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Methyltransferase-like protein 3 (METTL3) plays critical roles in acute myeloid leukemia (AML) progression, however, the mechanism of abnormal overexpression of METTL3 in AML remain elusive. In the current study, we uncovered that Yin Yang 1 (YY1) binds to the promoter region of METTL3 as a transcription factor and promotes its expression, which in turn enhances the proliferation of AML cells. Mechanistically, YY1 binds to HDAC1/3 and regulates METTL3 expression in a moderate liquid-liquid phase separation (LLPS) manner. After mutation of the HDAC-binding site of YY1 or HDAC inhibitor (HDACi) treatment, YY1 was separated from HDAC1/3, which resulted in an excessive LLPS state, thereby inhibiting the expression of METTL3 and the proliferation of AML cells. In conclusion, our study clarified the regulatory mechanism of the abnormal expression of METTL3 in AML, revealed the precise "Yin-Yang" regulatory mechanism of YY1 from the perspective of LLPS degree, and provided new ideas for the precise diagnosis and treatment of AML.
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Histona Desacetilasa 1 , Leucemia Mieloide Aguda , Metiltransferasas , Factor de Transcripción YY1 , Humanos , Sitios de Unión , Proliferación Celular/genética , Histona Desacetilasa 1/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Regiones Promotoras Genéticas/genética , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
Hernandezine is isolated from an herbal medicine that selectively inhibits multidrug resistance and improves the efficacy of drugs for cancer treatment. To date, no studies on hernandezine in melanoma have been conducted. In this study, hernandezine was found to inhibit proliferation and induce apoptosis in melanoma A375 cells and B16 cells. In hernandezine-treated melanoma cells, G0/G1 cycle arrest occurred accompanied by significantly downregulated levels of phosphorylated JAK2 and STAT3. In addition, the cycle arrest could be enhanced by AG490 (JAK2 inhibitor), suggesting that the JAK2/STAT3 pathway is involved in cell cycle regulation in hernandezine-treated melanoma cells. Hernandezine-treated melanoma cells exhibited autophagy-specific structures, autophagy markers (LC3II/LC3-I), and autophagic flow over time. Moreover, 3-MA (autophagy inhibitor) significantly inhibited apoptosis, indicating that hernandezine promotes apoptosis by inducing autophagy. Combined with differential expression of P-AMPK, P-ACC (downstream targets of adenine monophosphate activated protein kinase, AMPK), and P-p70S6K (downstream targets of mammalian target of rapamycin, mTOR) and significant inhibition of apoptosis by AMPK inhibitor complex C (CC) in hernandezine-treated melanoma cells suggested that hernandezine could induce autophagy via the AMPK-mTOR pathway, thereby inducing apoptosis. This study first analyzed the effect of melanoma cells by hernandezine and provided a theory for hernandezine in the treatment of melanoma.
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Proteínas Quinasas Activadas por AMP , Melanoma , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis , Autofagia , Bencilisoquinolinas , Línea Celular Tumoral , Proliferación Celular , Humanos , Melanoma/tratamiento farmacológico , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Objective: Dietary supplements (DS) may improve micronutrient deficiencies, but the unique eating habits and cultural customs of the Chinese Mongolian population affect their choice of DS. Therefore, this study adopted a cross-sectional method to explore the current status of DS use and to assess the influencing factors in the Mongolian population in Inner Mongolia, China. Methods: We used a multistage random cluster sampling method to select 1,434 Mongolian people aged ≥ 18 years in Hohhot and Xilinhot, Inner Mongolia. Data regarding general patient characteristics and DS use through questionnaire surveys were obtained, and the blood plasma was collected for biochemical index detection. The binary logistic regression and decision tree algorithm were used to predict the factors influencing DS use among the Mongolian population. Results: Among 1,434 participants that completed the baseline survey, the usage rate of DS was 18.83%, and more women than men used DS (P = 0.017). Higher use of DS was reported among individuals aged ≤ 34 years, but this difference is not statistically significant (P = 0.052). Usage rate was higher among those living in urban areas (P < 0.001), those with higher education (P < 0.001), those engaged in mental work (P < 0.001), and nonsmokers (P = 0.019). The biochemical test results showed that the proportion of people with abnormal total cholesterol levels using DS was lower (P = 0.003), but that of those with abnormal triglyceride levels using DS was higher (P = 0.001), compared with the proportion of those with normal levels in each case. The most commonly used supplement was calcium (58.15%). Education level was the main factor affecting DS intake. The results of the binary logistic regression model and decision tree model both showed that region, educational level, and abnormal triglyceride levels were significant factors influencing DS intake among Mongolians. Conclusion: Findings from this study indicate that DS intake is uncommon in the Mongolian population. In addition, sex, region, education level, and triglyceride levels may influence DS use.
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Pueblo Asiatico , Suplementos Dietéticos , Adolescente , Adulto , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , TriglicéridosRESUMEN
Polyphyllin I (PPI) purified from Polyphyllarhizomes displays puissant cytotoxicity in many kinds of cancers. Several researches investigated its anti-cancer activity. But novel mechanisms are still worth investigation. This study aimed to explore PPI-induced endoplasmic reticulum (ER) stress as well as the underlying mechanism in non-small cell lung cancer (NSCLC). Cell viability or colony-forming was detected by MTT or crystal violet respectively. Cell cycle, apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were assessed by flow cytometry. Gene and protein levels were evaluated by qRT-PCR and immunoblotting respectively. Protein interaction was determined by immunoprecipitation or immunofluorescence assay. Gene overexpression or silencing was carried out by transient transfection with plasmids or small interfering RNAs. The Cancer Genome Atlas (TCGA) database was used for Gene Set Enrichment Analysis (GSEA), survival analysis, gene expression statistics or pathway enrichment assay. PPI inhibited the propagation of NSCLC cells, increased non-viable apoptotic cells, arrested cell cycle at G2/M phase, induced ROS levels but failed to decrease mitochondrial membrane potential. High levels of GRP78 indicates poor prognosis in NSCLC patients. PPI selectively suppressed unfolded protein response (UPR)-induced GRP78 expression, subsequently protected CHOP from GRP78-mediated ubiquitination and degradation. We demonstrated that the natural product PPI, obtained from traditional herbal medicine, deserves for further study as a valuable candidate for lead compound in the chemotherapy of NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Diosgenina/análogos & derivados , Neoplasias Pulmonares , Factor de Transcripción CHOP/metabolismo , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Ciclo Celular , Línea Celular Tumoral , Supervivencia Celular , Diosgenina/farmacología , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Proteínas de Choque Térmico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Potencial de la Membrana Mitocondrial , Especies Reactivas de Oxígeno/metabolismo , Ubiquitinación , Respuesta de Proteína DesplegadaRESUMEN
OBJECTIVE: Iguratimod, an anti-rheumatic drug, has been widely used in the treatment of rheumatoid arthritis, but is still at an investigative stage for treatment of systemic lupus erythematosus (SLE). We examined the therapeutic effects of iguratimod and the mechanism underlying the efficacy in murine lupus model. METHODS: Pristane-induced lupus model of BALB/c mice (PI mice) were treated with iguratimod and mycophenolate mofetil. Proteinuria, anti-dsDNA antibodies and immunoglobulins production were measured. Renal pathology was evaluated. The percentage of Th17 and Treg cells in spleen and the expression of cytokines and mRNAs related to Th17 and Treg cells was analyzed. RESULTS: Iguratimod attenuated the severity of nephritis in PI mice in a dose-dependent manner. Proteinuria was continuously decreased and pathology of glomerulonephritis and tubulonephritis was significantly reduced along with reduction of glomerular immune complex deposition. Also, serum anti-dsDNA and total IgG and IgM levels were reduced by iguratimod in mice. It is worth mentioning that the efficacy of the 30 mg/kg/d iguratimod dose is comparable to, or even better than, 100 mg kg/d of mycophenolate mofetil. Furthermore, the percentage of Th17 cells was found decreased and the percentage of Treg cells increased. ROR-γt mRNA and serum cytokines (IL-17A and IL-22) of Th17 cells decreased accordingly. By contrast, Foxp3 mRNA and cytokines (TGF-ß and IL-10) of Treg cells increased. CONCLUSION: Iguratimod ameliorates nephritis of SLE and modulates the Th17/Treg ratio in murine nephritis of SLE, suggesting that Iguratimod could be an effective drug in treatment of SLE.
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Artritis Reumatoide/tratamiento farmacológico , Cromonas/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Anticuerpos Antinucleares/sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunoglobulinas/sangre , Ratones , Ratones Endogámicos BALB C , Proteinuria , Terpenos/administración & dosificaciónRESUMEN
BACKGROUND: Therapeutic failure and drug resistance are common and have important implications in the poor prognosis of advanced breast cancer. It is necessary to acquire a natural product to overcome the resistance of cancer and increase the sensitivity of drug-resistant cells to anticancer agents. PURPOSE: To demonstrate whether the compound Vielanin K (VK) has the potential to increase the sensitivity of MCF-7 and MCF-7/MDR cells to anticancer agents. METHODS: Cell viability and proliferative capacity were determined by MTT, colony formation and EdU assays. Apoptosis and Ca2+ accumulation were evaluated by flow cytometry. Then, proteins were detected by immunoblotting, and gene expression levels were explored by qRT-PCR. RESULTS: In MCF-7 and corresponding MDR cells, VK increased the fluorescence intensity of Rho123, but not CFDA. VK treatment did not affect the protein expression of P-gp, MRP1 or BCRP. VK treatment enhanced the DOX-induced apoptotic cascade, while VK combined with DOX increased JNK phosphorylation by activating the IRE1α-TRAF2 signaling pathway. In addition, Ca2+ was released from the endoplasmic reticulum following combination treatment, thereby giving rise to mitochondrial apoptosis. Silencing IRE1α and JNK with small interfering RNA (siRNA) efficiently attenuated combination treatment-induced apoptosis. These effects caused mitochondrial depolarization and reduced viability in MCF-7 and corresponding MCF-7/MDR cells. CONCLUSION: VK combined with DOX increases the apoptosis of MCF-7 and corresponding MCF-7/MDR cells by activating ER stress and mitochondrial apoptosis via IRE1α-TRAF2-JNK signaling.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Doxorrubicina/farmacología , Apoptosis/fisiología , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/administración & dosificación , Resistencia a Antineoplásicos/efectos de los fármacos , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células MCF-7 , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Factor 2 Asociado a Receptor de TNF/metabolismoRESUMEN
The plants of genus Toona are well known for diverse limonoid secondary metabolites, while polyacetylenes are rarely found from Toona species. In this work, six new polyacetylenes toonasindiynes A-F (1-6) and six known analogues (7-12) were isolated from the root bark of Toona sinensis. Their structures and absolute configurations were elucidated by HRESIMS, 1D and 2D NMR spectroscopic analysis, modified Mosher's method, and biosynthetic consideration. These polyacetylenes share the same 4,6-diyne moiety with different side chain length and different oxidation degree. Bioactivity screening revealed the cytotoxic activity of 3, 5, 9, and 11 against U2OS cells, and the inhibitory effects on nitric oxide (NO) production of 1, 2, 5, 8, 9, and 11 in lipopolysaccharide-induced RAW 264.7 cells.
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Antiinflamatorios/farmacología , Antineoplásicos Fitogénicos/farmacología , Polímero Poliacetilénico/farmacología , Toona/química , Animales , Antiinflamatorios/aislamiento & purificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , China , Humanos , Ratones , Estructura Molecular , Óxido Nítrico/metabolismo , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Raíces de Plantas/química , Polímero Poliacetilénico/aislamiento & purificación , Células RAW 264.7RESUMEN
Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder among children. The theory of traditional Chinese medicine (TCM) does not have a special term of this disease, and classifies ADHD to the category of " forgetfulness" " dysphoria" " injudiciousness" according to its clinical manifestations. TCM theoretic and clinical systems for treating ADHD have been developed, but current pharmacodynamics studies of TCM on ADHD have mostly focused on neurotransmitter metabolic system and its receptor signaling pathway to reflect the advantages of multi-component and multi-target effect of TCM, but failed to demonstrate the scientific connotations of TCM theory, such as " coordination between kidney and brain" and " steady Yin and vexed Yang" , and ignored the delay in cortical maturation as the core neuropathology of ADHD. The symptoms relating to " restlessness of Yang" due to Yin deficiency that cannot inhibit hyperactivity of Yang, kidney-Yin deficiency and liver-Yang excess syndrome is the most common syndrome of ADHD, and TCMs with effect of invigorating kidney and filling sea of marrow are mostly used by TCM practitioners. According to anatomy basis of neuronal development disorder, the new theory of " energy metabolism dysfunction" , the pathogenesis hypothesis of sea of marrow development disorder and its relevant clinical practices and experimental studies, substantial basis studies of the therapy for " invigorating kidney and filling sea of marrow" , as well as pharmacodynamics study of <italic>Rehmannia glutinosa</italic> (Shudihuang) for treating ADHD, we put forward ADHD pathogenesis that " restlessness of Yang due to Yin deficiency" is related to the disorder of executive function due to the delay in cortical maturation, energy metabolism dysfunction and neurodevelopmental disorder, and regarded that TCMs with effect of invigorating kidney and filling sea of marrow are the most commonly used to treat ADHD, and improve delay in cortical maturation corresponding to sea of marrow insufficiency by regulating dysfunction of neurodevelopment and energy metabolism, so as to relieve the core symptoms of ADHD. The new treatment model of TCM with effect of invigorating kidney and filling sea of marrow for treating ADHD will provide a theoretical basis for improving the clinical efficacy of ADHD.
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BACKGROUND: Multidrug resistance (MDR) refers to the phenotype of tumor cells that are resistant to various chemotherapeutic drugs with different structures and functions, which is clearly disadvantageous for patients. Finding a natural product that can effectively reverse the MDR of tumor cells is important for the treatment of patients. PURPOSE: To prove that tooniliatone A (TA), a novel typical limonoid, can effectively reverse the MDR of tumor cells and to explore its mechanism of action. METHODS: The MTT, CCK-8 and monoclonal formation assays, as well as flow cytometry, were used to evaluate the role of TA in reversing tumor multidrug resistance; then the mechanism of action for TA was explored by western blotting and real-time fluorescent quantitative PCR. RESULTS: TA significantly reversed the MDR of the K562/MDR and MCF-7/MDR cell lines. TA can inhibit the anti-apoptotic protein Bcl-xL to make cells sensitive to common chemotherapeutic drugs and activate the SAPK/JNK pathway to promote phosphorylation of JNK and its downstream cJun protein. Small interfering RNA-mediated knockdown of JNK and cJun could antagonize the MDR reversal effect of TA and the inhibition of Bcl-xL by TA. Therefore, we hypothesized that TA activates the JNK pathway to increase the transcription of the proapoptotic protein Bim, thereby inhibiting Bcl-xL and reversing MDR in tumor cells. CONCLUSION: Our study suggests that TA reverses tumor MDR by activating the SAPK/JNK pathway to inhibit the action of Bcl-xL. TA may be an effective tumor MDR reversal agent.
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Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Limoninas/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína bcl-X/metabolismo , Apoptosis/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica , Humanos , Células K562 , Sistema de Señalización de MAP Quinasas/genética , Células MCF-7 , Magnoliopsida/química , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Interferente Pequeño , Proteína bcl-X/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Cancer cells that are resistant to structurally and mechanically unrelated anticancer drugs are said to have multidrug resistance (MDR). The overexpression of the ATP-binding cassette (ABC) transporter is one of the most important mechanisms of MDR. Vielanin P (VP), a dimeric guaiane from the leaves of Xylopia vielana, has the potential to reverse multidrug resistance. PURPOSE: To evaluate the meroterpenoid compound VP as a low cytotoxicity MDR regulator and the related mechanisms. METHODS: Cell viability was determined by CCK-8 and MTT assays. Apoptosis and the accumulation of doxorubicin (DOX) and 5(6)-carboxyfluorescein diacetate (CFDA) were determined by flow cytometry. We determined mRNA levels by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were analyzed by Western blotting and immunofluorescence. RESULTS: In the MCF-7 and K562 DOX-resistant cell lines, VP treatment (10⯵M or 20⯵M) enhanced the activity of chemotherapeutic agents. We found that VP selectively inhibited MRP1 mRNA but not MDR1 mRNA. VP enhanced DOX-induced apoptosis and reduced colony formation in the presence of DOX in drug-resistant cells. Moreover, VP increased the accumulation of DOX and the MRP1-specific substrate CFDA. In addition, VP reversed MRP1 protein levels and the accumulation of DOX and CFDA in MRP1-overexpressing MCF-7 and K562 cells. Thus, the mechanism of MDR reversal by VP is MRP1-dependent. Furthermore, we found that the inhibitory effect of VP on MRP1 is PI3K/Nrf2-dependent. CONCLUSION: These results support the potential therapeutic value of VP as an MDR-reversal agent by inhibiting MRP1 via PI3K/Nrf2 signaling.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Sesquiterpenos de Guayano/farmacología , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Doxorrubicina/farmacología , Interacciones Farmacológicas , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células K562 , Células MCF-7 , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Xylopia/químicaRESUMEN
Triacylglycerol (TAG) composition of breast milk plays an important role in improving digestion, absorption, and metabolism when consumed by infants. This study characterized the TAG profile of human colostrum, transitional, and mature milk samples from 103 women. Significant differences in the TAGs composition of breast milk fat from three lactation stages were observed. The TAGs with high molecular weight and unsaturated fatty acid (such as 1,3-olein-2-palmitin (OPO) and 1(3)-olein-2-palmitin-3(1)-linolein (OPL)) were enriched in colostrum, while the TAGs containing medium-chain fatty acids were more abundant in transitional and mature milk than that in colostrum. Of note, OPL was the most common TAG in breast milk of Chinese women while the most common TAG in breast milk of Western women was OPO. This data will promote the development of infant formulas in terms of the TAG composition more suitable for infants.
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Calostro/química , Leche Humana/química , Triglicéridos/química , Adulto , China , Ácidos Grasos/química , Femenino , Humanos , Lactancia , Embarazo , Adulto JovenRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The genus Salvia is one of the largest genera of the Lamiaceae family. In China, about 40 Salvia species have been used as medicinal plants for treatment of various diseases, specifically hepatic and renal diseases and those of the cardiovascular and immune systems. AIM OF THIS REVIEW: This review aims to provide systematically organized information on the ethnopharmacology, phytochemistry, pharmacology, and toxicology of medicinal Salvia species in China to support their therapeutic potential in the treatment of human diseases. MATERIALS AND METHODS: Relevant information on the Chinese Salvia species was obtained from scientific online databases such as Google Scholar, PubMed, and SciFinder. Additional information was derived from other literature sources (e.g. Chinese Pharmacopoeia 2015 edition, Chinese herbal classic books, PhD and MSc thesis, etc). RESULTS: Our comprehensive analysis of the scientific literature indicates that many Chinese Salvia species are valuable and popular herbal medicines with therapeutic potentials to cure various ailments. Phytochemical analyses identified diterpenoids and phenolic acids as the major bioactive substances in Chinese Salvia species. Crude extracts and pure compounds isolated from the Chinese Salvia species exhibited various pharmacological activities, typically targeting the cardiovascular and immune systems and hepatic and renal diseases. CONCLUSION: This review summarizes the results from current studies about basic properties of medicinal Salvia species in China, such as active constituents and their mechanism of action, pharmacokinetics, underlying molecular mechanisms, toxicology, and efficacy, which are still being studied and explored to achieve integration into medical practice.
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Fitoterapia , Salvia , Animales , China , Etnobotánica , Etnofarmacología , Humanos , Medicina Tradicional , Fitoquímicos/análisis , Fitoquímicos/farmacología , Fitoquímicos/toxicidad , Preparaciones de Plantas/análisis , Preparaciones de Plantas/farmacología , Preparaciones de Plantas/uso terapéutico , Preparaciones de Plantas/toxicidadRESUMEN
BACKGROUND: Physakengose G (PG) is a new compound first isolated from Physalis alkekengi var. franchetii, an anticarcinogenic traditional Chinese medicine. PG has shown promising anti-tumor effects, but its underlying mechanisms remain unknown. PURPOSE: To investigate the anti-cancer effects of PG on human osteosarcoma cells and the underlying mechanisms. METHODS: Cell viability was measured by MTT assay. Apoptosis rates, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation, and acidic vesicular organelles (AVOs) formation were determined by flow cytometry. Protein levels were analyzed by immunofluorescence and western blotting. RESULTS: PG inhibited cell proliferation and induced apoptosis in human osteosarcoma cells. PG treatment blocked EGFR phosphorylation and suppressed epidermal growth factor (EGF)-induced activation of downstream signaling molecules, such as AKT and mTOR. PG treatment resulted in lysosome dysfunction by altering lysosome acidification and LAMP1 levels, which led to autophagosome accumulation and autophagic flux inhibition. CONCLUSION: PG inhibits cell proliferation and EGFR/mTOR signaling in human osteosarcoma cells. Moreover, PG induces apoptosis through the mitochondrial pathway and impedes autophagic flux via lysosome dysfunction. Our findings indicate that PG has the potential to play a significant role in the treatment of osteosarcoma.
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Neoplasias Óseas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Receptores ErbB/metabolismo , Osteosarcoma/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/química , Humanos , Proteínas de Membrana de los Lisosomas/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Osteosarcoma/patología , Physalis/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. Our previous study has shown that icariin could reverse MDR in MG-63 doxorubicin-resistant (MG-63/DOX) cells. It is reported that icariin is usually metabolized to icariside II and icaritin. Herein, we investigated the effects of icariin, icariside II, and icaritin (ICT) on reversing MDR in MG-63/DOX cells. Among these compounds, ICT exhibited strongest effect and showed no obvious cytotoxicity effect on both MG-63 and MG-63/DOX cells ranging from 1 to 10 µmol·L-1. Furthermore, ICT increased accumulation of rhodamine 123 and 6-carboxyfluorescein diacetate and enhanced DOX-induced apoptosis in MG-63/DOX cells in a dose-dependent manner. Further studies demonstrated that ICT decreased the mRNA and protein levels of multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1). We also verified that blockade of STAT3 phosphorylation was involved in the reversal effect of multidrug resistance in MG-63/DOX cells. Taken together, these results indicated that ICT may be a potential candidate in chemotherapy for osteosarcoma.
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Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Flavonoides/farmacología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/toxicidad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Osteosarcoma/patología , Fosforilación/efectos de los fármacos , Rodamina 123/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Triterpenos/farmacologíaRESUMEN
In SBR reactor, the mature granular sludge fed with sodium acetate was gradually cultivated with different carbon sources (sodium acetate/glucose ratio was 1:0, 3:1, 1:1, 1:3 and 0:1, in terms of COD, respectively). During the five stages, the physical, biochemical properties, extracellular polymeric substances (EPS), phosphorus fractions and nitrogen and phosphorus removal efficiency of granular sludge were studied. 705 days' experimental results were showed as follows. At stage â £, the granular sludge had the smallest diameter of 0.5 mm; moreover the phosphorus release/uptake rate, denitrification rate and the total phosphorus (TP) content were the lowest. While at stages â and â ¡, the phosphorus release/uptake and denitrification rates were the highest, meanwhile, the TP content reached up to 72.36 mg·g-1, and the EPS content was about 350 mg·g-1, as a result, the nitrogen and phosphorus removal efficiencies were both over 94%. Nevertheless at stage â ¤, the biochemical rates were slightly slower than values of stages â and â ¡, simultaneously the TP, glycogen and EPS contents in sludge were maintained at 69.60 mg·g-1, 224.18 mg·g-1 and 200 mg·g-1, respectively, while high nitrogen and phosphorus removal efficiency was obtained. During all stages, Ca-P was the main phosphorus fraction, and inorganic phosphorus(IP) was closely related to phosphorus removal of granular sludge.
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Carbono/química , Nitrógeno/aislamiento & purificación , Fósforo/aislamiento & purificación , Aguas del Alcantarillado/química , Eliminación de Residuos Líquidos , Reactores Biológicos , Desnitrificación , Glucógeno/químicaRESUMEN
BACKGROUND: Neuroinflammation plays a vital role in Alzheimer's disease (AD) and other neurodegenerative conditions. Sophora alopecuroides is widely used in traditional Uighur's medicine for the treatment of inflammation. Sophoraflavanone G (SG), a major flavonoid found in the S. alopecuroides, has also been reported to exhibit anti-inflammatory activity both in vitro and in vivo. However, the effect of S. alopecuroides and SG on microglia-mediated neuroinflammation has not been investigated. PURPOSE: The present study was designed to evaluate the anti-neuroinflammatory effect of S. alopecuroides and SG against lipopolysaccharide (LPS)-activated BV2 microglial cells and to explore the underlying mechanisms. METHODS: We measured the production of pro-inflammatory mediators and cytokines, and analyzed relevant mRNA and protein expressions by qRT-PCR and Western Blot. RESULTS: S. alopecuroides extract (SAE) and SG inhibited the LPS-induced release of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß). Additionally, SG reduced gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-6 and IL-1ß, and further decreased the protein expressions of iNOS and COX-2. Mechanism studies found that SG down-regulated phosphorylated mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase (PI3K)/AKT and Janus kinase/signal transducer and activator of transcription (JAK/STAT), and up-regulated heme oxygenase-1 (HO-1) expression via nuclear translocation of nuclear factor E2-related factor 2 (Nrf2). In addition, SG inhibited the cytotoxicity of conditioned medium prepared by LPS-activated BV2 microglia to neuronal PC12 cells and improved cell viability. CONCLUSION: S. alopecuroides and SG displayed anti-neuroinflammatory activity in LPS-activated BV2 microglia. SG was able to inhibit the neuroinflammation by MAPKs, PI3K/AKT, JAK/STAT and Nrf2/HO-1 signaling pathways and might act as a natural therapeutic agent to be further developed for the treatment of various neuroinflammatory conditions.
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Antiinflamatorios no Esteroideos/farmacología , Flavanonas/farmacología , Hemo-Oxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Microglía/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sophora/química , Animales , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Quinasas Janus/metabolismo , Lipopolisacáridos/farmacología , Ratones , Microglía/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factores de Transcripción STAT/metabolismoRESUMEN
The aberrant energy homeostasis that characterized by high rate of energy production (glycolysis) and energy consumption (mRNA translation) is associated with the development of cancer. As mammalian target of rapamycin (mTOR) is a critical regulator of aberrant energy homeostasis, it is an attractive target for anti-tumor intervention. The flavonoid compound Icariside II (IS) is a natural mTOR inhibitor derived from Epimedium. Koreanum. Herein, we evaluate the effect of IS on aberrant energy homeostasis. The reduction of glycolysis and mRNA translation in U2OS (osteosarcoma), S180 (fibrosarcoma) and SW1535 (chondrosarcoma) cells observed in our study, indicate that, IS inhibits aberrant energy homeostasis. This inhibition is found to be due to suppression of mammalian target of rapamycin complex 1 (mTORC1)-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) axis through blocking the assembly of mTORC1. Furthermore, IS inhibits the cap-dependent translation of c-myc through mTORC1-4E-BP1 axis which links the relationship between mRNA translation and glycolysis. Inhibition of aberrant energy homeostasis by IS, contributes to its in vitro and in vivo anti-proliferation activity. These data indicate that IS disrupts aberrant energy homeostasis of sarcoma cells through suppression of mTORC1-4E-BP1 axis, providing a novel mechanism of IS to inhibit cell proliferation in sarcoma cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Medicamentos Herbarios Chinos/farmacología , Epimedium/química , Flavonoides/farmacología , Homeostasis/efectos de los fármacos , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Sarcoma/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/uso terapéutico , Flavonoides/uso terapéutico , Glucólisis/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Fosfoproteínas/genética , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/genética , Interferencia de ARN , ARN Interferente Pequeño , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Proteína Reguladora Asociada a mTOR/genética , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this study, the anti-cancer effect of Icariside II (IS), a natural plant flavonoid, against hepatoblastoma cells and the underlying mechanisms were investigated. The in vitro and in vivo studies show that IS decreased the viability of human hepatoblastoma HepG2 cells in a concentration- and time-dependent manner and inhibited tumor growth in mice transplanted with H22 liver carcinomas. IS impaired mitochondria and lysosomes as evidenced by signs of induced mitochondrial and lysosomal membrane permeabilization, resulting in caspase activation and apoptosis. SQSTM1 up-regulation and autophagic flux measurements demonstrated that IS exposure also impaired autophagosome degradation which resulted in autophagosome accumulation, which plays a pro-survival role as the genetic knockdown of LC3B further sensitized the IS-treated cells. Electron microscopy images showed that autophagosome engulfs IS-impaired mitochondria and lysosomes, thus blocking cytotoxicity induced by further leakage of the hydrolases from lysosomes and pro-apoptosis members from mitochondria. In conclusion, these data suggest that IS plays multiple roles as a promising chemotherapeutic agent that induces cell apoptosis involving both mitochondrial and lysosomal damage.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia , Medicamentos Herbarios Chinos/farmacología , Flavonoides/farmacología , Hepatoblastoma/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Lisosomas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Hepatoblastoma/patología , Humanos , Neoplasias Hepáticas/patología , Lisosomas/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Mitocondrias/fisiologíaRESUMEN
3-Hydroxy-isobutyryl-coenzyme A (CoA) hydrolase (HBICH) deficiency is a rare cerebral organic aciduria caused by disturbance of valine catabolism that leads to the accumulation of toxic metabolites, methacrylyl-CoA. The major feature exhibited by a patient with HBICH deficiency includes multiple congenital malformations and abnormal neurologic findings. However, the pathophysiology of this disease remains unknown. The major treatment for HBICH deficiency involves a low-protein diet, especially restricting valine, supplemented with micronutrients and carnitine. To our knowledge, only four patients with HBICH deficiency have been reported. These patients were boys and presented with different clinical, biochemical, and genetic features than our patient. In this report, we described what was to our knowledge the first genetically confirmed girl with HBICH deficiency in China. A 5-mo nutritional intervention was given to the patient by a nutritional support team. On this regimen, the patient's symptoms were alleviated and her quality of life was improved.
Asunto(s)
Enfermedades Carenciales/dietoterapia , Dieta con Restricción de Proteínas , Estado Nutricional , Calidad de Vida , Tioléster Hidrolasas/deficiencia , Carnitina/uso terapéutico , Preescolar , China , Enfermedades Carenciales/tratamiento farmacológico , Enfermedades Carenciales/genética , Enfermedades Carenciales/metabolismo , Femenino , Humanos , Micronutrientes/uso terapéutico , Tioléster Hidrolasas/metabolismo , Valina/metabolismoRESUMEN
Doxorubicin (DOX) was first used in osteosarcoma in the early 1970s as a first-line antineoplastic drug. However, the occurrence of drug resistance in chemotherapeutic treatment has greatly restricted its use. When resistance to DOX treatment occurs, osteosarcoma may become not only resistant to the drug originally administered but also to a wide variety of structurally and mechanistically unrelated drugs. Thus, there is an urgent need to find ways of reversing DOX chemotherapy resistance in osteosarcoma. Plant-derived agents have great potential in preventing the onset of the carcinogenic process and enhancing the efficacy of conventional antitumor drugs. Alopecurone B (ALOB), a flavonoid, is isolated from Traditional Chinese Medicine Sophora alopecuroides L., and is reported to have potent inhibitory effect on multidrug resistance associated protein 1. In this study, a DOX-resistant osteosarcoma cell line (MG-63/DOX) was established by increasing the concentration gradient of DOX in a stepwise manner. MTT assay, flow cytometry analysis, dual-luciferase reporter gene assay, quantitative real-time polymerase chain reaction and Western blot analysis were applied to investigate the reversing effect of ALOB and its underlying mechanisms. The results indicated that ALOB mediated the resistance of MG-63/DOX cells to DOX by inhibiting P-glycoprotein function, transcription and expression. Besides, ALOB also enhanced the sensitivity of MG-63/DOX cells to other conventional chemotherapeutic drugs. Cell viability assay confirmed the reversing activity of ALOB. Furthermore, ALOB increased DOX-induced apoptosis at nontoxic concentration. In addition, ALOB showed inhibitory effect on NF-κB transcription in a DOX-independent manner. Furthermore, NF-κB signaling was suppressed by ALOB in an IKK-dependent manner. These studies not only demonstrate that ALOB is a potential agent for reversal of drug resistant cancers, but also testify that ALOB reverses multidrug resistance by inhibiting P-glycoprotein via NF-κB signaling.