ABSTRACT
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and poor prognosis. Meanwhile, doxorubicin, a chemotherapeutic agent for triple-negative breast cancer, has poor sensitivity. The objective of this study was to examine the effect of cordycepin on doxorubicin sensitivity and efficacy in the TNBC xenograft model and explore the relevant molecular pathways. The combination of the drugs in nude mice carrying MDA-MB-231 xenografts significantly reduced the volume, size, and weight of xenografts and improved the tumor inhibition rate. The drug combination was significantly more effective than cordycepin or doxorubicin alone, reflecting the fact that cordycepin enhanced the anti-tumor effects of doxorubicin in MDA-MB-231 xenografts. At the same time, the monitoring of several biological parameters failed to detect any obvious side effects associated with this treatment. After predicting the importance of the TNF pathway in inhibiting tumor growth using network pharmacology methods, we verified the expression of TNF pathway targets via immunohistochemistry and quantitative PCR. Furthermore, a TNF-α inhibitor was able to abrogate the beneficial effects of cordycepin and doxorubicin treatment in MDA-MB-231 cells. This clearly indicates the role of TNF-α, or related molecules, in mediating the therapeutic benefits of the combined treatment in animals carrying TNBC xenografts. The observations reported here may present a new direction for the clinical treatment of TNBC.
Subject(s)
Deoxyadenosines , Doxorubicin , Mice, Nude , Triple Negative Breast Neoplasms , Xenograft Model Antitumor Assays , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Deoxyadenosines/pharmacology , Deoxyadenosines/therapeutic use , Animals , Humans , Female , Mice , Cell Line, Tumor , Drug Synergism , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/genetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Proliferation/drug effects , Mice, Inbred BALB CABSTRACT
Polysaccharides have high antioxidant, hypoglycemic, hypolipidemic, hepatoprotective, anti-tumor, and anticancer activities. In this study, the ability of the Lyophyllum decastes fruiting body polysaccharide (LDFP) to protect against CCl4-induced acute liver injury in mice by activating the Nrf2 pathway was studied. LDFP can inhibit the activity of ALT, AST, TC, TG, tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) in serum; significantly improve the inflammatory state of the liver; increase the activity of superoxide dismutase (SOD) and the glutathione (GSH) content; decrease the malondialdehyde (MDA) content; alleviate the toxicity caused by reactive oxygen species; and alleviate liver injury. Immunohistochemistry and western blot showed that LDFP can activate the Nrf2 pathway, up-regulate the expression of Nrf2, down-regulate the expression of Keap1, and increase the expression of the anti-oxidation factors HO-1 and CuZn-SOD. At the same time, it was found that the expression of the transcription factors TLR-4 and NF-κB were decreased in the NF-κB signaling pathway, the synthesis and secretion of the pro-inflammatory factors IL-6 and TNF-α were decreased consequently. These results suggest that LDFP protects the liver by activating the Nrf2 pathway and reducing the inflammatory response. Generally, the results of this study could be used to aid the development of hepatoprotective products and their application.
Subject(s)
Agaricales , Antioxidants/pharmacology , Polysaccharides/pharmacology , Protective Agents/pharmacology , Animals , Animals, Outbred Strains , Antioxidants/therapeutic use , Carbon Tetrachloride , Chemical and Drug Induced Liver Injury/prevention & control , Disease Models, Animal , Fruit , Functional Food , Mice , NF-kappa B/metabolism , Polysaccharides/therapeutic use , Protective Agents/therapeutic use , Random Allocation , Signal Transduction/drug effectsABSTRACT
Mycogone perniciosa is the main causative agent of wet bubble disease, which causes severe damage to the production of the cultivated mushroom Agaricus bisporus around the world. Whole-genome sequencing of 12 isolates of M. perniciosa was performed using the Illumina sequencing platform, and the obtained paired-end reads were used to assemble complete mitochondrial genomes. Intraspecific comparisons of conserved protein-coding genes, transfer RNA (tRNA) and ribosomal RNA (rRNA) genes, introns, and intergenic regions were conducted. Five different mitochondrial DNA (mtDNA) haplotypes were detected among the tested isolates, ranging from 89,080 to 93,199 bp in length. All of the mtDNAs contained the same set of 14 protein-coding genes and 2 rRNA and 27 tRNA genes, which shared high sequence similarity. In contrast, the number, insertion sites, and sequences of introns varied greatly among the mtDNAs. Eighteen of 43 intergenic regions differed among the isolates, reflecting 65 single nucleotide polymorphisms, 76 indels, and the gain/loss of nine long fragments. Intraspecific comparison revealed that two introns were located within tRNA genes, which is the first detailed description of mitochondrial tRNA introns. Intronic sequence comparison within the same insertion sites revealed the formation process of two introns, which also illustrated a fast evolutionary rate of introns among M. perniciosa isolates. Based on the intron distribution pattern, a pair of universal primers and four pairs of isolate-specific primers were designed and were used to identify the five mtDNA types. In summary, the rapid gain or loss of mitochondrial introns could be an ideal marker for population genetics analysis.
