TBK1 como moduladora de la liberación de citocinas inflamatorias en la microglía de ratas wistar y su efecto en la generación de la resistencia a la insulina y diabetes tipo 2.

La obesidad está relacionada con la presencia de inflamación sistémica crónica y resistencia a la insulina. El desarrollo de inflamación a nivel del sistema nervioso central (SNC) se regula por la microglía. En el presente proyecto empleamos un modelo in vitro para determinar sí la toxicidad inducida por lípidos correlaciona con el incremento en la producción de citosinas inflamatorias en la microglía en cultivo y si la inducción de inflamación central en ratas Wistar, promueve alteraciones metabólicas asociadas a la diabetes tipo 2. Se emplearon cultivos primarios de microglía expuestos a lípidos saturados e insaturados para determinar su efecto sobre la liberación de citocinas inflamatorias y su correlación con la activación de la cascada inflamatoria TANK-binding kinase 1-IκB kinase-nuclear factor κ B (TBK1-IKKNF- κB) . Los resultados demuestran que la estimulación de la microglía con el lípido saturado ácido palmítico induce el incremento en la liberación de interleucina

Central Modulation of Neuroinflammation by Neuropeptides and Energy-Sensing Hormones during Obesity

Centralnervoussystem(CNS)sensesenergyhomeostasisbyintegratingbothperipheralandautonomicsignalsandrespondingto thembyneurotransmittersandneuropeptidesrelease.Althoughitispreviouslyconsideredanimmunologicallyprivilegedorgan, we now know that this is not so. Cells belonging to the immune system, such as B and T lymphocytes, can be recruited into the CNS to face damage or infection, in addition to possessing resident immunological cells, called microglia. In this way, positive energybalanceduringobesitypromotesaninflammatorystateintheCNS.Saturatedfattyacidsfromthediethavebeenpointed out as powerful candidates to trigger immune response in peripheral system and in the CNS. However, how central immunity communicatestoperipheralimmuneresponseremainstobeclarified.Recentlytherehasbeenagreatinterestintheneuropeptides, POMC derived peptides, ghrelin, and leptin, due to their capacity to suppress or induce inflammatory responses in the brain, respectively. These may be potential candidates to treat different pathologies associated with autoimmunity and inflammation. In this review, we will discuss the role of lipotoxicity associated with positive energy balance during obesity in proinflammatory responseinmicroglia,BandTlymphocytes,anditsmodulationbyneuropeptides

Dispersion and removal of two toxic trace metals (Ag and Cd) in the Strait of Georgia

Two highly toxic trace metals, silver (Ag) and cadmium (Cd) have been monitored in the sediments and water column of the Strait of Georgia since 2014. With the advent of nanotechnology, silver nanoparticles are widely used in medical applications and consumer products, and inevitably being discharged into the environment. Cd is of particular concern in the coastal waters of B.C. due to its naturally high concentration in the incoming Pacific water and possible anthropogenic sources. The sediment profile of a core taken near the Iona Island wastewater treatment plant outfall showed rising levels of both Ag and Cd in the upper 25 cm, which could be attributed to the start of effluent discharge through deep water diffusers in 1988. To confirm whether the Iona outfall is a significant point source, weekly effluent samples from Iona were analyzed for dissolved and total Ag and Cd over a year. Our results showed that the average dissolved Ag measured in the effluent is about 100 times higher than its expected concentration in the incoming Pacific water; whereas dissolved Cd concentrations are more variable, but in the same order of magnitude as in the Pacific water. Preliminary analysis using a steady-state box model of the Strait of Georgia suggests that the Iona outfall minimally impact the Cd level in the water column of the Strait, but could slightly enhance its dissolved Ag concentration. Ongoing time-series measurement of the concentrations of dissolved and particulate Ag and Cd in the Strait will provide further information on their temporal variability, sinking flux to the sediments, and bioaccumulation

Dissolved Cu concentrations in the Strait of Georgia: trends, speciation, and accumulation by local calanoid copepods

Most research on the effects of copper (Cu) on marine ecosystems has focused on benthic organisms and Cu concentrations in the sediments. In contrast, little is known about the effects of dissolved copper (dCu) in pelagic food webs. In most marine waters, more than 99.9% of dCu is bound to organic ligands. These ligands diminish dCu toxicity to aquatic organisms by lowering the concentrations of inorganic dCu, the most bioavailable species of Cu. For the past year, we have studied seasonal trends of dCu concentrations in the Strait of Georgia and have measured and characterized its speciation in seawater. Measurements taken in 2016 ranged from 5.4 to 23.3nM dCu, which are comparable to those found in San Francisco Bay and Puget Sound. Additionally, the highest concentrations were measured when the Fraser River flow rates were the fastest. Dissolved Cu levels were highest in the surface layer (0-50m), followed by the deep layer (200m to the bottom), with the lowest levels occurring in the intermediate waters. The concentrations in the intermediate layer coincide with those in the incoming low dCu- waters from the Pacific Ocean. Furthermore, using 64Cu as a radiotracer, we have measured uptake rates of Cu, from the dissolved and the particulate fractions, by local calanoid copepods exposed to in situ Cu levels. Our data show that copepods can easily accumulate Cu from the dissolved phase. This research provides much-needed information on dissolved Cu in a region historically known to harbor smelting and mining activities, and currently active maritime trade

Predictors of Changes in alcohol craving levels during a virtual reality cue exposure treatment among patients with alcohol use disorder

Background/Objective: Determining the predictive variables associated with levels of alcohol craving can ease the identification of patients who can benefit from treatments. This study aimed to describe changes (improvement or no change/deterioration) in alcohol craving levels and explore the predictors of these changes from admission to discharge in outpatients with alcohol use disorder (AUD) undergoing treatment-as-usual (TAU), or treatment-as-usual supplemented with virtual reality cue-exposure therapy (TAU + VR-CET). Method: A prospective cohort study was conducted amongst 42 outpatients with AUD (n = 15 TAU + VR-CET and n = 27 TAU) from a clinical setting. Changes in the levels of alcohol craving between admission and discharge were assessed with the Multidimensional Alcohol Craving Scale. Sociodemographic characteristics (age, gender, education, and socioeconomic and civil status), cognitive-a ective behavioral patterns (AUD severity, abstinence duration, psychiatric comorbidity, state anxiety, attentional bias, and substance use), and type of treatment (TAU + VR-CET and only TAU) were also evaluated. Results: The TAU + VR-CET group showed greater changes of improvement in the levels of alcohol craving than the TAU group ( 2 = 10.996; p = 0.001). Intragroup changes in alcohol craving from pre to post-treatment were significant in the TAU + VR-CET group ( 2 = 13.818; p = 0.003) but not within the TAU group ( 2 = 2.349; p = 0.503). The odds of an improvement in any of the craving levels between pre- and post-test was 18.18 (1/0.055) times higher in the TAU + VR-CET group with respect to the TAU group. The use of illicit drugs in the month prior to the test increased the odds of having a positive change by 18.18 (1/0.055) with respect to not having consumed. Conclusions: Including VR-CET in TAU programs may provide benefits in the treatment of AUDs mainly among patients with intense alcohol craving and individuals having used illicit substances prior to treatment

Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkbl alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1(K781), was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination

Stratification and therapeutic potential of PML in metastatic breast cancer.

Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.The work of A.C. is supported by the Ramón y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek), Health (2012111086) and Education (PI2012-03), Marie Curie (277043), Movember Foundation (GAP1), ISCIII (PI10/01484, PI13/00031), FERO (VIII Fellowship) and ERC (336343). N.M.-M. and P.A. are supported by the Spanish Association Against Cancer (AECC), AECC JP Vizcaya and Guipuzcoa, respectively. J.U. and F.S. are Juan de la Cierva Researchers (MINECO). L.A., A.A.-A. and L.V.-J. are supported by the Basque Government of education. M.L.-M.C. acknowledges SAF2014-54658-R and Asociación Española contra el Cancer. R.B. acknowledges Spanish MINECO (BFU2014-52282-P, Consolider BFU2014-57703-REDC), the Departments of Education and Industry of the Basque Government (PI2012/42) and the Bizkaia County. M.S., V.S. and J.B. acknowledge Banco Bilbao Vizcaya Argentaria (BBVA) Foundation (Tumour Biomarker Research Program). M.S. and J.B. are supported by NIH grant P30 CA008748. M.dM.V. is supported by the Institute of Health Carlos III (PI11/02251, PI14/01328) and Basque Government, Health Department (2014111145). A.M. is supported by ISCIII (CP10/00539, PI13/02277) and Marie Curie CIG 2012/712404. V.S. is supported by the SCIII (PI13/01714, CP14/00228), the FERO Foundation and the Catalan Agency AGAUR (2014 SGR 1331). R.R.G. research support is provided by the Spanish Ministry of Science and Innovation grant SAF2013-46196, BBVA Foundation, the Generalitat de Catalunya (2014 SGR 535), Institució Catalana de Recerca i Estudis Avançats, the Spanish Ministerio de Economia y Competitividad (MINECO) and FEDER funds (SAF2013-46196).This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1259