Introduction: Cisplatin (DDP) is the commonest chemo drug in lung adenocarcinoma (LUAD) treatment, and DDP resistance is a significant barrier to therapeutic therapy. This study attempted to elucidate the impact of PDK1 on DDP resistance in LUAD and its mechanism.
Methods: Bioinformatics analysis was used to determine the expression and enriched pathways of PDK1 in LUAD tissue. Subsequently, E2F8, the upstream transcription factor of PDK1, was predicted, and the binding relationship between the two was analyzed using dual-luciferase and ChIP experiments. PDK1 and E2F8 levels in LUAD tissues and cells were detected via qRT-PCR. Cell viability, proliferation, and apoptosis levels were assayed by CCK-8, EdU, and flow cytometry experiments, respectively. Comet assay was used to assess DNA damage, and immunofluorescence was used to assess the expression of γ-H2AX. NHEJ reporter assay was to assess DNA repair efficiency. Western blot tested levels of DNA damage repair (DDR)-related proteins. Immunohistochemistry assessed the expression of relevant genes. Finally, an animal model was constructed to investigate the influence of PDK1 expression on LUAD growth.
Results: PDK1 was found to be upregulated in LUAD and enhanced DDP resistance by mediating DDR. E2F8 was identified as an upstream transcription factor of PDK1 and was highly expressed in LUAD. Rescue experiments presented that knocking down E2F8 could weaken the promotion of PDK1 overexpression on DDR-mediated DDP resistance in LUAD. In vivo experiments showed that knocking down PDK1 plus DDP significantly reduced the growth of xenograft tumors.
Conclusion: Our results indicated that the E2F8/PDK1 axis mediated DDR to promote DDP resistance in LUAD. Our findings lead to an improved treatment strategy after drug resistance.
{"title":"Transcription Factor E2F8 Activates PDK1-Mediated DNA Damage Repair to Enhance Cisplatin Resistance in Lung Adenocarcinoma.","authors":"Hongliang Li, Junxia Sun, Haibo Hu, Yi Wang","doi":"10.1159/000537819","DOIUrl":"10.1159/000537819","url":null,"abstract":"<p><strong>Introduction: </strong>Cisplatin (DDP) is the commonest chemo drug in lung adenocarcinoma (LUAD) treatment, and DDP resistance is a significant barrier to therapeutic therapy. This study attempted to elucidate the impact of PDK1 on DDP resistance in LUAD and its mechanism.</p><p><strong>Methods: </strong>Bioinformatics analysis was used to determine the expression and enriched pathways of PDK1 in LUAD tissue. Subsequently, E2F8, the upstream transcription factor of PDK1, was predicted, and the binding relationship between the two was analyzed using dual-luciferase and ChIP experiments. PDK1 and E2F8 levels in LUAD tissues and cells were detected via qRT-PCR. Cell viability, proliferation, and apoptosis levels were assayed by CCK-8, EdU, and flow cytometry experiments, respectively. Comet assay was used to assess DNA damage, and immunofluorescence was used to assess the expression of γ-H2AX. NHEJ reporter assay was to assess DNA repair efficiency. Western blot tested levels of DNA damage repair (DDR)-related proteins. Immunohistochemistry assessed the expression of relevant genes. Finally, an animal model was constructed to investigate the influence of PDK1 expression on LUAD growth.</p><p><strong>Results: </strong>PDK1 was found to be upregulated in LUAD and enhanced DDP resistance by mediating DDR. E2F8 was identified as an upstream transcription factor of PDK1 and was highly expressed in LUAD. Rescue experiments presented that knocking down E2F8 could weaken the promotion of PDK1 overexpression on DDR-mediated DDP resistance in LUAD. In vivo experiments showed that knocking down PDK1 plus DDP significantly reduced the growth of xenograft tumors.</p><p><strong>Conclusion: </strong>Our results indicated that the E2F8/PDK1 axis mediated DDR to promote DDP resistance in LUAD. Our findings lead to an improved treatment strategy after drug resistance.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176215","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 Acetaminophen is commonly used as an antipyretic and analgesic agent. Excessive APAP can induce liver toxicity, known as APAP induced liver injury (ALI). The metabolism and pathogenesis of APAP have been extensively studied in recent years, and many cellular processes such as autophagy, mitochondrial oxidative stress, mitochondrial dysfunction and liver regeneration have been identified to be involved in the pathogenesis of ALI. Caveolin-1 (CAV-1) as a scaffold protein has also been shown to be involved in the development of various diseases, especially liver disease and tumorigenesis. The role of CAV-1 in the development of liver disease and the association between them remains a challenging and uncharted territory. SUMMARY In this review, we briefly explore the potential therapeutic effects of CAV-1 on APAP induced ALI through autophagy, oxidative stress, and lipid metabolism. Further research to better understand the mechanisms by which CAV-1 regulates liver injury will not only enhance our understanding of this important cellular process, but also help develop new therapies for human disease by targeting CAV-1 targets. KEY MESSAGES This review briefly summarizes the potential protective mechanisms of CAV-1 against liver injury caused by APAP.
背景对乙酰氨基酚通常用作解热镇痛药。过量的 APAP 可诱发肝脏毒性，即 APAP 引起的肝损伤（ALI）。近年来，人们对 APAP 的代谢和致病机理进行了广泛研究，发现许多细胞过程，如自噬、线粒体氧化应激、线粒体功能障碍和肝脏再生，都与 ALI 的发病机理有关。Caveolin-1（CAV-1）作为一种支架蛋白，也被证明参与了多种疾病的发生，尤其是肝脏疾病和肿瘤发生。本综述简要探讨了 CAV-1 通过自噬、氧化应激和脂质代谢对 APAP 诱导的 ALI 的潜在治疗作用。为更好地了解 CAV-1 调节肝损伤的机制而开展的进一步研究，不仅能加深我们对这一重要细胞过程的理解，还有助于针对 CAV-1 靶点开发治疗人类疾病的新疗法。
{"title":"A review of the role of caveolin-1 in APAP-induced liver injury.","authors":"Wei Jiang, Junping Wang, Jiarong Wang, Xueran Chen, Zhiyou Fang, Chengmu Hu","doi":"10.1159/000538017","DOIUrl":"https://doi.org/10.1159/000538017","url":null,"abstract":"BACKGROUND\u0000Acetaminophen is commonly used as an antipyretic and analgesic agent. Excessive APAP can induce liver toxicity, known as APAP induced liver injury (ALI). The metabolism and pathogenesis of APAP have been extensively studied in recent years, and many cellular processes such as autophagy, mitochondrial oxidative stress, mitochondrial dysfunction and liver regeneration have been identified to be involved in the pathogenesis of ALI. Caveolin-1 (CAV-1) as a scaffold protein has also been shown to be involved in the development of various diseases, especially liver disease and tumorigenesis. The role of CAV-1 in the development of liver disease and the association between them remains a challenging and uncharted territory.\u0000\u0000\u0000SUMMARY\u0000In this review, we briefly explore the potential therapeutic effects of CAV-1 on APAP induced ALI through autophagy, oxidative stress, and lipid metabolism. Further research to better understand the mechanisms by which CAV-1 regulates liver injury will not only enhance our understanding of this important cellular process, but also help develop new therapies for human disease by targeting CAV-1 targets.\u0000\u0000\u0000KEY MESSAGES\u0000 This review briefly summarizes the potential protective mechanisms of CAV-1 against liver injury caused by APAP.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140664806","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}
INTRODUCTION Ventricular arrhythmia is commonly provoked by acute cardiac ischemia through sympathetic exaggeration and is often resistant to antiarrhythmic therapies. Thoracic epidural anesthesia has been reported to terminate fatal ventricular arrhythmia; however, its underlying mechanism is unknown. METHODS Rats were randomly divided into four groups: sham, sham plus bupivacaine, ischemia/reperfusion (IR), and IR plus bupivacaine groups. Bupivacaine (1 mg/mL, 0.05 mL/100 g body weight) was injected intrathecally into the L5-L6 intervertebral space prior to establishing a myocardial ischemia/reperfusion rat model. Thereafter, cardiac arrhythmia, cardiac function, myocardial injury, and electrical activities of the heart and spinal cord were evaluated. RESULTS Intrathecal bupivacaine inhibited spinal neural activity, improved heart rate variability, reduced ventricular arrhythmia score, and ameliorated cardiac dysfunction in IR rats. Furthermore, intrathecal bupivacaine attenuated cardiac injury and myocardial apoptosis and regulated cardiomyocyte autophagy and connexin-43 distribution during myocardial IR. CONCLUSION Our results indicate that intrathecal bupivacaine blunts spinal neural activity to prevent cardiac arrhythmia and dysfunction induced by IR and that this antiarrhythmic activity may be associated with regulation of autonomic balance, myocardial apoptosis and autophagy, and cardiac gap junction function.
简介：室性心律失常通常是由急性心脏缺血通过交感神经兴奋引起的，而且通常对抗心律失常疗法具有抗药性。方法将大鼠随机分为四组：假组、假组加布比卡因组、缺血/再灌注（IR）组和 IR 加布比卡因组。在建立心肌缺血/再灌注大鼠模型之前，在 L5-L6 椎间隙内注射布比卡因（1 毫克/毫升，0.05 毫升/100 克体重）。结果鞘内注射布比卡因抑制了脊髓神经活动，改善了心率变异性，降低了室性心律失常评分，并改善了 IR 大鼠的心功能障碍。此外，鞘内注射布比卡因可减轻心肌损伤和心肌细胞凋亡，并调节心肌细胞自噬和心肌IR过程中Connexin-43的分布。结论我们的研究结果表明，鞘内注射布比卡因可减弱脊髓神经活动，从而预防红外诱发的心律失常和功能障碍，这种抗心律失常活性可能与自主神经平衡、心肌细胞凋亡和自噬以及心脏间隙连接功能的调节有关。
{"title":"Intrathecal anesthesia prevents ventricular arrhythmias in rats with myocardial ischemia/reperfusion.","authors":"Huabin Zhang, Yue Wang, Yong Wu, Zhongxu Luo, Minglong Zhong, Zongyuan Hong, Deguo Wang","doi":"10.1159/000538997","DOIUrl":"https://doi.org/10.1159/000538997","url":null,"abstract":"INTRODUCTION\u0000Ventricular arrhythmia is commonly provoked by acute cardiac ischemia through sympathetic exaggeration and is often resistant to antiarrhythmic therapies. Thoracic epidural anesthesia has been reported to terminate fatal ventricular arrhythmia; however, its underlying mechanism is unknown.\u0000\u0000\u0000METHODS\u0000Rats were randomly divided into four groups: sham, sham plus bupivacaine, ischemia/reperfusion (IR), and IR plus bupivacaine groups. Bupivacaine (1 mg/mL, 0.05 mL/100 g body weight) was injected intrathecally into the L5-L6 intervertebral space prior to establishing a myocardial ischemia/reperfusion rat model. Thereafter, cardiac arrhythmia, cardiac function, myocardial injury, and electrical activities of the heart and spinal cord were evaluated.\u0000\u0000\u0000RESULTS\u0000Intrathecal bupivacaine inhibited spinal neural activity, improved heart rate variability, reduced ventricular arrhythmia score, and ameliorated cardiac dysfunction in IR rats. Furthermore, intrathecal bupivacaine attenuated cardiac injury and myocardial apoptosis and regulated cardiomyocyte autophagy and connexin-43 distribution during myocardial IR.\u0000\u0000\u0000CONCLUSION\u0000Our results indicate that intrathecal bupivacaine blunts spinal neural activity to prevent cardiac arrhythmia and dysfunction induced by IR and that this antiarrhythmic activity may be associated with regulation of autonomic balance, myocardial apoptosis and autophagy, and cardiac gap junction function.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140677441","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}
A. C. R. Gonzaga, Jayane L D Quintão, Giovane Galdino, T. Romero, Grazielle Caroline da Silva, Virgínia Soares Lemos, G. Campolina-Silva, Cleida Aparecida de Oliveira, Germán Arturo Bohórquez Mahecha, Igor Dimitri Gama Duarte
INTRODUCTION Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1β, CXCL1, norepinephrine (NE) and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. METHODS Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. RESULTS The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-β, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-β injection; (3) The non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-β; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein. CONCLUSION These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-β.
{"title":"Endogenous cholinergic system involved in peripheral analgesic control in mice is activated by TNF-α, CXCL-1 and IL-1 β.","authors":"A. C. R. Gonzaga, Jayane L D Quintão, Giovane Galdino, T. Romero, Grazielle Caroline da Silva, Virgínia Soares Lemos, G. Campolina-Silva, Cleida Aparecida de Oliveira, Germán Arturo Bohórquez Mahecha, Igor Dimitri Gama Duarte","doi":"10.1159/000538995","DOIUrl":"https://doi.org/10.1159/000538995","url":null,"abstract":"INTRODUCTION\u0000Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-α, IL-1β, CXCL1, norepinephrine (NE) and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system.\u0000\u0000\u0000METHODS\u0000Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route.\u0000\u0000\u0000RESULTS\u0000The main findings of this study were as follows: (1) carrageenan (Cg), TNF-α, CXCL-1, IL1-β, NE, and PGE2 induced hyperalgesia; (2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-α, CXCL-1, and IL1-β injection; (3) The non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1; (4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-α, CXCL-1, and IL1-β; (5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit α4protein.\u0000\u0000\u0000CONCLUSION\u0000These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-α, CXCL-1, and IL1-β.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140682070","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}
INTRODUCTION This work was designed to delve into the effects of SKA3 on glycolysis and cisplatin (CDDP) resistance in LUAD cells and to find new possibilities for individualized treatment of LUAD. METHODS LUAD mRNA expression data from the TCGA database were procured to scrutinize the differential expression patterns of SKA3 in both tumor and normal tissues. GSEA and Pearson correlation analyses were employed to elucidate the impact of SKA3 on signaling pathways within the context of LUAD. In order to discern the upstream regulatory mechanisms, the ChEA and JASPAR databases were utilized to predict the transcription factors and binding sites associated with SKA3. qRT-PCR and Western blot were implemented to assay the mRNA and protein expression levels of SKA3 and TFAP2A. Chromatin immunoprecipitation (ChIP) and dual luciferase assays were performed to solidify the binding relationship between the two. Extracellular acidification rate, glucose consumption, lactate production, and glycolysis-related proteins (HK2, GLUT1, and LDHA) were used to evaluate the level of glycolysis. Cell viability under CDDP treatment was determined utilizing the CCK-8, allowing for the calculation of IC50. The expression levels of SKA3 and TFAP2A proteins were detected by immunohistochemistry (IHC). RESULTS SKA3 exhibited upregulation in LUAD tissues and cell lines, establishing a direct linkage with glycolysis pathway. Overexpression of SKA3 fostered glycolysis in LUAD, resulting in reduced sensitivity towards CDDP treatment. The upstream transcription factor of SKA3, TFAP2A, was also upregulated in LUAD and could promote SKA3 transcription. Overexpression of TFAP2A also fostered the glycolysis of LUAD. Rescue assays showed that TFAP2A promoted glycolysis in LUAD cells by activating SKA3, reducing the sensitivity of LUAD cells to CDDP. The IHC analysis revealed a positive correlation between high expression of SKA3 and TFAP2A and CDDP resistance. CONCLUSION In summary, TFAP2A can transcriptionally activate SKA3, promote glycolysis in LUAD, and protect LUAD cells from CDDP treatment, indicating that targeting the TFAP2A/SKA3 axis may become a plausible and pragmatic therapeutic strategy for the clinical governance of LUAD.
{"title":"TFAP2A upregulates SKA3 to promote glycolysis and reduce the sensitivity of lung adenocarcinoma cells to cisplatin.","authors":"Guijun Liu, Xiang Liu, Wei Zeng, Wangyan Zhou","doi":"10.1159/000536557","DOIUrl":"https://doi.org/10.1159/000536557","url":null,"abstract":"INTRODUCTION\u0000This work was designed to delve into the effects of SKA3 on glycolysis and cisplatin (CDDP) resistance in LUAD cells and to find new possibilities for individualized treatment of LUAD.\u0000\u0000\u0000METHODS\u0000LUAD mRNA expression data from the TCGA database were procured to scrutinize the differential expression patterns of SKA3 in both tumor and normal tissues. GSEA and Pearson correlation analyses were employed to elucidate the impact of SKA3 on signaling pathways within the context of LUAD. In order to discern the upstream regulatory mechanisms, the ChEA and JASPAR databases were utilized to predict the transcription factors and binding sites associated with SKA3. qRT-PCR and Western blot were implemented to assay the mRNA and protein expression levels of SKA3 and TFAP2A. Chromatin immunoprecipitation (ChIP) and dual luciferase assays were performed to solidify the binding relationship between the two. Extracellular acidification rate, glucose consumption, lactate production, and glycolysis-related proteins (HK2, GLUT1, and LDHA) were used to evaluate the level of glycolysis. Cell viability under CDDP treatment was determined utilizing the CCK-8, allowing for the calculation of IC50. The expression levels of SKA3 and TFAP2A proteins were detected by immunohistochemistry (IHC).\u0000\u0000\u0000RESULTS\u0000SKA3 exhibited upregulation in LUAD tissues and cell lines, establishing a direct linkage with glycolysis pathway. Overexpression of SKA3 fostered glycolysis in LUAD, resulting in reduced sensitivity towards CDDP treatment. The upstream transcription factor of SKA3, TFAP2A, was also upregulated in LUAD and could promote SKA3 transcription. Overexpression of TFAP2A also fostered the glycolysis of LUAD. Rescue assays showed that TFAP2A promoted glycolysis in LUAD cells by activating SKA3, reducing the sensitivity of LUAD cells to CDDP. The IHC analysis revealed a positive correlation between high expression of SKA3 and TFAP2A and CDDP resistance.\u0000\u0000\u0000CONCLUSION\u0000In summary, TFAP2A can transcriptionally activate SKA3, promote glycolysis in LUAD, and protect LUAD cells from CDDP treatment, indicating that targeting the TFAP2A/SKA3 axis may become a plausible and pragmatic therapeutic strategy for the clinical governance of LUAD.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140681274","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}
Yi Wang, Ying Zheng, Lijia Chen, Lingjie Lin, Binwu Chen, Zhengfeng Lin, Shihui Bao
OBJECTIVE To investigate the independent risk factors associated with iatrogenic withdrawal syndrome in pediatric intensive care units (PICUs) and to establish receiver operator characteristic (ROC) curve to facilitate the diagnosis of iatrogenic withdrawal syndrome in clinical settings. METHOD Pediatric patients who received analgesic and sedative medication at a tertiary hospital in the southern Zhejiang region of China between January 2016 and December 2022 were selected for the study. Clinical case data were retrospectively analyzed to gather information including age, gender, weight, total dose of analgesic and sedative medication, total treatment duration, average maintenance dose, and other relevant parameters. Medically-induced withdrawal symptom scores were assessed using the Sophia Observation Scale for Withdrawal Symptoms (SOS). Univariate and multivariate logistic regression analyses were conducted on the above indicators to identify the risk factors for iatrogenic withdrawal, and an ROC curve was constructed. RESULTS The study encompassed a total of 104 pediatric patients, comprising 47 patients in the SOS score ≥ 4 group and 57 patients in the SOS score ≤ 3 group. The incidence of iatrogenic withdrawal was 45.19%. Univariate analysis identified cumulative total dose of fentanyl, average daily dose of fentanyl, average daily dose of midazolam, and patient weight (p<0.05) as factors associated with iatrogenic withdrawal syndrome. The logistic multiple regression analysis revealed that the average daily dose of fentanyl was an independent risk factor for the occurrence of iatrogenic withdrawal syndrome in critically ill children (p<0.05). ROC curve analysis indicated an area under the curve of 0.711 (95% CI: 0.610-0.811) with sensitivity and specificity of 73.7% and 61.7%, respectively. CONCLUSION The average daily maintenance dose of fentanyl holds significant clinical value in diagnosing and evaluating the prognosis of iatrogenic withdrawal syndrome, and can provide a scientific foundation for enhancing sedative and analgesic management in clinical practice.
{"title":"Study on risk factors and receiver operator characteristic curve of iatrogenic withdrawal syndrome in pediatric intensive care units ---A retrospective study.","authors":"Yi Wang, Ying Zheng, Lijia Chen, Lingjie Lin, Binwu Chen, Zhengfeng Lin, Shihui Bao","doi":"10.1159/000538861","DOIUrl":"https://doi.org/10.1159/000538861","url":null,"abstract":"OBJECTIVE\u0000To investigate the independent risk factors associated with iatrogenic withdrawal syndrome in pediatric intensive care units (PICUs) and to establish receiver operator characteristic (ROC) curve to facilitate the diagnosis of iatrogenic withdrawal syndrome in clinical settings.\u0000\u0000\u0000METHOD\u0000Pediatric patients who received analgesic and sedative medication at a tertiary hospital in the southern Zhejiang region of China between January 2016 and December 2022 were selected for the study. Clinical case data were retrospectively analyzed to gather information including age, gender, weight, total dose of analgesic and sedative medication, total treatment duration, average maintenance dose, and other relevant parameters. Medically-induced withdrawal symptom scores were assessed using the Sophia Observation Scale for Withdrawal Symptoms (SOS). Univariate and multivariate logistic regression analyses were conducted on the above indicators to identify the risk factors for iatrogenic withdrawal, and an ROC curve was constructed.\u0000\u0000\u0000RESULTS\u0000The study encompassed a total of 104 pediatric patients, comprising 47 patients in the SOS score ≥ 4 group and 57 patients in the SOS score ≤ 3 group. The incidence of iatrogenic withdrawal was 45.19%. Univariate analysis identified cumulative total dose of fentanyl, average daily dose of fentanyl, average daily dose of midazolam, and patient weight (p<0.05) as factors associated with iatrogenic withdrawal syndrome. The logistic multiple regression analysis revealed that the average daily dose of fentanyl was an independent risk factor for the occurrence of iatrogenic withdrawal syndrome in critically ill children (p<0.05). ROC curve analysis indicated an area under the curve of 0.711 (95% CI: 0.610-0.811) with sensitivity and specificity of 73.7% and 61.7%, respectively.\u0000\u0000\u0000CONCLUSION\u0000The average daily maintenance dose of fentanyl holds significant clinical value in diagnosing and evaluating the prognosis of iatrogenic withdrawal syndrome, and can provide a scientific foundation for enhancing sedative and analgesic management in clinical practice.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140692947","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}
Zhengjun Chen, Qiang Shi, Xuxia Liu, Guodi Lu, Jie Yang, Wenrong Luo, Fude Yang
INTRODUCTION Chronic Obstructive Pulmonary Disease (COPD) is a non-specific chronic inflammatory lung disease with no known cure. Codonopsis Radix(CR) has been shown to exhibit anti-inflammatory and antioxidant effects. Therefore, this study aimed to investigate the potential anti-inflammatory effects of different CR variety on COPD mice. METHODS 60 male specified pathogen free (SPF)-grade C57BL/6J mice were randomly divided into 6 groups, 10 mice in each group. The COPD mice model was induced by cigarette smoke extract (CSE) combined with lipopolysaccharide (LPS), and the mice in each group were given corresponding drugs. Lung function was assessed in all mice. Lung tissues were stained with hematoxylin-eosin (HE), Masson, and periodic acid shiff (PAS) stains, and serum levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were detected using an enzyme-linked immunosorbent assay (ELISA). Further, serum and lung tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by colorimetric assay. Network pharmacology and molecular docking was used to predict signalling pathways, which were validated by western blot analysis. RESULTS Compared with the COPD group, the mice in each dosing group of CR exhibited significant reductions in serum IL-8 and TNF-α levels, serum and lung tissue MDA levels, and pathological lung tissue damage, alongside elevations in lung function and SOD levels (P<0.01). Western blot analysis also indicated significant down-regulation of p-p65/p65 and p-IκB-α/IκB-α protein expression, alongside significant up-regulation of Nrf2 protein expression in the lung tissues of mice treated with CR (P<0.01). CONCLUSION In summary, CR effectively enhances lung function, minimizes lung tissue damage, and inhibits inflammation and oxidative stress in mice with COPD. Additionally, these findings suggest that inhibition of the Nrf2/NF-κB axis may be a key mechanism of action of CR in the alleviation of COPD.
{"title":"Codonopsis Radix inhibits the inflammatory response and oxidative stress in Chronic Obstructive Pulmonary Disease mice through regulation of the Nrf2/NF-κB signaling pathway.","authors":"Zhengjun Chen, Qiang Shi, Xuxia Liu, Guodi Lu, Jie Yang, Wenrong Luo, Fude Yang","doi":"10.1159/000538490","DOIUrl":"https://doi.org/10.1159/000538490","url":null,"abstract":"INTRODUCTION\u0000Chronic Obstructive Pulmonary Disease (COPD) is a non-specific chronic inflammatory lung disease with no known cure. Codonopsis Radix(CR) has been shown to exhibit anti-inflammatory and antioxidant effects. Therefore, this study aimed to investigate the potential anti-inflammatory effects of different CR variety on COPD mice.\u0000\u0000\u0000METHODS\u000060 male specified pathogen free (SPF)-grade C57BL/6J mice were randomly divided into 6 groups, 10 mice in each group. The COPD mice model was induced by cigarette smoke extract (CSE) combined with lipopolysaccharide (LPS), and the mice in each group were given corresponding drugs. Lung function was assessed in all mice. Lung tissues were stained with hematoxylin-eosin (HE), Masson, and periodic acid shiff (PAS) stains, and serum levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were detected using an enzyme-linked immunosorbent assay (ELISA). Further, serum and lung tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by colorimetric assay. Network pharmacology and molecular docking was used to predict signalling pathways, which were validated by western blot analysis.\u0000\u0000\u0000RESULTS\u0000Compared with the COPD group, the mice in each dosing group of CR exhibited significant reductions in serum IL-8 and TNF-α levels, serum and lung tissue MDA levels, and pathological lung tissue damage, alongside elevations in lung function and SOD levels (P<0.01). Western blot analysis also indicated significant down-regulation of p-p65/p65 and p-IκB-α/IκB-α protein expression, alongside significant up-regulation of Nrf2 protein expression in the lung tissues of mice treated with CR (P<0.01).\u0000\u0000\u0000CONCLUSION\u0000In summary, CR effectively enhances lung function, minimizes lung tissue damage, and inhibits inflammation and oxidative stress in mice with COPD. Additionally, these findings suggest that inhibition of the Nrf2/NF-κB axis may be a key mechanism of action of CR in the alleviation of COPD.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140709344","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}
INTRODUCTION Concomitant use of drugs in the same or different indications can sometimes lead to undesirable interactions. The prevalence of drug interactions is high in cancer patients. In this study, we aimed to determine the frequency and clinical severity of drug interactions in outpatient lung cancer patients. METHODS The drugs used, kidney and liver blood analysis results of 160 outpatient lung cancer patients over the age of 18 who received chemotherapy between October 2020 and July 2021 were evaluated. The Lexi-Interact online database was used to identify the types of clinically significant drug interactions, frequently interacting drugs, and clinical outcomes predicted by the databases. RESULTS The average number of drugs per patient was 4.2±2.3. It was determined that there was a relationship between multi-drug use and comorbidity, and the number of drugs used increased as the number of diagnoses increased. A relationship was also found between potential drug-drug interactions (pDDI), which we observed in 52.5% of the patients, and the number of drugs used and age. The most common clinically significant C (36.9%), D (16.9%) and X (10.6%) type pDDI were detected between conventional paclitaxel-hydrochlorothiazide, conventional paclitaxel-carboplatin, and ipratropium-tiotropium, respectively. CONCLUSIONS The use of frequently interacting drugs in outpatient lung cancer patients can lead to pDDI. In these patients, the application of therapy by observing the drug-drug interaction may improve the quality of life.
{"title":"Potential drug-drug interactions in outpatient lung cancer patients in a university hospital.","authors":"M. Demirkapu, E. Çavdar","doi":"10.1159/000538742","DOIUrl":"https://doi.org/10.1159/000538742","url":null,"abstract":"INTRODUCTION\u0000Concomitant use of drugs in the same or different indications can sometimes lead to undesirable interactions. The prevalence of drug interactions is high in cancer patients. In this study, we aimed to determine the frequency and clinical severity of drug interactions in outpatient lung cancer patients.\u0000\u0000\u0000METHODS\u0000The drugs used, kidney and liver blood analysis results of 160 outpatient lung cancer patients over the age of 18 who received chemotherapy between October 2020 and July 2021 were evaluated. The Lexi-Interact online database was used to identify the types of clinically significant drug interactions, frequently interacting drugs, and clinical outcomes predicted by the databases.\u0000\u0000\u0000RESULTS\u0000The average number of drugs per patient was 4.2±2.3. It was determined that there was a relationship between multi-drug use and comorbidity, and the number of drugs used increased as the number of diagnoses increased. A relationship was also found between potential drug-drug interactions (pDDI), which we observed in 52.5% of the patients, and the number of drugs used and age. The most common clinically significant C (36.9%), D (16.9%) and X (10.6%) type pDDI were detected between conventional paclitaxel-hydrochlorothiazide, conventional paclitaxel-carboplatin, and ipratropium-tiotropium, respectively.\u0000\u0000\u0000CONCLUSIONS\u0000The use of frequently interacting drugs in outpatient lung cancer patients can lead to pDDI. In these patients, the application of therapy by observing the drug-drug interaction may improve the quality of life.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140735437","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}
Rahmad Abdillah, Milla Maulina, Afni Rahmatika, Netty Suharti, A. Armenia
INTRODUCTION Traditionally and empirically, Hibiscus sabdariffa L. have been used in treating diabetes mellitus due to their antioxidant activity. This study aims to investigate the effect of administering the ethyl acetate fraction of hibiscus calyxes on malondialdehyde (MDA) levels, Tumor Necrosis Factor-α (TNF-α) levels, bleeding time, and platelet count in male white rats induced with streptozotocin-induced diabetes. METHOD Thirty-six Wistar Kyoto rats were induced with intra-peritoneal streptozotocin at 55 mg/kg BW and stabilized for five days to obtain diabetic conditions. Diabetic animals were divided into four groups; the diabetic group was given vehicle, the glibenclamide group was given 0.45 mg/kg BW of Glibenclamide, and two groups were administered the ethyl acetate fraction of hibiscus calyxes (EAFHC) at doses of 100 mg/kg BW and 200 mg/kg BW for five days. Subsequently, the MDA, TNF-α, bleeding time and platelet count levels were examined on days 1, 3, and 5, respectively. All data were analyzed using two-way ANOVA followed by the Duncan Multiple Rank Test (DMRT). RESULTS EAFHC significantly reduced MDA and TNF-α levels (p<0.05). Additionally, this fraction appeared to shorten bleeding time and decrease platelet count in diabetic rats. Administration of the EAFHC for five days effectively lowered MDA and TNF-α levels significantly, decreased platelet counts and prolonged coagulation (p<0.05) in diabetic rats. CONCLUSION This study demonstrates that EAFHC effectively reduces MDA and TNF-α levels and reduces the risk of hypercoagulability in diabetic model.
{"title":"Roselle Calyx (Hibiscus Sabdariffa. L) Ethyl Acetate Fraction Lowering MDA, TNF-α and Reduce Hypercoagulability in Diabetic Model.","authors":"Rahmad Abdillah, Milla Maulina, Afni Rahmatika, Netty Suharti, A. Armenia","doi":"10.1159/000538362","DOIUrl":"https://doi.org/10.1159/000538362","url":null,"abstract":"INTRODUCTION\u0000Traditionally and empirically, Hibiscus sabdariffa L. have been used in treating diabetes mellitus due to their antioxidant activity. This study aims to investigate the effect of administering the ethyl acetate fraction of hibiscus calyxes on malondialdehyde (MDA) levels, Tumor Necrosis Factor-α (TNF-α) levels, bleeding time, and platelet count in male white rats induced with streptozotocin-induced diabetes.\u0000\u0000\u0000METHOD\u0000Thirty-six Wistar Kyoto rats were induced with intra-peritoneal streptozotocin at 55 mg/kg BW and stabilized for five days to obtain diabetic conditions. Diabetic animals were divided into four groups; the diabetic group was given vehicle, the glibenclamide group was given 0.45 mg/kg BW of Glibenclamide, and two groups were administered the ethyl acetate fraction of hibiscus calyxes (EAFHC) at doses of 100 mg/kg BW and 200 mg/kg BW for five days. Subsequently, the MDA, TNF-α, bleeding time and platelet count levels were examined on days 1, 3, and 5, respectively. All data were analyzed using two-way ANOVA followed by the Duncan Multiple Rank Test (DMRT).\u0000\u0000\u0000RESULTS\u0000EAFHC significantly reduced MDA and TNF-α levels (p<0.05). Additionally, this fraction appeared to shorten bleeding time and decrease platelet count in diabetic rats. Administration of the EAFHC for five days effectively lowered MDA and TNF-α levels significantly, decreased platelet counts and prolonged coagulation (p<0.05) in diabetic rats.\u0000\u0000\u0000CONCLUSION\u0000This study demonstrates that EAFHC effectively reduces MDA and TNF-α levels and reduces the risk of hypercoagulability in diabetic model.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140736657","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}
S. Rafiq, Irene Mungure, Y. Banz, Nicolas J. Niklaus, Thomas Kaufmann, Stefan Müller, A. Jacquel, G. Robert, P. Auberger, B. Torbett, Sylviane Muller, M. Tschan, Magali Humbert
INTRODUCTION Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapies are focused towards tumor debulking, all-trans retinoic acid (ATRA) induces neutrophil differentiation in the AML subtype acute promyelocytic leukemia (APL). Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects. On the contrary, the implications of chaperone-mediated autophagy (CMA) on the pathophysiology of diseases are still being explored and its role in AML has remains elusive. METHODS We took advantages of human AML primary samples and databases to analyze CMA gene expression and activity. Furthermore, we used ATRA-sensitive (NB4) and -resistant (NB4-R1) cells to further dissect a potential function for CMA in ATRA-mediated neutrophil differentiation. NB4-R1 cells are unique in that they do respond to retinoic acid transcriptionally, but do not mature in response to retinoid signaling alone unless maturation is triggered by adding cAMP. RESULTS Here, we report that CMA related mRNA transcripts are significantly higher expressed in immature hematopoietic cells as compared to neutrophils, contrasting the macroautophagy gene expression patterns. Accordingly, lysosomal degradation of an mCherry-KFERQ CMA reporter decreases during ATRA-induced differentiation of APL cells. On the other hand, using NB4-R1 cells we found that macroautophagy flux primed ATRA resistant NB4-R1 cells to differentiate upon ATRA treatment, but reduced association of lysosome-associated membrane protein type 2A (LAMP-2A) and heat shock protein family A (Hsp70) member 8 (HSPA8), which are necessary for complete neutrophil maturation. Accordingly, depletion of HSPA8 attenuated CMA activity and facilitated APL cell differentiation. In contrast, maintaining high CMA activity by ectopic expression of LAMP-2A impeded APL differentiation. CONCLUSION Overall, our findings suggest that APL neutrophil differentiation requires CMA inactivation and that this pathway predominantly depends on HSPA8 and is possibly assisted by other co-chaperones.
{"title":"HSPA8 chaperone complex drives chaperone-mediated autophagy regulation in acute promyelocytic leukemia cell differentiation.","authors":"S. Rafiq, Irene Mungure, Y. Banz, Nicolas J. Niklaus, Thomas Kaufmann, Stefan Müller, A. Jacquel, G. Robert, P. Auberger, B. Torbett, Sylviane Muller, M. Tschan, Magali Humbert","doi":"10.1159/000537864","DOIUrl":"https://doi.org/10.1159/000537864","url":null,"abstract":"INTRODUCTION\u0000Acute myeloid leukemia (AML) is a cancer of the hematopoietic system characterized by hyperproliferation of undifferentiated cells of the myeloid lineage. While most of AML therapies are focused towards tumor debulking, all-trans retinoic acid (ATRA) induces neutrophil differentiation in the AML subtype acute promyelocytic leukemia (APL). Macroautophagy has been extensively investigated in the context of various cancers and is often dysregulated in AML where it can have context-dependent pro- or anti-leukemogenic effects. On the contrary, the implications of chaperone-mediated autophagy (CMA) on the pathophysiology of diseases are still being explored and its role in AML has remains elusive.\u0000\u0000\u0000METHODS\u0000We took advantages of human AML primary samples and databases to analyze CMA gene expression and activity. Furthermore, we used ATRA-sensitive (NB4) and -resistant (NB4-R1) cells to further dissect a potential function for CMA in ATRA-mediated neutrophil differentiation. NB4-R1 cells are unique in that they do respond to retinoic acid transcriptionally, but do not mature in response to retinoid signaling alone unless maturation is triggered by adding cAMP.\u0000\u0000\u0000RESULTS\u0000Here, we report that CMA related mRNA transcripts are significantly higher expressed in immature hematopoietic cells as compared to neutrophils, contrasting the macroautophagy gene expression patterns. Accordingly, lysosomal degradation of an mCherry-KFERQ CMA reporter decreases during ATRA-induced differentiation of APL cells. On the other hand, using NB4-R1 cells we found that macroautophagy flux primed ATRA resistant NB4-R1 cells to differentiate upon ATRA treatment, but reduced association of lysosome-associated membrane protein type 2A (LAMP-2A) and heat shock protein family A (Hsp70) member 8 (HSPA8), which are necessary for complete neutrophil maturation. Accordingly, depletion of HSPA8 attenuated CMA activity and facilitated APL cell differentiation. In contrast, maintaining high CMA activity by ectopic expression of LAMP-2A impeded APL differentiation.\u0000\u0000\u0000CONCLUSION\u0000Overall, our findings suggest that APL neutrophil differentiation requires CMA inactivation and that this pathway predominantly depends on HSPA8 and is possibly assisted by other co-chaperones.","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140749918","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}
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