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Maternal infection and stress exposure, especially during childhood and adolescence, have been implicated as risk factors for schizophrenia. Both insults induce an exacerbated inflammatory response, which could mediate disturbance of neurodevelopmental processes and, ultimately, malfunctioning of neural systems observed in this disorder. Thus, anti-inflammatory drugs, such as PPARγ agonists, may potentially be used to prevent the development of schizophrenia. Microglia culture was prepared from the offspring of saline or poly(I:C)-injected mice. The cells were pretreated with pioglitazone and then, stimulated by LPS. Proinflammatory mediators and phagocytic activity were measured. Also, pregnant rats were injected with saline or poly(I:C) on GD17. The offspring were subjected to footshock during adolescence and subsequently injected with pioglitazone or vehicle. At adulthood, behavior and dopaminergic activity were evaluated. Pioglitazone reduced proinflammatory mediators induced by poly(I:C) microglia stimulated by LPS without affecting their decreased phagocytic activity. The PPARγ agonist also prevented the emergence of social and cognitive impairments, as well as attenuated the increased number of spontaneously active dopamine neurons in the VTA, observed in both males and females from poly(I:C) and stress group. Therefore, pioglitazone could potentially prevent the emergence of the schizophrenia-like alterations induced by the two-hit model via reduction of microglial activation., Competing Interests: Declaration of competing interest AAG received funds from Merck, Newron, Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, and SynAgile. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) is approved for the treatment of patients with platinum-sensitive relapsed ovarian cancer. Nevertheless, there is currently limited information regarding this treatment in elderly patients with ovarian cancer in a real-world setting., Methods: This observational and multicentric study retrospectively evaluated trabectedin plus PLD in a real-world setting treatment of elderly patients diagnosed with platinum-sensitive relapsed ovarian cancer, treated according to the Summary of Product Characteristics (SmPC) from 15 GEICO-associated hospitals. Patients ≥ 70 years old at the time of treatment initiation and platinum-free intervals ≥ 6 months were considered eligible., Results: Forty-three patients with a median age of 74.0 years were treated between January 1st, 2015, and December 31st, 2019 in 15 Spanish centers. Four patients achieved complete response (9.3%), 14 (32.6%) partial response, and 13 (30.2%) stable disease as the best radiological response. In the analysis of biological overall response according to CA125 serum levels (i.e., Rustin criteria), 14 responded to the treatment (32.6%), 11 responded and normalized (25.6%), three patients stabilized (7.0%) and three progressed (7.0%). Median progression-free survival (PFS) and overall survival (OS) in the study population were 7.7 and 19.5 months, respectively. The most common grade 3/4 adverse events were neutropenia (n = 8, 18.7%) and asthenia (n = 5, 11.6%)., Conclusions: This analysis demonstrated that trabectedin combined with PLD is a feasible and effective treatment in elderly patients with platinum-sensitive relapsed ovarian cancer, showing an acceptable safety profile, which is crucial in the palliative treatment of these patients., (© 2024. The Author(s).)

Background: Aldosterone has been described to initiate cardiovascular diseases by triggering exacerbated sterile vascular inflammation. The functions of CCL5 (C-C motif chemokine ligand 5) and its receptor CCR5 (C-C motif chemokine receptor 5) are well known in infectious diseases, their contributions to aldosterone-induced vascular injury and hypertension remain unknown., Methods: We analyzed the vascular profile, blood pressure, and renal damage in wild-type (CCR5 +/+ ) and CCR5 knockout (CCR5 -/- ) mice treated with aldosterone (600 µg/kg per day for 14 days) while receiving 1% saline to drink. Vascular function was analyzed in aorta and mesenteric arteries, blood pressure was measured by telemetry and renal injury and inflammation were analyzed via histology and flow cytometry. Endothelial cells were used to study the molecular signaling whereby CCL5 induces endothelial dysfunction., Results: Aldosterone treatment resulted in exaggerated CCL5 circulating levels and vascular CCR5 expression in CCR5 +/+ mice accompanied by endothelial dysfunction, hypertension, and renal inflammation and damage. CCR5 -/- mice were protected from these aldosterone-induced effects. Mechanistically, we demonstrated that CCL5 increased NOX1 (NADPH oxidase 1) expression, reactive oxygen species formation, NFκB (nuclear factor kappa B) activation, and inflammation and reduced NO production in isolated endothelial cells. These effects were abolished by antagonizing CCR5 with Maraviroc. Finally, aorta incubated with CCL5 displayed severe endothelial dysfunction, which is prevented by blocking NOX1, NFκB, or CCR5., Conclusions: Our data demonstrate that CCL5/CCR5, through activation of NFκB and NOX1, is critically involved in aldosterone-induced vascular and renal damage and hypertension placing CCL5 and CCR5 as potential therapeutic targets for conditions characterized by aldosterone excess., Competing Interests: None.