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PURPOSE: It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS: It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS: After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS: BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY: https://www.chictr.org.cn/showproj.html?proj=166181.
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Envejecimiento Prematuro , Medicamentos Herbarios Chinos , Calidad de Vida , Humanos , Método Doble Ciego , Masculino , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Persona de Mediana Edad , Femenino , Anciano , Envejecimiento Prematuro/tratamiento farmacológico , Adulto , Telomerasa , Fuerza de la Mano , Estudios Prospectivos , Telómero/efectos de los fármacosRESUMEN
This study aimed to investigate the effect and mechanism of 2α, 3α, 24-thrihydroxyurs-12-en-24-ursolic acid (TEOA) alone or in combination with cisplatin on oral cancer. TEOA, a pentacyclic triterpenoid compound isolated from the roots of Actinidia eriantha, has demonstrated antitumor activity in preclinical experiments. However, its role in oral cancer remains poorly understood. Our findings revealed that a low concentration of TEOA did not exhibit significant cytotoxicity against oral squamous cell carcinoma cells. However, when combined with cisplatin, TEOA showed a significant therapeutic effect. The combined treatments resulted in a significant inhibition of proliferation and migration and a significant increase in apoptosis of squamous cell carcinoma cells. Cisplatin exposure increased autophagy levels, which may contribute to chemoresistance. Of note, the presence of TEOA significantly inhibited cisplatin-induced autophagy, leading to improved chemotherapy efficacy. Our findings indicate that a mild low dosage of TEOA may enhance the cytotoxic effect of cisplatin by downregulating autophagy in oral cancer cells.
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Antineoplásicos , Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Ácido Ursólico , Carcinoma de Células Escamosas/patología , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Autofagia , Apoptosis , Resistencia a Antineoplásicos , Proliferación CelularRESUMEN
BACKGROUND: Sunitinib was approved several years ago as a first-line drug for treating metastatic renal cell carcinoma (mRCC); however, its high price and broad side effects when administered at the standard dose have limited its clinical use. A clinical trial (NCT02072031) confirmed that anlotinib could be used as the first-line treatment for mRCC. This study was conducted to evaluate the cost-effectiveness of anlotinib as a first-line treatment for mRCC compared to that of sunitinib in China. METHODS: A Markov model was established to compare the cost-effectiveness of anlotinib with that of sunitinib. Clinical data were obtained from a multi-center phase II trial (clinical trial information: NCT02072031). Utility values were obtained from the literature. Total costs were calculated from a Chinese societal perspective. A sensitivity analysis was conducted to assess the model uncertainty. The life-year (LY), quality-adjusted life-year (QALY), and incremental cost-effectiveness ratio were calculated. RESULTS: The base-case analysis over a lifetime horizon of 10 years showed that the anlotinib group had 2.196 LYs and 1.487 QALYs at a total cost of $68,597.84. The sunitinib group had 2.194 LYs and 1.432 QALYs at a total cost of $88,060.02. This resulted in incremental cost-effectiveness ratios (ICER) of anlotinib versus sunitinib of $-9,210,858.93 per LYs and $-354,117.07 per QALYs, suggesting that anlotinib is a more effective and less costly strategy than sunitinib. CONCLUSION: Anlotinib may be a more cost-effective first-line treatment strategy for mRCC than sunitinib in China.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Sunitinib/uso terapéutico , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Análisis de Costo-Efectividad , Análisis Costo-Beneficio , China , Años de Vida Ajustados por Calidad de VidaRESUMEN
Long-term exposure to diethylhexyl phthalate (DEHP), an endocrine-disrupting chemical (EDCs) and plasticizer widely used in consumer products, has been reported to be significantly positively correlated with increased risks of different human diseases, including various cancers, while the potential effect of DEHP on colorectal cancer progression was little studied. In the present study, we showed that DEHP could trigger the metabolic reprogramming of colorectal cancer cells, promote cell growth and decrease fluorouracil (5-FU) sensitivity. Mechanistic studies indicated that DEHP could reduce glycolysis activity and increase oxidative phosphorylation (OXPHOS) in SW620 cells. In addition, in vivo experiments showed that DEHP promoted tumorigenic progression and decreased survival time in mice. Collectively, our findings suggest that DEHP may be a potent risk factor for colorectal cancer development.
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Neoplasias Colorrectales , Dietilhexil Ftalato , Resistencia a la Insulina , Ratones , Humanos , Animales , Dietilhexil Ftalato/toxicidad , Plastificantes/toxicidadRESUMEN
OBJECTIVE: Neratinib plus capecitabine (Ner+Cap) were proved to be clinically beneficial as a third-line treatment for women with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The objective of this study was to evaluate the cost-effectiveness of Ner+Cap from the Chinese healthcare perspective. DESIGN: A three-state Markov simulation model was performed based on the results of NALA trial. The utilities of health state and disutilities of adverse events were derived from the published literature. Direct costs of anticancer agents, drug administration, routine follow-up and serious adverse events management were calculated in the model. Uncertainty was evaluated through univariate and probability sensitivity analysis. PARTICIPANTS: Patients with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1. A total of 621 patients were enrolled in the NALA trial. INTERVENTIONS: Third-line treatment with Ner+Cap or lapatinib plus capecitabine (Lap+Cap). MAIN OUTCOME MEASURES: The primary health outcomes of the model were costs, expected life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: When compared with Lap+Cap, Ner+Cap provided an additional 0.431 LYs and 0.339 QALYs, and increased the cost by $4299.2. The corresponding ICERs were 9970.1/LY and $12 670.2/QALY. Univariate sensitivity analyses suggested that the results were generally robust. Besides, Ner+Cap had a 100% probability of being cost-effective according to probabilistic sensitivity analysis. CONCLUSIONS: Ner+Cap was likely to be a cost-effective regimen as the third-line therapy for women with HER2-positive MBC at the willingness-to-pay threshold of $37 653.0/QALY in China.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Adolescente , Adulto , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Capecitabina/uso terapéutico , China , Análisis Costo-Beneficio , Lapatinib/uso terapéutico , Años de Vida Ajustados por Calidad de Vida , Receptor ErbB-2/metabolismo , Ensayos Clínicos como AsuntoRESUMEN
Defects in tRNA expressions and modifications had been linked to various types of tumorigenesis and progression in recent studies, including colorectal cancer. In the present study, we evaluated transcript levels of mitochondrial tyrosyl-tRNA synthetase YARS2 in both colorectal cancer tissues and normal colorectal tissues using qRT-PCR. The results revealed that the mRNA expression level of YARS2 in colorectal cancer tissues was significantly higher than those in normal intestinal tissues. Knockdown of YARS2 in human colon cancer cell-line SW620 leads to significant inhibition of cell proliferation and migration. The steady-state level of tRNATyr, OCR, and ATP synthesis were decreased in the YARS2 knockdown cells. Moreover, our data indicated that inhibition of YARS2 is associated with increased reactive oxygen species levels which sensitize these cells to 5-FU treatment. In conclusion, our study revealed that targeting YARS2 could inhibit colorectal cancer progression. Thus, YARS2 might be a carcinogenesis candidate gene and can serve as a potential target for clinical therapy.
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Neoplasias Colorrectales , Tirosina-ARNt Ligasa , Adenosina Trifosfato , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo , Humanos , Mutación , ARN Mensajero , ARN de Transferencia de Tirosina , Especies Reactivas de Oxígeno , Tirosina-ARNt Ligasa/genética , Tirosina-ARNt Ligasa/metabolismoRESUMEN
L1-cell adhesion molecule (L1CAM, L1) belongs to the immunoglobulin superfamily and was originally found to play a role in nerve cells. Recently, the expression and prognostic value of L1 has been established in several cancers, including colorectal cancer (CRC). However, its association with lymph node metastasis in CRC and the mechanisms underlying its effects remain unclear. In this study, we evaluated the L1 transcript levels in CRC (n=12) and normal intestinal tissues (n=15) by qRT-PCR. Western blotting was used to evaluate L1 and pERK1/2 expression levels. Immunohistochemistry was performed to evaluate the relationship between L1 and pERK1/2 in CRC tissues with different levels of differentiation. The mRNA expression levels in CRC tissues were significantly higher compared to normal intestinal tissues. Western blotting demonstrated that both L1 and pERK1/2 levels were higher in CRC than in normal tissues. Immunohistochemistry confirmed that L1 and pERK1/2 levels in adenomas with lymph node metastasis were significantly higher than in poorly and well-differentiated adenomas, indicating that L1 and pERK1/2 levels correlated with CRC lymph node metastasis. In conclusion, L1 and pERK1/2 were significantly up-regulated in CRC tissues and lymph node metastasis may occur via the L1CAM-mediated ERK pathway in CRC.
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The current study was designed to explore the role and underlying mechanism of lncRNA taurine up-regulated gene 1 (TUG1) in cardiac hypertrophy. Mice were treated by transverse aortic constriction (TAC) surgery to induce cardiac hypertrophy, and cardiomyocytes were treated by phenylephrine (PE) to induce hypertrophic phenotype. Haematoxylin-eosin (HE), wheat germ agglutinin (WGA) and immunofluorescence (IF) were used to examine morphological alterations. Real-time PCR, Western blots and IF staining were used to detect the expression of RNAs and proteins. Luciferase assay and RNA pull-down assay were used to verify the interaction. It is revealed that TUG1 was up-regulated in the hearts of mice treated by TAC surgery and in PE-induced cardiomyocytes. Functionally, overexpression of TUG1 alleviated cardiac hypertrophy both in vivo and in vitro. Mechanically, TUG1 sponged and sequestered miR-34a to increase the Dickkopf 1 (DKK1) level, which eventually inhibited the activation of Wnt/ß-catenin signalling. In conclusion, the current study reported the protective role and regulatory mechanism of TUG1 in cardiac hypertrophy and suggested that TUG1 may serve as a novel molecular target for treating cardiac hypertrophy.
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Cardiomegalia/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , MicroARNs/metabolismo , ARN Largo no Codificante/metabolismo , Vía de Señalización Wnt , Animales , Secuencia de Bases , Cardiomegalia/patología , Regulación de la Expresión Génica , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Modelos Biológicos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , ARN Largo no Codificante/genéticaRESUMEN
Non-small-cell lung cancer (NSCLC) is an extremely debilitating respiratory malignancy. However, the pathogenesis of NSCLC has not been fully clarified. The main objective of our study was to identify potential microRNAs (miRNAs) and their regulatory mechanism in NSCLC. Using a systematic review, two NSCLC-associated miRNA data sets (GSE102286 and GSE56036) were obtained from Gene Expression Omnibus, and the differentially expressed miRNAs (DE-miRNAs) were accessed by GEO2R. Survival analysis of candidate DE-miRNAs was conducted using the Kaplan-Meier plotter database. To further illustrate the roles of DE-miRNAs in NSCLC, their potential target genes were predicted by miRNet and were annotated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) program. Moreover, the protein-protein interaction (PPI) and miRNA-hub gene regulatory network were established using the STRING database and Cytoscape software. The function of DE-miRNAs in NSCLC cells was evaluated by transwell assay. Compared with normal tissues, a total of eight DE-miRNAs was commonly changed in two data sets. The survival analysis showed that six miRNAs (miR-21-5p, miR-31-5p, miR-708-5p, miR-30a-5p, miR-451a, and miR-126-3p) were significantly correlated with overall survival. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that target genes of upregulated miRNAs were enriched in pathways in cancer, microRNAs in cancer and proteoglycans in cancer, while the target genes of downregulated miRNAs were mainly associated with pathways in cancer, the PI3K-Akt signaling pathway and HTLV-I infection. Based on the miRNA-hub gene network and expression analysis, PTEN, EGFR, STAT3, RHOA, VEGFA, TP53, CTNNB1, and KRAS were identified as potential target genes. Furthermore, all six miRNAs exhibited significant effects on NSCLC cell invasion. These findings indicate that six DE-miRNAs and their target genes may play important roles in the pathogenesis of NSCLC, which will provide novel information for NSCLC treatments.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Neoplasias Pulmonares/genética , MicroARNs/genética , Células A549 , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mapas de Interacción de Proteínas , Programas InformáticosRESUMEN
Bevacizumab (BEV) is widely used for the treatment of patients with recurrent glioblastoma (GBM), but recent evidence demonstrated that BEV induced cytoprotective autophagy, which allows tumor cells to survive. Hydroxychloroquine (HCQ) inhibits lysosomal acidification and blocks autophagy via influencing autophagosome fusion and degradation. HCQ is often used to enhance the efficacy of chemoradiotherapy. However, whether HCQ sensitizes GBM cells to BEV and the molecular mechanism of this effect are not clear. We showed that high concentrations of BEV increased the LC3-II/LC3-I ratio and caused the degradation of Beclin1 in the LN18 and LN229 cell lines, indicating that high concentrations of BEV induced the autophagy of the LN18 and LN229 cells. However, BEV (100⯵g/ml) did not influence the autophagy of the LN18 and LN229 cells, and HCQ at less than 5⯵g/ml significantly accumulated LC3B-II and p62 proteins and blocked the autophagy process. Importantly, we found that HCQ (5⯵g/ml) potentiated the anti-cancer effect of BEV (100⯵g/ml). Therefore, HCQ is a novel strategy that may augment the efficacy of BEV for GBM via the inhibition of autophagy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Autofagia , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Autofagia/efectos de los fármacos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/ultraestructura , Línea Celular Tumoral , Sinergismo Farmacológico , Glioblastoma/patología , Glioblastoma/ultraestructura , Humanos , Hidroxicloroquina/farmacología , Proteínas de Neoplasias/metabolismoRESUMEN
Gastric cancer is an important cancer type worldwide, the antiangiogenic agent BC001 can target the vascular endothelial growth factor receptor 2 (VEGFR2), and significantly suppresses the growth of gastric cancer BGC823 cells in vitro and in vivo. However, numerous results indicated that antiangiogenic drugs could induce autophagy, and the inhibition of autophagy enhanced the anticancer effects of antiangiogenic agents. In the present study, hydroxychloroquine (HCQ), an inhibitor of autophagy, enhanced the antiproliferative and proapoptotic effects of BC001 in vitro. Furthermore, HCQ enhanced the antitumor effects of BC001 on BGC823 xenograft tumors in vivo. Of note, BC001 neither induced nor inhibited autophagy. RNAsequencing results revealed that HCQ regulated autophagy or lysosomalassociated genes, such as tumor protein p53inducible nuclear protein 1, interleukin (IL)1B, tumor necrosis factor (TNF), Mediterranean fever, ubiquitin specific peptidase 36, IL6, neuraminidase (NEU)1, ATPbinding cassette subfamily A member 1, proprotein convertase subtilisin/kexin type 9, myelin basic protein and NEU3. Importantly, HCQ was determined to affect multiple pathways, including 'negative regulation of endothelial cell proliferation', 'blood vessel remodeling', 'cell surface receptor signaling pathways' and 'notch receptor processing' associated with 'signal transduction', 'cancers' and 'immune system', through regulating CXC motif chemokine ligand 8, TNF, IL6, intercellular adhesion molecule 1 and FOS genes. In summary, HCQ was proposed to enhance the anticancer effects of BC001 in gastric cancer via complex mechanisms.
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Anticuerpos Monoclonales/farmacología , Antimaláricos/farmacología , Sinergismo Farmacológico , Hidroxicloroquina/farmacología , Neoplasias Gástricas/patología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Apoptosis , Proliferación Celular , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Células Tumorales Cultivadas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Fulvestrant is the FDA-approved "pure anti-estrogen" agent for malignant breast cancer therapy. But endocrine resistance causes drug failure. A new approach is desired for fulvestrant-resistant breast cancer (FRBC) therapy. This study aims to find an effective approach to inhibit FRBC for patients with advanced breast cancer. MTT assay was first performed to detect the effect of inhibitors of c-ABL (imatinib) and EGFR (lapatinib) on FRBC cells. Microarray analysis was carried out to identify microRNA which is significantly changed between parental and FRBC cells. The related mechanisms were analyzed by qRT-PCR, MTT, AO staining and western blotting. Dual treatment significantly inhibited cell growth of FRBC and upregulated microRNA-375 (miR-375). Overexpression of miR-375 inhibited growth of FRBC cells, reduced autophagy, and decreased expression of ATG7 and LC3-II. Dual treatment elevated expression of miR-375 more than any single one of these two inhibitors. Overexpression of miR-375 increased cell growth inhibition induced by dual treatment, and the effect was attenuated when miR-375 was inhibited. In conclusion, we identified that combined inhibition of EGFR and c-ABL can suppress the growth of FRBC cells and elucidated a mechanism within FRBC cells involving regulation of miR-375 and autophagy. Dual treatment may be useful for inhibiting fulvestrant-resistant breast cancer.
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Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Estradiol/análogos & derivados , Mesilato de Imatinib/farmacología , MicroARNs/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Estradiol/farmacología , Femenino , Fulvestrant , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidoresRESUMEN
OBJECTIVE: To investigate the protective effect of ginsenoside Rg1 on oxygen-glucose deprivation (OGD) in PC-12 cells, and preliminarily discuss the potential molecular mechanism of mTOR/Akt/FoxO3 signaling pathway. METHOD: The OGD PC-12 cell model was established. The cell viability was measured by MTT assay. After the pretreatment with Rg1 with the concentration of 10, 20, 40 micromol x L(-1) for 24 h, the cell viability was observed. Lactate dehydrogenase (LDH) release, superoxide dismutase (SOD) ac- tivity and malondialdehyde (MDA) level were detected by colorimetry assay. mTOR, p-Akt(ser473), p-Akt(tjr308), Akt, p-FoxO3, FoxO3 in cytoplasm and nucleus, and total FoxO3 protein expression were detected by Western blot assay. RESULT: OGD could significantly in- hibit cell proliferation in 4-24 h in a time-dependent manner. After pretreatment for 24 h, Rg1 (20, 40 micromol x L(-1)) could notably elevate the cell viability and SOD viability and reduce the LDH release and MDA content. Besides, Rg1 also inhibited OGD-induced mTOR and p-Akt(ser473) decreases. After treatment for 6 h, OGD could reduce FoxO3 phosphorylation and promote FoxO3 in cytoplasm. This data suggested that Rg1 could protect PC-12 cell injury through mTOR/p-Akt/FoxO3 signaling pathway. CONCLUSION: Ginsenoside Rg1 could attenuate OGD-induced PC-12 cell injury. Its action mechanism may be closely related to activation of mTOR/p-Akt/FoxO3 signaling pathway.
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Apoptosis/efectos de los fármacos , Factores de Transcripción Forkhead/metabolismo , Ginsenósidos/farmacología , Glucosa/metabolismo , Oxígeno/metabolismo , Sustancias Protectoras/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Células PC12 , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Hypoxia is a common phenomenon occurring in the majority of human tumors and has been proved to play an important role in tumor progression. However, it remains unclear that whether the action of hypoxia on macrophages is a main driving force of hypoxia-mediated aggressive tumor behaviors. In the present study, we observe that high density of M2 macrophages is associated with metastasis in adenocarcinoma Non-Small Cell Lung Cancer (NSCLC) patients. By applying the in vivo hypoxia model, the results suggest that intermittent hypoxia significantly promotes the metastasis of Lewis lung carcinoma (LLC), accompanied with more CD209+ macrophages infiltrated in primary tumor tissue. More intriguingly, by skewing macrophages polarization away from the M1- to a tumor-promoting M2-like phenotype, hypoxia and IL-6 cooperate to enhance the LLC metastasis both in vitro and in vivo. In addition, we also demonstrate that skewing of macrophage M2 polarization by hypoxia relies substantially on activation of ERK signaling. Collectively, these observations unveil a novel tumor hypoxia concept involving the macrophage phenotype shift and provide direct evidence for lung cancer intervention through modulating the phenotype of macrophages.
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Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas/fisiología , Macrófagos/patología , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Hipoxia de la Célula/fisiología , Línea Celular , Línea Celular Tumoral , Polaridad Celular/fisiología , Proliferación Celular/fisiología , Progresión de la Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , PorcinosRESUMEN
Hydroxysafflor yellow A (HSYA), the main active ingredient of the safflower plant (Carthamus tinctorius L.), is a hydrophilic drug with low oral bioavailability. Water-in-oil-in-water (w/o/w) double emulsions may enhance the oral absorption of HSYA. In this study, we prepared a self-double-emulsifying drug delivery system (SDEDDS) to improve the absorption of HSYA. SDEDDS consists of water in oil emulsions and hydrophilic surfactants that can self-emulsify into w/o/w double emulsions in the aqueous gastrointestinal environment. Confocal laser scanning micrographs showed that spherical droplets were uniformly distributed in the dispersion medium with narrow particle size distribution and could form fine w/o/w double emulsions upon dilution in dispersion medium with gentle stirring. The dispersed oil droplets contained small dispersed aqueous droplets consistent with the characteristics of double emulsions. Furthermore, in vitro cellular experiments were performed to study the mechanism of the absorption promoting effect of SDEDDS. The accumulation of rhodamine-123 in Caco-2 cells was used to evaluate the efflux transport of p-glycoprotein inhibitor. Histopathologic studies on the rat intestine showed that SDEDDS can cause mucosal damage to a certain degree of toxicity, however this was not serious. These results suggest that SDEDDS can greatly improve the oral absorption of HSYA. Given the toxicity demonstrated to the small intestine, the formulation prescription should be improved to enhance security in the future.
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Chalcona/análogos & derivados , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/química , Quinonas/farmacocinética , Absorción , Análisis de Varianza , Animales , Área Bajo la Curva , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Chalcona/química , Chalcona/farmacocinética , Chalcona/farmacología , Chalcona/toxicidad , Relación Dosis-Respuesta a Droga , Emulsiones/química , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Nanopartículas/administración & dosificación , Quinonas/química , Quinonas/farmacología , Quinonas/toxicidad , Ratas , Ratas Sprague-Dawley , Rodaminas/química , Rodaminas/farmacocinéticaRESUMEN
OBJECTIVE: Currently, there are no clinically used/routine biomarkers that accurately predict whether colorectal cancer (CRC) patients will or will not respond to adjuvant chemotherapy. The aim of this study was to investigate L1, ß-catenin, and E-cadherin expression in patients with CRC and their relationship to tumor progression, and to identify patients who will respond to chemotherapy. METHODS: A total of 142 patients who underwent surgical treatment for CRC were chosen retrospectively. The samples from these patients were analyzed by immunohistochemistry. SPSS-14 program package was used for statistical calculation. RESULTS: Expression of L1, ß-catenin, and E-cadherin were found to be strongly associated with invasion and metastasis of CRC. Cox multivariate analysis results indicated that L1 expression and stage of Dukes could be considered as the independent prognostic factors for survival. Furthermore, our study found that the 5-year survival rate was the significantly associated with the expression of L1, ß-catenin (normal and ectopic expression), and E-cadherin for Dukes' stage B (P < 0.01) patients. However, no such result was found for Dukes' stage A (P > 0.05) and C (P > 0.05) patients. CONCLUSION: Our study provided reference for identifying patients who need adjuvant chemotherapy. L1, ß-catenin, and E-cadherin could be considered as biomarkers to predict whether CRC patients will or will not respond to adjuvant chemotherapy.
Asunto(s)
Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Adolescente , Adulto , Anciano , Cadherinas/metabolismo , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto Joven , beta Catenina/metabolismoRESUMEN
OBJECTIVE: To study the effect and its mechanism of antihypertensive of drug combination of Jimaitong tablt and nifedipine on spontaneously hypertensive rats. METHOD: The spontaneously hypertensive rats (SHR) were treated by intragastric administration (ig) with Jimaitong (450 mg x kg(-1)), Jimaitong (300 mg x kg(-1)) combined with the nifedipine (0.5 mg x kg(-1)), nifedipine (5 mg x kg(-1)) for 8 weeks. Blood pressure and heart rate was measured. The level of oxidation indicators, lipid indicators, as well as hormones related to blood pressure was detected. RESULTS: Compared with that in the control group, systolic blood pressure, diastolic blood pressure, mean arterial pressure of SHR decreased significantly in all the three administration groups (P < 0.01). Heart rates of nifedipine group was faster than other groups (P < 0.05). In combination group, contents of URE, MDA, ET and Ang II were decreased significantly (P < 0.05, P < 0.05, P < 0.05, P < 0.01), the contents of NO and CAMP, SOD and NOS were significantly enhanced (P < 0.05). CONCLUSION: Combination use of Jimaitong and nifedipine has synergistic effects on anti-hypertension in spontaneously hypertensive rats. It indicates the potential applications of combination of traditional Chinese medicine and western medicine for the hypertension treatment.