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The response to unfolded proteins in schizophrenia and bipolar disorder
- C. Cachán, I. M. Valle, Y. Potes, A. González Rubio, N. Menéndez Coto, D. López Fanjul, I. Vega Naredo, B. Caballero, P. Saiz, J. Bobes, P. García Portilla, A. Coto Montes
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S636-S637
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Introduction
Schizophrenia (SCH) and bipolar disorder (BD) are severe mental disordes, which have high incidence (Whiteford et al. Lancet 2013; 381 1575-86) and are the main causes of diasibility in young people (WHO 2022; https://www.who.int/news-room/fact-sheets/detail/mental-disorders).
Psycological stress appears in different mental disorders, and this is directly related to oxidative stress (Moller et al. Chem Biol Interact. 1996; 102 17-36)(Pupic-Bakrac et al. 2020; Psychiatr Danub. 32 412-9). Oxidative stress causes reticulum edoplasmic stress (ER stress) and this produces high levels of misfolded proteins. Defective proteins are degraded by the proteasome, but but when the density of misfolded proteins exceeds the capacity of the proteosome, the Unfolded and Misfolded Protein Response (UPR) is triggered through three main pathways: Inositol-requiring enzyme 1α (IRE1α); transcription factor 6 alpha (ATF6α) and protein kinase RNA-Like ER kinase (PERK), trying to recover normal protein synthesis capacity (Bermejo-Millo et al. 2018; Mol Neurobiol. 55 7973-86) (González-Blanco et al. 2022; J Cachexia Sarcopenia Muscle 13 919-31).
ObjectivesCharacterizing ER stress and UPR in SCH and BD.
MethodsWe studied ER stress and UPR in peripheral blood mononuclear cells (PBMC) from 50 patients with SCH and an equal number of patients with BD compared to their corresponding controls in order to achieve our objectives.
Western Blot assay were performed following classical procedure () and the results was normalized to Ponceau as loanding control (Nie et al. 2017; BiochemByophys Resp 12 10-13) (Sander et al. 2019; Anal Biochem 575 44-53). Proteasome activity was assessed using Proteasome Activity Assay Kit (ab107921, Abcam, Cambridge, UK).
ResultsER stress was evaluated with BiP/GRP78. Our results showed significantly increased expression in SCH (p<0,01) and BD (p<0,05), being more increased in SCH. Proteasome activity was increased in SCH and BD, being only statistically significant in SQZ (p<0,05). UPR study showed IRE1a cascade significantly activated in SCH (p<0,001) and only slight increased in BD showed without statistical differences. ATF6a pathway is measured by cleavage to active protein (50-kDa). Results showed higher expression in SCH than in BD and controls (p<0,001). In addition, PERK pathway showed higher statistical levels of p-eIF2a/eiF2a ratio in SCH than in BD and control respectively (p<0,05 and p<0,01).
ConclusionsOur results showed a greater alteration in SCH than in BD at the level of protein synthesis, which implies a greater toxicity at the cellular level and, therefore, a clear risk for the survival of cells in this pathology.
Disclosure of InterestNone Declared
SOD and CAT as potential preliminary biomarkers for the differential diagnosis of schizophrenia and bipolar disorder in the first episode of psychosis
- C. Cachán-Vega, E. Antuña, C. García-González, J. C. Bermejo-Millo, F. Baena-Huerta, L. González-Blanco, B. Caballero, I. Vega-Naredo, J. Bobes, M. P. García-Portilla, A. Coto-Montes, Y. Potes
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S449-S450
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Introduction
Schizophrenia (SCH) and bipolar disorder (BD) are severe mental disorders which lead to psychotic, affective and cognitive symptoms and often cause a progressive functional deterioration of the individual. The current diagnosis of SCH and BD essentially depends on clinical observation that often leads to misdiagnosis and the introduction of non-specific treatments. Therefore, an early detection and intervention are determinant for a better prognosis. Improving outcomes of a First Episode of Psychosis (FEP) depends mainly on the identification of reliable and discriminatory biomarkers between both disorders.
ObjectivesGiven that oxidative stress has been tightly involved in multiple metal disorders, the major goal of this work was to characterize oxidative alterations in order to identify potential biomarkers which allow the differential diagnosis in an early stage.
MethodsThe study was carried out on samples from 49 subjects (14 women and 35 men), divided into four groups: a control group of 10 individuals not previously diagnosed with any serious mental disorder, 17 patients who had presented a FEP, 12 patients diagnosed with SCH and 10 patients diagnosed with BP. Biochemical analysis were conducted in erythrocyte fraction to characterize the cellular oxidative damage by measuring lipid peroxidation (LPO) levels and the antioxidant defense system by the evaluation of catalase (CAT) and superoxide dismutase (SOD) activities.
ResultsIn the present work, we observed a significant increase in LPO levels in both SCH and BD disorders that was not neutralized by the antioxidant defense. It was found that SCH patients, despite exhibiting greater activities of SOD and CAT compared to BD individuals, also showed significantly higher levels of oxidative damage. The differential oxidative profile observed between SCH and BD individuals allowed to perform an individually analysis of patients diagnosed with FEP. Although it was not possible to identify the type of psychotic disorder of all the patients with FEP, the results obtained showed that while several individuals exhibited an oxidative prolife similar to that observed in SCH patients, other individuals presented a prolife very similar to that found in patients with BD.
ConclusionsThe current work reveals that LPO is a potential indicator of worse prognosis after being differentially modified in both SCH and BD. Moreover, SOD and CAT have been identified, by presenting an opposite profile between patients with SCH and BD, as potential preliminary biomarkers for a discriminatory diagnosis in an early stage of the disorder.
Disclosure of InterestNone Declared
Effect of animal mixing as a stressor on biomarkers of autophagy and oxidative stress during pig muscle maturation
- A. Rubio-González, Y. Potes, D. Illán-Rodríguez, I. Vega-Naredo, V. Sierra, B. Caballero, E. Fàbrega, A. Velarde, A. Dalmau, M. Oliván, A. Coto-Montes
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The objective of this work was to study the postmortem evolution of potential biomarkers of autophagy (Beclin 1, LC3-II/LC3-I ratio) and oxidative stress (total antioxidant activity, TAA; superoxide dismutase activity, SOD and catalase activity, CAT) in the Longissimus dorsi muscle of entire male ((Large White×Landrace)×Duroc) pigs subjected to different management treatments that may promote stress, such as mixing unfamiliar animals at the farm and/or during transport and lairage before slaughter. During the rearing period at the farm, five animals were never mixed after the initial formation of the experimental groups (unmixed group at the farm, UF), whereas 10 animals were subjected to a common routine of being mixed with unfamiliar animals (mixed group at the farm, MF). Furthermore, two different treatments were used during the transport and lairage before slaughter: 10 pigs were not mixed (unmixed group during transport and lairage, UTL), whereas five pigs were mixed with unfamiliar animals on the lorry and during lairage (mixed group during transport and lairage, MTL). These mixing treatments were then combined into three pre-slaughter treatments – namely, UF-UTL, MF-UTL and MF-MTL. The results show that MF-UTL and MF-MTL increased significantly the muscle antioxidant defense (TAA, SOD and CAT) at short postmortem times (4 and 8 h; P<0.001), followed by an earlier depletion of the antioxidant activity at 24 h postmortem (P<0.05). We also found that mixing unfamiliar animals, both at the farm and during transport and lairage, triggers postmortem muscle autophagy, which showed an earlier activation (higher expression of Beclin 1 and LC3-II/LC3-I ratio at 4 h postmortem followed by a decreasing pattern of this ratio along first 24 h postmortem) in the muscle tissues of animals from the MF-UTL and MF-MTL groups, as an adaptive strategy of the muscle cells for counteracting induced stress. From these results, we propose that monitoring the evolution of the main biomarkers of autophagy (Beclin 1, LC3-II/LC3-I ratio) and muscle antioxidant defense (TAA, SOD, CAT) in the muscle tissue within the first 24 h postmortem may help the detection of animal stress and its potential effect on the postmortem muscle metabolism.