RESUMEN
IDH1 mutations frequently occur early in human glioma. While IDH1 mutation has been shown to promote gliomagenesis via DNA and histone methylation, little is known regarding its regulation in antiviral immunity. Here, we discover that IDH1 mutation inhibits virus-induced interferon (IFN) antiviral responses in glioma cells. Mechanistically, D2HG produced by mutant IDH1 enhances the binding of DNMT1 to IRF3/7 promoters such that IRF3/7 are downregulated, leading to impaired type I IFN response in glioma cells, which enhances the susceptibility of gliomas to viral infection. Furthermore, we identify DNMT1 as a potential biomarker predicting which IDH1mut gliomas are most likely to respond to oncolytic virus. Finally, both D2HG and ectopic mutant IDH1 can potentiate the replication and oncolytic efficacy of VSVΔ51 in female mouse models. These findings reveal a pivotal role for IDH1 mutation in regulating antiviral response and demonstrate that IDH1 mutation confers sensitivity to oncolytic virotherapy.
Asunto(s)
Neoplasias Encefálicas , Glioma , Viroterapia Oncolítica , Virus Oncolíticos , Animales , Femenino , Humanos , Ratones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Glioma/metabolismo , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Metilación , Mutación , Virus Oncolíticos/genética , Virus Oncolíticos/metabolismoRESUMEN
Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC.
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Neoplasias Colorrectales , Virus Oncolíticos , Animales , Ratones , Humanos , Proteína que Contiene Valosina , Antígeno B7-H1 , Inmunoterapia , Neoplasias Colorrectales/tratamiento farmacológico , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Adrenomedullin (ADM) is a novel cardiovascular peptide with anti-inflammatory and antioxidant properties. Chronic inflammation, oxidative stress and calcification play pivotal roles in the pathogenesis of vascular dysfunction in obesity-related hypertension (OH). Our study aimed to explore the effects of ADM on the vascular inflammation, oxidative stress and calcification in rats with OH. Eight-week-old Sprague Dawley male rats were fed with either a Control diet or a high fat diet (HFD) for 28 weeks. Next, the OH rats were randomly subdivided into two groups as follows: (1) HFD control group, and (2) HFD with ADM. A 4-week treatment with ADM (7.2 µg/kg/day, ip) not only improved hypertension and vascular remodeling, but also inhibited vascular inflammation, oxidative stress and calcification in aorta of rats with OH. In vitro experiments, ADM (10 nM) in A7r5 cells (rat thoracic aorta smooth muscle cells) attenuated palmitic acid (PA, 200 µM) or angiotensin II (Ang II, 10 nM) alone or their combination treatment-induced inflammation, oxidative stress and calcification, which were effectively inhibited by the ADM receptor antagonist ADM22-52 and AMP-activated protein kinase (AMPK) inhibitor Compound C, respectively. Moreover, ADM treatment significantly inhibited Ang II type 1 receptor (AT1R) protein expression in aorta of rats with OH or in PA-treated A7r5 cells. ADM improved hypertension, vascular remodeling and arterial stiffness, and attenuated inflammation, oxidative stress and calcification in OH state partially via receptor-mediated AMPK pathway. The results also raise the possibility that ADM will be considered for improving hypertension and vascular damage in patients with OH.
Asunto(s)
Adrenomedulina , Antiinflamatorios , Antioxidantes , Hipertensión , Obesidad , Animales , Masculino , Ratas , Adrenomedulina/farmacología , Adrenomedulina/uso terapéutico , Proteínas Quinasas Activadas por AMP , Calcinosis/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Hipertensión/metabolismo , Inflamación/complicaciones , Obesidad/complicaciones , Ratas Sprague-Dawley , Remodelación Vascular , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéuticoRESUMEN
Liver cancer is associated with high mortality, particularly in patients infected with the hepatitis B virus. Treatment methods remain very limited. Here, we explored the effects of 17ß-estradiol (E2) on apoptosis of various liver cell lines (LO2, HepG2, and HepG2.2.15 cells). Within a certain concentration range, 17ß-estradiol induced oxidative stress and apoptosis of HepG2 cells, downregulated ERα-36 expression, and increased Akt and Foxo3a phosphorylation. p-Foxo3a became localized around the nucleus but did not enter the organelle. The levels of mRNAs encoding manganese superoxide dismutase (MnSOD) and catalase, to the promoters of which Foxo3a binds to trigger gene expression, were significantly reduced in HepG2 cells. 17ß-estradiol had no obvious effects on LO2 or HepG2.2.15 cells. We speculate that 17ß-estradiol may induce oxidative stress in HepG2 cells by increasing Foxo3a phosphorylation, thus promoting apoptosis. This may serve as a new treatment for hepatocellular carcinoma.
RESUMEN
OBJECTIVE: To explore the effect of compositie salviae dropping pill (CSDP) on hyperlipemia patients with phlegm and blood stasis syndrome. METHOD: Hyperlipemia patients were divided randomly into two groups. One group of 40 patients were treated by CSDP, another group of 41 patients were treated by simvastatin. The TC, TG, HDL-C, LDL-C, ApoA and ApoB levels, ALT, r-GT, IL-6, MDA level and SOD activity were determined before and after being treated. RESULT: After 3 months treatment, the TC, TG and LDL-C levels were obviously decreased in two groups (P <0.01, P < 0.05), there is no significant difference between the effective rate of two groups. The ALT, r-GT, IL-8 and MDA levels of treatment group were obviously decreased (P < 0.01, P < 0.05), while the ApoA level and SOD activity increased obviously in those patients (P <0.05, P <0.01, respectively). However, the ALT, r-GT, IL-6, MDA, HDL-C, ApoA level and SOD activity had no significant difference after treatment in control group. CONCLUSION: Our study suggest that CSDP have the function of falling serum lipid level without damaging liver function, its function of protecting liver function might related to its function of improving of anti-oxidation and decreasing of inflammation, the mechanism of CSDP disparting and removing phlem and blood stasis in the processes lipid metabolism need to be studied further.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipertrigliceridemia/tratamiento farmacológico , Fitoterapia , Adulto , Alanina Transaminasa/sangre , Canfanos , Combinación de Medicamentos , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , Humanos , Hipercolesterolemia/sangre , Hipertrigliceridemia/sangre , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Panax notoginseng , Plantas Medicinales/química , Salvia miltiorrhiza/química , Superóxido Dismutasa/sangre , gamma-Glutamiltransferasa/sangreRESUMEN
OBJECTIVE: To explore the correlation of clinical effect and TCRV beta 7 expression of He Jie Decoction (HJD) on chronic hepatitis B patients. METHODS: 45 patients of chronic hepatitis B were divided randomly into two groups. 30 patients in the treated group were treated by HJD, and 15 patients in the control group were treated by usual western medicine. The TCRV beta 7 level were detected before and after being treated. RESULTS: After six months treatment, the ALT level of two groups were obviously decreased (P < 0.01), TCRV beta 7 expression were detected out in 6 patients of the treated group, and HBV-DNA and HBeAg of the 6 patients were negative conversion. The TCRV beta 7 expression couldn't be detected out in the control group, and HBV-DNA and HBeAg of the control group weren't negative conversion. There was no significant difference between the clinical total effective rate of the two groups (P > 0.05), but the apparent rate of the treated group was significantly higher than that of the control group (P < 0.01). CONCLUSION: HJD might have the effect on improving the TCRV beta 7 expression of chronic hepatitis B patients, which might be the ways of HJD inhibiting and killing hepatitis B virus.