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  • 1
    In: Journal of Experimental & Clinical Cancer Research, Springer Science and Business Media LLC, Vol. 40, No. 1 ( 2021-12)
    Abstract: Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.
    Type of Medium: Online Resource
    ISSN: 1756-9966
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2430698-8
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  • 2
    In: Cell Death & Disease, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-01-04)
    Abstract: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for the majority of breast cancer-related death. Due to the lack of specific therapeutic targets, chemotherapeutic agents (e.g., paclitaxel) remain the mainstay of systemic treatment, but enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs); thus development of a new and effective strategy for TNBC treatment is an unmet medical need. Cancer nanomedicine has transformed the landscape of cancer drug development, allowing for a high therapeutic index. In this study, we developed a new therapy by co-encapsulating clinically approved drugs, such as paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is a drug used in the treatment of macular degeneration and has recently been found to inhibit the Hippo/YAP (Yes-associated protein) pathway, which is known to promote the progression of breast cancer and the development of CSCs. CA4 is a vascular disrupting agent and has been tested in phase II/III of clinical trials. We found that our new three drug-NP not only effectively inhibited TNBC cell viability and cell migration, but also significantly diminished paclitaxel-induced and/or CA4-induced CSC enrichment in TNBC cells, partially through inhibiting the upregulated Hippo/YAP signaling. Combination of verteporfin and CA4 was also more effective in suppressing angiogenesis in an in vivo zebrafish model than single drug alone. The efficacy and application potential of our triple drug-NPs were further assessed by using clinically relevant patient-derived xenograft (PDX) models. Triple drug-NP effectively inhibited the viability of PDX organotypic slide cultures ex vivo and stopped the growth of PDX tumors in vivo. This study developed an approach capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.
    Type of Medium: Online Resource
    ISSN: 2041-4889
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2541626-1
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  • 3
    In: Advanced Therapeutics, Wiley, Vol. 3, No. 11 ( 2020-11)
    Abstract: Triple negative breast cancer (TNBC) accounts for the majority of breast cancer‐related deaths and remains the hardest breast cancer to treat due to the lack of specific therapeutic targets. While chemotherapy is the mainstay of systemic treatment for TNBC, it is associated with chemotherapy‐induced cancer stem cells (CSCs) and tumor regeneration. Here, it is found that Wnt and YAP target genes that have been closely associated with CSCs are highly expressed in TNBC patient tumors and negatively correlated with patient survival. Therefore, a nanotherapeutic strategy is employed, using nanomaterials that are approved by the FDA, and two co‐delivery nanoparticle platforms (NPs) are developed to target TNBC. These NPs contain Wnt inhibitor PRI‐724 (in clinical trials) and YAP/mevalonate inhibitor simvastatin (FDA‐approved). Toward clinical translation, nanotherapeutic efficacy is assessed in clinically relevant patient‐derived xenograft (PDX) models. These NPs in combination with the chemotherapeutic drug paclitaxel effectively halt the growth of both paclitaxel‐resistant and paclitaxel‐sensitive PDX tumors, and diminish the paclitaxel‐induced CSC enrichment around two to fourfold. Importantly, NPs also decrease the paclitaxel‐enhanced PDX tumorigenesis after secondary transplantation. Together, this study demonstrates the efficacy of two NP platforms using clinically translatable TNBC PDX models, suggesting their application potential for the treatment of TNBC.
    Type of Medium: Online Resource
    ISSN: 2366-3987 , 2366-3987
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2920320-X
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  • 4
    In: Clinical and Translational Medicine, Wiley, Vol. 11, No. 8 ( 2021-08)
    Type of Medium: Online Resource
    ISSN: 2001-1326 , 2001-1326
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2697013-2
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2018
    In:  Scientific Reports Vol. 8, No. 1 ( 2018-05-16)
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-05-16)
    Abstract: To enhance our understanding of molecular mechanisms and mine novel biomarkers of non-alcoholic fatty liver disease (NAFLD), RNA sequencing was performed to gain hepatic expression profiles of mRNAs and miRNAs in NAFLD and normal rats. Using DESeq with thresholds of a two-fold change and a false discovery rate (FDR) less than 0.05, 336 mRNAs and 21 miRNAs were identified as differentially expressed. Among those, 17 miRNAs (e.g., miR-144-3p, miR-99a-3p, miR-200b-3p, miR-200b-5p, miR-200c-3p, etc .) might serve as novel biomarkers of NAFLD. MiRNA target genes (13565) were predicted by the miRWalk database. Using DAVID 6.8, the intersection (195 genes) of differentially expressed mRNAs and miRNA-predicted target genes were enriched in 47 gene ontology (GO) terms and 28 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Using Cytoscape, pathway interaction and protein-protein interaction (PPI) networks were constructed, and hub genes (e.g., Abcg8, Cyp1a1, Cyp51, Hmgcr, etc .) associated with NAFLD were obtained. Moreover, 673 miRNA-mRNA negative regulatory pairs were obtained, and networks were constructed. Finally, several representative miRNAs and mRNAs were validated by real-time qPCR. In conclusion, potential molecular mechanisms of NAFLD could be inferred from integrated analysis of mRNA and miRNA profiles, which may indicate novel biomarkers of NAFLD.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 6
    Online Resource
    Online Resource
    Wiley ; 2022
    In:  Cochrane Database of Systematic Reviews Vol. 2022, No. 5 ( 2022-05-31)
    In: Cochrane Database of Systematic Reviews, Wiley, Vol. 2022, No. 5 ( 2022-05-31)
    Type of Medium: Online Resource
    ISSN: 1465-1858
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2038950-4
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  • 7
    In: Biomedicine & Pharmacotherapy, Elsevier BV, Vol. 160 ( 2023-04), p. 114319-
    Type of Medium: Online Resource
    ISSN: 0753-3322
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 1501510-5
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  • 8
    In: Biomedicine & Pharmacotherapy, Elsevier BV, Vol. 121 ( 2020-01), p. 109617-
    Type of Medium: Online Resource
    ISSN: 0753-3322
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1501510-5
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  • 9
    In: Evidence-Based Complementary and Alternative Medicine, Hindawi Limited, Vol. 2021 ( 2021-1-8), p. 1-14
    Abstract: Objective. This study aims to explore the therapeutic efficacy of San Zi Yang Qin Decoction (SZ) and its potential mechanism in the treatment of non-alcoholic fatty liver disease (NAFLD) based on network pharmacology and in vivo experiments. Methods. Effective chemicals and targets of SZ were searched in online databases, according to the drug-likeness of compounds and the binomial distribution of targets. A disease-target-chemical network was established using NAFLD-associated genes screened through GeneCards database, Gene Ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, animal experiments were conducted to verify the efficacy and mechanism of SZ predicted by network pharmacology. The NAFLD mouse model was established with C57BL/6J mice fed with a high-fat diet for 22 weeks. The mice in the control group were fed with a chow diet. From the 23rd week, the NAFLD mice were treated with intragastric SZ or normal saline for 8 weeks. After the glucose tolerance was measured, the mice were sacrificed, followed by the collection of serum and liver tissues. Pathological changes in liver tissues were examined by H & E staining. Additionally, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum fast blood glucose, and insulin levels were detected. Expression levels of TNF-α of serum and liver tissues were determined by ELISA and qRT-PCR, respectively. Western blot was used to detect the activation of AKT in liver tissues. Results. A total of 27 effective compounds and 20 targets of SZ were screened. GO analysis uncovered a significant correlation between the targets of SZ and those of NAFLD. KEGG analysis presented the signaling pathways enriched in SZ and NAFLD, including NAFLD, TNF-α, and apoptosis pathways. The area under the curve of major GO and KEGG pathways indicated the potential role of SZ in improving NAFLD. In vivo experiments demonstrated that SZ significantly alleviated hepatosteatosis and inflammatory cell infiltration in liver tissues, reduced serum transaminases, and improved insulin resistance and glucose tolerance of NAFLD mice. The protein level of phospho-AKT was upregulated by SZ. Additionally, SZ treatment obviously impaired the TNF-α level in the serum and liver tissue of NAFLD mice. Conclusions. According to the network pharmacology analysis and in vivo experiments, SZ could have therapeutic efficacy for NALFD. The mechanism mainly involves pathways relative to insulin resistance, TNF-α, and apoptosis. Our results provide a scientific basis for SZ in the clinical treatment of NAFLD.
    Type of Medium: Online Resource
    ISSN: 1741-4288 , 1741-427X
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2021
    detail.hit.zdb_id: 2148302-4
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  • 10
    Online Resource
    Online Resource
    Hindawi Limited ; 2022
    In:  Evidence-Based Complementary and Alternative Medicine Vol. 2022 ( 2022-1-7), p. 1-15
    In: Evidence-Based Complementary and Alternative Medicine, Hindawi Limited, Vol. 2022 ( 2022-1-7), p. 1-15
    Abstract: Background. There is still a lack of effective therapeutic drugs for nonalcoholic fatty liver disease (NAFLD) to date. In this study, we applied mouse model experiments to clarify the effect of Chinese herbal medicine “Lanzhang Granules (LZG)” on NAFLD and further explore the potential mechanism to provide an alternative method for NAFLD treatment. Methods. Male C57BL/6J mice were fed with a high-fat diet (HFD) for twenty-two weeks to induce the NAFLD model. LZG intervention was then performed by gavage daily for another eight weeks. At the end of the treatment, serum and liver tissues were collected. Serum biochemical indexes, insulin levels, and liver histopathology were measured to assess the effect of LZG on NAFLD. The liver tissues were then analyzed by RNA sequence for differentially expressed genes and signaling pathways. Results were further analyzed by Protein-Protein Interaction (PPI) networks between the LZG and model groups. The selected different genes and signaling pathways were further verified by RT-PCR and Western blot analysis. Moreover, alpha mouse liver 12 (AML12) cells with lipid accumulation induced by fatty acid were treated with LZG, Fenofibrate (PPARα agonist), or Gw6471 (PPARα antagonist) to confirm the potential pharmacological mechanism. Results. LZG was found to downregulate liver weight, body weight, liver index, and serum levels of ALT, AST, and serum lipid in HFD-induced NAFLD mice. HE and Oil Red O staining showed the improvement of hepatic steatosis and inflammatory infiltration in the mice with LZG treatment. The homeostasis model assessment-insulin resistance (HOMA-IR) index indicated that LZG improved the insulin resistance of NAFLD mice. The RNA sequencing and PPI analysis confirmed the role of LZG in lipid metabolism regulation and identified the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway as one of the major underlying mechanisms. Western blot and RT-PCR results verified the regulatory effect of LZG on the PPARα pathway, including the upregulation of PPARα, acyl-coenzyme A oxidase 1 (ACOX1), and enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase (EHHADH) and the downregulation of TNFα. In vitro experiments showed the effect of LZG in improving lipid accumulation and cell viability in AML12 cells induced by fatty acids, which were alleviated by Gw6471 coincubation. Gw6471could also reverse the transcription of PPAR target genes ACOX1 and EHHADH, which were upregulated by LZG treatment. Conclusion. LZG can improve NAFLD in mice or cell models. A major underlying mechanism may be the regulation of the PPARα signaling pathway to improve lipid metabolism and inhibit the inflammatory response. This study will help to promote the clinical application of LZG for the treatment of NAFLD.
    Type of Medium: Online Resource
    ISSN: 1741-4288 , 1741-427X
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2022
    detail.hit.zdb_id: 2148302-4
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