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JN.1, the dominating SARS-CoV-2 variant, is antigenically distinct from ancestral BA.1, BA.5 and XBB.1.5 variants, raising concern about effectiveness of updated COVID-19 vaccines. Here, we compared the neutralizing antibody response against JN.1, 1-month after receipt of the three available Moderna mRNA vaccines. Sera obtained from 37, 30 and 30 XBB.1.5, BA.1 and BA.4-5 -vaccine recipients, respectively, were tested for anti-RBD IgG and for JN-1 specific neutralizing antibody levels. Geometric mean fold rise (GMFR) in JN.1 specific neutralizing titers was 27 (95 % CI: 17-43.1), 10.1 (95 % CI: 6.48-15.7) and 8.77 (95 % CI: 5.69-13.5) following XBB.1.5, BA.1 and BA.4-5 vaccines, respectively, translating into a 64 % lower adjusted response (geometric mean ratio [GMR] = 0.36, 95 % CI: 0.21-0.6) in the BA.1 arm, and a 75 % lower response (GMR = 0.25, 95 % CI: 0.15-0.43) in the BA.4-5 arm. This suggests that XBB.1.5 vaccination will most likely, result in improved effectiveness against JN.1 compared with other COVID-19 vaccines.
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A significant progressive decline in beta-carotene (ßC) levels in the brain is associated with cognitive impairment and a higher prevalence of Alzheimer's disease (AD). In this study, we investigated whether the administration of 9-cis beta-carotene (9CBC)-rich powder of the alga Dunaliella bardawil, the best-known source of ßC in nature, inhibits the development of AD-like neuropathology and cognitive deficits. We demonstrated that in 3 AD mouse models, Tg2576, 5xFAD, and apoE4, 9CBC treatment improved long- and short-term memory, decreased neuroinflammation, and reduced the prevalence of ß-amyloid plaques and tau hyperphosphorylation. These findings suggest that 9CBC has the potential to be an effective preventive and symptomatic AD therapy.
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Enfermedad de Alzheimer , Enfermedades Neuroinflamatorias , Animales , Ratones , beta Caroteno/farmacología , beta Caroteno/uso terapéutico , Enfermedad de Alzheimer/tratamiento farmacológico , Dieta , Cognición , Modelos Animales de Enfermedad , Placa AmiloideRESUMEN
PURPOSE: To evaluate the addition of ofranergene obadenovec (ofra-vec, VB-111), a novel gene-based anticancer targeted therapy, to once a week paclitaxel in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS: This placebo-controlled, double-blind, phase III trial (ClinicalTrials.gov identifier: NCT03398655) randomly assigned patients with PROC 1:1 to receive intravenous ofra-vec every 8 weeks with once a week IV paclitaxel or placebo with paclitaxel until disease progression. The dual primary end points were overall survival (OS) and progression-free survival (PFS) as assessed by Blinded Independent Central Review. RESULTS: Between December 2017 and March 2022, 409 patients were randomly assigned. The median PFS was 5.29 months in the ofra-vec arm and 5.36 months in the control arm, hazard ratio (HR) 1.03 (CI, 0.83 to 1.29; P = .7823). The median OS with ofra-vec was 13.37 months versus 13.14 months, HR 0.97 (CI, 0.75 to 1.27; P = .8440). Objective response rates (ORRs) per RECIST 1.1 were similar in both arms: 28.9% with ofra-vec versus 29.6% with control. In both treatment arms, response to CA-125 was a substantial prognostic factor for both PFS and OS. In the ofra-vec arm, the HR in CA-125 responders compared with that in nonresponders for PFS was 0.2428 (CI, 0.1642 to 0.3588), and for OS, the HR was 0.3343 (CI, 0.2134 to 0.5238). Safety profile was characterized by common transient flu-like symptoms such as fever and chills. CONCLUSION: The addition of ofra-vec to paclitaxel did not improve PFS or OS. The PFS and ORR in the control arm exceeded the results that were anticipated on the basis of the AURELIA chemotherapy control arm. CA-125 response was a substantial prognostic biomarker for PFS and OS in patients with PROC treated with paclitaxel.
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Neoplasias Ováricas , Paclitaxel , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Supervivencia sin Progresión , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE: Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy. EXPERIMENTAL DESIGN: N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival. RESULTS: Optimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. CONCLUSIONS: Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/diagnóstico por imagen , Glioblastoma/tratamiento farmacológico , Bevacizumab/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/tratamiento farmacológico , Irinotecán/uso terapéutico , Imagen por Resonancia Magnética/métodosRESUMEN
The pathophysiology of atherosclerosis initiation and progression involves many inflammatory cytokines, one of them is interleukin (IL)-1α that has been shown to be secreted by activated macrophages. We have previously shown that IL-1α from bone marrow-derived cells is critical for early atherosclerosis development in mice. It is known that endoplasmic reticulum (ER) stress in macrophages is involved in progression to more advanced atherosclerosis, but it is still unknown whether this effect is mediated through cytokine activation or secretion. We previously demonstrated that IL-1α is required in ER stress-induced activation of inflammatory cytokines in hepatocytes and in the associated induction of steatohepatitis. In the current study, we aimed to examine the potential role of IL-1α in ER stress-induced activation of macrophages, which is relevant to progression of atherosclerosis. First, we demonstrated that IL-1α is required for atherosclerosis development and progression in the apoE knockout (KO) mouse model of atherosclerosis. Next, we showed that ER stress in mouse macrophages results in the protein production and secretion of IL-1α in a dose-dependent manner, and that IL-1α is required in ER stress-induced production of the C/EBP homologous protein (CHOP), a critical step in ER stress-mediated apoptosis. We further demonstrated that IL-1α-dependent CHOP production in macrophages is specifically mediated through the PERK-ATF4 signaling pathway. Altogether, these findings highlight IL-1α as a potential target for prevention and treatment of atherosclerotic cardiovascular disease.
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Aterosclerosis , Interleucina-1alfa , Animales , Ratones , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apoptosis , Aterosclerosis/genética , Aterosclerosis/metabolismo , Estrés del Retículo Endoplásmico , Eliminación de Gen , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Macrófagos/metabolismo , Ratones NoqueadosRESUMEN
OBJECTIVES: The capability of the SARS-CoV-2 Omicron variant to escape immunity conferred by mRNA vaccines has led to the development of Omicron-adapted vaccines. In this study, we aimed to compare the immune response with the ancestral strain and with the BA.1 Omicron variant after administration of the original vaccine and the Omicron-adapted vaccine. METHODS: This is an ongoing phase 3, double-blinded randomized controlled trial, comparing the original BNT161b2 vaccine, monovalent Omicron BA.1-adapted BNT161b2 vaccine, and bivalent combinations. Each vaccine was given at a 30 µg and 60 µg dose. Primary outcomes considered included neutralization titers of SARS-CoV-2 ancestral strain and Omicron BA.1. Exploratory endpoints included neutralization titers for Omicron BA.5, and the incidence of COVID-19 cases. RESULTS: Overall, 122 individuals (22, 19, 20, 20, 20, 20, and 21 in each arm) completed a 90-day follow-up. Three months after vaccination, adjusting for baseline levels, neutralizing antibody titers were 0.63 (95% CI: 0.3-1.32) and 0.54 (0.24-1.2) for monovalent/60 µg, 0.9 (0.42-1.92) and 2.69 (1.17-6.17) times for monovalent-Omi.BA.1/30 µg, 1.28 (0.6-2.75) and 2.79 (1.21-6.41) times for monovalent-Omi.BA.1/60 µg, 0.96 (0.46-1.97) and 2.07 (0.93-4.58) times for bivalent-Omi.BA.1/30 µg, and 0.79 (0.38-1.63) and 1.95 (0.88-4.32) times for bivalent-Omi.BA.1/60 µg when compared with BNT162b2/30 µg against the ancestral strain and BA.1 variant, respectively. DISCUSSION: BA.1-adapted mRNA vaccines lead to a stronger neutralizing antibody response against the Omicron BA.1 sub-variant.
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COVID-19 , Vacunas , Humanos , Vacuna BNT162 , Estudios de Seguimiento , COVID-19/prevención & control , SARS-CoV-2/genética , Vacunas de ARNm , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
Booster doses for the ongoing COVID-19 pandemic are under consideration in many countries. We report a three-month follow-up of 700 participants in a fourth vaccine dose study, comparing BNT162b2 and mRNA1273, administered four months after a third BNT162b2 dose. The primary outcomes are the levels of IgG, neutralizing antibodies, and microneutralization and the secondary outcomes are the levels of IgA and T cell activation, and clinical outcomes of SARS-CoV-2 infection and substantial symptomatic disease. Waning of the immune response is evident during follow-up, with an 11% (ß = 0.89, 95% CI, 0.88-0.9) and 21% (ß = 0.79, 95% CI, 0.76-0.82) multiplicative decay per week of IgG and neutralizing antibodies, respectively, in the mRNA1273 group, and of 14% (ß = 0.86, 95% CI, 0.86-0.87) and 26% (ß = 0.74, 95% CI, 0.72-0.76), respectively, in the BNT162b2 group. Direct neutralization of Omicron variants is low relative to ancestral strains. Cumulatively over the study period, both vaccines show little efficacy against infection but were highly efficacious against substantial symptomatic disease [89% [(IRR 0.11, 95% CI, 0.02-0.37) and 71% (IRR 0.29, 95% CI, 0.13-0.57) for mRNA1273 and BNT162b2, respectively]. These results are informative for further boosting policy-making. Trial registration numbers (clinicaltrials.gov): NCT05231005 and NCT05230953.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , Vacuna BNT162 , Estudios de Seguimiento , Pandemias , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Inmunoglobulina G , Anticuerpos AntiviralesRESUMEN
We assess the immunogenicity and efficacy of Spikevax and Comirnaty as fourth dose COVID-19 vaccines. Six months post-fourth-dose, IgG levels were higher than pre-fourth dose at 1.58-fold (95% CI: 1.27-1.97) in Spikevax and 1.16-fold (95% CI: 0.98-1.37) in Comirnaty vaccinees. Nearly 60% (159/274) of vaccinees contracted SARS-CoV-2. Infection hazard ratios (HRs) for Spikevax (0.82; 95% CI: 0.62-1.09) and Comirnaty (0.86; 95% CI: 0.65-1.13) vaccinees were similar, as were substantial-disease HRs, i.e. 0.28 (95% CI: 0.13-0.62) and 0.51 (95% CI: 0.27-0.96), respectively.
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Vacunas contra la COVID-19 , COVID-19 , COVID-19/prevención & control , Estudios de Seguimiento , Humanos , Inmunoglobulina G , Israel/epidemiología , ARN Mensajero , SARS-CoV-2/genéticaRESUMEN
Vitamin A and provitamin A carotenoids are involved in the regulation of adipose tissue metabolism and inflammation. We examined the effect of dietary supplementation using all-trans and 9-cis ß-carotene-rich Dunaliella bardawil alga as the sole source of vitamin A on obesity-associated comorbidities and adipose tissue dysfunction in a diet-induced obesity mouse model. Three-week-old male mice (C57BL/6) were randomly allocated into two groups and fed a high-fat, vitamin A-deficient diet supplemented with either vitamin A (HFD) or ß-carotene (BC) (HFD-BC). Vitamin A levels in the liver, WATs, and BAT of the HFD-BC group were 1.5-2.4-fold higher than of the HFD group. BC concentrations were 5-6-fold greater in BAT compared to WAT in the HFD-BC group. The eWAT mRNA levels of the Mcp-1 and Cd68 were 1.6- and 2.1-fold lower, respectively, and the plasma cholesterol and triglyceride concentrations were 30% and 28% lower in the HFD-BC group compared with the HFD group. Dietary BC can be the exclusive vitamin A source in mice fed a high-fat diet, as shown by the vitamin A concentration in the plasma and tissues. Feeding BC rather than vitamin A reduces adipose tissue macrophage recruitment markers and plasma lipid concentrations.
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Chlorophyceae , beta Caroteno , Tejido Adiposo/metabolismo , Animales , Chlorophyceae/metabolismo , Dieta Alta en Grasa/efectos adversos , Expresión Génica , Hígado , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Triglicéridos/metabolismo , Vitamina A/farmacología , beta Caroteno/metabolismo , beta Caroteno/farmacologíaRESUMEN
Maternal docosahexaenoic acid (DHA) is required during pregnancy to supply for normal fetal growth and development. This pilot study aimed to assess the unknown fatty acid (FA) composition in a cohort of non-pregnant and pregnant Israeli women at term and their offspring on a normal diet without n-3 FA supplementation. The fatty acid profile, analyzed using gas chromatography, showed significantly higher plasma monounsaturated (MUFA) and lower n-6 FA percent distribution with similar n-3 index, in pregnant compared to non-pregnant women. RBC exhibited significantly higher MUFA with similar n-3 index, in pregnant compared to non-pregnant women. N-3 FA significantly correlated between neonates' plasma, with higher n-3 index, and pregnant women's DHA. Conclusion: DHA levels in non-pregnant and pregnant Israeli women at term were comparable and the DHA in pregnant women's plasma positively correlated with their neonate's level, suggesting an efficient mother-fetus FA transfer and/or fetal fatty acid metabolism to longer FA products.
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Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Intercambio Materno-Fetal , Adulto , Proteínas de Arabidopsis/sangre , Ligasas de Carbono-Oxígeno/sangre , Estudios de Casos y Controles , Ácidos Docosahexaenoicos/sangre , Ácidos Grasos Esenciales/sangre , Ácidos Grasos Insaturados/sangre , Femenino , Humanos , Recién Nacido , Israel , Fenómenos Fisiologicos Nutricionales Maternos , Proyectos Piloto , Embarazo , Triglicéridos/sangre , Ácido alfa-Linolénico/sangre , Ácido gammalinolénico/sangreRESUMEN
Docosahexaenoic acid (DHA) is critical for normal brain development and function. DHA is in danger of being significantly reduced in the human food supply, and the question of whether its metabolic precursor, the essential n-3 alpha linolenic acid (ALA) during pregnancy, can support fetal brain DHA levels for optimal neurodevelopment, is fundamental. Female mice were fed either ALA-enriched or Control diet during pregnancy and lactation. The direct effect of maternal dietary ALA on lipids was analyzed in liver, red blood cells, brain and brain vasculature, together with genes of fatty acid metabolism and transport in three-week-old offspring. The long-term effect of maternal dietary ALA on brain fatty acids and memory was studied in 19-week-old offspring. Three-week-old ALA offspring showed higher levels of n-3 fatty acids in liver, red blood cell, blood-brain barrier (BBB) vasculature and brain parenchyma, DHA enrichment in brain phospholipids and higher gene and protein expression of the DHA transporter, major facilitator superfamily domain containing 2a, compared to Controls. 19-week-old ALA offspring showed higher brain DHA levels and better memory performance than Controls. The increased brain DHA levels induced by maternal dietary ALA during pregnancy-lactation, together with the up-regulated levels of major facilitator superfamily domain containing 2a, may indicate a mode for greater DHA uptake with long-term impact on better memory in ALA offspring.
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Encéfalo/metabolismo , Suplementos Dietéticos , Ácidos Docosahexaenoicos/metabolismo , Ácido alfa-Linolénico/farmacología , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Femenino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Embarazo , DesteteRESUMEN
Vitamin A deficiency (VAD) is a major health problem, especially in developing countries. In this study, we investigated the effect of VAD from weaning to adulthood in apoE-/- mice. Three-week-old male mice were allocated into four diet groups: I. VAD II. VAD+vitamin A (VA), 1500 IU retinyl-palmitate; III. VAD+ß-carotene (BC), 6 g/kg feed, containing 50% all-trans and 50% 9-cis BC. IV. VAD with BC and VA (BC+VA). After 13 weeks, we assessed the size of atherosclerotic plaques and measured VA in tissues and BC in plasma and tissues. VAD resulted in diminished hepatic VA levels and undetectable brain VA levels compared to the other groups. BC completely replenished VA levels in the liver, and BC+VA led to a two-fold elevation of hepatic VA accumulation. In adipose tissue, mice fed BC+VA accumulated only 13% BC compared to mice fed BC alone. Atherosclerotic lesion area of BC group was 73% lower compared to VAD group (p < 0.05). These results suggest that BC can be a sole source for VA and inhibits atherogenesis.
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Apolipoproteínas E/deficiencia , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Suplementos Dietéticos , Fitoterapia , Deficiencia de Vitamina A/tratamiento farmacológico , beta Caroteno/administración & dosificación , Animales , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
OBJECTIVE: Report final results of a phase I/II study of VB-111, a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response, in combination with paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Study NCT01711970 was a prospective, open label, dose escalation study assessing combination treatment of VB-111 and weekly paclitaxel. In the Phase I part of the study, patients were treated with escalating doses of intravenous VB-111 and paclitaxel. In Phase 2, patients were treated with therapeutic doses of VB-111 and paclitaxel 80 mg/m2. Assessments included safety, overall survival (OS), progression free survival (PFS), and tumor response (CA-125 and RECIST). RESULTS: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled. 17/21 received the therapeutic dose. Patients had a median of 3 prior lines of therapy. Half of the subjects were platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and associated with mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients. The median OS was 16.6 months in patients treated with therapeutic dose compared to 5.8 months in sub-therapeutic dose (p = 0.028). Tumor specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells in regions of apoptotic cancer cells. CONCLUSIONS: Treatment with VB-111 in combination with paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia/métodos , Neoplasias Ováricas/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bleomicina/farmacología , Bleomicina/uso terapéutico , Cisplatino/farmacología , Cisplatino/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Vinblastina/farmacología , Vinblastina/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Mediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet. METHODS AND RESULTS: Forty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed). Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). CONCLUSION: These results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.
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Aterosclerosis/prevención & control , Dieta Alta en Grasa , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Aceite de Oliva/administración & dosificación , Animales , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Biomarcadores/sangre , Quimiocina CCL2/metabolismo , Colesterol/sangre , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Femenino , Interleucina-6/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Ácido Oléico/administración & dosificación , Ácido Oléico/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factores de TiempoRESUMEN
PURPOSE: Lipoxygenases (LOX) have been implicated in carcinogenesis, however both pro- and anti-carcinogenic effects have been reported in different cancer models. Using transgenic mice, which specifically overexpress human 15-lipoxygenase (ALOX15) in endothelial cells (EC), we previously demonstrated significant inhibition of tumor development. In the Lewis lung carcinoma (LLC) model, the primary tumor developed similarly in both wild type (WT) and ALOX15 overexpressing mice. However, metastases development was significantly inhibited in the transgenic mice. Here, we explored the molecular basis for the anti-metastatic effect of endothelial cell specific ALOX15 overexpression. MATERIALS/METHODS: We used ALOX15 overexpressing mice, and in-vitro cell model to evaluate the molecular effect of ALOX15 on EC and LLC cells. RESULTS: When LLC cells were injected in WT and ALOX15 overexpressing mice, we observed a higher degree of apoptosis and necrosis in primary and metastatic tumors of ALOX15 overexpressing animals. These anti-carcinogenic and anti-metastatic effects were paralleled by augmented expression of cyclin-dependent kinase inhibitor 1A (CDKN1A; p21) and of the peroxisome proliferators-activated receptor (PPAR)γ and by downregulation of the steady state concentrations of connexin26 mRNA. Consistent with these in vivo effects, ALOX15 overexpression in LLC and HeLa cancer cells in vitro significantly reduced cell viability in culture. In contrast, similar treatment of non-cancerous B2B epithelial cells did not impact cell viability. CONCLUSIONS: Taken together, our data suggests that endothelial cell specific overexpression of ALOX15 promotes apoptosis and necrosis in primary and metastatic tumors in mice, by upregulation of P21 and PPARγ expression in adjacent cancer cells.
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Apoptosis , Araquidonato 15-Lipooxigenasa/fisiología , Biomarcadores de Tumor/metabolismo , Carcinoma Pulmonar de Lewis/patología , Modelos Animales de Enfermedad , Células Endoteliales/patología , Animales , Biomarcadores de Tumor/genética , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Proliferación Celular , Células Endoteliales/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Tumorales CultivadasRESUMEN
INTRODUCTION: The tight regulation of the cytokine network during macrophage activation is of prime importance to enable a fast and potent innate immune response against exogenous pathogens. The inflammation mediating ubiquitin-like protein HLA-F adjacent transcript number 10 (FAT10) was shown to be transcriptionally regulated by and also regulate the nuclear factor-κB (NFκB) signaling pathway. However, very little is known about the regulation of FAT10 gene expression during macrophage activation. RESULTS: RNA sequencing of interferon (IFN)γ-stimulated mouse peritoneal macrophages analyzed by ingenuity pathway analysis revealed significant involvement of tumor necrosis factor receptor 1 (TNFR1) signaling in addition to IFNγ signaling. Subsequently, IFNγ robustly upregulated FAT10 expression compared to a milder induction seen with TNFα or lipopolysaccharide (LPS) stimulation. While low dose IFNγ with TNFα synergistically elevated FAT10 expression, preincubation of macrophages with IFNγ strongly augmented TNFα-induced FAT10 expression. Moreover, a short preincubation with IFNγ, which did not elevate FAT10, was sufficient to potentiate the induction of FAT10 by TNFα. A double augmentation mechanism of TNFα signaling was demonstrated, where IFNγ rapidly induced the expression of TNFα and TNFR1, which further augmented the induction of TNFα and TNFR1 expression by TNFα. Importantly, the induction of FAT10 by IFNγ in macrophages from TNFα-deficient or TNFR1-deficient mice was completely inhibited compared to macrophages from wild type (WT) mice. Finally, we show that TNFα-induced FAT10 expression is dependent on NFκB signaling. CONCLUSION: IFNγ potentiates the TNFα/TNFR1 signaling pathway to induce FAT10 expression in mouse macrophages, mediated through NFκB network.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Interferón gamma/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Transducción de Señal/inmunología , Ubiquitinas/biosíntesis , Animales , Inmunidad Innata/inmunología , Interferón gamma/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Noqueados , FN-kappa B/inmunología , FN-kappa B/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. OBJECTIVES: The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. METHODS: Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, ß-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). RESULTS: We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. CONCLUSIONS: Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.