Pub Date : 2024-08-30eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S489524
Guanyu Yang, Qinjun Chu
{"title":"Effects of Propofol, Low and High Doses of Remimazolam on Hemodynamic and Inflammatory Response in Laparoscopic Surgery [Letter].","authors":"Guanyu Yang, Qinjun Chu","doi":"10.2147/DDDT.S489524","DOIUrl":"10.2147/DDDT.S489524","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S491658
Vidak Raičević
{"title":"Flavopereirine Suppresses the Progression of Human Oral Cancer by Inhibiting the JAK-STAT Signaling Pathway via Targeting LASP1 [Letter].","authors":"Vidak Raičević","doi":"10.2147/DDDT.S491658","DOIUrl":"10.2147/DDDT.S491658","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Secukinumab, a monoclonal antibody targeting interleukin (IL)-17A, is approved for the treatment of psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, enthesitis-related arthritis, and hidradenitis suppurativa. This study compared the pharmacokinetics (PK), safety, and immunogenicity of CMAB015, a candidate secukinumab biosimilar, with the reference product secukinumab (Cosentyx®) in healthy Chinese male subjects.
Patients and methods: This double-blind, parallel-group study randomized healthy Chinese male subjects (N=130) to receive either a single dose of 150 mg CMAB015 or secukinumab subcutaneously. Primary study endpoints were PK parameters such as the maximum concentration (Cmax) and area under the curve from zero to infinity (AUC0-inf), while safety and immunogenicity were secondary endpoints.
Results: The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of Cmax and AUC0-inf for CMAB015 to secukinumab were all within the bioequivalence limits (80.00-125.00%). Other PK parameters were comparable between the groups. The safety profile of CMAB015 was similar to that of secukinumab, with no serious adverse events related to treatment. The incidence of TEAEs was slightly higher in the CMAB015 group, but these events were mild to moderate in severity and did not lead to any withdrawals from the study. Immunogenicity analysis revealed low rates of anti-drug antibody (ADA) positivity, with similar rates between CMAB015 and secukinumab.
Conclusion: This study demonstrated equivalent PK, comparable safety, and immunogenicity of CMAB015 to secukinumab in healthy Chinese male subjects. These findings support further clinical evaluation of CMAB015 as a secukinumab biosimilar.
Trial registration: The trial was registered on Clinicaltrials.gov (Identifier No. NCT05734482) and Chinadrugtrials.org.cn (Identifier No. CTR20230105).
{"title":"A Randomized, Double-Blind, Parallel-Group Phase I Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of CMAB015, a Candidate Secukinumab Biosimilar, with Its Reference Product Cosentyx<sup>®</sup> in Healthy Chinese Male Subjects.","authors":"Feng Yao, Chenguang Wang, Jie Ding, Qian Zhang, Liang Zheng, Qin Zhang, Tianshu Yang, Xunmin Zhang, Yong Shan, Sheng Hou, Hao Wang, Renpeng Zhou, Wei Hu","doi":"10.2147/DDDT.S470619","DOIUrl":"10.2147/DDDT.S470619","url":null,"abstract":"<p><strong>Purpose: </strong>Secukinumab, a monoclonal antibody targeting interleukin (IL)-17A, is approved for the treatment of psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, enthesitis-related arthritis, and hidradenitis suppurativa. This study compared the pharmacokinetics (PK), safety, and immunogenicity of CMAB015, a candidate secukinumab biosimilar, with the reference product secukinumab (Cosentyx<sup>®</sup>) in healthy Chinese male subjects.</p><p><strong>Patients and methods: </strong>This double-blind, parallel-group study randomized healthy Chinese male subjects (N=130) to receive either a single dose of 150 mg CMAB015 or secukinumab subcutaneously. Primary study endpoints were PK parameters such as the maximum concentration (C<sub>max</sub>) and area under the curve from zero to infinity (AUC<sub>0-inf</sub>), while safety and immunogenicity were secondary endpoints.</p><p><strong>Results: </strong>The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of C<sub>max</sub> and AUC<sub>0-inf</sub> for CMAB015 to secukinumab were all within the bioequivalence limits (80.00-125.00%). Other PK parameters were comparable between the groups. The safety profile of CMAB015 was similar to that of secukinumab, with no serious adverse events related to treatment. The incidence of TEAEs was slightly higher in the CMAB015 group, but these events were mild to moderate in severity and did not lead to any withdrawals from the study. Immunogenicity analysis revealed low rates of anti-drug antibody (ADA) positivity, with similar rates between CMAB015 and secukinumab.</p><p><strong>Conclusion: </strong>This study demonstrated equivalent PK, comparable safety, and immunogenicity of CMAB015 to secukinumab in healthy Chinese male subjects. These findings support further clinical evaluation of CMAB015 as a secukinumab biosimilar.</p><p><strong>Trial registration: </strong>The trial was registered on Clinicaltrials.gov (Identifier No. NCT05734482) and Chinadrugtrials.org.cn (Identifier No. CTR20230105).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S470684
Ting Liu, Luxu Wang, Tuo Shi, Hongrui Liu, Bo Liu, Jie Guo, Minqi Li
Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms.
Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3β signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels.
Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3β activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3β inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression.
Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3β signaling pathway is involved in the regulation of BMAL1.
{"title":"ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1.","authors":"Ting Liu, Luxu Wang, Tuo Shi, Hongrui Liu, Bo Liu, Jie Guo, Minqi Li","doi":"10.2147/DDDT.S470684","DOIUrl":"10.2147/DDDT.S470684","url":null,"abstract":"<p><strong>Purpose: </strong>Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms.</p><p><strong>Methods: </strong>A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3β signaling pathway. DCFH-DA staining was used to detect reactive oxygen species (ROS) levels.</p><p><strong>Results: </strong>ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3β activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3β inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression.</p><p><strong>Conclusion: </strong>ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3β signaling pathway is involved in the regulation of BMAL1.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S467066
Jingjing Wei, Zhaoyang Liu, Mingming Li, Lingyun Du, Xia Zhu, Yi Leng, Changyu Han, Qingqing Xu, Chunhong Zhang
Background: Psoriasis is an immune-mediated chronic inflammatory disease. Qingre Lishi Decoction (QRLSD) has achieved great clinical effect in the treatment of psoriasis. However, the potential bioactive components and the mechanisms are yet unclear.
Aim: To analyze the serum parameters of rats fed with QRLSD, screen out the active components of QRLSD, and explore the potential targets and pathway of QRLSD in the treatment of psoriasis.
Materials and methods: The active components of serum containing QRLSD were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The targets of QRLSD in the treatment of psoriasis were predicted by network pharmacology and molecular docking. In vitro experiments verified the underlying mechanism.
Results: By UPLC-Q-TOF/MS, 15 prototype components and 22 metabolites were identified in serum containing QRLSD. Subsequently, 260 chemical composition targets and 218 psoriasis targets were overlapped to obtain 23 intersection targets, including LGALS3, TNF, F10, DPP4, EGFR, MAPK14, STAT3 and others. TNF, IL-10, GAPDH, STAT3, EGFR, ITGB1, LGALS3 genes were identified as potential drug targets in the PPI network analyzed by CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that QRLSD may improve psoriasis by regulating immune and inflammatory pathways, the cytokine mediated signal transduction pathways and other signaling pathways. Molecular docking results showed that the main active components of the serum containing QRLSD had higher affinities for TNF and LGALS3. In vitro experiments confirmed that QRLSD may decrease levels of inflammatory cytokines by suppressing the NF-κB signaling pathway activated by TNF-α in human keratinocytes.
Conclusion: This study explores the potential compounds, targets and signaling pathways of QRLSD in the treatment of psoriasis, which will help clarify the efficacy and mechanism of QRLSD.
{"title":"Based on UPLC-Q-TOF/MS and Network Pharmacology to Explore the Mechanism of Qingre Lishi Decoction in the Treatment of Psoriasis.","authors":"Jingjing Wei, Zhaoyang Liu, Mingming Li, Lingyun Du, Xia Zhu, Yi Leng, Changyu Han, Qingqing Xu, Chunhong Zhang","doi":"10.2147/DDDT.S467066","DOIUrl":"10.2147/DDDT.S467066","url":null,"abstract":"<p><strong>Background: </strong>Psoriasis is an immune-mediated chronic inflammatory disease. Qingre Lishi Decoction (QRLSD) has achieved great clinical effect in the treatment of psoriasis. However, the potential bioactive components and the mechanisms are yet unclear.</p><p><strong>Aim: </strong>To analyze the serum parameters of rats fed with QRLSD, screen out the active components of QRLSD, and explore the potential targets and pathway of QRLSD in the treatment of psoriasis.</p><p><strong>Materials and methods: </strong>The active components of serum containing QRLSD were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The targets of QRLSD in the treatment of psoriasis were predicted by network pharmacology and molecular docking. In vitro experiments verified the underlying mechanism.</p><p><strong>Results: </strong>By UPLC-Q-TOF/MS, 15 prototype components and 22 metabolites were identified in serum containing QRLSD. Subsequently, 260 chemical composition targets and 218 psoriasis targets were overlapped to obtain 23 intersection targets, including LGALS3, TNF, F10, DPP4, EGFR, MAPK14, STAT3 and others. TNF, IL-10, GAPDH, STAT3, EGFR, ITGB1, LGALS3 genes were identified as potential drug targets in the PPI network analyzed by CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that QRLSD may improve psoriasis by regulating immune and inflammatory pathways, the cytokine mediated signal transduction pathways and other signaling pathways. Molecular docking results showed that the main active components of the serum containing QRLSD had higher affinities for TNF and LGALS3. In vitro experiments confirmed that QRLSD may decrease levels of inflammatory cytokines by suppressing the NF-κB signaling pathway activated by TNF-α in human keratinocytes.</p><p><strong>Conclusion: </strong>This study explores the potential compounds, targets and signaling pathways of QRLSD in the treatment of psoriasis, which will help clarify the efficacy and mechanism of QRLSD.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11366256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Currently, there is still no clear treatment for polycystic ovary syndrome (PCOS). YJKL has better therapeutic effects and lower toxic side effects for PCOS type infertility. This study aims to clarify the potential mechanism of YJKL Decoction in the treatment of PCOS based on network pharmacology and experiments verification.
Patients and methods: Network pharmacology and experimental validation approach were used to investigate the bioactive ingredients, critical targets and potential mechanisms of YJKL Decoction against PCOS. Firstly, we use network pharmacology methods to collect core targets, and then validate their effects on diseases through experiments.
Results: Five core targets were screened, Threonine kinase 1 (AKT1), Cellular tumor antigen p53 (TP53), Tumor necrosis factor (TNF), Albumin (ALB) and Vascular endothelial growthfactor A (VEGFA). KEGG analysis showed that YJKL treatment for PCOS mainly include AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway and HIF-1 signaling pathway. The molecular docking results showed that compounds have higher affinity with targets. Finally, experimental results had shown that YJKL Decoction had an better therapeutic effects in the treatment of PCOS.
Conclusion: Based on a systematic network pharmacology approach and experimental verification, our results comprehensively illustrated the active ingredients, potential targets, and molecular mechanism of YJKL for application to PCOS and helps to illustrate mechanism of action on a comprehensive level.
{"title":"Mechanism of YJKL Decoction in Treating of PCOS Infertility by Integrative Approach of Network Pharmacology and Experimental Verification.","authors":"Rongrong Zhang, Wenjun Xu, Hongquan Wei, Boshi Li, Yaoxing Wang, Xueqing He, Jun Cao, Xinyu He, Mingxiang Xu, Wenjie Lu, Youzhi Xu","doi":"10.2147/DDDT.S456656","DOIUrl":"10.2147/DDDT.S456656","url":null,"abstract":"<p><strong>Purpose: </strong>Currently, there is still no clear treatment for polycystic ovary syndrome (PCOS). YJKL has better therapeutic effects and lower toxic side effects for PCOS type infertility. This study aims to clarify the potential mechanism of YJKL Decoction in the treatment of PCOS based on network pharmacology and experiments verification.</p><p><strong>Patients and methods: </strong>Network pharmacology and experimental validation approach were used to investigate the bioactive ingredients, critical targets and potential mechanisms of YJKL Decoction against PCOS. Firstly, we use network pharmacology methods to collect core targets, and then validate their effects on diseases through experiments.</p><p><strong>Results: </strong>Five core targets were screened, Threonine kinase 1 (AKT1), Cellular tumor antigen p53 (TP53), Tumor necrosis factor (TNF), Albumin (ALB) and Vascular endothelial growthfactor A (VEGFA). KEGG analysis showed that YJKL treatment for PCOS mainly include AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway and HIF-1 signaling pathway. The molecular docking results showed that compounds have higher affinity with targets. Finally, experimental results had shown that YJKL Decoction had an better therapeutic effects in the treatment of PCOS.</p><p><strong>Conclusion: </strong>Based on a systematic network pharmacology approach and experimental verification, our results comprehensively illustrated the active ingredients, potential targets, and molecular mechanism of YJKL for application to PCOS and helps to illustrate mechanism of action on a comprehensive level.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11366254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S464004
Na Yan, Xianggui Wang, Zufang Xu, Linling Zhong, Jiangyong Yang
Introduction: Apigenin is a natural flavonoid compound with promising potential for the attenuation of myocardial hypertrophy (MH). The compound can also modulate the expression of miR-185-5p that both promote MH and suppress autophagy. The current attempts to explain the anti-MH effect of apigenin by focusing on changes in miR-185-5p-mediated autophagy.
Methods: Hypertrophic symptoms were induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using Ang II and then handled with apigenin. Changes in myocardial function and structure and cell viability and surface area were measured. The role of miR-185-5p in the anti-MH function of apigenin was explored by detecting changes in autophagic processes and miR-185-5p/SREBP2 axis.
Results: TAC surgery induced weight increase, structure destruction, and collagen deposition in hearts of model rats. Ang II suppresses cardiomyocyte viability and increased cell surface area. All these impairments were attenuated by apigenin and were associated with the restored level of autophagy. At the molecular level, the expression of miR-185-5p was up-regulated by TAC, while the expression of SREBP2 was down-regulated, which was reserved by apigenin both in vivo and in vitro. The induction of miR-185-5p in cardiomyocytes could counteracted the protective effects of apigenin.
Discussion: Collectively, the findings outlined in the current study highlighted that apigenin showed anti-MH effects. The effects were related to the inhibition of miR-185-5p and activation of SREBP, which contributed to the increased autophagy.
简介芹菜素是一种天然类黄酮化合物,具有减轻心肌肥厚(MH)的潜力。该化合物还能调节 miR-185-5p 的表达,而 miR-185-5p 既能促进心肌肥厚,又能抑制自噬。方法:用横向主动脉收缩法(TAC)诱导大鼠出现肥厚症状,用 Ang II 诱导心肌细胞出现肥厚症状,然后用芹菜素处理。测量了心肌功能和结构的变化以及细胞活力和表面积。通过检测自噬过程和 miR-185-5p/SREBP2 轴的变化,探讨了 miR-185-5p 在芹菜素抗 MH 功能中的作用:结果:TAC手术导致模型大鼠心脏重量增加、结构破坏和胶原沉积。血管紧张素 II 可抑制心肌细胞活力并增加细胞表面积。芹菜素减轻了所有这些损伤,并与自噬水平的恢复有关。在分子水平上,TAC 上调了 miR-185-5p 的表达,同时下调了 SREBP2 的表达。心肌细胞中miR-185-5p的诱导可抵消芹菜素的保护作用:总之,本研究概述的发现突出表明芹菜素具有抗心肌缺血的作用。这些作用与抑制 miR-185-5p 和激活 SREBP 有关,而后者有助于增加自噬。
{"title":"Apigenin Attenuates Transverse Aortic Constriction-Induced Myocardial Hypertrophy: The Key Role of miR-185-5p/SREBP2-Mediated Autophagy.","authors":"Na Yan, Xianggui Wang, Zufang Xu, Linling Zhong, Jiangyong Yang","doi":"10.2147/DDDT.S464004","DOIUrl":"10.2147/DDDT.S464004","url":null,"abstract":"<p><strong>Introduction: </strong>Apigenin is a natural flavonoid compound with promising potential for the attenuation of myocardial hypertrophy (MH). The compound can also modulate the expression of miR-185-5p that both promote MH and suppress autophagy. The current attempts to explain the anti-MH effect of apigenin by focusing on changes in miR-185-5p-mediated autophagy.</p><p><strong>Methods: </strong>Hypertrophic symptoms were induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using Ang II and then handled with apigenin. Changes in myocardial function and structure and cell viability and surface area were measured. The role of miR-185-5p in the anti-MH function of apigenin was explored by detecting changes in autophagic processes and miR-185-5p/SREBP2 axis.</p><p><strong>Results: </strong>TAC surgery induced weight increase, structure destruction, and collagen deposition in hearts of model rats. Ang II suppresses cardiomyocyte viability and increased cell surface area. All these impairments were attenuated by apigenin and were associated with the restored level of autophagy. At the molecular level, the expression of miR-185-5p was up-regulated by TAC, while the expression of SREBP2 was down-regulated, which was reserved by apigenin both in vivo and in vitro. The induction of miR-185-5p in cardiomyocytes could counteracted the protective effects of apigenin.</p><p><strong>Discussion: </strong>Collectively, the findings outlined in the current study highlighted that apigenin showed anti-MH effects. The effects were related to the inhibition of miR-185-5p and activation of SREBP, which contributed to the increased autophagy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S461769
Yujie Li, Yadong Yin, Juan Xiong, Zhipeng Zhang, Linglong Li, Baoshun Zhang, Feng Zhang, Dehong Mao
Background: Yujiang Paidu Decoction (YJPD) has demonstrated clinical efficacy in the treatment of chronic rhinosinusitis. However, the effects and mechanisms of the YJPD on chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear.
Purpose: This study aimed to elucidate the potential mechanism of action of YJPD in the treatment of CRSwNP based on network pharmacology, transcriptomics and experiments.
Methods: A CRSwNP mouse model was established using ovalbumin (OVA) and staphylococcus aureus enterotoxin B (SEB) for 12 weeks and the human nasal epithelial cell (HNEpC) model was induced with IL-13 in vitro. Behavioral tests, scanning electron microscopy (SEM), micro-CT and pathological change of nasal tissues were observed to investigate the therapeutic effects of YJPD. Network pharmacology and transcriptomics were launched to explore the pharmacological mechanisms of YJPD in CRSwNP treatment. Finally, an ELISA, immunofluorescence, RT-qPCR, Western blotting and Tunel were performed for validation.
Results: Different doses of YJPD intervention effectively alleviated rubbing and sneezing symptoms in CRSwNP mice. Additionally, YJPD significantly reduced abnormal serological markers, structural damage of the nasal mucosa, inflammatory cell infiltration, goblet cell increases, and inhibited OVA-specific IgE levels and the secretion of Th2 cytokines such as IL-4, IL-5, and IL-13. Moreover, transcriptomics and network pharmacology analyses indicated that YJPD may exert anti-inflammatory and anti-apoptotic effects by inhibiting the MAPK/AP-1 signaling pathway. The experimental findings supported this conclusion, which was further corroborated by similar results observed in IL13-induced HNEpCs in vitro.
Conclusion: YJPD could alleviate inflammatory status and epithelial apoptosis by inhibiting aberrant activation of MAPK/AP-1 signaling pathway. This finding provides a strong basis for using YJPD as a potential treatment in CRSwNP.
{"title":"Combining Network Pharmacology and Transcriptomics to Investigate the Mechanisms of Yujiang Paidu Decoction in the Treatment of Chronic Rhinosinusitis with Nasal Polyps.","authors":"Yujie Li, Yadong Yin, Juan Xiong, Zhipeng Zhang, Linglong Li, Baoshun Zhang, Feng Zhang, Dehong Mao","doi":"10.2147/DDDT.S461769","DOIUrl":"10.2147/DDDT.S461769","url":null,"abstract":"<p><strong>Background: </strong>Yujiang Paidu Decoction (YJPD) has demonstrated clinical efficacy in the treatment of chronic rhinosinusitis. However, the effects and mechanisms of the YJPD on chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear.</p><p><strong>Purpose: </strong>This study aimed to elucidate the potential mechanism of action of YJPD in the treatment of CRSwNP based on network pharmacology, transcriptomics and experiments.</p><p><strong>Methods: </strong>A CRSwNP mouse model was established using ovalbumin (OVA) and staphylococcus aureus enterotoxin B (SEB) for 12 weeks and the human nasal epithelial cell (HNEpC) model was induced with IL-13 in vitro. Behavioral tests, scanning electron microscopy (SEM), micro-CT and pathological change of nasal tissues were observed to investigate the therapeutic effects of YJPD. Network pharmacology and transcriptomics were launched to explore the pharmacological mechanisms of YJPD in CRSwNP treatment. Finally, an ELISA, immunofluorescence, RT-qPCR, Western blotting and Tunel were performed for validation.</p><p><strong>Results: </strong>Different doses of YJPD intervention effectively alleviated rubbing and sneezing symptoms in CRSwNP mice. Additionally, YJPD significantly reduced abnormal serological markers, structural damage of the nasal mucosa, inflammatory cell infiltration, goblet cell increases, and inhibited OVA-specific IgE levels and the secretion of Th2 cytokines such as IL-4, IL-5, and IL-13. Moreover, transcriptomics and network pharmacology analyses indicated that YJPD may exert anti-inflammatory and anti-apoptotic effects by inhibiting the MAPK/AP-1 signaling pathway. The experimental findings supported this conclusion, which was further corroborated by similar results observed in IL13-induced HNEpCs in vitro.</p><p><strong>Conclusion: </strong>YJPD could alleviate inflammatory status and epithelial apoptosis by inhibiting aberrant activation of MAPK/AP-1 signaling pathway. This finding provides a strong basis for using YJPD as a potential treatment in CRSwNP.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S472660
Elis Susilawati, Jutti Levita, Yasmiwar Susilawati, Sri Adi Sumiwi
Background: The twigs and roots of Erythrina subumbrans (Hassk). Merr. Was reported to possess antidiabetic activity by reducing the activity of α-glucosidase and α-amylase. TNF-α is a pro-inflammatory cytokine in obesity and diabetes mellitus (DM). It inhibits the action of insulin, causing insulin resistance. Adiponectin is an anti-inflammatory peptide synthesized in white adipose tissue (WAT) and its high levels are linked with a decreased risk of DM. However, information about the effect of Erythrina subumbrans (Hassk). Merr. on insulin resistance are still lacking.
Purpose: To obtain the effects of the ethanol extract of E. subumbrans (Hassk) Merr. leaves (EES) in improving insulin resistance conditions.
Methods: The leaves were collected at Ciamis, West Java, Indonesia, and were extracted using ethanol 96%. The effects of EES were studied in fructose-induced adult male Wistar rats by performing the insulin tolerance test (ITT) and assessing blood glucose, TNF-α, adiponectin, and FFA levels. The number of WAT and BAT of the adipose tissues was also studied. The total phenols and flavonoids in EES were determined by the spectrophotometric method and the presence of quercetin in EES was analyzed using the LC-MS method.
Results: EES significantly reduced % weight gain, TNF-α levels, and increased adiponectin levels in fructose-induced Wistar rats. EES significantly reduced the FFA levels of fructose-induced Wistar rats and significantly affected the formation of BAT similar to that of metformin. All rats in EES and metformin groups improved insulin resistance as proven by higher ITT values (3.01 ± 0.91 for EES 100 mg/kg BW; 3.01 ± 1.22 for EES 200 mg/kg BW; 5.86 ± 3.13 for EES 400 mg/kg BW; and 6.44 ± 2.58 for metformin) compared with the fructose-induced group without treatment (ITT = 2.62 ± 1.38). EES contains polyphenol compounds (2.7638 ± 0.0430 mg GAE/g extract), flavonoids (1.9626 ± 0.0152 mg QE/g extract), and quercetin 0.246 µg/mL at m/z 301.4744.
Conclusion: Erythrina subumbrans (Hassk). Merr. extract may have the potential to be further explored for its activity in improving insulin resistance conditions. However, further studies are needed to confirm its role in alleviating metabolic disorders.
背景:Erythrina subumbrans (Hassk).Merr.据报道,它能降低α-葡萄糖苷酶和α-淀粉酶的活性,从而具有抗糖尿病活性。TNF-α 是肥胖症和糖尿病(DM)中的一种促炎细胞因子。它抑制胰岛素的作用,导致胰岛素抵抗。脂联素是一种在白色脂肪组织(WAT)中合成的抗炎肽,其高水平与降低糖尿病风险有关。然而,有关 Erythrina subumbrans (Hassk).目的:了解 E. subumbrans (Hassk) Merr. 叶子的乙醇提取物(EES)对改善胰岛素抵抗状况的影响:方法:在印度尼西亚西爪哇的 Ciamis 采集叶片,用 96% 的乙醇提取。通过对果糖诱导的成年雄性 Wistar 大鼠进行胰岛素耐受试验(ITT)并评估血糖、TNF-α、脂肪连接蛋白和 FFA 水平,研究 EES 的效果。此外,还研究了脂肪组织中 WAT 和 BAT 的数量。采用分光光度法测定了 EES 中的总酚和黄酮类化合物,并采用 LC-MS 方法分析了 EES 中槲皮素的含量:结果:EES能明显降低果糖诱导的Wistar大鼠的体重增加率、TNF-α水平,并增加脂肪连蛋白水平。EES 能明显降低果糖诱导的 Wistar 大鼠体内的 FFA 水平,并能明显影响 BAT 的形成,其效果与二甲双胍相似。与果糖诱导组(ITT = 2.62 ± 1.38)相比,所有 EES 组和二甲双胍组大鼠的 ITT 值均有所提高(EES 100 mg/kg BW 为 3.01 ± 0.91;EES 200 mg/kg BW 为 3.01 ± 1.22;EES 400 mg/kg BW 为 5.86 ± 3.13;二甲双胍为 6.44 ± 2.58),这证明 EES 组和二甲双胍组大鼠的胰岛素抵抗均有所改善。EES 含有多酚化合物(2.7638 ± 0.0430 mg GAE/g提取物)、类黄酮(1.9626 ± 0.0152 mg QE/g提取物)和槲皮素 0.246 µg/mL m/z 301.4744:结论:Erythrina subumbrans (Hassk).结论:Erythrina subumbrans (Hassk)err.然而,还需要进一步的研究来证实其在缓解代谢紊乱方面的作用。
{"title":"<i>Erythrina subumbrans</i> (Hassk) Merr. (Fabaceae) Inhibits Insulin Resistance in the Adipose Tissue of High Fructose-Induced Wistar Rats.","authors":"Elis Susilawati, Jutti Levita, Yasmiwar Susilawati, Sri Adi Sumiwi","doi":"10.2147/DDDT.S472660","DOIUrl":"10.2147/DDDT.S472660","url":null,"abstract":"<p><strong>Background: </strong>The twigs and roots of <i>Erythrina subumbrans</i> (Hassk). Merr. Was reported to possess antidiabetic activity by reducing the activity of α-glucosidase and α-amylase. TNF-α is a pro-inflammatory cytokine in obesity and diabetes mellitus (DM). It inhibits the action of insulin, causing insulin resistance. Adiponectin is an anti-inflammatory peptide synthesized in white adipose tissue (WAT) and its high levels are linked with a decreased risk of DM. However, information about the effect of <i>Erythrina subumbrans</i> (Hassk). Merr. on insulin resistance are still lacking.</p><p><strong>Purpose: </strong>To obtain the effects of the ethanol extract of <i>E. subumbrans</i> (Hassk) Merr. leaves (EES) in improving insulin resistance conditions.</p><p><strong>Methods: </strong>The leaves were collected at Ciamis, West Java, Indonesia, and were extracted using ethanol 96%. The effects of EES were studied in fructose-induced adult male Wistar rats by performing the insulin tolerance test (ITT) and assessing blood glucose, TNF-α, adiponectin, and FFA levels. The number of WAT and BAT of the adipose tissues was also studied. The total phenols and flavonoids in EES were determined by the spectrophotometric method and the presence of quercetin in EES was analyzed using the LC-MS method.</p><p><strong>Results: </strong>EES significantly reduced % weight gain, TNF-α levels, and increased adiponectin levels in fructose-induced Wistar rats. EES significantly reduced the FFA levels of fructose-induced Wistar rats and significantly affected the formation of BAT similar to that of metformin. All rats in EES and metformin groups improved insulin resistance as proven by higher ITT values (3.01 ± 0.91 for EES 100 mg/kg BW; 3.01 ± 1.22 for EES 200 mg/kg BW; 5.86 ± 3.13 for EES 400 mg/kg BW; and 6.44 ± 2.58 for metformin) compared with the fructose-induced group without treatment (ITT = 2.62 ± 1.38). EES contains polyphenol compounds (2.7638 ± 0.0430 mg GAE/g extract), flavonoids (1.9626 ± 0.0152 mg QE/g extract), and quercetin 0.246 µg/mL at m/z 301.4744.</p><p><strong>Conclusion: </strong><i>Erythrina subumbrans</i> (Hassk). Merr. extract may have the potential to be further explored for its activity in improving insulin resistance conditions. However, further studies are needed to confirm its role in alleviating metabolic disorders.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27eCollection Date: 2024-01-01DOI: 10.2147/DDDT.S475535
Chuanjiang Dong, Yueqing Wang, Yi Cai, Yuhuang Wu, Wei Chen, Lu Wang, Xiaowen Liu, Lili Zou, Jun Wang
Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs.
Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model.
Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity.
Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.
目的:结核病(TB)仍然是全球主要的健康威胁,耐药性结核病(DR)的传播阻碍了全球疾病负担的减轻。依布色林(EbSe)以细菌硫氧还原酶(bTrxR)为靶标,导致细菌氧化还原状态失衡。先前的工作表明,EbSe 对 bTrxR 的协同作用和对普通抗生素的增敏作用是治疗 DR 病原体的一种很有前景的策略。因此,我们旨在评估 EbSe 是否能增强抗结核药物对马林分枝杆菌(M. marinum)的作用:方法:通过微量稀释法测定异烟肼(INH)、利福平(RFP)和链霉素(SM)对马林桿菌的最小抑菌浓度(MIC)。Bliss Independence 模型用于确定 EbSe 对抗结核药物的辅助作用。使用 DTNB 试验测定了硫代氧化还原酶的活性,并通过细胞内 ROS 水平和细胞内 GSH 水平的升高验证了 EbSe 对细菌氧化还原平衡的影响。EbSe 作为抗结核药物的辅助疗效在小鼠 M. marinum 感染模型中得到了进一步评估。在巨噬细胞 Raw264.7 和小鼠模型中观察到了细胞毒性:结果表明,EbSe 比 SM 对 M. marinum 起着抗生素辅助作用。EbSe+SM通过抑制bTrxR的活性,破坏了M. marinum细胞内的氧化还原微环境,可将小鼠从高细菌负荷中解救出来,并加速尾部损伤的恢复,且对哺乳动物的毒性较低:上述研究表明,EbSe 能显著增强 SM 的抗 Mtb 作用,其协同组合在体外和体内均表现出较低的哺乳动物毒性。需要进一步研究 EbSe 作为抗生素辅助剂与抗结核药物 MS 联用的内在机制。
{"title":"Enhance the Antimycobacterial Activity of Streptomycin with Ebselen as an Antibiotic Adjuvant Through Disrupting Redox Homeostasis.","authors":"Chuanjiang Dong, Yueqing Wang, Yi Cai, Yuhuang Wu, Wei Chen, Lu Wang, Xiaowen Liu, Lili Zou, Jun Wang","doi":"10.2147/DDDT.S475535","DOIUrl":"10.2147/DDDT.S475535","url":null,"abstract":"<p><strong>Purpose: </strong>Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against <i>Mycobacterium marinum</i> (<i>M. marinum</i>) which is genetically related to <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) and resistant to many antituberculosis drugs.</p><p><strong>Methods: </strong>Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against <i>M. marinum</i> were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of <i>M. marinum</i> infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model.</p><p><strong>Results: </strong>The results reveal that EbSe acts as an antibiotic adjuvant over SM on <i>M. marinum</i>. EbSe + SM disrupted the intracellular redox microenvironment of <i>M. marinum</i> by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity.</p><p><strong>Conclusion: </strong>The above studies suggest that EbSe significantly enhanced the anti-<i>Mtb</i> effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}