MOLECULAR BIOLOGY REPORTS
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2021
·Vol. 49
·期 2
·1223-1232
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IF 2.316
Su Qi,Wu Qing,Chen Kun,Wang Jingjing,Sarwar Ammar,Zhang Yanmin
Background Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) can be potentially targeted for breast cancer therapy. Methods and results TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting, ERβ siRNA, ERβ plasmid transfection and hypoxia cell models. TAD1822-7 upregulated ERβ causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERβ. Enhanced levels of microtubule associated protein1 light chain 3 (LC3)-II and p62/SQSTM1 (p62) indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, TAD1822-7 modulated hypoxia inducible factor (HIF) functions and autophagy via the inhibition of HIF-1β in the context of hypoxia-induced autophagy. ERβ overexpression and ERβ agonist showed similar effects, whereas ERβ siRNA abrogated TAD1822-7-induced cell death, the inhibition of PI3K/AKT pathway and autophagy. The involvement of PI3K/AKT pathway and autophagy was also demonstrated in TAD1822-7-treated hypoxic breast cancer cells. Conclusions These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERβ-mediated pathways in breast cancer cells.
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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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Lei Zhu,Guan Zhang,Jiasai Kang,Xinru Xu,Haoshu Zhang,Yingying Pu,Yong Huang,Dewen Tong,Qian Du
Background Folium Isatidis (Da Qing Ye), a traditional Chinese medicine, exhibits broad-spectrum antiviral and immunomodulatory properties and has been widely used in treating respiratory diseases. Porcine circovirus type 2 (PCV2), a widespread swine virus, causes respiratory disease complex in piglets and leads to substantial economic losses in the global swine industry. This study aimed to evaluate the anti-PCV2 activity of Folium Isatidis . Materials and methods The anti-PCV2 activity of Folium Isatidis was first validated through both in vivo and in vitro experiments. Potential targets of Folium Isatidis were identified using TCMSP, BATMAN-TCM, and SwissTargetPrediction databases, and intersected with PCV2-related targets. Mechanism exploration involved PPI network analysis, GO annotation, and KEGG enrichment. Molecular docking analyzed component-target interactions, followed by experimental validation of the core component. Finally, the anti-PCV2 effect of the core component was verified through in vitro and in vivo experiments. Results A total of 135 overlapping targets between Folium Isatidis components and PCV2-related disease targets were identified. Key targets, including AKT1 and TNF-α, were implicated in the therapeutic effects of Folium Isatidis against PCV2. Isovitexin was identified to be the core component that directly binds to AKT1 and TNF-α, thereby inhibiting the PI3K/AKT signaling pathway and regulating TNF-α expression and activity to suppress PCV2 replication and alleviate PCV2-induced lung injury. Conclusions Our study reveals that Isovitexin, the core anti-PCV2 component of Folium Isatidis , exerts its effect by inhibiting the PI3K/AKT pathway and modulating TNF-α, thereby outlining a novel therapeutic strategy for combating PCV2 infection and associated respiratory injuries.
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JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY
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2026
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IF 3.4
Yanliang Li,Siqiang Niu,Haipeng Wang,Jianhua Li
Gemcitabine (GEM) resistance remains a major challenge in the treatment of gallbladder cancer (GBC). This study investigated the synergistic effect of curcumin (CUR) combined with the probiotic Lactobacillus rhamnosus GG (LGG) in reversing chemoresistance through modulation of the gut microbiota. In GEM-resistant GBC-SD cells, the CUR–LGG combination significantly inhibited cell proliferation, suppressed migration and invasion, and induced apoptosis, as demonstrated by CCK-8, wound healing, Transwell, and flow cytometry assays. Western blot analysis revealed corresponding regulation of proliferation markers (Ki67, PCNA), apoptosis-related proteins (Bcl-2, Bax, cleaved Caspase-3), and epithelial–mesenchymal transition markers. In xenograft models, the combined treatment markedly suppressed tumor growth and altered gut microbial composition, increasing beneficial bacteria ( Lactobacillus , Bifidobacterium ) while reducing pathogenic taxa. LC–MS analysis further demonstrated restoration of bile acid homeostasis, characterized by elevated primary bile acids (GCA, CDCA) and decreased secondary bile acids (DCA, LCA). Mechanistically, the intervention significantly inhibited PI3K/AKT signaling, as confirmed by Western blot and immunohistochemistry. Bioinformatic analysis further identified PI3K/AKT as a central regulatory pathway. These findings indicate that probiotic-assisted CUR therapy reverses GEM resistance by remodeling the gut microbiota and its metabolic outputs, thereby suppressing oncogenic signaling pathways. This strategy provides a promising microbiota-based approach for improving therapeutic outcomes in GBC.
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BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Huimin Qiu,Xinqi Tan,Quan Sheng,Na Yang,Chunming Jiang,Lulu Wang
Metabolic dysfunction-associated steatohepatitis (MASH) frequently induces renal injury, forming a “liver-kidney axis” vicious cycle. Current therapies primarily target hepatic lesions, failing to interrupt the cross-organ injury cascade, creating an urgent need for novel strategies. To explore dapagliflozin’s therapeutic efficacy and core mechanism in MASH and associated renal injury, we utilized in vitro models (free fatty acid [FFA]-induced HepG2 hepatocyte MASH model, HK2 renal tubular epithelial cell injury model, Transwell co-culture system) and an in vivo MASH mouse model induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Results showed dapagliflozin dose-dependently improved dysregulated lipid metabolism, suppressed inflammation, and alleviated fibrosis in vitro and in mouse liver/kidney tissues, while upregulating SIRT1/PPARα and downregulating SREBP-1c to restore lipid homeostasis. Molecularly, dapagliflozin specifically bound to ferroptosis key regulator solute carrier family 7 member 11 (SLC7A11), upregulated its abnormally reduced expression, and inhibited PI3K/AKT pathway hyperactivation—an effect mediated via a “liver-kidney axis” paracrine mechanism with β-hydroxybutyrate (β-HB) as the key mediator. Additionally, SLC7A11 knockdown in cells conversely confirmed that the lipid-lowering effect of dapagliflozin is mediated by SLC7A11.Collectively, dapagliflozin forms hydrogen bonds with SLC7A11, modulates the SIRT1/PPARα/SREBP-1c axis, and inhibits PI3K/AKT, thereby exerting therapeutic effects on MASH and associated renal injury.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Zhun Li,Sixia Yang,Wei Liu,Long Ling,Hailan Hu,Yanming Cao,Shouyu Xiang
Salidroside, one of the main active compounds extracted from Rhodiola, has shown promising potential for the treatment of osteoporosis. Our previous study demonstrated that salidroside alleviated cognitive dysfunction in senescence-accelerated mouse prone 8(SAMP8) mice. In this study, we further investigated the effect of salidroside on osteoporosis in SAMP8 mice and explored the mechanism. The results of micro-computed tomography(micro-CT) and histology showed that salidroside significantly increased trabecular bone formation and improved bone microstructure in senile osteoporotic SAMP8 mice, and upregulated the protein expression levels of phosphatidylinositol-3-kinase(PI3K), glutathione peroxidase 4(GPX4), and Runt-related transcription factor 2(RUNX2) in the distal femur. Cell-based assays, including the Cell Counting Kit-8(CCK-8) assay, senescence-associated β-galactosidase (SA-β-galactosidase) staining, alkaline phosphatase (ALP) staining, Alizarin Red staining, and lipid peroxide detection, demonstrated that salidroside significantly promoted the proliferation and osteogenic differentiation of senile osteoporotic bone marrow stromal cells (BMSCs) and decreased lipid peroxide levels. Furthermore, real-time polymerase chain reaction (RT-PCR) and Western blotting analysis showed that salidroside increased protein and gene expression levels of solute carrier family 7 member 11(SLC7A11), GPX4, and ferroptosis suppressor protein 1(FSP1). Additionally, salidroside also increased the phosphorylation of PI3K, AKT, and mTOR, an effect reversed by LY294002.In conclusion, our investigation showed that salidroside could prevent ferroptosis, promote proliferation, and enhance osteogenic differentiation in senile osteoporotic BMSCs, thereby alleviating senile osteoporosis in SAMP8 mice. The PI3K/AKT/mTOR signaling pathway might play a crucial role in this mechanism. These findings suggest that salidroside has the potential to prevent senile osteoporosis and may serve as a candidate for therapeutic development.
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HEREDITAS
·
2025
·Vol. 162
·期 1
·232
·
IF 2.5
Xiaohui Yu,Jie Li,Jiangqiao Zhou
Background Coptisine (COP) is a natural compound extracted from Rhizoma Coptidis , and it represses the malignant biological behaviors of bladder cancer cells. However, the underlying molecular mechanism has not been fully elucidated. The aim of this study was to clarify the downstream mechanism by which COP treats bladder cancer. Materials and methods SwissTargetPrediction, STITCH, SymMap, ETCM, TCMSP, CTD databases were used to collect the related targets of COP. GeneCards, DisGeNET, TTD and OMIM databases were used to obtain the related targets of bladder cancer. A Venn diagram was used to identify the potential targets of COP in bladder cancer treatment. The protein-protein interaction network was constructed using STRING database, and Cytoscape 3.9.0 software was used to screen the hub targets. The binding relationship between COP and the hub targets was verified by molecular docking and molecular dynamics simulation. After the bladder cell lines T24 and BIU-87 were treated with different doses of COP, the regulatory effects of COP on PI3K/AKT pathway were investigated with western blotting. Additionally, the tumor-suppressive properties of COP on bladder cancer cells were validated with tumorigenesis model and metastasis model in nude mice. Results RAC-alpha serine/threonine-protein kinase 1 (AKT1), glycogen synthase kinase 3 beta (GSK3B), caspase-3 (CASP3), tumor necrosis factor (TNF) and cyclin D1 (CCND1) were identified as the main hub targets of COP in bladder cancer treatment. PI3K/AKT pathway was predicted to be a crucial pathway regulated by COP. The binding affinities between COP and AKT1, GSK3B, CASP3, TNF and CCND1 were high. COP treatment markedly repressed the phosphorylation level of ERK1/2, AKT1, PI3K p85 and mTOR in T24 and BIU-87 cells, and repressed the tumorigenesis and lung/liver metastasis of T24 cells in vivo. Conclusion COP may be a natural inhibitor for AKT1, GSK3B, CASP3, TNF and CCND1. COP represses PI3K/AKT pathway to suppress the progression of bladder cancer.
研究领域:
药理学
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肿瘤学
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计算生物学
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分子生物学
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天然产物研究
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MOLECULAR NEUROBIOLOGY
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2023
·
IF 5.1
Wu Yuhan,Zhu Zhanpeng,Lan Tian,Li Shuhan,Li Ye,Wang Changmin,Feng Yabo,Mao Xueqin,Yu Shuyan
Depression is a common psychological disease with high morbidity and mortality. Recently, the involvement of synaptic plasticity in the pathogenesis of depression has shed light on the direction of developing novel antidepressants. Levomilnacipran is a newly approved medication for the treatment of adult major depressive disorder. However, the detailed mechanisms underlying its antidepressant-like effects have yet to be illuminated. In this study, we aimed to investigate the role of levomilnacipran in regulating synaptic plasticity and explore the possible molecular mechanisms of its antidepressant effects using a rat model of depression induced by lipopolysaccharide (LPS). The results demonstrated that levomilnacipran (30 mg/kg, i.p.) significantly ameliorated depression-like behaviors in rats, alleviated the dysregulation of synaptic plasticity, and suppressed neuroinflammation within hippocampus induced by LPS-treatment. Levomilnacipran increased the expression of postsynaptic dense 95 (PSD-95) and synaptophysin (Syn) and reversed the imbalance between pro- and anti-inflammatory cytokines within hippocampus of depressed rats. Additionally, levomilnacipran elevated expression level of brain-derived neurotrophic factor (BDNF), accompanied by increased tyrosine kinase B (TrkB), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR). Taken together, these results suggest that levomilnacipran may exert antidepressant effects via upregulating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway to improve synaptic plasticity. These findings reveal potential mechanisms for the antidepressant effects of levomilnacipran and offer new insights into the treatments for depression. Graphical Abstract
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2022
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IF 7.129
Tianmeng Zhang,Zhuhua Dong,Feixue Liu,Enzhuang Pan,Nana He,Fenfen Ma,Guanglu Wang,Yan Wang,Jingquan Dong
Avermectin, a "low toxicity insecticide", has been widely used in recent years, but its non-target toxicity, especially to aquatic organisms, has been neglected. In this study, we evaluated the neurotoxic effects of avermectin on carp by establishing a 96 h avermectin acute toxicity test, and its possible mechanism was discussed. The 96 h LC 50 of avermectin in carp was found to be 24.04 μg/L. Therefore, 3.005 μg/L and 12.02 μg/L were used as the low-dose and high-dose groups, respectively, to investigate the neurotoxic effects of avermectin on carp. The results of high-performance liquid chromatography (HPLC) analysis showed that avermectin accumulated in the carp brain. Histopathological observation and immunohistochemical analysis (IHC) of TNF-α and Bax showed that avermectin exposure led to inflammatory cell infiltration and neuronal necrosis. The mRNA levels of tight junction genes and the IHC results of ZO-1 and Occludin showed that the structure of the blood-brain barrier (BBB) was destroyed. Biochemical analysis showed that avermectin induced the accumulation of MDA in the brain and decreased the activity of antioxidant enzymes CAT and SOD, leading to oxidative stress. In addition, avermectin induces brain inflammation by activating NF-κB pathway and releasing inflammatory factors IL-1β, IL-6, TNF-α and iNOS. TEM and TUNEL assays showed that exposure to avermectin induced apoptosis in brain. what is more, the expression of apoptosis-related genes and proteins suggested that avermectin-induced apoptosis may be associated with inhibition of the PI3K/Akt signaling pathway. This study also showed that avermectin-induced NF-κB signaling activation was partially dependent on its upstream PI3K/Akt signaling pathway. Therefore, this study concludes that avermectin can induce neurotoxicity in carp by disrupting the blood-brain barrier structure and generating oxidative stress, inflammation, and apoptosis and that NF-κB and PI3K/Akt signaling pathways are involved in this process.
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Journal of Oleo Science
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2022
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IF 1.628
Runzhou Sun,Ruixin Xiao,Pengfei Lv,Feifei Guo,Yanling Gong,Meixing Yan
Pink lotus essential oil (PLEO) is the volatile components extracted from lotus flowers and there are few relevant research. The purpose of this study was to observe the effect of PLEO on NAFLD in vitro model and its possible mechanism. The ingredients of PLEO were determined by gas chromatography-mass spectrometry (GS-MS) and its lipid-lowering and hepatoprotective activities were investigated. HepG2 cells were treated with free fatty acid (FFA) to establish a cell model of NAFLD. Cell viability was evaluated by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Total cholesterol (TC), triglyceride (TG), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were determined by Enzyme-Linked Immune Sorbent Assay (ELISA). Oil red O staining was performed to observe the lipid accumulation in the HepG2 cells. Lipid metabolism enzymes including fatty acid synthase (FAS), acetyl-coA carboxylase (ACC), stearoyl-CoA desaturase 1 (SCD-1), and carnitine palmitoyltransferase-1 (CPT-1), insulin signaling pathways including phosphatidylinositol 3 kinase (PI3K) and protein kinase B Akt, inflammatory signaling pathways such as nuclear factor kappa-B (NF-κB), were determined by Western blotting. There were 46 components determined in PLEO with many terpenoids compounds. PLEO decreased TC and TG contents in the FFA-treated HepG2 cells. Furthermore, PLEO inhibited TNF-α, IL-6 and IL-1β excretion, decreased NF-κB, FAS, ACC and SCD-1 while increased phosphorylation of NF-κB, PI3K, Akt, and CPT-1 expression. It is the first time to reveal that PLEO alleviates FFA-induced steatosis in HepG2 cells by regulating lipid metabolism, inhibiting inflammatory response, and improving insulin sensitivity.
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Food Science and Human Wellness
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2023
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IF 7
Qihong Jiang,Lin Chen,Rui Wang,Yin Chen,Shanggui Deng,Guoxin Shen,Shulai Liu,Xingwei Xiang
Type 2 diabetes mellitus (T2DM) is a complex metabolic disease threatening human health. We investigated the effects of Tegillarca granosa polysaccharide (TGP) and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin. TGP (5.1 × 10 3 Da) was composed of mannose, glucosamine, rhamnose, glucuronic acid, galactosamine, glucose, galactose, xylose, and fucose. It could significantly alleviate weight loss, reduce fasting blood glucose levels, reverse dyslipidemia, reduce liver damage from oxidative stress, and improve insulin sensitivity. RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance. TGP increased the abundance of Allobaculum , Akkermansia , and Bifidobacterium , restored the microbiota abundance in the intestinal tracts of mice with T2DM, and promoted short-chain fatty acid production. This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.
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Experimental and Therapeutic Medicine
·
2021
·Vol. 21
·期 3
·1-1
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IF 2.447
Qing Lin,Weili Wang,Liping Yang,Xiaohua Duan
Damage to the blood‑brain barrier (BBB) during the process of cerebral ischemic injury is a key factor that affects the treatment of this condition. The present study aimed to assess the potential effects of 4‑methoxybenzyl alcohol (4‑MA) on brain microvascular endothelial cells (bEnd.3) against oxygen‑glucose deprivation/reperfusion (OGD/Rep) using an in vitro model that mimics in vivo ischemia/reperfusion injury. In addition, the present study aimed to explore whether this underlying mechanism was associated with the inhibition of pro‑inflammatory factors and the activation status of the PI3K/Akt signaling pathway. bEnd.3 cells were subjected to OGD/Rep‑induced injury before being treated with 4‑MA, following which cell viability, lactate dehydrogenase (LDH) release and levels of nitric oxidase (NO) were detected by colorimetry, pro‑inflammatory factors including tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6, were detected by ELISA. The expression levels of occluding and claudin‑5were evaluated by immunofluorescence staining. The expression levels of AKT, phosphorylated (p)‑Akt, endothelial nitric oxide synthase (eNOS) and p‑eNOS were also measured by western blot analysis. After bEnd.3 cells were subjected to OGD/Rep‑induced injury, cell viability and NO levels were significantly decreased, whilst LDH leakage and inflammatory factor (TNF‑α, IL‑1β and IL‑6) levels were significantly increased. Treatment with 4‑MA significantly ameliorated cell viability, LDH release and the levels of NO and pro‑inflammatory factors TNF‑α, IL‑1β and IL‑6 as a result of OGD/Rep. Furthermore, treatment with 4‑MA upregulated the expression of occludin, claudin‑5, Akt and eNOS, in addition to increasing eNOS and AKT phosphorylation in bEnd.3 cells. These results suggest that 4‑MA can alleviate OGD/Rep‑induced injury in bEnd.3 cells by inhibiting inflammation and by activating the PI3K/AKT signaling pathway as a possible mechanism. Therefore, 4‑MA can serve as a potential candidate for treating OGD/Rep‑induced injury.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2021
·Vol. 25
·期 8
·4073-4087
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IF 5.31
Farooq Riaz,Qian Chen,Kaikai Lu,Ezra Kombo Osoro,Litao Wu,Lina Feng,Rong Zhao,Luyun Yang,Yimeng Zhou,Yingli He,Li Zhu,Xiaojuan Du,Muhammad Sadiq,Xudong Yang,Dongmin Li
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl 4 )-induced mice, TGF-β1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl 4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl 4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
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