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The Therapeutic Potential of Targeting the Connexin43 as a New Approach to Reducing Post-surgical Adhesion 以 Connexin43 为靶点的治疗潜力是减少手术后粘连的新方法。
Pub Date : 2024-01-01 DOI: 10.2174/0118761429302171240621101944
Alireza Moslem, Rozita Khodashahi, Gordon A Ferns, Mohsen Aliakbarian, Mohammad-Hassan Arjmand

Post-surgical peritoneal adhesions are a serious problem causing complications, such as bowel obstruction, infertility, and pain. There are currently no effective ways of preventing post-surgical adhesions. Excess secretion of proinflammatory cytokines and profibrotic molecules by immune cells and adherent fibroblasts are the main mechanism that promotes post-operative fibrotic scars. Although many studies have been conducted on the pathological causes of this disorder, there are still many unknown facts in this matter, so assessment of the role of different molecules in causing inflammation and adhesion can lead to the creation of new treatment methods. Connexins are a group of proteins related to gap junctions that have a role in cell communication and transmitted signaling between adjacent cells. Between different types of connexin protein isoforms, connexin43 is known to be involved in pathological conditions related to inflammation and fibrosis. Recent studies have reported that inhibition of connexin43 has the potential to reduce inflammation and fibrosis by reducing the expression of molecules like α-SMA and plasminogen activator inhibitor (PAI) that are involved in the early stages of adhesion formation. As well as, inhibition of connexin43 may have therapeutic potential as a target to prevent post-surgical peritoneal adhesions.

手术后腹膜粘连是一个严重的问题,会导致肠梗阻、不孕和疼痛等并发症。目前还没有预防手术后粘连的有效方法。免疫细胞和粘附的成纤维细胞分泌过多的促炎细胞因子和促纤维化分子是导致术后纤维化疤痕的主要机制。尽管已经对这种疾病的病理原因进行了许多研究,但仍有许多未知的事实,因此,评估不同分子在引起炎症和粘连中的作用可有助于创造新的治疗方法。连接蛋白是一组与间隙连接有关的蛋白质,在相邻细胞间的细胞通讯和信号传递中发挥作用。在不同类型的连接蛋白异构体中,已知连接蛋白43参与了与炎症和纤维化相关的病理状况。最近的研究报告称,通过减少参与粘连形成早期阶段的 α-SMA 和纤溶酶原激活物抑制剂(PAI)等分子的表达,抑制 connexin43 有可能减轻炎症和纤维化。此外,作为预防手术后腹膜粘连的靶点,抑制 connexin43 可能具有治疗潜力。
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引用次数: 0
Repair Effect of siRNA Double Silencing of the Novel Mechanically Sensitive Ion Channels Piezo1 and TRPV4 on an Osteoarthritis Rat Model. siRNA双沉默对新型机械敏感离子通道Piezo1和TRPV4在骨关节炎大鼠模型中的修复作用
Pub Date : 2024-01-01 DOI: 10.2174/0118761429317745241017114020
Zhuqing Jia, Jibin Wang, Xiaofei Li, Qining Yang, Jianguo Han

Objective: This study aimed to explore the repair effect of siRNA-mediated double silencing of the mechanically sensitive ion channels Piezo1 and TRPV4 proteins on a rat model of osteoarthritis.

Methods: Piezo1 and TRPV4 interference plasmids were constructed using siRNA technology. Sprague Dawley (SD) rats were divided into four groups: the model group, siRNA-Piezo1, siRNA-TRPV4, and double gene silencing groups. Improved Mankin and OARSI scores were calculated based on H&E staining and Safranin O-fast green staining. Immunohistochemical staining was used to determine expression levels of aggrecan and Collagen II proteins. Piezo1, TRPV4, Aggrecan, and Collagen II mRNA expression in knee joint cartilage tissue were assessed using qRT-PCR.

Results: Lentivirus-mediated siRNA plasmids (siRNA-Piezo1, siRNA-TRPV4, and double-gene siRNA silencing plasmids) achieved > 90% transfection efficiency in chondrocytes. RT-PCR results indicated that double-gene siRNA silencing plasmids silenced Piezo1 and TRPV4 mRNA expression (P < 0.05). Modified Mankin and OARSI scores revealed that the repair effect in the double gene silencing group was significantly better than that of the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05). Relative expression of aggrecan and collagen II mRNA in the double gene-silenced group was significantly higher than in the siRNA-Piezo1 and siRNA-TRPV4 groups (P < 0.05).

Conclusion: Double silencing Piezo1 and TRPV4 plays a key role in cartilage repair in an osteoarthritic rat model by promoting the expression of Aggrecan and Collagen II.

目的:探讨sirna介导的机械敏感离子通道Piezo1和TRPV4蛋白双沉默对骨关节炎大鼠模型的修复作用。方法:采用siRNA技术构建Piezo1和TRPV4干扰质粒。SD大鼠分为模型组、siRNA-Piezo1组、siRNA-TRPV4组和双基因沉默组。根据H&E染色和Safranin O-fast绿色染色计算改善的Mankin和OARSI评分。免疫组织化学染色检测聚集蛋白和II型胶原蛋白的表达水平。采用qRT-PCR检测膝关节软骨组织中Piezo1、TRPV4、Aggrecan和Collagen II mRNA的表达。结果:慢病毒介导的siRNA质粒(siRNA- piezo1、siRNA- trpv4和双基因siRNA沉默质粒)在软骨细胞中的转染效率达到了约90%。RT-PCR结果显示,双基因siRNA沉默质粒沉默了Piezo1和TRPV4 mRNA的表达(P <;0.05)。改良的Mankin和OARSI评分显示,双基因沉默组的修复效果明显优于siRNA-Piezo1和siRNA-TRPV4组(P <;0.05)。双基因沉默组中聚集蛋白和胶原II mRNA的相对表达量显著高于siRNA-Piezo1和siRNA-TRPV4组(P <;0.05)。结论:双沉默Piezo1和TRPV4通过促进Aggrecan和Collagen II的表达,在骨关节炎模型大鼠软骨修复中起关键作用。
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引用次数: 0
RBM3 Inhibits the Cell Cycle of Cutaneous Squamous Cell Carcinoma through the PI3K/AKT Signaling Pathway. RBM3 通过 PI3K/AKT 信号通路抑制皮肤鳞状细胞癌的细胞周期
Pub Date : 2024-01-01 DOI: 10.2174/0118761429323760240712050006
Yan Huang, Weichao Sun, Danli Zhu, Li Liu, Jianguo Feng, Qian Yi

Background: RBM3 is a key RNA-binding protein that has been implicated in various cellular processes, including cell proliferation and cell cycle regulation. However, its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood.

Aims: We aimed to investigate the expression levels of RNA-binding motif protein 3 (RBM3) in patients with cSCC and evaluate its effect on cell ability in cSCC and its underlying regulatory mechanisms.

Methods: The expression of RBM3 in cSCC tissues and A431 cells was determined via immunohistochemistry and western blotting. Plenti-CMV-RBM3- Puro was used to overexpress RBM3. The effect of RBM3 on the proliferation ability of cSCC cells was evaluated using MTT and colony formation assay. Cell apoptosis and cell cycle were determined using flow cytometry, while the protein expressions of BAX, NF-κB, BCL2, CASPASE 3, CYCLIN B, CYCLIN E, CDK1, phosphorylated (P)-CDK1, CDK2, P-CDK2, ERK, P-ERK, P-AMPK, AKT, P-AKT, MDM2, and P53 were assessed using western blotting.

Results: RBM3 expression was significantly downregulated in cSCC tissues and A431 cells. RBM3 overexpression significantly inhibited the cell proliferation and colony formation ability of A431. Notably, RNA-seq results showed that the differentially expressed genes associated with RBM3 were primarily involved in the regulation of the cell cycle, oocyte meiosis, and P53 signaling pathway, as well as the modulation of the MAPK, AMPK, Hippo, mTOR, PI3K/AKT, Wnt, FoxO, and NF-κB signaling pathways. Additionally, our findings demonstrated that overexpression of RBM3 inhibited cell proliferation and induced cell cycle arrest of cSCC through modulation of the PI3K/AKT signaling pathway.

Conclusion: This study provides novel insights into the suppressive roles of RBM3 in cell proliferation and the cell cycle in cSCC and highlights its therapeutic potential for cSCC.

背景:RBM3是一种关键的RNA结合蛋白,与细胞增殖和细胞周期调控等多种细胞过程有关。目的:我们旨在研究 RNA 结合图案蛋白 3(RBM3)在 cSCC 患者中的表达水平,并评估其对 cSCC 细胞能力的影响及其潜在调控机制:方法:通过免疫组化和免疫印迹法检测RBM3在cSCC组织和A431细胞中的表达。采用 Plenti-CMV-RBM3- Puro 超表达 RBM3。使用 MTT 和集落形成试验评估了 RBM3 对 cSCC 细胞增殖能力的影响。流式细胞仪测定细胞凋亡和细胞周期,Western印迹法评估 BAX、NF-κB、BCL2、CASPASE 3、CYCLIN B、CYCLIN E、CDK1、磷酸化(P)-CDK1、CDK2、P-CDK2、ERK、P-ERK、P-AMPK、AKT、P-AKT、MDM2 和 P53 的蛋白表达:结果:RBM3在cSCC组织和A431细胞中的表达明显下调。结果:RBM3 在 cSCC 组织和 A431 细胞中的表达明显下调,RBM3 的过表达明显抑制了 A431 细胞的增殖和集落形成能力。值得注意的是,RNA-seq结果显示,与RBM3相关的差异表达基因主要参与细胞周期、卵母细胞减数分裂和P53信号通路的调控,以及MAPK、AMPK、Hippo、mTOR、PI3K/AKT、Wnt、FoxO和NF-κB信号通路的调控。此外,我们的研究结果表明,过表达RBM3可通过调节PI3K/AKT信号通路抑制cSCC的细胞增殖并诱导细胞周期停滞:本研究为RBM3在cSCC细胞增殖和细胞周期中的抑制作用提供了新的见解,并突出了其治疗cSCC的潜力。
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引用次数: 0
Neuroprotective Potential of Tanshinone-IIA in Mitigating Propionic Acidinduced Experimental Autism-like Behavioral and Neurochemical Alterations: Insights into c-JNK and p38MAPK Pathways 丹参酮-IIA 在减轻丙酸诱导的实验性自闭症样行为和神经化学改变中的神经保护潜力:洞察 c-JNK 和 p38MAPK 通路。
Pub Date : 2024-01-01 DOI: 10.2174/0118761429326799241121104310
Kajal Sherawat, Sidharth Mehan, Zuber Khan, Aarti Tiwari, Ghanshyam Das Gupta, Acharan S Narula

Introduction: Autism is a neurodevelopmental disorder associated with mitochondrial dysfunction, apoptosis, and neuroinflammation. These factors can lead to the overactivation of c-JNK and p38MAPK.

Methods: In rats, stereotactic intracerebroventricular (ICV) injection of propionic acid (PPA) results in autistic-like characteristics such as poor social interaction, repetitive behaviours, and restricted communication. Research has demonstrated the beneficial effects of phytochemicals derived from plants in treating neurological disorders. Tanshinone-IIA (Tan-IIA) is a chemical found in the root of Salvia miltiorrhiza. It has neuroprotective potential by inhibiting c-JNK and p38MAPK against behavioral and neurochemical alterations in PPA-induced autistic rats. We observe behavioral changes, alterations in apoptotic markers, myelin basic protein (MBP), neurofilament-Light (NEFL), inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and neurotransmitter imbalances using different brain regions (cerebral cortex, hippocampus, striatum), as well as biological samples, cerebrospinal fluid (CSF), and blood plasma.

Results: Persistent administration of 30 mg/kg and 60 mg/kg Tan-IIA via intraperitoneal injection reduced these alterations dose-dependently. Anisomycin (3 mg/kg.,i.p.) as a SAPK (c-JNK and p38MAPK) agonist was administered to assess the neuroprotective effect of Tan-IIA in autistic rats. Tan- IIA's molecular interactions with c-JNK and p38MAPK were confirmed using silico analysis. We also observed gross morphological, histopathological, and Luxol Fast Blue (LFB) myelin straining changes in whole and coronal brain sections.

Conclusion: Thus, Tan-IIA has a neuroprotective potential by inhibiting the c-JNK and p38MAPK signalling pathways, which reduces the behavioral and neurochemical abnormalities induced by PPA in adult Wistar rats, indicating that current results should be studied further for the diagnosis and treatment of autism.

简介自闭症是一种神经发育障碍,与线粒体功能障碍、细胞凋亡和神经炎症有关。这些因素可导致 c-JNK 和 p38MAPK 过度激活:大鼠脑室内立体定向注射丙酸(PPA)会导致类似自闭症的特征,如社会交往能力差、行为重复和交流受限。研究表明,从植物中提取的植物化学物质对治疗神经系统疾病有益。丹参酮-IIA(Tan-IIA)是一种存在于丹参根部的化学物质。它通过抑制 c-JNK 和 p38MAPK 来对抗 PPA 诱导的自闭症大鼠的行为和神经化学改变,从而具有神经保护潜力。我们使用不同的脑区(大脑皮层、海马、纹状体)以及生物样本、脑脊液(CSF)和血浆观察行为变化、凋亡标志物、髓鞘碱性蛋白(MBP)、神经丝光(NEFL)、炎症细胞因子、脑源性神经营养因子(BDNF)和神经递质失衡:通过腹腔注射持续给予 30 毫克/千克和 60 毫克/千克 Tan-IIA 可剂量依赖性地减少这些改变。为了评估Tan-IIA对自闭症大鼠神经的保护作用,我们给自闭症大鼠注射了作为SAPK(c-JNK和p38MAPK)激动剂的安妥霉素(3毫克/千克,静注)。Tan- IIA与c-JNK和p38MAPK的分子相互作用已通过硅学分析得到证实。我们还观察了整个脑切片和冠状切片的形态学、组织病理学和Luxol快速蓝(LFB)髓鞘应变:因此,Tan-IIA 通过抑制 c-JNK 和 p38MAPK 信号通路,具有神经保护潜力,可减少 PPA 诱导的成年 Wistar 大鼠行为和神经化学异常。
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引用次数: 0
Short-term Uridine Treatment Alleviates Endoplasmic Reticulum Stress via Regulating Inflammation and Oxidative Stress in Lithium-Pilocarpine Model of Status Epilepticus 通过调节锂-匹罗卡品癫痫状态模型中的炎症和氧化应激,短期尿苷治疗可缓解内质网应激
Pub Date : 2024-01-01 DOI: 10.2174/0118761429315851240909104349
Birnur Aydin, Cansu Koc, Mehmet Cansev, Tülin Alkan

Background: Status Epilepticus (SE) leads to the development of epilepsy with the contribution of Endoplasmic Reticulum (ER) stress. Uridine, a pyrimidine nucleoside, has been shown to have neuroprotective and antiepileptogenic effects in animal models. This study aimed to determine whether uridine ameliorates ER stress and apoptosis following epileptogenic insult. Secondly, this study aimed to establish the effect of uridine on inflammatory and oxidative stress parameters that contribute to ER stress.

Methods: Status epilepticus was induced using lithium-pilocarpine in adult male Sprague-Dawley rats. Following SE termination, rats were treated with uridine, 4-phenylbutyric acid (4-PBA), or saline twice daily for 48 h. Expressions of hippocampal glucose-regulated protein 78 (GRP78), Inositol- Requiring Protein 1 (IRE1α), Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and C/EBP Homologous Protein (CHOP) were determined by western blotting 48 h after SE. Uridine's effects on apoptosis, inflammation or oxidation were evaluated by analyses of cleaved caspase-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein expressions or pro-inflammatory cytokine levels or levels of oxidative stress markers, respectively.

Results: Expressions of all ER stress-related proteins significantly increased 48 h after SE. Uridine treatment markedly decreased GRP78, IRE1α, and CHOP levels. A decrease in the PERK level was observed following the administration of 4-PBA; however, uridine had no effect. Cleaved caspase-3 and PARP1 levels were increased in the SHAM group, while uridine and 4-PBA treatment effectively decreased their expressions. Treatment with uridine significantly reduced Myeloperoxidase (MPO) and Malondialdehyde (MDA) levels while tending to increase Catalase (CAT) and Glutathione Peroxidase (GPx) levels. Uridine treatment also significantly attenuated levels of TNF-α and IL-1β, the pro-inflammatory cytokines, which increased 48 h post-SE.

Conclusion: Our data indicate that uridine alleviates ER stress after SE. This effect may be attributed to the regulation of inflammation and oxidative stress. Uridine shows promise as a potential preventive agent for epilepsy.

背景:癫痫状态(SE)在内质网(ER)应激的作用下导致癫痫的发生。尿苷作为一种嘧啶核苷,已被证明在动物模型中具有神经保护和抗致痫作用。本研究旨在确定尿苷是否能改善致痫损伤后的ER应激和细胞凋亡。其次,本研究旨在确定尿苷对导致ER应激的炎症和氧化应激参数的影响:方法:使用锂-匹罗卡品诱发成年雄性 Sprague-Dawley 大鼠癫痫状态。癫痫状态终止后,大鼠接受尿苷、4-苯基丁酸(4-PBA)或生理盐水治疗,每天两次,持续48小时。癫痫状态48小时后,通过Western印迹法测定海马葡萄糖调节蛋白78(GRP78)、肌醇需要蛋白1(IRE1α)、蛋白激酶RNA样内质网激酶(PERK)和C/EBP同源蛋白(CHOP)的表达。通过分析裂解的caspase-3和聚(ADP-核糖)聚合酶1(PARP1)蛋白的表达、促炎细胞因子水平或氧化应激标记物水平,分别评估尿苷对细胞凋亡、炎症或氧化的影响:结果:所有ER应激相关蛋白的表达在SE 48小时后均显著增加。尿苷治疗明显降低了GRP78、IRE1α和CHOP的水平。施用 4-PBA 后,观察到 PERK 水平下降;但尿苷没有影响。SHAM组中裂解的caspase-3和PARP1水平升高,而尿苷和4-PBA能有效降低它们的表达。尿苷治疗可明显降低髓过氧化物酶(MPO)和丙二醛(MDA)的水平,同时提高过氧化氢酶(CAT)和谷胱甘肽过氧化物酶(GPx)的水平。尿苷治疗还能显著降低 TNF-α 和 IL-1β(促炎细胞因子)的水平:我们的数据表明,尿苷可减轻SE后的ER应激。结论:我们的数据表明,尿苷可减轻 SE 后的 ER 应激,这种作用可能归因于对炎症和氧化应激的调节。尿苷有望成为一种潜在的癫痫预防药物。
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引用次数: 0
Extracts from Artemisia annua Alleviates Myocardial Remodeling through TGF-β1/Smad2/3 Pathway and NLRP3 Inflammasome 青蒿素通过TGF-β1/Smad2/3途径和NLRP3炎症体缓解心肌重塑
Pub Date : 2024-01-01 DOI: 10.2174/0118761429304142240528093541
Zizhe Ma, Zhenzhou Bai, Bohan Li, Yue Zhang, Wei Liu

Background and objectives: Artemisinin and its derivatives, the well-known anti-malarial drugs extracted from traditional Chinese medicine, Artemisia annua, have been implicated in treating fibrotic diseases. However, whether artemisinin affects cardiac fibrosis in the pathogenesis of heart failure is still unknown. This study aimed to evaluate the possible effects of artemisinin on cardiac function and myocardial fibrosis in the heart failure model and to explore the underlying mechanisms.

Methods: Isoproterenol was injected subcutaneously for induction of the cardiac fibrosis model. Proteomic analysis was performed after 4 four weeks of artemisinin treatment. Echocardiography was used to evaluate cardiac function and structure. Hematoxylin and eosin (H&E) staining, as well as Masson trichrome staining, were performed for histopathology. The α-SMA, collagen I, and III expression in the myocardium was detected by immunohistochemical staining. The ratio of heart weight to body weight (HW/BW, mg/kg) and the ratio of heart weight to tibia length (HW/TL, mg/mm) were calculated as indicators for cardiac remodeling. Brain natriuretic peptide (BNP) levels were quantified in rat plasma using enzymelinked immunosorbent assay (ELISA). In contrast, the protein levels of TGF-β1, p-Smad2/3, and Smad2/3 were assessed in the myocardium andfibroblasts via western blot analysis. RT-qPCR was performed to analysis the expression of Col-I, Col-III, α-SMA, NLRP3, Caspase-1, IL-1β, andIL-18.

Results: Proteomic analysis identified 227 differentially expressed proteins (DEPs), including 119 upregulated and 108 downregulated proteins. These proteins were identified as the core proteins targeted by artemisinin for improving myocardial remodeling. GO annotation of the DEPs indicated that the DEPs were mainly associated with biological processes such as inflammation regulation. In the in vivo study of an isoproterenol-inducedrat cardiac remodeling model, we found that artemisinin administration significantly ameliorated cardiac dysfunction and reduced collagen production by suppressing TGFβ-1/Smads signaling and inhibiting NLRP3 inflammasome activation. As manifested by downregulating the expression of α-SMA, Col-I, and Col-III, NLRP3, IL-1β, IL-18, Caspase-1 mRNA, and TGF-β1, p-SMAD 2/3 protein in the myocardium. Similar beneficial effects of artemisinin were consistently observed in TGF-β1 treated primary cardiac fibroblasts.

Conclusions: Extracts from Artemisia annua relieves myocardial remodeling through TGF-β1/Smad2/3 pathway and NLRP3 inflammasome

背景和目的:青蒿素及其衍生物是从传统中药中提取的著名抗疟疾药物,被认为可用于治疗纤维化疾病。然而,青蒿素是否会影响心衰发病机制中的心脏纤维化仍是未知数。本研究旨在评估青蒿素在心衰模型中对心功能和心肌纤维化的可能影响,并探讨其潜在机制:方法:皮下注射异丙肾上腺素诱导心脏纤维化模型。方法:皮下注射异丙肾上腺素诱导心脏纤维化模型,青蒿素治疗4周后进行蛋白质组分析。超声心动图用于评估心脏功能和结构。组织病理学检查采用了苏木精和伊红(H&E)染色以及马森染色法。通过免疫组化染色检测心肌中α-SMA、胶原蛋白I和III的表达。心脏重量(HW)与体重之比(HW/BW,mg/kg)和心脏重量与胫骨长度之比(HW/TL,mg/mm)被计算为心脏重塑的指标。使用酶联免疫吸附试验(ELISA)对大鼠血浆中的脑钠肽水平进行了定量。而心肌和成纤维细胞中的 TGF-β1、p-Smad2/3 和 Smad2/3 蛋白水平则通过 Western 印迹分析进行评估。对心脏中的Col-I、Col-III、α-SMA、NLRP3、Caspase-1、IL-1β和IL-18进行了RT-qPCR分析:结果:蛋白质组分析发现了227个差异表达蛋白(DEPs),包括119个上调蛋白和108个下调蛋白。这些蛋白质被确定为青蒿素改善心肌重塑的核心蛋白。DEPs的GO注释表明,DEPs主要与TGF-β和NLRP3炎性体调控等生物过程有关。在异丙肾上腺素诱导的SD大鼠心脏重塑模型的体内研究中,我们发现青蒿素通过抑制TGFβ-1/Smads信号传导和抑制NLRP3炎性体激活,显著改善了心脏功能障碍并减少了胶原蛋白的生成。具体表现为下调心肌中 α-SMA、Col-I、Col-III、NLRP3、IL-1β、IL-18、Caspase-1 mRNA 和 TGF-β1、p-SMAD 2/3 蛋白的表达。在经 TGF-β1 处理的原发性心脏成纤维细胞中也持续观察到了类似的青蒿素有益作用:青蒿素通过TGF-β1/Smad2/3途径和NLRP3炎性体缓解心肌重塑。
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引用次数: 0
Exploring the Pharmacological Mechanisms of P-hydroxylcinnamaldehyde for Treating Gastric Cancer: A Pharmacological Perspective with Experimental Confirmation. 对羟基肉桂醛治疗胃癌的药理机制探讨:药理学角度的实验证实。
Pub Date : 2024-01-01 DOI: 10.2174/0118761429322420241112051105
Sumaya Fatima, Yanru Song, Zhe Zhang, Yuhui Fu, Ruinian Zhao, Khansa Malik, Lianmei Zhao

Background: Momordica cochinchinensis is a dried and mature seed of Cucurbitaceae plants, which has the effect of dispersing nodules, detumescence, attacking poison, and treating sores, and is used in the treatment of tumors in the clinic. P-hydroxylcinnamaldehyde (CMSP) is an ethanol extract of cochinchina momordica seed (CMS). Our previous studies have found that CMSP is an effective anti-tumor component with good anti-tumor effects on melanoma and esophageal tumors. However, the inhibitory effect of CMSP on gastric cancer (GC) and its potential mechanism remain to be further elucidated.

Methods: First, we utilized network pharmacology to predict potential targets and mechanisms of action for the treatment of GC. Subsequently, a series of biological function experiments were conducted to assess the effects of CMSP on the proliferation and apoptosis of GC cells in vitro. To elucidate the molecular mechanism of CMSP, bioinformatics and high-efficiency liquid chromatography tandem mass spectrometry (HPLC-MS/MS) were employed for analysis. Additionally, a resistant cell line of the chemotherapy drug paclitaxel for GC was established, and the impact of 10μg/mL CMSP on the sensitivity of GC-resistant cells was examined.

Results: The network pharmacology results demonstrated that the active components of CMS exert an anti-GC effect through multi-target and multipathway mechanisms. The main pathways involved included the PI3K/Akt pathway, p53 signaling pathway, multi-species apoptosis pathway, as well as ADRB2 and CAV1 genes. Cell experiments revealed that CMSP can effectively inhibit the proliferation and induce apoptosis of GC cells in vitro. However, it did not show any sensitizing effect on paclitaxel-resistant cells. Importantly, CMSP exhibited no toxic or side effects on normal gastric epithelial cells. Furthermore, differential protein expression patterns following CMSP treatment were elucidated using HPLCMS/ MS and western blot analysis, highlighting its role in regulating apoptosis signaling pathways.

Conclusion: Our study presents novel evidence regarding pertinent potential target genes and signaling pathways through which CMSP mediates its anti-GC effects, with a particular emphasis on its role in modulating apoptotic signaling pathways. Collectively, these findings underscore the promising candidacy of CMSP as a therapeutic agent for GC that merits further investigation in clinical contexts.

背景:番荔枝是葫芦科植物的一种干燥成熟的种子,具有散瘤、消肿、解毒、治疮的作用,临床上用于肿瘤的治疗。对羟基肉桂醛(CMSP)是一种从槟榔籽(CMS)中提取的乙醇提取物。我们前期研究发现CMSP是一种有效的抗肿瘤成分,对黑色素瘤和食管肿瘤均有良好的抗肿瘤作用。然而,CMSP对胃癌(GC)的抑制作用及其潜在机制仍有待进一步阐明。方法:首先,利用网络药理学预测GC治疗的潜在靶点和作用机制。随后,我们进行了一系列生物学功能实验,以评估CMSP对体外GC细胞增殖和凋亡的影响。为阐明CMSP的分子机制,采用生物信息学和高效液相色谱-串联质谱(HPLC-MS/MS)技术对其进行分析。建立化疗药物紫杉醇GC耐药细胞株,观察10μg/mL CMSP对GC耐药细胞敏感性的影响。结果:网络药理学结果表明,中药有效成分通过多靶点、多途径发挥抗gc作用。主要涉及的通路包括PI3K/Akt通路、p53信号通路、多物种凋亡通路以及ADRB2和CAV1基因。细胞实验表明,CMSP能有效抑制胃癌细胞的增殖和诱导凋亡。但对紫杉醇耐药细胞无增敏作用。重要的是,CMSP对正常胃上皮细胞无毒副作用。此外,通过hplc / MS和western blot分析,揭示了CMSP处理后的差异蛋白表达模式,强调了其在调节细胞凋亡信号通路中的作用。结论:我们的研究为CMSP介导其抗gc作用的相关潜在靶基因和信号通路提供了新的证据,特别强调了其在调节凋亡信号通路中的作用。总的来说,这些发现强调了CMSP作为胃癌治疗剂的候选性,值得在临床环境中进一步研究。
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引用次数: 0
Evaluating the Anti-inflammatory Efficacy of a Novel Bipyrazole Derivative in Alleviating Symptoms of Experimental Colitis. 评估一种新型联吡唑衍生物在缓解实验性结肠炎症状方面的抗炎功效
Pub Date : 2024-01-01 DOI: 10.2174/0118761429333261241021034043
Yousra Bseiso, Omar Gammoh, Mohammad Alqudah, Sara Altaber, Esam Qnais, Mohammed Wedyan, Abdelrahim Alqudah, Badriyah S Alotaibi

Aims: This aims to assess the efficacy of 2', 3, 3, 5'-Tetramethyl-4'-nitro-2'H-1, 3'-bipyrazole (TMNB), a novel compound, in colitis treatment.

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with limited effective treatments available. The exploration of new therapeutic agents is critical for advancing treatment options.

Objective: To assess the effect of TMNB in alleviating symptoms of experimental colitis in mice and to compare its effectiveness with that of sulfasalazine, a standard treatment.

Methods: Experimental colitis was induced in mice, which were subsequently treated with TMNB at dosages of 50, 100, and 150 mg/kg. The outcomes were evaluated based on colitis symptoms, Colon damage, Disease Activity Index (DAI) scores, and inflammation markers, including nitric oxide (NO) and myeloperoxidase (MPO) levels. Additional assessments included spleen cell proliferation, pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β), and inflammatory genes expression (IL-1β, IL-6, TNF-α, COX2, and iNOS).

Results: TMNB treatment significantly alleviated colitis symptoms (100 and 150 mg/kg). These higher doses notably reduced colonic damage, inflammation, hyperemia, edema, and ulceration (p<0.01). The treatment also effectively decreased Disease Activity Index (DAI) scores, demonstrating a marked improvement in clinical signs of colitis (100 mg/kg, p<0.05; 150 mg/kg, p<0.01). Additionally, TMNB substantially lowered myeloperoxidase (MPO) levels, indicating reduced neutrophil activity and inflammation (100 mg/kg, p<0.05; 150 mg/kg, p<0.01), and nitric oxide (NO) levels, suggesting diminished oxidative stress (100 mg/kg, p<0.05; 150 mg/kg, p<0.01). The treatment also led to a significant reduction in spleen cell proliferation (100 mg/kg, p<0.05; 150 mg/kg, p<0.01) and pro-inflammatory cytokine levels, with TNF-α, IL-1β, and IL-6 all showing decreases comparable to those observed with sulfasalazine (p<0.01). Moreover, TMNB effectively downregulated IL-1β, IL-6, TNF-α, COX2, and iNOS (p<0.01), affirming its broad-spectrum anti-inflammatory and immunomodulatory effects.

Conclusion: TMNB exhibits potent anti-inflammatory and immunomodulatory activities, suggesting that TMNB could be a new therapeutic agent for managing inflammatory bowel disease. This study supports the need for further clinical trials to explore TMNB's efficacy and safety in human subjects.

目的:本研究旨在评估新型化合物 2', 3, 3, 5'-Tetramethyl-4'-nitro-2'H-1, 3'-bipyrazole (TMNB) 治疗结肠炎的疗效:背景:炎症性肠病(IBD)是一种慢性胃肠道炎症,目前有效的治疗方法有限。探索新的治疗药物对于推进治疗方案至关重要:评估 TMNB 在减轻小鼠实验性结肠炎症状方面的效果,并将其与标准治疗药物磺胺沙拉嗪的效果进行比较:方法:诱导小鼠患实验性结肠炎,然后用 50、100 和 150 毫克/千克剂量的 TMNB 治疗。结果根据结肠炎症状、结肠损伤、疾病活动指数(DAI)评分以及炎症标志物(包括一氧化氮和髓过氧化物酶水平)进行评估。其他评估包括脾细胞增殖、促炎细胞因子产生(TNF-α、IL-6、IL-1β)和炎症基因表达(IL-1β、IL-6、TNF-α、COX2 和 iNOS):结果:TMNB 治疗可明显缓解结肠炎症状(100 和 150 毫克/千克)。这些较高剂量明显减轻了结肠损伤、炎症、充血、水肿和溃疡(p<0.01)。治疗还有效降低了疾病活动指数(DAI)评分,明显改善了结肠炎的临床症状(100 毫克/千克,p<0.05;150 毫克/千克,p<0.01)。此外,TMNB 还大大降低了髓过氧化物酶 (MPO) 水平,表明中性粒细胞活性和炎症有所降低(100 毫克/千克,p<0.05;150 毫克/千克,p<0.01),并降低了一氧化氮 (NO) 水平,表明氧化应激有所减轻(100 毫克/千克,p<0.05;150 毫克/千克,p<0.01)。治疗还显著降低了脾脏细胞的增殖(100 毫克/千克,p<0.05; 150 毫克/千克,p<0.01)和促炎细胞因子水平,TNF-α、IL-1β和 IL-6 的降幅与磺胺沙拉嗪的降幅相当(p<0.01)。此外,TMNB 还能有效降低 IL-1β、IL-6、TNF-α、COX2 和 iNOS 的浓度(p<0.01),这肯定了它的广谱抗炎和免疫调节作用:结论:TMNB 具有强大的抗炎和免疫调节活性,这表明 TMNB 可以成为治疗炎症性肠病的一种新疗法。这项研究证明,有必要进一步开展临床试验,探索 TMNB 对人体的疗效和安全性。
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引用次数: 0
Aloperine Alleviates Atherosclerosis by Inhibiting NLRP3 Inflammasome Activation in Macrophages and ApoE-/- Mice. Aloperine通过抑制巨噬细胞和ApoE-/-小鼠NLRP3炎性体激活来缓解动脉粥样硬化。
Pub Date : 2024-01-01 DOI: 10.2174/0118761429342447241214044859
Zengxu Wang, Yuchuan Wang, Faisal Raza, Hajra Zafar, Chunling Guo, Weihua Sui, Yongchao Yang, Ran Li, Yifen Fang, Bao Li

Background and aims: Atherosclerosis is a chronic cardiovascular disease which is regarded as one of the most common causes of death in the elderly. Recent evidence has shown that atherosclerotic patients can benefit by targeting interleukin-1 beta (IL-1β). Aloperine (ALO) is an alkaloid which is mainly isolated from Sophora alopecuroides L. and has been recognized as an anti-inflammatory disease. Herein, the effect of ALO on atherosclerosis was investigated.

Methods: ApoE-/- mice fed with western diet received ALO once daily. Plaques in the aortas were evaluated using oil red O and hematoxylin & eosin (H&E) staining. Inflammation, lipids and kinases phosphorylation levels were evaluated using ELISA assay and western blot. Pyroptosis was examined by THP-1 cells treated with oxidized low-density lipoprotein (ox-LDL).

Results: Plaque development in aortic sinus and en face aortas were reduced after ALO treatment in ApoE-/- miceTreatment with ALO ameliorated inflammation and profile of blood lipid. Western blot assay showed that ALO treatment substantially inhibited phosphorylation of p38 and Jun Nterminal kinase (JNK) in aorta of ApoE-/- mice. Meanwhile, ALO significantly inhibited levels of IL-1β and IL-18 in serum and cleaved caspase-1 and IL-1β expression in aorta of ApoE-/- mice. Interestingly, ALO mildly increased pro-caspase-1 expression in ApoE-/- aorta in comparison with saline group. In a dose dependent fashion, ALO treatment markedly inhibited ox-LDL-induced IL-1β and IL-18 levels in THP-1 cells and reduced cleaved caspase-1 and IL-1β expression and caspase-1 activity, while ALO had little effect on nod-like receptor protein containing pyrin-3 (NLRP3), apoptosis associated speck-like protein containing a caspase-1 recruitment domain (ASC).

Conclusion: It is of great practical significance to find the natural product to regulate macrophage pyroptosis, which are key drivers to accelerate the progression of atherosclerosis. ALO could inhibit NLRP3 inflammasome activation in macrophages during atherogenesis, which may serve as a potential candidate for the treatment of atherosclerosis.

背景与目的:动脉粥样硬化是一种慢性心血管疾病,是老年人最常见的死亡原因之一。最近的证据表明,动脉粥样硬化患者可以通过靶向白介素-1β (IL-1β)获益。苦荞麦碱(Aloperine, ALO)是一种主要从苦荞麦中分离得到的生物碱,具有抗炎作用。本文研究了ALO对动脉粥样硬化的影响。方法:ApoE-/-小鼠以西餐喂养,每日1次给予ALO治疗。采用油红O和苏木精伊红(H&E)染色评估主动脉斑块。采用ELISA法和western blot检测炎症、脂质和激酶磷酸化水平。用氧化低密度脂蛋白(ox-LDL)处理THP-1细胞,观察细胞的焦亡情况。结果:对ApoE-/-小鼠进行ALO治疗后,主动脉窦和面主动脉斑块的形成减少,并改善了炎症和血脂水平。Western blot结果显示,ALO显著抑制ApoE-/-小鼠主动脉p38和JNK的磷酸化。同时,ALO显著抑制ApoE-/-小鼠血清中IL-1β和IL-18的水平,并破坏ApoE-/-小鼠主动脉中caspase-1和IL-1β的表达。有趣的是,与生理盐水组相比,ALO轻度增加了ApoE-/-主动脉中前caspase-1的表达。在剂量依赖性的情况下,ALO治疗显著抑制ox- ldl诱导的THP-1细胞中IL-1β和IL-18水平,降低了裂解型caspase-1和IL-1β的表达和caspase-1活性,而ALO对含有pyrin-3的nod样受体蛋白(NLRP3)和含有caspase-1募集结构域(ASC)的凋亡相关斑点样蛋白几乎没有影响。结论:巨噬细胞凋亡是动脉粥样硬化加速发展的关键驱动因素,寻找调节巨噬细胞凋亡的天然产物具有重要的现实意义。ALO可以抑制动脉粥样硬化过程中巨噬细胞NLRP3炎性体的激活,这可能是治疗动脉粥样硬化的潜在候选药物。
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引用次数: 0
Alnustone: A Review of its Sources, Pharmacology, and Pharmacokinetics 烯ustone:其来源、药理学和药代动力学综述 .
Pub Date : 2024-01-01 DOI: 10.2174/0118761429252459231115060139
Zahra Salari, Maryam Alavi, Hojjat Rezaii-Zadeh, Abdelhakim Bouyahya, Ammar Alfergah, Sahar Afsari Sardari, Ehsan Amiri-Ardekani

Alnustone (4(E)-,6(E)-1,7-Diphenyl-hepta-4,6-dien-3-one) is a non-phenolic natural diarylheptanoid, which was first isolated and identified from the male flower of Alnus pendula (Betulaceae). It can also be isolated from Curcuma xanthorrhiza Roxb (Zingiberaceae) rhizomes and Alpinia katsumadai Hayata (Zingiberaceae) seeds. It was first synthesized through a five-step process from β-phenyl propionyl chloride. In later years, new methods for synthesizing Alnustone were designed and performed with different yields. Due to the various therapeutic effects exhibited by alnustone like other diarylheptanoids, its biological activities such as antioxidant, antibacterial, and anti-inflammatory properties have been the subject of many studies.This article has reviewed different aspects of this valuable natural compound, including its natural and synthetic sources, therapeutic effects, and pharmacokinetics as a potential future therapeutic agent.

烯雌酮(4(E)-,6(E)-1,7-二苯基庚-4,6-二烯-3-酮)是一种非酚类天然二芳基庚烷类化合物,最早是从桦木科植物 Alnus pendula 的雄花中分离鉴定出来的。它还可以从莪术(Zingiberaceae)根茎和桔梗(Zingiberaceae)种子中分离出来。它最初是由β-苯基丙酰氯通过五个步骤合成的。后来,人们设计并采用了新的方法合成 Alnustone,并取得了不同的产量。由于烯雌酮和其他二芳基庚烷类化合物一样具有多种治疗效果,其抗氧化、抗菌和抗炎等生物活性已成为许多研究的主题。本文综述了这种珍贵天然化合物的各个方面,包括其天然和合成来源、治疗效果以及作为未来潜在治疗药物的药代动力学。
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引用次数: 0
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Current molecular pharmacology
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