HEREDITAS
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2026
·Vol. 163
·期 1
·43
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IF 2.6
Wu Ting,Jiang Jingwen,Zhang Yunfang,Zhang Hui,Fu Mingquan,Chen Fazhang,Fan Yilin,Yuan Huan,Wang Kaining
Background Colorectal cancer (CRC) remains one of the most commonly diagnosed malignancies worldwide and is associated with high recurrence and poor survival outcomes, particularly in its advanced stages. Zi-Shen-Gu-Sui Decoction (ZSGSD), a traditional Chinese medicinal formula, has been clinically applied in CRC treatment and postoperative rehabilitation; however, its pharmacological mechanisms are not yet fully elucidated. This study aimed to explore the anti-CRC efficacy and molecular mechanisms of ZSGSD, with particular attention to the PI3K/AKT/mTOR signaling axis. Methods UPLC-Q-Orbitrap HRMS was utilized to characterize the chemical profile of ZSGSD. Network pharmacology was employed to identify key signaling pathways and bioactive compounds, and molecular docking was conducted to predict potential interactions between major constituents and PI3K/AKT/mTOR proteins. A xenograft mouse model of CRC was established to evaluate tumor suppression. Histological staining was used to assess apoptosis, and the expression of PI3K, AKT, and mTOR was quantified via RT-qPCR, Western blotting, and immunofluorescence assays. Results Sixty compounds were identified in ZSGSD, with flavonoids comprising approximately 50%. Network analysis suggested potential involvement of the PI3K/AKT/mTOR pathway, and docking results indicated favorable predicted binding between key flavonoids (including Genistein, Apigenin, and Naringenin) and proteins within this pathway. In vivo, ZSGSD treatment suppressed tumor growth in a dose-responsive fashion, with tumor inhibition rates ranging from 30.83% to 75.23% ( p < 0.05). Histological evaluations revealed reduced nuclear-to-cytoplasmic ratios and enhanced apoptotic activity, as confirmed by TUNEL staining ( p < 0.05). Molecular analyses showed a dose-related reduction in PI3K, AKT, and mTOR expression at the transcript and protein levels, indicating that this pathway may be modulated during ZSGSD treatment ( p < 0.05). Conclusion ZSGSD demonstrates notable tumor-suppressive and pro-apoptotic effects in a CRC xenograft model. These outcomes appear to be associated with modulation of the PI3K/AKT/mTOR signaling pathway, although further functional studies are required to confirm pathway specificity and clarify causal mechanisms.
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PHYTOTHERAPY RESEARCH
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2026
·
IF 8.1
Pengru Wang,Xin Hu,Haiyan Pu,Junjie Bai,Lei Sun,Tingting Ma,Yichao Du,Wenguang Fu
Hepatic ischemia–reperfusion (I/R) injury complicates transplantation, resection, and shock, yet lacks effective pharmacotherapy. We evaluated Leonurine (SCM-198) as a hepatoprotective agent. Male C57BL/6 mice were pretreated with SCM-198 for 7 days, then subjected to hepatic I/R and sampled at the reperfusion endpoint. AML12 cells were pretreated with SCM-198 for 24 h, exposed to hypoxia/reoxygenation (H/R), and immediately analyzed. Injury, inflammation, apoptosis, and cell-cycle changes were assessed using assay kits, histology, IHC, WB, and qPCR; network pharmacology, docking, and MD simulations explored potential targets. SCM-198 sharply cut hepatic necrosis and serum transaminases, suppressed pro-inflammatory cytokines, reduced leukocyte infiltration, blocked apoptosis and restored cyclin D1/cyclin E1. In hypoxia-reoxygenation AML12 cells, it improved viability, limited oxidative stress and mirrored the anti-apoptotic effects. Network and dynamic simulation identified stable phosphoinositide 3-kinase (PI3K) binding, and the compound raised PI3K, protein kinase B and mammalian target of rapamycin phosphorylation; the PI3K inhibitor LY294002 abolished these changes. SCM-198 protects liver I/R by curbing inflammation, apoptosis, and cell-cycle arrest via PI3K/AKT/mTOR activation, offering a promising therapeutic candidate.
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CHEMICAL & PHARMACEUTICAL BULLETIN
·
2021
·
IF 1.645
Bai-ling Sun,En-bo Cai,Yan Zhao,Yu Wang,Li-min Yang,Jing-Yao Wang
Arctigenin(ARG) , a natural lignans compound isolated from Arctium lappa L. In this study, the anti-tumor effect of ARG on prostate cancer cell PC-3M and the mechanism of apoptosis and autophagy induced by PI3K/Akt/mTOR signaling pathway were discussed, and further confirmed by the joint treatment of ARG and PI3K inhibitor LY294002. Here, the effect of ARG on cell viability was evaluated in PC-3M cells by CCK-8 assay. After the treatment of ARG, colony formation assay was used to detect the anti-proliferation effect. Annexin V-FITC/PI kit and DAPI staining were used to detect the apoptosis level, and cell cycle changes were analyzed by flow cytometry. The expression of autophagy was detected by acridine orange staining. In addition, the expression levels of apoptosis and autophagy-related proteins were analyzed by western blot. The result showed that different concentrations of ARG inhibited the proliferation of PC-3M cells. DAPI staining and flow cytometry showed that ARG induced PC-3M cell apoptosis and arrested cell in G0/G1 phase. Acridine orange staining showed that ARG induced autophagy in PC-3M cells. Western blot experiments showed that ARG inhibited the expression of Bcl-2 , promoted the expression of Bax and cleaved caspase-3. At the same time, the expression of autophagy-related proteins LC3B-II and Beclin-1 increased after ARG treatment, but P62 decreased. In addition, further studies have shown that treatment with LY294002 enhanced the effects of ARG on the expression of proteins associated with apoptosis and autophagy , indicating that ARG may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway.
研究领域:
肿瘤学
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细胞生物学
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药理学
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LIFE SCIENCES
·
2018
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IF 3.234
Han Zhang,Fenfen Qin,Anlong Liu,Qinmei Sun,Qisheng Wang,Shuwu Xie,Shengfeng Lu,Dong Zhang,Zhigang Lu
Aims Electro-acupuncture (EA) is frequently recommended as a complementary therapy for premature ovarian failure (POF) in the clinical. However, little information exists about its potential treatment mechanisms. The study was designed to observe the effect of EA to ovarian function and fertility in POF mice model, and investigated its potential mechanisms on PI3K/AKT/mTOR signaling pathway. Materials and methods Forty-five female C57/BL6 mice were divided into the Control, the Model and the EA group. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. The protein expression of PI3K, phospho-PI3K, AKT, phospho-AKT, mTOR, phospho-mTOR, S6, phospho-S6, 4E-BP1 and phospho-4E-BP1 were detected by western blotting. The data was presented as the ratio of phosphorylation protein to total protein. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E 2 ) and anti-Mullerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. Key findings We found that primordial follicle counts were increased in EA group compared to Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in EA group significantly reduced compared to Model group. Serum FSH and LH levels in EA group were decreased compared to Model group, while, serum E 2 and AMH levels in EA group were increased compared with Model group. The litter size in EA group was improved compared to Model group. Significance The effects of EA on the PI3K/AKT/mTOR signaling pathway may represent one of the mechanisms involved in attenuating the mice POF.
研究领域:
生殖生物学
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针灸疗法
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信号转导
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Long Zhang,Weibin Li,Xiaohui Chen,Dongmin Cao,Siyuan You,Fan Shi,Zhengqiong Luo,Hongyu Li,Xiangchen Zeng,Yabin Song,Na Li,Yoshie Akimoto,Gang Rui,Yu Chen,Zuoxing Wu,Ren Xu
Bone metastases caused by breast cancer pose a major challenge to the successful treatment of breast cancer patients. Many researchers have suggested that herbal medicines are extremely effective at preventing and treating cancer-associated osteolysis. Previous studies have revealed that Morusin (MOR) is cytotoxic to many cancer cells ex vivo . Nevertheless, how MOR contributes to osteolysis induced by breast cancer is still unknown, and the potential mechanism of action against osteolysis is worthy of further study. The protective effect and molecular mechanism of MOR in inhibiting breast cancer cell-induced osteolysis were verified by experiments and network pharmacology. Cell function was assessed by cell proliferation, osteoclast (OC) formation, bone resorption, and phalloidin staining. Tumour growth was examined by micro-CT scanning in vivo . To identify potential MOR treatments, the active ingredient–target pathway of breast cancer was screened using network pharmacology and molecular docking approaches. This study is the first to report that MOR can prevent osteolysis induced by breast cancer cells. Specifically, our results revealed that MOR inhibits RANKL-induced osteoclastogenesis and restrains the proliferation, invasion and migration of MDA-MB-231 breast cells through restraining the PI3K/AKT/MTOR signalling pathway. Notably, MOR prevented bone loss caused by breast cancer cell-induced osteolysis in vivo , indicating that MOR inhibited the development of OCs and the resorption of bone, which are essential for cancer cell-associated bone distraction. This study showed that MOR treatment inhibited osteolysis induced by breast cancer in vivo . MOR inhibited OC differentiation and bone resorption ex vivo and in vivo and might be a potential drug candidate for treating breast cancer-induced osteolysis.
研究领域:
肿瘤学
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药理学
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分子生物学
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高影响因子
Molecular Medicine Reports
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2019
·Vol. 19
·期 5
·3658-3666
·
IF 1.851
Jin Xu,Yin Ying,Gaoyun Xiong,Liqin Lai,Qingliang Wang,Yue Yang
Nasopharyngeal carcinoma (NPC) is a type of cancer originating in the nasopharynx. There are no NPC‑specific treatments available at present. Serpin peptidase inhibitor clade C member 1 (SERPINC1) serves roles in anticoagulation and anti‑inflammation. The aim of the present study was to investigate the role of SERPINC1 in the proliferation and apoptosis of NPC cells. Tumor and adjacent healthy tissue samples were collected from patients with NPC. Additionally, the SERPINC1 gene was silenced in the HNE3 cell line using short interfering RNA targeted against SERPINC1 (SERPINC1‑siRNA). Cell viability was determined via a Cell Counting Kit‑8 assay; furthermore, proliferation and apoptosis were investigated via flow cytometry. Western blotting and reverse transcription‑quantitative polymerase chain reaction analysis were performed to determine the expression levels of protein and mRNA. It was revealed that the expression levels of SERPINC1 mRNA and protein were increased in NPC tumor tissues compared with in adjacent healthy tissues. The expression of SERPINC1 mRNA and protein in HNE3 cells decreased following SERPINC1‑siRNA transfection. Furthermore, knockdown of SERPINC1 promoted apoptosis and inhibited proliferation. It was also demonstrated that silencing SERPINC1 upregulated the expression of B‑cell lymphoma-2 (Bcl‑2)‑associated X protein and p53 mRNA and protein, and downregulated that of Bcl‑2, survivin and cyclin D1. Downregulation of SERPINC1 reduced the phosphorylation of phosphatidylinositol 3‑kinase (PI3K), protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Thus, SERPINC1 knockdown may promote the apoptosis of HNE3 cells and inhibit proliferation via the suppression of the PI3K/Akt/mTOR signaling pathway.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2017
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IF 2.466
Menglu Zhou,Shuying Shen,Xin Zhao,Xingguo Gong
Autophagy has attracted a great deal of interest in tumour therapy research in recent years. However, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, on autophagy remains poorly understood in human lung cells. In the present study, we have investigated the anticancer effects of luteoloside on non-small cell lung cancer (NSCLC) cells and demonstrated that luteoloside effectively inhibited cancer cell proliferation , inducing G 0 /G 1 phase arrest associated with reduced expression of CyclinE, CyclinD1 and CDK4; we further found that treatment with luteoloside did not strongly result in apoptotic cell death in NSCLC (A549 and H292) cells. Interestingly, luteoloside induced autophagy in lung cancer cells, which was correlated with the formation of autophagic vacuoles, breakdown of p62, and the overexpression of Beclin-1 and LC3-II, but not in a human bronchial epithelial cell line (BEAS-2B). Notably, pretreatment of cancer cells with 3-MA, an autophagy inhibitor, protected against autophagy and promoted cell viability but not apoptosis. To further clarify whether luteoloside-induced autophagy depended on the PI3K/AKT/mTOR/p70S6K signalling pathway , a major autophagy-suppressive cascade, cells were treated with a combination of AKT inhibitor (LY294002) and mTOR inhibitor (Rap). These results demonstrated that luteoloside induced autophagy in lung cancer cell lines by inhibiting the pathway at p -Akt (Ser473), p -mTOR and p-p70S6K (Thr389). Moreover, we observed that luteoloside-induced cell autophagy was correlated with production of reactive oxygen species (ROS). NAC-mediated protection against ROS clearly implicated ROS in the activation of autophagy and cell death. In addition, the results showed that ROS served as an upstream effector of the PI3K/AKT/mTOR/p70S6K pathway. Taken together, the present study provides new insights into the molecular mechanisms underlying luteoloside-mediated cell death in NSCLC cells and supports luteoloside as a potential anti-cancer agent for targeting NSCLC through the induction of autophagy, inhibition of proliferation and PI3K/AKT/mTOR/p70S6K signalling.
研究领域:
肿瘤学
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药理学
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分子生物学
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OncoTargets and Therapy
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2022
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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.
研究领域:
肿瘤学
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药理学
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分子生物学
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传统中药
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高影响因子
TOXICOLOGY LETTERS
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2026
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IF 3.1
Lele Zhou,Lingbin Chen,Cailin Zheng,Jinneng Wu,Meihua Zhong,Zhixiong Huang,Zhiming Xin,Zhou Chen
Tripchlorolide, a low-toxicity derivative of the natural product triptolide, exhibits significant therapeutic potential for inflammatory and autoimmune diseases; however, its profile of male reproductive toxicity remains a major concern for clinical translation. To address this, we first established its median lethal dose at 33.13 mg/kg in mice to guide safe exposure levels. We then systematically evaluated its reproductive toxicity in male rats following 8-week intraperitoneal administration (2.5, 5, and 10 μg/kg/day). Our results demonstrated a clear dose-dependent toxicity, characterized by significant reductions in testicular and epididymal coefficients, impaired sperm count and motility, disrupted testosterone, follicle-stimulating hormone, and luteinizing hormone levels, and evident histopathological damage in the testes and epididymides. Encouragingly, these adverse effects showed signs of reversal after a 4-week recovery period, suggesting that the impairment is reversible. Through an integrated approach combining network pharmacology prediction and molecular docking, we identified the inhibition of the PI3K/Akt/mTOR signaling pathway as the pivotal molecular event. This mechanism was conclusively validated by our in vivo rescue experiment, where co-administration of the Akt activator SC79 markedly attenuated the tripchlorolide-induced reproductive impairments. Our study provides a comprehensive toxicological profile, defining the dose-response, reversibility, and mechanistic basis of tripchlorolide's male reproductive toxicity, thereby offering critical insights for its risk assessment and potential repurposing.
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Frontiers in Pharmacology
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2025
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IF 4.8
Xiaoli Deng,Chunjie Hu,Lin Li,Guixian Yang,Chikun Li,Wanxun Zhang,Guangyu Cheng
Background Lung cancer is a leading cause of cancer-related deaths, with cisplatin being a cornerstone of treatment. However, resistance to cisplatin presents a significant challenge. β-elemene, a natural compound, has demonstrated potential to reverse cisplatin resistance. LncRNA LINC00511 has been implicated in cisplatin resistance through its role in activating the PI3K/AKT/mTOR pathway, which supports tumor survival and proliferation. Purpose This study aims to investigate the mechanism by which β-elemene overcomes cisplatin resistance in lung cancer by regulating LINC00511. Methods Human lung adenocarcinoma cells (A549 and A549/DDP) were treated with β-elemene and cisplatin. Cell proliferation and apoptosis were assessed using CCK-8, EdU staining, and flow cytometry. LINC00511 expression was measured by qRT-PCR, and protein levels of PI3K, AKT, and mTOR were evaluated via Western blot. A xenograft model was used to confirm in vivo effects. Results β-elemene significantly enhanced cisplatin-induced apoptosis in A549/DDP cells, reduced LINC00511 expression, and inhibited the PI3K/AKT/mTOR pathway. LINC00511 knockdown further potentiated these effects, both in vitro and in vivo . Xenograft models confirmed the enhanced anti-tumor effects of the combination treatment. Conclusion β-elemene overcomes cisplatin resistance in lung cancer by downregulating LINC00511 and inhibiting the PI3K/AKT/mTOR pathway. These findings propose a promising therapeutic strategy for treating cisplatin-resistant lung cancer.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2021
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IF 6.291
Min Kang,Jie Luo,Ling Zhao,Fei Shi,Gang Ye,Xiaoli He,Suqi Hao,Dan Yang,Helin Chen,Hongrui Guo,Yinglun Li,Huaqiao Tang
Nano-copper (nano-Cu) is widely used in the pharmaceutical field as well as a feed additive for animals owing to its unique physicochemical characteristics and bioactivities. In our previous study, nano-Cu was found to hamper fetal development; however, the toxicity of nano-Cu and its effects in placental function have not been elucidated. Therefore, we investigated the toxic effects of nano-Cu using rat placenta. Pregnant Sprague-Dawley rats were orally exposed to different copper sources from the third day of gestation (GD 3) to GD 18. We found that nano-Cu (180 mg/kg) and CuCl 2 .2 H 2 O increased the accumulation of copper. Besides, nano-Cu and CuCl 2 .2 H 2 O disrupted the placental morphology and induced oxidative stress. Micro-copper (micro-Cu) caused similar toxicity in the placenta, but its effects were weaker than that of nano-Cu and CuCl 2 .2 H 2 O. In addition, exposure to nano-Cu (180 mg/kg) and CuCl 2 .2 H 2 O induced inflammation in the rat placenta. Furthermore, nano-Cu, micro-Cu, and CuCl 2 .2 H 2 O upregulated the expression of the autophagy-related proteins, Beclin-1 and LC3 II/ LC3 I, and downregulated that of p62. Moreover, nano-Cu, micro-Cu, and CuCl 2 .2 H 2 O downregulated the protein expression of PI3K, p-AKT/AKT, and p-mTOR/mTOR in rat placentas, whereas the protein expression of p-AMPK/AMPK was upregulated. Taken together, our data indicated that prenatal exposure to nano-Cu induced autophagy via the PI3K/AKT/mTOR and AMPK/mTOR pathways, which associated with oxidative stress and inflammation in rat placenta.
研究领域:
毒理学
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药理学
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生殖生物学
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xinyi Li,Hui Song,Yiwen Yuan,Na Jiang,Wei Duan,Tianzhao Xu,Chang Liu,Xinghui Liu
Cardiovascular diseases have long posed a significant threat to public health. Among them, myocarditis is a major category of cardiovascular disorders that is characterized by high mortality during its acute phase, necessitating urgent medical attention. This study aims to explore the therapeutic effects and underlying mechanisms of Spi1-mediated gene regulation in chemotherapy induced cardiomyopathy. To validate our findings, we employed bioinformatics analysis methods and established myocarditis models using the chemotherapeutic drug doxorubicin in both cellular and animal models. Our results demonstrated that the inhibition of Spi1 significantly suppressed inflammatory factor expression in H9C2 rat cardiomyocytes. Furthermore, in C57BL/6 mouse model, Spi1 inhibition was shown to improve cardiac function and alleviate both myocardial inflammation and fibrosis in mice with doxorubicin-induced myocarditis. Mechanistic investigations revealed that Spi1 suppression altered the expression of genes associated with immune response, cell differentiation and proliferation. Notably, Spi1 modulates the expression of YTHDF2, thereby influencing the PI3K/AKT/mTOR signaling pathway and subsequently regulating the inflammatory response. Collectively, these findings suggest that Spi1 plays a pivotal role in doxorubicin-induced myocarditis by mitigating inflammatory responses and myocardial injury through the regulation of YTHDF2 and the PI3K/AKT/mTOR signaling pathways, offering a promising therapeutic target for the treatment of myocarditis.
研究领域:
心血管研究
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分子生物学
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药理学
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肿瘤学
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信号转导
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高影响因子
危险品化学品经营许可证（带存储）