MOLECULAR BIOLOGY REPORTS
·
2024
·Vol. 51
·期 1
·1-12
·
IF 2.6
Zheng Ruzhen,He Yibo,Yang Lingrong,Chen Yidan,Wang Rui,Xie Shangnao
Background Our previous study has demonstrated that Nischarin (NISCH) exerts its antitumor effects in breast cancer (BC) by suppressing cell migration and invasion. This study aims to explore the underlying mechanism through which NISCH functions in BC. Methods and results The relevance between EGF Like Repeats and Discoidin Domains 3 (EDIL3) mRNA expression and the overall survival of tumor patients was depicted by the Kaplan-Meier curve. The findings revealed that overexpressed NISCH attenuated cell motility and colony-forming capacities of Hs578T cells, yet silenced NISCH in MDA-MB-231 cells led to contrasting results. Western blot (WB) analysis indicated that overexpression of NISCH significantly down-regulated the Vimentin and Slug expression, and inactivated the FAK/ERK signaling pathway. RNA sequencing (RNA-seq) was performed in NISCH-overexpressed Hs578T cells and the control cells to analyze differentially expressed genes (DeGs), and the results showed a significant down-regulation of EDIL3 mRNA level upon overexpression of NISCH. Subsequent functional analyses demonstrated that overexpression of EDIL3 attenuated the inhibitory effect of NISCH on cell migration, invasion, colony formation, and tube formation. Conclusion In summary, our finding preliminarily revealed that NISCH inhibits the epithelial-mesenchymal transition (EMT) process and angiogenesis in BC cells by down-regulating EDIL3 to inactivate the FAK/ERK signaling pathway, thereby suppressing the progression of BC. Our results hold promise for contributing to the deep understanding of BC pathogenesis and identifying new therapeutic strategies for clinical application.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
高影响因子
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
·
2021
·Vol. 26
·期 7
·793-808
·
IF 3.358
Chen Jincan,Deng Yuanyuan,Wang Jie,Chen Suxiang,Peng Fa,He Xuerong,Liu Meijun,Luo Hui,Zhang Jingjing,Chen Lanmei
Abstract Two new cyclometalated Ru(II)-β-carboline complexes, [Ru(dmb) 2 (Cl-Ph-βC)](PF 6 ) (dmb = 4,4′-dimethyl-2,2′-bipyridine; Cl-Ph-βC = Cl-phenyl-9H-pyrido[3,4-b]indole; RuβC-3 ) and [Ru(bpy) 2 (Cl-Ph-βC)](PF 6 ) (bpy = 2,2′-bipyridine; RuβC-4 ) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC 50 values of 3.2 ± 0.4 μM ( RuβC-3 ) and 4.1 ± 0.6 μM ( RuβC-4 ), which were considerably lower than that of non-cyclometalated Ru(II)-β-carboline complex [Ru(bpy) 2 (1-Py-βC)] (PF 6 ) 2 (61.2 ± 3.9 μM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RuβC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RuβC-3 -induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RuβC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs. Graphic Abstract
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
Reproductive Sciences
·
2025
·
IF 2.5
Qiu Yingying,Wei Xinjun,Cao Jian,Wang Jindan,Dou Qianru,Zhou Fangfang,Chen Xi,Liu Yongli,Wan Guiping,Huang Meihua,Li Zhenli,Gui Tao
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial–mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Graphical
研究领域:
妇科学
·
干细胞生物学
·
分子生物学
·
细胞信号传导
·
癌症生物学
·
免疫学
·
microRNA研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR IMMUNOLOGY
·
2024
·
IF 3.2
Zhou Si Yun,Song Zhihua,Tian Xuelian,Xia Min,Hu Rongjing,Luo Mei
Chlamydia trachomatis (CT) is the leading cause of bacterial sexually transmitted diseases worldwide, which can cause diseases such as pelvic inflammatory disease, and cervical and fallopian tube inflammation, and poses a threat to human health. Rosmarinic acid (RosA) is an active ingredient of natural products with anti-inflammatory and immunomodulatory effects. This study aimed to investigate the role of RosA in inhibiting autophagy-regulated immune cells-CD8+ T cells via the Ras/Raf/MEK/ERK signaling pathway in a CT-infected mouse model. Mice were inoculated with CT infection solution vaginally, and the mechanistic basis of RosA treatment was established using H&E staining, flow cytometry, immunofluorescence, transmission electron microscopy, and western blot. The key factors involved in RosA treatment were further validated using the MEK inhibitor cobimetinib. Experimental results showed that both RosA and the reference drug azithromycin could attenuate the pathological damage to the endometrium caused by CT infection; flow cytometry showed that peripheral blood CD8+ T cells increased after CT infection and decreased after treatment with RosA and the positive drug azithromycin (positive control); immunofluorescence showed that endometrial CD8 and LC3 increased after CT infection and decreased after RosA and positive drug treatment; the results of transmission electron microscopy showed that RosA and the positive drug azithromycin inhibited the accumulation of autophagosomes; western bolt experiments confirmed the activation of autophagy proteins LC3Ⅱ/Ⅰ, ATG5, Beclin-1, and p62 after CT infection, as well as the inhibition of Ras/Raf/MEK/ERK signaling. RosA and azithromycin inhibition of autophagy proteins activates Ras/Raf/MEK/ERK signaling. In addition, the MEK inhibitor cobimetinib attenuated RosA's protective effect on endometrium by further activating CD8+ T cells on a CT-induced basis, while transmission electron microscopy, immunofluorescence, and western blots showed that cobimetinib blocked ERK signals activation and further induced phagocytosis on a CT-induced basis. These data indicated that RosA can activate the Ras/Raf/MEK/ERK signaling pathway to inhibit autophagy, and RosA could also regulate the activation of immune cells-CD8+T cells to protect the reproductive tract of CT-infected mice.
研究领域:
免疫学
·
微生物学
·
药理学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Dong-mei Li,Fu-cui Zhu,Jie Wei,Jia-xiu Xie,Jun-hui He,Dong-mei Wei,Yi Li,Ke-dao Lai,Li-min Liu,Qi-biao Su,Gui-ning Wei,Bin Wang,Yan-cheng Liu
Ethnopharmacological relevance Polyrhachis vicina Roger ( P. vicina ), a traditional Chinese medicinal animal, has been used to treat rheumatoid arthritis , hepatitis, cancer, and other conditions. Due to its anti-inflammatory properties, our previous pharmacological investigations have demonstrated that it is effective against cancer, depression, and hyperuricemia . Nevertheless, the key active components and targets of P. vicina in cancers are still unexplored. Aim of the study The study aimed to evaluate the pharmacological treatment mechanism of the active fraction of P. vicina (AFPR) in treating colorectal cancer (CRC) and to further reveal its active ingredients and key targets. Methods To examine the inhibitory impact of AFPR on CRC growth, tumorigenesis assays, cck-8 assays, colony formation assays, and MMP detection were utilized. The primary components of AFPR were identified by GC-MS analysis. The network pharmacology , molecular docking, qRT-PCR, western blotting , CCK-8 assays, colony formation assay, Hoechst staining, Annexin V-FITC/PI double staining, and MMP detection were performed to pick out the active ingredients and potential key targets of AFPR. The function of Elaidic acid on necroptosis was investigated through siRNA interference and the utilization of inhibitors. Elaidic acid's effectiveness to suppress CRC growth in vivo was assessed using a tumorigenesis experiment. Results Studies confirmed that AFPR prevented CRC from growing and evoked cell death. Elaidic acid was the main bioactive ingredient in AFPR that targeted ERK. Elaidic acid greatly affected the ability of SW116 cells to form colonies, produce MMP, and undergo necroptosis. Additionally, Elaidic acid promoted necroptosis predominantly by activating ERK/RIPK1/RIPK3/MLKL. Conclusion According to our findings, Elaidic acid is the main active component of AFPR, which induced necroptosis in CRC through the activation of ERK. It represents a promising alternative therapeutic option for CRC. This work provided experimental support for the therapeutic application of P. vicina Roger in the treatment of CRC.
研究领域:
药理学
·
肿瘤学
·
传统中药
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Hongwei Han,Minkai Yang,Zhongling Wen,Feng Mei,Qingqing Chen,Yudi Ma,Xiaohui Lai,Yahan Zhang,Rongjun Fang,Tongming Yin,Shucun Sun,Xiaoming Wang,Jinliang Qi,Hongyan Lin,Yonghua Yang
Triple negative breast cancer (TNBC) is associated with a poor prognosis and limited response to traditional chemotherapy, necessitating the exploration of novel treatment approaches. Recent researches have highlighted the interconnected roles of the PI3K/AKT pathway and MAPK pathway in TNBC cells, contributing to the efficacy of treatments. Therefore, the concurrent inhibition of both pathways presents a potential new therapeutic strategy for TNBC patients. This study aimed to evaluate the antitumor efficacy of M17, an AKT allosteric inhibitor and a new synthesized shikonin derivative, both alone and in combination with the MEK inhibitor trametinib. We applied various cellular assays and a subcutaneous 4T1 tumor bearing BALB/c mice model were utilized to assess the in vitro and in vivo antitumor effects. Computational docking and Bio-Layer Interferometry (BLI) were employed to investigate the binding of M17 with AKT. Additionally, flow cytometry, transwell assays, western blotting, and tumor xenograft assays were conducted to explore the potential synergistic mechanisms of the combined therapy. The results demonstrated that M17 exhibited moderate antitumor activity against TNBC cells, but significantly enhanced the apoptotic effects and inhibited proliferation and migration when combined with trametinib. Furthermore, the combination of M17 and trametinib showed even more pronounced antitumor activity in vivo . Mechanistically, the dual therapy synergistically suppressed TNBC by targeting the AKT/mTOR and MEK/ERK signaling pathways and inhibiting epithelial-mesenchymal transition. In conclusion, the findings suggested that the combination of M17 and trametinib holds promise as a synergistic treatment option for TNBC patients.
研究领域:
肿瘤学
·
癌症研究
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2018
·
IF 3.616
Qiaozhu Tan,Ming Zhang,Lujing Geng,Zhenghua Xia,Cen Li,Muhammad Usman,Yuzhi Du,Lixin Wei,Hongtao Bi
Methylmercury (MeHg + ) is an extremely toxic organomercury cation that can induce severe neurological damage. Once it enters the body, methylmercury binds to amino acids or proteins containing free sulfhydryl groups. In particular, methylmercury is known to bind with human serum albumin (HSA) in human plasma; however, the effects of methylmercury-HSA conjugate (MeHg-HSA) on the central nervous system (CNS) are not fully understood. In the present study, we used the microglial cell line N9 as the target cells to evaluate the effect of MeHg-HSA on physiological function of the CNS preliminarily. The various factors in the cell culture were monitored by MTT assay, total lactate dehydrogenase assay, ELISA , qPCR, Western blot and flow cytometry techniques. The results showed that low-dose treatment with MeHg-HSA activated N9 cells, promoting cell proliferation and total cell number, enhancing NO and intracellular Ca 2+ levels, and suppressing the release of TNFα and IL1β without cytotoxic effects; while high-dose MeHg-HSA exhibited cytotoxic effects on N9 cells, including promoting cell death and increasing the secretion of TNFα and IL1β. These results indicate that MeHg-HSA causes hormesis in microglia N9 cells. Furthermore, ERK/MAPKs and STAT3 signaling pathways related to the hormesis of MeHg-HSA on N9 cells. In addition, low dose of MeHg-HSA might be viewed as something very close to a lowest observed adverse effect level (LOAEL) for N9 cells. These findings will be useful for investigating the hormesis mechanism of MeHg + and exploring the specific functions of MeHg-sulfhydryl conjugates on the central nervous system.
研究领域:
神经毒理学
·
细胞生物学
·
药理学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Bike Zhang,Dan Su,Yonggui Song,Huizhen Li,Changlian Chen,Liangliang Liao,Hongjie Zhang,Jian Luo,Ming Yang,Genhua Zhu,Zhifu Ai
Phytochemical investigation of the volatile oil of Yueju (YJVO) and its constituent herbs induced the detection of 52 compounds in YJVO, mainly monoterpenes and sesquiterpenes as well as a small amount of aromatic and aliphatic compounds. 5 of these compounds were found only in the YJVO instead of the volatile oil of its constituent herbs. The anti-depressant effect of YJVO was proved by behavioral tests in chronic unpredictable mild stress (CUMS) mice. An acute oral toxicity evaluation determined the LD 50 of YJVO was 5.780 mL/kg. Doppler ultrasound and laser speckle imaging have detected that the YJVO could improve depression-related cerebral blood flow. In addition, related neurotransmitters and proteins were analyzed through targeted metabolomics and immunofluorescence. The potential antidepressant mechanisms of YJVO related to significantly decreasing Glu in CUMS mice by up-regulating the ERK/AKT-mediated expression of GLT-1.
研究领域:
药理学
·
神经科学
·
植物化学
·
行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Xiao-Meng Liu,Zhe Li,Xin-Ru Xie,Jia-Qian Wang,Xin Qiao,Xin Qiao,Cheng-Zhi Xie,Jing-Yuan Xu
Exploring multi-targeting chemotherapeutants with advantages over single-targeting agents and drug combinations is of great significance in drug discovery. Herein, we employed phytogenic evodiamine (EVO) and conventional Pt(II) drugs to design and synthesize multi-target EVO–Pt(IV) anticancer prodrugs (4–14). Among them, compound 10 exhibited a 118-fold enhancement in the IC50 value compared to cisplatin and low toxicity to normal cells. Further studies proved that 10 significantly enhanced intracellular Pt accumulation and DNA damage, perturbed mitochondrial membrane potential, inhibited cell migration and invasion, upregulated reactive oxygen species levels, and induced apoptosis and autophagic cell death. Molecular docking assay revealed that 10 fits perfectly into the extracellular signal-regulated protein kinase (ERK)-1 pocket, which was verified to produce profound ERK suppression. Most strikingly, compound 10 exhibited superior in vivo antitumor efficiency and effectively attenuated systemic toxicity. Our results emphasize that functionalizing platinum drugs with the multi-target EVO could generate synergistically excellent anticancer activity with low toxicity and decreased resistance, which may represent a brand-new cancer therapy modality.
研究领域:
药理学
·
肿瘤学
·
化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2015
·
IF 2.084
Shimei Qi,Xianjuan Kou,Jun Lv,Zhilin Qi,Liang Yan
Our results showed that ampelopsin significantly inhibited cell viability of hepatoma HepG2 cells using MTT assay. We further investigated the mechanism of anticancer activity by ampelopsin, it showed that ampelopsin induced apoptosis of HepG2 cells using DAPI assay and flow cytometry, which was confirmed by activation of PARP. Next, activation of the caspase cascades were demonstrated, including caspase-8, -9 and -3. We also found that ampelopsin increased the levels of death receptor 4 (DR4), death receptor 5 (DR5) and decreased the expression of Bcl-2 protein, which led to an increase of the Bax/Bcl-2 ratio. Meanwhile, the release of cytochrome c from mitochondria was observed. Ampelopsin decreased the levels of iNOS and COX-2 but had no impact on the level of reactive oxygen species (ROS). In addition, ampelopsin activated ERK1/2 and P38, but little JNK1/2 activation was detected. Further investigation showed that suppression of P38 activation by SB203580 increased the cell viability and also prevented cleavage of caspase-3 and PARP, inhibition of ERK1/2 with U0126 had the opposite action. In conclusion, our results indicated that ampelopsin mainly elicited apoptosis through extrinsic and intrinsic pathway and that ERK1/2 and P38 had opponent effects on the apoptosis.
研究领域:
癌症生物学
·
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
PHYTOTHERAPY RESEARCH
·
2023
·Vol. 37
·期 4
·1422-1434
·
IF 7.2
Yanfei Ban,Yang Wang,Liming Qiao,Chengzhong Zhang,Hongrui Wang,Xuhui He,Dan Jia,Chengjian Zheng
The seeds of Vitex negundo have been used for inflammation-related disease treatment in traditional medicine. This study focused on the anti-osteoarthritis (OA) effects of the total lignans of V. negundo seeds (TOV) in monosodium iodoacetate-induced osteoarthritis rats and its pharmacokinetic properties, as well as the effects and potential mechanism of its main components VN1 (6-hydroxy-4-(4-hydroxy-3-methoxy-phenyl)-3-hydro-xymethyl-7-methoxy-3,4-dihydro-2-naphthaldehydeb) and VN2 (vitedoin A) on receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs). TOV significantly attenuated osteoarthritis, leading to an increase in pain thresholds, improvement of knee articular cartilages and chondrocytes loss, and decreased total joint scores and serum levels of TNF-α, interleukin-1β (IL-1β), and prostaglandin E2 (PGE2) in osteoarthritis rats. The half-time (T 1/2 ) was 2.82 h and 1.33 h, and the bioavailability was 15.34%–21.89% and 16.29%–22.11%, for VN1 and VN2, respectively. VN2, rather than VN1, remarkably inhibited tartrate-resistant acid phosphatase (TRAP) activity, reduced the number of TRAP-positive multinuclear cells, diminished the formation of actin ring, and decreased mRNA levels of cathepsin K (CTSK), TRAP, nuclear factor of activated T cell 1 (NFATc1), and osteoclast-associated receptor, as well as downregulated protein levels of p-ERK (phosphorylated extracellular signal-regulated kinase), TRAP, CTSK and NFATc1 in BMMs. These findings suggest TOV has promising therapeutic potential for OA treatment and VN2, in particular, attenuates osteoclast differentiation by suppressing ERK/NFATc1 signaling and actin ring, mainly accounting for the anti-OA efficacy of TOV.
研究领域:
药理学
·
风湿病学
·
传统医学
·
分子生物学
·
药代动力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 11
·5939
·
IF 4.9
Jian Ouyang,Na Hu,Honglun Wang
Petanin, an acylated anthocyanin from the Solanaceae family, shows potential in tyrosinase inhibitory activity and anti-melanogenic effects; however, its mechanism remains unclear. Therefore, to investigate the underlying mechanism of petanin’s anti-melanogenic effects, the enzyme activity, protein expression and mRNA transcription of melanogenic and related signaling pathways in zebrafish using network pharmacology, molecular docking and molecular dynamics simulation were combined for analysis. The results showed that petanin could inhibit tyrosinase activity and melanogenesis, change the distribution and arrangement of melanocytes and the structure of melanosomes, reduce the activities of catalase (CAT) and peroxidase (POD) and enhance the activity of glutathione reductase (GR). It also up-regulated JNK phosphorylation, inhibited ERK/RSK phosphorylation and down-regulated CREB/MITF-related protein expression and mRNA transcription. These results were consistent with the predictions provided through network pharmacology and molecular docking. Thus, petanin could inhibit the activity of tyrosinase and the expression of tyrosinase by inhibiting and negatively regulating the tyrosinase-related signaling pathway ERK/CREB/MITF through p-JNK. In conclusion, petanin is a good tyrosinase inhibitor and anti-melanin natural compound with significant market prospects in melanogenesis-related diseases and skin whitening cosmetics.
研究领域:
药理学
·
生物化学
·
分子生物学
·
斑马鱼研究
·
化妆品科学
✓ 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）