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P21 is an immunomodulatory protein expressed throughout the life cycle of Trypanosoma cruzi , the etiologic agent of Chagas disease. In vitro and in vivo studies have shown that P21 plays an important role in the invasion of mammalian host cells and establishment of infection in a murine model. P21 functions as a signal transducer, triggering intracellular cascades in host cells and resulting in the remodeling of the actin cytoskeleton and parasite internalization. Furthermore, in vivo studies have shown that P21 inhibits angiogenesis, induces inflammation and fibrosis, and regulates intracellular amastigote replication. In this study, we used the CRISPR/Cas9 system for P21 gene knockout and investigated whether the ablation of P21 results in changes in the phenotypes associated with this protein. Ablation of P21 gene resulted in a lower growth rate of epimastigotes and delayed cell cycle progression, accompanied by accumulation of parasites in G1 phase. However, P21 knockout epimastigotes were viable and able to differentiate into metacyclic trypomastigotes, which are infective to mammalian cells. In comparison with wild-type parasites, P21 knockout cells showed a reduced cell invasion rate, demonstrating the role of this protein in host cell invasion. However, there was a higher number of intracellular amastigotes per cell, suggesting that P21 is a negative regulator of amastigote proliferation in mammalian cells. Here, for the first time, we demonstrated the direct correlation between P21 and the replication of intracellular amastigotes, which underlies the chronicity of T. cruzi infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Teixeira, Chiurillo, Lander, Rodrigues, Onofre, Ferreira, Yonamine, Santos, Mortara, da Silva and Silveira.)

Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. We reported previously lower NDEL1 enzyme activity in blood of treated first episode psychosis and chronic schizophrenia (SCZ) compared to healthy control subjects, with even lower activity in treatment resistant chronic SCZ patients, implicating NDEL1 activity in SCZ. Herein, higher NDEL1 activity was observed in the blood and several brain regions of a validated animal model for SCZ at baseline. In addition, long-term treatment with typical or atypical antipsychotics, under conditions in which SCZ-like phenotypes were reported to be reversed in this animal model for SCZ, showed a significant NDEL1 activity reduction in blood and brain regions which is in line with clinical data. Importantly, these results support measuring NDEL1 enzyme activity in the peripheral blood to predict changes in NDEL1 activity in the CNS. Also, acute administration of psychostimulants, at levels reported to induce SCZ-like phenotype in normal rat strains, increased NDEL1 enzyme activity in blood. Therefore, alterations in NDEL1 activity after treatment with antipsychotics or psychostimulants may suggest a possible modulation of NDEL1 activity secondary to neurotransmission homeostasis and provide new insights into the role of NDEL1 in SCZ pathophysiology.

Background: Our previous studies showed increased angiotensin I-converting enzyme (ACE) activity in chronic schizophrenia (SCZ) patients compared to healthy control (HC) volunteers, and the relevance of combining ACE genotype and activity for predicting SCZ was suggested., Methods: ACE activity was measured in plasma of ACE insertion/deletion (I/D) genotyped HC volunteers (N = 53) and antipsychotic-naïve first-episode psychosis (FEP) patients (N = 45), assessed at baseline (FEB-B) and also after 2-months (FEP-2M) of treatment with the atypical antipsychotic risperidone., Results: ACE activity measurements showed significant differences among HC, FEP-B and FEP-2M groups (F = 5.356, df = 2, p = 0.005), as well as between HC and FEP-2M (post-hoc Tukey's multiple comparisons test, p = 0.004). No correlation was observed for ACE activity increases and symptom severity reductions in FEP as assessed by total PANSS (r = -0.131, p = 0.434). FEP subgrouped by ACE I/D genotype showed significant ACE activity increases, mainly in the DD genotype subgroup. No correlation between ACE activity and age was observed in FEP or HC groups separately (r = 0.210, p = 0.392), but ACE activity levels differences observed between these groups were influenced by age., Conclusions: The importance of measuring the ACE activity in blood plasma, associated to ACE I/D genotyping to support the follow-up of FEP patients did not show correlation with general symptoms amelioration in the present study. However, new insights into the influence of age and I/D genotype for ACE activity changes in FEP individuals upon treatment was demonstrated., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations., Competing Interests: AG received PhD fellowship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), while AMV was a recipient of a fellowship from CNPq. MAS and CMY are recipients of a fellowship from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). VO, VA, RAB and MAFH are all supported by FAPESP, CAPES and CNPq. MAFH is also the recipient of a fellowship from CNPq (311815/2012-0). RAB has also received lecture fees from Astra Zeneca, Bristol, Janssen and Lundbeck, with research grants from private companies such as Janssen, Eli Lilly, Lundbeck, Novartis and Roche, and Fundação Safra and Fundação ABADS. RAB is also a shareholder of Radiopharmacus Ltda and Biomolecular Technology Ltda. The remaining authors declare no conflict of interest.