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The Role of Dapagliflozin in the Modulation of Hypothermia and Renal Injury Caused by Septic Shock in Euglycemic and Hyperglycemic Rat Models. 达格列净在正常血糖和高血糖大鼠模型中对脓毒性休克引起的低温和肾损伤的调节作用。
Pub Date : 2024-01-01 DOI: 10.2174/0118761429329635241016054513
Wael A Alanazi, Turki Alharbi, Khalid M Bin Anzan, Musab K Alyahiya, Doaa M El-Nagar, Mohammed M Alanazi, Mohammed M Almutairi, Hussain N Alhamami, Abdullah M Albogami, Mohamed Mohany

Background: Recent research has validated the efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in reducing glucose levels and exerting a nephroprotective role.

Objective: This study aimed to examine the impact of dapagliflozin in preventing sepsis-induced acute kidney injury (AKI) and related consequences. The study used both normal and diabetic rat models to investigate whether the effectiveness of dapagliflozin is influenced by glycemia levels.

Methods: Normal and diabetic Wistar albino rats were treated with dapagliflozin for two weeks and then received a single dose of lipopolysaccharide (LPS). After sepsis induction, skin and deep body temperatures were recorded every two hours. Blood and kidneys were collected for analysis using histological examination and biochemical assays.

Results: Dapagliflozin attenuated the consequences of sepsis through mitigation of LPS-induced hypothermia and AKI in the normal and diabetic septic groups. Dapagliflozin regulated the serum levels of AKI markers, including creatinine and blood urea nitrogen, as well as ion levels. Dapagliflozin attenuated LPS-induced AKI through modulation of renal inflammation and oxidative stress, which showed well-abundant glomeruli. These results indicated the protective effect of dapagliflozin against LPS-induced hypothermia and AKI, which was likely unrelated to its glucose-lowering properties, as evidenced in the non-diabetic septic group.

Conclusion: The outcomes suggest that dapagliflozin has a potential impact in preventing sepsis-induced hypothermia and AKI via modulation of inflammation and oxidative stress, irrespective of glycemic levels.

背景:最近的研究证实了钠-葡萄糖共转运蛋白-2抑制剂(SGLT2i)在降低血糖水平和发挥肾保护作用方面的有效性。目的:本研究旨在探讨达格列净在预防脓毒症引起的急性肾损伤(AKI)中的作用及其相关后果。本研究使用正常和糖尿病大鼠模型来研究达格列净的有效性是否受到血糖水平的影响。方法:采用达格列净给药2周后再给予单剂量脂多糖(LPS)。脓毒症诱导后,每2小时记录一次皮肤和体温。采集血液和肾脏进行组织学检查和生化分析。结果:达格列净在正常和糖尿病脓毒症组中通过减轻lps诱导的低温和AKI来减轻脓毒症的后果。达格列净调节AKI标志物的血清水平,包括肌酐和血尿素氮,以及离子水平。达格列净通过调节肾脏炎症和氧化应激来减轻lps诱导的AKI,显示出丰富的肾小球。这些结果表明,达格列净对lps诱导的低温和AKI具有保护作用,这可能与其降血糖特性无关,正如在非糖尿病性败血症组中所证明的那样。结论:结果表明,不管血糖水平如何,达格列净通过调节炎症和氧化应激,在预防败血症性低体温和AKI方面具有潜在的影响。
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引用次数: 0
Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease. 砷暴露和淀粉样前体蛋白加工:阿尔茨海默病的焦点。
Pub Date : 2023-10-25 DOI: 10.2174/0118761429272806231020045840
Ravikant Sharma, M D Abubakar, Priya Bisht, Mahesh Rachamalla, Arun Kumar, Krishna Murti, Velayutham Ravichandiran, Nitesh Kumar

Background: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition.

Aims: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease.

Methods: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus.

Description: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by β-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article.

Conclusion: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.

背景:在世界各地,地下水、土壤和食品中的砷含量都超过了允许的安全限值。这增加了对人类的接触,并以各种方式影响健康。认知的改变就是其中之一。流行病学研究以认知能力下降的形式反映了砷暴露对儿童的影响。目的:考虑到这一事实,本研究综述了砷对淀粉样蛋白前体蛋白的影响,淀粉样蛋白是已知的最常见的认知障碍之一,如阿尔茨海默病。方法:本研究通过Pubmed和Scopus发表的文章回顾了砷在导致阿尔茨海默病的前体淀粉样蛋白β生成中的作用,这与认知障碍有关。砷还通过增加RAGE的表达影响血脑屏障清除途径。砷通过增加APP的表达,随后通过β-分泌酶和早老素对其进行处理,从而触发促糜蛋白酶生成途径。砷还影响线粒体动力学、DNA修复途径和表观遗传学变化。本综述文章解释了所有这些变化背后的机制。结论:砷暴露水平升高会影响淀粉样蛋白前体蛋白,这是阿尔茨海默病早期沉淀的一个因素。
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引用次数: 0
All-trans Retinoic Acid Increased Transglutaminase 2 Expressions in BV-2 Cells and Cultured Astrocytes. 全反式维甲酸增加了BV-2细胞和培养的星形胶质细胞中转谷氨酰胺酶2的表达。
Pub Date : 2023-10-24 DOI: 10.2174/0118761429254388230922112915
Katsura Takano-Kawabe, Tatsuhiko Izumo, Tomoki Minamihata Minamihata, Mitsuaki Moriyama

Background: Activation of microglia and astrocytes has been observed in Alzheimer's disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.

Objective: We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.

Methods: After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.

Results: In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.

Conclusion: These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.

背景:在阿尔茨海默病(AD)中观察到小胶质细胞和星形胶质细胞的活化。据报道,转谷氨酰胺酶2(TG2)在AD中被激活,并参与细胞增殖、分化和炎症。此外,淀粉样蛋白β(Aβ)聚集被检测为AD大脑的一种特征性病理,并且已知是TG2的底物。全反式维甲酸(ATRA)可以改变细胞增殖和分化,据报道对AD病理有治疗作用。目的:我们旨在评估小胶质细胞和星形胶质细胞中ATRA对TG2表达和神经胶质功能的影响。方法:用ATRA处理后,测定小鼠小胶质细胞BV-2细胞和培养的大鼠脑星形胶质细胞中TG2的表达和TG活性。还评估了BV-2细胞的内分泌活性和星形胶质细胞条件培养基对Aβ的聚集。结果:在BV-2细胞和培养的星形胶质细胞中,ATRA均增加了TG2的表达和TG活性。这种增加被RA受体拮抗剂AGN194310阻断。ATRA增强了BV-2细胞的内吞活性,AGN194310的加入逆转了这种活性。竞争性TG抑制剂胱胺的加入也降低了ATRA增强的内吞活动。另一方面,与对照星形胶质细胞条件培养基相比,ATRA处理的星形胶质细胞培养基增强了Aβ聚集。结论:ATRA通过RA受体增加小胶质细胞和星形胶质细胞中TG2的表达和TG活性。ATRA增强的TGs可能参与吞噬和Aβ聚集。对小胶质细胞和星形胶质细胞中TGs表达和功能的充分控制可能是AD病理的一个重要因素。
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引用次数: 0
SGLT2 Inhibitors and Diabetic Kidney Disease: Targeting Multiple and Interrelated Signaling Pathways for Renal Protection. SGLT2抑制剂与糖尿病肾病:针对肾脏保护的多种和相关信号通路。
Pub Date : 2023-10-23 DOI: 10.2174/0118761429261105231011101200
Georgios Papaetis

Almost 20-40% of all patients suffering from diabetes mellitus experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). The implication of several pathophysiological mechanisms (hemodynamic, tubular, metabolic and inflammatory) in the pathogenesis of diabetic kidney disease generates an urgent need to develop multitarget therapeutic strategies to face its development and progression. SGLT2 inhibitors are undoubtedly a practice-changing drug class for individuals who experience type 2 diabetes and diabetic kidney disease. In vitro studies, exploratory research, sub-analyses of large randomized controlled trials, and investigation of several biomarkers have demonstrated that SGLT2 inhibitors achieved multiple beneficial activities, targeting several renal cellular and molecular pathways independent of their antihyperglycemic activity. These mainly include the reduction in intraglomerular pressure through the restoration of TGF, impacts on the renin-angiotensin-aldosterone system, improvement of renal hypoxia, adaptive metabolic alterations in substrate use/energy expenditure, improvement of mitochondrial dysfunction, and reduction of inflammation, oxidative stress and fibrosis. This manuscript thoroughly investigates the possible mechanisms that underlie their salutary renal effects in patients with diabetes, focusing on several pathways involved and the interplay between them. It also explores their upcoming role in ameliorating the evolution of chronic kidney disease in patients with diabetes.

几乎20-40%的糖尿病患者患有慢性肾脏疾病,这与较高的死亡率(心血管和全因)有关。糖尿病肾病发病机制中的几种病理生理机制(血液动力学、肾小管、代谢和炎症)的意义迫切需要制定多靶点治疗策略来应对其发展和进展。SGLT2抑制剂无疑是一种改变2型糖尿病和糖尿病肾病患者药物类别的实践。体外研究、探索性研究、大型随机对照试验的亚分析以及对几种生物标志物的研究表明,SGLT2抑制剂具有多种有益活性,靶向几种肾脏细胞和分子途径,与它们的抗高血糖活性无关。这些主要包括通过恢复TGF降低肾小球内压,对肾素-血管紧张素-醛固酮系统的影响,改善肾脏缺氧,底物使用/能量消耗的适应性代谢改变,改善线粒体功能障碍,以及减少炎症、氧化应激和纤维化。这篇手稿深入研究了它们对糖尿病患者有益肾脏影响的可能机制,重点研究了涉及的几种途径及其相互作用。它还探讨了它们在改善糖尿病患者慢性肾脏疾病演变中即将发挥的作用。
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引用次数: 0
Regulating miRNAs Expression by Resveratrol: Novel Insights based on Molecular Mechanism and Strategies for Cancer Therapy. 白藜芦醇调节miRNA表达:基于癌症治疗分子机制和策略的新见解。
Pub Date : 2023-10-23 DOI: 10.2174/0118761429249717230920113227
Atoosa Keshavarzmotamed, Vahide Mousavi, Niloufar Masihipour, Atefe Rahmati, Rohollah Mousavi Dehmordi, Behrooz Ghezelbash, Mina Alimohammadi, Alireza Mafi

Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.

白藜芦醇是一种多酚类植物抗毒素,存在于包括葡萄、浆果和花生在内的多种植物中,是一种经过广泛研究的植物化学物质,具有独特的药理能力,具有影响各种癌症中许多靶点的惊人潜力。白藜芦醇的抗癌活性是由于其靶向参与癌症发病机制的多种细胞和分子机制和关键过程,如促进生长停滞、刺激细胞凋亡、抑制细胞增殖、诱导自噬、调节氧化应激和炎症,以及改善一些其他化学治疗剂的影响。微小RNA(miRNA)是通过降解mRNA或抑制翻译来调节基因表达的非编码RNA。miRNA在广泛的生物学活动中发挥着关键作用,miRNA表达的破坏与癌症的进展密切相关。最近的研究表明,白藜芦醇通过调节miRNA网络具有抗增殖和/或促凋亡特性,从而抑制肿瘤细胞增殖、激活细胞凋亡或提高传统癌症治疗效果。因此,利用白藜芦醇靶向miRNA将是一种独特且潜在的抗癌方法。在此,我们讨论了白藜芦醇调节miRNA表达的主要进展,以及白藜芦醇在不同类型癌症中可能影响的几种miRNA,以及这种天然药物作为癌症治疗中有前途的策略的意义。
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引用次数: 0
Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model. 龙胆苦苷改善DDC诱导的小鼠胆管疾病模型中的导管反应和炎症反应。
Pub Date : 2023-10-19 DOI: 10.2174/0118761429251911231011092145
Juan Hao, Jian Wu, Quanjun Yang, Kan Lu, Yi Xu, Yiyue Chen, Jibo Liu, Xiaohong Shao, Chunling Zhu, Yaqin Ding, Xin Xie

Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.

Objective: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.

Methods: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.

Results: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.

Conclusion: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.

背景:胆管疾病包括一系列没有治疗方法的疾病。基于胆汁酸(BA)代谢调节的药理学治疗代表了治疗胆管疾病的有前景的治疗策略。龙胆苦苷(GPS)来源于中草药龙胆,具有调节胆汁酸代谢和氧化应激的药理作用。目的:本研究旨在探讨GPS对3,5-二乙氧羰基-1,4-二氢吡啶(DDC)诱导的胆管病变的影响。方法:设计两个独立的动物实验来评估GPS对DDC饮食诱导的慢性胆管疾病的综合作用,包括胆管闭塞、导管反应、BA代谢重编程、肝纤维化、氧化应激和炎症反应。结果:在第一个药理学实验中,向喂食DDC饮食的小鼠腹膜内注射三个剂量的GPS(5、25和125mg/kg),持续14天。DDC诱导了典型的导管反应,增加了导管周围纤维化和门区混合炎症细胞浸润。GPS治疗显示出导管反应、BA代谢、纤维化、氧化应激和炎症反应的剂量依赖性改善。在第二个实验中,将高剂量的GPS腹膜内注射到对照小鼠中28天,导致肝功能没有明显的组织学变化和显著的血清学异常。然而,GPS抑制DDC诱导的氧化应激、血清和肝脏BA积累、促炎细胞因子产生和免疫细胞浸润。具体而言,GPS处理组显示单核细胞衍生的巨噬细胞、CD4+和CD8+T淋巴细胞以及保存的库普弗细胞的浸润减少。结论:GPS通过改善导管反应、导管周围纤维化、氧化应激和炎症反应,减轻了DDC饮食诱导的慢性胆管疾病。其剂量依赖性药理作用表明,GPS值得在胆管病的临床试验中进一步评估。
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引用次数: 0
Dual Role of Pregnane X Receptor in Nonalcoholic Fatty Liver Disease. 妊娠X受体在非酒精性脂肪肝中的双重作用。
Pub Date : 2023-10-13 DOI: 10.2174/0118761429259143230927110556
Yuan Xu, Ziming An, Shufei Wang, Yiming Ni, Mingmei Zhou, Qin Feng, Xiaojun Gou, Meiling Xu, Ying Qi

The incidence of nonalcoholic fatty liver disease (NAFLD) has been rising worldwide in parallel with diabetes and metabolic syndrome. NAFLD refers to a spectrum of liver abnormalities with a variable course, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma. Pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a prominent part in the regulation of endogenous metabolic genes in NAFLD. Recent studies have suggested that PXR has therapeutic potential for NAFLD, yet the relationship between PXR and NAFLD remains controversial. In this review, PXR is proposed to play a dual role in the development and progression of NAFLD. Its activation will aggravate steatosis of the liver, reduce inflammatory response, and prevent liver fibrosis. In addition, the interactions between PXR, substance metabolism, inflammation, fibrosis, and gut microbiota in non-alcoholic fatty liver were elucidated. Due to limited therapeutic options, a better understanding of the contribution of PXR to the pathogenesis of NAFLD should facilitate the design of innovative drugs targeting NAFLD.

非酒精性脂肪肝(NAFLD)的发病率在全球范围内与糖尿病和代谢综合征同时上升。NAFLD是指一系列具有可变病程的肝脏异常,从非酒精性脂肪肝(NAFL)到非酒精性脂性肝炎(NASH),最终导致肝硬化和肝细胞癌。孕X受体(PXR)是核受体超家族的一员,在NAFLD内源性代谢基因的调节中发挥着重要作用。最近的研究表明PXR对NAFLD具有治疗潜力,但PXR与NAFLD之间的关系仍存在争议。在这篇综述中,PXR被认为在NAFLD的发展和进展中发挥双重作用。它的激活会加重肝脏的脂肪变性,减少炎症反应,防止肝纤维化。此外,还阐明了非酒精性脂肪肝中PXR、物质代谢、炎症、纤维化和肠道微生物群之间的相互作用。由于治疗选择有限,更好地了解PXR对NAFLD发病机制的贡献应该有助于设计针对NAFLD的创新药物。
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引用次数: 0
Current strategies for the management of psoriasis with potential pharmacological pathways using herbals and immuno-biologicals. 使用草药和免疫生物制剂治疗银屑病的当前策略,具有潜在的药理学途径。
Pub Date : 2023-09-15 DOI: 10.2174/1874467217666230915125613
Kiran Singh Sharma, Sumit Kumar

Background: Psoriasis is an acute to chronic multifunctional inflammatory skin disorder mediated through T-cell activation, dendritic cell intervention, local vascular variations, atypical keratinocyte proliferation, and neutrophil activation, leading to a skin disorder with no permanent cure.

Objective: This review aims to find a potent, secure, and dependable medication, with a more scientific examination of herbal resources and recent targeted immunobiological therapies.

Method: Reports evaluating the effectiveness of biologics & herbal remedies for the topical therapy of psoriasis against control therapies were taken into consideration (placebo or active therapy). The work examined cellular circuits involved in inflammation with its immunogenetic mechanism behind various options available for treating psoriasis in addition to the role of agents inducing psoriasis.

Results: The extent of psoriasis can range from small, localized spots to total body coverage, and it can happen at any stage of life. Several theories exist for clarification however, the exact cause of psoriasis is not entirely understood. Researchers have discovered genetic loci linkages, environmental changes, drug induction, lifestyle conditions, some infections, etc. resulting in this disorder. There are numerous known conventional medical treatments for psoriasis, ranging from topical and systemic medicines to phototherapy or combinations of both with recent immunobiological treatment. However, the majority of these treatments are ineffective and have a variety of side effects that limit their long-term usage, such as cutaneous atrophy, tissue toxicity, mutagenicity, and immunosuppression.

Conclusion: Herbal extracts or isolated compounds can be considered as a substitute for conventional psoriasis treatment. Unfortunately, many investigations often provide a small amount of facts about the safety and effectiveness of topically applied herbal remedies for the treatment of psoriasis. Thus, further factual evidences and validations are needed to promote herbal options, which must be supported by rigorous animal studies or clinical trials using standardised materials and compositions.

背景:银屑病是一种急性至慢性多功能炎症性皮肤病,通过T细胞活化、树突状细胞干预、局部血管变异、非典型角质形成细胞增殖和中性粒细胞活化介导,导致无法永久治愈的皮肤病。目的:本综述旨在寻找一种有效、安全、可靠的药物,对草药资源和最近的靶向免疫生物疗法进行更科学的检查。方法:将评估银屑病局部治疗的生物制剂和草药与对照疗法(安慰剂或活性疗法)的有效性的报告纳入考虑范围。这项工作检查了参与炎症的细胞回路及其免疫遗传机制,这些机制除了诱导银屑病的药物的作用外,还包括治疗银屑病的各种选择。结果:银屑病的范围从小的局部斑点到全身覆盖,它可以发生在生命的任何阶段。有几个理论需要澄清,然而,银屑病的确切原因还不完全清楚。研究人员发现了导致这种疾病的遗传基因座联系、环境变化、药物诱导、生活方式条件、一些感染等。银屑病有许多已知的传统医学治疗方法,从局部和全身药物到光疗,或两者与最近的免疫生物学治疗相结合。然而,这些治疗方法大多无效,并有各种副作用,限制了它们的长期使用,如皮肤萎缩、组织毒性、致突变性和免疫抑制。结论:中药提取物或分离的化合物可作为传统银屑病治疗的替代品。不幸的是,许多研究往往提供了少量关于局部应用草药治疗银屑病的安全性和有效性的事实。因此,需要进一步的事实证据和验证来推广草药选择,这必须得到严格的动物研究或使用标准化材料和成分的临床试验的支持。
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引用次数: 0
PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway. PF-04449913通过ERK/p65途径下调MMP9的表达,抑制大肠癌癌症细胞的增殖和转移。
Pub Date : 2023-09-15 DOI: 10.2174/1874467217666230915125622
Yejiao Ruan, Guangrong Lu, Yaojun Yu, Yue Luo, Hao Wu, Yating Shen, Zejun Gao, Yao Shen, Zhenzhai Cai, Liyi Li

Introduction: Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed.

Method: In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression.

Results: Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression.

Conclusion: Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

简介:癌症结直肠癌仍然是一种危及生命的恶性肿瘤,其发病率和死亡率在全球范围内不断上升。因此,迫切需要新的、有效的抗结直肠癌癌症治疗方法。方法:本研究对PF-04449913的抗肿瘤特性及潜在机制进行了研究。PF-04449913以剂量依赖性方式降低了结直肠癌癌症细胞的活力。Transwell试验表明,该药物减弱了恶性结肠细胞的迁移和侵袭能力。此外,PF-04449913抑制ERK和其他蛋白质的磷酸化水平以及MMP9的表达水平。在BALB/c裸鼠模型中证实了该药物的体内抗肿瘤作用,PF-04449913抑制了结直肠癌癌症细胞的恶性表型,包括缩小肿瘤大小和促进细胞凋亡。在分子水平上,PF-04449913诱导ERK和p65蛋白磷酸化水平显著降低,并抑制MMP9蛋白表达。结果:体内和体外结果均显示PF-04449913具有抗肿瘤作用,这被认为是通过阻断ERK/p65信号通路和随后抑制MMP9表达来介导的。结论:本研究为PF-04449913在大肠癌治疗中的潜在临床应用提供了新的视角。
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Current molecular pharmacology
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