The role of miR-125b-mitochondria-caspase-3 pathway in doxorubicin resistance and therapy in human breast cancer.

MicroRNAs (miRNAs) are a class of naturally occurring, small, non-coding RNAs which play important roles in diverse biological processes and are acting as key regulators of tumorigenesis and chemotherapy resistance. In this study, a downregulation of miR-125b was observed in breast cancer cell lines, suggesting miR-125b is a tumor suppressor in breast cancer. Moreover, the miR-125b levels were significantly decreased in doxorubicin-resistant MCF-7 (MCF-7/DR) cells compared with MCF-7 cells. Transfection of miR-125b significantly enhanced the cytotoxicity of doxorubicin to MCF-7/DR cells. However, the overexpression of miR-125b did not influence the doxorubicin accumulation but downregulated the myeloid cell leukemia-1 (Mcl-1) levels, which may be the mechanism of apoptosis induction caused by doxorubicin combining with miR-125b in MCF-7/DR cells. Furthermore, luciferase reporter assay proved that Mcl-1 is the target of miR-125b. Importantly, we found that the sensitization of miR-125b to doxorubicin cytotoxicity is caspase-dependent in MCF-7/DR cells, which can be inhibited by zVAD-fmk. Finally, we indicated that the treatment of miR-125b plus doxorubicin leads to loss of mitochondrial membrane potential (MMP) and mitochondria outer membrane permeability (MOMP), which were interacted with the activation of caspases. Thus, this study revealed the role of miR-125b in doxorubicin resistance and therapy, which may provide novel approaches for the treatment of breast cancer.

Elemene Injection Overcomes Paclitaxel Resistance in Breast Cancer through AR/RUNX1 Signal: Network Pharmacology and Experimental Validation.

BACKGROUND: Paclitaxel (PTX) is a cornerstone chemotherapy for Breast Cancer (BC), yet its impact is limited by emerging resistance. Elemene Injection (EI) has shown potential in overcoming chemotherapy resistance. However, the efficacy by which EI restores PTX sensitivity in BC and the implicated molecular mechanism remain uncharted. METHODS: Network pharmacology and bioinformatic analysis were conducted to investigate the targets and mechanisms of EI in overcoming PTX resistance. A paclitaxel-resistant MCF-7 cell line (MCF-7PR) was established. The efficacy of EI and/or PTX in inhibiting cell viability was evaluated using sulforhodamine B assay, while cell proliferation was assessed using EdU staining. Furthermore, protein and gene expression analysis was performed through Western blotting and qPCR. RESULTS: The EI containing three active components exhibited a multifaceted impact by targeting an extensive repertoire of 122 potential molecular targets. By intersecting with 761 differentially expressed genes, we successfully identified 9 genes that displayed a direct association with resistance to PTX in BC, presenting promising potential as therapeutic targets for the EI to effectively counteract PTX resistance. Enrichment analysis indicated a significant correlation between these identified targets and critical biological processes, particularly DNA damage response and cell cycle regulation. This correlation was further substantiated through meticulous analysis of single-cell datasets. Molecular docking analysis revealed robust binding affinities between the active components of the EI and the identified molecular targets. Subsequently, in vitro experiments unequivocally demonstrated the dose- and time-dependent inhibitory effects of the EI on both PTX-resistant and sensitive BC cell lines, effectively mitigating the resistance phenotype associated with PTX administration. Furthermore, our findings have indicated EI to effectively suppress the protein expression levels of AR and RUNX1 in MCF-7 and MCF-7PR cells under PTX treatment, as well as downregulate the mRNA expression levels of stem-like properties' markers, KLF4 and OCT4, in these cell lines. CONCLUSION: Elemene Injection (EI) application has exhibited a significant capability to mitigate PTX resistance in BC, which has been achieved through targeted suppression of the AR/RUNX1 axis, revealing a key strategy to overcome chemotherapeutic resistance.

A Network Pharmacology Study on the Cervix Prescription for Treatment of Cervical Cancer.

Purpose: Based on the method of network pharmacology to explore the mechanism of the cervical prescription (CP) in the treatment of cervical cancer (CC). Methods: We obtained the active ingredients and potential targets in the CP from the literature and the systematic pharmacological analysis platform of traditional Chinese medicine (BATMAN-TCM); the database was used to search for targets related to cervical cancer and to map CP and targets; the core targets were screened, and the protein-protein interaction network (PPI) was constructed using the TCM compound-target network and STRING database. Gene ontology (GO) and Kyoto Gene and Genome Encyclopedia (KEGG) pathway enrichment analysis of overlapping targets were performed using DAVID 6.8 online tool. Results: The CP contains 2 active ingredients, corresponding to 301 nonreactive targets; 10 GO biological process related items and 73 signal pathways were obtained. Cell experiments confirmed that the medicated serum of CP could effectively inhibit the proliferation and invasion ability of Hela cells. Conclusion: This study provides valuable information for TCM researchers and clinicians to better understand the main therapeutic targets and therapeutic roles of herbal decoctions in clinical settings. The results of our study preliminarily clarified that the cervical prescription has an inhibitory effect on cervical cancer cells.

ß-elemene induced apoptosis and senescence of triple-negative breast cancer cells through IGF1/IGF1R pathway.

PURPOSE: ß-elemene has a wide range of anticancer effects and can be used in a variety of cancer types. This study mainly explored its mechanism of action on TNBC cells and provided theoretical basis for the treatment of TNBC. METHODS: Firstly, TNBC cells were treated with different concentrations of ß-elemene, and screened out an appropriate concentration for subsequent research. Then, through the bioinformatics website, predicted genes that have a binding relationship with ß-elemene. Then, the overexpression vector of the selected gene was transfected into the cell. The effects of ß-elemene and its target genes on the proliferation and apoptosis of TNBC cells were detected by CCK-8, Edu assay, and flow cytometry, and the senescence of cells was determined by SA-ß-gal experiment. Western blotting was used to detect the expression of apoptosis and aging-related proteins. RESULTS: ß-elemene inhibited TNBC cell viability and proliferation in a concentration-dependent manner, and induces apoptosis and senescence. Through the screening of candidate genes, IGF1 was finally determined to be an effective target gene of ß-elemene. The expression level of IGF1 was decreased in cells treated with ß-elemene. Overexpression of IGF1 significantly alleviated ability of ß-elemene to inhibit cell viability, proliferation, and induced cell apoptosis and senescence. In addition, ß-elemene inhibited the expression of IGF1R and Bcl-2, and promoted the expression of Cleaved Caspase-3 and senescence-related proteins (p27, p16, p53 and p21), and these effects were reversed by overexpression of IGF1. CONCLUSION: ß-elemene induced apoptosis and senescence of triple-negative breast cancer cells through IGF1/IGF1R pathway.

Research on Radiosensitivity of the Protein Kinase B Signaling Pathway in Cervical Cancer.

The main characteristics of cervical cancer are abnormal and uncontrolled cell proliferation, and it regulates cell growth, differentiation, and cell death through genetic and epigenetic changes. This paper mainly discusses the radiosensitivity of the cervical cancer protein kinase B signaling pathway and discusses the specific mechanisms that affect the occurrence and development of cervical cancer. In addition, this paper studies the effect of transient transfection knocking down the expression of TRIP4 in cervical cancer cells on the expression of key proteins in related signaling pathways and explores the mechanism of its specific effects and finds the mechanism of TRIP4's effect on cervical cancer radiosensitivity. The findings of this study show for the first time that knocking down TRIP4 inhibits cell viability by inhibiting the P13K/AKT and MAPK/ERK pathways, and this corresponds to the first part of the experimental results, which show that knocking down TRIP4 inhibits colony formation and increases apoptosis in HeLa and SiHa cells. Moreover, simultaneous inhibition of TRIP4 and hTERT proteins can increase the radiosensitivity of cervical cancer cells. These findings indicate that the inhibition of TRIP4 may be a new type of treatment that selectively targets the P13K/AKT and MAPK/ERK pathways and hTERT pathways in cervical cancer cells and provides a therapeutic option for the treatment of cervical cancer.

Dexamethasone for preventing postoperative nausea and vomiting after mastectomy.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a common complication after mastectomy. Although many researches have been studied the prophylactic effect of antiemetics, none of the results are effective. To overcome this problem, dexamethasone was used to relieve the occurrence of PONV. Since concerns about steroid-related morbidity still remain, We carried out a meta-analysis to evaluate the impact of prophylactic dexamethasone on PONV, post-operative pain undergoing mastectomy. METHODS: Literature search was conducted through PubMed, Web of Science, EMBASE, MEDLINE, and Cochrane library database till June 2019 to identify eligible studies. Meanwhile, we also consulted some Chinese periodicals, such as China Academic Journals, Wanfang and Weipu. The research was reported according to the preferred reporting items for systematic reviews and meta-analysis guidelines. Randomized controlled trials were included in our meta-analysis. Meanwhile, the assessment of the risk of bias was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions version. The pooled data are processed by software RevMan 5.3. RESULTS: Four studies with 490 patients were enrolled to this meta-analysis. Our study demonstrated that the dexamethasone group was significantly more effective than the placebo group in term of PONV (risk ratio [RR] = 0.46, 95% confidence intervals [CI]: 0.30-0.70, P = .0003), nausea (RR = 0.26, 95% CI: 0.10-0.68, P = .006) and vomiting (RR = 0.15, 95% CI: 0.04∼0.55, P = .004). The visual analog scale score was significantly diminished at 1 hour (weighted mean difference = -1.40, 95% CI: -1.53 to -1.26, P < .00001) in the dexamethasone group, while, no statistically significant difference was observed between the two groups in terms of visual analog scale at 24 hours (weighted mean difference = -0.56, 95% CI: -1.24 to 0.13, P = 0.11). CONCLUSION: Not only does Dexamethasone reduce the incidence of PONV but also decreases postoperative pain. However, we still need larger samples and higher quality studies to determine the relationship between symptoms and administration time to reach the conclusion. TRIAL REGISTRATION NUMBER: PROSPERO CRD 42018118575.