Editorial

3 pages, 189 KiB

Open AccessEditorial

Multi-Omics for the Understanding of Brain Diseases

by Chiara Villa and Jong Hyuk Yoon

Life 2021, 11(11), 1202; https://doi.org/10.3390/life11111202 - 07 Nov 2021

Cited by 6 | Viewed by 1831

Brain diseases, including both neurodegenerative diseases and mental disorders, represent the third largest healthcare problem in developed countries, after cardiovascular disorders and cancer [...] Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

Research

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32 pages, 3669 KiB

Open AccessArticle

Proteomic Analysis Unveils Expressional Changes in Cytoskeleton- and Synaptic Plasticity-Associated Proteins in Rat Brain Six Months after Withdrawal from Morphine

by Zdenka Drastichova, Lucie Hejnova, Radka Moravcova and Jiri Novotny

Life 2021, 11(7), 683; https://doi.org/10.3390/life11070683 - 13 Jul 2021

Cited by 11 | Viewed by 3221

Abstract

Drug withdrawal is associated with abstinence symptoms including deficits in cognitive functions that may persist even after prolonged discontinuation of drug intake. Cognitive deficits are, at least partially, caused by alterations in synaptic plasticity but the precise molecular mechanisms have not yet been [...] Read more.

Drug withdrawal is associated with abstinence symptoms including deficits in cognitive functions that may persist even after prolonged discontinuation of drug intake. Cognitive deficits are, at least partially, caused by alterations in synaptic plasticity but the precise molecular mechanisms have not yet been fully identified. In the present study, changes in proteomic and phosphoproteomic profiles of selected brain regions (cortex, hippocampus, striatum, and cerebellum) from rats abstaining for six months after cessation of chronic treatment with morphine were determined by label-free quantitative (LFQ) proteomic analysis. Interestingly, prolonged morphine withdrawal was found to be associated especially with alterations in protein phosphorylation and to a lesser extent in protein expression. Gene ontology (GO) term analysis revealed enrichment in biological processes related to synaptic plasticity, cytoskeleton organization, and GTPase activity. More specifically, significant changes were observed in proteins localized in synaptic vesicles (e.g., synapsin-1, SV2a, Rab3a), in the active zone of the presynaptic nerve terminal (e.g., Bassoon, Piccolo, Rims1), and in the postsynaptic density (e.g., cadherin 13, catenins, Arhgap35, Shank3, Arhgef7). Other differentially phosphorylated proteins were associated with microtubule dynamics (microtubule-associated proteins, Tppp, collapsin response mediator proteins) and the actin–spectrin network (e.g., spectrins, adducins, band 4.1-like protein 1). Taken together, a six-month morphine withdrawal was manifested by significant alterations in the phosphorylation of synaptic proteins. The altered phosphorylation patterns modulating the function of synaptic proteins may contribute to long-term neuroadaptations induced by drug use and withdrawal. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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14 pages, 1282 KiB

Open AccessArticle

Description of a CSF-Enriched miRNA Panel for the Study of Neurological Diseases

by María Muñoz-San Martín, Imma Gomez, Albert Miguela, Olga Belchí, René Robles-Cedeño, Ester Quintana and Lluís Ramió-Torrentà

Life 2021, 11(7), 594; https://doi.org/10.3390/life11070594 - 22 Jun 2021

Cited by 7 | Viewed by 1814

Abstract

Background: The study of circulating miRNAs in CSF has gained tremendous attention during the last years, as these molecules might be promising candidates to be used as biomarkers and provide new insights into the disease pathology of neurological disorders. Objective: The main aim [...] Read more.

Background: The study of circulating miRNAs in CSF has gained tremendous attention during the last years, as these molecules might be promising candidates to be used as biomarkers and provide new insights into the disease pathology of neurological disorders. Objective: The main aim of this study was to describe an OpenArray panel of CSF-enriched miRNAs to offer a suitable tool to identify and characterize new molecular signatures in different neurological diseases. Methods: Two hundred and fifteen human miRNAs were selected to be included in the panel, and their expression and abundance in CSF samples were analyzed. In addition, their stability was studied in order to propose suitable endogenous controls for CSF miRNA studies. Results: miR-143-3p and miR-23a-3p were detected in all CSF samples, while another 80 miRNAs were detected in at least 70% of samples. miR-770-5p was the most abundant miRNA in CSF, presenting the lowest mean Cq value. In addition, miR-26b-5p, miR-335-5p and miR-92b-3p were the most stable miRNAs and could be suitable endogenous normalizers for CSF miRNA studies. Conclusions: These OpenArray plates might be a suitable and efficient tool to identify and characterize new molecular signatures in different neurological diseases and would improve the yield of miRNA detection in CSF. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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27 pages, 5994 KiB

Open AccessArticle

Orthosiphon stamineus Proteins Alleviate Hydrogen Peroxide Stress in SH-SY5Y Cells

by Yin-Sir Chung, Pervaiz Khalid Ahmed, Iekhsan Othman and Mohd. Farooq Shaikh

Life 2021, 11(6), 585; https://doi.org/10.3390/life11060585 - 20 Jun 2021

Cited by 3 | Viewed by 2271

Abstract

The neuroprotective potential of Orthosiphon stamineus leaf proteins (OSLPs) has never been evaluated in SH-SY5Y cells challenged by hydrogen peroxide (H₂O₂). This work thus aims to elucidate OSLP neuroprotective potential in alleviating H₂O₂ stress. OSLPs at [...] Read more.

The neuroprotective potential of Orthosiphon stamineus leaf proteins (OSLPs) has never been evaluated in SH-SY5Y cells challenged by hydrogen peroxide (H₂O₂). This work thus aims to elucidate OSLP neuroprotective potential in alleviating H₂O₂ stress. OSLPs at varying concentrations were evaluated for cytotoxicity (24 and 48 h) and neuroprotective potential in H₂O₂-induced SH-SY5Y cells (24 h). The protective mechanism of H₂O₂-induced SH-SY5Y cells was also explored via mass-spectrometry-based label-free quantitative proteomics (LFQ) and bioinformatics. OSLPs (25, 50, 125, 250, 500, and 1000 µg/mL; 24 and 48 h) were found to be safe. Pre-treatments with OSLP doses (250, 500, and 1000 µg/mL, 24 h) significantly increased the survival of SH-SY5Y cells in a concentration-dependent manner and improved cell architecture—pyramidal-shaped cells, reduced clumping and shrinkage, with apparent neurite formations. OSLP pre-treatment (1000 µg/mL, 24 h) lowered the expressions of two major heat shock proteins, HSPA8 (heat shock protein family A (Hsp70) member 8) and HSP90AA1 (heat shock protein 90), which promote cellular stress signaling under stress conditions. OSLP is, therefore, suggested to be anti-inflammatory by modulating the “signaling of interleukin-4 and interleukin-13” pathway as the predominant mechanism in addition to regulating the “attenuation phase” and “HSP90 chaperone cycle for steroid hormone receptors” pathways to counteract heat shock protein (HSP)-induced damage under stress conditions. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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16 pages, 3054 KiB

Open AccessArticle

Spatiotemporal 22q11.21 Protein Network Implicates DGCR8-Dependent MicroRNA Biogenesis as a Risk for Late Fetal Cortical Development in Psychiatric Diseases

by Liang Chen, Wenxiang Cai, Weidi Wang, Zhe Liu and Guan-Ning Lin

Life 2021, 11(6), 514; https://doi.org/10.3390/life11060514 - 31 May 2021

Cited by 3 | Viewed by 2324

Abstract

The chromosome 22q11.21 copy number variant (CNV) is a vital risk factor that can be a genetic predisposition to neurodevelopmental disorders (NDD). As the 22q11.21 CNV affects multiple genes, causal disease genes and mechanisms affected are still poorly understood. Thus, we aimed to [...] Read more.

The chromosome 22q11.21 copy number variant (CNV) is a vital risk factor that can be a genetic predisposition to neurodevelopmental disorders (NDD). As the 22q11.21 CNV affects multiple genes, causal disease genes and mechanisms affected are still poorly understood. Thus, we aimed to identify the most impactful 22q11.21 CNV genes and the potential impacted human brain regions, developmental stages and signaling pathways. We constructed the spatiotemporal dynamic networks of 22q11.21 CNV genes using the brain developmental transcriptome and physical protein–protein interactions. The affected brain regions, developmental stages, driver genes and pathways were subsequently investigated via integrated bioinformatics analysis. As a result, we first identified that 22q11.21 CNV genes affect the cortical area mainly during late fetal periods. Interestingly, we observed that connections between a driver gene, DGCR8, and its interacting partners, MECP2 and CUL3, also network hubs, only existed in the network of the late fetal period within the cortical region, suggesting their functional specificity during brain development. We also confirmed the physical interaction result between DGCR8 and CUL3 by liquid chromatography-tandem mass spectrometry. In conclusion, our results could suggest that the disruption of DGCR8-dependent microRNA biogenesis plays a vital role in NDD for late fetal cortical development. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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13 pages, 1626 KiB

Open AccessArticle

Human Brain Lipidomics: Utilities of Chloride Adducts in Flow Injection Analysis

by Paul L. Wood, Kathleen A. Hauther, Jon H. Scarborough, Dustin J. Craney, Beatrix Dudzik, John E. Cebak and Randall L. Woltjer

Life 2021, 11(5), 403; https://doi.org/10.3390/life11050403 - 28 Apr 2021

Cited by 10 | Viewed by 1829

Abstract

Ceramides have been implicated in a number of disease processes. However, current means of evaluation with flow infusion analysis (FIA) have been limited primarily due to poor sensitivity within our high-resolution mass spectrometry lipidomics analytical platform. To circumvent this deficiency, we investigated the [...] Read more.

Ceramides have been implicated in a number of disease processes. However, current means of evaluation with flow infusion analysis (FIA) have been limited primarily due to poor sensitivity within our high-resolution mass spectrometry lipidomics analytical platform. To circumvent this deficiency, we investigated the potential of chloride adducts as an alternative method to improve sensitivity with electrospray ionization. Chloride adducts of ceramides and ceramide subfamilies provided 2- to 50-fold increases in sensitivity both with analytical standards and biological samples. Chloride adducts of a number of other lipids with reactive hydroxy groups were also enhanced. For example, monogalactosyl diacylglycerols (MGDGs), extracted from frontal lobe cortical gray and subcortical white matter of cognitively intact subjects, were not detected as ammonium adducts but were readily detected as chloride adducts. Hydroxy lipids demonstrate a high level of specificity in that phosphoglycerols and phosphoinositols do not form chloride adducts. In the case of choline glycerophospholipids, the fatty acid substituents of these lipids could be monitored by MS² of the chloride adducts. Monitoring the chloride adducts of a number of key lipids offers enhanced sensitivity and specificity with FIA. In the case of glycerophosphocholines, the chloride adducts also allow determination of fatty acid substituents. The chloride adducts of lipids possessing electrophilic hydrogens of hydroxyl groups provide significant increases in sensitivity. In the case of glycerophosphocholines, chloride attachment to the quaternary ammonium group generates a dominant anion, which provides the identities of the fatty acid substituents under MS² conditions. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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15 pages, 2585 KiB

Open AccessArticle

Integrative Analysis Identified Key Schizophrenia Risk Factors from an Abnormal Behavior Mouse Gene Set

by Miao Chen, Weidi Wang, Weicheng Song, Wei Qian and Guan Ning Lin

Life 2021, 11(2), 172; https://doi.org/10.3390/life11020172 - 23 Feb 2021

Cited by 2 | Viewed by 2319

Abstract

Schizophrenia (SCZ) is a severe chronic psychiatric illness with heterogeneous symptoms. However, the pathogenesis of SCZ is unclear, and the number of well-defined SCZ risk factors is limited. We hypothesized that an abnormal behavior (AB) gene set verified by mouse model experiments can [...] Read more.

Schizophrenia (SCZ) is a severe chronic psychiatric illness with heterogeneous symptoms. However, the pathogenesis of SCZ is unclear, and the number of well-defined SCZ risk factors is limited. We hypothesized that an abnormal behavior (AB) gene set verified by mouse model experiments can be used to better understand SCZ risks. In this work, we carried out an integrative bioinformatics analysis to study two types of risk genes that are either differentially expressed (DEGs) in the case-control study data or carry reported SCZ genetic variants (MUTs). Next, we used RNA-Seq expression data from the hippocampus (HIPPO) and dorsolateral prefrontal cortex (DLPFC) to define the key genes affected by different types (DEGs and MUTs) in different brain regions (DLPFC and HIPPO): DLPFC-kDEG, DLPFC-kMUT, HIPPO-kDEG, and HIPPO-kMUT. The four hub genes (SHANK1, SHANK2, DLG4, and NLGN3) of the biological functionally enriched terms were strongly linked to SCZ via gene co-expression network analysis. Then, we observed that specific spatial expressions of DLPFC-kMUT and HIPPO-kMUT were convergent in the early stages and divergent in the later stages of development. In addition, all four types of key genes showed significantly larger average protein–protein interaction degrees than the background. Comparing the different cell types, the expression of four types of key genes showed specificity in different dimensions. Together, our results offer new insights into potential risk factors and help us understand the complexity and regional heterogeneity of SCZ. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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Review

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24 pages, 1723 KiB

Open AccessEditor’s ChoiceReview

Microfluidic Platforms to Unravel Mysteries of Alzheimer’s Disease: How Far Have We Come?

by Pragya Prasanna, Shweta Rathee, Vedanabhatla Rahul, Debabrata Mandal, Macherla Sharath Chandra Goud, Pardeep Yadav, Susan Hawthorne, Ankur Sharma, Piyush Kumar Gupta, Shreesh Ojha, Niraj Kumar Jha, Chiara Villa and Saurabh Kumar Jha

Life 2021, 11(10), 1022; https://doi.org/10.3390/life11101022 - 28 Sep 2021

Cited by 7 | Viewed by 9259

Abstract

Alzheimer’s disease (AD) is a significant health concern with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and [...] Read more.

Alzheimer’s disease (AD) is a significant health concern with enormous social and economic impact globally. The gradual deterioration of cognitive functions and irreversible neuronal losses are primary features of the disease. Even after decades of research, most therapeutic options are merely symptomatic, and drugs in clinical practice present numerous side effects. Lack of effective diagnostic techniques prevents the early prognosis of disease, resulting in a gradual deterioration in the quality of life. Furthermore, the mechanism of cognitive impairment and AD pathophysiology is poorly understood. Microfluidics exploits different microscale properties of fluids to mimic environments on microfluidic chip-like devices. These miniature multichambered devices can be used to grow cells and 3D tissues in vitro, analyze cell-to-cell communication, decipher the roles of neural cells such as microglia, and gain insights into AD pathophysiology. This review focuses on the applications and impact of microfluidics on AD research. We discuss the technical challenges and possible solutions provided by this new cutting-edge technique to understand disease-associated pathways and mechanisms. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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11 pages, 1125 KiB

Open AccessReview

NADomics: Measuring NAD⁺ and Related Metabolites Using Liquid Chromatography Mass Spectrometry

by Nady Braidy, Maria D. Villalva and Ross Grant

Life 2021, 11(6), 512; https://doi.org/10.3390/life11060512 - 31 May 2021

Cited by 11 | Viewed by 5622

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) and its metabolome (NADome) play important roles in preserving cellular homeostasis. Altered levels of the NADome may represent a likely indicator of poor metabolic function. Accurate measurement of the NADome is crucial for biochemical research and developing [...] Read more.

Nicotinamide adenine dinucleotide (NAD⁺) and its metabolome (NADome) play important roles in preserving cellular homeostasis. Altered levels of the NADome may represent a likely indicator of poor metabolic function. Accurate measurement of the NADome is crucial for biochemical research and developing interventions for ageing and neurodegenerative diseases. In this mini review, traditional methods used to quantify various metabolites in the NADome are discussed. Owing to the auto-oxidation properties of most pyridine nucleotides and their differential chemical stability in various biological matrices, accurate assessment of the concentrations of the NADome is an analytical challenge. Recent liquid chromatography mass spectrometry (LC-MS) techniques which overcome some of these technical challenges for quantitative assessment of the NADome in the blood, CSF, and urine are described. Specialised HPLC-UV, NMR, capillary zone electrophoresis, or colorimetric enzymatic assays are inexpensive and readily available in most laboratories but lack the required specificity and sensitivity for quantification of human biological samples. LC-MS represents an alternative means of quantifying the concentrations of the NADome in clinically relevant biological specimens after careful consideration of analyte extraction procedures, selection of internal standards, analyte stability, and LC assays. LC-MS represents a rapid, robust, simple, and reliable assay for the measurement of the NADome between control and test samples, and for identifying biological correlations between the NADome and various biochemical processes and testing the efficacy of strategies aimed at raising NAD⁺ levels during physiological ageing and disease states. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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20 pages, 1439 KiB

Open AccessReview

Zinc Metalloproteins in Epigenetics and Their Crosstalk

by Abdurrahman Pharmacy Yusuf, Murtala Bello Abubakar, Ibrahim Malami, Kasimu Ghandi Ibrahim, Bilyaminu Abubakar, Muhammad Bashir Bello, Naeem Qusty, Sara T. Elazab, Mustapha Umar Imam, Athanasios Alexiou and Gaber El-Saber Batiha

Life 2021, 11(3), 186; https://doi.org/10.3390/life11030186 - 26 Feb 2021

Cited by 21 | Viewed by 4225

Abstract

More than half a century ago, zinc was established as an essential micronutrient for normal human physiology. In silico data suggest that about 10% of the human proteome potentially binds zinc. Many proteins with zinc-binding domains (ZBDs) are involved in epigenetic modifications such [...] Read more.

More than half a century ago, zinc was established as an essential micronutrient for normal human physiology. In silico data suggest that about 10% of the human proteome potentially binds zinc. Many proteins with zinc-binding domains (ZBDs) are involved in epigenetic modifications such as DNA methylation and histone modifications, which regulate transcription in physiological and pathological conditions. Zinc metalloproteins in epigenetics are mainly zinc metalloenzymes and zinc finger proteins (ZFPs), which are classified into writers, erasers, readers, editors, and feeders. Altogether, these classes of proteins engage in crosstalk that fundamentally maintains the epigenome’s modus operandi. Changes in the expression or function of these proteins induced by zinc deficiency or loss of function mutations in their ZBDs may lead to aberrant epigenetic reprogramming, which may worsen the risk of non-communicable chronic diseases. This review attempts to address zinc’s role and its proteins in natural epigenetic programming and artificial reprogramming and briefly discusses how the ZBDs in these proteins interact with the chromatin. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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14 pages, 323 KiB

Open AccessReview

Sudden Infant Death Syndrome: Beyond Risk Factors

by Serafina Perrone, Chiara Lembo, Sabrina Moretti, Giovanni Prezioso, Giuseppe Buonocore, Giorgia Toscani, Francesca Marinelli, Francesco Nonnis-Marzano and Susanna Esposito

Life 2021, 11(3), 184; https://doi.org/10.3390/life11030184 - 26 Feb 2021

Cited by 12 | Viewed by 8067

Abstract

Sudden infant death syndrome (SIDS) is defined as “the sudden death of an infant under 1 year of age which remains unexplained after thorough investigation including a complete autopsy, death scene investigation, and detailed clinical and pathological review”. A significant decrease of SIDS [...] Read more.

Sudden infant death syndrome (SIDS) is defined as “the sudden death of an infant under 1 year of age which remains unexplained after thorough investigation including a complete autopsy, death scene investigation, and detailed clinical and pathological review”. A significant decrease of SIDS deaths occurred in the last decades in most countries after the beginning of national campaigns, mainly as a consequence of the implementation of risk reduction action mostly concentrating on the improvement of sleep conditions. Nevertheless, infant mortality from SIDS still remains unacceptably high. There is an urgent need to get insight into previously unexplored aspects of the brain system with a special focus on high-risk groups. SIDS pathogenesis is associated with a multifactorial condition that comprehends genetic, environmental and sociocultural factors. Effective prevention of SIDS requires multiple interventions from different fields. Developing brain susceptibility, intrinsic vulnerability and early identification of infants with high risk of SIDS represents a challenge. Progress in SIDS research appears to be fundamental to the ultimate aim of eradicating SIDS deaths. A complex model that combines different risk factor data from biomarkers and omic analysis may represent a tool to identify a SIDS risk profile in newborn settings. If high risk is detected, the infant may be referred for further investigations and follow ups. This review aims to illustrate the most recent discoveries from different fields, analyzing the neuroanatomical, genetic, metabolic, proteomic, environmental and sociocultural aspects related to SIDS. Full article

(This article belongs to the Special Issue Multi-Omics for the Understanding of Brain Diseases)

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