤(20mg /kg;试验第5天末单次腹腔注射);APC +MTX(在MTX诱导肾毒性前5天和后5天口服APC)。第11天,收集样本以评估肾功能生物标志物、氧化应激、促炎细胞因子和其他分子靶标。与MTX对照组相比,APC治疗显著降低尿素、肌酐和KIM-1水平,改善肾脏组织学改变。此外,APC恢复了氧化/抗氧化平衡,MDA、GSH、SOD和MPO水平显著降低。iNOS、NO、p-NF-κB-p65、acenf -κB-p65、TLR4、p-p38-MAPK、p-JAK1、p-STAT-3表达降低,i -κ b α、PPAR-γ、SIRT1、FOXO3表达显著升高。在NRK-52E细胞中,APC以浓度依赖的方式保护mtx诱导的细胞毒性。此外,APC可降低mtx处理的NRK-52E细胞中p-STAT-3和p-JAK1/2表达水平的升高。体外实验显示,apc保护的mtx介导的肾小管上皮细胞通过抑制JAK/STAT3通路而受损。此外,通过分子对接和网络药理学分析预测计算药理学结果,验证了我们的体内和体外结果。综上所述,我们的研究结果表明,由于APC具有很强的抗氧化和抗炎生物活性,因此APC可能是mtx诱导的肾损伤的良好候选者。
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引用次数: 6
Engineered fibrotic liver-targeted truncated transforming growth factor β receptor type II variant for superior anti-liver fibrosis therapy 工程纤维化肝靶向截断转化生长因子β受体II型变异体用于卓越的抗肝纤维化治疗
IF 6.7 3区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2023-03-11 DOI: 10.1007/s12272-023-01435-4
Manman Ma, Xiaohua Wang, Xiaohui Liu, Yang Han, Yanhui Chu, Yanzhong Guan, Haifeng Liu

Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody ZPDGFβR to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.

截断型转化生长因子β受体II (tTβRII)是一种很有前途的抗肝纤维化候选者,因为它通过与野生型TβRII (wtTβRII)竞争,作为结合过量TGF-β1的陷阱。然而,由于其纤维化肝归巢能力差,t - β rii在肝纤维化治疗中的广泛应用受到限制。本文通过将血小板衍生生长因子β受体(PDGFβR)特异性粘附体ZPDGFβR融合到t β rii的n端,设计了一种新的t β rii变体z -t β rii。目的蛋白Z-tTβRII通过大肠杆菌表达系统得到。体外和体内研究表明,Z-tTβRII通过参与pdgf β r-过表达的活化肝星状细胞(aHSCs)在肝纤维化中具有优越的特异性纤维化肝靶向潜力。此外,z - tt -β rii显著抑制细胞迁移和侵袭,下调TGF-β1刺激的HSC-T6细胞的纤维化和TGF-β1/Smad通路相关蛋白水平。此外,z - tt -β rii显著改善ccl4诱导的肝纤维化小鼠的肝脏组织病理学,减轻纤维化反应,阻断TGF-β1/Smad信号通路。更重要的是,z -t - β rii比其亲本t - β rii或前变体BiPPB-t - β rii (pdgf - β r结合肽BiPPB修饰的t - β rii)具有更高的纤维化肝靶向潜力和更强的抗纤维化作用。此外,Z-tTβRII在肝纤维化小鼠的其他重要器官中未显示出明显的潜在副作用迹象。综上所述,我们得出结论,Z-tTβRII具有高纤维化肝归巢潜力,在体外和体内对肝纤维化具有卓越的抗纤维化活性,可能是肝纤维化靶向治疗的潜在候选药物。
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引用次数: 2
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Archives of Pharmacal Research
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