JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Jue Liu,Yue-Xuan Liu,Yu-Song Song,Chen-Kai Liu,Fei-Xue Yu,Gao Liu,Tian-Rui Xu,Jun Sang
Ethnopharmacological relevance Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz., known as “Chonglou” in traditional Chinese medicine, is clinically used in cancer therapy, with saponins identified as the key antitumor constituents. However, the therapeutic potential and mechanisms of the total saponins from P. polyphylla var. yunnanensis (PPT) against bladder cancer, particularly their ability to overcome chemoresistance, remain unexplored. Aim of the study This study aimed to investigate PPT's anti-bladder cancer effects and mechanisms, with a focus on its potential to overcome cisplatin resistance. Materials and methods We established a UPLC-DAD method for saponin profiling and developed an eco-friendly extraction protocol using hydroxypropyl- β -cyclodextrin-assisted extraction combined with macroporous resin purification to prepare PPT. Anti-cancer efficacy was assessed in bladder cancer cell lines, mouse/zebrafish xenograft models, and cisplatin-resistant models. Mechanistic investigations integrated network pharmacology, metabolomics, molecular docking, and experimental validations (siRNA silencing, western blotting, flow cytometry, molecular dynamics simulations, cellular thermal shift assay, and surface plasmon resonance). Results The hydroxypropyl- β -cyclodextrin-based extraction system enhanced PPT purity by 15-fold, with the purified fraction showing dose-dependent anti-bladder cancer activity in vitro and in vivo . Mechanistically, PPT exerted anti-proliferative, pro-apoptotic, anti-lipogenic, and chemosensitizing effects by inhibiting the growth factor receptor binding protein 2 (GRB2)-mediated Akt-SREBP1 signaling axis. Notably, polyphyllin VII, a key constituent of PPT, was identified as a novel GRB2 inhibitor, potently suppressing bladder cancer progression and overcoming cisplatin resistance. Conclusion This study demonstrates that targeting the GRB2-Akt-SREBP1 signaling axis is a promising strategy for bladder cancer therapy, further establishing PPT as a multicomponent phytomedicine and PPVII as a novel GRB2 inhibitor with high translational potential.
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CURRENT CANCER DRUG TARGETS
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2022
·Vol. 22
·期 1
·86-95
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IF 2.907
Yiyan SongYang,Yang Songyisha,Li Dejia,Li Wen
Background: Non-Small-Cell Lung Cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all lung cancer cases and resulting in high morbidity and mortality. Previous studies have demonstrated that 1,25-dihydroxy-vitamin-D3 (vitamin D) exhibited
anti-cancer activity against breast and prostate cancer. Objectives: The aim of the current study is to investigate the effect of vitamin D on NSCLC and its underlying mechanism. Methods: The effects of vitamin D on stemness maintenance and the Warburg effect in NSCLC cells were
investigated both in vitro and in vivo. Results and Discussion: In vitro experiments revealed that vitamin D inhibited glycolysis and stemness maintenance in A549 and NCI-H1975 cells. Both in vitro and in vivo experiments indicated that vitamin D attenuated the expression of metabolism-related
enzymes associated with the Warburg effect (GLUT1, LDHA, HK2, and PKM2). In addition, vitamin D down-regulated the expression of stemness-related genes (Oct-4, SOX-2, and Nanog) and the expression of PI3K, AKT, and mTOR. Conclusion: Overall, these findings suggest that vitamin D suppresses
the Warburg effect and stemness maintenance in NSCLC cells via the inactivation of PI3K/AKT/mTOR signaling, thereby inhibiting the progression of NSCLC. The current study indicates that vitamin D is a potential candidate in therapeutic strategies against NSCLC.
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STEROIDS
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2020
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IF 1.948
Jingwen Xu,Mingmei Zhang,Xiaoying Lin,Yihai Wang,Xiangjiu He
Allium chinense , as a side dish on Asian table, is often used in folk medicine for its health benefits. (25R)-5α-spirostan-3β-yl-3-O-acetyl-O-β- d -glucopyranosyl-(1 → 2)-O-[β- d -glucopyranosyl-(1 → 3)]-O-β- d -glucopyranosyl-(1 → 4)-β- d -galactopyranoside (A-24) is a bioactive steroidal saponin isolated from Allium chinense . Previously, we have shown that A-24 has cytotoxic effects on cancer cells, but not on normal cells. To further explore the underlying mechanisms, in this study, we investigated the anticancer activity of A-24 in human gastric cancer cell lines in terms of cell proliferation, colony formation, cell cycle, induction of apoptosis/autophagy, and PI3K/Akt/mTOR pathway. A-24 showed dose-dependent cytotoxicity in SGC-7901 and AGS cell lines, it induced intrinsic mitochondrial pathway of apoptosis as well as autophagy, G2/M phase arrest and modulation of cyclinB1, p-cdc2, p-wee1 and p-Histone H3 expression. Furthermore, A-24 downregulated the phosphorylation of Akt at Ser473 and mTOR at Ser2448 in PI3K/Akt/mTOR pathway, and its downstream substrates p-p70S6K and p-4EBP1 in a dose-dependent manner. In addition, the pre-treatment of tumor cells with 3-methyladenine (3-MA) and LY294002 increased A-24-induced apoptosis. Collectively, these findings highlight the significance of downregulation of PI3K/Akt/mTOR pathway in A-24-induced apoptosis and autophagy, and the potential application of A-24 as a novel candidate in the treatment of human gastric adenocarcinoma.
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BMC Pregnancy and Childbirth
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2026
·Vol. 26
·期 1
·363
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IF 3.1
Xie Xinping,Yan Jianying,Chen Xiaoyun,He Lidan,Wu Jianbo,Lu Lin
Background Insulin resistance (IR) is a pivotal determinant in the pathophysiological processes underlying gestational diabetes mellitus (GDM). Angiopoietin-like protein 8 (ANGPTL8) exhibits an ambiguous influence on glucose metabolism in the onset and progression of GDM. However, the functions of ANGPTL8 in the metabolic profiles of insulin-resistant (IR) HepG2 cells, glucose tolerance in GDM mice, and the possible underlying mechanisms require further exploration. Methods ANGPTL8 knockout and over-expressing HepG2 cell lines were established. Glucose uptake capacity in three clones (wild-type, ANGPTL8 knockout, and over-expressing) of insulin-resistant HepG2 cells was detected. Proteomic analysis of the IR HepG2 cells identified a cluster of relevant signaling pathways, and the effect of ANGPTL8 on metabolomic changes was evaluated. The GDM model was induced by a high-fat diet (HFD) and intraperitoneal injection of Streptozotocin (STZ) in pregnant mice. An oral glucose tolerance test (OGTT) was performed in both GDM mice and ANGPTL8 over-expressing GDM mice. Results The PI3K/Akt signaling cascade was stimulated by insulin resistance, and this activation could be effectively suppressed by inhibitors targeting PI3K, Akt, and GSK-3β. HepG2 cells over-expressing ANGPTL8 and exposed to high insulin concentrations demonstrated a marked enhancement in glucose uptake capacity, as opposed to their wild-type counterparts or ANGPTL8 knockout cells under IR conditions. The most substantial down-regulation was observed in lactate and branched-chain amino acids (BCAAs), which exhibited a positive correlation with IR. Promoted translation of ANGPTL8 was found in the liver, pancreas, and placental tissues of GDM mice. Significantly better glucose tolerance was observed in GDM mice transfected with m-ANGPTL8 compared with those that were not. Furthermore, the activation of Akt was observed in the primary hepatocytes of ANGPTL8 over-expressing GDM mice. Conclusion Over-expression of ANGPTL8 may increase glucose uptake capacity and influence the metabolic profiles in IR HepG2 cells, enhancing the insulin-mediated activation of the PI3K/Akt/GSK-3β pathway. ANGPTL8 may improve glucose tolerance in GDM mice. These findings might contribute to a new understanding of the roles of ANGPTL8 in glucose metabolism during the onset and progression of insulin resistance, providing novel insights for the clinical therapy of GDM.
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NEUROTOXICOLOGY
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2026
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IF 3.8
Xuening Li,Linglong Meng,Qiang Niu,Runjiang Ma,Yuhan Li,Hailing Zhou,Xiaoya Fu,Wenjie Chen,Juan Tang,Shangzhi Xu
This study investigated the mechanisms by which a region-specific simulated PM 2.5 from Shihezi, China, exacerbates Alzheimer’s disease (AD) pathology, focusing on the protein kinase B (AKT)/mitogen-activated protein kinase (MAPK) signaling axis. APP/PS1 and wild-type mice were exposed to a simulated Shihezi PM 2.5 suspension. Cognitive function, neuroinflammation, oxidative stress, signaling activity, apoptosis, and amyloid-β (Aβ)/Tau pathology were assessed. Simulated PM 2.5 exposure aggravated cognitive deficits, induced neuroinflammation and oxidative stress, and triggered a significant AKT/MAPK imbalance characterized by MAPK hyperactivation and AKT suppression. This imbalance promoted neuronal apoptosis and exacerbated both Aβ deposition and Tau hyperphosphorylation. Our findings reveal that simulant PM 2.5 -induced neuroinflammation and oxidative stress dysregulate the AKT/MAPK axis, driving neuronal loss and AD progression, and suggest a molecular mechanism by which environmental PM 2.5 exposure may contribute to accelerated neurodegeneration.
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Food Bioscience
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2026
·
IF 6.2
Xiao Qiang,Mengyuan Gao,Zongshuo Li,Weidong Li
SQLE is a potential functional food for alleviating spleen deficiency syndrome. • SQLE contains diverse bioactive compounds with flavonoids as major components. • SQLE restores gut microbiota homeostasis and promotes SCFAs production. • SQLE improves spleen deficiency via the PI3K/Akt/NF-κB/AQP3 signaling pathway. Spleen deficiency syndrome (SDS) manifests as impaired digestive function, fatigue, and metabolic issues, which are closely associated with dysbiosis of the gut microbiota. Shen-Qi-Ling extract (SQLE) is a natural extract prepared from food-medicine homologous resources, primarily consisting of Codonopsis pilosula , Astragalus membranaceus , and Poria cocos . However, the bioactive constituents and mechanisms by which it alleviates SDS remain unclear. In this study, we systematically characterized the chemical constituents of SQLE and elucidated its potential mechanisms of action against SDS in mice. Using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) analysis, 137 compounds were identified in SQLE, with flavonoids being the most abundant, followed by coumarins, phenylpropanoids, and organic acids. Molecular docking analysis indicated that SQLE might have a spleen-strengthening effect. Treatment with SQLE, particularly SQLE-M, significantly enhanced intestinal absorption, exercise performance, tissue damage, and oxidative stress. Moreover, SQLE-M restored gut microbial homeostasis, increased the relative abundance of potentially beneficial bacteria, and promoted the production of short-chain fatty acids (SCFAs). Notably, SQLE-M normalized the intestinal barrier dysfunction and metabolic disorders by activating the PI3K/Akt signaling pathway, inhibiting NF-κB-mediated inflammatory responses, and upregulating aquaporin 3 (AQP3) expression. Collectively, SQLE mitigates SDS, which may be associated with alterations in the gut microbiota-metabolite axis and the PI3K/Akt/NF-κB/AQP3 signaling pathway, offering new perspectives for developing spleen-strengthening functional foods derived from food-medicine homologous resources. Download: Download high-res image (462KB) Download: Download full-size image
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Sun Jia-Yi,Liu Yi-Tong,Jiang Sheng-Nan,Guo Peng-Mei,Wu Xin-Yu,Yu Jia
For thousands of years, the roots of Paeonia lactiflora Pall (PLP) has been considered by traditional Chinese medicine as a drug that can improve mental or emotional disorders, including depression, anxiety and affective disorders. Unfortunately, the research on the mechanism of action and active ingredients of this beneficial drug is not comprehensive. This study focused on the activity of essential oil from PLP (EOP), systematically studied the antidepressant effect of EOP for the first time, and discussed the potential mechanism of its antidepressant effect. In this study, we used a mouse model of corticosterone (CORT)-induced depression, and found that EOP had a significant antidepressant effect on the symptoms of CORT-induced depression in mice, and significantly down-regulated the levels of CRH, ACTH and cortisol in the brain tissues of mice. In addition, we found that EOP treatment alleviated CORT-induced hippocampal neuron injury in mice In vitro experiments. It was also found that EOP could inhibit CORT-induced apoptosis and improve the proliferation ability and cell viability of PC12 cells. Further, with the help of network analysis, it was revealed that PI3K-Akt might be one of the main signaling pathways of EOP against CORT-induced hippocampal neuron apoptosis. In this study, we also found that EOP up-regulated the phosphorylation of PI3K and Akt in CORT-induced mouse hippocampal neurons and PC12 cells, and promoted the nuclear transcription of Nrf2 in CORT-induced PC12 cells. In conclusion, with the integrated approach, we demonstrated that EOP exerted anti-apoptotic effects on hippocampal neurons through PI3K/Akt/Nrf2 signaling pathway.
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Food & Function
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2022
·Vol. 13
·期 19
·9931-9946
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IF 6.317
Xiyi Hu,Zhenguo Liu,Yuntao Lu,Xuepeng Chi,Kai Han,Hongfang Wang,Ying Wang,Lanting Ma,Baohua Xu
10-Hydroxy-2-decenoic acid (10-HDA) is a principal active ingredients of royal jelly. Several recent studies demonstrated that 10-HDA has potential anti-type 2 diabetes mellitus (T2DM) properties. To evaluate the anti-T2DM effect of 10-HDA and explore its underlying molecular mechanisms, we used high fat diet (HFD) combined with streptozotocin (STZ) injection to establish a diabetes model. Mice were randomly divided into four groups (8 mice per group): control group, 10-HDA group, T2DM group, and T2DM + 10-HDA group. The 10-HDA and T2DM + 10-HDA groups were administered intragastric 10-HDA (100 mg per kg body weight), while the control and T2DM groups were administered a vehicle, daily for 4 weeks. Our analysis indicated that there was no significant difference in body weight between T2DM + 10-HDA and control group mice (P > 0.05). Treatment with 10-HDA reduced fasting blood glucose and increased insulin levels in diabetic mice (P < 0.05), as well as increasing the area of pancreatic islets (P < 0.05), and alleviating vacuolar degeneration in the liver. Further, 10-HDA intervention increased superoxide dismutase, catalase, and glutathione peroxidase activities in diabetic mouse liver, alleviated lipid peroxidation, inhibited liver NF-κB nuclear translocation, decreased IL-6 and TNF-α content, and increased P-PI3K, P-AKT, and P-GSK3β protein levels (all P < 0.05). Fifteen potential biomarkers were screened by analysis of liver metabolomics data, of which hexadecanamide, stearamide, pentadecanoic acid, and fatty acid esters of hydroxy fatty acids (16:0/18:1) were highly abundant. In conclusion, 10-HDA has clear hypoglycemic effects on diabetic mice, through the PI3K/AKT/GSK3β signaling pathway.
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Frontiers in Pharmacology
·
2022
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IF 5.988
Liao Wenli,Rao Zhiwei,Wu Lingling,Chen Yong,Li Cairong
Background: Doxorubicin (DOX) is a potent chemotherapeutic agent with limited usage due to its cumulative cardiotoxicity. The Na+/H+ exchanger isoform 1 (NHE1) is a known regulator of oxidative stress, inflammation, and apoptosis. The present study was designed to investigate the possible protective effect of cariporide (CAR), a selective inhibitor of NHE1, against DOX-induced cardiotoxicity in rats.Methods: Male Sprague-Dawley rats were intraperitoneally injected with DOX to induce cardiac toxicity and CAR was given orally for treatment. The injured H9c2 cell model was established by incubation with DOX in vitro. Echocardiography, as well as morphological and ultra-structural examination were performed to evaluate cardiac function and histopathological changes. The biochemical parameters were determined according to the manufacturer’s guideline of kits. ROS were assessed by using an immunofluorescence assay. The serum levels and mRNA expressions of inflammatory cytokines were measured by using ELISA or qRT-PCR. Cardiac cell apoptosis and H9c2 cell viability were tested by TUNEL or MTT method respectively. The protein expressions of Cleaved-Caspase-3, Bcl-2, Bax, Akt, GSK-3β, and Sirt1 were detected by western blot.Results: Treatment with CAR protected against DOX-induced body weight changes, impairment of heart function, leakage of cardiac enzymes, and heart histopathological damage. In addition, CAR significantly attenuated oxidative stress and inhibited the levels and mRNA expressions of inflammatory cytokines (TNF-α, IL-6, IL-18, and IL-1β), which were increased by DOX treatment. Moreover, CAR significantly suppressed myocardial apoptosis and Cleaved-Caspase-3 protein expression induced by DOX, which was in agreement with the increased Bcl-2/Bax ratio. Also, DOX suppressed phosphorylation of Akt and GSK-3β, which was significantly reversed by administration of CAR. Furthermore, CAR treatment prevented DOX-induced down-regulation of Sirt1 at the protein level in vitro and in vivo. Finally, Sirt1 inhibitor reversed the protective effects of CAR, as evidenced by reduced cell viability and Sirt1 protein expression in vitro.Conclusion: Taken together, we provide evidence for the first time in the current study that CAR exerts potent protective effects against DOX-induced cardiotoxicity in rats. This cardio-protective effect is attributed to suppressing oxidative stress, inflammation, and apoptosis, at least in part, through regulation of Akt/GSK-3β and Sirt1 signaling pathway, which has not been reported to date.
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PHARMACEUTICAL BIOLOGY
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2020
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IF 2.971
Zhaohui Wang,Zhi Chen,Bingsheng Li,Bo Zhang,Yongchao Du,Yuhang Liu,Yao He,Xiang Chen
Context Renal interstitial fibrosis (RIF) is characterized by the accumulation of inflammatory cytokines and epithelial-mesenchymal transition (EMT). Curcumin exerts antifibrogenic, anti-inflammatory and antiproliferative effects.Objective To explore the mechanisms underlying the effects of curcumin on RIF.Materials and methods Eight-week-old male C57BL/6 mice were intragastrically administered curcumin (50 mg/kg/day) for 14 days after undergoing unilateral ureteral obstruction (UUO) operations. Renal function (blood urea nitrogen [BUN] and serum creatinine [Scr]) and inflammatory cytokine levels were tested using colorimetric assays and ELISA, respectively. EMT markers were evaluated through immunohistochemistry, western blotting and qPCR. Transforming growth factor beta 1 (TGF-β1; 10 ng/mL) and lipopolysaccharides (LPS; 100 ng/mL) were used to stimulate EMT and an inflammatory response in human renal proximal tubular epithelial (HK-2) cells, respectively, for further investigation.Results In vivo, curcumin significantly improved the levels of BUN and Scr by 28.7% and 21.3%, respectively. Moreover, curcumin reduced the levels of IL-6, IL-1β and TNF-α by 22.5%, 30.3% and 26.7%, respectively, and suppressed vimentin expression in UUO mice. In vitro, curcumin reduced the expression of vimentin and α-smooth muscle actin in TGF-β1-induced HK-2 cells. In LPS-induced HK-2 cells, curcumin decreased the release of IL-6, IL-1β and TNF-α by 43.4%, 38.1% and 28.3%, respectively. In addition, curcumin reduced the expression of TLR4, p-PI3K, p-AKT, p-NF- κB and p-IκBα in both LPS- and TGF-β1-induced HK-2 cells.Discussion and conclusions Curcumin repressed EMT and the inflammatory response by inhibiting the TLR4/NF-κB and PI3K/AKT pathways, demonstrating its potential utility in RIF treatment.
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JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Pan Su,Mengdi Wu,Xiaoting Yin,Mengyuan Li,Yucheng Li,Ming Bai,Baoying Wang,Erping Xu
Ethnopharmacological relevance Modified Xiaoyao San (MXYS), a clinical empirical modified formula based on famous traditional Chinese herbal prescription Xiaoyao San, according to the “yu syndrome” theory of traditional Chinese medicine . MXYS has been shown to be an excellent effective therapy for depression patients in clinic, but the antidepressant mechanisms remain unclear. Aim of the study A growing body of evidence indicates the microglia autophagy and M1 polarized microglia (proinflammatory phenotype)-mediated neuroinflammation act critical roles in the pathogenesis of depression. This study aimed to investigate whether MXYS exerts antidepressant efficacy through inhibition of M1 polarized microglia-mediated neuroinflammation and modulation of autophagy involved in PI3K/Akt/mTOR pathway. Materials and methods In present research, the lipopolysaccharide (LPS)-induced depressive mice and LPS-stimulated N9 microglia cell line were utilized. Behavioral tests (sucrose preference, tail suspension and open field tests) were carried out to evaluate the antidepressant effect of MXYS. The neuronal damage was measured by Nissl's staining in LPS-treated mice. The proinflammatory cytokine levels, the autophagic markers, microglia M1 polarization as well as the PI3K/Akt/mTOR pathway related proteins of MXYS treatment were analyzed by ELISA kits, Western blot and immunofluorescence staining in vivo and vitro . Finally, the influence of autophagy antagonist (3-MA) on the protective effect of MXYS-containing serum in the LPS-stimulated N9 microglia was investigated. Results Treatment of LPS-induced depressive mice with MXYS significantly reversed depression-like behaviors, accompanied by reduction of proinflammatory cytokine levels (TNF-α, IL-1β) and amelioration of neuronal damage in prefrontal cortex. MXYS suppressed microglia M1 polarization and promoted autophagy in prefrontal cortex and LPS-stimulated N9 cells. Importantly, the remarkable inhibitory effect of the MXYS-medicated serum on microglia M1 polarization was blocked by autophagy antagonist 3-MA in LPS-stimulated N9 cells. Meanwhile, the MXYS treatment exhibited an excellent inhibition effect of PI3K/Akt/mTOR pathway in vivo and vitro . Conclusion Our research suggests that the antidepressant effect of MXYS in LPS-induced depressive mice may be related to alleviate neuroinflammation through suppression of microglia M1 polarization via enhancing autophagy involved in inactivation of the PI3K/Akt/mTOR pathway.
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PHYTOMEDICINE
·
2023
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IF 7.9
Yuhong Li,Shuying Hu,Yueqi Chen,Xing Zhang,Hanchi Gao,Jing Tian,Jian Chen
Background Triple-negative breast cancer (TNBC) is a heterogeneous carcinoma characterized by the most aggressive phenotype among all breast cancer subtypes. However, therapeutic options for TNBC patients have limited clinical efficacy due to lack of specific target and efficient targeted therapeutics. Aim To investigate the biological characteristics of a novel estrogen receptor (ER)-α splice variant ER-α30 in breast cancer cells , and its possible role in the anticancer effects of calycosin , a typical phytoestrogen derived from the herbal plant Astragalus membranaceus , against TNBC. This may also provide a better understanding of the inhibitory activity of calycosin on TNBC progression. Methods Breast cancer tissues and para-cancer tissues were collected and analyzed for the expression levels of ER-α30 using immunohistochemistry (IHC), and its expression in two TNBC cell lines (MDA-MB-231 and BT-549) was detected by western blot and qRT-PCR assays. Then the alteration of cell viability , apoptosis , migration, invasion and epithelial-mesenchymal transition (EMT) in response to overexpression or knockdown of ER-α30 was separately determined by CCK-8, Hoechst 33258 , wound healing, transwell and western blot assays in two TNBC cell lines. Next, the anticancer effects of calycosin on MDA-MB-231 cells were evaluated through CCK-8, colony formation, flow cytometry, Hoechst 33258 and western blot assays, along with the role of ER-α30 in these effects and the possible downstream targets of ER-α30. In addition, the in vivo experiments were carried out using MDA-MB-231 xenograft model intraperitoneally treated with calycosin. The volume and weight of xenograft tumor were measured to evaluate the in vivo anticancer activities of calycosin, while the corresponding changes of ER-α30 expression in tumor tissues were detected by IHC. Results It was demonstrated that the novel ER-α splice variant ER-α30 was primarily distributed in the nucleus of TNBC cells. Compared with normal breast tissues, ER-α30 expression was found in significantly higher levels in breast cancer tissues of ER- and progesterone receptor (PR)-negative subtype, so did in TNBC cell lines (MDA-MB-231 and BT-549) when compared to normal breast cell line MCF10A. Moreover, ER-α30 overexpression strikingly enhanced cell viability, migration, invasion and EMT progression and reduced apoptosis in TNBC cells, whereas shRNA-mediated knockdown of ER-α30 revealed the opposite results. Notably, calycosin suppressed the expression of ER-α30 in a dose-dependent manner, accompanied with the inhibition of TNBC growth and metastasis . A similar finding was observed for the xenografts generated from MDA-MB-231 cells. The treatment with calycosin suppressed the tumor growth and decreased ER-α30 expression in tumor tissues. Furthermore, this inhibition by calycosin was more pronounced in ER-α30 knockdown cells. Meanwhile, we found a positive relationship between ER-α30 and the activity of PI3K and AKT, which could also be inactivated by calycosin treatment. Conclusion For the first time, it is demonstrated that the novel estrogen receptor-α splice variant ER-α30 could function as pro-tumorigenic factor in the context of TNBC by participating in cell proliferation , apoptosis, invasion and metastasis, thus it may serve as a potential therapeutic target for TNBC therapy. Calycosin could reduce the activation of ER-α30-mediated PI3K/AKT pathway, thereby inhibited TNBC development and progression, suggesting that calycosin may be a potential therapeutic option for TNBC.
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