Objectives: Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase.
Methods: We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect.
Results: Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients.
Conclusion: This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.
{"title":"A prediction method for the individual serum concentration and therapeutic effect for optimizing adalimumab therapy in inflammatory bowel disease.","authors":"Koji Kimura, Atsushi Yoshida","doi":"10.1093/jpp/rgae092","DOIUrl":"https://doi.org/10.1093/jpp/rgae092","url":null,"abstract":"<p><strong>Objectives: </strong>Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase.</p><p><strong>Methods: </strong>We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect.</p><p><strong>Results: </strong>Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients.</p><p><strong>Conclusion: </strong>This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objectives: Migraine, typically occurs on one side of the head, lasts for hours to days. Trigemino-vascular system (TVS) plays a vital role in pain generation, with neurogenic inflammation and oxidative stress playing key roles in its pathophysiology.
Methods: This study aimed to investigate genistein's potential as anti-inflammatory and anti-oxidant agent in mitigating migraine pain. Genistein (20 and 50 mg/kg) was administered intraperitoneally (IP) to nitroglycerin (NTG; 10 mg/kg)-induced migraine model in rats. Behavioral analysis, antioxidant assay, immunohistochemistry (IHC), histopathological examination, ELISA, and RT-PCR were conducted to evaluate the antimigraine potential of genistein.
Key findings: In-silico analysis showed genestien's ACE values of -4.8 to -9.2 Kcal/mol against selected protein targets. Genistein significantly reversed mechanical and thermal nociception, light phobicity, and head scratching; increased the intensities of GST, GSH, catalase; and down regulated lipid peroxidase (LPO) in cortex and trigeminal nucleus caudalis (TNC). It also reduced Nrf2, NF-kB, and IL6 expression, analyzed through IHC, improved histopathological features, and increased COX-2 and decreased PPAR-γ expressions, while RT-PCR analysis revealed increased PPAR-γ expressions in genistein-treated rats.
Conclusion: Genistein exhibited potent antioxidant and anti-inflammatory properties in migraine treatment, acting through multifactorial mechanisms by modulating the expression of numerous proteins in the region cortex and TNC.
{"title":"Pharmacological investigation of genistein for its therapeutic potential against nitroglycerin-induced migraine headache.","authors":"Qirrat Sajjad, Arif-Ullah Khan, Aslam Khan","doi":"10.1093/jpp/rgae084","DOIUrl":"https://doi.org/10.1093/jpp/rgae084","url":null,"abstract":"<p><strong>Objectives: </strong>Migraine, typically occurs on one side of the head, lasts for hours to days. Trigemino-vascular system (TVS) plays a vital role in pain generation, with neurogenic inflammation and oxidative stress playing key roles in its pathophysiology.</p><p><strong>Methods: </strong>This study aimed to investigate genistein's potential as anti-inflammatory and anti-oxidant agent in mitigating migraine pain. Genistein (20 and 50 mg/kg) was administered intraperitoneally (IP) to nitroglycerin (NTG; 10 mg/kg)-induced migraine model in rats. Behavioral analysis, antioxidant assay, immunohistochemistry (IHC), histopathological examination, ELISA, and RT-PCR were conducted to evaluate the antimigraine potential of genistein.</p><p><strong>Key findings: </strong>In-silico analysis showed genestien's ACE values of -4.8 to -9.2 Kcal/mol against selected protein targets. Genistein significantly reversed mechanical and thermal nociception, light phobicity, and head scratching; increased the intensities of GST, GSH, catalase; and down regulated lipid peroxidase (LPO) in cortex and trigeminal nucleus caudalis (TNC). It also reduced Nrf2, NF-kB, and IL6 expression, analyzed through IHC, improved histopathological features, and increased COX-2 and decreased PPAR-γ expressions, while RT-PCR analysis revealed increased PPAR-γ expressions in genistein-treated rats.</p><p><strong>Conclusion: </strong>Genistein exhibited potent antioxidant and anti-inflammatory properties in migraine treatment, acting through multifactorial mechanisms by modulating the expression of numerous proteins in the region cortex and TNC.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141620261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG).
Methods: The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies.
Results: FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking.
Conclusion: FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid.
{"title":"Exploring the anxiolytic mechanism of Fructus gardeniae based on metabolomics, network pharmacology, and molecular docking.","authors":"Yue Tian, Fuli Yuan, Jiao Kong, Zhenshuang Yuan, Chunxue Jia, Hongqian Kui, Ziqiang Yin, Chuanxin Liu, Jianmei Huang","doi":"10.1093/jpp/rgad102","DOIUrl":"https://doi.org/10.1093/jpp/rgad102","url":null,"abstract":"<p><strong>Objective: </strong>To explore the effect and anxiolytic mechanism of a natural remedy called Fructus gardeniae (FG).</p><p><strong>Methods: </strong>The elevated-plus maze (EPM) test was used to confirm the anxiolytic effect of FG. The potential and anxiolytic components, targets, and route processes of FG were investigated using the network pharmacology method in conjunction with metabolomics and molecular docking technologies.</p><p><strong>Results: </strong>FG could greatly enhance the proportion of time and times of opening arms, according to the EPM data. As to the metabolomics findings, a total of 61 distinct metabolites were found, mainly involved in glycine, serine, and threonine metabolism as well as alanine, aspartate, and glutamate metabolism. The primary active ingredients of FG, nicotiflorin, jasminodiol, and crocetin, demonstrated substantial binding affinities with monoamine oxidase A (MAOA), monoamine oxidase A (ACHE), malate dehydrogenase 2 (MDH2), glutamate decarboxylase 2 (GAD2), glutamate decarboxylase 1 (GAD1), and nitric oxide synthase (NOS1), according to the findings of network pharmacology and molecular docking.</p><p><strong>Conclusion: </strong>FG exerts an anxiolytic action via targeting MAOA, ACHE, MDH2, GAD2, GAD1, and NOS1, and regulating the metabolism of glycine, serine, and threonine as well as alanine, aspartic acid, and glutamic acid.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zeyu Song, Zhenyuan Li, Tao Pan, Teng Liu, Baifang Gong, Zhixia Wang, Ke Liu, Huaying Fan
Objectives: Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms.
Methods: In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins.
Results: PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system.
Conclusion: PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.
目的:顺铂(CDDP)引起的急性肾损伤(AKI)是一种复杂的危重疾病,目前尚无有效或特异的治疗方法。本研究的目的是评估原人参二醇(PPD)对 CDDP 诱导的 AKI 模型肾脏的保护作用及其可能的机制:方法:在体外,在HK-2中评估PPD的保护作用。方法:在体外,评估 PPD 对 HK-2 的保护作用;在体内,给 KM 小鼠注射 CDDP 诱导 AKI 模型。测定血尿素氮和血清肌酐(SCr),并通过组织病理学检查病理变化。采用免疫染色和 Western 印迹分析蛋白质的表达水平:结果:PPD能提高被CDDP损伤的HK-2细胞的存活率,改善细胞形态,缓解小鼠AKI症状。此外,PPD还能下调TRF的蛋白表达,上调铁蛋白重链、谷胱甘肽过氧化物酶4和铁突变抑制蛋白1的蛋白表达,降低细胞和肾组织中的铁含量,恢复抗氧化防御系统:结论:PPD对顺铂诱导的肾毒性有抑制作用,这可能与通过调节铁代谢和脂质过氧化抑制铁变态反应有关。
{"title":"Protopanaxadiol prevents cisplatin-induced acute kidney injury by regulating ferroptosis.","authors":"Zeyu Song, Zhenyuan Li, Tao Pan, Teng Liu, Baifang Gong, Zhixia Wang, Ke Liu, Huaying Fan","doi":"10.1093/jpp/rgae050","DOIUrl":"10.1093/jpp/rgae050","url":null,"abstract":"<p><strong>Objectives: </strong>Acute kidney injury (AKI) caused by cisplatin (CDDP) is a complex, critical illness with no effective or specific treatment. The purpose of the study was to assess the protective effect of protopanaxadiol (PPD) on the kidneys in CDDP-induced AKI models and its possible mechanisms.</p><p><strong>Methods: </strong>In vitro, the protection of PPD was assessed in HK-2. KM mice were injected with CDDP to induce AKI models in vivo. The determination of blood urea nitrogen and serum creatinine (SCr) was performed, and pathological changes were examined by histopathological examination. Immunostaining and western blot analyses were used to analyze the expression levels of proteins.</p><p><strong>Results: </strong>PPD can increase the viability of HK-2 cells damaged by CDDP, improve cell morphology, and alleviate the symptoms of AKI in mice. In addition, PPD can down-regulate the protein expression of TRF and up-regulate the protein expression of Ferritin heavy chain, Glutathione peroxidase 4, and ferroptosis suppressor protein 1 reduce the iron content in cells and kidney tissues, and restore the antioxidant defense system.</p><p><strong>Conclusion: </strong>PPD has an inhibitory effect on cisplatin-induced nephrotoxicity, which may be related to the inhibition of ferroptosis by regulating iron metabolism and lipid peroxidation.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lili Guan, Lei Zhang, Dezheng Gong, Pengcheng Li, Shengnan Zhu, Jiulan Tang, Man Du, Maokun Zhang, Yuan Zou
Objectives: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats.
Methods: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined.
Key findings: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously.
Conclusions: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.
目的:胆汁酸(BA)作为调节新陈代谢的信号分子,受到了广泛关注。吉尼平是从藁本中提取的一种铱类化合物,已被证明可以缓解肥胖和代谢综合征。在此,我们研究了吉尼平对抗饮食诱导肥胖(DIO)大鼠肥胖的机制及其与 BAs 信号的关系:方法:给 DIO 大鼠腹腔注射吉尼平 10 天。方法:给 DIO 大鼠腹腔注射吉尼平 10 天,测定其体重、内脏脂肪、肝脏脂质代谢、棕色脂肪中致热基因的表达、BAs 代谢和信号以及合成 BAs 的关键酶:主要研究结果:吉尼平抑制了DIO大鼠肝脏中脂肪的合成,促进了脂肪的分解,并上调了棕色脂肪组织中致热基因的表达。吉尼平提高了胆汁流速,并上调了肝脏中水汽蛋白 8 和 BAs 转运体的表达。此外,吉尼平通过促进胆汁酸合成的替代途径和抑制经典途径改变了胆汁酸的组成,并同步上调了胆汁酸受体的表达:这些结果表明,吉尼平可通过 BAs 介导的信号通路改善肥胖症。
{"title":"Genipin improves obesity through promoting bile secretion and changing bile acids composition in diet-induced obese rats.","authors":"Lili Guan, Lei Zhang, Dezheng Gong, Pengcheng Li, Shengnan Zhu, Jiulan Tang, Man Du, Maokun Zhang, Yuan Zou","doi":"10.1093/jpp/rgae055","DOIUrl":"10.1093/jpp/rgae055","url":null,"abstract":"<p><strong>Objectives: </strong>Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats.</p><p><strong>Methods: </strong>The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined.</p><p><strong>Key findings: </strong>Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously.</p><p><strong>Conclusions: </strong>These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: Brusatol (BT) is a quassinoid compound extracted from Brucea javanica that is a traditional Chinese herbal medicine. Brusatol possesses biological and medical activity, including antitumor, antileukemia, anti-inflammatory, antitrypanosomal, antimalarial, and antitobacco mosaic virus activity. To summarize and discuss the antitumor effects of BT and its mechanisms of actions, we compiled this review by combining the extensive relevant literature and our previous studies.
Methods: We searched and retrieved the papers that reported the pharmacological effects of BT and the mechanism of BT antitumor activity from PubMed until July 2023.
Key findings: Numerous studies have shown that BT is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor that acts on various signaling pathways and has good antitumor properties. Brusatol shows great potential in cancer therapy by inhibiting cell proliferation, blocking the cell cycle, promoting tumor cell differentiation, accelerating tumor cell apoptosis, inducing autophagy, suppressing angiogenesis, inhibiting tumor invasion and metastasis, and reversing multidrug resistance.
Conclusion: This review summarizes recent updates on the antitumor activity and molecular mechanisms of BT and provides references for future development and clinical translation of BT and its derivatives as antitumor drugs.
{"title":"Brusatol's anticancer activity and its molecular mechanism: a research update.","authors":"Wenyi Xi, Chenhui Zhao, Zeyu Wu, Tongtong Ye, Rui Zhao, Xiaochun Jiang, Shizhang Ling","doi":"10.1093/jpp/rgae017","DOIUrl":"10.1093/jpp/rgae017","url":null,"abstract":"<p><strong>Objective: </strong>Brusatol (BT) is a quassinoid compound extracted from Brucea javanica that is a traditional Chinese herbal medicine. Brusatol possesses biological and medical activity, including antitumor, antileukemia, anti-inflammatory, antitrypanosomal, antimalarial, and antitobacco mosaic virus activity. To summarize and discuss the antitumor effects of BT and its mechanisms of actions, we compiled this review by combining the extensive relevant literature and our previous studies.</p><p><strong>Methods: </strong>We searched and retrieved the papers that reported the pharmacological effects of BT and the mechanism of BT antitumor activity from PubMed until July 2023.</p><p><strong>Key findings: </strong>Numerous studies have shown that BT is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor that acts on various signaling pathways and has good antitumor properties. Brusatol shows great potential in cancer therapy by inhibiting cell proliferation, blocking the cell cycle, promoting tumor cell differentiation, accelerating tumor cell apoptosis, inducing autophagy, suppressing angiogenesis, inhibiting tumor invasion and metastasis, and reversing multidrug resistance.</p><p><strong>Conclusion: </strong>This review summarizes recent updates on the antitumor activity and molecular mechanisms of BT and provides references for future development and clinical translation of BT and its derivatives as antitumor drugs.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139940139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objectives: Lung cancer is one of the malignant tumors that threaten human health seriously. Long non-coding RNA (lncRNA) is an important factor affecting tumorigenesis and development. However, the mechanism of lncRNA in lung cancer progression remains to be further explored.
Methods: In this study, the TCGA database was analyzed, and LINC01572 was found to be increased in lung adenocarcinoma (LUAD) tissues. Thereafter, with the help of databases including lncBase, TargetScan, and mirDIP, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, LINC01572/miRNA-338-5p/TTK regulatory axis and downstream p53 signaling pathway were excavated. qRT-PCR was adopted to detect levels of LINC01572, miRNA-338-5p, and TTK in LUAD cells. The role that LINC01572 played in LUAD cells was validated by CCK-8 assay, flow cytometry, colony formation, Transwell, and scratch healing assays. The binding ability between LINC01572/TTK and miRNA-338-5p was then verified by dual-luciferase and RIP analysis.
Key findings: The results of this study demonstrated that LINC01572 was elevated in LUAD cells compared with normal cells. The overexpression of LINC01572 promoted the proliferative and migratory properties of LUAD cells but inhibited cell apoptosis. The inhibition of LINC01572 resulted in the opposite result. In addition, rescue experiments revealed that LINC01572, as a molecular sponge of miRNA-338-5p, targeted TTK to manipulate p53 for facilitating LUAD cell malignant progression. Apart from this, we constructed a mouse xenograft model and confirmed that the knockdown of LINC01572 hindered the growth of LUAD solid tumors in vivo.
Conclusions: Our findings illuminated the molecular mechanism of LINC01572 influencing LUAD and provided new insights for targeted therapy of LUAD cells.
{"title":"LINC01572 promotes the malignant progression of lung adenocarcinoma by modulating p53 mediated by miRNA-338-5p/TTK axis.","authors":"Shilan Liu, Xiao Liu, Qinghui Yang, Chunhua Zeng, Gang Hu, Bochen Ren","doi":"10.1093/jpp/rgad128","DOIUrl":"10.1093/jpp/rgad128","url":null,"abstract":"<p><strong>Objectives: </strong>Lung cancer is one of the malignant tumors that threaten human health seriously. Long non-coding RNA (lncRNA) is an important factor affecting tumorigenesis and development. However, the mechanism of lncRNA in lung cancer progression remains to be further explored.</p><p><strong>Methods: </strong>In this study, the TCGA database was analyzed, and LINC01572 was found to be increased in lung adenocarcinoma (LUAD) tissues. Thereafter, with the help of databases including lncBase, TargetScan, and mirDIP, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, LINC01572/miRNA-338-5p/TTK regulatory axis and downstream p53 signaling pathway were excavated. qRT-PCR was adopted to detect levels of LINC01572, miRNA-338-5p, and TTK in LUAD cells. The role that LINC01572 played in LUAD cells was validated by CCK-8 assay, flow cytometry, colony formation, Transwell, and scratch healing assays. The binding ability between LINC01572/TTK and miRNA-338-5p was then verified by dual-luciferase and RIP analysis.</p><p><strong>Key findings: </strong>The results of this study demonstrated that LINC01572 was elevated in LUAD cells compared with normal cells. The overexpression of LINC01572 promoted the proliferative and migratory properties of LUAD cells but inhibited cell apoptosis. The inhibition of LINC01572 resulted in the opposite result. In addition, rescue experiments revealed that LINC01572, as a molecular sponge of miRNA-338-5p, targeted TTK to manipulate p53 for facilitating LUAD cell malignant progression. Apart from this, we constructed a mouse xenograft model and confirmed that the knockdown of LINC01572 hindered the growth of LUAD solid tumors in vivo.</p><p><strong>Conclusions: </strong>Our findings illuminated the molecular mechanism of LINC01572 influencing LUAD and provided new insights for targeted therapy of LUAD cells.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140850143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chunjing Yang, Li Bao, Zhengyuan Shi, Xiqiao Xv, Dechun Jiang, Longtai You
Background: Phillyrin, the major lignin compound of Forsythia suspense (Thunb.) Vahl, has been shown the effects of anti-inflammatory and antioxidant. Our study was aimed to explore the protective effect of phillyrin on glomerular mesangial cells (HBZY-1) and the potential mechanism.
Methods: Cell viability, cytokine production, levels of reactive oxygen radicals (ROS), glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD), as well as autophagy and apoptosis levels were determined to verify the mechanism of phillyrin on HBZY-1 cells.
Results: Our result indicated that phillyrin significantly inhibited HG-induced HBZY-1 proliferation by inhibiting Bcl-2 expression and upregulating Bad, cleaved caspase-3, and -9 expression. Also, phillyrin suppressed HG-induced mesangial extracellular matrix accumulation by inhibiting the expression of fibronectin and transforming growth factor-β1. Further, phillyrin inhibited oxidative stress and inflammation by decreasing ROS, MDA, TNF-α, IL-1β, and IL-6 contents and increasing SOD and GSH expression. Phillyrin also promoted autophagy by increasing LC3-II/LC3-I ratio and down-regulating p62 expression. Furthermore, WB assay showed that phillyrin inhibited oxidative stress caused by HG via activating Nrf2 signaling pathway, while attenuated proliferation and inflammation in HBZY-1 cells through inactivating PI3K/Akt/mTOR and NF-κB pathways.
Conclusion: All results showed that phillyrin might be a promising therapeutic agent for the treatment of DN.
{"title":"Phillyrin alleviates high glucose-induced oxidative stress and inflammation in HBZY-1 cells through inhibition of the PI3K/Akt signaling pathway.","authors":"Chunjing Yang, Li Bao, Zhengyuan Shi, Xiqiao Xv, Dechun Jiang, Longtai You","doi":"10.1093/jpp/rgae028","DOIUrl":"10.1093/jpp/rgae028","url":null,"abstract":"<p><strong>Background: </strong>Phillyrin, the major lignin compound of Forsythia suspense (Thunb.) Vahl, has been shown the effects of anti-inflammatory and antioxidant. Our study was aimed to explore the protective effect of phillyrin on glomerular mesangial cells (HBZY-1) and the potential mechanism.</p><p><strong>Methods: </strong>Cell viability, cytokine production, levels of reactive oxygen radicals (ROS), glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD), as well as autophagy and apoptosis levels were determined to verify the mechanism of phillyrin on HBZY-1 cells.</p><p><strong>Results: </strong>Our result indicated that phillyrin significantly inhibited HG-induced HBZY-1 proliferation by inhibiting Bcl-2 expression and upregulating Bad, cleaved caspase-3, and -9 expression. Also, phillyrin suppressed HG-induced mesangial extracellular matrix accumulation by inhibiting the expression of fibronectin and transforming growth factor-β1. Further, phillyrin inhibited oxidative stress and inflammation by decreasing ROS, MDA, TNF-α, IL-1β, and IL-6 contents and increasing SOD and GSH expression. Phillyrin also promoted autophagy by increasing LC3-II/LC3-I ratio and down-regulating p62 expression. Furthermore, WB assay showed that phillyrin inhibited oxidative stress caused by HG via activating Nrf2 signaling pathway, while attenuated proliferation and inflammation in HBZY-1 cells through inactivating PI3K/Akt/mTOR and NF-κB pathways.</p><p><strong>Conclusion: </strong>All results showed that phillyrin might be a promising therapeutic agent for the treatment of DN.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Elevated reactive oxygen species levels promote excessive osteoclastogenesis and bone resorption. Puerarin, a natural antioxidant, can prevent bone loss through its antioxidant effects; however, the underlying molecular mechanism remains unclear. This study aimed to explore the effects of puerarin on osteoclast differentiation and bone resorption by regulating the PI3K/AKT/FoxO1 signaling pathway.
Materials and methods: An ovariectomized (OVX) rat model of osteoporosis and H2O2-induced oxidative cell model of RAW 264.7 cells were established. The following indices were measured including bone μ-CT scanning and the protein expression levels of FoxO1, p-FoxO1, and catalase were detected using western blotting.
Results: Puerarin strongly alleviated oxidative stress-induced bone loss in OVX rats in vivo owing to its antioxidant effects. Puerarin improved the oxidative stress status of cells and inhibited osteoclast formation in vitro. Moreover, the protein expression of FoxO1 and its downstream target, catalase, was upregulated by puerarin.
Conclusions: Puerarin improved the OPG/RANKL ratio, upregulated the protein expression and transcriptional activity of FoxO1, and suppressed the differentiation of RAW264.7 cells into osteoclasts. FoxO1 is a pivotal target of puerarin to confer anti-osteoporosis effects.
背景:活性氧水平升高会促进破骨细胞过度生成和骨吸收。葛根素是一种天然抗氧化剂,可通过其抗氧化作用防止骨质流失;然而,其潜在的分子机制仍不清楚。本研究旨在探讨葛根素通过调节PI3K/AKT/FoxO1信号通路对破骨细胞分化和骨吸收的影响:建立卵巢切除(OVX)大鼠骨质疏松症模型和 H2O2 诱导的 RAW 264.7 细胞氧化模型。测量指标包括骨μ-CT扫描,并用Western印迹法检测FoxO1、p-FoxO1和过氧化氢酶的蛋白表达水平:结果:葛根素具有抗氧化作用,能有效缓解氧化应激诱导的OVX大鼠体内骨质流失。葛根素能改善细胞的氧化应激状态,抑制体外破骨细胞的形成。此外,葛根素还能上调FoxO1及其下游靶标过氧化氢酶的蛋白表达:结论:葛根素能改善OPG/RANKL比率,上调FoxO1的蛋白表达和转录活性,抑制RAW264.7细胞向破骨细胞的分化。FoxO1是葛根素抗骨质疏松作用的关键靶点。
{"title":"FoxO1 as the critical target of puerarin to inhibit osteoclastogenesis and bone resorption.","authors":"Yanling Feng, Xulei Tang","doi":"10.1093/jpp/rgae033","DOIUrl":"10.1093/jpp/rgae033","url":null,"abstract":"<p><strong>Background: </strong>Elevated reactive oxygen species levels promote excessive osteoclastogenesis and bone resorption. Puerarin, a natural antioxidant, can prevent bone loss through its antioxidant effects; however, the underlying molecular mechanism remains unclear. This study aimed to explore the effects of puerarin on osteoclast differentiation and bone resorption by regulating the PI3K/AKT/FoxO1 signaling pathway.</p><p><strong>Materials and methods: </strong>An ovariectomized (OVX) rat model of osteoporosis and H2O2-induced oxidative cell model of RAW 264.7 cells were established. The following indices were measured including bone μ-CT scanning and the protein expression levels of FoxO1, p-FoxO1, and catalase were detected using western blotting.</p><p><strong>Results: </strong>Puerarin strongly alleviated oxidative stress-induced bone loss in OVX rats in vivo owing to its antioxidant effects. Puerarin improved the oxidative stress status of cells and inhibited osteoclast formation in vitro. Moreover, the protein expression of FoxO1 and its downstream target, catalase, was upregulated by puerarin.</p><p><strong>Conclusions: </strong>Puerarin improved the OPG/RANKL ratio, upregulated the protein expression and transcriptional activity of FoxO1, and suppressed the differentiation of RAW264.7 cells into osteoclasts. FoxO1 is a pivotal target of puerarin to confer anti-osteoporosis effects.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140329906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: The Duhuo-Jisheng pair is the ruling herb in Duhuo Jisheng decoction, which is a classic formula first recorded in the preparedness and urgency of the thousand jewels.
Methods: We obtained the primary constituents of Duhuo-Jisheng and their associated protein targets from the TCMSP database. We constructed a composite target network using Cytoscape 3.9.1. To identify potential targets for the treatment of osteoarthritis (OA), we retrieved disease targets from OMIM and GeneCards databases and compared them with the composite targets. We imported the overlapping targets into the STRING database to construct a protein-protein interaction (PPI) network. We also conducted Gene ontology (GO) and KEGG enrichment analyses on the targets.
Results: The component target network consisted of numerous nodes and edges. Notably, quercetin, ammidin, and β-sitosterol were identified as the compounds with high degrees. The PPI network identified tumour necrosis factor (TNF), TP53, and NOS2 as proteins with high degrees. The results of GO and KEGG analyses revealed that the signalling pathways used by DHQJD to treat OA included the NF-κB, PI3K-AKT, and TNF pathways.
Conclusion: Our study provides insights into the effective components and potential molecular mechanisms of Duhuo-Jisheng in treating OA, thus serving as a reference for further basic research in this field.
目的:杜藿济生对是杜藿济生煎的主药:杜霍济生对是杜霍济生煎中的主药,是最早记载于《千金备急》中的经典方剂:方法:我们从中医药数据库(TCMSP)中获得了杜霍济生的主要成分及其相关蛋白靶标。我们使用 Cytoscape 3.9.1 构建了一个复合靶标网络。为了确定治疗骨关节炎(OA)的潜在靶点,我们从 OMIM 和 GeneCards 数据库中检索了疾病靶点,并与复合靶点进行了比较。我们将重叠的靶点导入 STRING 数据库,构建了蛋白质-蛋白质相互作用(PPI)网络。我们还对靶标进行了基因本体(GO)和KEGG富集分析:结果:靶标网络由许多节点和边缘组成。值得注意的是,槲皮素、杏仁苷和β-谷甾醇被确定为具有较高程度的化合物。在 PPI 网络中,肿瘤坏死因子(TNF)、TP53 和 NOS2 被确定为高度蛋白。GO和KEGG分析结果显示,DHQJD用于治疗OA的信号通路包括NF-κB、PI3K-AKT和TNF通路:我们的研究深入揭示了杜霍集生片治疗 OA 的有效成分和潜在分子机制,为该领域的基础研究提供了参考。
{"title":"Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Duhuo-Jisheng pair against osteoarthritis.","authors":"Haiyang Kou, Jianbing Ma","doi":"10.1093/jpp/rgad117","DOIUrl":"10.1093/jpp/rgad117","url":null,"abstract":"<p><strong>Objective: </strong>The Duhuo-Jisheng pair is the ruling herb in Duhuo Jisheng decoction, which is a classic formula first recorded in the preparedness and urgency of the thousand jewels.</p><p><strong>Methods: </strong>We obtained the primary constituents of Duhuo-Jisheng and their associated protein targets from the TCMSP database. We constructed a composite target network using Cytoscape 3.9.1. To identify potential targets for the treatment of osteoarthritis (OA), we retrieved disease targets from OMIM and GeneCards databases and compared them with the composite targets. We imported the overlapping targets into the STRING database to construct a protein-protein interaction (PPI) network. We also conducted Gene ontology (GO) and KEGG enrichment analyses on the targets.</p><p><strong>Results: </strong>The component target network consisted of numerous nodes and edges. Notably, quercetin, ammidin, and β-sitosterol were identified as the compounds with high degrees. The PPI network identified tumour necrosis factor (TNF), TP53, and NOS2 as proteins with high degrees. The results of GO and KEGG analyses revealed that the signalling pathways used by DHQJD to treat OA included the NF-κB, PI3K-AKT, and TNF pathways.</p><p><strong>Conclusion: </strong>Our study provides insights into the effective components and potential molecular mechanisms of Duhuo-Jisheng in treating OA, thus serving as a reference for further basic research in this field.</p>","PeriodicalId":16960,"journal":{"name":"Journal of Pharmacy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139111034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}