Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.021 by the authors. Licensee MDPI, Basel, Switzerland

Hormonal Differences in Intimate Partner Violence Perpetrators When They Cope with Acute Stress: A Pilot Study

Background: Only a few studies have paid attention to the ability of perpetrators of intimate partner violence (IPVAW) against women to cope with acute stress, including hormonal parameters. In fact, previous studies assessed how salivary testosterone (Tsal) and cortisol (Csal) changed after coping with an acute emotional stressor (directly related to IPVAW), and they concluded that an imbalance between the two hormones might be characteristic of these men. Nevertheless, they neglected to examine the role of other hormones, such as salivary oxytocin (OXsal), which also seemed to play an important role in behavioral regulation, and whether this response could be generalized to other types of stress not directly related to IPVAW. Methods: This study aims to assess whether IPVAW perpetrators (n = 19) present differential hormonal (Tsal, Csal, OXsal and their ratios) and psychological state (anxiety, anger, and general affect) responses when coping with an acute cognitive laboratory stressor (a set of neuropsychological tests performed in front of an expert committee) in comparison with non-violent men (n = 16). This quasi-experimental study also assessed whether the psychological state variables drive this different hormonal response. Results: Our results revealed that IPVAW perpetrators had lower Csal and higher Tsal/Csal ratio levels during the post-task period, as well as higher total levels (average) of OXsal than controls. We also found that, only in IPVAW perpetrators, high levels of baseline anxiety and negative affect were related to high rises in Csal during the stress task. Conclusions: These data present a background showing that IPVAW perpetrators and non-violent men cope differently with stress. These findings might help to identify idiosyncratic profiles of IPVAW perpetrators that can then be employed to establish their therapeutic needs. Moreover, we reinforced the importance of combining biological markers with self-reports, thus increasing the reliability of these forensic assessments

Reduced salivary oxytocin after an empathic induction task in intimate partner violence perpetrators: importance of socio-affective functions and its impact on prosocial behavior

Intimate Partner Violence (IPV) has been linked to difficulties in socio-affective functions. Nevertheless, the underlying psychobiological mechanisms that might be responsible for them remain unclear. Oxytocin (OXT) stands out as an important hormone that may favor the salience of social information, due to its relevance in empathy and prosocial behavior. Thus, the study of salivary OXT (sOXT) may provide further information about potential impairments in social cognition in IPV perpetrators. This study analyzed the effects of an empathic induction task, performed through negative emotion-eliciting videos, on endogenous sOXT levels, mood state, and emotional perception in 30 IPV perpetrators compared to 32 controls. Additionally, we explored their performance on prosocial behavior after the empathic induction task, using Hare's donation procedure. Lower sOXT levels were found in IPV perpetrators after the task compared to controls, along with a general decreasing tendency in their sOXT levels. Additionally, IPV perpetrators exhibited no change in their mood state and perceived others' emotions as more positive and less intense. Moreover, the mood state response and alexithymia traits, respectively, positively and negatively predicted the sOXT levels after the empathic induction task in the entire sample. Finally, we did not observe a lower appearance of prosocial behaviors in IPV perpetrators; however, higher sOXT levels after the empathic induction task were found in subjects who donated when considering the whole sample. In sum, IPV perpetrators exhibited differences in their sOXT levels when empathizing, compared to controls, with alexithymia and the emotional response potentially explaining the sOXT levels after the task. Furthermore, prosocial behavior was more related to these sOXT levels than to IPV. As our knowledge about the emotional processing of IPV perpetrators increases, we will be better able to develop and include coadjutant treatments in current psychotherapeutic programs, in order to focus on their emotional needs, which, in turn, would reduce the future risk of recidivism

Targeting Alzheimer's disease with multimodal polypeptide-based nanoconjugates

Alzheimer’s disease (AD), the most prevalent form of dementia, remains incurable mainly due to our failings in the search for effective pharmacological strategies. Here, we describe the development of targeted multimodal polypeptide-based nanoconjugates as potential AD treatments. Treatment with polypeptide nanoconjugates bearing propargylamine moieties and bisdemethoxycurcumin or genistein afforded neuroprotection and displayed neurotrophic effects, as evidenced by an increase in dendritic density of pyramidal neurons in organotypic hippocampal culture. The additional conjugation of the Angiopep-2 targeting moiety enhanced nanoconjugate passage through the blood-brain barrier and modulated brain distribution with nanoconjugate accumulation in neurogenic areas, including the olfactory bulb. Nanoconjugate treatment effectively reduced neurotoxic β amyloid aggregate levels and rescued impairments to olfactory memory and object recognition in APP/PS1 transgenic AD model mice. Overall, this study provides a description of a targeted multimodal polyglutamate-based nanoconjugate with neuroprotective and neurotrophic potential for AD treatment

Exchangeable Self-Assembled Lanthanide Antennas for PLIM Microscopy

This is the published manuscript version of the following manuscript: Exchangeable Self-Assembled Lanthanide Antennas for PLIM Microscopy, Angew. Chem. Int. Ed. 2023, e202314595 doi: https://doi.org/10.1002/anie.202314595 This article may be used for non-commercial purposes in accordance with Wiley Sharing Policies. Supplementary Materials accompanying this article can be found on-line at the publisher’s site.Lanthanides have unique photoluminescence (PL) emission properties, including very long PL life- times. This makes them ideal for biological imaging applications, especially using PL lifetime imaging micro- scopy (PLIM). PLIM is an inherently multidimensional technique with exceptional advantages for quantitative biological imaging. Unfortunately, due to the required prolonged acquisitions times, photobleaching of lantha- nide PL emission currently constitutes one of the main drawbacks of PLIM. In this study, we report a small aqueous-soluble, lanthanide antenna, 8-methoxy-2-oxo- 1,2,4,5-tetrahydrocyclopenta[de]quinoline-3-phosphonic acid, PAnt, specifically designed to dynamically interact with lanthanide ions, serving as exchangeable dye aimed at mitigating photobleaching in PLIM microscopy in cellulo. Thus, self-assembled lanthanide complexes that may be photobleached during image acquisition are continuously replenished by intact lanthanide antennas from a large reservoir. Remarkably, our self-assembled lanthanide complex clearly demonstrated a significant reduction of PL photobleaching when compared to well- established lanthanide cryptates, used for bioimaging. This concept of exchangeable lanthanide antennas opens new possibilities for quantitative PLIM bioimaging.Grant PID2020-114256RB-I00 funded by AEI/10.13039/501100011033Grant PID2019- 104366RB-C22 funded by AEI/10.13039/501100011033/ FEDER “Una manera de hacer Europa”Grants P21_00212, A-FQM-386-UGR20 and 2021/00627/001-FEDER_UJA_ 2020 funded by FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y UniversidadesCSIC grant 202180E073Acción 1 from Universidad de JaénFunding for open access charge: Universidad de Granada/CBUASpanish Ministerio de Educación y Formación Profesional for the FPU Ph.D. scholarshi

Impaired brain glymphatic flow in experimental hepatic encephalopathy

Background & Aims: Neuronal function is exquisitely sensitive to alterations in the extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain is thought to result from liver disease and may contribute to neuronal dysfunction and cognitive impairment. This study was designed to test the hypothesis that the accumulation of these substances, such as bile acids, may result from reduced clearance from the brain. Methods: In a rat model of chronic liver disease with minimal HE (the bile duct ligation [BDL] model), we used emerging dynamic contrast-enhanced MRI and mass-spectroscopy techniques to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. Immunofluorescence of aquaporin-4 (AQP4) and behavioural experiments were also performed. Results: We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic clearance in BDL rats, which aligned with cognitive/behavioural deficits. Reduced AQP4 expression was observed in the olfactory bulb and prefrontal cortex in HE, which could contribute to the pathophysiological mechanisms underlying the impairment in glymphatic function in BDL rats. Conclusions: This study provides the first experimental evidence of impaired glymphatic flow in HE, potentially mediated by decreased AQP4 expression in the affected regions. Lay summary: The 'glymphatic system' is a newly discovered brain-wide pathway that facilitates clearance of various sub-stances that accumulate in the brain due to its activity. This study evaluated whether the function of this system is altered in a model of brain dysfunction that occurs in cirrhosis. For the first time, we identified that the clearance of substances from the brain in cirrhosis is reduced because this clearance system is defective. This study proposes a new mechanism of brain dysfunction in patients with cirrhosis and provides new targets for therapy

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria.

Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum-infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter-endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin-induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC-induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised