Meiotic nuclear divisions 1(MND1)fuels cell cycle progression by activating a KLF6/E2F1 positive feedback loop in lung adenocarcinoma

Background:Considering the increase in the proportion of lung adenocarcinoma(LUAD)cases among all lung cancers and its considerable contribution to cancer-related deaths worldwide,we sought to identify novel oncogenes to provide potential targets and facilitate a better understanding of the malignant progression of LUAD.Methods:The results from the screening of transcriptome and survival analyses according to the integrated Gene Expression Omnibus(GEO)datasets and The Cancer Genome Atlas(TCGA)data were combined,and a promising risk biomarker called meiotic nuclear divisions 1(MND1)was selectively acquired.Cell viability assays and subcutaneous xenograftmodelswere used to validate the oncogenic role ofMND1 in LUADcell proliferation and tumor growth.Aseries of assays,including mass spectrometry,co-immunoprecipitation(Co-IP),and chromatin immunoprecipitation(ChIP),were performed to explore the underlying mechanism.Results:MND1 up-regulation was identified to be an independent risk factor for overall survival in LUAD patients evaluated by both tissue microarray staining and third party data analysis.In vivo and in vitro assays showed that MND1 promoted LUAD cell proliferation by regulating cell cycle.The results of the Co-IP,ChIP and dual-luciferase reporter assays validated that MND1 competitively bound to tumor suppressor Kruppel-like factor 6(KLF6),and thereby protecting E2F transcription factor 1(E2F1)from KLF6-induced transcriptional repression.Luciferase reporter and ChIP assays found that E2F1 activated MND1 transcription by binding to its promoter in a feedback manner.Conclusions:MND1,KLF6,and E2F1 form a positive feedback loop to regulate cell cycle and confer DDP resistance in LUAD.MND1 is crucial for malignant progression and may be a potential therapeutic target in LUAD patients.

Stimuli responsive co-delivery of celecoxib and BMP2 from micro-scaffold for periodontal disease treatment

Controlling inflammation meanwhile facilitating tissue regeneration has been considered as a promising strategy to treat inflammatory bone defect. Herein, we describe the synthesis of a bio-sensitive poly(lactic-co-glycolic acid)/mesoporous silica nanocarriers core-shell porous microsphere(PLGA/MSNsPMS) encapsulated poly(L-lactic acid)(PLLA) spongy nanofibrous micro-scaffold as a new generation of therapeutic platform for effective reconstruction of bone defects caused by periodontal diseases.The PLGA/MSNs-PMS were designed as stimuli-responsive carriers for on-demand co-delivery of multiple biomolecules to provide proper physiological environment, while the multi-level(from macro-,micro-to nanometers) nanofibrous and porous structures in PLLA micro-scaffold were in charge of the reconstruction of ECM, which synergistically contribute to the enhancement of new tissue formation under inflammatory condition. After local injection into periodontal tissue, this construct could sequentially release bone growth factor(BMP-2) as well as anti-inflammatory drug(celecoxib) loaded MSNs in response to the over-expressed matrix metalloproteinases(MMP) in periodontal region. During alveolar bone regeneration induced by BMP-2 and ECM like structure, the MSNs would further deliver celecoxib in target cells to achieve inflammation inhibition, resulting in effective treatment of periodontal disease.

Redox-responsive micelles integrating catalytic nanomedicine and selective chemotherapy for effective tumor treatment

Chemotherapy is one of the most conventional modalities for cancer therapy.However,the high multidrug resistance of tumor cells still limited the clinical application of current chemotherapy.Considering the ability of nitric oxide(NO) to modulate potent P-glycoprotein to inhibit multi-drug resistance,a synergistic methodology combining chemotherapy and sustained NO generation is an ideal way to further promote the chemotherapy.Herein,a multi-functional micelle with tumor-selective chemotherapy driven by redox-triggered doxorubicin(DOX) release and drug resistance inhibition based on intracellular NO generation was fabricated for effective tumor treatment.The micelle consists of DOX as core,arginine/glucose oxidase(Arg/GOx) as shell and redox-responsive disulfide bond as a linker,which is denoted as micelle-DOX-Arg-GOx.The Arg serves as the biological precursor of nitric oxide for inhibition of multi-drug resistance to promote chemotherapy and GOx catalyzes glucose to produce hydrogen peroxide(H_(2) O_(2)) for increasing the generation of NO.Moreover,the glucose supply could be simultaneously blocked by the catalytic process,which further enhanced therapeutic efficiency.This micelle requests a tumor-specific microenvironment(a considerable amount of GSH) to perform synergistic therapeutics including chemotherapy,starvation therapy(catalytic medicine),and gas therapy for tumor treatment,which resulted in significant cytotoxicity to tumor tissue.