PHYTOMEDICINE
·
2024
·
IF 6.7
Pingping Tuo,Risheng Zhao,Ning Li,Shuang Yan,Gege Yang,Chunmei Wang,Jinghui Sun,Haiming Sun,Mengyang Wang
Background Ang II induces hypertensive heart failure (HF) via hemodynamic and non-hemodynamic actions. Lycorine (LYC) is an alkaloid derived from Lycoris bulbs, and it possesses anti-cardiovascular disease-related activities. Herein, we explored the potential LYC-mediated regulation of Ang II-induced HF. Methods Over 4 weeks, we established a hypertensive HF mouse model by infusing Ang II into C57BL/6 mice using a micro-osmotic pump. For the final two weeks, mice were administered LYC via intraperitoneal injection. The LYC signaling network was then deduced using RNA sequencing. Results LYC administration strongly suppressed hypertrophy, myocardial fibrosis, and cardiac inflammation. As a result, it minimized heart dysfunction while causing no changes in blood pressure. The Nuclear Factor kappa B (NF-κB) network/phosphoinositol-3-kinase (PI3K)-protein kinase B (AKT) was found to be a major modulator of LYC-based cardioprotection using RNA sequencing study. We further confirmed that in cultured cardiomyocytes and mouse hearts, LYC reduced the inflammatory response and downregulated the Ang II-induced PI3K-AKT/NF-κB network. Moreover, PI3K-AKT or NF-κB axis depletion in cardiomyocytes completely abrogated the anti-inflammatory activities of LYC. Conclusion Herein, we demonstrated that LYC safeguarded hearts in Ang II -stimulated mice by suppressing the PI3K-AKT/NF-κB-induced inflammatory responses. Given the evidence mentioned above, LYC is a robust therapeutic agent for hypertensive HF.
研究领域:
心脏病学
·
药理学
·
分子生物学
·
炎症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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.
研究领域:
药理学
·
肿瘤学
·
纳米技术
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Yang Zhang,Shan Liu,Jiu-Long Ma,Chen Chen,Peng Huang,Jia-Hua Ji,Di Wu,Li-Qun Ren
Background Doxorubicin (DOX) is a broad-spectrum anti-tumor drug that has been associated with cardiotoxicity. Plant extracts have been shown to confer protection against DOX-induced cardiotoxicity. Apocynum venetum L . belongs to the Apocynaceae family. Flavonoid extracted from Apocynum venetum L . possess various biological effects, such as lowering blood pressure levels, sedation, diuresis, anti-aging, and improving immunity. Purpose This study investigated the mechanism by which dry leaf extract of Apocynum venetum L. (AVLE) alleviates DOX-induced cardiomyocyte apoptosis. Methods HPLC-MS/MS and HPLC methods were used to analyze the components of AVLE. The effects of DOX and AVLE on apoptosis of H9c2 and HMC cells were assessed using the MTT assay. Calcein AM/PI, TUNEL, and flow cytometry were carried out to determine the effects of AVLE on DOX-induced apoptosis. The effect of AVLE on DOX-induced oxidative stress in cardiomyocytes was investigated using ELISA test. Mito-Tracker Red CMXRos, JC-1, and RT-qPCR assays were performed to evaluate the impact of AVLE on DOX-induced cardiomyocyte mitochondrial activity and membrane permeability. Western blot assay was carried out to determine the activation of multiple signaling molecules, including phosphorylated-protein kinase B (p-AKT), Cytochrome c, Bcl-2 family, and caspase family in the apoptosis pathway. The AKT inhibitor was used to block AKT/Bcl-2 signaling pathway to investigate the role of AKT in the protection conferred by AVLE against DOX-induced cardiotoxicity. Results A total of 8 compounds, including rutin, hyperoside, isoquercetin, unidentified compounds, myricetin, quercetin, quercetin-3-O-glucuronide and kaempferol, were detected in AVLE. Of note, DOX suppressed lactate dehydrogenase (LDH) levels, aggravated oxidative stress, and promoted cardiomyocyte apoptosis. It also upregulated the mRNA expression levels of voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD), while suppressing mitochondrial activity and mitochondrial membrane permeability. Treatment with DOX altered the expression levels of apoptosis-associated proteins, Bcl-2 and Bax. However, AVLE treatment alleviated DOX-induced effects on cardiomyocytes. In addition, application of AKT inhibitors promoted DOX-induced apoptosis and reversed the inhibitory effects of AVLE on DOX-induced apoptosis. Conclusions AVLE confer cardio protection by suppressing oxidative stress and apoptosis of cardiomyocytes via AKT/Bcl-2 signaling pathway.
研究领域:
药理学
·
心脏病学
·
植物科学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Yingjie Wu,Mingxiang Fan,Shixiang Tan,Qiucheng Guo,Hegui Xu
Objective To examine and talk about the mechanism of the Huoxue Jiegu compound capsule's effects on osteoblasts and the PI3K/Akt/mTOR signal pathway in rabbits suffering from tibial fractures. Method In vitro, CCK8 was used to assess the survival rates. Alizarinred staining was used to evaluate mineralized nodules. ALP staining was used to observe the osteoblasts. qRT-PCR was used to determine the mRNA expression of the bone formation-related factors BMP-2, bFGF, and TGF-β. In vivo, three groups of nine male rabbits each were randomly assigned to three groups: the Model group, the Huoxue Jiegu compound capsule group (HXJGC group), and the inhibitor group (HXJGC+3-MA), four weeks following the intervention. HE staining was employed to examine the rabbits' bone histology. immunohistochemistry was employed to examine the relative expression of the proteins VEGF and LC3-II. Western Blot was utilized to examine the relative expression of the proteins Beclin-1, LC3-II/Ⅰ, p62, p-PI3K, p-AKT, and p-mTOR. Results Compared to the control group, the medium- and high-dose groups exhibited considerably higher survival rates ( P < 0.05), as well as enhanced cell proliferation and differentiation ( P < 0.05) and more pronounced mineralized nodules. ( P < 0.05), but the low-dose groups showed no appreciable variation. In the low, medium, and high-dose groups, there was a substantial reduction in the expression of bFGF mRNA, whereas the levels of BMP-2 and TGF-β mRNA were considerably higher than in the control group ( P < 0.05). In vivo, after four weeks of treatment, the model control group and inhibito group had a large amount of fibrous hyperplasia accompanied by bleeding and a small amount of inflammatory cell infiltration. But in the HXJGC group, new cartilage appeared, and the surface of the cartilage was smooth and flat. Beclin-1 and LC3-II/I expression in the HXJGC+3 MA group was significantly lower than in the HXJGC and Model groups ( P < 0.05). The HXJGC group showed lower p62 expression than the HXJGC+3 MA and model groups ( P < 0.05). The HXJGC group exhibited significantly reduced levels of p-PI3K, p-AKT, and p-mTOR expression in comparison to HXJGC+3 MA groups ( P < 0.05). Conclusion Rabbits with tibial fractures can be treated with HXJGC, which can control the expression of the PI3K/Akt/mTOR signal pathway. It can promote the differentiation and maturation of osteoblasts at the fracture end of rabbits, accelerate the recovery of fractures, and achieve the purpose of treating the disease.
研究领域:
医学
·
生物学
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DOI
PubMed
高影响因子
Oncotarget
·
2017
·
IF 5.168
Jingwei Shao,Guirong Zheng,Hongning Chen,Jian Liu,Aixiao Xu,Fan Chen,Tao Li,Yusheng Lu,Jianguo Xu,Ning Zheng,Lee Jia
Therapies targeting epidermal growth factor receptor (EGFR) can effectively treat with non-small cell lung cancer (NSCLC), but NSCLC’s drug resistance makes it intractable. Herein, we showed that RU486 metabolite metapristone inhibited the proliferation of various NSCLC cell lines with either wild (A549, H1299, H520) or mutated EGFR (H1975, HCC827). The suppression was resulted from inhibition by metapristone of EGFR signaling pathways through down-regulating the EGFR, PTEN, as well as AKT and ERK proteins. In addition, metapristone inhibited anti-apoptotic marker Bcl-2, and activated pro-apoptotic key signaling proteins caspase-3, and poly (ADP-ribose) polymerase. Metapristone induced A549 and H1975 cell cycle via arrest at the G0-G1 stage. What’s more, metapristone inhibited the growth of NSCLC xenografts in BALB/c nude mice through decreasing the expression of tumor growth biomarkers PCNA and EGFR. Taken together, the present study demonstrated that metapristone suppressed NSCLC proliferation by promoting apoptosis via decrease the cellular EGFR-mediated PI3K/AKT pathways. The results suggest metapristone a new treatment for EGFR-overexpressed NSCLC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2025
·
IF 20.3
Jieying Liu,Fuze Liu,Cairong Li,Zhengyao Li,Tianle Li,Yuanhao Wu,Di Wu,Yue Huang,Hui Chen,Hai Wang,Yuxiao Lai,Zhihong Wu
Background Iron oxide nanoparticles (IONPs)-based bone scaffolds have attracted increasing attention because of their potential to enhance osteogenesis and angiogenesis. However, the underlying mechanisms remain incompletely understood. Methods We fabricated a biocompatible bone scaffold by incorporating γ-Fe 2 O 3 magnetic nanoparticles into a PLGA matrix using 3D printing technology. The biosafety and effectiveness of the scaffold was validated through in vitro cell assays and in vivo implantation studies. To evaluate osteogenesis and neovascularization, we employed micro-CT imaging with a vascular contrast agent. In-depth mechanistic investigations were conducted via label-free proteomic profiling and pathway enrichment analysis. Results The PLGA/Fe 2 O 3 scaffolds demonstrated excellent biocompatibility and promoted both bone formation and angiogenesis in vitro and in vivo . Micro-CT analysis revealed enhanced new bone and vessel formation in the presence of magnetic scaffolds. Proteomic analysis revealed that alpha-B crystallin (CRYAB) is a key regulatory protein upregulated under a static magnetic field, thereby activating the PI3K/AKT signaling cascade and promoting osteogenic differentiation. In endothelial cells, we observed the upregulation of nuclear NF-κB and HIF-1α, leading to VEGF expression and angiogenic activation. Conclusion Our findings provide direct evidence that 3D-printed PLGA/Fe 2 O 3 scaffolds promote osteogenesis and angiogenesis both in vitro and in vivo . Importantly, we report for the first time that CRYAB-mediated stabilization of β-catenin plays a central role in magnetic scaffold-induced bone regeneration, offering new insights into the design of functional bone substitutes.
研究领域:
生物材料学
·
组织工程
·
分子生物学
·
转化医学
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骨骼系统生物学
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血管生物学
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纳米医学
·
再生医学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2025
·
IF 3.9
Yijun Yang,Nengyi Wang,Yuankun Chen,Tianpeng Ma,Minhua Weng,Haifeng Wu,Qiuping Wu,Yiqiang Xie,Chuanwu Zhu,Wenting Li
Nonalcoholic fatty liver disease (NAFLD) has posed a huge threat to public health globally, but there are currently no approved drugs available. Growing evidence has proved the close association between increased Th17 cells and NAFLD progression. Interleukin-4 induced protein 1 (IL4I1), an amino acid oxidase secreted by immune cells, was reported to regulate the Th17 cells, but its exact role in NAFLD progression has not been fully explained yet. We found that IL4I1 was highly expressed in the liver of C57BL/6J mice with NAFLD induced by an 8-weeks western diet. To explore the IL4I1’s effect, mice were injected with AAV8 encoding IL4I1 1 week before western diet administration. The results showed that IL4I1 overexpression inhibited the NAFLD progression, demonstrated by relieved liver damage and lipid accumulation. The underlying mechanism in which IL4I1 acts on NAFLD might be attributed to the inactivated AKT/forkhead box protein O1 (FOXO1) signaling pathway–mediated decrease of Th17 cells in liver tissues. Subsequently, by culturing naive CD4 + T cells isolated from the spleen of mice in Th17 cell-polarizing conditions, we determined that IL4I1 overexpression inhibited Th17 cell differentiation by inactivating the AKT/FOXO1 pathway, whereas its knockdown exhibited opposite effects. Further, the AKT activator SC79 reversed the effect of IL4I1 overexpression on Th17 cell differentiation. Collectively, our study supports that compensatory upregulation of IL4I1 protects against liver damage and lipid accumulation in NAFLD progression, partially by inhibiting the activated AKT/FOXO1 signaling pathway-induced Th17 cell differentiation.
研究领域:
免疫学
·
肝病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2020
·
IF 2.985
Gen Liu,Bo-fang Zhang,Qi Hu,Xiao-pei Liu,Jing Chen
Syringic acid is an abundant phenolic acid compound that possesses anti-oxidant, anti-microbial, anti-inflammatory, and anti-endotoxic properties. However, the research of pretreatment with syringic acid against myocardial ischemia reperfusion is still limited. Thus, our research revealed the protective effect of syringic acid in the rat model with myocardial ischemia reperfusion injury. Histological analysis was performed by hematoxylin and eosin (H&E). The myocardial systolic function was detected by echocardiographic. Myocardial infarct size was measured by Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining. The apoptosis index was recorded by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining (TUNEL). The contents of creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were determined by a commercial kit. The expression of the PI3K/Akt/GSK-3β signaling pathway-related molecules and apoptosis-associated indicators was detected by western blotting or real-time PCR. We found that pretreatment with syringic acid obviously increased the myocardial systolic function (LVEF and LVFS) and decreased the infarct size, the apoptosis index as well as the serum level of CK-MB and LDH. Meanwhile, syringic acid also remarkably augmented the contents of p-PI3K, p-Akt, p-GSK-3β, Bcl-2 and mitochondria cytochrome c . However, the expression of caspase-3, -9 and Bax significantly reduced. Interestingly, co-treatment with PI3K inhibitor of LY294002 counteracted those effects induced by syringic acid. In conclusion, pretreatment with syringic acid can mitigate myocardial ischemia reperfusion injury by inhibiting mitochondria-induced apoptosis which is regulated by the PI3K/Akt/GSK-3β signaling pathway .
研究领域:
药理学
·
心脏病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Liu Nannan,Fan Xuefei,Shao Yubao,Chen Suhuan,Wang Taorong,Yao Tao,Chen Xiaoyu
Background and purposeInterstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway.Methods We established an arthritis model by combining chicken type II collagen and complete Freund’s adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-β1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1β in combination with TGF-β1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD.Results Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-β1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD.Conclusion In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.Graphical Abstract
研究领域:
药理学
·
免疫学
·
肺科学
·
风湿病学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
·
IF 2.5
Jianyu Xia,Pengju Guo,Jing Yang,Tao Zhang,Kejian Pan,He Wei
Background Colorectal cancer (CRC) is a prevalent malignancy and poses a significant clinical challenge. Piperine, an alkaloid molecule extracted from Piper nigrum and Piper longum, has emerged as a promising anticancer agent. However, the molecular mechanisms of piperine’ antitumor effects in CRC need to be further elucidated. Methods Human colorectal cancer cells were treated with piperine in vitro . CCK-8 and clone formation assays were adopted to detect cell viability. The accumulation of autophagosomes was assessed by Western blotting and immunofluorescence. Apoptosis and reactive oxygen species (ROS) levels were analyzed by flow. In vivo , a xenograft tumor mouse model was constructed using CT26 cells. Results Piperine inhibited CRC cell viability and suppressed tumor weight and volume in a mouse model. Additionally, piperine treatment induced the accumulation of autophagosomes in CRC cells. This effect was attributed to the inhibition of the AKT/mTOR pathway and the accumulation of ROS. activation of AKT or clearance of ROS attenuated piperine-mediated tumor suppression. Conclusion This study shows that piperine induces autophagy-dependent cell death in CRC cells by increasing ROS production and inhibiting Akt/mTOR signaling.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Huan Liu,Longsheng Wang,Xiaokai Shi,Lei Yin,Wei Zhai,Shenglin Gao,Yonghui Chen,Tao Zhang
Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Hai-Tao Yang,Guan Wang,Peng-Cheng Zhu,Zhao-Yang Xiao
Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation , and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro . EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo . In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.
研究领域:
心血管疾病
·
分子生物学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）