Genome-wide kinase-MAM interactome screening reveals the role of CK2A1 in MAM Ca2+ dynamics linked to DEE66.

The endoplasmic reticulum (ER) and mitochondria form a unique subcellular compartment called mitochondria-associated ER membranes (MAMs). Disruption of MAMs impairs Ca2+ homeostasis, triggering pleiotropic effects in the neuronal system. Genome-wide kinase-MAM interactome screening identifies casein kinase 2 alpha 1 (CK2A1) as a regulator of composition and Ca2+ transport of MAMs. CK2A1-mediated phosphorylation of PACS2 at Ser207/208/213 facilitates MAM localization of the CK2A1-PACS2-PKD2 complex, regulating PKD2-dependent mitochondrial Ca2+ influx. We further reveal that mutations of PACS2 (E209K and E211K) associated with developmental and epileptic encephalopathy-66 (DEE66) impair MAM integrity through the disturbance of PACS2 phosphorylation at Ser207/208/213. This, in turn, causes the reduction of mitochondrial Ca2+ uptake and the dramatic increase of the cytosolic Ca2+ level, thereby, inducing neurotransmitter release at the axon boutons of glutamatergic neurons. In conclusion, our findings suggest a molecular mechanism that MAM alterations induced by pathological PACS2 mutations modulate Ca2+-dependent neurotransmitter release.

Molecular and Metabolic Phenotyping of Hepatocellular Carcinoma for Biomarker Discovery: A Meta-Analysis.

Identifying and translating hepatocellular carcinoma (HCC) biomarkers from bench to bedside using mass spectrometry-based metabolomics and lipidomics is hampered by inconsistent findings. Here, we investigated HCC at systemic and metabolism-centric multiomics levels by conducting a meta-analysis of quantitative evidence from 68 cohorts. Blood transcript biomarkers linked to the HCC metabolic phenotype were externally validated and prioritized. In the studies under investigation, about 600 metabolites were reported as putative HCC-associated biomarkers; 39, 20, and 10 metabolites and 52, 12, and 12 lipids were reported in three or more studies in HCC vs. Control, HCC vs. liver cirrhosis (LC), and LC vs. Control groups, respectively. Amino acids, fatty acids (increased 18:1), bile acids, and lysophosphatidylcholine were the most frequently reported biomarkers in HCC. BAX and RAC1 showed a good correlation and were associated with poor prognosis. Our study proposes robust HCC biomarkers across diverse cohorts using a data-driven knowledge-based approach that is versatile and affordable for studying other diseases.

Unveiling potentially convergent key events related to adverse outcome pathways induced by silver nanoparticles via cross-species omics-scale analysis.

The adverse effects of silver nanoparticles (AgNPs) have been studied in various models. However, there has been discordance between molecular responses across the literature, attributed to methodological biases and the physicochemical variability of AgNPs. In this study, a gene pathway meta-analysis was conducted to identify convergent and divergent key events (KEs) associated with AgNPs and explore common patterns of these KEs across species. We performed a cross-species analysis of transcriptomic data from multiple studies involving various AgNPs exposure. Pathway enrichment analysis revealed a set of pathways linked to oxidative stress, apoptosis, and metabolite and lipid metabolism, which are considered potentially conserved KEs across species. Subsequently, experiments confirmed that oxidative stress responses could be early KEs in both Caenorhabditis elegans and HepG2 cells. Moreover, AgNPs preferentially impaired the mitochondria, as evidenced by mitochondrial fragmentation and dysfunction. Furthermore, disruption of amino acids, nucleotides, sulfur compounds, glycerolipids, and glycerophospholipids metabolism were in good agreement with gene pathway shreds of evidence. Our findings imply that, although there may be organism-specific responses, potentially conserved events could exist regardless of species and physicochemical factors. These results provide valuable insights into the development of adverse outcome pathways of AgNPs across species and the regulatory toxicity of AgNPs.

Caenorhabditis elegans deep lipidome profiling by using integrative mass spectrometry acquisitions reveals significantly altered lipid networks.

Lipidomics coverage improvement is essential for functional lipid and pathway construction. A powerful approach to discovering organism lipidome is to combine various data acquisitions, such as full scan mass spectrometry (full MS), data-dependent acquisition (DDA), and data-independent acquisition (DIA). Caenorhabditis elegans (C. elegans) is a useful model for discovering toxic-induced metabolism, high-throughput drug screening, and a variety of human disease pathways. To determine the lipidome of C. elegans and investigate lipid disruption from the molecular level to the system biology level, we used integrative data acquisition. The methyl-tert-butyl ether method was used to extract L4 stage C. elegans after exposure to triclosan (TCS), perfluorooctanoic acid, and nanopolystyrene (nPS). Full MS, DDA, and DIA integrations were performed to comprehensively profile the C. elegans lipidome by Q-Exactive Plus MS. All annotated lipids were then analyzed using lipid ontology and pathway analysis. We annotated up to 940 lipids from 20 lipid classes involved in various functions and pathways. The biological investigations revealed that when C. elegans were exposed to nPS, lipid droplets were disrupted, whereas plasma membrane-functionalized lipids were likely to be changed in the TCS treatment group. The nPS treatment caused a significant disruption in lipid storage. Triacylglycerol, glycerophospholipid, and ether class lipids were those primarily hindered by toxicants. Finally, toxicant exposure frequently involved numerous lipid-related pathways, including the phosphoinositide 3-kinase/protein kinase B pathway. In conclusion, an integrative data acquisition strategy was used to characterize the C. elegans lipidome, providing valuable biological insights into hypothesis generation and validation.

Metabolic and Cardiovascular Benefits of Apple and Apple-Derived Products: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Quantitative evidence of the metabolic and cardiovascular effects of apples (Malus domestica) is lacking in interventional studies. This study aimed to summarize the available evidence of the beneficial effects of apples and apple-derived products (ADPs) on metabolic and cardiovascular markers. Methods: Peer-reviewed randomized controlled trials (RCTs) were identified from four databases on May 3, 2021 and regularly updated until the end of May 2021. Demographic characteristics, intervention types, and evaluation parameters were extracted. A meta-analysis on the mean difference of change scores was conducted on commonly presented outcomes in the RCTs. Results: The metabolic and cardiovascular effects of diverse regimens, including whole apple, apple extract, and apple juice, were examined in 18 eligible RCTs. Nine common evaluation outcomes were eventually introduced to the meta-analysis, including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride, glucose, insulin, C-reactive protein, and systolic/diastolic blood pressures. The levels of TC (-2.69 mg/dL; 95% CI: -5.43, 0.04 mg/dL) and LDL (-2.80 mg/dL; 95% CI: -5.78, 0.17 mg/dL) showed a non-significant decreasing tendency after at least a week of apple consumption. Further subgroup analysis, particularly, a comparison with placebo as a control, showed a significant reduction in TC and LDL levels. When stratified by the baseline level, subjects with high TC and LDL level were shown to have more benefits from the apple intake. Intriguingly, apple and ADPs significantly reduced HDL levels to a small extent (-1.04 mg/dL; 95% CI: -1.79, -0.29 mg/dL). The other markers were mostly unaffected by the intervention. Conclusion: Our investigation revealed that apples could improve blood cholesterol levels. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020215977].

Effects of Oats (Avena sativa L.) on Inflammation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Oat and its compounds have been found to have anti-inflammatory effects. Through this systematic review and meta-analysis, we aimed to determine an evidence-based link between oat consumption and inflammatory markers. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. By the end of April 2021, we included randomized controlled trials (RCTs) that investigated the anti-inflammatory effect of oat and oat-related products through screening PubMed, Embase, Web of Science, ClinicalTrial.gov, and CENTRAL. Meta-analysis was conducted with a random-effect model on the standardized mean difference (SMD) of the change scores of inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). Subgroup analyses were conducted to stratify confounding variables. The risk of bias was evaluated using the Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was applied to report the quality of evidence. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42021245844). Results: Systematic screening of five databases yielded 4,119 studies, of which 23 RCTs were finally selected. For the four systemic inflammatory markers analyzed, no significant alterations were found after oat consumption. However, oat intake was found to significantly decrease CRP levels in subjects with one or more health complications (SMD: -0.18; 95% CI: -0.36, 0.00; P = 0.05; I 2 = 10%). Furthermore, IL-6 levels were significantly decreased in subjects with dyslipidemia (SMD = -0.34; 95% CI: -0.59, -0.10; P = 0.006; I 2 = 0%). These beneficial effects might be attributed to the effects of avenanthramide and ß-glucan. Conclusions: Overall evidence supporting the alleviation of inflammatory response by oat intake was poor, calling for future studies including a larger sample size to confirm the findings.