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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein's influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection., Methods: Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n = 7) or placebo (n = 7) therapies every 12 h for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D)., Results: In vitro protocols have shown that rhein, diacerein's primary metabolite, decreased IL-1β secretion caused by SARS-CoV-2 infection in human PBMCs ( p < 0.05), and suppressed viral replication when administered either before or after the virus incubation ( p < 0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CL pro ) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PL pro ) virus and in the phosphorylation of proteins related cytoskeleton network ( p < 0.05). Diacerein-treated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo ( p < 0.05)., Conclusion: The indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials., Competing Interests: DB discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, GlaxoSmithKline, Hims, SFJ, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hô pitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and United States national co-leader, funded by Bayer), WebMD (CME steering committees), (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women' s Hospital who assigned to Lexicon; neither I nor Brigham and Women' s Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo. AS discloses the following relationships - Research Funding: Amgen, AstraZeneca, National Council for Scientific and Technological Development (CNPq) and Fundaç and#227; o de Apoio and#224; Pesquisa do Estado de Sã o Paulo (FAPESP). Dr. Pedro Gonç alves de Oliveira is responsible for R&D activities at TRB Pharma Indú stria Quí mica e Farmace utica Ltda, SP, Brazil. TRB Pharma is the owner of the product ARTRODAR® a diacerein-based product for osteoarthritis treatment. The remaining 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 © 2024 Carmo, Castillo, Bonilha, Gomes, Barreto, Moura, Davanzo, de Brito Monteiro, Muraro, Fabiano de Souza, Morari, Galdino, Brunetti, Reis-de-Oliveira, Carregari, Nadruz, Martins-de-Souza, Farias, Velloso, Proenca-Modena, Mori, Loh, Bhatt, Yellon, Davidson, De Oliveira, Moraes-Vieira and Sposito.)

Shotgun proteomics analysis presents multifaceted challenges, demanding diverse tool integration for insights. Addressing this complexity, OmicScope emerges as an innovative solution for quantitative proteomics data analysis. Engineered to handle various data formats, it performs data pre-processing - including joining replicates, normalization, data imputation - and conducts differential proteomics analysis for both static and longitudinal experimental designs. Empowered by Enrichr with over 224 databases, OmicScope performs Over Representation Analysis (ORA) and Gene Set Enrichment Analysis (GSEA). Additionally, its Nebula module facilitates meta-analysis from independent datasets, providing a systems biology approach for enriched insights. Complete with a data visualization toolkit and accessible as Python package and a web application, OmicScope democratizes proteomics analysis, offering an efficient and high-quality pipeline for researchers., (© 2024. The Author(s).)

COVID-19, a complex multisystem disorder affecting the central nervous system, can also have psychiatric sequelae. In addition, clinical evidence indicates that a diagnosis of a schizophrenia spectrum disorder is a risk factor for mortality in patients with COVID-19. In this study, we aimed to explore brain-specific molecular aspects of COVID-19 by using a proteomic approach. We analyzed the brain proteome of fatal COVID-19 cases and compared it with differentially regulated proteins found in postmortem schizophrenia brains. The COVID-19 proteomic dataset revealed a strong enrichment of proteins expressed by glial and neuronal cells and processes related to diseases with a psychiatric and neurodegenerative component. Specifically, the COVID-19 brain proteome enriches processes that are hallmark features of schizophrenia. Furthermore, we identified shared and distinct molecular pathways affected in both conditions. We found that brain ageing processes are likely present in both COVID-19 and schizophrenia, albeit possibly driven by distinct processes. In addition, alterations in brain cell metabolism were observed, with schizophrenia primarily impacting amino acid metabolism and COVID-19 predominantly affecting carbohydrate metabolism. The enrichment of metabolic pathways associated with astrocytic components in both conditions suggests the involvement of this cell type in the pathogenesis. Both COVID-19 and schizophrenia influenced neurotransmitter systems, but with distinct impacts. Future studies exploring the underlying mechanisms linking brain ageing and metabolic dysregulation may provide valuable insights into the complex pathophysiology of these conditions and the increased vulnerability of schizophrenia patients to severe outcomes., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

COVID-19 induces acute and persistent neurological symptoms in mild and severe cases. Proposed concomitant mechanisms include direct viral infection and strain, coagulopathy, hypoxia, and neuroinflammation. However, underlying molecular alterations associated with multiple neurological outcomes in both mild and severe cases are majorly unexplored. To illuminate possible mechanisms leading to COVID-19 neurological disease, we retrospectively investigated in detail a cohort of 35 COVID-19 mild and severe hospitalized patients presenting neurological alterations subject to clinically indicated cerebrospinal fluid (CSF) sampling. Clinical and neurological investigation, brain imaging, viral sequencing, and cerebrospinal CSF analyses were carried out. We found that COVID-19 patients presented heterogeneous neurological symptoms dissociated from lung burden. Nasal swab viral sequencing revealed a dominant strain at the time of the study, and we could not detect traces of SARS-CoV-2's spike protein in patients' CSF by multiple reaction monitoring analysis. Patients presented ubiquitous systemic hyper-inflammation and broad alterations in CSF proteomics related to inflammation, innate immunity, and hemostasis, irrespective of COVID-19 severity or neuroimaging alterations. Elevated CSF interleukin-6 (IL6) correlated with disease severity (sex-, age-, and comorbidity-adjusted mean Severe 24.5 pg/ml, 95% confidence interval (CI) 9.62-62.23 vs. Mild 3.91 pg/mL CI 1.5-10.3 patients, p = 0.019). CSF tumor necrosis factor-alpha (TNFα) and IL6 levels were higher in patients presenting pronounced neuroimaging alterations compared to those who did not (sex-, age-, and comorbidity-adjusted mean TNFα Pronounced 3.4, CI 2.4-4.4 vs. Non-Pronounced 2.0, CI 1.4-2.5, p = 0.022; IL6 Pronounced 33.11, CI 8.89-123.31 vs Non-Pronounced 6.22, CI 2.9-13.34, p = 0.046). Collectively, our findings put neuroinflammation as a possible driver of COVID-19 acute neurological disease in mild and severe cases., Competing Interests: none., (© 2024 The Authors.)

The COVID-19 pandemic was initiated by the rapid spread of a SARS-CoV-2 strain. Though mainly classified as a respiratory disease, SARS-CoV-2 infects multiple tissues throughout the human body, leading to a wide range of symptoms in patients. To better understand how SARS-CoV-2 affects the proteome from cells with different ontologies, this work generated an infectome atlas of 9 cell models, including cells from brain, blood, digestive system, and adipocyte tissue. Our data shows that SARS-CoV-2 infection mainly trigger dysregulations on proteins related to cellular structure and energy metabolism. Despite these pivotal processes, heterogeneity of infection was also observed, highlighting many proteins and pathways uniquely dysregulated in one cell type or ontological group. These data have been made searchable online via a tool that will permit future submissions of proteomic data ( https://reisdeoliveira.shinyapps.io/Infectome&#95;App/ ) to enrich and expand this knowledgebase., (© 2024. The Author(s).)

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction with antipsychotics is necessary to advance our understanding of the basis of schizophrenia, as well as our capacity to treat this disease. In this regard, the development of human brain-derived models that are amenable to studying the neurobiology of schizophrenia may contribute to filling the gaps left by the widely employed animal models. Here, we assessed the proteomic changes induced by the NMDA glutamate receptor antagonist MK-801 on human brain slice cultures obtained from adult donors submitted to respective neurosurgery. Initially, we demonstrated that MK-801 diminishes NMDA glutamate receptor signaling in human brain slices in culture. Next, using mass-spectrometry-based proteomics and systems biology in silico analyses, we found that MK-801 led to alterations in proteins related to several pathways previously associated with schizophrenia pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, and synaptic vesicle cycle. We also evaluated the impact of both typical and atypical antipsychotics on MK-801-induced proteome changes. Interestingly, the atypical antipsychotic clozapine showed a more significant capacity to counteract the protein alterations induced by NMDAr hypofunction than haloperidol. Finally, using our dataset, we identified potential modulators of the MK-801-induced proteome changes, which may be considered promising targets to treat NMDAr hypofunction in schizophrenia. This dataset is publicly available and may be helpful in further studies aimed at evaluating the effects of MK-801 and antipsychotics in the human brain., (© 2024 International Society for Neurochemistry.)

Background Suicide is one of the leading global causes of death. Behavior patterns from suicide ideation to completion are complex, involving multiple risk factors. Advances in technologies and large-scale bioinformatic tools are changing how we approach biomedical problems. The "omics" field may provide new knowledge about suicidal behavior to improve identification of relevant biological pathways associated with suicidal behavior. Methods We reviewed transcriptomic, proteomic, and metabolomic studies conducted in blood and post-mortem brains from individuals who experienced suicide or suicidal behavior. Omics data were combined using systems biology in silico, aiming at identifying major biological mechanisms and key molecules associated with suicide. Results Post-mortem samples of suicide completers indicate major dysregulations in pathways associated with glial cells (astrocytes and microglia), neurotransmission (GABAergic and glutamatergic systems), neuroplasticity and cell survivor, immune responses and energy homeostasis. In the periphery, studies found alterations in molecules involved in immune responses, polyamines, lipid transport, energy homeostasis, and amino and nucleic acid metabolism. Limitations We included only exploratory, non-hypothesis-driven studies; most studies only included one brain region and whole tissue analysis, and focused on suicide completers who were white males with almost none confounding factors. Conclusions We can highlight the importance of synaptic function, especially the balance between the inhibitory and excitatory synapses, and mechanisms associated with neuroplasticity, common pathways associated with psychiatric disorders. However, some of the pathways highlighted in this review, such as transcriptional factors associated with RNA splicing, formation of cortical connections, and gliogenesis, point to mechanisms that still need to be explored., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Schizophrenia is a complex and severe neuropsychiatric disorder, with a wide range of debilitating symptoms. Several aspects of its multifactorial complexity are still unknown, and some are accepted to be an early developmental deficiency with a more specifically neurodevelopmental origin. Understanding the timepoints of disturbances during neural cell differentiation processes could lead to an insight into the development of the disorder. In this context, human brain organoids and neural cells differentiated from patient-derived induced pluripotent stem cells are of great interest as a model to study the developmental origins of the disease., Results: Here we evaluated the differential expression of proteins of schizophrenia patient-derived neural progenitors (NPCs), early neurons, and brain organoids in comparison to healthy individuals. Using bottom-up shotgun proteomics with a label-free approach for quantitative analysis, we found multiple dysregulated proteins since NPCs, modified, and disrupted the 21DIV neuronal differentiation, and cerebral organoids. Our experimental methods have shown impairments in pathways never before found in patient-derived induced pluripotent stem cells studies, such as spliceosomes and amino acid metabolism; but also, those such as axonal guidance and synaptogenesis, in line with postmortem tissue studies of schizophrenia patients., Conclusion: In conclusion, here we provide comprehensive, large-scale, protein-level data of different neural cell models that may uncover early events in brain development, underlying several of the mechanisms within the origins of schizophrenia., (© 2022. The Author(s).)

Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212-2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

COVID-19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID-19. Here, we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS-CoV-2 infected Syrian hamsters. We show that SARS-CoV-2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real-time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro. SARS-CoV-2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID-19, as memory loss, confusion, and cognitive impairment., (© 2022 International Society for Neurochemistry.)

Two protein post-translational modifications, lysine succinylation and malonylation, are implicated in protein regulation, glycolysis, and energy metabolism. The precursors of these modifications, succinyl-CoA and malonyl-CoA, are key players in central metabolic processes. Both modification profiles have been proven to be responsive to metabolic stimuli, such as hypoxia. As mitochondrial dysfunction and metabolic dysregulation are implicated in schizophrenia and other psychiatric illnesses, these modification profiles have the potential to reveal yet another layer of protein regulation and can furthermore represent targets for biomarkers that are indicative of disease as well as its progression and treatment. In this work, data from shotgun mass spectrometry-based quantitative proteomics were compiled and analyzed to probe the succinylome and malonylome of postmortem brain tissue from patients with schizophrenia against controls and the human oligodendrocyte precursor cell line MO3.13 with the dizocilpine chemical model for schizophrenia, three antipsychotics, and co-treatments. Several changes in the succinylome and malonylome were seen in these comparisons, revealing these modifications to be a largely under-studied yet important form of protein regulation with broad potential applications.

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

Modeling schizophrenia is challenging due to the uniquely human component of psychiatric disorders. Despite several advances in cellular and animal modeling, postmortem brain tissue derived from patients is still one of the extremely few sources of information that comprises brain complexity, human genetics, and patient experiences. Additionally, postmortem tissue from patients with schizophrenia can be used to drive hypotheses that can then be validated in other models, involving either other animals or an in vitro approach. While evaluating high-throughput and sensitive techniques, shotgun proteomics allows for the identification and quantitation of thousands of proteins present in biological systems. In the context of schizophrenia, proteomics can map differentially regulated proteins throughout brain regions of patients with schizophrenia, generating a large amount of information regarding the disorder's pathophysiology. In this chapter, our aim is to bring the literature up to date regarding proteomics tools applied to postmortem brains from patients with schizophrenia, additionally discussing new findings, roads, and perspectives for the comprehension of this severe disorder., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Glutamatergic neurotransmission dysfunction and the early involvement of the hippocampus have been proposed to be important aspects of the pathophysiology of schizophrenia. Here, we performed proteomic analysis of hippocampus postmortem samples from schizophrenia patients as well as neural cells-neurons and oligodendrocytes-treated with MK-801, an NMDA receptor antagonist. There were similarities in processes such as oxidative stress and apoptotic process when comparing hippocampus samples with MK-801-treated neurons, and in proteins synthesis when comparing hippocampus samples with MK-801-treated oligodendrocytes. This reveals that studying the effects of glutamatergic dysfunction in different neural cells can contribute to a better understanding of what it is observed in schizophrenia patients' postmortem brains., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

hnRNP represent a large family of RNA-binding proteins related to regulation of transcriptional and translational processes. More specifically, hnRNPs play pivotal roles in the myelination of the central nervous system. The regulation of these proteins are associated with neurodegenerative and psychiatric disorders, including schizophrenia. hnRNPs were shown differentially regulated on schizophrenia postmortem brain tissue as well as in cultured oligodendrocytes treated with clozapine, a common antipsychotic used in schizophrenia treatment. Here we employed co-immunoprecipitation of hnRNP C1/C2 to investigate for the first time in a large-scale manner its interaction partners on cultured oligodendrocytes (MO3.13). Even preliminarily, results bring a more comprehensive description of hnRNP C1/C2 interaction network, and therefore insights regarding the potential role of this protein in the central nervous system in health and disease, warranting further investigation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Disturbances in the myelin sheath drive disruptions in neural transmission and brain connectivity as seen in schizophrenia. Here, the myelin proteome was characterised in schizophrenia patients and healthy controls to visualise differences in proteomic profiles., Methods: A liquid chromatography tandem mass spectrometry-based shotgun proteomic analysis was performed of a myelin-enriched fraction of postmortem brain samples from schizophrenia patients ( n  = 12) and mentally healthy controls ( n  = 8). In silico pathway analyses were performed on the resulting data., Results: The present characterisation of the human myelinome led to the identification of 480 non-redundant proteins, of which 102 proteins are newly annotated to be associated with the myelinome. Levels of 172 of these proteins were altered between schizophrenia patients and controls. These proteins were mainly associated with glial cell differentiation, metabolism/energy, synaptic vesicle function and neurodegeneration. The hub proteins with the highest degree of connectivity in the network included multiple kinases and synaptic vesicle transport proteins., Conclusions: Together these findings suggest disruptive effects on synaptic activity and therefore neural transmission and connectivity, consistent with the dysconnectivity hypothesis of schizophrenia. Further studies on these proteins may lead to the identification of potential drug targets related to the synaptic dysconnectivity in schizophrenia and other psychiatric and neurodegenerative disorders.

Here, we describe a proteomic pipeline to use a human microglial cell line as a biological model to study schizophrenia. In order to maximize the proteome coverage, we apply two-dimensional liquid chromatography coupled with ultra-definition MS E mass spectrometry (LC-UDMS E ) using a data-independent acquisition (DIA) approach, with an optimization of drift time collision energy.

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19., Competing Interests: Declaration of Interests Authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine + D-serine co-treatment, which has emerged lately as an alternative type of treatment. This was accomplished by employing shotgun proteomics, using nanoESI-LC-MS/MS label-free quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine + D-serine treatment. In this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia.

Here we describe a mass spectrometry-based proteomics workflow to discovery proteins differentially regulated in brains collected postmortem from mental, neurological, or substance abuse disorders (MNS) patients. One way to maximize protein detection is to carry out enrichment of cellular compartments such as the nucleus, mitochondria and cytosol. Subcellular fractionation improves proteome coverage and may shed light on the role of these organelles in the pathophysiology of MNS.

Brain disorders are among the most complex and difficult to understand of human disorders in terms of pathophysiology and etiology. Differently from other human diseases such as cancer, which uses biomarkers in clinical practice, there are no prognostic and diagnostic biomarkers available for psychiatric disorders. Those associated with the likelihood of a successful medication are also not existent, impairing treatment strategies. Proteomics is a suitable tool for identifying such biomarkers to be validated and further implemented in the clinic. Here we present a protocol for the proteome analyses of blood plasma and serum collected in vivo, aiming for the discovery of potential biomarkers and the comprehension of the molecular bases of diseases and treatments.

Most biomarker candidates arising from proteomic studies of psychiatric disorders have not progressed for use in clinical studies due to insufficient validation steps. Here we describe a selective reaction monitoring mass spectrometry (SRM-MS) approach that could be used as a follow-up validation tool of proteins identified in blood serum or plasma. This protocol specifically covers the stages of peptide selection and optimization. The increasing application of SRM-MS should enable fast, sensitive, and robust methods with the potential for use in clinical studies involving sampling of serum or plasma. Understanding the molecular mechanisms and identifying potential biomarkers for risk assessment, diagnosis, prognosis, and prediction of drug response goes toward the implementation of translational medicine strategies for improved treatment of patients with psychiatric disorders and other debilitating diseases.

Patients with psychiatric disorders exhibit dysfunctions in peripheral and central metabolism. This may be a root cause of impaired neuronal function, manifested as changes in mood, behavior, and cognitive capabilities in patients suffering with these conditions. Here we describe a selective reaction monitoring mass spectrometry (SRM-MS)-based targeted proteomic protocol for precise simultaneous quantitation of three glycolytic enzymes in postmortem brain tissue extracts. The SRM-MS approach has several advantages in terms of sensitivity, reproducibility, and reduced sample consumption, compared to traditional MS methods.

Psychiatric disorders are one of the biggest burdens to society, with significant personal and economical costs. Schizophrenia (SCZ), among them, is still poorly understood, and its molecular characterization is crucial to improve patients' diagnosis and treatment. The combination of genetic, biochemical, and environmental factors leads to systemic alterations, which are yet to be fully comprehended. Thus, understanding those missing links by connecting some molecular reports of SCZ is essential. From postmortem brain to animal models and cell culture, new tools are emerging, including recent advances in proteomics, and there is a need to apply them to solve these problems. Here, we review some of those features, mainly related to where proteomics could help, and discuss whether those new technologies could and should be applied to psychiatric disorder studies., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)