INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 5
·2251
·
IF 4.9
Canhong Wang,Yulan Wu,Bao Gong,Xiangsheng Zhao,Hui Meng,Junyu Mou,Xiaoling Cheng,Yinfeng Tan,Jianhe Wei
Dalbergia odoriferais widely used to treat cardiovascular diseases. Our research group found thatDalbergia odoriferavolatile oil has a good anti-myocardial ischemic effect, and its main pharmacodynamic components are trans-nerolol and its oxides. However, the exact mechanisms underlying this effect have not yet been elucidated. This study aimed to explore the potential myocardial protective effects of trans-nerolol and its underlying molecular mechanisms. Molecular docking was used to predict and visualize the possible mechanism of the anti-apoptotic myocardial protection by trans-nerolol. The myocardial protective effect of trans-nerolol was evaluated by observing pathological injury, myocardial enzyme levels, oxidation, antioxidant levels, and the expression of related proteins. Molecular docking results showed that trans-nerolol binds closely to cytochrome C (Cytc) and apoptosis-related proteins, suggesting that it may play a role in interacting with these target proteins. The results showed that pre-treatment with dose-dependent trans-nerolol significantly mitigated the myocardial histological damage; decreased lactate dehydrogenase (LDH), creatinine kinase (CK), alanine transaminase (ALT), and aspartate transaminase (AST) levels; reduced nitric oxide (NO) production, hydrogen peroxide (H2O2), and lipid peroxide (LPO); and increased the total antioxidant content (T-AOC), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) activities compared with the model group. In addition, dose-dependent trans-nerolol significantly increased the Na+-K+-ATPase and Ca2+-Mg2+-ATPase levels. Moreover, trans-nerolol markedly reduced the endogenous and external apoptotic pathways; downregulated the protein expression of Cytc, apoptotic protease activating factor-1 (Apaf1), Fibroblast-associated (Fas), Cysteine-aspartate protease 3 (Caspase3), Cysteine-aspartate protease 8 (Caspase8), and Cysteine-aspartate protease 9 (Caspase9); and upregulated the expression of Heat shock protein 70 (Hsp70) and B-cell lymphoma-2 (Bcl-2). These data indicate that trans-nerolol exerts protective effects against myocardial ischemia (MI), and its mechanism is associated with the suppression of the Cytc- and caspase-signaling pathways. Trans-nerolol has a therapeutic effect on MI, and its mechanism of action is related to its anti-apoptotic effect. These results suggest thatDalbergia odoriferahas a potential role to be developed as an MI-promoting therapeutic agent.
研究领域:
药理学
·
心血管疾病
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomolecules
·
2025
·Vol. 15
·期 5
·618
·
IF 4.8
Zizheng Wu,Xing Chen,Jiahao Ye,Xiaoyi Wang,Zhixi Hu
This research proposes to systematically investigate the cardioprotective mechanisms ofPericarpium Trichosanthisinjection (PTI) against acute myocardial ischemia through an integrated approach combining ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) constituent profiling, UNIFI database-assisted component identification, network pharmacology-guided target prediction, molecular docking verification, and in vivo experimental validation. The multimodal methodology is designed to comprehensively uncover the therapeutic benefits and molecular pathways underlying this traditional Chinese medicine formulation. Methods: UPLC-Q-TOF/MS and the UNIFI database were used in conjunction with a literature review to screen and validate the absorbed components of PTI. Using network pharmacology, we constructed protein-protein interaction (PPI) networks for pinpointing prospective therapeutic targets. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify potential signaling pathways. In vivo experiments were conducted to investigate the mechanisms by which PTI ameliorated isoproterenol-induced myocardial injury in rats. All animal experiments have adhered to ARRIVE guidelines. Results: UPLC-Q-TOF/MS revealed 11 core active components in PTI. Network pharmacology prioritization identified pseudoaspidin, ciryneol C, cynanoside M, daurinol, and n-butyl-β-D-fructopyranoside as central bioactive constituents within the compound-target interaction network. Topological analysis of the protein interactome highlighted AKT1, EGFR, MMP9, SRC, PTGS2, STAT3, BCL2, CASP3, and MAPK3 as the most interconnected nodes with the highest betweenness centrality. Pathway enrichment analysis established the PI3K/Akt signaling cascade as the principal mechanistic route for PTI’s cardioprotective effects. Molecular docking simulations demonstrated high-affinity interactions between characteristic components (e.g., cynanoside M, darutigenol) and pivotal targets including PTGS2, MAPK3, CASP3, and BCL2. In vivo investigations showed PTI treatment markedly attenuated myocardial tissue degeneration and collagen deposition (p< 0.05), normalized electrocardiographic ST-segment deviations, and suppressed pro-inflammatory cytokine production (IL-6, TNF-α). The formulation concurrently reduced circulating levels of cardiac injury indicators (LDH, cTnI) and oxidative stress parameters (ROS, MDA), Regarding apoptosis regulation, PTI reduced Bax, caspase-3, and caspase-9, while elevating Bcl-2 (p< 0.05), effectively inhibiting myocardial cell apoptosis with all therapeutic outcomes reaching statistical significance. These findings highlight PTI’s protective effects against myocardial injury through multi-target modulation of inflammation, oxidation, and apoptosis. Conclusions: PTI exerts its therapeutic effects in treating acute myocardial ischemia by regulating and suppressing inflammatory responses, and inhibiting cardiomyocyte apoptosis.
研究领域:
中药学
·
心血管药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Yuru Pang,Qiqi Meng,Yangchen Cui,Shiyi Liu,Huihui Jiang,Chenlan Xu,Yan An,Yang Jiao,Qi Zhang,Jihua Nie
Background: Lung cancer is the leading cause of cancer-related death in the worldwide. Although cisplatin and other platinum-based drugs are widely used as radiosensitizers in radiotherapy and considered the first-line treatment for advanced lung cancer, their clinical utility is often limited by drug resistance and severe cytotoxic side effects. In recent years, iridium-based complexes and other transition metal cation complexes with similar structural properties have garnered increasing research interest due to their potential anticancer properties.Methods: Recently, we synthesized a novel iridium (III) complex (Ir-1) and evaluated its safety and stability. The present study aimed to identify Ir-1 with potent anticancer activity by assessing its cytotoxic effects on lung cancer cells in vitro. Additionally, it investigated Ir-1's radiosensitizing efficacy and the underlying mechanisms.Results: The results demonstrated that Ir-1 exhibited significant radiosensitizing effects on lung cancer cells. Ir-1 effectively reduced cell viability and colony formation, arrested the cell cycle at the G2/M phase, inhibited cell migration and invasion, decreased mitochondrial membrane potential, and increased reactive oxygen species (ROS) generation in lung cancer cells. Importantly, these cytotoxic effects were selective, with minimal impact on normal cells. Mechanistic studies showed that Ir-1 enhanced radiation-induced cancer cell death by disrupting mitochondrial function and activating the mitochondrial apoptotic pathway. This was evidenced by upregulated expression levels of Bax, Cytochrome c (Cyt-C), and Caspase9 proteins, along with reduced level of Bcl-2 protein. Notably, the addition of a Cyt-C inhibitor significantly reduced the expression of Cyt-C and Caspase9 proteins. Similarly, treatment with the Caspase9 inhibitor Z-LEHD-FMK also reduced Caspase9 protein level.Conclusion: This study provides robust evidence that Ir-1 is a promising and safe radiosensitizer for lung cancer therapy. Its ability to enhance radiation-induced cytotoxicity through mitochondrial dysfunction and activation of apoptotic pathways highlights its potential for clinical application.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2018
·Vol. 392
·期 2
·177-187
·
IF 2.238
Qiao Zhe,Cheng Yao,Liu Shiyuan,Ma Zhenchuan,Li Shaomin,Zhang Wei
Casticin, a flavonoid isolated from Vitex species, has been found to have anti-tumor property in multiple human cancers. The present study aimed to investigate the effect of casticin on the proliferation and apoptosis of esophageal cancer (EC) cells, and further illustrate the underlying mechanisms. In in vitro studies, human EC cell lines TE-1 and ECA-109 were treated with various concentrations of casticin (low-, middle-, and high-dose groups). The results showed that casticin dose-dependently inhibited the proliferation and clonogenicity of EC cells and induced cell cycle arrest in sub-G1 and G2 phases. Furthermore, casticin markedly enhanced EC cell apoptosis as detected by flow cytometry and Hoechst 33342 staining. The level of anti-apoptotic Bcl-2 protein was decreased, while the levels of pro-apoptotic Bax, cleaved-caspase-3, cleaved-caspase-9, and cleaved-PARP were conversely increased in casticin-treated TE-1 and ECA-109 cells. Moreover, casticin decreased the mitochondrial membrane potential and increased the release of mitochondrial cytochrome C into cytoplasm. In addition, the JNK signaling pathway was involved in casticin-medicated anti-proliferation and pro-apoptosis. Cells pretreated with SP600125, a JNK pathway inhibitor, partially abolished the effect of casticin. Finally, the anti-tumor property of casticin was confirmed in in vivo xenograft models. Overall, we provided both in vitro and in vivo evidences that casticin inhibited the proliferation and induced apoptosis of EC cells, and the anti-tumor action of casticin was mediated, in part, by the mitochondrial-dependent apoptosis and the activation of JNK signaling pathway.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 51
·29711-29720
·
IF 3.049
Yan Zhang,Yunyun Wang,Yuxun Zhao,Wen Gu,Yongqiang Zhu,Shifa Wang
A series of novel camphor-based pyrimidine derivatives (3a–3x) have been synthesized; their structures were determined by using conventional methods and compound 3f was further confirmed through single crystal XRD analysis. The cytotoxic activity of the target compounds against a panel of human normal (GES-1) and cancer cell lines (MDA-MB-231, RPMI-8226, A549) was evaluated by MTS assay. Here we found that compound 3f exhibited the strongest anti-tumor activity, comparable to that of etoposide, and had much lower cytotoxicity to normal GES-1 cells (IC50 > 50 μM) than the reference drug (IC50 = 8.89 μM). Subsequent mechanism studies in MDA-MB-231 cells revealed that compound 3f caused G0/G1 phase arrest and apoptosis in a dose dependent manner. Moreover, the loss of mitochondrial membrane potential and enhancement of cellular ROS levels were also observed upon 3f treatment, which indicated that 3f exerted cytotoxic activity by a ROS-mediated mitochondrial apoptosis pathway. This result was confirmed by a significant increase in the expression of pro-apoptotic proteins Bax, cytochrome C and caspase-3, and downregulation of anti-apoptosis protein Bcl-2. Overall, 3f can be adopted for further investigation in the development of antitumor agents based on natural products.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zhou Shican,Wu Hang,Ning Wenjuan,Wu Xiao,Xu Xiaoxiao,Ma Yuanqiao,Li Xingwang,Hu Junhong,Wang Chenyu,Wang Junpeng
Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. Ivermectin, an antiparasitic drug, has been shown to possess anti-inflammation, anti-virus, and antitumor properties. However, whether ivermectin affects CRC is still unclear. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. We used CCK-8 assay to determine the cell viability, used an optical microscope to measure cell morphology, used Annexin V-FITC/7-AAD kit to determine cell apoptosis, used Caspase 3/7 Activity Apoptosis Assay Kit to evaluate Caspase 3/7 activity, used Western blot to determine apoptosis-associated protein expression, and used flow cytometry and fluorescence microscope to determine the reactive oxygen species (ROS) levels and cell cycle. The results demonstrated that ivermectin dose-dependently inhibited colorectal cancer SW480 and SW1116 cell growth, followed by promoting cell apoptosis and increasing Caspase-3/7 activity. Besides, ivermectin upregulated the expression of proapoptotic proteins Bax and cleaved PARP and downregulated antiapoptotic protein Bcl-2. Mechanism analysis showed that ivermectin promoted both total and mitochondrial ROS production in a dose-dependent manner, which could be eliminated by administering N-acetyl-l-cysteine (NAC) in CRC cells. Following NAC treatment, the inhibition of cell growth induced by ivermectin was reversed. Finally, ivermectin at low doses (2.5 and 5 µM) induced CRC cell arrest. Overall, ivermectin suppressed cell proliferation by promoting ROS-mediated mitochondrial apoptosis pathway and inducing S phase arrest in CRC cells, suggesting that ivermectin might be a new potential anticancer drug therapy for human colorectal cancer and other cancers.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Cuiping Li,Mengfan Pang,Yaping Li,Lirong Han,Yajiao Fan,Xuelian Xin,Xian Zhang,Ning Zhang,Yan Qin
Tetrachlorobenzoquinone (TCBQ) is an active metabolite of pentachlorophenol, and stimulates the accumulation of ROS to trigger apoptosis. The preventive effect of vitamin C (Vc) against TCBQ-induced apoptosis in HepG2 cells is unknown. And there is little known about TCBQ-triggered 5-hydromethylcytosine (5hmC)-dependent apoptosis. Here, we confirmed that Vc alleviated TCBQ-induced apoptosis. Through investigating the underlying mechanism, we found TCBQ downregulated 5hmC levels of genomic DNA in a Tet-dependent manner, with a particularly pronounced decrease in the promoter region, using UHPLC-MS-MS analysis and hydroxymethylated DNA immunoprecipitation sequencing. Notably, TCBQ exposure resulted in alterations of 5hmC abundance to ∼91% of key genes at promoters in the mitochondrial apoptosis pathway, along with changes of mRNA expression in 87% of genes. By contrast, 5hmC abundance of genes only exhibited slight changes in the death receptor/ligand pathway. Interestingly, the pretreatment with Vc, a positive stimulator of 5hmC generation, restored 5hmC in the genomic DNA to near-normal levels. More notably, Vc pretreatment further counter-regulated TCBQ-induced alteration of 5hmC abundance in the promoter with 100% of genes, accompanying the reverse modulation of mRNA expressions in 89% of genes. These data from Vc pretreatment supported the relationship between TCBQ-induced apoptosis and the altered 5hmC abundance. Additionally, Vc also suppressed TCBQ-stimulated generation of ROS, and further increased the stability of mitochondria. Our study illuminates a new mechanism of TCBQ-induced 5hmC-dependent apoptosis, and the dual mechanisms of Vc against TCBQ-stimulated apoptosis via reversely regulating 5hmC levels and scavenging ROS. The work also provided a possible strategy for the detoxification of TCBQ.
研究领域:
毒理学
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2015
·Vol. 5
·期 1
·1-10
·
IF 5.578
Zhang Yong,Qin Wei,Zhang Longyin,Wu Xianxian,Du Ning,Hu Yingying,Li Xiaoguang,Shen Nannan,Xiao Dan,Zhang Haiying,Li Zhange,Zhang Yue,Yang Huan,Gao Feng,Du Zhimin,Xu Chaoqian,Yang Baofeng
Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial apoptosis plays a vital role in the initiation and progression of atherosclerotic lesions. Although a subset of microRNAs (miRs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In our study, we found that miR-26a expression was substantially reduced in the aortic intima of ApoE −/− mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with oxidized low-density lipoprotein (ox-LDL) suppressed miR-26a expression. Forced expression of miR-26a inhibited endothelial apoptosis as evidenced by MTT assay and TUNEL staining results. Further analysis identified TRPC6 as a target of miR-26a and TRPC6 overexpression abolished the anti-apoptotic effect of miR-26a. Moreover, the cytosolic calcium and the mitochondrial apoptotic pathway were found to mediate the beneficial effects of miR-26a on endothelial apoptosis. Taken together, our study reveals a novel role of miR-26a in endothelial apoptosis and indicates a therapeutic potential of miR-26a for atherosclerosis associated with apoptotic cell death.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
·
2022
·
IF 6.117
Huawu Gao,Xin Lei,Shu Ye,Ting Ye,Rupeng Hua,Guoquan Wang,Hang Song,Peng Zhou,Yan Wang,Biao Cai
Genistein (GS), an isoflavone compound found in soybean, plays a neuroprotective role in Alzheimer's disease (AD). However, the mechanism of its action remains unclear. Herein, binding ability between GS and GRP78 was predicted by molecular docking , and the effect of GS in vivo and vitro were further studied. In this study, the effects of GS on learning and memory ability, changes of hippocampal neurons and ultrastructure of hippocampal CA3 region in AD rats were investigated. Besides, the protein or mRNA levels of the related proteins were detected. The results showed GS could effectively improve the learning and the memory ability, reduce the damage of hippocampal neurons, and decrease the protein or mRNA expression levels of GRP78, CHOP, Caspase-12, Cle-Caspase-9, Cle-Caspase-3, PERK, and p-PERK. Taken together, our data reveal GS has a neuroprotective effect by inhibiting the ERS-mediated apoptotic pathway, which may be a new therapeutic target for the treatment of AD .
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 11
·6228-6240
·
IF 5.882
Tiantian Qin,Jinzhu Zhao,Xiaojie Liu,Leilei Li,Xueyan Zhang,Xiaoli Shi,Yu Ke,Weihua Liu,Junfeng Huo,Yalong Dong,Yiwei Shen,Yanyu Li,Mingjing He,Shuhua Han,Linlin Li,Chengxue Pan,Cong Wang
Although paclitaxel is a promising frontline chemotherapy agent for various malignancies, the clinical applications have been restricted by side effects, drug resistance, and cancer metastasis. The combination of paclitaxel and other agents could be the promising strategies against malignant tumor, which enhances the antitumor effect through synergistic effects, reduces required drug concentrations, and also suppresses tumorigenesis in multiple ways. In this study, we found that luteolin, a natural flavonoid compound, combined with low-dose paclitaxel synergistically regulated the proliferation, migration, epithelial–mesenchymal transition (EMT), and apoptosis of esophageal cancer cells in vitro, as well as synergistically inhibited tumor growth without obvious toxicity in vivo. The molecular mechanism of inhibiting cell migration and EMT processes may be related to the inhibition of SIRT1, and the mechanism of apoptosis induction is associated with the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) pathway–mediated activation of mitochondrial apoptotic pathway.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2014
·
IF 2.723
Qingyong Li,Tianyu Liu,Yunchao Li,Shuyue Luo,Qiaochu Zhu,Li Zhang,Tengfei Zhao
Camptothecin-20(s)-O-glycine ester-[N-(3′α, 12′α-dihydroxy-24′-carbonyl-5′β-cholan)] (A2), 10-(3′α,12′α-dihydroxy-5′β-cholan-24′-carboxyl)-(20 s)-camptothecin (C2), and 10-O-(3-O-(3′α, 12′α-dihydroxy-24′-carbonyl-5′β-cholan)-propyl)-(20S)-camptothecin (D2) are novel camptothecin-deoxycholic acid analogues. MTT assays were performed to assess the anticancer activity of these compounds against hepatocellular carcinoma SMMC-7721, breast carcinoma MCF-7, and colorectal carcinoma HCT-116 cells. A2 had a high killing ability on SMMC-7721 cells selectively, but C2 and D2 did not exhibit selectivity with regard to SMMC-7721 killing. Uptake assays were performed in an effort to elucidate the transport mechanisms of A2 into SMMC-7721 cells. A2 increased the mRNA expression of OATP1B3 (an organic anion-transporting polypeptide) and uptake of A2 was inhibited by rifampin (inhibitor of OATP1B3), which indicated that the transporter-mediated transport of A2 was mediated by OATP1B3. In addition, according to the western blot and apoptosis assays, we found that A2 killed SMMC-7721 cells by inducing cell apoptosis mainly via an AIF (apoptosis-inducing factor) pathway and a caspase-dependent mitochondria apoptosis pathway.
研究领域:
药理学
·
肿瘤学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2021
·
IF 6.291
Zekun Li,Jun Guo,Kun Jia,Zhiguo Zheng,Xiaomei Chen,Zhonghui Bai,Yuhao Yang,Bo Chen,Wei Yuan,Weihua Chen,Jian Yang
Oxyfluorfen (OXY) is widely used in agriculture as a herbicide, resulting in its continuous accumulation in the environment. The presence of OXY can be detected in soil and rivers. However, until now, the potential toxicity of OXY to aquatic organisms has not been evaluated. In this study, zebrafish was used as a model animal to evaluate OXY-induced liver toxicity. The study found that 0.25, 0.5, and 1 mg/L of OXY affected the early development of zebrafish and severely damaged the lipid and sugar metabolism in the liver of zebrafish larvae. Furthermore, a metabolic function disorder caused liver damage. OXY also caused inflammation by upregulating the inflammatory factors IL-6 , IL-8 , and TNF-α , and activated the apoptotic pathway to inhibit hepatocyte proliferation, resulting in zebrafish liver toxicity. Our research showed that OXY had certain toxic effects on zebrafish development and liver and could cause potential harm to other aquatic organisms and humans.
研究领域:
环境毒理学
·
水生生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）