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Identifying chondroprotective diet-derived bioactives and investigating their synergism.

ABSTRACT: Osteoarthritis (OA) is a multifactorial disease and nutrition is a modifiable factor that may contribute to disease onset or progression. A detailed understanding of mechanisms through which diet-derived bioactive molecules function and interact in OA is needed. We profiled 96 diet-derived, mainly plant-based bioactives using an in vitro model in chondrocytes, selecting four candidates for further study. We aimed to determine synergistic interactions between bioactives that affected the expression of key genes in OA. Selected bioactives, sulforaphane, apigenin, isoliquiritigenin and luteolin, inhibited one or more interleukin-1-induced metalloproteinases implicated in OA (MMP1, MMP13, ADAMTS4, ADAMTS5). Isoliquiritigenin and luteolin showed reactive oxygen species scavenging activity in chondrocytes whereas sulforaphane had no effect and apigenin showed only a weak trend. Sulforaphane inhibited the IL-1/NF?B and Wnt3a/TCF/Lef pathways and increased TGF?/Smad2/3 and BMP6/Smad1/5/8 signalling. Apigenin showed potent inhibition of the IL-1/NF?B and TGF?/Smad2/3 pathways, whereas luteolin showed only weak inhibition of the IL-1/NF?B pathway. All four bioactives inhibited cytokine-induced aggrecan loss from cartilage tissue explants. The combination of sulforaphane and isoliquiritigenin was synergistic for inhibiting MMP13 gene expression in chondrocytes. We conclude that dietary-derived bioactives may be important modulators of cartilage homeostasis and synergistic relationships between bioactives may have an anti-inflammatory and chondroprotective role.

SUBMITTER: Davidson RK

PROVIDER: S-EPMC6249298 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Identifying chondroprotective diet-derived bioactives and investigating their synergism.

Davidson Rose K RK Green Jonathan J Gardner Sarah S Bao Yongping Y Cassidy Aedin A Clark Ian M IM

Scientific reports 20181121 1

Osteoarthritis (OA) is a multifactorial disease and nutrition is a modifiable factor that may contribute to disease onset or progression. A detailed understanding of mechanisms through which diet-derived bioactive molecules function and interact in OA is needed. We profiled 96 diet-derived, mainly plant-based bioactives using an in vitro model in chondrocytes, selecting four candidates for further study. We aimed to determine synergistic interactions between bioactives that affected the expressi ...[more]

PMID: 30464238

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Project description:ImportanceAccurate clinical staging is important in rectal cancer because it determines the appropriate treatment and prognosis. Despite the use of multiple diagnostic imaging tools, it is sometimes difficult to clinically distinguish stage I tumors from stage II or III locally advanced disease. Identification of differentiating microRNAs (miRNAs) between these 2 groups may improve the clinical diagnostic power and provide insight into the biology of tumor progression.ObjectivesTo investigate differences in the expression of miRNAs in stage I vs stage II or III rectal cancers and integrate matched mRNA profiling data to identify possible functional roles of these miRNAs.Design, setting, and participantsThe primary tumor specimens from patients who were enrolled in 2 prospective clinical trials between March 24, 2004, and November 16, 2012 (American College of Surgeons Oncology Group [ACOSOG] Z6041 and Timing of Rectal Cancer Response to Chemoradiation [TIMING]) were sequenced to arrive at a set of 127 cases (41 stage I and 86 stage II or III tumors) with matched miRNA and messenger RNA (mRNA) profiling data. These findings were also evaluated in an independent cohort of 127 patient specimens (29 stage I and 98 stage II or III tumors) from The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) that also had matched miRNA and mRNA data. Data analysis was performed from September 1, 2019, to September 1, 2020.Main outcomes and measuresAlterations in miRNA expression between stage I and stage II or III tumors and their potential gene targets.ResultsA total of 254 pretreatment rectal adenocarcinoma specimens were analyzed in this study as 2 distinct cohorts: 127 samples in the ACOSOG/TIMING (stage I group: 27 [66%] male; mean [SD] age, 64.4 [10.8] years; stage II or III group: 47 [55%] male; mean [SD] age, 57.0 [11.4] years), and another 127 samples from TCGA-READ (stage I group: 17 [59%] male; mean [SD] age, 63.6 [12.0] years; stage II or III group: 48 [49%] male; mean [SD] age, 64.5 [11.4] years). A total of 19 miRNAs were overexpressed in stage II or III vs stage I tumors in both cohorts. This miRNA signature had an excellent discriminative value for distinguishing stage II or III from stage I rectal tumors (area under the curve, 0.88; 95% CI, 0.83-0.94 in ACOSOG/TIMING cohort and area under the curve, 0.84; 95% CI, 0.77-0.91 in the TCGA-READ cohort). Integrative analysis revealed 3 miRNA-mRNA pairs that exhibited significant correlations in both cohorts: miR-31-5p-SATB2, miR-143-3p-KLF5, and miR-204-5p-EZR.Conclusions and relevanceThis diagnostic study found that many of the dysregulated miRNAs in stage II or III vs stage I rectal cancers have biological implications for tumor progression. The results of this study suggest that these miRNAs could assist as diagnostic biomarkers to better identify patients with locally advanced rectal cancer.

Dataset Information

Identifying chondroprotective diet-derived bioactives and investigating their synergism.

Publications

Identifying chondroprotective diet-derived bioactives and investigating their synergism.

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