PHYTOMEDICINE
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2023
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IF 7.9
Anni Zhu,Zhiguang Duan,Yanru Chen,Chenhui Zhu,Daidi Fan
Background The aging of skeletal muscle is the leading cause of physical disability in older adults, currently effective treatment methods are lacking. Ginsenoside Rh4, an active component extracted from ginseng , possesses beneficial anti-inflammatory and anti-oxidative effects. Purpose The aim of this study was to elucidate the antioxidant effect of ginsenoside Rh4 on aging skeletal muscle and its molecular mechanism of anti-aging of skeletal muscle. Study design In this study, we employed a D-galactose-induced model of skeletal muscle aging to investigate whether ginsenoside Rh4 can delay the process of skeletal muscle senescence. Methods The effects of ginsenoside Rh4 on oxidative damage and inflammation in aging skeletal muscle were analyzed using immunofluorescence, immunohistochemistry , ELISA kits, H&E staining, flow cytometry, and protein immunoblotting . The changes of ginsenoside Rh4 on mitochondrial morphology were observed by transmission electron microscopy , and ELISA kits and protein immunoblotting analyzed the effects of ginsenoside Rh4 on mitochondrial homeostasis in skeletal muscle cells . The influence of ginsenoside Rh4 on the SIRT1 signaling pathway in aging skeletal muscle were investigated by protein immunoblotting, immunofluorescence, and β-galactosidase staining. Results Our results showed that Rh4 improved the morphology of muscle fibers and produced an anti-inflammatory response. Furthermore, in vitro experiments indicated that ginsenosides reduced the production of senescent cells, while Rh4 effectively alleviated oxidative damage in skeletal muscle and restored mitochondrial balance. Transcriptome analysis and molecular docking showed that Rh4 improved mitochondrial homeostasis and delayed skeletal muscle aging by regulating the PGC-1α-TFAM and HIF-1α-c-Myc pathways via targeting SIRT1. Conclusion Ginsenoside Rh4 improves oxidative stress and inflammation in skeletal muscle by activating SIRT1, deacetylating Nrf2, regulating PGC-1α-TFAM and HIF-1α-c-Myc pathways, and enhancing mitochondrial homeostasis, thus achieving the effect of delaying skeletal muscle aging.
研究领域:
药理学
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老年学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2019
·Vol. 34
·期 4
·817-824
·
IF 3.766
Mingming Zhu,Xi Yu,Zongmei Zheng,Jiaming Huang,Xuepan Yang,Hongfei Shi
Cancer stem cells (CSCs) are considered as the origin and driving cells of cancer, and play a key role in the progress of cancer. Studies have shown that capsaicin exerted inhibitory effect on prostate cancer cells, however, the effects of capsaicin on prostate CSCs remain undefined. In the present study, we showed that capsaicin could downregulate prostate CSCs markers and inhibit the growth of PC-3 and DU145 prostate cancer stem cells. Further, we found capsaicin suppressed the expression of Wnt-2, p-GSK3β and β-catenin, along with downregulation of Wnt/β-catenin pathway target genes c-myc and cyclinD1. Using LiCl, a activator of Wnt/β-catenin pathway, we found activation of Wnt/β-catenin pathway could ameliorate the downregulation of prostate CSCs markers and the growth inhibition induced by capsaicin in prostate cancer stem cells. Those data suggested that the inhibition effect of capsaicin on prostate cancer stem cells and the anti-cancer effect of capsaicin on prostate cancer stem cell may be mediated by Wnt/β-catenin pathway. Findings from this study reveals for the first time the potential role and mechanisms of capsaicin on prostate cancer stem cells.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
DRUG RESISTANCE UPDATES
·
2024
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IF 15.8
Dajun Gao,Yanting Shen,Lingfan Xu,Yi Sun,Hailiang Hu,Bin Xu,Zhong Wang,Huan Xu
Aims Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC). Methods We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies. Results The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume. Conclusion Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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前列腺癌
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激素治疗
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2024
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IF 4.5
Kai Wang,Meixu Jiang,Huimin Liu,Chen Meng,Mengyuan Li,Haibin Lu
Reactivating p53 activity to restore its anticancer function is an attractive cancer treatment strategy. In this study, we designed and synthesized a series of novel PROTACs to reactivate p53 via the co-degradation of CK1α and CDK7/9 proteins. Bioactivity studies showed that the selected PROTAC 13i exhibited potency antiproliferative activity in MV4-11 (IC 50 = 0.096 ± 0.012 μM) and MOLM-13 (IC 50 = 0.072 ± 0.014 μM) cells, and induced apoptosis of MV4-11 cells. Western-blot analysis showed that PROTAC 13i triple CK1α and CDK7/9 protein degradation resulted in the significantly increased expression of p53. At the same time, the transcriptional repression due to the degradation significantly reduced downstream gene expression of MYC, MDM2, BCL-2 and MCL-1, and reduced the inflammatory cytokine levels of TNF-α, IL-1β and IL-6 in PMBCs. These results indicate the beneficial impact of simultaneous CK1α and CDK7/9 degradation for acute myeloid leukemia therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
OncoTargets and Therapy
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2023
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IF 4
Gang Wang,Yue Jing,Lingsen Cao,Changchang Gong,Zhunan Gong,Xiangrong Cao
Activation of the transcription factor, signal transducers and activators of transcription 3 (STAT3), has been linked to the proliferation and migration of a variety of human cancer cells. These actions occur via the upregulation or downregulation of cell survival and tumor suppressor genes, respectively. Importantly, agents that can suppress STAT3 activation have the potential for use in the prevention and treatment of various cancers. In this study, an Asiatic acid (AA) derivative, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), is reported to dose dependently suppress constitutive STAT3 activation in gastric cancer cells. This inhibition was mediated by blockade of Janus-activated kinase 2. Additionally, AA-PMe regulated the expression of STAT3-modulated gene products, including cyclin D1, Bax, Bcl-2, c-Myc, and matrix metalloproteinase (MMP)-2 and MMP-9. Finally, transfection with both a STAT3 mimic and an inhibitor reversed the AA-PMe-driven modulation of STAT3 downstream gene products. Overall, these results suggest that AA-PMe is a novel blocker of STAT3 activation and has the potential for the prevention and treatment of gastric cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
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2024
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IF 5.3
Liangrui Lv,Wei Yuan,Juanjuan Hu,Xuyuan Chen,Tingting Zhang,Jie Cheng,Xiaoying Wang
Protein tumor marker (PTM) analysis is of great significance for the early diagnosis and process monitoring of tumors. However, the clinical reference value of a single PTM is restricted, and existing tests for multiple PTMs majorly suffer from complex processes and poor sensitivity. Herein, a cancerous inhibitor of protein phosphatase 2A (CIP2A) and protein c-Myc (AGc-Myc) with a positive feedback path in oral squamous cell carcinoma (OSCC) was chosen as a dual PTM, and a magnetic electrochemical immunosensor (MEI) for their simultaneous detection was successfully established. Fe3O4 coated with a gold nanoparticle (MAu)-functionalized magnetic electrode (f-MGE) was of benefit to immobilize two capture antibodies (CAb) through internal forces and external magnetic fields. By a mechanical alloying (MA) method, two photoelectric materials osmosed bimetallic-matrix nanospheres (Bi-MPE), including luminol and Ru(bpy)32+ osmosed AuNPs–AgNPs nanoalloy (Lu@AuAg and Ru@AuAg), were prepared as innovative signal probes. Lu@AuAg and Ru@AuAg not only exhibit superior electrochemical properties than photoelectric material osmosed monometallic-matrix nanospheres but can directly label detection antibodies (DAb) without complex reaction conditions and additional functionalization. After immunological reactions, the distinguishable differential voltammetry pulse signals were obtained at +0.48 and +1.13 V, corresponding to AGc-Myc and CIP2A, respectively. The proposed assay showed a good linear response range from 5 pg L–1 to 5 ng L–1 for AGc-Myc and 50 pg L–1 to 50 ng L–1 for CIP2A, and a low limit of detection of 2.5 pg L–1 and 25 pg mL–1, respectively. The MEI also exhibited satisfactory selectivity, stability, and reproducibility. Moreover, when the proposed method and the ELISA kit were simultaneously applied to saliva samples of OSCC patients, the obtained results were completely consistent, reflecting the clinical practicability of this work.
研究领域:
生物化学
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生物技术
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分析化学
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医学诊断
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纳米技术
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电化学
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癌症研究
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产品关联
DOI
高影响因子
Cell Death Discovery
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2024
·Vol. 10
·期 1
·1-16
·
IF 6.1
Liu Zhaohong,Xiang Peng,Zeng Shengmei,Weng Ping,Wen Yilin,Zhang Wanping,Hu Hui,Zhao Dezhang,Ma Limei,Yu Chao
Vascular endothelial injury initiates atherosclerosis (AS) progression. N -Acetylneuraminic acid (Neu5Ac) metabolic disorder was found to intensify endothelial mitochondrial damage. And GLS2-associated glutaminolysis disorder contributed to mitochondrial dysfunction. However, mechanisms underlying Neu5Ac-associated mitochondrial dysfunction as well as its association with GLS2 remains unclear. In this study, we constructed GLS2 −/− ApoE −/− mice by using HBLV-GLS2 shRNA injection. And methods like immunofluorescence, western blotting, transmission electron microscopy were applied to detect profiles of endothelial injury and AS progression both in vivo and in vitro. We demonstrated that Neu5Ac accumulation increased GLS2 expression and promoted glutaminolysis disorder, which further induced endothelial mitochondrial dysfunction via a pyroptosis-dependent pathway in vivo and in vitro. Mechanically, Neu5Ac interacted with SIRT3 and led to FOXO3a deacetylation and phosphorylation, further facilitated c-Myc antagonism and ultimately increased GLS2 levels. Inhibition of GLS2 could improve mitochondrial function and mitigate pyroptosis process. In addition, blocking Neu5Ac production using neuraminidases (NEUs) inhibitor could rescue endothelial damage and alleviate AS development in ApoE −/− mice. These findings proposed that Neu5Ac induced GLS2-mediated glutaminolysis disorder and then promoted mitochondrial dysfunction in a pyroptosis-dependent pathway. Targeting GLS2 or inhibiting Neu5Ac production could prevent AS progression.
研究领域:
心血管疾病
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分子生物学
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细胞生物学
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病理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2024
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IF 3.3
Zhen Xu,Yilin Guo,Lu Wang,Jinquan Cui
HECW1 belongs to ubiquitin ligase (E3) HECT family, and is found to be involved in tumorigenesis and tumor progression. However, the function of HECW1 in cervical cancer (CC) remains unknown. Clinical analysis showed that HECW1 is significantly decreased in CC tumor tissues. Ectopic expression of HECW1 suppressed cell growth, promoting cell cycle arrest and apoptosis in CC cells, while downregulation of HECW1 reversed these trends, impeded proliferation and accelerated cell cycle progression of CC cells. Overexpressing of HECW1 reduced mitochondrial membrane potential and the protein expression of voltage-dependent anion channel 1 (VDAC1). In addition, upregulation of HECW1 inhibited nuclear β-catenin accumulation, downregulated β-catenin/TCF/LEF-mediated transcriptional activity and the expression of downstream gene c-Myc, whereas inhibition of HECW1 received opposite results. Further results confirmed HECW1 affects the protein expression of dishevelled-1 (DVL1), a potent activator of Wnt/β‐catenin, and inhibition of HECW1 inhibited the ubiquitination of DVL1, upregulating its expression. Inhibition of DVL1 restrained the promotion effect of HECW1 suppression on cell proliferation. In vivo experiments also verified that HECW1 suppression promoted the tumor formation of CC cells. Summary, we demonstrated that HECW1 inhibits CC cell proliferation and tumor formation by downregulating DVL1 induced Wnt/β‐catenin signaling pathway activation.
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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产品关联
DOI
PubMed
高影响因子
INDUSTRIAL CROPS AND PRODUCTS
·
2022
·
IF 6.449
Shu Diao,Yini Zhang,Qifu Luan,Xianyin Ding,Jiaming Sun,Jingmin Jiang
Oleoresin terpenoids have been widely used in the food , pharmaceutical, and chemical industries. A thorough understanding of oleoresin terpenoid biosynthesis is important for the metabolic engineering of high-valued terpenoid products in plants and microbes and the improvement of oleoresin traits using molecular breeding strategies. TPS-d subfamily members, specific to conifers, determine the oleoresin terpenoid compound diversity. Here, we aimed to identify the TPS-d genes in slash pine ( Pinus elliottii ) and characterize their function and expression patterns in population. Our study reveals two main results: (1) A total of 52 terpene synthase (TPS) candidate genes were identified based on long-read transcripts of slash pine, 12 of which were successfully cloned from the secondary developing xylem RNA. Two levopimaradiene/abietadiene synthases (LAS), one monofunctional isopimaradiene synthase (mISO1)-like, and two α-pinene synthases were identified by comparing with previously known TPS. Next, the two α-pinene synthases and one β-pinene synthase producing multiple products were validated through heterologous expression and in vitro enzyme activity assays, which showed different product profiles from previously identified TPS. (2) The expression status of the cloned TPS genes in 240 slash pine individuals were analyzed. Four exhibited very low expression levels, including those identical to copalyl diphosphate synthases, hemiterpene synthases, diterpene synthases without activity, and one obtained without soluble protein in the heterologous expression. The expression levels of eight TPS genes participating in slash pine oleoresin biosynthesis varied in different individuals and were highly correlated with multiple transcriptional regulators, namely, MYB and MYC. The expression of two α-pinene synthase genes was significantly higher than that of the other TPS genes. Some TPS gene expression levels were positively correlated with the corresponding oleoresin component content. Our results provide an essential reference for exploring the mechanisms of terpene biosynthesis and regulation.
研究领域:
植物生物化学
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分子生物学
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遗传学
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代谢工程
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产品关联
DOI
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 8
·4567-4578
·
IF 5.882
Tianfeng Yang,Jian Huo,Rui Xu,Yanmin Zhang
Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β-catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.
研究领域:
肿瘤学
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药理学
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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
OncoTargets and Therapy
·
2022
·
IF 4.345
Yue Jing,Gang Wang,Ying Ge,Minjie Xu,Shuainan Tang,Zhunan Gong
Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
LABORATORY INVESTIGATION
·
2022
·Vol. 102
·期 5
·494-504
·
IF 5.502
Tao Lianyuan,Li Deyu,Mu Sengmao,Tian Guanjing,Yan Guoyi
We explored the biological role of long non-coding RNA (lncRNA) MAPKAPK5_AS1 (MAAS) and the mechanism of its differential expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Differentially expressed lncRNAs in HBV-related HCC were determined using bioinformatics analysis. Gain-of-function experiments were conducted to evaluate the effect of MAAS on cell proliferation. A xenograft model was established for in vivo experiments. Dual-luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and methylated RNA immunoprecipitation were performed to elucidate the underlying molecular mechanisms. MAAS was upregulated in HBV-related HCC cancerous tissues and its high expression was closely related to the poor survival probability of patients. Functional assays revealed that MAAS overexpression facilitated the proliferation of HBV + HCC cells in vitro and in vivo. Mechanistically, MAAS promoted the MYC proto-oncogene (c-Myc)-induced transcriptional activation of cyclin-dependent kinase 4 (CDK4), CDK6, and S-phase kinase associated protein 2 via stabilizing c-Myc protein, thereby facilitating G1/S transition. The latter contributed to the paradoxical proliferation of HBV + HCC cells. Although MAAS was upregulated in HBV-related HCC cancerous tissues, it was highly expressed in M2 macrophages, a major phenotype of tumor-associated macrophages in HBV-related HCC, instead of in HBV + HCC cells. HBeAg, an HBV-associated antigen, further elevated the MAAS level in M2 macrophages by enhancing the methyltransferase-like 3-mediated N6-methyladenosine modification of MAAS. The increased MAAS in the M2 macrophages was then transferred to HBV + HCC cells through the M2 macrophage-derived exosomes, promoting cell proliferation. Our findings show that HBV + HCC cell-secreted HBeAg upregulates MAAS expression in M2 macrophages by affecting its m 6 A modification. The upregulated MAAS is then transferred to HBV + HCC cells via exosomes, facilitating the proliferation of HBV + HCC cells by targeting c-Myc.
研究领域:
分子生物学
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肿瘤学
·
病毒学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）