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Molecular properties prediction, anticancer and anti-inflammatory activities of some pyrimido[1,2-b]pyridazin-2-one derivatives 一些嘧啶[1,2-b]吡嗪-2- 1衍生物的分子性质预测及抗癌和抗炎活性
4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-10 DOI: 10.34172/bi.2023.27688
Ali Zeiz, Ranin Kawtharani, Mirvat Elmasri, Ghada Khawaja, Eva Hamade, Aida Habib, Abeer J. Ayoub, Mohamed Abarbri, Mohammad H. El-Dakdouki
Introduction: The anticancer and anti-inflammatory activities of a novel series of eleven pyrimido[1,2-b]pyridazin-2-one analogues substituted at position 7 were assessed in the current study. Methods: The physicochemical characteristics were studied using MolSoft software. The antiproliferative activity was investigated by MTT cell viability assay, and cell cycle analysis elucidated the antiproliferative mechanism of action. Western blot analysis examined the expression levels of key pro-apoptotic (Bax, p53) and pro-survival (Bcl-2) proteins. The anti-inflammatory activity was assessed by measuring the production levels of nitric oxide in RAW264.7 cells, and the expression levels of COX-2 enzyme in LPS-activated THP-1 cells. In addition, the gene expression of various pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α) and chemokines (CCL2, CXCL1, CXCL2, CXCL3) was assessed by RT-qPCR. Results: Compound 1 bearing a chlorine substituent displayed the highest cytotoxic activity against HCT-116 and MCF-7 cancer cells where IC50 values of 49.35 ± 2.685 and 69.32 ± 3.186 µM, respectively, were achieved. Compound 1 increased the expression of pro-apoptotic proteins p53 and Bax while reducing the expression of pro-survival protein Bcl-2. Cell cycle analysis revealed that compound 1 arrested cell cycle at the G0/G1 phase. Anti-inflammatory assessments revealed that compound 1 displayed the strongest inhibitory activity on NO production with IC50 of 29.94 ± 2.24 µM, and down-regulated the expression of COX-2. Compound 1 also induced a statistically significant decrease in the gene expression of various cytokines and chemokines. Conclusion: These findings showed that the pyrimidine derivative 1 displayed potent anti-inflammatory and anticancer properties in vitro, and can be selected as a lead compound for further investigation.
简介:本研究评估了一系列取代7位的新型11嘧啶[1,2-b]吡嗪-2- 1类似物的抗癌和抗炎活性。方法:采用MolSoft软件对其理化特性进行研究。通过MTT细胞活力试验研究其抗增殖活性,细胞周期分析阐明其抗增殖作用机制。Western blot检测关键促凋亡蛋白(Bax、p53)和促生存蛋白(Bcl-2)的表达水平。通过测定RAW264.7细胞中一氧化氮的产生水平和lps激活的THP-1细胞中COX-2酶的表达水平来评估抗炎活性。RT-qPCR检测各促炎因子(IL-6、IL-8、IL-1β、TNF-α)和趋化因子(CCL2、CXCL1、CXCL2、CXCL3)的基因表达。结果:含氯取代基的化合物1对HCT-116和MCF-7的细胞毒活性最高,IC50值分别为49.35±2.685和69.32±3.186µM。化合物1增加促凋亡蛋白p53和Bax的表达,降低促存活蛋白Bcl-2的表达。细胞周期分析显示化合物1在G0/G1期阻滞细胞周期。抗炎实验结果显示,化合物1对NO生成的抑制作用最强,IC50为29.94±2.24µM,并能下调COX-2的表达。化合物1还诱导各种细胞因子和趋化因子的基因表达有统计学意义的降低。结论:嘧啶衍生物1在体外具有较强的抗炎和抗癌作用,可作为进一步研究的先导化合物。
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引用次数: 0
Essential role of CD38 in platelet aggregation through the PKC- mediated internalization and activation CD38通过PKC介导的内化和激活在血小板聚集中的重要作用
4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-30 DOI: 10.34172/bi.2023.27780
Mazhar Mushtaq, Maira Mahmood, Uzma Jabbar, Uh-Hyun Kim
Introduction: CD38 is a multifunctional enzyme with a potent Ca2+ mobilizing effect, cyclic ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP). Here, we aimed to demonstrate the role of CD38 in platelets via protein kinase C (PKC)-mediated internalization and activation. Methods: Mouse platelets were used in this study. Thrombin, an agonist of platelet function, provoked a prompt and long-lasting increase in intracellular Ca2+ concentration ([Ca2+]i), resulting from an interplay of multifold Ca2+ mobilizing messengers.The signaling pathway was delineated using different inhibitors and techniques such as platelet aggregation assay, intracellular calcium measurements, immunoprecipitation, immunoblotting, and flow cytometry. Results: We observed a sequential formation of cADPR and NAADP through CD38 activation by PKC of non-muscle myosin heavy chain IIA (MHCIIA), resulting in phospholipase C (PLC) activation in the thrombin-stimulated platelets. These findings reveal that PKC is fundamental in activating CD38 and elicits a physiological response in the murine platelets. Conclusion: PKC is involved in many signaling pathways. Specifically, PKC is involved in the internalization of CD38 via MHCIIA in CD38+/+ wild-type (WT) and CD38-/- knockout mice (KO). CD38 generates calcium-mobilizing agents that act on specific receptors of the calcium stores. Calcium triggered platelet aggregation while serving as a secondary messenger.
CD38是一种多功能酶,具有强大的Ca2+动员作用,环adp核糖(cADPR)和烟酸腺嘌呤二核苷酸磷酸(NAADP)。在这里,我们旨在通过蛋白激酶C (PKC)介导的内化和激活来证明CD38在血小板中的作用。方法:采用小鼠血小板进行实验。凝血酶是血小板功能的激动剂,引起细胞内Ca2+浓度([Ca2+]i)的迅速和持久的增加,这是由多重Ca2+动员信使的相互作用引起的。使用不同的抑制剂和技术,如血小板聚集测定、细胞内钙测量、免疫沉淀、免疫印迹和流式细胞术,描绘了信号通路。结果:我们观察到,通过PKC激活非肌球蛋白重链IIA (MHCIIA)的CD38,导致凝血酶刺激的血小板中磷脂酶C (PLC)激活,cADPR和NAADP序列形成。这些发现表明PKC是激活CD38的基础,并在小鼠血小板中引发生理反应。结论:PKC参与多种信号通路。具体来说,PKC在CD38+/+野生型(WT)和CD38-/-敲除小鼠(KO)中通过MHCIIA参与CD38的内化。CD38产生钙动员剂,作用于钙储存的特定受体。钙作为次级信使触发血小板聚集。
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引用次数: 0
Introduction of a new recombinant vaccine based on GRP78 for breast cancer immunotherapy and evaluation in a mouse model 一种基于GRP78的乳腺癌免疫治疗重组疫苗的介绍及小鼠模型评价
4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-18 DOI: 10.34172/bi.2023.27829
Hamed Zare, Hamid Bakherad, Arman Nasr Esfahani, Mohamad Norouzi, Hossein Aghamollaei, Seyed Latif Mousavi Gargari, Fatemeh Mahmoodi, Mahdi Aliomrani, Walead Ebrahimizadeh
Introduction: Breast cancer is one of the most prevalent malignancies in women. Several treatment options are available today, including surgery, chemotherapy, and radiotherapy. Immunotherapy, as a highly specific therapy, involves adaptive immune responses and immunological memory. In our present research, we used the recombinant C-terminal domain of the GRP78 (glucose- regulated protein 78) protein to induce an immune response and investigate its therapeutic impact in the 4T1 breast cancer model. Methods: BALB/c mice were immunized with the cGRP78 protein. The humoral immune response was assessed by ELISA. Then, BALB/c mice were injected subcutaneously with 1×106 4T1 tumor cells. Subsequently, tumor size and survival rate measurements, MTT, and cytokine assays were performed. Results: The animals receiving the cGRP78 vaccine showed significantly more favorable survival and slower tumor growth rates compared with unvaccinated tumor-bearing mice as the negative control mice. Circulating levels of tumoricidal cytokines such as IFNγ were higher, whereas tolerogenic cytokines such as IL-2, 6, and 10 either did not increase or had a decreasing trend in mice receiving cGRP78. Conclusion: cGRP78 vaccines generated potent immunotherapeutic effects in a breast cancer mouse model. This novel strategy of targeting the GRP78 protein can promote the development of cancer vaccines and immunotherapies for breast cancer malignancies.
乳腺癌是女性中最常见的恶性肿瘤之一。目前有几种治疗方法可供选择,包括手术、化疗和放疗。免疫治疗是一种高度特异性的治疗方法,涉及适应性免疫反应和免疫记忆。在我们目前的研究中,我们利用GRP78(葡萄糖调节蛋白78)蛋白的重组c端结构域诱导免疫应答,并研究其在4T1乳腺癌模型中的治疗作用。方法:用cGRP78蛋白免疫BALB/c小鼠。采用酶联免疫吸附测定体液免疫应答。然后,给BALB/c小鼠皮下注射1×106 4T1肿瘤细胞。随后,进行肿瘤大小和存活率测量、MTT和细胞因子测定。结果:与未接种cGRP78疫苗的荷瘤小鼠相比,接种cGRP78疫苗的小鼠存活率明显提高,肿瘤生长速度明显减慢。在接受cGRP78的小鼠中,IFNγ等杀肿瘤细胞因子的循环水平较高,而IL-2、6和10等耐受性细胞因子没有增加或呈下降趋势。结论:cGRP78疫苗在乳腺癌小鼠模型中具有较强的免疫治疗作用。这种靶向GRP78蛋白的新策略可以促进乳腺癌恶性肿瘤疫苗和免疫疗法的发展。
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引用次数: 0
Benchmarking different docking protocols for predicting the binding poses of ligands complexed with cyclooxygenase enzymes and screening chemical libraries 对不同对接方案进行基准测试,预测配体与环加氧酶的结合姿态,筛选化学文库
4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-12 DOI: 10.34172/bi.2023.29955
Sara Shamsian, Babak Sokouti, Siavoush Dastmalchi
Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) constitute an important class of pharmaceuticals acting on cyclooxygenase COX-1 and COX-2 enzymes. Due to their numerous severe side effects, it is necessary to search for new selective, safe, and effective anti-inflammatory drugs. In silico design of novel therapeutics plays an important role in nowadays drug discovery pipelines. In most cases, the design strategies require the use of molecular docking calculations. The docking procedure may require case-specific condition for a successful result. Additionally, many different docking programs are available, which highlights the importance of identifying the most proper docking method and condition for a given problem. Methods: In the current work, the performances of five popular molecular docking programs, namely, GOLD, AutoDock, FlexX, Molegro Virtual Docker (MVD) and Glide to predict the binding mode of co- crystallized inhibitors in the structures of known complexes available for cyclooxygenases were evaluated. Furthermore, the best performers, Glide, AutoDock, GOLD and FlexX, were further evaluated in docking-based virtual screening of libraries consisted of active ligands and decoy molecules for cyclooxygenase enzymes and the obtained docking scores were assessed by receiver operating characteristics (ROC) analysis. Results: The results of docking experiments indicated that Glide program outperformed other docking programs by correctly predicting the binding poses (RMSD less than 2 Å) of all studied co-crystallized ligands of COX-1 and COX-2 enzymes (i.e., the performance was 100%). However, the performances of the other studied docking methods for correctly predicting the binding poses of the ligands were between 59% to 82%. Virtual screening results treated by ROC analysis revealed that all tested methods are useful tools for classification and enrichment of molecules targeting COX enzymes. The obtained AUCs range between 0.61-0.92 with enrichment factors of 8 – 40 folds. Conclusion: The obtained results support the importance of choosing appropriate docking method for predicting ligand-receptor binding modes, and provide specific information about docking calculations on COXs ligands.
非甾体类抗炎药(NSAIDs)是一类作用于环氧化酶COX-1和COX-2的重要药物。由于其众多严重的副作用,有必要寻找新的选择性,安全,有效的抗炎药物。新型治疗药物的芯片设计在当今的药物研发过程中扮演着重要的角色。在大多数情况下,设计策略需要使用分子对接计算。对接过程可能需要特定于案例的条件才能获得成功的结果。此外,有许多不同的对接方案可供选择,这突出了针对给定问题确定最合适的对接方法和条件的重要性。方法:通过对GOLD、AutoDock、FlexX、Molegro Virtual Docker (MVD)和Glide五种常用的分子对接程序的性能进行评价,预测共结晶抑制剂在已知环加氧酶配合物结构中的结合模式。此外,对表现最佳的Glide、AutoDock、GOLD和FlexX进行了基于对接的虚拟筛选,对环加氧酶活性配体和诱饵分子组成的文库进行了进一步评估,并通过受试者工作特征(ROC)分析评估了获得的对接分数。结果:对接实验结果表明,Glide程序能够正确预测COX-1和COX-2酶共结晶配体的结合位姿(RMSD小于2 Å),即预测准确率为100%,优于其他对接程序。然而,其他研究的对接方法正确预测配体结合姿态的性能在59%到82%之间。经ROC分析处理的虚拟筛选结果显示,所有测试方法都是针对COX酶的分子分类和富集的有用工具。得到的auc范围为0.61 ~ 0.92,富集系数为8 ~ 40倍。结论:所得结果支持了选择合适的对接方法对预测配体-受体结合模式的重要性,并为cox配体对接计算提供了具体信息。
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引用次数: 0
Comparative molecular docking and toxicity between carbon-capped metal oxide nanoparticles and standard drugs in cancer and bacterial infections 碳顶金属氧化物纳米颗粒与标准药物在癌症和细菌感染中的分子对接和毒性比较
4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-05 DOI: 10.34172/bi.2023.27778
Navid Mohammadjani, Sahand Karimi, Musa Moetasam Zorab, Morahem Ashengroph, Mehran Alavi
Introduction: Nanoparticles (NPs) are of great interest in the design of various drugs due to their high surface-to-volume ratio, which result from their unique physicochemical properties. Because of the importance of examining the interactions between newly designed particles with different targets in the case of various diseases, techniques for examining the interactions between these particles with different targets, many of which are proteins, are now very common. Methods: In this study, the interactions between metal oxide nanoparticles (MONPs) covered with a carbon layer (Ag2O3, CdO, CuO, Fe2O3, FeO, MgO, MnO, and ZnO NPs) and standard drugs related to the targets of Cancer and bacterial infections were investigated using the molecular docking technique with AutoDock 4.2.6 software tool. Finally, the PRO TOX-II online tool was used to compare the toxicity (LD50) and molecular weight of these MONPs to standard drugs. Results: According to the data obtained from the semi flexible molecular docking process, MgO and Fe2O3 NPs performed better than standard drugs in several cases. MONPs typically have a lower 50% lethal dose (LD50) and a higher molecular weight than standard drugs. MONPs have shown a minor difference in binding energy for different targets in three diseases, which probably can be attributed to the specific physicochemical and pharmacophoric properties of MONPs. Conclusion: The toxicity of MONPs is one of the major challenges in the development of drugs based on them. According to the results of these molecular docking studies, MgO and Fe2O3 NPs had the highest efficiency among the investigated MONPs.
纳米粒子(NPs)由于其独特的物理化学性质而具有很高的表面体积比,因此在各种药物的设计中引起了极大的兴趣。由于检测新设计的颗粒与不同靶标之间的相互作用在各种疾病中的重要性,检测这些颗粒与不同靶标(其中许多是蛋白质)之间相互作用的技术现在非常普遍。方法:利用AutoDock 4.2.6软件工具,采用分子对接技术,研究碳层覆盖的金属氧化物纳米粒子(Ag2O3、CdO、CuO、Fe2O3、FeO、MgO、MnO、ZnO纳米粒子)与癌症和细菌感染相关靶点标准药物之间的相互作用。最后,使用PRO TOX-II在线工具比较这些MONPs与标准药物的毒性(LD50)和分子量。结果:根据半柔性分子对接过程获得的数据,MgO和Fe2O3 NPs在某些情况下优于标准药物。MONPs通常比标准药物具有更低的50%致死剂量(LD50)和更高的分子量。在三种疾病中,MONPs对不同靶点的结合能表现出微小的差异,这可能与MONPs特有的物理化学和药理特性有关。结论:MONPs的毒性是基于其开发药物的主要挑战之一。根据这些分子对接研究的结果,MgO和Fe2O3 NPs在所研究的MONPs中效率最高。
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引用次数: 0
Targeting long non-coding RNAs as new modulators in anti-EGFR resistance mechanisms 靶向长链非编码rna作为抗egfr耐药机制的新调节剂
4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-29 DOI: 10.34172/bi.2023.27696
Mostafa Akbarzadeh-Khiavi, Azam Safary, Yadollah Omidi
Epidermal growth factor receptor (EGFR) is a cell surface protein that plays a vital role in regulating cell growth and division. However, certain tumors, such as colorectal cancer (CRC), can exhibit an overexpression of EGFR, resulting in uncontrolled cell growth and tumor progression. To address this issue, therapies targeting and inhibiting EGFR activity have been developed to suppress cancer growth. Nevertheless, resistance to these therapies poses a significant obstacle in cancer treatment. Recent research has focused on comprehending the underlying mechanisms contributing to anti-EGFR resistance and identifying new targets to overcome this striking challenge. Long non-coding RNAs (lncRNAs) are a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. Emerging evidence suggests that lncRNAs may participate in modulating resistance to anti-EGFR therapies in CRC. Consequently, combining lncRNA targeting with the existing treatment modalities could potentially yield improved clinical outcomes. Illuminating the involvement of lncRNAs in anti-EGFR resistance mechanisms of cancer cells can provide valuable insights into the development of novel anti-EGFR therapies in several solid tumors.
表皮生长因子受体(Epidermal growth factor receptor, EGFR)是一种细胞表面蛋白,在调节细胞生长和分裂中起重要作用。然而,某些肿瘤,如结直肠癌(CRC),可以表现出EGFR的过表达,导致不受控制的细胞生长和肿瘤进展。为了解决这个问题,已经开发出靶向和抑制EGFR活性的疗法来抑制癌症的生长。然而,对这些疗法的耐药性对癌症治疗构成了重大障碍。最近的研究集中在理解导致抗egfr耐药的潜在机制,并确定新的靶点来克服这一惊人的挑战。长链非编码RNA (Long non-coding RNA, lncRNAs)是一类不编码蛋白质但在基因调控和细胞过程中起关键作用的RNA分子。新出现的证据表明,lncrna可能参与调节结直肠癌患者对抗egfr治疗的耐药性。因此,将lncRNA靶向与现有治疗方式相结合可能会改善临床结果。阐明lncRNAs在癌细胞抗egfr耐药机制中的作用,可以为几种实体肿瘤的新型抗egfr疗法的开发提供有价值的见解。
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引用次数: 0
Mosaic Vaccine Design Targeting Mutational Spike Protein of SARS-COV-2 : an Immunoinformatics Approaches 针对严重急性呼吸系统综合征冠状病毒2型突变刺突蛋白的嵌合疫苗设计:一种免疫信息学方法
IF 2.6 4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-19 DOI: 10.34172/bi.2023.26443
Ysrafil Ysrafil, A. Imran, Prisca Syafriani Wicita, Vyani Kamba, Fihrina Mohamad, Ismail Ismail, Ayyub Harly Nurung, Noviyanty Indjar Gama, Sari Eka Pratiwi, I. Astuti, Deepak Chandran, F. Alhumaydhi, F. Nainu, T. Emran
Introduction: Presently, the development of effective vaccines against SARS-CoV-2 is absolutely necessary, especially regarding the emerging of new variants that cause increasing fatalities. Methods: In the present study we designed a mosaic vaccine targeting the mutational spike protein of coronavirus disease 2019 (COVID-19) using a bioinformatics approach. Various immunoinformatics tools were utilized to provide the highest potential for a mosaic vaccine that could activate immune responses against COVID-19. Results: The evaluation of the constructed vaccine revealed that it is antigenic and immunogenic as well as nonallergenic. The physicochemical properties also show promising characteristics, including being highly stable and hydrophilic. As expected, the vaccine shows strong interactions with several important receptors including angiotensin-converting enzyme (ACE)2, Toll-like receptor (TLR)3 and TLR8 by the lowest energy level, docking score and binding free energy. The vaccine binds to receptors via certain amino acids using various types of binding including salt bridges, hydrogen bonds and other means. As shown in computationally derived models, the interactions promote activation of the immune response by eliciting the release of various cytokines, antibodies, memory B and T cells, as well as increasing of natural killer cell and dendrite cell counts. Conclusion: Therefore, the novel designed mosaic vaccine could be considered as a potential vaccine candidate for immediate production to stem the continuing and tragic effects of the COVID-19 pandemic. However, several advanced experimental studies should be conducted to ensure and verify the effectivity and safety against SARS‑CoV‑2 in vivo.
引言:目前,开发针对严重急性呼吸系统综合征冠状病毒2型的有效疫苗是绝对必要的,特别是在出现导致死亡人数增加的新变种方面。方法:在本研究中,我们使用生物信息学方法设计了一种针对2019冠状病毒病(新冠肺炎)突变刺突蛋白的马赛克疫苗。利用各种免疫信息学工具为马赛克疫苗提供了最高潜力,该疫苗可以激活针对新冠肺炎的免疫反应。结果:构建的疫苗具有抗原性、免疫原性和非致敏性。理化性质也显示出有前景的特性,包括高度稳定和亲水性。正如预期的那样,该疫苗以最低的能量水平、对接得分和结合自由能与包括血管紧张素转换酶(ACE)2、Toll样受体(TLR)3和TLR8在内的几种重要受体表现出强烈的相互作用。疫苗通过某些氨基酸与受体结合,使用各种类型的结合,包括盐桥、氢键和其他方式。如计算推导的模型所示,相互作用通过引发各种细胞因子、抗体、记忆B和T细胞的释放,以及自然杀伤细胞和树突细胞计数的增加,促进免疫反应的激活。结论:因此,新设计的马赛克疫苗可以被视为立即生产的潜在候选疫苗,以阻止新冠肺炎大流行的持续和悲剧性影响。然而,应进行几项先进的实验研究,以确保和验证体内对抗严重急性呼吸系统综合征冠状病毒2型的有效性和安全性。
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引用次数: 0
Optimized Cutaneous Delivery of Anti-wrinkle Dipeptide KT via Molecular Modification: Preformulation, Permeation, and the Importance of Conjugate Chain Length 通过分子修饰优化皱纹二肽KT的皮肤递送:预成型、渗透和共轭链长度的重要性
IF 2.6 4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-07-18 DOI: 10.34172/bi.2023.27558
Mahsa Sayed Tabatabaei, F. Kobarfard, R. Aboofazeli, Sorour Ramezanpour, H. Moghimi
Introduction: Anti-aging peptides, such as dipeptide KT, are promising rejuvenating agents and have recently received significant attention. However, their hydrophilic nature makes skin absorption therapeutically inadequate. The excessive hydrophilicity of peptides is partially solved by lipoidal conjugates, however, the increased molecular weight due to conjugation creates a new obstacle to skin permeation. Methods: In an attempt to concurrently solve these limitations, here we have studied different short-mid chain fatty acids (C6-C18) conjugates of dipeptide KT. Different fatty acid chain lengths of C6, C8, C10, C12, C14, C16, and C18 were considered to be conjugated with KT and screened in-silico. Of those, C8, C10, and C12 were preferred and synthesized alongside two controls of the parent drug (KT) and C16 (Pal-KT) as the commercialized form to be studied mechanistically. Subsequently, they were structurally characterized and underwent preformulation, supramolecular investigations (e.g., thermal behavior, solubility, surface-acting, crystalline structure), and skin absorption studies. Results: Data showed that the synthesized conjugates substantially outperformed Pal-KT in terms of molecular weight, lipophilicity, melting point, and aqueous solubility. In addition, unlike KT, they all demonstrated amphiphilicity-related features. The maximum and minimum skin permeation were assigned to C8-KT (33.2%) and KT (0.004%). Moreover, permeability coefficients (Kp) of the C8-KT, C10-KT, C12-KT, and C16-KT were calculated to be about 22000, 3800, 3400, and 1600 times higher than KT, respectively. Conclusion: Conjugate selection with lower molecular weight fatty acids and optimal lipophilicity can positively affect the molecular properties, skin absorption, and the ability to form supramolecular structures and consequently pave the way to ‘better’ anti-wrinkle products and formulations.
引言:抗衰老肽,如二肽KT,是一种很有前途的抗衰老剂,最近受到了极大的关注。然而,它们的亲水性使皮肤吸收治疗不足。肽的过度亲水性通过类脂缀合物部分解决,然而,由于缀合而增加的分子量对皮肤渗透造成了新的障碍。方法:为了同时解决这些限制,我们研究了二肽KT的不同短中链脂肪酸(C6-C18)偶联物。C6、C8、C10、C12、C14、C16和C18的不同脂肪酸链长被认为与KT偶联并在计算机上进行筛选。其中,C8、C10和C12是优选的,并与母体药物(KT)和C16(Pal-KT)的两个对照物一起合成,作为有待机制研究的商业化形式。随后,对它们进行了结构表征,并进行了预成型、超分子研究(如热行为、溶解度、表面作用、晶体结构)和皮肤吸收研究。结果:数据显示,合成的偶联物在分子量、亲脂性、熔点和水溶性方面显著优于Pal-KT。此外,与KT不同的是,它们都表现出了与两栖性相关的特征。最大和最小皮肤渗透分别为C8-KT(33.2%)和KT(0.004%)。此外,C8-KT、C10-KT、C12-KT和C16-KT的渗透系数(Kp)分别是KT的22000、3800、3400和1600倍。结论:低分子量脂肪酸和最佳亲脂性的结合物选择可以积极影响分子性质、皮肤吸收和形成超分子结构的能力,从而为“更好”的防皱产品和配方铺平道路。
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引用次数: 0
Injectable thermosensitive chitosan/gelatin hydrogel for dental pulp stem cells proliferation and differentiation. 注射热敏壳聚糖/明胶水凝胶用于牙髓干细胞的增殖和分化。
IF 2.6 4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.34172/bi.2022.23904
Mohammad Samiei, Elaheh Dalir Abdollahinia, Nazanin Amiryaghoubi, Marziyeh Fathi, Jaleh Barar, Yadollah Omidi

Introduction: Biocompatible and biodegradable scaffolds based on natural polymers such as gelatin and chitosan (CS) provide suitable microenvironments in dental tissue engineering. In the present study, we report on the synthesis of injectable thermosensitive hydrogel (PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel) for osteogenic differentiation of human dental pulp stem cells (hDPSCs). Methods: The CS-g-PNIPAAm was synthesized using the reaction of carboxyl terminated PNIPAAm with CS, which was then mixed with various amounts of gelatin solution in the presence of genipin as a chemical crosslinker to gain a homogenous solution. The chemical composition and microstructures of the fabricated hydrogels were confirmed by FT-IR and SEM analysis, respectively. To evaluate the mechanical properties (e.g., storage and loss modulus of the gels), the rheological analysis was considered. Calcium deposition and ALP activity of DPSCs were carried out using alizarin red staining and ALP test. While the live/dead assay was performed to study its toxicity, the real-time PCR was conducted to investigate the osteogenic differentiation of hDPSCs cultured on prepared hydrogels. Results: The hydrogels with higher gelatin incorporation showed a slightly looser network compared to the other ones. The hydrogel with less gelatin indicates a rather higher value of G', indicating a higher elasticity due to more crosslinking reaction of amine groups of CS via a covalent bond with genipin. All the hydrogels contained viable cells with negligible dead cells, indicating the high biocompatibility of the prepared hydrogels for hDPSCs. The quantitative results of alizarin red staining displayed a significant rise in calcium deposition in hDPSCs cultured on prepared hydrogels after 21 days. Further, hDPSCs cultured on hydrogel with more gelatin displayed the most ALP activity. The expression of late osteogenic genes such as OCN and BMP-2 were respectively 6 and 4 times higher on the hydrogel with more gelatin than the control group after 21 days. Conclusion: The prepared PNIPAAm-g-CS copolymer/gelatin hybrid hydrogel presented great features (e.g., porous structure, suitable rheological behavior, and improved cell viability), and resulted in osteogenic differentiation necessary for dental tissue engineering.

基于明胶和壳聚糖(CS)等天然聚合物的生物相容性和可生物降解支架为口腔组织工程提供了合适的微环境。在本研究中,我们报道了用于人牙髓干细胞成骨分化的可注射热敏水凝胶(PNIPAAm-g-CS共聚物/明胶混合水凝胶)的合成。方法:以端羧基PNIPAAm与CS反应合成CS-g-PNIPAAm,以皂角素为化学交联剂,将CS-g-PNIPAAm与不同量的明胶溶液混合,得到均相溶液。通过FT-IR和SEM对制备的水凝胶的化学成分和微观结构进行了表征。为了评估机械性能(例如,凝胶的储存和损失模量),考虑了流变学分析。采用茜素红染色和ALP试验检测DPSCs的钙沉积和ALP活性。通过活/死实验研究其毒性,real-time PCR检测制备的水凝胶培养的hdpsc的成骨分化情况。结果:明胶掺入量高的水凝胶,其网状结构略松散。明胶含量较少的水凝胶G′值较高,说明CS的胺基与龙胆平共价键发生交联反应较多,具有较高的弹性。所有的水凝胶都含有活细胞,死亡细胞可以忽略不计,表明制备的水凝胶对hdpsc具有很高的生物相容性。茜素红染色定量结果显示,在制备的水凝胶上培养21天后,hdpsc的钙沉积显著增加。此外,在含有较多明胶的水凝胶上培养的hDPSCs显示出最高的ALP活性。21 d后,加入明胶的水凝胶组OCN、BMP-2等后期成骨基因的表达分别比对照组高6倍和4倍。结论:制备的PNIPAAm-g-CS共聚物/明胶杂化水凝胶具有多孔结构、适宜的流变行为、提高细胞活力等特点,可实现口腔组织工程所需的成骨分化。
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引用次数: 6
Cloth-based microfluidic devices integrated onto the patch as wearable colorimetric sensors for simultaneous sweat analysis. 布基微流控装置集成到贴片上,作为可穿戴的比色传感器,用于同时进行汗液分析。
IF 2.6 4区 工程技术 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2023-01-01 DOI: 10.34172/bi.2023.24195
Bambang Kuswandi, Lukman H Irsyad, Ayik R Puspaningtyas

Introduction: In this work, a flexible, and wearable point-of-care (POC) device integrated on a pain relief patch as wearable colorimetric sensors have been developed for sweat analysis, such as lactic acid, sodium ions, and pH simultaneously. Herein, the patch has still functioned as pain relief, while it allows for sweat monitoring during exercise, and in daily activities.

Methods: It was constructed on cotton cloth using wax printing technology (batik stamp) as cloth-based microfluidic devices (CMDs). Here, it uses micro volumes of samples to perform the reaction in the sensing zones, where the sensitive reagents are immobilized so that it can collect and analyze the sweat (lactic acid, sodium ions, and pH) as the model for sweat analytes. The colorimetric analysis was conducted via a smartphone camera by using a free app (Color Grab) for a color image analysis that uses for quantitative analysis or naked eye for semi-qualitative analysis.

Results: The ∆RGB value of the CMDS shows the excellent linear correlation vs analytes concentration, where the coefficient of correlations was found for lactic acid (R2 = 0.994), sodium ion (R2 = 0.998), and pH (R2 = 0.994). The ∆RGB value shows the appropriate color value for the linear correlation of the analyte target concentrations in the sweat samples. Here, the limit of detection (LOD) was found at 45.73 µg/mL for lactic acid and 56.46 µg/mL for sodium ions. The reproducibility was found at 0.79% and 0.89%, for lactic acid and sodium ions respectively.

Conclusion: It was applied for sweat analysis during exercise, and the results show in agreement with the standard methods used in a clinical laboratory.

在这项工作中,一种灵活的、可穿戴的护理点(POC)设备集成在疼痛缓解贴片上,作为可穿戴的比色传感器,已被开发用于汗液分析,如乳酸、钠离子和pH值。在这里,贴片仍然起到缓解疼痛的作用,同时它允许在运动和日常活动中监测汗液。方法:采用蜡染印花技术在棉布上构建布基微流控装置(CMDs)。在这里,它使用微体积的样品在感应区进行反应,在感应区固定敏感试剂,以便它可以收集和分析汗液(乳酸,钠离子和pH)作为汗液分析物的模型。比色分析是通过智能手机摄像头进行的,使用免费的彩色图像分析应用程序(Color Grab)进行定量分析,或肉眼进行半定性分析。结果:CMDS的∆RGB值与分析物浓度呈良好的线性相关,其中乳酸(R2 = 0.994)、钠离子(R2 = 0.998)、pH (R2 = 0.994)均具有良好的相关系数。∆RGB值表示汗液样品中分析物目标浓度线性相关的适当颜色值。乳酸的检出限为45.73µg/mL,钠离子的检出限为56.46µg/mL。乳酸和钠离子的重现性分别为0.79%和0.89%。结论:该方法可用于运动时的汗液分析,结果与临床实验室标准方法一致。
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引用次数: 1
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Bioimpacts
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