INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2017
·
IF 3.671
Wenjie Jiang,Yanna Cheng,Na Zhao,Lian Li,Yikang Shi,Aizhen Zong,Fengshan Wang
Previous studies demonstrated that SIP-SII, a sulfated derivative of SIP that is isolated from the ink of Sepiella maindroni , showed significant inhibition of tumor growth and metastasis. In this study, the effects of SIP-SII on the migration, invasion and molecular mechanism in ovarian cancer cell line, SKOV-3 cells, were investigated. The flow cytometry, confocal microscope observation, western blot and RT-PCR results indicated that SIP-SII located on cell membrane and inhibited the expression and activation of epidermal growth factor receptor (EGFR). Moreover, the binding capacity of SIP-SII with EGFR was confirmed by surface plasmon resonance (SPR) analysis and co-localization of EGFR and SIP-SII. Accordingly, SIP-SII was proved to attenuate the EGF-induced EGFR phosphorylation and migration by western blot and wound healing assay, respectively. Additionally, SIP-SII inhibited p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells significantly. What is more, SIP-SII showed amplified inhibitory activity on migration, invasion, and MMP-2 expression in combination with p38-specific inhibitor, PI3K-specific inhibitor or mTOR-specific inhibitor in SKOV-3 cells. Therefore, the mechanism that SIP-SII suppressed EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways to inhibit migration and invasion of SKOV-3 cells was demonstrated. These findings suggested that SIP-SII might be used as a potential inhibitor against tumor metastasis.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Oncology
·
2019
·
IF 4.137
Roy Gaurab,Guan Su,Liu Hexiang,Zhang Lei
Hepatocellular carcinoma (HCC) is the fourth largest cause of cancer-related deaths worldwide with limited therapeutic interventions. Renewed interest in natural products as drug leads has resulted in a paradigm shift toward the rapid screening of medicinal plants for the discovery of new chemical entities. Rotundic acid (RA), a plant-derived triterpenoid, has been anecdotally reported to possess anti-inflammatory and cardio-protective abilities. The present study highlights the anti-cancer efficacy of RA on HCC in vitro and in vivo. The inhibitory effects of RA on HCC cell viability was determined by MTT. Soft agar colony formation and clonogenic assays also showed that RA inhibited HCC cell proliferation. Flow cytometry, confocal, and western blot results further indicated that RA induced cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways. Besides the suppression of migration and invasion, tube formation and VEGF-ELISA revealed the anti-angiogenic abilities of RA on HCC. Moreover, RA also inhibited tumor growth in a HepG2 xenograft mouse model. To our best knowledge, this is the first extensive study of the anticancer activity of RA on HCC. The results demonstrate that RA could be a potential drug candidate for HCC treatment.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
癌症研究
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2019
·
IF 5.574
Jin-Feng Teng,Da-Lian Qin,Qi-Bing Mei,Wen-Qiao Qiu,Rong Pan,Rui Xiong,Ya Zhao,Betty Yuen-Kwan Law,Vincent Kam-Wai Wong,Yong Tang,Chong-Lin Yu,Feng Zhang,Jian-Ming Wu,An-Guo Wu
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Our previous studies have proven that Trillium tschonoskii Maxim. (TTM), a traditional Chinese medicine , possesses potent anti-tumor effect. However, the detailed components and molecular mechanism of TTM in anti-NSCLC are still unknown. In the present experiment, polyphyllin VI (PPVI) was successfully isolated from TTM with guidance of the anti-proliferative effect in A549 cells, and the cell death of PPVI treated A549 and H1299 cells was closely linked with the increased intracellular ROS levels. In addition, PPVI induced apoptosis by promoting the protein expression of Bax/Bcl2, caspase-3 and caspase-9, and activated autophagy by improving LC3 II conversion and GFP-LC3 puncta formation in A549 and H1299 cells. The mechanism study found that the activity of mTOR which regulates cell growth, proliferation and autophagy was significantly suppressed by PPVI. Accordingly, the PI3K/AKT and MEK/ERK pathways positively regulating mTOR were inhibited, and AMPK negatively regulating mTOR was activated. In addition, the downstream of mTOR, ULK1 at Ser 757 which downregulates autophagy was inhibited by PPVI. The apoptotic cell death induced by PPVI was confirmed, and it was significantly suppressed by the overexpression of AKT, ERK and mTOR, and the induced autophagic cell death which was depended on the Atg7 was decreased by the inhibitors, such as LY294002 (LY), Bafilomycin A1 (Baf), Compound C (CC) and SBI-0206965 (SBI). Furthermore, the mTOR signaling pathway was regulated by the increased ROS as the initial signal in A549 and H1299 cells. Finally, the anti-tumor growth activity of PPVI in vivo was validated in A549 bearing athymic nude mice . Taken together, our data have firstly demonstrated that PPVI is the main component in TTM that exerts the anti-proliferative effect by inducing apoptotic and autophagic cell death in NSCLC via the ROS-triggered mTOR signaling pathway, and PPVI may be a promising candidate for the treatment of NSCLC in future.
研究领域:
肿瘤学
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药理学
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细胞生物学
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中药学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Jindan Xiao,Liuming Xie,Bing Zheng,Wenjie Ma,Yi Chen,Jianhua Xie,Xiaobo Hu,Qiang Yu
Autophagy is pivotal for the management of intestinal homeostasis, modulation of intestinal immunity response and anti-microbial protection. Previous studies have documented the protective function of Polygonatum cyrtonema Saponin (PCS) against intestinal injury, but whether PCS modulated autophagy and its associated responses remained unknown. A model of dextran sodium sulfate (DSS)- elicited intestinal injury was employed to confirm this hypothesis. The results showed that PCS effectively relieved the typical symptoms of DSS-induced weight reduction, shortened colon length, and augmented disease activity index score, down-regulated organ indices, reduced hepatic oxidative stress, and inhibited excessive inflammatory mediators. Meanwhile, PCS intervention ameliorated the intestinal barrier dysfunction via promoting the differentiation of goblet cells and augmenting the expression of tight junction proteins (TJs). It also suppressed apoptosis in intestinal cells by altering the Bcl-2/Bax ratios and diminishing the expressions of Caspase-9 and Caspase-3. Additionally, PCS remarkably enhanced autophagy by modulating the PI3K/AKT/mTOR signal pathway. More importantly, the classical autophagy inducer rapamycin augmented the beneficial effects of PCS. In contrast, the autophagy inhibitor 3-methyladenine essentially eliminated the above effects, revealing a role for autophagy in the response. Further studies have demonstrated that PCS intervention improved the diversities of the intestinal flora, increased occupancy of beneficial bacteria in Lachnospiraceaeae and Akkermansia , which was closely associated with autophagy. Taken together, these findings demonstrated that PCS is a potential supplier of prebiotics by modulating immunity, repairing intestinal mucosal injury, regulating autophagy and intestinal flora, and autophagy is a key target for PCS-mediated intestinal barrier protection.
研究领域:
胃肠病学
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免疫学
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分子生物学
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药理学
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产品关联
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yassmin Raafat Hassan,Riham A. El-Shiekh,Hala M. El Hefnawy,Osama G. Mohamed,Karema Abu-Elfotuh,Ahmed M. Hamdan,Alshaymaa Darwish,Ayah M.H. Gowifel,Ashootosh Tripathi,Camilia George Michael
Ethnopharmacological relevance Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as “African mango” or “bush mango”, belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health. Aim of the study The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction . Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat , metformin , and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways. Materials and methods Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days. Results More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 μg Gallic acid equivalent/mg extract and 8.039 ± 0.53 μg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways. Conclusion Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3β/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.
研究领域:
民族药理学
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药理学
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神经科学
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代谢组学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 3.9
Yi Zhou,Yawen Chen,Yuanyuan Zhao,Qiaohui Lu,Shihao Li,Wen-song Tan,Yan Zhou
Hydrostatic pressure (HP) is one of the important mechanical stimuli to maintain the structure and function of bone tissue. Under non-physiological conditions, abnormal increases or decreases in HP can lead to loss of bone tissue function. Although HP has been proven to affect osteogenic differentiation, the rules and mechanisms of its regulatory effect are still unclear. In this study, the HP showed a marginal effect on promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The regulation of osteogenic differentiation by HP is closely related to the Piezo1 ion channel. On the one hand, the activity of mTOR is inhibited by HP through the CaMKK2/AMPKα/mTOR signaling axis, thereby promoting the osteogenic differentiation. On the other hand, the cell morphology is also regulated by HP and tends to be round, which is not conducive to osteogenesis. The two regulatory modes jointly control the ultimate osteogenic differentiation ability of BMSCs in a complex way. This study provides new insights into the mechanism by which HP regulates osteogenic differentiation, suggesting the need to consider the role of signaling cascades and physical changes simultaneously.
研究领域:
生物力学
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干细胞生物学
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骨组织工程
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DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Zhishen Xie,Er-wen Li,Gai Gao,Yueyue Du,Mengyao Wang,Hui Wang,Pan Wang,Yonghui Qiao,Yunfang Su,Jiangyan Xu,Xiaowei Zhang,Zhenqiang Zhang
Ethnopharmacological relevance Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect. Aim of the study : To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/mTOR/SREBPs pathway. Materials and methods WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic . The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro . Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis. Results ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo . ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN , HMGCR , etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo . Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond . Conclusion Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.
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产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2025
·Vol. 26
·期 1
·1-17
·
IF 5
Ren Shencheng,Zhu Junkan,Shan Guangyao,Liang Jiaqi,Bian Yunyi,Lin Han,Shi Haochun,Pan Binyang,Zhao Guangyin,Yang Huiqin,Huang Xiaolong,Zhan Cheng,Ge Di,Bi Guoshu
Background Lung cancer remains the leading cause of cancer-related mortality globally, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Despite extensive research efforts, the role of transcription factors in LUAD progression remains largely uncharacterized. In this study, we focused on ZNF266, a transcription factor whose impacts on LUAD have not been investigated. Methods Using high-throughput sequencing data, we observed a significant downregulation of ZNF266 expression in LUAD tissues. To validate this finding, we conducted a retrospective analysis of nearly three thousand LUAD patients’ data from public databases and our institution. Functional studies were performed using cell lines, organoids, and xenograft models to assess the role of ZNF266 in LUAD progression. RNA sequencing, chromatin immunoprecipitation, DNA pull-down assays, and dual-luciferase reporter assays were employed to elucidate the underlying mechanism. Additionally, adeno-associated virus (AAV)-mediated overexpression of ZNF266 was used to evaluate its therapeutic potential. Results Patients with low ZNF266 expression had poorer prognosis compared to those with high expression. ZNF266 inhibits the malignant phenotypes of LUAD, including proliferation, migration, and invasion. Mechanistically, ZNF266 binds to the promoter region of CA9, suppressing its transcription. This leads to a reduction in intracellular pH and subsequent inhibition of the mTOR signaling pathway, which is crucial for cancer cell growth and survival. Furthermore, AAV-mediated overexpression of ZNF266 significantly inhibited tumor growth in patient-derived xenograft models. Conclusions Our study demonstrated that ZNF266 inhibits LUAD progression in a pH-dependent manner via modulating CA9 expression, uncovering its therapeutic significance for LUAD treatment.
研究领域:
肿瘤学
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分子生物学
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医学遗传学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF MICROBIOLOGY
·
2024
·Vol. 206
·期 6
·1-11
·
IF 2.3
Zhuang Cuicui,Zhang Ruoqing,Bai Jiangang,Zhang Xinying,Zhao Jinhui
Escherichia coli ( E. coli ) can induce severe clinical bovine mastitis, which is to blame for large losses experienced by dairy farms. Macrophage polarization into various states is in response to pathogen infections. Lycopene, a naturally occurring hydrocarbon carotenoid, relieved inflammation by controlling M1/M2 status of macrophages. Thus, we wanted to explore the effect of lycopene on polarization states of macrophages in E. coli -induced mastitis. Macrophages were cultivated with lycopene for 24, before E. coli inoculation for 6 h. Lycopene (0.5 μmol/L) significantly enhanced cell viabilities and significantly reduced lactic dehydrogenase (LDH) levels in macrophages, whereas 2 and 3 μmol/L lycopene significantly enhanced LDH activities. Lycopene treatment significantly reduced the increase in LDH release, iNOS, CD86, TNF-α, IL-1β and phosphatase and tensin homolog (PTEN) expressions in E. coli group. 0.5 μmol/L lycopene significantly increased E. coli -induced downregulation of CD206, arginase I (ARG1), indoleamine 2,3-dioxygenase (IDO), chitinase 3-like 3 (YM1), PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR), p-mTOR, jumonji domain-containing protein-3 (JMJD3) and interferon regulatory factor 4 (IRF4) levels. Moreover, Ginkgolic acid C17:1 (a specific PTEN inhibitor), 740YPDGFR (a specific PI3K activator), SC79 (a specific AKT activator) or CHPG sodium salt (a specific NF-κB activator) significantly decreased CD206, AGR1, IDO and YM1 expressions in lycopene and E. coli -treated macrophages. Therefore, lycopene increased M2 macrophages via inhibiting NOTCH1-PI3K-mTOR-NF-κB-JMJD3-IRF4 pathway in response to E. coli infection in macrophages. These results contribute to revealing the pathogenesis of E. coli -caused bovine mastitis, providing the new angle of the prevention and management of mastitis.
研究领域:
免疫学
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微生物学
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药理学
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细胞生物学
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兽医学
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产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2022
·
IF 3.715
Lin Bai,Yingying Wu,Ruike Wang,Rundong Liu,Mengchen Liu,Qiong Li,Yue Ba,Huizhen Zhang,Guoyu Zhou,Fangfang Yu,Hui Huang
As a ubiquitous toxic heavy metal, lead (Pb) exposure is known to be implicated in the onset and development of neurodegenerative diseases which may cause more serious health hazards with age and the accumulation of Pb in the body. Autophagy is the main degradation route for abnormal aggregated proteins and damaged cell organelles. Here, we aimed to study the effects of adolescent Pb exposure on autophagy at different life nodes. In this study, we developed a time-series model of Pb exposure in mice and randomly divided 4-week-old male C57BL/6 mice into six groups (4 C, 13 C, 16 C, 4Pb, 13Pb and 16Pb). Mice in Pb groups was consumed deionized water containing 0.2 % Pb(Ac) 2 for 3 months and then reared to anticipated life nodes, while the control group consumed deionized water. Western blot and Real-time qPCR were used to assess the effects of developmental Pb exposure on individual components of the autophagy machinery and modulation of microtubule-associated protein 1 light chain 3 (LC3) at each age stage. Our results showed that Pb exposure during adolescence reduced the p-mTOR/mTOR ratios with enhanced expression of Beclin-1, Atg12 and Atg7in both the hippocampus (HPC) and prefrontal cortex (PFC) of senescent mice while upregulation of LC3II/LC3I ratios and p62 suggested that autophagy mediates degradation was interrupted. Overall, we confirm that Pb exposure during adolescence promotes autophagic processes in the aged mice brain and that autophagic degradation is hindered, ultimately leading to a failure of autophagic degradation.
研究领域:
毒理学
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神经科学
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分子生物学
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发育生物学
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衰老研究
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DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2022
·
IF 4.345
Xiaoli Li,Guangbei Zhu,Xintong Yao,Ning Wang,Ronghui Hu,Qingxin Kong,Duanfang Zhou,Liangyuan Long,Jiali Cai,Weiying Zhou
Background Celastrol is a major active component of the thunder god vine (Tripterygium wilfordii) used in traditional Chinese medicine to treat chronic inflammatory and autoimmune diseases. Celastrol inhibits PI3K–Akt–mTOR signaling, which is frequently dysregulated in tumors and critical for tumor-cell proliferation and survival, but the underlying mechanisms are still not fully understood. In the present study, we investigated detailed mechanisms of celastrol inhibition of mTOR signaling in breast cancer cells.Methods First, we evaluated the effect of celastrol on breast cancer-cell growth using MTT assays. Second, we examined the effects of celastrol on mTOR phosphorylation and expression using Western blot. Furthermore, we investigated the cause of mTOR downregulation by celastrol using immunoprecipitation assays. In addition, we evaluated the effect of celastrol on an MDA-MB231 cell-derived xenograft model.Results Celastrol suppressed breast cancer cell growth in vitro and in vivo. Celastrol inhibited mTOR phosphorylation and induced mTOR ubiquitination, resulting in its proteasomal degradation. Mechanistically, we found that mTOR is a client of Hsp90–Cdc37 chaperone complex, and celastrol disrupts mTOR interaction with chaperone Hsp90 while promoting mTOR association with cochaperone Cdc37.Conclusion Our study reveals that celastrol suppresses mTOR signaling, at least in part through regulating its association with chaperones and inducing its ubiquitination.
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xianghong Wang,Rong Lin,Dehai Li,Weiyuan Ye,Zhe Yang,Niujian Wu,Qiong Wen,Jingyi Tan,Chuanchuan Sun,Zhinan Yin,Hongyun Lu,Hengwen Yang
Previous studies have established that γδ T cells play a significant role in liver fibrosis. However, their specific functions and mechanisms in fibrotic liver tissue remain unclear. Using online microarray expression profiles, we observed that USF3 was upregulated in patients with liver fibrosis and was associated with immune cells. Additionally, increases in the expression of USF3 correlated with elevated levels of interferon-gamma (IFN-γ) in γδ T cells. However, the regulatory impact of USF3 on T cells, particularly in relation to fibrosis, has not been sufficiently elucidated. In this study, we employed conditional knockout mice (USF3 f/f ; CD2-cre) to investigate the role of USF3 in γδ T cells. The conditional knockout of USF3 resulted in an increase in both the number and proliferation of γδ T cells, which was associated with mTOR signaling pathway activation. The absence of USF3 significantly enhanced the expression of Eomes in γδ T cells, leading to an increase in IFN-γ production. Importantly, liver fibrosis was alleviated in USF3 conditional knockout mice, which was potentially linked to the enhanced proliferation of γδ T cells and the elevated expression of cytotoxic molecules, including IFN-γ. In summary, targeting USF3 in γδ T cells may represent a promising immunotherapeutic approach for liver fibrosis.
研究领域:
免疫学
·
肝脏病学
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分子生物学
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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）