MATERIALS & DESIGN
·
2022
·
IF 9.417
Yuqin Yang,Desheng Cai,Yisong Shu,Zhihua Yuan,Wenmin Pi,Yaozhi Zhang,Jihui Lu,Jingyi Jiao,Xuehao Cheng,Feifei Li,Penglong Wang,Haimin Lei
It is crucial to inhibit tumor growth and distant metastasis for breast cancer (BC) therapy. However, the treatment primarily dependent on surgery, chemotherapy, and radiotherapy is far from satisfactory. It had been demonstrated that the CXCL1/2-S100A8/9 axis played an essential role in BC therapy. Therefore, we constructed a natural product hydrogel for BC therapy by blocking CXCL1 signaling. The GK-GA (phytochemicals of Genkwa Flos -glycyrrhizic acid) hydrogel was designed in a one-step “green” approach. The pharmacodynamics study showed GK-GA exhibited significant anti-tumor and anti-lung metastasis activities, resulting in the inhibition rate of tumor growth (IRG) over 90 % at 6.25 mg·kg −1 , and did not display any obvious toxicity. In addition, the potent antitumor efficiency was also attributed to aggregation/assembly-induced retention (AIR) property. RNA sequencing analysis revealed the gene expression was significantly down-regulated in the GK-GA group, which were BCL2, CASP3, CXCL1, CXCL2, CXCR2, S100A8, S100A9, and confirmed further by western blot (WB). Our findings indicated natural product GK-GA hydrogel inhibited tumor growth and lung metastasis via the BCL2-CASP3 mitochondrial apoptosis pathway as well as the CXCL1/2-S100A8/9 pathway. This study provides inspiration for the fabrication of new excipients-free nano-dispersion in a one-step, no‐carrier‐added, organic solvent-free, “green” approach, particularly for small molecular antitumor agents.
研究领域:
肿瘤学
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药学
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分子生物学
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癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2024
·
IF 3.9
Huanyan Wu,Linlin Qu,Xue Bai,Chenhui Zhu,Yuan Liu,Zhiguang Duan,Hongyan Liu,Rongzhan Fu,Daidi Fan
Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Recent studies have shown that suppression of autophagy plays an important role in the development of HCC. Ginsenoside Rk1 is a protopanaxadiol saponin isolated from ginseng and has a significant anti-tumor effect, but its role and mechanism in HCC are still unclear. In this study, a mouse liver cancer model induced by diethylnitrosamine and carbon tetrachloride (DEN + CCl 4 ) was employed to investigate the inhibitory effect of Rk1 on HCC. The results demonstrate that ginsenoside Rk1 effectively inhibits liver injury, liver fibrosis, and cirrhosis during HCC progression. Transcriptome data analysis of mouse liver tissue reveals that ginsenoside Rk1 significantly regulates the AMPK/mTOR signaling pathway, autophagy pathway, and apoptosis pathway. Subsequent studies show that ginsenoside Rk1 induces AMPK protein activation, upregulates the expression of autophagy marker LC3-II protein to promote autophagy, and then downregulates the expression of Bcl2 protein to trigger a caspase cascade reaction, activating AMPK/mTOR-induced toxic autophagy to promote cells death. Importantly, co-treatment of ginsenoside Rk1 with autophagy inhibitors can inhibit apoptosis of HCC cells, once again demonstrating the ability of ginsenoside Rk1 to promote autophagy-dependent apoptosis. In conclusion, our study demonstrates that ginsenoside Rk1 inhibits the development of primary HCC by activating toxic autophagy to promote apoptosis through the AMPK/mTOR pathway. These findings confirm that ginsenoside Rk1 is a promising new strategy for the treatment of HCC.
研究领域:
肿瘤学
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药理学
·
分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2020
·Vol. 295
·期 20
·6958-6971
·
IF 4.238
Chunyan Liao,Binxiang Cai,Yufeng Feng,Jingmeng Chen,Yiping Wu,Jingbin Zhuang,Zuguo Liu,Yalin Wu
Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4−/− Rdh8−/− mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4−/−Rdh8−/− mice. Of note, intraperitoneal administration of JNK–IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4−/−Rdh8−/− mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.
研究领域:
眼科学
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细胞生物学
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分子生物学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Xue Yang,Fang Gao,Wenan Zhang,Huipeng Li,Xinzhi Huang,Jiajia Wei,Jiayi Bian,Ying Yang,Chenggen Qian,Minjie Sun
Invasion and metastasis of tumor cells is one of the major obstacles in cancer therapy. The process of tumor metastasis and diffusion is coordinated by multiple pathways associated with chemokine signals and migration microenvironment. In our previous work, chemokine CXC receptor 4 (CXCR4) antagonists showed significant anti-metastatic effects by blocking the CXCR4/stromal cell-derived factor-1(SDF-1) axis in pancreatic cancer and breast cancer. Here, we proposed to achieve migration chain-treatment for metastatic tumors by introducing a cell adhesion molecules CD44 inhibitor (Star miR-34a) to deprive of cell migration capability on the basis of CXCR4 antagonism (cyclam monomer , CM). Dextrin modified 1.8 k PEI with CM-end was prepared to deliver therapeutic miR-34a (named DPC/miR-34a) for efficient anti-metastasis by downregulating adhesion protein CD44 and targeting the CXCR4/SDF-1 axis. Additionally, reduced expression of the anti-apoptotic protein Bcl2 caused by miR-34a could enhance the anti-tumor efficacy of DPC/miR-34a nanoplex administration. Compared with inhibition of the CXCR4/SDF-1 axis or CD44 expression, the multidimensional therapy (DPC/miR-34a) exhibited considerable suppression of cancer cell invasion as assessed by an in vitro cell invasion assay and in vivo anti-metastasis model. Moreover, DPC/miR-34a demonstrated a superior antitumor and anti-metastatic efficacy both in lung metastatic model and orthotopic MDA-MB-231 tumor models, thus providing an efficient approach for combating metastatic tumors.
研究领域:
肿瘤学
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分子生物学
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药学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Enjuan Shi,Xiaoqin Wang,Huili Jing,Yayuan Xu,Lei Feng,Fatao He,Dajing Li,Zhuqing Dai
In this study, N -Methyl-N-nitrosourea (MNU) was intraperitoneally injected to construct a mouse retinitis pigmentosa (RP) model to evaluate the protective effect of chitosan and β-carotene on RP. The results demonstrated that chitosan synergized with β-carotene significantly reduced retinal histopathological structural damage in RP mice. The co-treatment group of β-carotene and chitosan restored the retinal thickness and outer nuclear layer thickness better than the group treated with the two alone, and the thickness reached the normal level. The content of β-carotene and retinoids in the liver of chitosan and β-carotene co-treated group increased by 46.75 % and 20.69 %, respectively, compared to the β-carotene group. Chitosan and β-carotene supplement suppressed the expressions of Bax, Calpain2, Caspase3, NF-κB, TNF-α, IL-6, and IL-1β, and promoted the up-regulation of Bcl2. Chitosan and β-carotene interventions remarkably contributed to the content of SCFAs and enhanced the abundance of Ruminococcaceae , Rikenellaceae , Odoribacteraceae and Helicobacteraceae . Correlation analysis demonstrated a strong association between gut microbiota and improvement in retinitis pigmentosa. This study will provide a reference for the study of the gut-eye axis.
研究领域:
眼科学
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药理学
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分子生物学
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微生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 10
·2306
·
IF 4.2
Danyang Zhang,Xiaoshi He,Ting Wang,Yan Xing,Zhilong Xiu,Yongming Bao,Yuesheng Dong
Methylglyoxal-induced ROS elevation is the primary cause of neuronal damage. Metformin is a traditional hypoglycemic drug that has been reported to be beneficial to the nervous system. In this study, flavonoids were found to enhance the protective effect of metformin when added at a molar concentration of 0.5%. The structure–activity relationship (SAR) analysis indicated that ortho- substitution in the B ring, and the absence of double bonds between the 2 and 3 position combined with the gallate substitution with R configuration at the 3 position in the C ring played crucial roles in the synergistic effects, which could be beneficial for designing a combination of the compounds. Additionally, the mechanism study revealed that a typical flavonoid, EGCG, enhanced ROS scavenging and anti-apoptotic ability via the BCL2/Bax/Cyto C/Caspase-3 pathway, and synergistically inhibited the expression of GSK-3β, BACE-1, and APP in PC-12 cells when used in combination with metformin. The dose of metformin used in the combination was only 1/4 of the conventional dose when used alone. These results suggested that ROS-mediated apoptosis and the pathways related to amyloid plaques (Aβ) formation can be the targets for the synergistic neuroprotective effects of flavonoids and metformin.
研究领域:
药理学
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神经科学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2020
·
IF 4.679
Hang Qu,Shuang Liu,Cuilin Cheng,Haitian Zhao,Xin Gao,Zhenyu Wang,Juanjuan Yi
Previously, we obtained a purified polysaccharide (PNP40c-1) from Pinus koraiensis pine nut and reported its protective effect on carbon tetrachloride (CCl 4 )-induced liver injury in vitro . The object of this study is to investigate its hepatoprotective activity in vivo and elucidate the mechanism underlying the hepatoprotection . PNP40c-1 effectively prevented the accumulation of serum liver injury biomarkers including alanine aminotransferase , aspartate aminotransferase, alkaline phpsphatase and total bilirubin stimulated by CCl 4 . The pathological changes in PNP40c-1-treated mice livers were also markedly ameliorated. Results showed that PNP40c-1 suppressed the production of reactive oxygen species (ROS) and lipid peroxidation, upregulated Nrf2/ARE pathway and enhanced the antioxidant capacity of hepatocytes. Furthermore, the reaction between Nrf2 and ARE promoted the generation of Mkp1 , which inhibited the activation of JNK induced by CCl 4 , and suppressed hepatocytes apoptosis by regulating the protein expression of Bax, cleaved-Caspase-3 and Bcl2, exerting hepatoprotective activity. Taken together, upregulation of Nrf2/ARE pathway and suppression of JNK activation via Nrf2/ARE/Mkp1/JNK signaling pathways are the main mechanisms underlying the hepatoprotective effect of PNP40c-1 against CCl 4 -induced mice liver injury. These results indicated that PNP40c-1 has potential to serve as a hepatoprotective agent against chemical induced hepatotoxicity.
研究领域:
药理学
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毒理学
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生物化学
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分子生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Jin-hua Fan,Min-min Xu,Li-ming Zhou,Zheng-wei Gui,Lu Huang,Xue-gang Li,Xiao-li Ye
Background and purpose Zuojin capsule (ZJC), a classical prescription, is outstanding in improving the conditions of patients with gastrointestinal diseases and colorectal cancer (CRC). Although ZJC has multi-ingredient and multi-target characteristics, its pharmacological effect on colorectal cancer and the underlying mechanism remain unclear. Method Here, the activity of ZJC against CRC was evaluated by the experiments with CRC cells and HCT-116 xenografted mice. The key genes of CRC were obtained from the cancer genome atlas (TCGA). The genes potentially targeted by ZJC were collected from traditional Chinese medicine systems pharmacology (TCMSP) database. The underlying pathways related to selected targets were analyzed through gene ontology (GO) and pathway enrichment analyses. Western blot (WB), cellular thermal shift assay (CETSA), molecular docking and quantitative real-time PCR (QRT-PCR) were carried out to confirm the validity of the targets. Results In vitro and in vivo results indicated that ZJC may inhibit CRC cells and tumor growth. The network pharmacological analysis indicated that 22 compounds, 51 targets and 20 pathways were involved in the compound-target-pathway network. Our results confirmed that ZJC inhibited cycle progression, migration and induced apoptosis by targeting candidate genes ( CDKN1A, Bcl2, E2F1, PRKCB, MYC, CDK2 , and MMP9 ). We found that ZJC could directly change the protein level by regulating the protein stability and transcriptional activity of the target. Conclusions In summary, combined network pharmacology and biological experiments proved that the main ingredients of ZJC such as quercetin, (R)-Canadine, palmatine, rutaecarpine, evodiamine, beta-sitosterol and berberine can target CDKN1A, Bcl2, E2F1, PRKCB, MYC, CDK2 and MMP9 to combat colorectal cancer. The results of this study provide a basic theory for the clinical trials of Zuojin Capsules against colorectal cancer.
研究领域:
药理学
·
肿瘤学
·
系统生物学
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中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Hao Yan,Xiangliang Huang,Jiangxin Xu,Ying Zhang,Jiajia Chen,Zhifei Xu,Hui Li,Zeng Wang,Xiaochun Yang,Bo Yang,Qiaojun He,Peihua Luo
Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second-generation BCR-ABL1 inhibitor in the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl-XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib-induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl-XL. The intervention effect is dependent on the alleviation of the nilotinib-induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl-XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl-XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.
研究领域:
药理学
·
肿瘤学
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Zijin Xu,Susu Lin,Zheren Tong,Suhong Chen,Yifeng Cao,Qiaoqiao Li,Yuli Jiang,Weijie Cai,Yingpeng Tong,Bathaie S. Zahra,Ping Wang
Ethnopharmacological relevance Traditional Chinese medicine considers that the etiology and pathogenesis of non-alcoholic fatty liver disease (NAFLD) are related to liver depression and qi stagnation . Saffron and its active ingredient, crocetin (CCT), are used for the treatment of metabolic diseases owing to their “Liver deobstruent” and “Liver tonic” effects. However, the effect of CCT on NAFLD has not been fully elucidated. In the present study, the effect and potential molecular mechanism of CCT were explored in both in vivo and in vitro models of NAFLD. Materials and methods CCT was isolated from saffron and purity and structure characterization were performed using HPLC, MS , 1 H-NMR, and 13 C-NMR. The effect of CCT on the viability of L02 cells and its maximum tolerable concentration (MTC) in zebrafish were investigated. Free fatty acids (FFA) and thioacetamide (TAA) were used to induce lipid accumulation in L02 cells and steatosis in zebrafish, respectively. The effects of CCT on indexes related to lipid metabolism, oxidative stress, and mitochondrial function in NAFLD models were explored using biochemical assay kits, Western blot analysis , Reverse Transcription-Polymerase Chain Reaction (RT-PCR), histopathology analysis, and determination of mitochondrial membrane potential ( ΔΨm ). Morphological analysis of mitochondria was performed using transmission electron microscopy (TEM). Results The levels of triglyceride (TG), total cholesterol (TC), malondialdehyde (MDA), and alanine/aspartate aminotransferases (ALT/AST) activities in FFA treated L02 cells were significantly reduced after CCT treatment. CCT treatment significantly increased ATP concentration, ΔΨm , and activities of superoxide dismutase (SOD), catalase (CAT), and cytochrome c oxidase (COX IV) in FFA treated L02 cells. TEM images showed restoration of mitochondrial morphology. CCT decreased ATP concentration and upregulated expression of B-cell lymphoma-2 (Bcl-2) and COX IV, whereas, CCT downregulated expression of BCL2-Associated X (Bax) and cleaved caspase-3 in TAA treated zebrafish. These findings indicated that mitochondrial dysfunction was alleviated after CCT treatment. Oil Red O staining of L02 cells and zebrafish showed that CCT treatment reversed the accumulation of lipid droplets . Conclusion In summary, CCT treatment effectively alleviated the symptoms of NAFLD and restored mitochondrial function in L02 cells and zebrafish NAFLD model.
研究领域:
药理学
·
分子生物学
·
细胞生物学
·
民族药理学
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代谢组学
·
病理生理学
✓ 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）