DRUG DEVELOPMENT RESEARCH
·
2020
·Vol. 81
·期 7
·875-884
·
IF 1.902
Xiaonan Zhang,Fenglan Huang,Xiaoyong Chen,Xiaoqing Wu,Jinyu Zhu
Ginsenoside Rg3, a ginsenoside isolated from Panax ginseng , can regulate autophagy via AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. AMPK/mTOR signaling and autophagy have been reported to be involved in osteogenesis. Here, the effect of Rg3 on ovariectomy (OVX)-induced osteoporosis is explored. In vivo, rats were treated with 20 mg/kg Rg3 after OVX and the body weight (BW) was monitored. Bone mineral density (BMD), hematoxylin–eosin staining of femur tissues, osteogenesis, autophagy, and AMPK/mTOR signaling were analyzed. In vitro, MC3T3-E1 cells were treated with 0, 1, 5, 10, 20, and 100 μmol/L Rg3. 10 and 20 μmol/L Rg3, which had no significant effect on cell viability and significantly affected AMPK/mTOR signaling, were chosen for further analysis. Then osteogenic differentiation was induced with Rg3 or/and AMPK inhibitor (Compound C). AMPK/mTOR signaling, autophagy, osteogenic differentiation, and mineralization by Alizarin Red staining were analyzed. The expression or activity of AMPK/mTOR signaling-related proteins, autophagy markers, and osteogenesis markers was measured by western blotting or commercial kits, and cell viability by cell counting kit-8 assay kits. Rg3 significantly alleviated OVX-induced BW increases, BMD declines and histological changes of femur tissues, promoted osteogenesis, autophagy, and AMPK signaling, but inhibited mTOR signaling in vivo. Moreover, Rg3 significantly enhanced AMPK signaling, autophagy, osteogenic differentiation, and mineralization, but suppressed mTOR signaling in vitro. However, Compound C significantly reversed Rg3-induced alterations in vitro, indicating that Rg3 regulated autophagy, osteogenic differentiation, and mineralization via AMPK/mTOR signaling. Hence, it was speculated that Rg3 might attenuate OVX-induced osteoporosis via AMPK/mTOR signaling pathway.
研究领域:
药理学
·
内分泌学
·
骨科
·
细胞生物学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2021
·Vol. 82
·期 7
·969-979
·
IF 4.36
Ruixian Xing,Xuewen Liu,Buxian Tian,Yan Cheng,Longguang Li
Parkinson's disease (PD) is a disabling neurodegenerative disease mainly caused by degeneration of mesencephalic dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neuroprotective role of Na + /H + exchangers isoform-1 (NHE1) inactivation in cerebral ischemic damage has been elucidated. The current study aimed to investigate the impacts of NHE1 in PD. In this study, 6-hydroxydopamine (6-OHDA)-induced PD rat models were established to attempt to illuminate the role and underlying mechanisms of NHE1 in SNpc neurons of PD. Meanwhile, nerve growth factor-stimulated PC12 cells followed by 6-OHDA treatment was used to mimic PD in vitro. Results showed that the protein levels of NHE1 were significantly increased in the SNpc neurons of rats and differentiated PC12 cells after 6-OHDA treatment. Inactivation of NHE1 with chemical inhibitor HOE642 suppressed SNpc neuronal loss and NHE1 expression in PD rats. The overlays of tyrosine hydroxylase and NHE1 displayed that NHE1 expression was not colocalized but closely associated with TH. Besides, treatment with HOE642 relieved the dyskinesia, mitochondrial dysfunction, and neuronal apoptosis. Further in vitro evidence confirmed that inhibition of NHE1 by genetic-knockdown prevented mitochondrial dysfunction and apoptosis. Our study represents the first experimental evidence of a potential role for NHE1 in the pathogenesis of PD.
研究领域:
神经科学
·
神经退行性疾病
·
药理学
·
细胞生物学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2022
·Vol. 83
·期 5
·1176-1189
·
IF 5.004
Yanbo Xie,Xueyu Zhu,Ping Liu,Yunxiao Liu,Yadi Geng,Lei Zhang
Lung cancer is the cancer with the highest mortality, and non-small cell lung cancer (NSCLC) accounts for more than 80%. Tumor cells often have high reactive oxygen species (ROS) and antioxidant capacity. Redox balance is very important for tumor. The decline of antioxidant capacity and excessive ROS will induce the death of tumor cells. Destroying the redox balance of tumor cells is a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. We observed that xanthatin induced the up regulation of mitochondrial ROS and mitochondrial damage. Meanwhile, our results showed that xanthatin could inhibit system x c − and reduce glutathione (GSH) synthesis. Antioxidant GSH and N -acetyl- l -cysteine (NAC) significantly reversed cell proliferation inhibition and apoptosis induced by xanthatin. β-Mercaptoethanol (β-ME) which can avoid inhibition of system x c − can also reverse the inhibition of cell proliferation induced by xanthatin, si-SLC7A11 was the opposite. Based on these results, we believe that the inhibition of xanthatin on the proliferation of NSCLC cells may be related to breaking the intracellular redox balance. Our data suggest that xanthatin is a promising antitumor candidate for the treatment of NSCLC.
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
DRUG DEVELOPMENT RESEARCH
·
2021
·Vol. 83
·期 1
·64-74
·
IF 4.36
Yang Yang,Tao Cheng,Peng Xie,Lishan Wang,Hong Chen,Zhangjun Cheng,Jiahua Zhou
To explore the biological activity of transmembrane prostateandrogen induced RNA (PMEPA1) in human pancreatic cancer (hPAC) cells and its drug sensitivity to gemcitabine (GEM) and cisplatin (DDP). Gene Expression Profiling Interactive Analysis (GEPIA) and Cancer Cell Line Encyclopedia (CCLE) were consulted to indicate the expression of PMEPA1 in hPAC tissues and cells. Quantitative real-time PCR (RT-qPCR) and western blot were performed to verify the indication. RT-qPCR and western blot also detected the expressions of PTEN/PI3K/AKT before and after transfection of PMEPA1 siRNA plasmids. Cell counting Kit-8 (CCK-8) and EdU staining were performed to examine cell proliferation before and after transfection of phosphatase and tensin homologue delet2ed on chromosome ten (PTEN) siRNA plasmids. Transwell and wound healing detected the invasion and migration of hPAC cells. The expressions of MMP-2 and MMP-9 were detected by western blot. After GEM or DDP treatment, cell viability was observed by commercial kits and cell apoptosis by flow cytometry. GEPIA and CCLE predicted increased expression of PMEPA1 in hPAC tissues and cells, which was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot. PMEPA1 was also shown to be associated with disease-free survival. Transfection of PMEPA1 siRNA plasmids affected the expressions of PTEN/PI3K/AKT. PMEPA1 interference inhibited the proliferation, invasion and migration of hPAC cells. Furthermore, PMEPA1 interference also enhanced the sensitivity of hPAC cells to GEM and DDP via PTEN interference. PMEPA1 interference inhibits the proliferation, invasion and migration of pancreatic cancer cells and enhances the sensitivity to GEM and cisplatin by activating PTEN/PI3K/AKT signaling.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 1
·e70051
·
IF 4.2
Qiwen Shi,Tao Zhou,Wenjun Hou,Yuqi Zhou,Shufen Deng,Ying Song
Diabetes nephropathy (DN) is a severe diabetic chronic microvascular complication and the major cause of end-stage renal disease (ESRD). Our study aimed to investigate the effects of isoliquiritigenin (ISL) a natural flavonoid compound on DN and to explore the underlying mechanisms. The db/db mice were received intragastric treatments of ISL (5, 10, or 20 mg/kg), vehicle or positive drug metformin (300 mg/kg) once a day for 12 weeks, and the db/m mice treated with vehicle were used as controls. ISL significantly ameliorated pathological changes and functional injury in the kidneys of db/db mice in a dose-dependent manner. The administration of 20 mg/kg ISL reduced the levels of serum creatinine (Scr; 49.0 ± 1.7 vs. 56.9 ± 2.9 μmol/L; p < 0.01), blood urine nitrogen (BUN; 9.6 ± 1.3 vs. 12.0 ± 1.1 mmol/L; p < 0.05), albumin to creatinine ratio (ACR; 1925.8 ± 798.1 vs. 4269.4 ± 925.6 μg/mg; p < 0.01) and urinary albumin (276.2 ± 39.9 vs. 576.9 ± 108.9 μg; p < 0.05). Further study identified advanced glycation end product (AGE)–receptor for AGE (RAGE) axis as a target of ISL. ISL (20 mg/kg) lowered renal AGE level (2.5 ± 0.5 vs. 3.8 ± 0.6 μg/mg; p < 0.01) and RAGE expression, leading to improvements in renal fibrosis, oxidative stress, and inflammation. To sum up, our study demonstrated that ISL displayed preventive effects on the experimental model of DN through suppressing AGE–RAGE pathway, and provided some insights into the application of ISL in DN treatment.
研究领域:
药理学
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内分泌学
·
肾病学
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2026
·Vol. 87
·期 2
·e70265
·
IF 4.2
Jiao Li,Mingrong Song,Yifan Bu,Jing Chen
Vascular dementia (VD) is a cerebrovascular disease-associated cognitive disorder characterized by chronic neuroinflammation. Cinnamic acid (CA), a natural aromatic carboxylic acid, has been demonstrated to mitigate neurological dysfunction. In this study, a two-vessel occlusion (2-VO) rat model was established, and the rats were treated with CA at doses of 45 mg/kg and 90 mg/kg via intragastric gavage. CA treatment significantly restored cognitive function in 2-VO rats, which was attributed to the reduction of neuronal apoptosis. Furthermore, CA administration downregulated the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the hippocampal tissues, while upregulating the expressions of arginase-1 (Arg-1), found in inflammatory zone 1 (Fizz1), and chitinase 3-like 3 (YM-1). These observations suggest that CA promotes the alternatively activated (M2) polarization of microglia in hippocampal tissues. To simulate the neuroinflammatory environment in vitro, BV2 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. CA pretreatment promotes M2 polarization in OGD/R-induced BV2 cells, opposing OGD/R-driven M1 polarization in these cells. Importantly, network pharmacology analysis identified poly (ADP-ribose) polymerase 1 (PARP1) as a downstream target of CA. PARP1 expression was upregulated in the hippocampal tissues of 2-VO rats and OGD/R-induced BV2 cells, while CA treatment significantly reduced PARP1 expression. Notably, exogenous PARP1 reversed the CA-induced promotion of the microglial M2 phenotype, as evidenced by increased iNOS expression and decreased Arg-1 expression. In conclusion, CA targets PARP1 to promote the M2 polarization of microglia, thereby alleviating neuroinflammation and contributing to the recovery of neurological function in 2-VO rats.
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DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2026
·Vol. 87
·期 6
·e70366
·
IF 4.2
Keqi Zhang,Jinzhu Zhao,Linlin Li,Zixin Wang,Xinyi Mao,Jie Yan,Shuhua Han,Mingjing He,Bingjie Bi,Qiang Xu,Cong Wang
Tumor drug resistance and metastasis are leading causes of cancer‑related mortality, both of which are tightly governed by multiple signaling pathways. The AKT‑GSK‑3β axis is a critical regulator of tumor progression, mediating drug resistance and epithelial‑mesenchymal transition (EMT) through its downstream targets. Aberrantly activated AKT‑GSK‑3β signaling modulates the expression and degradation of the drug efflux pump P‐gp, which expels chemotherapeutic agents, including paclitaxel (PTX), from cancer cells, resulting in chemotherapy failure and drug resistance. Moreover, hyperactivated AKT‑GSK‑3β signaling drives EMT, a key process closely linked to tumor metastasis and malignant progression. Dioscin (Dio), a natural steroidal saponin, exhibits significant anti‑tumor activity in multiple cancers. However, whether Dio reverses chemoresistance and inhibits tumor growth by targeting the AKT‑GSK‑3β pathway to promote P‐gp degradation and suppress EMT remains elusive, which is the central focus of this study. To explore whether Dio enhances the sensitivity of drug‐resistant cancer cells to PTX and inhibits cancer metastasis and the EMT process, as well as its potential mechanism(s). Paclitaxel‐resistant TE‐1/PTX and HeLa/PTX cells were subjected to SRB, colony formation, Rh123 accumulation, wound‐healing, and Transwell assays to evaluate Dio's chemosensitizing, anti‐EMT, and anti‐metastatic effects. Network pharmacology, molecular docking, CETSA, and proteolysis assays verified a direct Dio‐AKT1 interaction. Western blotting, Co‐IP, and MG132 and MK2206 rescue experiments clarified AKT/GSK3β‐dependent P‐gp ubiquitin‐proteasomal degradation and EMT suppression. HeLa/PTX xenograft models were generated; H&E staining and immunoblotting were used to assess tumor growth, biosafety, and intratumoral protein profiles for in vivo validation. Dio sensitized PTX‐resistant cells to paclitaxel, increased intracellular Rh123 accumulation, and inhibited cell migration and invasion. Mechanistically, Dio directly bound AKT1 to suppress AKT/GSK3β signaling, promoted ubiquitin‐proteasomal degradation of P‐gp, and reversed EMT by upregulating epithelial markers and repressing mesenchymal markers and EMT transcription factors. In vivo, Dio restrained xenograft tumor growth with negligible systemic toxicity, and intratumoral expression patterns of AKT/GSK3β, P‐gp, and EMT‐related proteins mirrored in vitro findings. Dio has the potential to be a safe and effective agent for drug‐resistant cancer therapy.
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 3
·e70090
·
IF 4.2
Cailan Wang,Xinyi Lin,Shichun Guan,Qiaoyuan Wu,Shixiong Liang
Dihydroartemisinin (DHA) is a derivative of artemisinin, which affects inflammation, oxidative stress, and immune regulation. However, the mechanism underlying its effects remains largely unknown. This study aims to explore the mechanism by which DHA affects radiation-induced lung injury (RILI), providing new insights for lung radiotherapy. To elucidate its mechanism of action, C57BL/6 J mice were irradiated with 15 Gy whole chest. RILI was evaluated by qRT-PCR, ELISA, histology, Western blot analysis, immunohistochemistry, and RILI signaling cascade studies. In addition, small interfering RNAs were employed to knockdown cGAS proteins in the cGAS-STING signaling pathway in the human bronchial epithelium cell line (BEAS-2B). Both In Vivo and Vitro experiments were conducted to investigate the specific mechanism by which DHA alleviated RILI. We observed the activation of the cGAS-STING pathway, along with the phosphorylation of the downstream target NF-κB and an increase in inflammatory factor levels in the mouse model following radiation exposure. In the cell model, irradiation also triggered the activation of the cGAS-STING signaling pathway and its downstream targets, leading to elevated levels of inflammatory factors. Notably, knocking down the cGAS using small interfering RNA in the BEAS-2B cells significantly alleviated RILI in the cell model. Our study elucidated the mechanism of DHA reducing RILI through the cGAS/STING/NF-κB signaling pathway, and revealed that the GAS/STING/NF-κB axis may be a potential therapeutic target for RILI.
研究领域:
医学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 7
·e70174
·
IF 4.2
Zhenfei Yu,Xiaoling Qian,Weihua Wu,Meiqi Zhang,Ying Li
Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin−eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.
研究领域:
神经病学
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分子医学
·
药理学
·
自由基生物学
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脑血管病
·
神经保护机制
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 7
·e70171
·
IF 4.2
Hao Ling,Chunli Song
Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0–200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA ( p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.
研究领域:
心血管病学
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分子生物学
·
药理学
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线粒体生物学
·
氧化应激
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 2
·e70047
·
IF 4.2
Kangmin Chen,Yanni Zhao,Tianyang Jin,Tingxin Xu,Conglun Zhu,Hui Shen,Xiaohong Xu,Yongsheng Jiang,Yi Wang,Shihang Xue
Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.
研究领域:
肿瘤学
·
免疫学
·
药理学
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2026
·Vol. 87
·期 2
·e70236
·
IF 4.2
Chenghua Wu,Xiaobin Zhuo,Jianxin Yang,Yuxiao Tang,Weili Wang,Mengpu Wu,Gen Miao,Chenqi Li,Hui Shen,Jianxin Qian,Dongyao Wang
Inhibiting the malignant proliferation is crucial for managing the cancer progression. NCAPG (Non-SMC condensin I complex subunit G) is a main component in cell proliferation, which is highly expressed in liver tumors and negatively correlated with the overall survival of hepatocellular carcinoma (HCC) patients. In this study, we identified bufalin as a molecular glue for the first time that specifically degraded NCAPG by coupling it to cathepsin V (CTSV). Distinguished from traditional PROTACs, bufalin served as a molecular glue with the distinct advantages of a smaller molecular weight and superior bioavailability. This degradation inhibited the proliferation of HCC cells by inducing G2/M phase cell cycle arrest at low doses (20–40 nM), but did not trigger the apoptosis signaling. Using co-immunoprecipitation and confocal microscopy, we confirmed the interaction between CTSV and NCAPG by bufalin. Knockdown of CTSV or NCAPG attenuated the anti-proliferation effects of bufalin in HCC cells. Cell cycle analysis also showed significantly reduced G2/M arrest in knockdown cells. The downstream proliferation regulators Cyclin D1 and CDK1 were also regulated by bufalin in a CTSV/NCAPG-dependent manner. Our study not only identified the CTSV-NCAPG complex as a novel therapeutic target but also discovered a potential molecular glue, bufalin, which exerts anti-proliferation effects through cell cycle regulation. These findings highlight the potential clinical translational value of bufalin as a promising, bioavailable therapeutic agent for the targeted treatment of liver cancer.
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PubMed
高影响因子
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