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Experimental results from [...].
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Cancer stem-like cells (CSLCs) are involved in cancer initiation, development, and metastasis, and microRNAs (miRNAs) play pivotal roles in regulating CSLCs. miRNA-based therapeutic strategy associated with CSLCs might promise potential new therapeutic approaches. In the present study, we found that miR-1290 was increased in CD133(+) cells. Antagomir-1290 significantly suppressed tumor volume and weight initiated by CD133(+) cells in vivo. Furthermore, antagomir-1290 significantly inhibited the proliferation, clonogenicity, invasion, and migration of CD133(+) cells by targeting fyn-related Src family tyrosine kinase. These findings provide insights into the clinical prospect of miR-1290-based therapies for non-small cell lung cancer.
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Antígenos CD/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Glicoproteínas/genética , MicroRNAs/biossíntese , Proteínas de Neoplasias/biossíntese , Peptídeos/genética , Proteínas Tirosina Quinases/biossíntese , Antígeno AC133 , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/antagonistas & inibidores , Invasividade Neoplásica/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Proteínas Tirosina Quinases/genéticaRESUMO
Lung cancer is the major cause of cancer related lethality worldwide, and metastasis to distant organs is the pivotal cause of death for the vast majority of lung cancer patients. Accumulated evidence indicates that lung cancer stem-like cells (CSLCs) play important roles in metastagenesis, and these circulating CSLCs may be important targets to inhibit the subsequent metastasis. The present study was aimed at establishing CSLC-targeting polylactic acid (PLA) encapsulated docetaxel nanoparticles for antimetastatic therapy. Cyclic binding peptides were screened on CSLCs in vitro and the peptide CVKTPAQSC exhibiting high specific binding ability to pulmonary adenocarcinoma tissue was subsequently conjugated to the nanoparticles loaded with docetaxel (NDTX). Antimetastatic effect of CSLC-targeting nanoparticles loaded with docetaxel (TNDTX) was evaluated in a nude mouse model of liver metastasis. Results showed that, in the absence of targeting peptide, NDTX hardly exhibited any antimetastatic effect. However, TNDTX treatment significantly decreased the metastatic tumor area in the nude mouse liver. Histopathological and serological results also confirmed the antimetastatic efficacy of TNDTX. To our knowledge, this is the first report on establishing a CSLC-based strategy for lung cancer metastatic treatment, and we hope this will offer a potential therapeutic approach for management of metastatic lung cancer.
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Antineoplásicos/administração & dosagem , Ácido Láctico/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Células Neoplásicas Circulantes/efeitos dos fármacos , Polímeros/química , Taxoides/administração & dosagem , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Peso Corporal , Linhagem Celular Tumoral , Docetaxel , Portadores de Fármacos , Feminino , Glicoproteínas/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanomedicina , Nanopartículas/química , Metástase Neoplásica , Peptídeos/química , Peptídeos/metabolismo , PoliésteresRESUMO
Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults, the early symptoms and signs of which are non-specific. The discovery of microRNAs (miRNAs) provides a new avenue for the early diagnosis and treatment of OS. miR-126 has been reported to be highly expressed in vascularized tissues, and is recently widely studied in cancers. Herein, we explored the expression and significance of miR-126 in OS. Using TaqMan RT-PCR analysis, we analyzed the expression of miR-126 in 32 paired OS tumor tissues and 4 OS cell lines and found that miR-126 was consistently under-expressed in OS tissues and cell lines compared with normal bone tissues and normal osteoblast cells (NHOst), respectively. As miR-126 is significantly decreased in OS tissues and cell lines, we sought to compensate for its loss through exogenous transfection into MG-63 cells with a miR-126 mimic. Ectopic expression of miR-126 inhibited cell proliferation, migration and invasion, and induced apoptosis of MG-63 cells. Moreover, bioinformatic prediction suggested that the sex-determining region Y-box 2 (Sox2) is a target gene of miR-126. Using mRNA and protein expression analysis, luciferase assays and rescue assays, we demonstrate that restored expression of Sox2 dampened miR-126-mediated suppression of tumor progression, which suggests the important role of miR-126/Sox2 interaction in tumor progression. Taken together, our data indicate that miR-126 functions as a tumor suppressor in OS, which exerts its activity by suppressing the expression of Sox2.
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Neoplasias Ósseas/genética , MicroRNAs/metabolismo , Osteossarcoma/genética , Fatores de Transcrição SOXB1/genética , Regiões 3' não Traduzidas , Apoptose , Sequência de Bases , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular , Humanos , Oligonucleotídeos Antissenso/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fatores de Transcrição SOXB1/metabolismo , Alinhamento de SequênciaRESUMO
The discovery of immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4, has played an important role in the development of cancer immunotherapy. However, immune-related adverse events often occur because of the enhanced immune response enabled by these agents. Antibiotics are widely applied in clinical treatment, and they are inevitably used in combination with immune checkpoint inhibitors. Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors. Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics, although the exact mechanisms remain unclear. This review focuses on the interactions between immune checkpoint inhibitors and antibiotics, with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota, as well as other new combination strategies.
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Inibidores de Checkpoint Imunológico , Neoplasias , Antibacterianos/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1RESUMO
In recent years, the incidence of breast cancer has been increasing on an annual basis. Human epidermal growth factor receptor-2 (HER-2) is overexpressed in 15-20% human breast cancers, which is associated with poor prognosis and a high recurrence rate. Trastuzumab is the first humanized monoclonal antibody against HER-2. The most significant adverse effect of trastuzumab is cardiotoxicity, which has become an important factor in limiting the safe use of the drug. Unfortunately, the mechanism causing this cardiotoxicity is still not completely understood, and the use of preventive interventions remains controversial. This article focuses on trastuzumab-induced cardiotoxicity, reviewing the clinical application, potential cardiotoxicity, mechanism and discussing the potential interventions through summarizing related researches over the past tens of years.
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Therapies for lung adenocarcinoma (LUAD) are mainly limited by drug resistance, metastasis or recurrence related to cancer stem cells (CSCs) with high proliferation and self-renewing. This research validated that miR-31 was over-expressed in LUAD by the analysis of generous clinical samples data. And the results of clinical data analysis showed that high expression of miR-31 was more common in patients with worse prognosis. The genes differentially expressed in LUAD tissues compared with normal tissues and A549CD133+ cells (LUAD CSCs) compared with A549 cells were separately screened from Gene Expression Profiling Interactive Analysis and GEO datasets. The target genes that may play a role in the regulation of lung adenocarcinoma was screened by comparison between the differential genes and the target genes of miR-31. The functional enrichment analysis of GO Biological Processes showed that the expression of target genes related to cell proliferation was increased, while the expression of target genes related to cell invasion and metastasis was decreased in LUAD tissues and A549CD133+ cells. The results suggested that miR-31 may have a significant inhibitory effect on the differentiation, invasion, metastasis and adhesion of LUAD CSCs, which was verified in vivo and in vitro experiments. Knock down of miR-31 accelerated xenograft tumor growth and liver metastasis in vivo. Likewise, the carcinogenicity, invasion and metastasis of A549CD133+ CSCs were promoted after miR-31 knockdown. The study validated that miR-31 was up regulated in LUAD and its expression may affect the survival time of patients with lung adenocarcinoma, which indicated that miR-31 may have potential value for diagnosis and prognosis of LUAD. However, the inhibitory effect of miR-31 on tumorigenesis, invasion and metastasis of lung adenocarcinoma CSCs suggested its complexity in the regulation of lung adenocarcinoma, which may be related to its extensive regulation of various target genes.
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OBJECTIVE: To observe the effect of acupuncture on intelligence quotient (IQ) in children with mental retardation (MR). METHODS: One hundred children with MR were randomly divided into an acupuncture group and a control group, 50 in each. There were 37 and 36 cases with complete data in the former and latter group respectively. Four-week treatment constituted a course, the comprehensive therapeutic effect of two groups was compared after 3 courses of treatment, and the influence of acupuncture on IQ was estimated. RESULTS: The total effective rate in the acupuncture group was 78.4%, better than 30.56% in the control group, the difference being significant (P < 0.01). Both groups were improved in IQ but the effect of the former group was better than that of the latter group (P < 0.05). CONCLUSION: Acupuncture can obviously improve IQ of children suffering from MR.
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Terapia por Acupuntura , Deficiência Intelectual/psicologia , Deficiência Intelectual/terapia , Inteligência , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Hepatocellular carcinoma (HCC), as the major primary liver cancer, is one of the most prevalent malignant diseases with a high mortality rate worldwide. Prior studies have demonstrated that dihydroartemisinin (DHA), the semisynthetic derivative of artemisinin, possesses anti-HCC activity. The multikinase inhibitor sorafenib has been approved for the treatment of HCC. However, the anti-HCC efficacy of DHA combined with sorafenib has not been reported. In this study, we confirmed the significantly enhanced anti-HCC efficacy of DHA in combination with sorafenib compared with that of each agent alone. Tandem Mass Tag (TMT) peptide labeling coupled with LC-MS/MS was used to quantify the proteins from the control, DHA, sorafenib, and DHA + sorafenib groups. In total, 532, 426, 628 differentially expressed proteins (fold change >1.20 or <0.83 and P-value <0.05) were determined by comparing DHA versus control, sorafenib versus control and DHA + sorafenib versus control groups, respectively. Moreover, optimized screening was performed, and 101 optimized differentially expressed proteins were identified. The results of functional analysis of the optimized differentially expressed proteins suggested that they were enriched in cell components such as membrane-bound vesicles, extracellular vesicles, and organelle lumens, and they were mainly involved in biological processes such as cellular component organization, response to stress, and response to chemicals; in addition, they were related to various molecular functions such as protein binding, chromatin binding and enzyme binding. KEGG pathway analysis showed that the optimized differentially expressed proteins were enriched in pyrimidine metabolism, RNA polymerase, base excision repair, and osteoclast differentiation. Protein-protein interaction (PPI) networks of some of the optimized upregulated proteins suggested that they might not only affect vitamin and fat digestion and absorption but may also be involved in tight junctions. In the PPI network, some of the optimized downregulated proteins were enriched in base excision repair, RNA polymerase, purine metabolism, pyrimidine metabolism and mucin type O-glycan biosynthesis. Overall, this research explored the anti-HCC efficacy of DHA combined with sorafenib by using the TMT-based quantitative proteomics technique and might facilitate the understanding of the related anti-HCC molecular mechanism.
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Antineoplásicos/farmacologia , Artemisininas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/farmacologia , Antimaláricos/administração & dosagem , Antimaláricos/farmacologia , Antineoplásicos/administração & dosagem , Artemisininas/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sorafenibe/administração & dosagem , Regulação para CimaRESUMO
As an important derivative of the herb medicine Artemisia annua L., dihydroartemisinin (DHA) exhibits anti-hepatocellular carcinoma (HCC) activities. However, the underlying molecular mechanism is still unclear. In the present study, the network pharmacology method was used to construct the ingredient-target network of DHA that was responsible for the anti-HCC effect and 11 targets including ALB, ATP5A1, CCT3, CLIC1, ENO1, HSPA8, HSPB1, NPM1, PPIA, PRDX1, and ZYX were selected. Functional category analysis showed that the anti-HCC effect of DHA might be related to the biological process of cell-cell adhesion. ß1,6-branching of N-linked carbohydrate as one kind of glycosylation could participate in regulating cell-cell adhesion and has been reported to be overexpressed in HCC cells and tissues. Further lectin immunofluorescence and lectin blot analysis showed that DHA could down-regulate the expression of ß1,6-branching of N-linked carbohydrate by suppressing the transcription of MGAT5. This study will provide a scientific basis for the elucidation of the mechanisms of DHA in anti-HCC from the angle of glycosylation.
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Antineoplásicos/farmacologia , Artemisininas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Artemisininas/uso terapêutico , Carcinoma Hepatocelular/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Glicosilação/efeitos dos fármacos , Humanos , Lectinas/metabolismo , Neoplasias Hepáticas/patologia , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/metabolismo , NucleofosminaRESUMO
Lung cancer is the leading cause of cancer-related deaths. Ginsenoside Rg3 is the main ingredient of Ginseng which is used to treat non-small cell lung cancer (NSCLC). It has been found to enhance the efficiency of chemotherapy thereby reducing its side effects. Previous studies found that ginsenoside Rg3 can reduce the occurrence of NSCLC by inducing DNA damage. Yet, its anti-DNA damaging effects and mechanisms in tumor cells are still not fully understood. This study explored the effect of ginsenoside Rg3 on DNA repair and VRK1/P53BP1 signaling pathway. Ginsenoside Rg3 treatment significantly decreased the incidence and invasionin a mouse model of lung cancer induced by urethane. The results of cell survival assay and single cell gel electrophoresis showed that ginsenoside Rg3 protected lung adenocarcinoma cells from DNA damage as well as inhibited the proliferation of tumor cells. Ginsenoside Rg3 increased the mRNA and protein expression of VRK1 in NSCLC cells as measured by RT-qPCR and western blot, respectively. These findings suggests that ginsenoside Rg3 regulates VRK1 signaling. Immunofluorescence assays showed that P53BP1 and VRK1 protein level increased, and the VRK1 protein translocated between the nuclei and cytoplasm. Finally, this conclusion was confirmed by the reverse validation in VRK1-knockdown cells. Taken together, these results show that ginsenoside Rg3 upregulate VRK1 expression and P53BP1 foci formation in response to DNA damage thereby inhibiting the tumorigenesis and viability of cancer cells. These findings reveal the role of Rg3 in lung cancer and provides therapeutic targets for developing new drugs in the prevention and treatment of lung cancer.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Panax/química , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the inhibitory effect of Sumu (Lignum Sappan) plus Fuzi (Radix Aconiti Lateralis Praeparata) (SF) on the growth and metastasis of Lewis lung carcinoma. METHODS: A lung carcinoma model was established by subcutaneously inoculating Lewis lung carcinoma cells into C57BL/6 mice. The mice were randomly divided into four groups of 13 mice (control, low-dose, moderate-dose, and high-dose), and gavaged once-daily for 21 consecutive days. The rates of tumor inhibition, metastasis, and metastasis inhibition were observed. The differential expressions of sP-selectin and vascular endothelial growth factor C (VEGFC) were compared between the treatment groups and the control group. RESULTS: The tumor weights differed significantly between the treatment groups and the control group (P < 0.05). Administration of SF in the moderate-dosage and low-dose groups significantly inhibited the expression of sP-selectin and VEGFC (both P < 0.05), suggesting anti-tumor activity. CONCLUSION: SF can inhibit the growth and metastasis of Lewis lung carcinoma.
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The aim of this study was to evaluate the efficacy and clinical application of iliac bone flaps pedicled with sartorius muscular fascia around superficial circumflex iliac vessels for the treatment of Association for Research on Osseous Circulation (ARCO) stage II-III osteonecrosis of the femoral head (ONFH) in young adults. In total, 35 patients with ONFH at ARCO stage II-III were treated with iliac bone flaps pedicled with sartorius muscular fascia around superficial circumflex iliac vessels. Patients were classified according to etiological factors and ARCO stages. Postoperative clinical assessment was accomplished with Harris hip scores (HHSs), and ARCO stage change was evaluated with imaging. All 35 patients completed the follow-up. The HHS results indicated that hip function was improved significantly from the preoperative status of 56.53±7.66 points to the postoperative status of 87.49±5.89 points (P<0.0001). Postoperative imaging displayed apparent osteogenesis and satisfactory structural remodeling in 32 patients, presenting no staging progress. Three patients exhibited mild collapse (<2 mm) compared with preoperative collapse. No patients developed osteoarthritis or required total hip arthroplasty. The clinical success rate was 91.43%. Iliac bone flaps pedicled with sartorius muscular fascia around superficial circumflex iliac vessels is a feasible means for treating ARCO stage II-III ONFH in young adults, who have abundant blood circulation, good osteogenesis and function of the hip. It is also an effective means for retaining the femoral head.
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Accumulated evidences suggested that microRNAs (miRs) play an important role in non-small cell lung cancer (NSCLC). However, how miRs perform their functions in lung adenocarcinoma cancer stem cells (CSCs) remains unknown. Notably, most studies pay more attention to the effects of miRNAs on the metastasis traits whereas the growth activities of CSCs are rather undervalued. In our report, using A549CD133+cells, we examined the inhibitory effects and the underlying mechanisms of microRNA-31 (miR-31) on the growth of lung adenocarcinoma CSC-like cells. Initially, we determined the level of miR-31 in A549 and A549CD133+ cells. Over-expression of miR-31 was found in A549CD133+ cells by microarray and real-time quantitative PCR (RTqPCR) assays. Experiments in multiple NSCLC cell lines in vitro and A549CD133+ cells xenograft models in vivo confirmed that down regulation of miR-31 resulted in increase of A549CD133+ cells growth, whereas overexpression of miR-31 led to the inhibition of adenocarcinoma cell proliferation. Also, MET proto-oncogene has been determined to be a direct target of miR-31 by dual luciferase report, RT-qPCR and western blot analysis. Down regulation of MET inhibited viability of A549CD133+ cells. The levels of PI3Kinase, Akt and p-Akt as well as downstream proteins were consequently decreased. These results suggest that miR-31 might inhibit the growth of lung adenocarcinoma cancer stem-like cells via down regulation of the MET-PI3K-Akt signaling pathway.
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Adenocarcinoma/patologia , Regulação para Baixo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/deficiência , Proteínas Proto-Oncogênicas c-akt/deficiência , Proteínas Proto-Oncogênicas c-met/deficiência , Transdução de Sinais , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol 3-Quinases/biossíntese , Fosfatidilinositol 3-Quinases/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/metabolismoRESUMO
Although conventional anticancer drugs exhibit excellent efficacy, serious adverse effects and/or even toxicity have occurred due to their nonselectivity. Moreover, active targeting approaches have not consistently led to successful outcomes. Ligands that simultaneously possess targeting capability and exert a strong influence on intracellular signaling cascades may be expected to improve the therapeutic efficacy of active targeting nanoparticulate carriers. In this study, we screened a targeting peptide, LPLTPLP, which specifically bound to non-small cell lung cancer (NSCLC) specimens in vitro. Surprisingly, this peptide inhibited the expression of Hsp90 and induced apoptosis by preventing autophagy in A549 cells treated with docetaxel. The results suggested that this peptide might be used as a promising dual-functional ligand for cancer treatment. Based on these findings, we designed and developed a novel active targeting delivery system by modifying docetaxel nanoparticles (DNP) with the dual-functional ligand LPLTPLP. We consistently demonstrated that the cellular uptake of nanoparticles (NPs) was significantly enhanced in vitro. Furthermore, the targeting NPs exhibited significantly improved antitumor efficacy and biodistribution compared with nontargeting nanodrug and free docetaxel. These findings demonstrate the feasibility of dual-functional NPs for efficient anticancer therapy.
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Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Proteínas de Choque Térmico HSP90/metabolismo , Nanopartículas/química , Peptídeos/química , Taxoides/administração & dosagem , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Células 3T3 BALB , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Docetaxel , Sistemas de Liberação de Medicamentos , Feminino , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Terapia de Alvo Molecular , Nanopartículas/ultraestrutura , Taxoides/farmacologia , Taxoides/uso terapêutico , Distribuição TecidualRESUMO
The objective of the present study was to explore the molecular mechanism with which a single nucleotide polymorphism (rs61764370) interferes with the interaction between the 3'-untranslated region (3'-UTR) of Kirsten rat sarcoma viral oncogene homolog (KRAS) and let-7a, and its association with the metastasis of osteosarcoma (OS). In this study, we confirmed that KRAS is a target of let-7a in OS cells, and the introduction of rs61764370 minor allele into KRAS 3'-UTR significantly compromised the microRNA (miRNA)/mRNA interaction using a luciferase reporter system. Additionally, a total of 36 OS tissue samples of three different genotypes (TT,22; TG,10; GG,4) were obtained, and the expression of let-7a and KRAS was determined. We showed that let-7a mRNA expression was similar between each group whereas the mRNA and protein expression of KRAS in the TT genotype group was significantly lower than that in the GT or GG genotype groups. Moreover, we identified a negative regulatory relationship between let-7a and KRAS. Furthermore, we demonstrated that let-7a and KRAS interfered with the viability, invasiveness and migration of OS cells genotyped as TT. In the OS cells genotyped as TG, let-7a exerted minimal effects, and the effect of KRAS siRNA remained. Taken together, the findings of the present study demonstrated that the KRAS 3'-UTR rs61764370 polymorphism interfered with miRNA/mRNA interaction, and showed that the minor allele was associated with an elevated risk of developing metastatic disease in OS.
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Regiões 3' não Traduzidas/genética , Neoplasias Ósseas/genética , MicroRNAs/genética , Osteossarcoma/genética , Polimorfismo de Nucleotídeo Único , Sequência de Bases , Western Blotting , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Ligação Proteica/genética , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
PURPOSE: To investigate the effect and underlying mechanism of Aceglutamide on motor dysfunction in rats after cerebral ischemia-reperfusion. METHODS: Adult male Sprague-Dawley rats were subjected to 2 h transient middle cerebral artery occlusion (MCAO). Aceglutamide or vehicle was intraperitoneally given to rats at 24 h after reperfusion and lasted for 14 days. Subsequently functional recovery was assessed and number of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) was analyzed. Tumor necrosis factor receptor-associated factor 1(TRAF1), P-Akt and Bcl-2/Bax were determined in mesencephalic tissue by Western blot method. PC12 cells and primary cultured mesencephalic neurons were employed to further investigate the mechanism of Aceglutamide. RESULTS: Aceglutamide treatment improved behavioral functions, reduced the infarction volume, and elevated the number of TH-positive neurons in the SN. Moreover, Aceglutamide significantly attenuated neuronal apoptosis in the SN. Meanwhile Aceglutamide treatment significantly inhibited the expression of TRAF1 and up-regulated the expression of P-Akt and Bcl-2/Bax ratio both in vitro and in vivo. CONCLUSIONS: Aceglutamide ameliorated motor dysfunction and delayed neuronal death in the SN after ischemia, which involved the inhibition of pro-apoptotic factor TRAF1 and activation of Akt/Bcl-2 signaling pathway. These data provided experimental information for applying Aceglutamide to ischemic stroke treatment.
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Isquemia Encefálica/tratamento farmacológico , Glutamina/análogos & derivados , Transtornos dos Movimentos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Animais , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutamina/química , Glutamina/farmacologia , Infarto da Artéria Cerebral Média , Injeções Intraperitoneais , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Transtornos dos Movimentos/patologia , Transtornos dos Movimentos/fisiopatologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Células PC12 , Ratos , Ratos Sprague-Dawley , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Resultado do TratamentoRESUMO
Small cell lung cancer (SCLC) is one of the most malignant cancers in the world and 5-year survival rate has not been significantly improved with conventional chemotherapy. Targeting treatment may be a promising alternative to enhance the antitumor efficacy. Present study was aimed at establishing a targeting nanodrug delivery system for SCLC therapy. A targeting peptide (AHSGMYP, named AP), screened in H446 cells by phage display technology, was conjugated to the docetaxel (DTX) encapsulated polylactic acid nanoparticles (DN) to prepare the targeting DTX nanoparticles (AP-DN). Cell cytotoxicity, cellular uptake, therapeutic efficacy and biodistribution of AP-DN were investigated in vitro and in vivo experiment. The mean particle size of AP-DN was 260 nm with encapsulation efficiency >94% and a sustained release profile. Cytotoxicity of AP-DN against H446 cell was superior to that of DTX and DN. AP-DN exhibited excellent antitumor efficacy and particularly effectively inhibited the liver metastases with better tolerance. Results of cellular uptake and biodistribution indicated that the excellent antitumor efficacy of AP-DN was attributed to both the increased accumulation of drug and cellular uptake. To our knowledge, this is the first report on establishing SCLC targeting delivery system which offers a potential therapeutic alterative for SCLC therapy.
Assuntos
Ácido Láctico/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Nanopartículas/administração & dosagem , Polímeros/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/patologia , Taxoides/administração & dosagem , Taxoides/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Docetaxel , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ácido Láctico/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Nanopartículas/química , Tamanho da Partícula , Poliésteres , Polímeros/química , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Taxoides/química , Taxoides/uso terapêuticoAssuntos
Terapia por Acupuntura/história , Adulto , Idoso , Criança , China , Feminino , Herpes Zoster/terapia , História do Século XX , História do Século XXI , Humanos , Masculino , Caxumba/terapia , Paroniquia/terapia , Ciática/terapiaRESUMO
OBJECTIVE: To explore the effective therapeutic method in the treatment of idiopathic sudden hearing loss (ISHL). METHODS: One hundred and eighty-eight cases of ISHL were randomized into a warming-promoting needling group (74 cases), a conventional acupuncture group (56 cases) and a medication group (58 cases). In the conventional acupuncture group, the conventional needling technique was applied to Baihui (GV 20), Fengchi (GB 20), Yifeng (TE 17), Tinggong (SI 19), Touqiaoyin (GB 11) and Zhigou (TE 6) on the affected side. The treatment was given 5 times each week. Totally, the treatment of 6 weeks was required. In the warming-promoting needling group, on the basic treatment as the conventional acupuncture group, the warming-promoting needling technique was applied to Fengchi (GB 20). In the medication group, the intravenous drop with salvia injectio and mecobalamin was prescribed, once per day, for 10 days totally. Meanwhile, Erlong Zuoci Wan was prescribed for oral administration, 8 pills each time, three times a day for 30 days continuously. RESULTS: All of the three therapeutic methods achieved the effect on ISHL. The total effective rate was 89.2% (66/74) in the warming-promoting needling group, which was better than 62.5% (35/56) in the conventional acupuncture group and 53.4% (31/58) in the medication group (both P<0.01). CONCLUSION: The warming-promoting needling techinque achieves the significant efficacy on ISHL. The hearing improvement is superior to that treated with either the conventional needling technique or medication.