MOLECULAR PHARMACEUTICS
·
2017
·
IF 4.44
Yiyue Wang,Jing Li,Jing Jing Chen,Xuan Gao,Zun Huang,Qi Shen
The polylactic-co-glycolic acid polyethylene glycol conjugated with cell penetrating peptide R7 (PLGA–PEG-R7)/polysulfadimethoxine-folate nanoparticles loaded with docetaxel (DTX) and GDC0941 (R7/PSD-Fol NPs) were prepared to overcome multidrug resistance (MDR) and enhance the antitumor activity. First, polysulfadimethoxine-folate was synthesized to construct the R7/PSD-Fol NPs. The R7/PSD-Fol NPs were prepared with the abilities of effective entrapment and drug loading. Due to the pH-sensitive effect of PSD-folate, the releasing of DTX and GDC0941 from the R7/PSD-Fol NPs was lower in pH 7.4 buffer solution than that in pH 5.0 buffer solution. The half maximal inhibitory concentration (IC50) of MCF-7 and resistant to doxorubicin (MCF-7/Adr) cells illustrated the cytotoxicity of R7/PSD-Fol nanoparticles by using the MTT method. The uptake of R7/PSD-Fol NPs was visualized by using the fluorescence of Rh-123 to detect the targeting effect of folate on the surface of R7/PSD-Fol NPs. The results of the cell apoptosis and the depolarization of mitochondrial membrane potential (MMP) were adopted to show the cytotoxicity of the R7/PSD-Fol NPs on MCF-7/Adr cells. The Western blot revealed the inhibition of PI3K/Akt pathway in MCF-7/Adr cells induced by R7/PSD-Fol NPs. Finally, both in vivo distribution and in vivo antitumor showed the R7/PSD-Fol NPs displayed the better distribution at tumor site and the stronger suppression of tumor growth in the tumor bearing nude mice compared with control group. It was concluded that R7/PSD-Fol NPs loaded with DTX and GDC0941 could overcome MDR and enhance the antitumor effect further.
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Qiqi Yang,Yuan Yao,Junping Wang,Mengdi Pang,Jinyan Wu,Fusheng Yin,Jun He,Yanyan Wang,Weidong Chen
Non-small cell lung cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung cancer by injecting Lewis cells, and evaluated the therapeutic efficacy in vivo . The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting cancer cell apoptosis and reducing serum tumor marker levels. In vitro experiments revealed that this combination synergistically inhibited lung cancer cell proliferation and induced apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/AKT signaling, leading to enhanced apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP via PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/AKT pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Li Li,Wenqian Cai,Hao Zhang,Jiuren Tang,Yongjie Yang,Yang Huang,Qing Xi,Rongxin Zhang
Renal fibrosis is the most common pathway for the development of end-stage renal disease (ESRD) in various kidney diseases. Currently, the treatment options for renal fibrosis are limited. Ferroptosis is iron-mediated lipid peroxidation, triggered mainly by iron deposition and ROS generation. Notably, the kidney is the most sensitive of all tissues to iron-dependent ferroptosis, and the inhibition of ferroptosis is an effective therapeutic strategy for the treatment of kidney fibrosis. Nonetheless, the pathways involved in ferroptosis in renal fibrosis are still unclear. Bergapten, a natural coumarin derivative, is mainly found in bergapten essential oil, grapefruit juice, and other commonly used plants, and it has various pharmacological effects. However, the role that ferroptosis plays in renal fibrosis and the potential therapeutic benefits of bergapten remain unclear. In this study, we investigated the therapeutic effects of bergapten on renal fibrosis and its mechanisms. We investigated the anti-fibrotic effects of bergapten in in vivo and in vitro models of renal fibrosis. Initially, network pharmacological analysis was employed to predict the potential therapeutic impact of bergapten on renal fibrosis. We then explored the potential therapeutic role of bergapten in obstructive nephropathy, which is due to unilateral ureteral obstruction (UUO). Furthermore, RNA-Seq was conducted to investigate the possible mechanism of bergapten against renal fibrosis. Additionally, Bergapten demonstrated a significant improvement in TGF-β1-induced fibrosis and RSL3-induced renal tubular epithelial cell ferroptosis; these findings are consistent with those of the in vivo studies. Our findings indicate that bergapten is a potential treatment for renal fibrosis. Treatment with bergapten significantly reduced the expression of fibronectin and α-SMA in the damaged kidneys of UUO mice, thereby improving fibrosis. Meanwhile, bergapten protected against fibrosis caused by TGF-β1 and ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibitor RSL3. Significantly, bergapten therapy alleviated renal fibrosis by modulating ferroptosis. We found that bergapten inhibited PI3K phosphorylation and indirectly restored GPX4 expression. In conclusion, we have revealed the nephroprotective effect of bergapten, whose mechanism of action is related to the inhibition of ferroptosis, and it is expected that it will be developed as a therapeutic agent for the treatment of renal fibrosis. This study aims to explore the effect of bergapten on renal fibrosis ferroptosis. Collectively, these results demonstrate that bergapten is an inhibitor of ferroptosis and provides a new treatment strategy for diseases associated with ferroptosis.
研究领域:
肾病学
·
药理学
·
分子生物学
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PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
JingjingLi,Juan Gu,SijiaPan,Nuo Deng,Muhammad Khan,Lingyan Li,Xiao Wu,Yongming Li
Despite continuous therapeutic interventions, the prognosis of hepatocellular carcinoma (HCC) remains very poor. Thus, quest for novel treatment strategies to improve therapeutic window of HCC therapy is paramount. Arsenic trioxide (ATO) is commonly used as the first-line treatment for acute promyelocytic leukemia (APL). Isoliquiritigenin (ISL) is a potential plant-based bioactive molecule with versatile biological and pharmacological effects including anticancer effect. The present study aimed to investigate the potential synergistic effects of combination of ISL and ATO in HCC cells. The data revealed that the combination of ISL and ATO synergistically inhibited HCC cell proliferation. The collective data demonstrate that synergistic anticancer effect of combined treatment of ISL + ATO was achieved via cooperative induction of mitochondrial apoptosis through ROS generation and inhibition of PI3K/Akt/mTOR pathway. In addition, ROS generation and suppression of PI3K/Akt/mTOR pathway were found to be two independent events in induction of apoptosis. Finally, we observed that combination treatment effectively suppressed tumor growth in nude mice xenograft model through induction of intrinsic apoptosis and inhibition of PI3K/Akt/mTOR pathway. In conclusion, the findings of this study suggest that both drugs work synergistically to exert anti-tumor effect in HCC, both in-vitro and in-vivo and could offer novel strategy for liver cancer treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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PubMed
高影响因子
CELLULAR SIGNALLING
·
2025
·
IF 3.7
Tingjuan Huang,Ziyi Shang,Lina Nie,Haichao Diao,Qizhi Shuai,Junjie Ren,Jun Xu,Jun Xie
Hepatic stellate cells (HSCs) are the central link of the occurrence and development of hepatic fibrosis, and autophagy promotes HSCs activation. N6-methyladenosine (m6A) RNA modification can also control autophagy by targeting selected autophagy-associated genes. but up to now, little research has been done on the m6A modification autophagy-related genes (ATGs) in hepatic fibrosis. Here, we identify ATG9A as a previously unrecognized m6A modified ATG using m6A-sequencing (m6A-seq). Importantly, ATG9A is upregulated in liver fibrosis mice and primary biliary cirrhosis (PBC) patient liver tissue. Mechanistically, based on the presence of m6A binding sites on ATG9A, ATG9A promotes HSCs autophagy in an m6A dependent manner, thereby enhancing HSCs activation. Noteworthy, FTO is identified as the upstream of ATG9A, and knockdown of ATG9A can prevent FTO-induced HSCs autophagy and activation. In bile duct ligation (BDL) or CCL4-induced liver fibrosis mouse models, lowering ATG9A alleviated liver fibrosis through PI3K/AKT/mTOR pathway and TGFβ1/smad3 pathway. Taken together, our results provided that ATG9A is a potential prognostic biomarker and therapeutic target for patients with liver fibrosis.
研究领域:
分子生物学
·
遗传学
·
肝病学
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PubMed
高影响因子
Microorganisms
·
2024
·Vol. 12
·期 6
·1132
·
IF 4.1
Peng Jin,Lin-Sheng Zhao,Tong-Qiang Zhang,Han Di,Wei Guo
Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed toMycoplasma pneumoniae(MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15–20 min) and intratracheal administration (6–50 μL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 108CFU/50 μL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP.
研究领域:
医学研究
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病理学
·
免疫学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2025
·
IF 12.5
Jinyan Gu,Mouming Zhao,Lijun You,Lianzhu Lin
Rhamnogalacturonan-I type pectin polysaccharide from wolfberry has immunity activity, but its intestinal immunity activity and structure-activity relationship in the small intestine was still unclear. This study comparatively investigated the intestinal immune activity of wolfberry-derived high and low branched Rhamnogalacturonan-I type pectin polysaccharides (H-LBP and L-LBP) and explored the interaction mechanism with mechanical barrier. In the normal mechanical barrier model, both H-LBP and L-LBP could cross mechanical barrier with transport rates of 23.2 % and 25 %, thereby directly enhancing macrophage viability and phagocytic ability after crossing the mechanical barrier. The transport mechanism of H-LBP in mechanical barrier included the clathrin- and caveolin-mediated pathways. In the damaged mechanical barrier model, H-LBP could significantly enhance mechanical barrier integrity, reduce the production of neurotransmitter (NO) and inflammatory cytokine (TNF-α), thereby exerting indirectly intestinal immune activity. Transcriptome analysis showed that the interaction mechanism between H-LBP and damaged mechanical barrier mainly involved signaling pathway regulating cell growth and survival (PI3K-AKT). Western blot experiment and molecular docking simulation confirmed that H-LBP could reduce the expression of p-PI3K, p-AKT and cleaved Caspase3. H-LBP had stronger directly and indirectly intestinal immune activity than L-LBP. These findings were useful for the application of H-LBP in improving intestinal immunity oral formulations.
研究领域:
食品科学
·
免疫学
·
分子生物学
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PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Chaojin Si,Hongjun Yang,Xiaoyan Wang,Qiaoxin Wang,Min Feng,Huayue Li,Yuqi Feng,Jiayuan Zhao,Ying Liao
Beta-cypermethrin (β-CYP) consists of four chiral isomers, acting as an environmental estrogen and causing reproductive toxicity, neurotoxicity, and dysfunctions in multiple organ systems. This study investigated the toxic effects of β-CYP, its isomers, metabolite 3-phenoxybenzoic acid (3-PBA), and 17β-estradiol (E2) on HTR-8/SVneo cells. We focused on the toxic mechanisms of β-CYP and its specific isomers. Our results showed that β-CYP and its isomers inhibit HTR-8/SVneo cell proliferation similarly to E2, with 100 μM 1S-trans-αR displaying significant toxicity after 48 h. Notably, 1S-trans-αR, 1R-trans-αS, and β-CYP were more potent in inducing apoptosis and cell cycle arrest than 1R-cis-αS and 1S-cis-αR at 48 h. AO/EB staining and flow cytometry indicated dose-dependent apoptosis in HTR-8/SVneo cells, particularly at 100 μM 1R-trans-αS. Scratch assays revealed that β-CYP and its isomers variably reduced cell migration. Receptor inhibition assays demonstrated that post-ICI 182780 treatment, which inhibits estrogen receptor α (ERα) or estrogen receptor β (ERβ), β-CYP, its isomers, and E2 reduced HTR-8/SVneo cell viability, whereas milrinone, a phosphodiesterase 3 A (PDE3A) inhibitor, increased viability. Molecular docking studies indicated a higher affinity of β-CYP, its isomers, and E2 for PDE3A than for ERα or ERβ. Consequently, β-CYP, its isomers, and E2 consistently led to decreased cell viability. Transcriptomics and RT-qPCR analyses showed differential expression in treated cells: up-regulation of Il24 and Ptgs2 , and down-regulation of Myo7a and Pdgfrb , suggesting the PI3K-AKT signaling pathway as a potential route for toxicity. This study aims to provide a comprehensive evaluation of the cytotoxicity of chiral pesticides and their mechanisms.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
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PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2025
·
IF 2.5
Shao-Jun Zheng,Xiao-Han Diao,Xiao-Yan Gao,Nai-Dong Chen
Dendrobium officinale polysaccharides (DOP) exhibit anticancer potential against colorectal cancer (CRC), yet their mechanisms remain unclear. This study investigated DOP's effects on HCT-116 cells. DOP dose- and time-dependently inhibited proliferation and induced apoptosis, evidenced by elevated cleaved caspase-3/-9, poly ADP-ribose polymerase (PARP), Bax, and reduced Bcl-2. Concurrently, DOP activated autophagy (increased LC3-II/I, Beclin-1; decreased p62) via phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) suppression. Combining DOP with the autophagy inhibitor chloroquine enhanced apoptosis (higher cleaved PARP, Bax; lower Bcl-2) and reactivated PI3K/Akt/mTOR signaling. These findings demonstrate DOP inhibits CRC by dual induction of apoptosis and autophagy blockade through PI3K/Akt/mTOR inhibition, with autophagy suppression synergistically augmenting apoptosis. The study highlights DOP's translational potential as a functional food or adjuvant therapy, proposing a novel combinatorial strategy for CRC treatment. Graphical Dendrobium officinale polysaccharides (DOP) inhibit HCT-116 colorectal cancer cell proliferation and induce apoptosis by upregulating cleaved caspase-3/-9, PARP, and Bax while downregulating Bcl-2. DOP activates autophagy via PI3K/Akt/mTOR inhibition. Combining DOP with chloroquine enhances apoptosis, revealing autophagy blockade as a synergistic anticancer mechanism.
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PubMed
高影响因子
Discover Oncology
·
2024
·Vol. 15
·期 1
·1-13
·
IF 2.8
Lei Ruiwen,Yao Chaoling,Huang Renfeng,Wu Wanming,Ou Linyang,Yang Chuansheng
To investigate the effects of higher cellular stanniocalcin 2 (STC2) on suppressing the migration and invasion but promoting the apoptosis of triple-negative breast cancer (TNBC). STC2 in TNBC and the para-carcinoma tissues were analyzed by immunohistochemistry (IHC), while the mRNA level was measured by qPCR. Over-expressing or silencing STC2 was established in MDA-MB-231 cells. Epithelial mesenchymal transition (EMT) related proteins, cell migration, invasion, proliferation and apoptosis were detected. MDA-MB-231 with over-expressing or silencing STC2 were injected into nude mice to formatting tumors, and then EMT related proteins were measured by IHC. Lower STC2 expressed in TNBC tissues than in the para-carcinoma tissues. Silencing STC2 promoted EMT of TNBC cell MDA-MB-231, as well as cell migration, invasion and proliferation, but suppressed MDA-MB-231 apoptosis, while over-expressing STC2 had the opposite results, which might be related to PKC/PI3K/AKT/mTOR pathway. STC2 was the protective gene in TNBC, by suppressing migration and invasion to inhibit MDA-MB-231 cell EMT but promote cell apoptosis, in order to suppress TNBC progression.
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
Biomaterials Research
·
2025
·
IF 9.6
Jian Wu,Minghui Liu,Meng Gao,Yongchao Li,Youjie Zhang,Liang Tang,Hao Yu,Zhangcheng Liao,Yu Cui,Feng Zeng,Hequn Chen,Zewu Zhu
Although tea consumption has been suggested to affect kidney stone formation, epidemiological evidence remains inconsistent, and the underlying molecular mechanisms are unclear. To assess the association between tea intake and kidney stone risk, we initially conducted a prospective cohort analysis of 481,393 participants from the UK Biobank and a 2-sample Mendelian randomization (MR) analysis. Our findings revealed that heavy tea drinkers (>5 cups/day) had a significantly reduced risk of kidney stones (hazard ratio: 0.79, 95% confidence interval [CI]: 0.72 to 0.86, P < 0.001), and MR analyses confirmed a causal association (inverse variance weighted OR: 0.45, 95% CI: 0.32 to 0.62, P < 0.001). We next explored the effect of epigallocatechin gallate (EGCG), the main bioactive component in tea, on calcium oxalate (CaOx) stone formation. EGCG was found to inhibit the glucose-regulated protein 94/phosphatidylinositol 3-kinase/protein kinase B (GRP94/PI3K/AKT) pathway in human proximal renal tubular epithelial cells, thereby attenuating CaOx crystal-induced oxidative stress and inflammation, and inhibiting crystal-cell adhesion. This finding aligned with the observation that the activated GRP94/PI3K/AKT pathway was positively associated with inflammation-related molecules in renal papillary tissues of CaOx stone formers. Moreover, to enhance renal targeting and therapeutic potential, we synthesized cell membrane-coated EGCG-loaded poly(lactic-co-glycolic acid) (TP-EGCG) nanoparticles, which enhanced renal EGCG delivery and substantially reduced CaOx crystal deposition in a mouse model of CaOx nephrolithiasis. In conclusion, tea consumption protects against kidney stone formation, an effect exerted by EGCG through the GRP94/PI3K/AKT axis, and our novel TP-EGCG nanoparticles show strong potential for targeted prevention and treatment.
研究领域:
肾脏病学
·
分子生物学
·
药理学
·
营养流行病学
·
纳米医学
·
信号转导
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DOI
PubMed
高影响因子
CELL AND TISSUE RESEARCH
·
2019
·Vol. 378
·期 1
·113-125
·
IF 3.36
Zheng Rongzong,Huang Shuming,Zhu Junkun,Lin Wei,Xu Huan,Zheng Xiang
Rotator cuff tears (RCTs), the most common tendon injury, are always accompanied by muscle atrophy, which is characterized by excessive protein degradation. Autophagy–lysosome systems are the crucial proteolytic pathways and are activated in atrophying muscle. Thus, inhibition of the autophagy–lysosome pathway might be an alternative way to minimize skeletal muscle atrophy. In this present study, combined with a tendon transection-induced rat model of massive rotator cuff tears, HE staining and transmission electron microscopy methods, we found leucine supplementation effectively prevented muscle atrophy, muscle injury and autophagosome formation. Utilizing immunoblotting, we discovered that leucine supplementation is able to inhibit the rise in autophagy-related protein expression (including LC3, Atrogin-1, MuRF1, Bnip3 and FoxO3) driven by tendon transection. The PI3K/AKT/mTOR pathway that was essential in autophagosome formation and autophagy was blocked in atrophying muscle and reactivated in the presence of leucine. Once administrated with LY294002 (PI3K inhibitor) and Rapamycin (mTOR inhibitor), leucine mediated by the anti-atrophic effects was nearly blunted. These results suggest that leucine potentially attenuates tendon transection-induced muscle atrophy through autophagy inhibition via activating the PI3K/AKT/mTOR pathway.
研究领域:
骨骼肌生物学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）