BackgroundCumulatively, evidences revealed that fenofibrate used in the therapy of hyperlipidemia and hypercholesterolemia has anti-cancer effect in multiple cancer types. However, its function and underlying mechanism of chemosensitization in breast cancer remain poorly understood.Materials and methodsThe cytotoxicity of fenofibrate and anti-cancer drugs in breast cancer cells was determined by MTT. Apoptosis and mitochondrial membrane potential were measured using flow cytometry. Caspases and PARP cleavage, the Bcl-2 family members’ protein expression, as well as the activation of AKT and NF-κB signaling pathways were evaluated using Western blot assay. Real-time PCR was used to determine the mRNA expression of Bcl-2 family members.ResultsOur data indicated that fenofibrate suppressed SKBR3 and MDA-MB-231 cell growth in a dose-dependent manner, in the same way as paclitaxel, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ABT-737, and doxorubicin. Subtoxic levels of fenofibrate significantly augmented paclitaxel, TRAIL, ABT-737, and doxorubicin-induced apoptosis in both these two cell lines. Fenofibrate-promoted chemosensitivity is predominantly mediated by caspase-9 and caspase-3 activation and mitochondrial outer membrane permeabilization. Meanwhile, chemosensitivity promoted by fenofibrate also increased the expression of Bax and Bok and decreased the expression of Mcl-1 and Bcl-xl. Mechanistically, fenofibrate effectively reduced the phosphorylation levels of AKT and NF-κB. In addition, imiquimod, an NF-κB activator, could reverse fenofibrate-induced susceptibility to ABT-737-triggered apoptosis.ConclusionThe present study provided the evidence of the underlying mechanisms on chemosensitization of fenofibrate by inducing the apoptosis of breast cancer in an AKT/NF-κB-dependent manner and implicated the potential application of fenofibrate in potentiating chemosensitivity in breast cancer therapy.
MicroRNA (miR)-1246 is abnormally expressed and has pro-oncogenic functions in multiple types of cancer. In the present study, its functions in breast cancer and the underlying mechanisms were further elucidated. The clinical relevance of miR-1246 was analyzed and its expression in clinical specimens and cell lines was examined by reverse transcription-quantitat000000ive PCR analysis. FACS was used to detect cell apoptosis and mitochondrial transmembrane potential. A Transwell system was used to detect cell migration and invasion. Luciferase assay was used to confirm the target gene of miR-1246. Xenograft and metastasis mouse models were constructed to determine the function of miR-1246 in vivo. miR-1246 was found to be negatively associated with overall survival in breast cancer. miR-1246 inhibitor could effectively increase the cytotoxicity of docetaxel (Doc) by inducing apoptosis, and impair cell migration and invasion by suppressing epithelial-to-mesenchymal transition. Nuclear factor (erythroid 2)-like factor 3 (NFE2L3) was confirmed as a new target gene of miR-1246, and its overexpression was shown to reduce drug resistance and migration of MDA-MB-231 cells. More importantly, NFE2L3-silencing attenuated the effect of miR-1246 inhibitor. Finally, the inhibition of miR-1246 effectively enhanced the cytotoxicity of Doc in xenografts and impaired breast cancer metastasis. Therefore, miR-1246 may promote drug resistance and metastasis in breast cancer by targeting NFE2L3.
Background Numerous studies have shown the detrimental effects of overt hyperthyroidism on sexual functioning but a quantitative result has not yet been synthesized. Aim To conduct a systematic review and meta-analysis that quantifies the association between overt hyperthyroidism and the risk of sexual dysfunction (SD). Methods A meta-analysis of studies in the literature published prior to February 1, 2020, from 4 electronic databases (MEDLINE, Embase, Cochrane Library databases, and PsychINFO) was conducted. All analyses were performed using the random-effects model comparing individuals with and without overt hyperthyroidism. Outcomes The strength of the association between overt hyperthyroidism and risk of SD was quantified by calculating the relative risk (RR) and the standard mean difierences with 95% CI. The quality of evidence for the reported outcome was based on the Grading of Recommendations Assessment, Development, and Evaluation approach. Results Of 571 publications, a total of 7 studies involving 323,257 individuals were included. Synthetic results from 7 eligible studies indicated that overt hyperthyroidism led to significant SD in both sexes (pooled RR = 2.59, 95% CI: 1.3–5.17, P = .007; heterogeneity: I2 = 98.8%, P < .001). When we analyzed the data of men and women independently, the pooled results consistently showed that men and women with overt hyperthyroidism were at over 2-fold higher risk of SD than the general populations (RR for males = 2.59, 95% CI: 1.03–6.52, P = .044; RR for females = 2.51, 95% CI: 1.47–4.28, P = .001). Combined standard mean diffierences from those studies providing the Female Sexual Function Index (FSFI) suggested that women with overt hyperthyroidism were associated with a significantly lower FSFI value in FSFI total scores, subscale sexual arousal, lubrication, orgasm, and satisfaction domain (all P < .05). The overall quality of evidence in our study was considered to be moderate. Clinical Implications Clinicians should know the detrimental effects of overt hyperthyroidism on sexual functioning in clinical practice. Measurement of thyroid hormones should be included in the assessment of patients presenting with SD when they show symptoms of clinical hyperthyroidism. Strengths & Limitations This is the first meta-analysis quantifying the relationship between overt hyperthyroidism and the risks of SD. However, the combined results were derived from limited retrospective studies along with substantial heterogeneities. Conclusion Our study has confirmed the potentially devastating sexual health consequences caused by overt hyperthyroidism. However, additional rigorous studies with sizable samples are still needed to better elucidate this evidence.
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