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      Glycine-Serine-Threonine Metabolic Axis Delays Intervertebral Disc Degeneration through Antioxidant Effects: An Imaging and Metabonomics Study

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          Abstract

          Although intervertebral disc degeneration (IDD) can be described as different stages of change through biological methods, this long and complex process cannot be defined in stages by single or simple combination of biological techniques. Under the background of the development of nuclear magnetic resonance (NMR) technology and the emerging metabonomics, we based on animal models and expanded to the study of clinical human degeneration models. The characteristics of different stages of IDD were analyzed by omics. Omics imaging combined with histology, cytology, and proteomics was used for screening of the intervertebral disc (IVD) of research subjects. Furthermore, mass spectrometry nontargeted metabolomics was used to explore profile of metabolites at different stages of the IDD process, to determine differential metabolic pathways and metabolites. NMR spectroscopy was used to qualitatively and quantitatively identify markers of degeneration. NMR was combined with mass spectrometry metabolomics to explore metabolic pathways. Metabolic pathways were determined through protein molecular biology and histocytology of the different groups. Distinguishing advantages of magnetic resonance spectroscopy (MRS) for analysis of metabolites and effective reflection of structural integrity and water molecule metabolism through diffusion tensor imaging (DTI) were further used to verify the macrometabolism profile during degeneration. A corresponding model of in vitro metabolomics and in vivo omics imaging was established. The findings of this study show that a series of metabolic pathways associated with the glycine-serine-threonine (Gly-Ser-Thr) metabolic axis affects carbohydrate patterns and energy utilization efficiency and ultimately delays disc degeneration through antioxidant effects.

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          Inflammaging: a new immune–metabolic viewpoint for age-related diseases

          Ageing and age-related diseases share some basic mechanistic pillars that largely converge on inflammation. During ageing, chronic, sterile, low-grade inflammation - called inflammaging - develops, which contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self). A limited number of receptors, whose degeneracy allows them to recognize many signals and to activate the innate immune responses, sense these stimuli. In this situation, metaflammation (the metabolic inflammation accompanying metabolic diseases) is thought to be the form of chronic inflammation that is driven by nutrient excess or overnutrition; metaflammation is characterized by the same mechanisms underpinning inflammaging. The gut microbiota has a central role in both metaflammation and inflammaging owing to its ability to release inflammatory products, contribute to circadian rhythms and crosstalk with other organs and systems. We argue that chronic diseases are not only the result of ageing and inflammaging; these diseases also accelerate the ageing process and can be considered a manifestation of accelerated ageing. Finally, we propose the use of new biomarkers (DNA methylation, glycomics, metabolomics and lipidomics) that are capable of assessing biological versus chronological age in metabolic diseases.
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            IL11 is a crucial determinant of cardiovascular fibrosis

            Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
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              Biomarkers in lung cancer screening: achievements, promises and challenges

              The present review is an update of the research and development efforts regarding the use of molecular biomarkers in the lung cancer screening setting. The two main unmet clinical needs, namely, the refinement of risk to improve the selection of individuals undergoing screening and the characterization of undetermined nodules found during the computed tomography-based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising molecular candidates, such as autoantibodies, complement fragments, microRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow, such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies, and the integration of next-generation sequencing into study of circulating DNA. We also underline the importance of integrating different molecular technologies together with imaging, radiomics, and artificial intelligence. We list a number of completed, ongoing, or planned trials to show the clinical utility of molecular biomarkers. Finally, we comment on future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test the clinical utility of one or several candidate biomarkers.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2021
                25 August 2021
                : 2021
                : 5579736
                Affiliations
                1Department of Orthopedics, The Affiliated Hospital of Qingdao University, Qingdao, China 266003
                2Department of Rehabilitation, The Affiliated Hospital of Qingdao University, Qingdao, China 266000
                3School of Medicine-Wichita, University of Kansas, 929 N St. Francis Street, Wichita, KS, USA 67214
                4Cancer Institute, The Qingdao University, Qingdao, China 266003
                5School of Life Sciences, Tsinghua University, Beijing, China 100084
                6Shandong First Medical University, Taian 271016, China
                Author notes

                Academic Editor: Jan Gebicki

                Author information
                https://orcid.org/0000-0002-6200-7000
                https://orcid.org/0000-0003-3085-4202
                https://orcid.org/0000-0003-1933-4484
                https://orcid.org/0000-0002-2137-3733
                https://orcid.org/0000-0002-6460-9160
                https://orcid.org/0000-0003-3529-4187
                https://orcid.org/0000-0002-3869-4170
                https://orcid.org/0000-0002-8835-5302
                https://orcid.org/0000-0002-2359-0440
                https://orcid.org/0000-0001-6599-688X
                https://orcid.org/0000-0002-6044-5357
                https://orcid.org/0000-0002-5400-4352
                https://orcid.org/0000-0002-5026-5918
                Article
                10.1155/2021/5579736
                8416401
                34484565
                42d2cc69-c260-4c0c-b789-4239c837e6c8
                Copyright © 2021 Xiaolin Wu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 February 2021
                : 3 August 2021
                Funding
                Funded by: National Key Research and Development Project
                Award ID: 2019YFC0121404
                Funded by: Shandong Higher Education Young Science and Technology Support Program
                Award ID: 2020KJL005
                Funded by: Qingdao Postdoctoral Applied Research Project
                Award ID: 2020
                Funded by: Young Taishan Scholars Program
                Award ID: tsqn201909190
                Funded by: Shandong Provincial Science Foundation of China
                Award ID: ZR2019BH084
                Funded by: National Natural Science Foundation of China
                Award ID: 81772412
                Award ID: 81802190
                Categories
                Research Article

                Molecular medicine
                Molecular medicine

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