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Beige fat plays key roles in the regulation of systemic energy homeostasis; however, detailed mechanisms and safe strategy for its activation remain elusive. In this study, we discovered that local hyperthermia therapy (LHT) targeting beige fat promoted its activation in humans and mice. LHT achieved using a hydrogel-based photothermal therapy activated beige fat, preventing and treating obesity in mice without adverse effects. HSF1 is required for the effects since HSF1 deficiency blunted the metabolic benefits of LHT. HSF1 regulates Hnrnpa2b1 (A2b1) transcription, leading to increased mRNA stability of key metabolic genes. Importantly, analysis of human association studies followed by functional analysis revealed that the HSF1 gain-of-function variant p.P365T is associated with improved metabolic performance in humans and increased A2b1 transcription in mice and cells. Overall, we demonstrate that LHT offers a promising strategy against obesity by inducing beige fat activation via HSF1-A2B1 transcriptional axis.
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Tejido Adiposo Beige , Tejido Adiposo Blanco , Hipertermia Inducida , Obesidad/terapia , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismoRESUMEN
Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.
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Adenocarcinoma del Pulmón , Colesterol , Progresión de la Enfermedad , Factor Nuclear 3-gamma del Hepatocito , Neoplasias Pulmonares , Colesterol/metabolismo , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Animales , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Ratones , Factor Nuclear 3-gamma del Hepatocito/metabolismo , Factor Nuclear 3-gamma del Hepatocito/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento CelularRESUMEN
Pharmacological inhibition of IDO1 exhibits great promise as a strategy in cancer therapy. However, the failure of phase III clinical trials has raised the pressing need to understand the underlying reasons for this outcome. To gain comprehensive insights into the reasons behind the clinical failure of IDO1 inhibitors, it is essential to investigate the entire tumor microenvironment rather than focusing solely on individual cells or relying on knockout techniques. In this study, we conducted single-cell RNA sequencing to determine the overall response to apo-IDO1 inhibitor administration. Interestingly, although apo-IDO1 inhibitors were found to significantly activate intratumoral immune cells (mouse colon cancer cell CT26 transplanted in BALB/C mice), such as T cells, macrophages, and NK cells, they also stimulated the infiltration of M2 macrophages. Moreover, these inhibitors prompted monocytes and macrophages to secrete elevated levels of IL-6, which in turn activated the JAK2/STAT3 signaling pathway in tumor cells. Consequently, this activation enables tumor cells to survive even in the face of heightened immune activity. These findings underscore the unforeseen adverse effects of apo-IDO1 inhibitors on tumor cells and highlight the potential of combining IL-6/JAK2/STAT3 inhibitors with apo-IDO1 inhibitors to improve their clinical efficacy.
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Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Interleucina-6 , Neoplasias , Animales , Ratones , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Linfocitos T/metabolismo , Microambiente TumoralRESUMEN
Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, glucolipid metabolism, and inflammation. Thiazolidinediones are PPARγ full agonists with potent insulin-sensitizing effects, whereas their oral usage is restricted because of unwanted side effects, including obesity and cardiovascular risks. Here, via virtual screening, microscale thermophoresis analysis, and molecular confirmation, we demonstrate that diosmin, a natural compound of wide and long-term clinical use, is a selective PPARγ modulator that binds to PPARγ and blocks PPARγ phosphorylation with weak transcriptional activity. Local diosmin administration in subcutaneous fat (inguinal white adipose tissue [iWAT]) improved insulin sensitivity and attenuated obesity via enhancing browning of white fat and energy expenditure. Besides, diosmin ameliorated inflammation in WAT and liver and reduced hepatic steatosis. Of note, we determined that iWAT local administration of diosmin did not exhibit obvious side effects. Taken together, the present study demonstrated that iWAT local delivery of diosmin protected mice from diet-induced insulin resistance, obesity, and fatty liver by blocking PPARγ phosphorylation, without apparent side effects, making it a potential therapeutic agent for the treatment of metabolic diseases.
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Tejido Adiposo Pardo , Tejido Adiposo Blanco , Diosmina , Hígado Graso , Resistencia a la Insulina , PPAR gamma , Animales , Ratones , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Dieta Alta en Grasa , Diosmina/farmacología , Diosmina/metabolismo , Diosmina/uso terapéutico , Hígado Graso/metabolismo , Inflamación/metabolismo , Ratones Endogámicos C57BL , Obesidad/metabolismo , PPAR gamma/metabolismo , Tejido Adiposo Pardo/metabolismoRESUMEN
P-glycoprotein (P-gp)-mediated herb-drug interactions (HDIs) may impact drug efficacy and safety. Tenacissoside G (Tsd-G), a major active component of Marsdenia tenacissima, exhibits anticancer activity. To analyze the effect of Tsd-G on the pharmacokinetics of paclitaxel (PTX), researchers selected 30 Sprague-Dawley (SD) rats, randomized into a solvent control group, a verapamil positive control group, and 20, 40, and 60 mg/kg Tsd-G groups. After seven consecutive days of intraperitoneal injection of verapamil or Tsd-G, a single dose of 6 mg/kg PTX was injected intravenously. Plasma samples were collected at different time points, and proteins were precipitated using a methanol-acetonitrile solution. An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed, with docetaxel as an internal standard, and quantified using positive ion multiple reaction monitoring (MRM) mode. This analytical method's specificity, accuracy, precision, recovery, matrix effect, and sample stability meet the requirements for biological sample determination. After Tsd-G administration in rats, the mean residence time of PTX was significantly prolonged. And Tsd-G can stably bind to P-gp by forming hydrogen bonds and inhibiting the expression of P-gp in rat liver. Although the metabolites of PTX were not detected in this study, the above results still indicate the existence of HDIs between Tsd-G and PTX, and P-gp may be the main target to mediate HDIs.
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The present study aimed to explore the main active components and underlying mechanisms of Marsdenia tenacissima in the treatment of ovarian cancer(OC) through network pharmacology, molecular docking, and in vitro cell experiments. The active components of M. tenacissima were obtained from the literature search, and their potential targets were obtained from SwissTargetPrediction. The OC-related targets were retrieved from Therapeutic Target Database(TTD), Online Mendelian Inheritance in Man(OMIM), GeneCards, and PharmGKB. The common targets of the drug and the disease were screened out by Venn diagram. Cytoscape was used to construct an "active component-target-disease" network, and the core components were screened out according to the node degree. The protein-protein interaction(PPI) network of the common targets was constructed by STRING and Cytoscape, and the core targets were screened out according to the node degree. GO and KEGG enrichment analyses of potential therapeutic targets were carried out with DAVID database. Molecular docking was used to determine the binding activity of some active components to key targets by AutoDock. Finally, the anti-OC activity of M. tenacissima extract was verified based on SKOV3 cells in vitro. The PI3K/AKT signaling pathway was selected for in vitro experimental verification according to the results of GO function and KEGG pathway analyses. Network pharmacology results showed that 39 active components, such as kaempferol, 11α-O-benzoyl-12ß-O-acetyltenacigenin B, and drevogenin Q, were screened out, involving 25 core targets such as AKT1, VEGFA, and EGFR, and the PI3K-AKT signaling pathway was the main pathway of target protein enrichment. The results of molecular docking also showed that the top ten core components showed good binding affinity to the top ten core targets. The results of in vitro experiments showed that M. tenacissima extract could significantly inhibit the proliferation of OC cells, induce apoptosis of OC cells through the mitochondrial pathway, and down-regulate the expression of proteins related to the PI3K/AKT signaling pathway. This study shows that M. tenacissima has the characteristics of multi-component, multi-target, and multi-pathway synergistic effect in the treatment of OC, which provides a theoretical basis for in-depth research on the material basis, mechanism, and clinical application.
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Medicamentos Herbarios Chinos , Marsdenia , Neoplasias Ováricas , Humanos , Femenino , Simulación del Acoplamiento Molecular , Farmacología en Red , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Bases de Datos Genéticas , Extractos Vegetales , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
Oxaliplatin resistance inevitably occurs in almost all cases of metastatic colorectal cancer (CRC), and it is important to study the roles of lncRNAs and their specific regulatory mechanisms in oxaliplatin resistance. Exosomes are increasingly designed for drug or functional nucleic acid delivery due to their properties, thereby improving the effectiveness of cancer therapy. The results of this study show that the low expression of PGM5 antisense RNA 1 (PGM5-AS1) in colon cancer is induced by transcription inhibitor, GFI1B. PGM5-AS1 prevents proliferation, migration, and acquired oxaliplatin tolerance of colon cancer cells. Exosomes encapsulating oxaliplatin and PGM5-AS1 can reverse drug resistance. For identifying differentially expressed target genes regarding PGM5-AS1, RNA transcriptome sequencing was performed. The mechanism by which PGM5-AS1 regulates its target genes was explored by performing experiments such as fluorescent in situ hybridization assay, dual-luciferase reporter gene assay, and RNA immunoprecipitation. The results show that by recruiting SRSF3, PGM5-AS1 activates alternate splicing to downregulate PAEP expression. For hsa-miR-423-5p, PGM5-AS1 can also act as a sponge to upregulate the NME1 expression.
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Neoplasias del Colon , Exosomas , MicroARNs , ARN Largo no Codificante , Proliferación Celular/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Resistencia a Medicamentos , Exosomas/genética , Exosomas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Hibridación Fluorescente in Situ , MicroARNs/genética , MicroARNs/metabolismo , Oxaliplatino/farmacología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismoRESUMEN
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N6 -methyladenosine (m6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. APPROACH AND RESULTS: In the present study, by m6 A sequencing and RNA sequencing, we found that both m6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin-receptor-deficient db/db mice. Importantly, our results showed that YT521-B homology domain-containing 2 (Ythdc2), an m6 A reader, was markedly down-regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c, fatty acid synthase, stearoyl-CoA desaturase 1, and acetyl-CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. CONCLUSIONS: Our findings describe an important role of the m6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.
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Lipogénesis/genética , Hígado/embriología , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/complicaciones , ARN Helicasas/metabolismo , Estabilidad del ARN/genética , Animales , Ácido Graso Sintasas/metabolismo , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/enzimología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/enzimología , Obesidad/genética , Obesidad/patología , ARN Helicasas/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/metabolismoRESUMEN
Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti-PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti-PD-1 treatment. Then the effect of fruquintinib plus anti-PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti-PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti-PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti-PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Benzofuranos/farmacología , Neoplasias Colorrectales/terapia , Quinazolinas/farmacología , Microambiente Tumoral/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzofuranos/uso terapéutico , Antígenos CD8/genética , Línea Celular Tumoral/trasplante , Quimioterapia Adyuvante/métodos , Colectomía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Ratones , Ratones Noqueados , Inestabilidad de Microsatélites , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Quinazolinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Adulto JovenRESUMEN
Background: Platelet-to-lymphocyte ratio (PLR) is reported to be related to the outcome of intensive care unit (ICU) patients. However, little is known about their associations with prognosis in newborn patients in neonatal ICU (NICU). The aim of the present study was to investigate the prognostic significance of the PLR for newborn patients in the NICU. Methods: Data on newborn patients in the NICU were extracted from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC III) database. The initial PLR value of blood examinations within 24 h was analyzed. Spearman's correlation was used to analyze the association of PLR with the length of hospital and ICU stays. The chi-square test was used to analyze the association of PLR with mortality rate. Multivariable logistic regression was used to determine whether the PLR was an independent prognostic factor of mortality. The area under the receiver operating characteristic (ROC) curve was used to assess the predictive ability of models combining PLR with other variables. Results: In total, 5240 patients were enrolled. PLR was negatively associated with length of hospital stay and ICU stay (hospital stay: ρ = −0.416, p < 0.0001; ICU stay: ρ = −0.442, p < 0.0001). PLR was significantly correlated with hospital mortality (p < 0.0001). Lower PLR was associated with higher hospital mortality (OR = 0.85, 95% CI = 0.75−0.95, p = 0.005) and 90-day mortality (OR = 0.85, 95% CI = 0.76−0.96, p = 0.010). The prognostic predictive ability of models combining PLR with other variables for hospital mortality was good (AUC for Model 1 = 0.804, 95% CI = 0.73−0.88, p < 0.0001; AUC for Model 2 = 0.964, 95% CI = 0.95−0.98, p < 0.0001). Conclusion: PLR is a novel independent risk factor for newborn patients in the NICU.
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Unidades de Cuidado Intensivo Neonatal , Linfocitos , Recién Nacido , Humanos , Recuento de Plaquetas , Estudios Retrospectivos , Curva ROC , PronósticoRESUMEN
BACKGROUND & AIMS: Chronic endoplasmic reticulum (ER) stress in the liver has been shown to play a causative role in non-alcoholic fatty liver disease (NAFLD) progression, yet the underlying molecular mechanisms remain to be elucidated. Forkhead box A3 (FOXA3), a member of the FOX family, plays critical roles in metabolic homeostasis, although its possible functions in ER stress and fatty liver progression are unknown. METHODS: Adenoviral delivery, siRNA delivery, and genetic knockout mice were used to crease FOXA3 gain- or loss-of-function models. Tunicamycin (TM) and a high-fat diet (HFD) were used to induce acute or chronic ER stress in mice. Chromatin immunoprecipiation (ChIP)-seq, luciferase assay, and adenoviral-mediated downstream gene manipulations were performed to reveal the transcriptional axis involved. Key axis protein levels in livers from healthy donors and patients with NAFLD were assessed via immunohistochemical staining. RESULTS: FOXA3 transcription is specifically induced by XBP1s upon ER stress. FOXA3 exacerbates the excessive lipid accumulation caused by the acute ER-inducer TM, whereas FOXA3 deficiency in hepatocytes and mice alleviates it. Importantly, FOXA3 deficiency in mice reduced diet-induced chronic ER stress, fatty liver, and insulin resistance. In addition, FOXA3 suppression via siRNA or adeno-associated virus delivery ameliorated the fatty liver phenotype in HFD-fed and db/db mice. Mechanistically, ChIP-Seq analysis revealed that FOXA3 directly regulates Period1 (Per1) transcription, which in turn promotes the expression of lipogenic genes, including Srebp1c, thus enhancing lipid synthesis. Of pathophysiological significance, FOXA3, PER1, and SREBP1c levels were increased in livers of obese mice and patients with NAFLD. CONCLUSION: The present study identified FOXA3 as the bridging molecule that links ER stress and NAFLD progression. Our results highlighted the role of the XBP1s-FOXA3-PER1/Srebp1c transcriptional axis in the development of NAFLD and identified FOXA3 as a potential therapeutic target for fatty liver disease. LAY SUMMARY: The molecular mechanisms linking endoplasmic reticulum stress to non-alcoholic fatty liver disease (NAFLD) progression remain undefined. Herein, via in vitro and in vivo analysis, we identified Forkhead box A3 (FOXA3) as a key bridging molecule. Of pathophysiological significance, FOXA3 protein levels were increased in livers of obese mice and patients with NAFLD, indicating that FOXA3 could be a potential therapeutic target in fatty liver disease.
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Estrés del Retículo Endoplásmico , Factor Nuclear 3-gamma del Hepatocito/metabolismo , Animales , Descubrimiento de Drogas , Hepatocitos/metabolismo , Humanos , Lipogénesis/genética , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Proteínas Circadianas Period/metabolismo , Transducción de Señal , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
5-Fluorouracil (5-FU)-based chemotherapy is the first-line recommended regimen in colorectal cancer (CRC), but resistance limits its clinical application. Andrographolide sulfonate, a traditional Chinese medicine, is mainly used to treat infectious diseases. In the present study, we reported that andrographolide sulfonate could significantly inhibit the growth of transplanted CT26 colon cancer in mice and improve survival when combined with 5-FU. Furthermore, TUNEL assay and immunohistochemistry analysis of proliferating cell nuclear antigen, Ki-67 and p-STAT3 confirmed that co-treatment could inhibit tumor proliferation and promote apoptosis. In tumor tissues of groups that received 5-FU and andrographolide sulfonate, CD4+ and CD8+ T cell infiltration was increased, and the expression of IFN-γ and Granzyme B detected by immunohistochemistry and qPCR was upregulated, reflecting improved antitumor immunity. Finally, we verified that 5-FU significantly activated the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in myeloid-derived suppressor cells (MDSCs) and that andrographolide sulfonate reversed this process to sensitize cells to 5-FU. In summary, andrographolide sulfonate synergistically enhanced antitumor effects and improved antitumor immunity by inhibiting 5-FU-induced NLRP3 activation in MDSCs. These findings provide a novel strategy to address 5-FU resistance in the treatment of CRC.
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Antiinflamatorios/administración & dosificación , Antimetabolitos Antineoplásicos/administración & dosificación , Diterpenos/administración & dosificación , Fluorouracilo/administración & dosificación , Células Supresoras de Origen Mieloide/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Sinergismo Farmacológico , Femenino , Ratones , Ratones Endogámicos BALB C , Células Supresoras de Origen Mieloide/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
BACKGROUND: Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood. MATERIALS AND METHODS: Eighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed. RESULTS: We found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/ß-catenin pathway. Specifically, apatinib induced the degradation of ß-catenin and decreased its transcriptional activity through Akt/GSK-3ß repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer. CONCLUSION: Our study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/ß-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.
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Two high-performance liquid chromatography-tandem mass spectrometry methods were developed and validated for the quantification of edaravone (method A) or taurine (method B) in human plasma. After protein precipitation, separations were achieved on an Ultimate XB-C8 (2.1 × 50 mm, 3.0 µm) column for edaravone and a ZORBAX SB-Aq column (2.1 × 100 mm, 3.5 µm) for taurine, respectively. The detection used electrospray ionization source via multiple reaction monitoring in positive-ion mode for edaravone and negative-ion mode for taurine, respectively. The lower limits of quantification were 10.0 ng/mL for edaravone and 3.00 µg/mL for taurine. The selectivity, accuracy, and precision of the methods were all within acceptable limits. Two methods were successfully applied to a drug-drug interaction study and a pharmacokinetic study of edaravone and taurine in healthy Chinese volunteers after intravenous infusion of single or compound injection. The results showed that co-administration of edaravone with taurine increased the Cmax and AUC0-24 of taurine in human plasma while taurine did not affect the systemic exposure of edaravone. Edaravone and taurine have the dose-dependent pharmacokinetic profiles in human.
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Edaravona/sangre , Edaravona/farmacocinética , Taurina/sangre , Taurina/farmacología , Calibración , Cromatografía Líquida de Alta Presión , Interacciones Farmacológicas , Edaravona/administración & dosificación , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Control de Calidad , Espectrometría de Masas en Tándem , Taurina/administración & dosificación , Distribución TisularRESUMEN
Counting rate is an important factor for CdZnTe photon counting detectors as high-flux devices. Until recently, there has been a lack of knowledge on the relationship between X-ray photocurrent response and the photon counting performance of CdZnTe detectors. In this paper, the performance of linear array 1 × 16-pixel CdZnTe photon counting detectors operated under different applied biases is investigated. The relation between experimental critical flux and applied bias show an approximate quadratic dependence, which agrees well the theoretical prediction. The underlying relationship among X-ray photocurrents, carrier transport properties, and photon counting performance was obtained by analyzing X-ray current-voltage and time current curves. The typical X-ray photocurrent curve can be divided into three regions, which may be explained by the photoconductive gain mechanism and electric field distortion characteristics. To keep CdZnTe photon counting detectors working in a "non-polarized state", the applied bias should be set on the left side of the "valley region" (high bias direction) in the X-ray I-V curves. This provides an effective measurement for determining the proper working bias of CdZnTe detectors and screening photon counting detector crystals.
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The effect of deep-level defects is a key issue for the applications of CdZnTe high-flux photon counting devices of X-ray irradiations. However, the major trap energy levels and their quantitive relationship with the device's performance are not yet clearly understood. In this study, a 16-pixel CdZnTe X-ray photon counting detector with a non-uniform counting performance is investigated. The deep-level defect characteristics of each pixel region are analyzed by the current-voltage curves (I-V), infrared (IR) optical microscope photography, photoluminescence (PL) and thermally stimulated current (TSC) measurements, which indicate that the difference in counting performance is caused by the non-uniformly distributed deep-level defects in the CdZnTe crystals. Based on these results, we conclude that the CdZnTe detectors with a good photon counting performance should have a larger Te cd 2 + and Cd vacancy-related defect concentration and a lower A-center and Tei concentration. We consider the deep hole trap Tei, with the activation energy of 0.638-0.642 eV, to be the key deep-level trap affecting the photon counting performance. In addition, a theoretical model of the native defect reaction is proposed to understand the underlying relationships of resistivity, deep-level defect characteristics and photon counting performance.
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Triptolide (TP), a major active ingredient of Tripterygium wilfordii, exerts potent immunosuppressive effects in the treatment of rheumatoid arthritis but is not widely used in clinical practice due to its multiorgan toxicity, particularly hepatotoxicity, nephrotoxicity, and reproductive toxicity. An LC-MS/MS approach was employed to explore the endocrine-disrupting effects of TP. The endocrine-disrupting effects of various concentrations (0-100 nM) of TP for 48 hour were firstly investigated using an in vitro model (H295R cell line). It was found that TP did not decrease cell viability. The transcriptional levels of steroidogenic enzymes in H295R cells were assessed by quantificational real-time polymerase chain reaction. The possible adrenal and endocrine effects of oral administration of TP (0, 50, and 500 µg/kg) for 28 days on both normal and collagen-induced arthritis (CIA) rats were also explored. The serum and adrenal tissue hormone levels (corticosterone and progesterone) and adrenal histopathology were analyzed, with the results that TP significantly decreased the level of cortisol in H295R cells and the level of plasma corticosterone in both normal and CIA rats. Histological alterations in adrenal cortex were observed at the dose of 500 µg/kg. Exposure to TP for 48 hour had an obvious inhibitory effect on the messenger RNA transcript levels of HSD3B2, CYP21A2, CYP17A1, and CYP11B1, which is essential for the synthesis of corticosteroids. In a word, TP leads to the disorder of corticosteroid synthesis and secretion, and corticosteroid may be a potential biomarker for the treatment of multiorgan toxicity of TP.
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Corticoesteroides/metabolismo , Diterpenos/toxicidad , Hormonas Gonadales/metabolismo , Fenantrenos/toxicidad , Extractos Vegetales/toxicidad , Corteza Suprarrenal/patología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Compuestos Epoxi/toxicidad , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Progesterona Reductasa/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Esteroide Hidroxilasas/metabolismo , Espectrometría de Masas en Tándem , Tripterygium/químicaRESUMEN
BACKGROUND: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) has been proven to be involved in various human cancers; however, the function of PLOD3 in gastric cancer (GC) remains unclear. In this study, the role of PLOD3 in GC was evaluated. METHODS: The expression of PLOD3 in GC tissues and normal tissues was predicted by The Cancer Genome Atlas (TCGA). The kmplot online tool was performed to evaluate the impact of PLOD3 expression on GC patients' survival. Real-time PCR was conducted to verify PLOD3 expression in our own clinical samples and GC cells. The Cell Counting Kit-8 and the colony formation assay were used to detect GC cell proliferation ability. RESULTS: PLOD3 was upregulated in human GC tissues (compared to adjacent normal tissues, p < 0.001) and GC cells. High expression of PLOD3 was significantly correlated with larger tumor size (p = 0.007) and poor prognosis. Inhibition of PLOD3 could suppress cell proliferation in GC. CONCLUSIONS: These results revealed that PLOD3 may promote the progression of GC.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/genética , Neoplasias Gástricas/genética , Regulación hacia Arriba , Línea Celular Tumoral , Proliferación Celular/genética , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Procolágeno-Lisina 2-Oxoglutarato 5-Dioxigenasa/metabolismo , Pronóstico , Interferencia de ARN , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3's expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.
Asunto(s)
Tejido Adiposo/fisiología , Factor Nuclear 3-gamma del Hepatocito/fisiología , Receptores de Glucocorticoides/fisiología , Tejido Adiposo/metabolismo , Animales , Glucocorticoides/efectos adversos , Hiperlipidemias/genética , Ratones , Regiones Promotoras Genéticas , Transcripción GenéticaRESUMEN
The effects of sub-band-gap light radiation on the performance of CdZnTe photon-counting X-ray detectors were studied using infrared light with different wavelengths in the region of 980â»1550 nm. The performance of the detectors for X-ray detection was improved by the radiation of infrared light with the wavelengths of 1200 nm and 1300 nm. This was because the increase of the electron indirect transition, and the weakening of the built-in electric field induced by the trapped holes, reduced the drift time of the carrier, and increased the charge collection efficiency. To further analyze the intrinsic behavior of the trapped charge, the deep-level defects of CdZnTe crystal were measured by thermally stimulated current spectroscopy (TSC). The deep-level defect indicated by the trap named T4 in TSC spectra with the ionization energy of 0.43 eV should be responsible for the performance deterioration of CdZnTe detectors.