scholarly journals Metabolic reprogramming of fibro/adipogenic progenitors facilitates muscle regeneration

2020 ◽  
Vol 3 (3) ◽  
pp. e202000646 ◽  
Author(s):  
Alessio Reggio ◽  
Marco Rosina ◽  
Natalie Krahmer ◽  
Alessandro Palma ◽  
Lucia Lisa Petrilli ◽  
...  
Keyword(s):  
High Sensitivity ◽  
Adverse Outcomes ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Novel Approach ◽  
Significant Amelioration ◽  
Proteomic Dataset ◽  
Histological Phenotype ◽  
Dystrophin Protein

In Duchenne muscular dystrophy (DMD), the absence of the dystrophin protein causes a variety of poorly understood secondary effects. Notably, muscle fibers of dystrophic individuals are characterized by mitochondrial dysfunctions, as revealed by a reduced ATP production rate and by defective oxidative phosphorylation. Here, we show that in a mouse model of DMD (mdx), fibro/adipogenic progenitors (FAPs) are characterized by a dysfunctional mitochondrial metabolism which correlates with increased adipogenic potential. Using high-sensitivity mass spectrometry–based proteomics, we report that a short-term high-fat diet (HFD) reprograms dystrophic FAP metabolism in vivo. By combining our proteomic dataset with a literature-derived signaling network, we revealed that HFD modulates the β-catenin–follistatin axis. These changes are accompanied by significant amelioration of the histological phenotype in dystrophic mice. Transplantation of purified FAPs from HFD-fed mice into the muscles of dystrophic recipients demonstrates that modulation of FAP metabolism can be functional to ameliorate the dystrophic phenotype. Our study supports metabolic reprogramming of muscle interstitial progenitor cells as a novel approach to alleviate some of the adverse outcomes of DMD.

scholarly journals The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model

2020 ◽  
Vol 13 (10) ◽  
pp. dmm044925 ◽  
Author(s):  
Éva Saskői ◽  
Zoltán Hujber ◽  
Gábor Nyírő ◽  
István Likó ◽  
Barbara Mátyási ◽  
...  
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Familial Cancer ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Sdhb Mutation ◽  
Mutation Site ◽  
Atp Production ◽  
B Subunit ◽  
Mitochondrial Number

ABSTRACTThe conserved B-subunit of succinate dehydrogenase (SDH) participates in the tricarboxylic acid cycle (TCA) cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In Caenorhabditiselegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His), which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis, whereby only Arg244His (not null) worms demonstrate elevated lactate/pyruvate levels, pointing to a missense-induced, Warburg-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site. We hypothesize that the Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach could illuminate wider SDH pathology.This article has an associated First Person interview with the first author of the paper.

scholarly journals Metabolic Reprogramming Promotes Metastasis of Acidosis-Adapted Pancreatic Ductal Adenocarcinoma Cells Via AMPK/YAP/MMP1 Axis

2021 ◽  
Author(s):  
Siyuan Chen ◽  
Bo Ning ◽  
Jinwen Song ◽  
Zihan Yang ◽  
Li Zhou ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Metastatic Potential ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
Invasion And Metastasis ◽  
Migration Ability ◽  
Atp Production

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Acidic microenvironment, namely acidosis, is closely related to cancer development and progression, but the regulatory mechanism remains to be elucidated. Methods We generated acidosis-adapted PDAC cells (PANC-1 and SW1990) by continuously culturing under pH 6.5 medium. Metabonomic assay (LC-MS and LC-MS) was used to detect the metabolites. Transcriptomic microarray was applied to reveal the gene expression profile. The in vivo metastatic potential was assessed by tail vein injection. Wound healing assay and transwell assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation were performed to determine cell proliferation. Flow cytometry was used to test cell cycle and apoptosis. Results These acidosis-adapted PDAC cells had stronger invasion and migration ability, accompanied by increased EMT markers expression. In addition, the proliferation rate of acidosis-adapted PDAC cells increased while apoptosis decreased under acidic medium. Metabonomic analysis showed that the glycolysis and AMP was decreased, and ATP was increased in acidosis-adapted cells. The metabolic shift led to the inactivation of AMPK. Transcriptomic analysis revealed that the differentially expressed genes in acid-adapted cells were enriched in extracellular matrix modification, Hippo signaling and others. MMP1, a matrix metalloproteinase, was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway. Knockdown of MMP1 significantly reduced invasion and metastasis capacity of acidosis-adapted cells. The AMPK activator MK8722 could reduce both YAP and MMP1 level in acidosis-adapted PDAC cells. Conclusion Altogether, the present study showed that the metabolic reprogramming towards elevated ATP production promotes invasion and metastasis of acidosis-adapted PDAC cells via depressing AMPK/Hippo signaling, thus upregulating MMP1.

scholarly journals Marker for the pre-clinical development of bone substitute materials

2017 ◽  
Vol 3 (2) ◽  
pp. 711-715
Author(s):  
Michael de Wild ◽  
Simon Zimmermann ◽  
Marcel Obrecht ◽  
Michel Dard
Keyword(s):  
Bone Graft ◽  
Mechanical Stability ◽  
Clinical Performance ◽  
Ex Vivo ◽  
Region Of Interest ◽  
Defect Site ◽  
Novel Approach ◽  
Bone Substitute Materials ◽  
Clinical Experiments

AbstractThin mechanically stable Ti-cages have been developed for the in-vivo application as X-ray and histology markers for the optimized evaluation of pre-clinical performance of bone graft materials. A metallic frame defines the region of interest during histological investigations and supports the identification of the defect site. This standardization of the procedure enhances the quality of pre-clinical experiments. Different models of thin metallic frameworks were designed and produced out of titanium by additive manufacturing (Selective Laser Melting). The productibility, the mechanical stability, the handling and suitability of several frame geometries were tested during surgery in artificial and in ex-vivo bone before a series of cages was preclinically investigated in the female Göttingen minipigs model. With our novel approach, a flexible process was established that can be adapted to the requirements of any specific animal model and bone graft testing.

scholarly journals Persistent luminescence nanoparticles for cancer theranostics application

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Nian Liu ◽  
Xiao Chen ◽  
Xia Sun ◽  
Xiaolian Sun ◽  
Junpeng Shi
Keyword(s):  
Uv Light ◽  
Combined Therapy ◽  
Tumor Therapy ◽  
High Sensitivity ◽  
Persistent Luminescence ◽  
Therapeutic Drugs ◽  
High Penetration ◽  
Recent Developments ◽  
Cancer Theranostics

AbstractPersistent luminescence nanoparticles (PLNPs) are unique optical materials that emit afterglow luminescence after ceasing excitation. They exhibit unexpected advantages for in vivo optical imaging of tumors, such as autofluorescence-free, high sensitivity, high penetration depth, and multiple excitation sources (UV light, LED, NIR laser, X-ray, and radiopharmaceuticals). Besides, by incorporating other functional molecules, such as photosensitizers, photothermal agents, or therapeutic drugs, PLNPs are also widely used in persistent luminescence (PersL) imaging-guided tumor therapy. In this review, we first summarize the recent developments in the synthesis and surface functionalization of PLNPs, as well as their toxicity studies. We then discuss the in vivo PersL imaging and multimodal imaging from different excitation sources. Furthermore, we highlight PLNPs-based cancer theranostics applications, such as fluorescence-guided surgery, photothermal therapy, photodynamic therapy, drug/gene delivery and combined therapy. Finally, future prospects and challenges of PLNPs in the research of translational medicine are also discussed.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

scholarly journals Ubiquitylome Analysis Reveals a Central Role for the Ubiquitin-Proteasome System in Plant Innate Immunity

2021 ◽  
Author(s):  
Xiyu Ma ◽  
Chao Zhang ◽  
Do Young Kim ◽  
Yanyan Huang ◽  
Elizabeth Chatt ◽  
...  
Keyword(s):  
Plant Immunity ◽  
High Sensitivity ◽  
Ubiquitin Proteasome System ◽  
Immune Recognition ◽  
Atpase Subunit ◽  
Ample Evidence ◽  
Network Analyses ◽  
Affinity Enrichment ◽  
Regulatory Loop

Abstract Protein ubiquitylation profoundly expands proteome functionality and diversifies cellular signaling processes, with recent studies providing ample evidence for its importance to plant immunity. To gain a proteome-wide appreciation of ubiquitylome dynamics during immune recognition, we employed a two-step affinity enrichment protocol based on a 6His-tagged ubiquitin (Ub) variant coupled with high sensitivity mass spectrometry to identify Arabidopsis proteins rapidly ubiquitylated upon plant perception of the microbe-associated molecular pattern (MAMP) peptide flg22. The catalog from 2-week-old seedlings treated for 30 minutes with flg22 contained 690 conjugates, 64 Ub footprints, and all seven types of Ub linkages, and included previously uncharacterized conjugates of immune components. In vivo ubiquitylation assays confirmed modification of several candidates upon immune elicitation, and revealed distinct modification patterns and dynamics for key immune components, including poly- and monoubiquitylation, as well as induced or reduced levels of ubiquitylation. Gene ontology and network analyses of the collection also uncovered rapid modification of the Ub-proteasome system itself, suggesting a critical auto-regulatory loop necessary for an effective MAMP-triggered immune response and subsequent disease resistance. Included targets were UBIQUITIN-CONJUGATING ENZYME 13 (UBC13) and proteasome component REGULATORY PARTICLE NON-ATPASE SUBUNIT 8b (RPN8b), whose subsequent biochemical and genetic analyses implied negative roles in immune elicitation. Collectively, our proteomic analyses further strengthened the connection between ubiquitylation and flg22-based immune signaling, identified components and pathways regulating plant immunity, and increased the database of ubiquitylated substrates in plants.

scholarly journals Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer K. Dowling ◽  
Remsha Afzal ◽  
Linden J. Gearing ◽  
Mariana P. Cervantes-Silva ◽  
Stephanie Annett ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Mitochondrial Dynamics ◽  
Interleukin 10 ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Macrophage Polarisation ◽  
Inflammatory Status ◽  
Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

scholarly journals DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 926
Author(s):  
Veronica Vella ◽  
Marika Giuliano ◽  
Maria Luisa Nicolosi ◽  
Maria Giovanna Majorana ◽  
Małgorzata Anna Marć ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cells ◽  
Cell Metabolism ◽  
Growth Factor Receptor ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Igf System ◽  
Putative Target ◽  
Collagen Receptor ◽  
Discoidin Domain Receptor 1

The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR / IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.

scholarly journals From Multiplex Serology to Serolomics—A Novel Approach to the Antibody Response against the SARS-CoV-2 Proteome

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 749
Author(s):  
Julia Butt ◽  
Rajagopal Murugan ◽  
Theresa Hippchen ◽  
Sylvia Olberg ◽  
Monique van Straaten ◽  
...  
Keyword(s):  
Antibody Response ◽  
High Throughput ◽  
Large Population ◽  
High Sensitivity ◽  
Population Based ◽  
Antibody Responses ◽  
Hek293 Cells ◽  
Novel Approach ◽  
Assay Performance ◽  
Multiplex Serology

The emerging SARS-CoV-2 pandemic entails an urgent need for specific and sensitive high-throughput serological assays to assess SARS-CoV-2 epidemiology. We, therefore, aimed at developing a fluorescent-bead based SARS-CoV-2 multiplex serology assay for detection of antibody responses to the SARS-CoV-2 proteome. Proteins of the SARS-CoV-2 proteome and protein N of SARS-CoV-1 and common cold Coronaviruses (ccCoVs) were recombinantly expressed in E. coli or HEK293 cells. Assay performance was assessed in a COVID-19 case cohort (n = 48 hospitalized patients from Heidelberg) as well as n = 85 age- and sex-matched pre-pandemic controls from the ESTHER study. Assay validation included comparison with home-made immunofluorescence and commercial enzyme-linked immunosorbent (ELISA) assays. A sensitivity of 100% (95% CI: 86–100%) was achieved in COVID-19 patients 14 days post symptom onset with dual sero-positivity to SARS-CoV-2 N and the receptor-binding domain of the spike protein. The specificity obtained with this algorithm was 100% (95% CI: 96–100%). Antibody responses to ccCoVs N were abundantly high and did not correlate with those to SARS-CoV-2 N. Inclusion of additional SARS-CoV-2 proteins as well as separate assessment of immunoglobulin (Ig) classes M, A, and G allowed for explorative analyses regarding disease progression and course of antibody response. This newly developed SARS-CoV-2 multiplex serology assay achieved high sensitivity and specificity to determine SARS-CoV-2 sero-positivity. Its high throughput ability allows epidemiologic SARS-CoV-2 research in large population-based studies. Inclusion of additional pathogens into the panel as well as separate assessment of Ig isotypes will furthermore allow addressing research questions beyond SARS-CoV-2 sero-prevalence.

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