CELL BIOLOGY INTERNATIONAL
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2018
·Vol. 42
·期 8
·994-1005
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IF 1.936
Kuiyuan Song,Guanqun Zheng,Yue Zhao
Lung cancer is one of life-threatening cancers in the worldwide. Liver kinase B1 (LKB1) has been reported to be closely related to cancers; however, the underlying mechanism of LKB1 in lung cancer remains unclear. In our study, a LKB1 specific shRNA was employed to down-regulate LKB1 levels and a LKB1 over-expression plasmid was constructed to up-regulate LKB1 levels. Thereafter, growth of lung cancer cells was assessed by MTT assay and flow cytometry. Effects of LKB1 on the activation of sonic hedgehog (Shh) signaling pathway were detected by Western blot. Effects of LKB1 on lung cancer growth and Shh signaling pathway activation were also assessed in vivo. Our results showed that LKB1 inhibited proliferation of lung cancer cells and induced their apoptosis. Moreover, LKB1 inhibited Shh signaling pathway activation. Our in vivo study also showed that LKB1 inhibited lung cancer growth in vivo and modulated Shh signaling pathway. Treatment with cyclopamine, a Shh signaling pathway inhibitor, reversed the effects of LKB1 silencing and enhanced the effects of LKB1 over-expression. Results of our study demonstrate that LKB1 inhibits lung cancer growth in vitro and in vivo through Shh signaling pathway.
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
JOURNAL OF CONTROLLED RELEASE
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2022
·
IF 11.467
Qian Chen,Yanan Li,Shuai Zhou,Dali Chen,Muye Zhou,Qinying Chen,Yuren Lu,Naicong Cai,Can Liu,Yumeng Guo,Zijie Qiu,Xiaoyan Hou,Jiasheng Tu,Weiyang Shen,Chunmeng Sun
Postsurgical treatment is of great importance to combat tumor recurrence and metastasis. Anti-CD47 antibodies (aCD47) can block the CD47-signal regulatory protein-alpha (CD47-SIRPα) pathway to restore immunity. Here, an in-situ gel implantation was engineered by crosslinking chitosan (CS) and pullulan (Pul) for postsurgical treatment. A highly selected chemotherapeutic, cyclopamine (Cyc), encapsulated in liposomes (Cyc-Lip) was co-loaded with aCD47 in gels for chemoimmunotherapy. Importantly, a sequential drug release kinetics can be achieved. Nanotherapeutics were confirmed to be released prior to aCD47 in a burst-release manner, which was benefit for immediately killing residual tumor cells followed by releasing tumor antigens . Meanwhile, aCD47 was released in a sustained-release manner to restore macrophage functions and exert anti-tumor immune responses. Afterwards, the efficacy of in-situ chemoimmunotherapy was confirmed on 4T1 mouse breast cancer models, which could not only efficiently augment anti-tumor effect to inhibit tumor recurrence but also establish a long-term immune memory to combat tumor metastasis.
研究领域:
肿瘤学
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生物材料学
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免疫学
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DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2023
·
IF 4.7
Ju Li,Jinmei Zuo,Xiaoyan Lv,Jiahe Ma,Xiaohong Li,Simiao Fu,Jinsheng Sun
Tissue autotomy is a unique adaptive response to environmental stress, followed by regeneration process compensating for the loss of body parts. The crustaceans present remarkable activity of appendage autotomy and regeneration, however, the molecular mechanism is still unclear. In this study, the Eriocheir sinensis Hedgehog ( EsHH ) and Smoothened ( EsSMO ) were identified in the regenerative limbs, and the function of Hedgehog signaling pathway on limb regeneration was evaluated. At the blastema growth stage of limb regeneration, the expression of EsHH and EsSMO was up-regulated in response to limb autotomy stress, and down-regulated at blastema differentiation stage. To clarify the effect of Hedgehog pathway during limb regeneration, the regenerative efficiency was evaluated with Smoothened inhibitor cyclopamine or RNAi ( ds-HH ) injection. We observed that the regenerative efficiency was significantly repressed with blockage of Hedgehog pathway at both the basal growth stage and the proecdysial growth stage, which was indicated by the delay of wound healing and blastema growth, as well as a decrease in the size of newly formed limbs. In addition, gene expression and BrdU incorporation assay showed that the proliferation and myogenic differentiation of blastema cells were suppressed with either cyclopamine or ds- HH injection. Thus, these results suggest that Hedgehog signaling pathway is essential for the establishment of limb regeneration in E. sinensis through promoting the proliferation and myogenic differentiation of blastema cells.
研究领域:
发育生物学
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分子生物学
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再生医学
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
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2018
·Vol. 6
·期 12
·1834-1843
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IF 4.776
Chan Feng,Kun Wang,Yun Lin,Zhiwang Song,Yonglin Lu,Jie Liu,Donglei Zhu,Yongyong Li,Chunyan Dong
Compared with intracellular drug delivery, drugs with extracellular targeting sites are rarely considered. As one of these drugs, cyclopamine (CYC) is a promising anticancer drug that functions by targeting the cell membrane receptor. For improving therapeutic effect, an albumin-based nano-system (ABN) with the capacity for extracellular retention was developed. The ABN was formulated by incorporating bovine serum albumin (BSA) into nanoparticles at the denaturing temperature of BSA, with CYC acting as a hydrophobic nucleation site, followed by stabilization upon heat-induced disulfide cross-linking. The resultant ABNs are negatively charged with a nanoparticle size that can be delicately regulated by varying the reaction time. In MDA-MB-231 cells, the size and charge of ABNs significantly affected the extracellular retention capacity, with ABN-300 nm exhibiting an enhanced cytotoxic effect. In vivo fluorescence imaging revealed obvious and persistent tumor accumulation of ABNs. A therapeutic study in an orthotopic mammary fat pad tumor model shows that ABN-300 nm possesses the most remarkable antitumor effect compared with the control groups. These results provide a new strategy for improving the efficacy of drug targeting at extracellular sites.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2023
·
IF 5.1
Huanxian Wu,Lishun Zhang,Boyu Chen,Baofang Ou,Jiahuan Xu,Nannan Tian,Danni Yang,Yangcheng Ai,Qianqing Chen,Dongling Quan,Tingting Zhang,Lin Lv,Yuanxin Tian,Jiajie Zhang,Shaoyu Wu
Abnormal activation of Hedgehog (Hh) signaling pathway mediates the genesis and progression of various tumors [1] . Currently, three drugs targeting the Hh signaling component Smoothened (Smo) have been marketed for the clinical treatment of basal cell tumors or acute myeloid leukemia. However, drug resistance is a common problem in those drugs, so the study of Smo inhibitors that can overcome drug resistance has important guiding significance for clinical adjuvant drugs. MTT assay, clone formation assay and EdU assay were used to detect the proliferation inhibitory activity of the drugs on tumor cells. The effect of B13 on cell cycle and apoptosis were detected by flow cytometry. An acute toxicity test was used to detect the toxicity of B13 in vivo , and xenograft tumor model was used to detect the efficacy of B13 in vivo . The binding of B13 to Smo was studied by BODIPY-cyclopamine competitive binding assay and molecular docking. The effect of B13 on the expression and localization of downstream target gene Gli1/2 of Smo was investigated by Western Blot and immunofluorescence assay. Smo D473H mutant cell line was constructed to study the effect of B13 against drug resistance. (1) B13 had the strongest inhibitory activity against colorectal cancer cells. (2) B13 can effectively inhibit the clone formation and EdU positive rate of colon cancer cells. (3) B13 can block the cell cycle in the G2/M phase and cell apoptosis. (4) B13 has low toxicity in vivo , and its efficacy in vivo is better than that of the Vismodegib. (5) Molecular docking and BODIPY-cyclopamine experiments showed that B13 could bind to Smo protein. (6) B13 can inhibit the protein expression of Gli1, the downstream of Smo, and inhibit its entry into the nucleus. (7) B13 could inhibit the expression of Gli1 in the HEK293 cells with Smo D473H , and the molecular docking results showed that B13 could bind Smo D473H protein. B13 with the best anti-tumor activity was screened out by MTT assay. In vitro , pharmacodynamics experiments showed that B13 could effectively inhibit the proliferation and metastasis of colorectal cancer cells, induce cell cycle arrest, and induce cell apoptosis. In vivo pharmacodynamics experiments showed that B13 was superior to Vismodegib in antitumor activity and had low toxicity in vivo . Mechanism studies have shown that B13 can bind Smo protein, inhibit the expression of downstream Gli1 and its entry into the nucleus. Notably, B13 overcomes resistance caused by Smo D473H mutations.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
·
IF 3.118
Tingting Lv,Lei Shen,Lei Yang,Wenxiu Diao,Zhenming Yang,Ying Zhang,Shijie Yu,Yanxia Li
Background Inflammation, oxidative stress and epithelial barrier dysfunction have been implicated in inflammatory bowel disease (IBD) pathology. The targeted inhibition of these features may represent a promising therapeutic strategy for IBD. Polydatin is an effective natural antioxidant that possesses strong antioxidant and anti-apoptotic properties. Thus, we studied the protective effects of polydatin treatments on a mouse model of experimental colitis . Methods Acute colitis was experimentally induced by adding 3% dextran sulfate sodium (DSS) to the drinking water provided to mice for 7 days and by administering different doses of polydatin (15, 30, or 45 mg/kg) during the same period. Mice were also treated with the Sonic hedgehog (Shh) pathway inhibitor cyclopamine to estimate the efficacy of polydatin and Shh inhibitors on colitis. The disease activity index (DAI), colon length, histology, levels of oxidative and apoptotic mediators and levels of Shh pathway components were evaluated. Results The polydatin treatment significantly attenuated the DAI, colon shortening and histological damage. In addition, polydatin administration effectively decreased malondialdehyde (MDA) levels and increased the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Polydatin also inhibited apoptosis in mice with colitis by downregulating the expression of the pro-apoptotic proteins Bax , caspase 3 and cleaved caspase 3 and increasing the expression of the anti-apoptotic protein Bcl-2. Furthermore, polydatin modulated Shh signaling pathway activation. After polydatin treatment, the main components of the Shh pathway, including Shh, Patched (Ptc), Smoothened (Smo), and glioblastoma-1 (Gli1), were upregulated at the mRNA and protein levels. Blockade of the Shh pathway using cyclopamine abolished the effects of polydatin on mice with colitis. Conclusion Based on these observations, polydatin may suppress experimental colitis at least partially by regulating the Shh signaling pathway.
研究领域:
药理学
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免疫学
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病理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2018
·Vol. 15
·期 5
·4284-4290
·
IF 1.41
Sha Feng,Jue Liu,Biao Cheng,Aiping Deng,Hong Zhang
It has been acknowledged that environmental stress is a risk factor for developing mental disorders. Chronic stress may contribute to the hyperactivation of the hypothalamic‑pituitary‑adrenal (HPA) axis and a sustained rise in the levels of glucocorticoids (GCs). A high concentration of corticosterone (CORT) damages neuronal PC12 cells. It has been reported that (‑)‑Epigallocatechin‑3‑gallate (EGCG), a major component of green tea, exhibits neuroprotective activity. However, the protective effect of EGCG on neuronal cells injured by CORT remains to be elucidated. The present study aimed to identify the effects of EGCG on CORT‑injured neuronal PC12 cells and its associated mechanisms of action. CORT‑injured PC12 cells were pretreated with EGCG with or without cyclopamine. Cell viability was assessed using an MTT assay, changes in cell morphology were observed using phase‑contrast microscopy, cellular apoptosis was assessed by Hoechst 33342 staining, cell proliferation was measured using a cell counting kit‑8 assay, mRNA levels were measured by reverse transcription‑quantitative polymerase chain reaction and protein expression was assessed using western blot analysis. The current study demonstrated that exposure to high concentrations of CORT induced cytotoxicity and downregulated the Sonic hedgehog pathway (Shh) in PC12 cells. These effects were attenuated by EGCG. However, the EGCG‑mediated neuroprotective effects, as well as upregulation of the Shh pathway were all attenuated by the Shh signaling inhibitor cyclopamine. These results indicate that EGCG protects PC12 cells from CORT‑induced neurotoxicity via activation of the Shh signaling pathway.
研究领域:
神经科学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
Journal of Cell Communication and Signaling
·
2023
·
IF 4.1
Zhao Ye,Wang Huiling,He Tianhua,Ma Bo,Chen Guoguang,Tzeng Chimeng
Liver fibrosis is an aberrant wound healing response to tissue injury characterized by excessive extracellular matrix deposition and loss of normal liver architecture. Hepatic stellate cells (HSCs) activation is regards to be the major process in liver fibrogenesis which is dynamic and reversible. Both Hippo signaling core factor Yap and Hedgehog (Hh) signaling promote HSCs transdifferentiation thereby regulating the repair process of liver injury. However, the molecular function of YAP and the regulation between Yap and Hh during fibrogenesis remain uncertain. In this study, the essential roles of Yap in liver fibrosis were investigated. Yap was detected to be increased in liver fibrotic tissue by the thioacetamide (TAA)-induced zebrafish embryonic and adult models. Inhibition of Yap by both embryonic morpholino interference and adult’s inhibitor treatment was proved to alleviate TAA-induced liver lesions by and histology and gene expression examination. Transcriptomic analysis and gene expression detection showed that Yap and Hh signaling pathway have a cross talking upon TAA-induced liver fibrosis. In addition, TAA induction promoted the nuclear colocalization of YAP and Hh signaling factor GLI2α. This study demonstrates that Yap and Hh play synergistic protective roles in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression. Graphical abstract
研究领域:
分子生物学
·
肝病学
·
细胞信号传导
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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）