scholarly journals Antiproliferative, Antiangiogenic, and Antimetastatic Therapy Response by Mangiferin in a Syngeneic Immunocompetent Colorectal Cancer Mouse Model Involves Changes in Mitochondrial Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Julio César Rodriguez-Gonzalez ◽  
Ivones Hernández-Balmaseda ◽  
Ken Declerck ◽  
Claudina Pérez-Novo ◽  
Emilie Logie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Mouse Model ◽  
Mangifera Indica ◽  
High Rate ◽  
Pathway Enrichment Analysis ◽  
Colon Cells ◽  
Mitochondrial Energy Metabolism

In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic immunocompetent allograft mouse model of murine CT26 colon carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits tumor growth, metastasis and angiogenesis by multi-targeting of mitochondrial oxidoreductase and fatty acid β-oxidation metabolism, PPAR, SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on fatty acid β-oxidation metabolism and carnitine palmitoyltransferase 1 (CPT1) protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

Abstract A54: Changes in fatty acid profile indicate a chemo-preventive response to navy bean extract in an inflammation-associated colorectal cancer mouse model

2016 ◽  
Author(s):  
Thushanthi H. Perera ◽  
Matthew R. Young ◽  
Shakir M. Saud ◽  
Christopher R. Dextras ◽  
Yava L. Jones-Hall ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acid ◽  
Mouse Model ◽  
Fatty Acid Profile ◽  
Navy Bean

scholarly journals Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism

2019 ◽  
Vol 20 (11) ◽  
pp. 2772 ◽  
Author(s):  
Consiglia Pacelli ◽  
Giovannina Rotundo ◽  
Lucia Lecce ◽  
Marta Menga ◽  
Eris Bidollari ◽  
...  
Keyword(s):  
Stem Cells ◽  
Quality Control ◽  
Energy Metabolism ◽  
Clock Genes ◽  
Expression Patterns ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Energy Metabolism ◽  
Tight Connection ◽  
Induced Pluripotent

Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.

scholarly journals SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Ying Yang ◽  
Jiaxing He ◽  
Bo Zhang ◽  
Zhansheng Zhang ◽  
Guozhan Jia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lipid Metabolism ◽  
Energy Metabolism ◽  
Cell Apoptosis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Growth And Survival ◽  
Metabolism Regulation

AbstractAbnormal lipid metabolism has been commonly observed in various human cancers, including colorectal cancer (CRC). The mitochondrial citrate carrier SLC25A1 (also known as mitochondrial citrate/isocitrate carrier, CIC), has been shown to play an important role in lipid metabolism regulation. Our bioinformatics analysis indicated that SLC25A1 was markedly upregulated in CRC. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in CRC remain unexplored. Here, we found that SLC25A1 expression was significantly increased in tumor samples of CRC as compared with paired normal samples, which is associated with poor survival in patients with CRC. Knockdown of SLC25A1 significantly inhibited the growth of CRC cells by suppressing the progression of the G1/S cell cycle and inducing cell apoptosis both in vitro and in vivo, whereas SLC25A1 overexpression suppressed the malignant phenotype. Additionally, we demonstrated that SLC25A1 reprogrammed energy metabolism to promote CRC progression through two mechanisms. Under normal conditions, SLC25A1 increased de novo lipid synthesis to promote CRC growth. During metabolic stress, SLC25A1 increased oxidative phosphorylation (OXPHOS) to protect protects CRC cells from energy stress-induced cell apoptosis. Collectively, SLC25A1 plays a pivotal role in the promotion of CRC growth and survival by reprogramming energy metabolism. It could be exploited as a novel diagnostic marker and therapeutic target in CRC.

scholarly journals 4-Acetyl-Antroquinonol B Suppresses SOD2-Enhanced Cancer Stem Cell-Like Phenotypes and Chemoresistance of Colorectal Cancer Cells by inducing hsa-miR-324 re-Expression

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 269 ◽  
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Ching-Kuo Yang ◽  
Wei-Hong Cheng ◽  
David T.W. Tzeng ◽  
Kuang-Tai Kuo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Aberrant Expression ◽  
Colon Cells ◽  
Colorectal Cancer Cells ◽  
Enhanced Expression ◽  
Polymerase Chain ◽  
Interfering Rna

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored. Experimental approach: In this present study, we employed relatively new bioinformatics approaches, analyses of microarray data, Western blot, real-time polymerase chain reaction (RT-PCR), and functional assays to show that hsa-miR-324-5p expression is significantly suppressed in CRC cells, and inversely correlates with the aberrant expression of SOD2. Results: This converse hsa-miR-324-5p/SOD2 relationship is associated with enhanced oncogenicity, which is effectively inhibited by 4-acetylantroquinonol B (4-AAQB), as evidenced by inhibited cell viability and proliferation, as well as attenuated migration, invasion, and clonogenicity in 4-AAQB-treated DLD1 and HCT116 cells. Interestingly, 4-AAQB did not affect the viability and proliferation of normal colon cells. We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins. Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo. Additionally, 4-AAQB synergistically potentiates the FOLFOX (folinate (leucovorin), fluorouracil (5FU), and oxaliplatin) anticancer effect by eliciting the re-expression of SOD2-suppressed hsa-miR-324, and inhibiting SOD2-mediated tumorigenicity. Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.

scholarly journals Energy metabolism adaptations and gene expression reprogramming in a cellular MAFLD model

2021 ◽  
Author(s):  
Tian-Ran Zhou ◽  
Cagla Cömert ◽  
Xiaoyu Zhou ◽  
Lin Lin ◽  
Lars Bolund ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Cell Model ◽  
Critical Role ◽  
Huh7 Cell ◽  
Mitochondrial Superoxide ◽  
Expression Of Genes ◽  
Bioenergetic Analysis ◽  
Vitro Model

Mitochondrial dysfunction plays a critical role in metabolic associated fatty liver disease (MAFLD). This study aims to characterize mitochondrial dysfunctions in a human MAFLD Huh7 cell model triggered by free fatty acid (FFA) (palmitate and oleate) overload for 24 hours. We investigate its impact on cellular energy metabolism and identify potential targets for MAFLD treatment. FFA-treated cells displayed an accumulation of lipid droplets and slightly decreased viability but no significant changes in mitochondrial superoxide levels. Bioenergetic analysis showed a shift to more respiration and less glycolytic fermentation. Comprehensive transcriptomics and proteomics analyses identified changes in the expression of genes prominently involved in fatty acid handling and metabolism. The expressions of seven genes were consistently and significantly (p<0.05) altered (4 upregulated and 3 downregulated genes) in both proteomics and transcriptomics. The FFA-treated Huh7 cell model is an appropriate in vitro model to study fatty acid metabolism and suitable to investigate the role of mitochondria, glycolysis, and multiple metabolic pathways in MAFLD. Our comprehensive analyses form a basis for drug discovery and screening using this model.

scholarly journals Differentiation but not ALS mutations in FUS rewires motor neuron metabolism

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tijs Vandoorne ◽  
Koen Veys ◽  
Wenting Guo ◽  
Adria Sicart ◽  
Katlijn Vints ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Motor Neuron ◽  
Tca Cycle ◽  
Metabolic Dysfunction ◽  
Lactate Oxidation ◽  
Metabolic Switch ◽  
Mitochondrial Energy Metabolism ◽  
Human Ipscs ◽  
Induced Pluripotent

Abstract Energy metabolism has been repeatedly linked to amyotrophic lateral sclerosis (ALS). Yet, motor neuron (MN) metabolism remains poorly studied and it is unknown if ALS MNs differ metabolically from healthy MNs. To address this question, we first performed a metabolic characterization of induced pluripotent stem cells (iPSCs) versus iPSC-derived MNs and subsequently compared MNs from ALS patients carrying FUS mutations to their CRISPR/Cas9-corrected counterparts. We discovered that human iPSCs undergo a lactate oxidation-fuelled prooxidative metabolic switch when they differentiate into functional MNs. Simultaneously, they rewire metabolic routes to import pyruvate into the TCA cycle in an energy substrate specific way. By comparing patient-derived MNs and their isogenic controls, we show that ALS-causing mutations in FUS did not affect glycolytic or mitochondrial energy metabolism of human MNs in vitro. These data show that metabolic dysfunction is not the underlying cause of the ALS-related phenotypes previously observed in these MNs.

scholarly journals Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model

2013 ◽  
Vol 36 (3) ◽  
pp. 247-257 ◽  
Author(s):  
Mengde Cao ◽  
Victor Prima ◽  
David Nelson ◽  
Stanislav Svetlov
Keyword(s):  
Fatty Acid ◽  
Liver Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Liver Cancer Cells
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