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Cell & Bioscience Aug 2021Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of... (Review)
Review
BACKGROUND
Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns.
METHODS
In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification.
RESULTS
Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, β-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/β-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA‑PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34-beclin-1-related bone mineralization via vascular calcification.
CONCLUSION
The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.
PubMed: 34399835
DOI: 10.1186/s13578-021-00639-9 -
Immunity Sep 2022The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein,...
The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline.
Topics: Aging; Humans; Inflammation; Interferons; Macrophages; Osteonectin
PubMed: 35963236
DOI: 10.1016/j.immuni.2022.07.007 -
American Journal of Physiology. Cell... Aug 2022Megakaryocyte hyperplasia associated with myeloproliferative neoplasms commonly leads to abnormal bone tissue deposition in the bone marrow, known as osteosclerosis. In...
Megakaryocyte hyperplasia associated with myeloproliferative neoplasms commonly leads to abnormal bone tissue deposition in the bone marrow, known as osteosclerosis. In this study, we aimed to synthesize the known proteomics literature describing factors released by megakaryocytes and platelets and to examine if any of the secreted factors have a known ability to stimulate the bone-forming cells, osteoblasts. Using a systematic search of Medline, we identified 77 articles reporting on factors secreted by platelets and megakaryocytes. After a full-text screening and analysis of the studies, we selected seven papers that reported proteomics data for factors secreted by platelets from healthy individuals. From 60 proteins reported in at least two studies, we focused on 23 that contained a putative signal peptide, which we searched for a potential osteoblast-stimulatory function. From nine proteins with a positive effect on osteoblast formation and function, two extracellular matrix (ECM) proteins, secreted protein acidic and rich in cysteine (SPARC) and tissue inhibitor of metalloproteinase-1 (TIMP1), and three cellular proteins with known extracellular function, the 70-kDa heat shock protein (HSP70), thymosin-β4 (TB4), and super dismutase (SOD), were identified as hypothetical candidate molecules to be examined as potential mediators in mouse models of osteomyelofibrosis. Thus, careful analysis of prior literature can be beneficial in assisting the planning of future experimental studies.
Topics: Animals; Blood Platelets; Extracellular Matrix Proteins; Mice; Osteoblasts; Osteonectin; Secretome; Tissue Inhibitor of Metalloproteinase-1
PubMed: 35675640
DOI: 10.1152/ajpcell.00187.2022 -
The Journal of Clinical Investigation Oct 2023The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in...
The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.
Topics: Animals; Humans; Mice; Adipose Tissue; Diet, High-Fat; Inflammasomes; Inflammation; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Osteonectin
PubMed: 37781916
DOI: 10.1172/JCI169173 -
Annals of Oncology : Official Journal... Nov 2021
Topics: Humans; Lymphoma; Macrophages; Osteonectin
PubMed: 34492312
DOI: 10.1016/j.annonc.2021.08.2152 -
American Journal of Physiology. Cell... Sep 2021In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how... (Review)
Review
In organisms from flies to mammals, the initial formation of a functional tendon is completely dependent on chemical signals from muscles (myokines). However, how myokines affect the maturation, maintenance, and regeneration of tendons as a function of age is completely unstudied. Here we discuss the role of four myokines-fibroblast growth factors (FGF), myostatin, the secreted protein acidic and rich in cysteine (SPARC) miR-29-in tendon development and hypothesize a role for these factors in the progressive changes in tendon structure and function as a result of muscle wasting (disuse, aging, and disease). Because of the close relationship between mechanical loading and muscle and tendon regulation, disentangling muscle-tendon cross talk from simple mechanical loading is experimentally quite difficult. Therefore, we propose an experimental framework that hopefully will be useful in demonstrating muscle-tendon cross talk in vivo. Though understudied, the promise of a better understanding of muscle-tendon cross talk is the development of new interventions that will improve tendon development, regeneration, and function throughout the lifespan.
Topics: Aging; Animals; Biomechanical Phenomena; Exosomes; Fibroblast Growth Factors; Gene Expression Regulation; Humans; MicroRNAs; Muscle Cells; Muscle, Skeletal; Muscular Atrophy; Myostatin; Osteonectin; Signal Transduction; Tendons
PubMed: 34319830
DOI: 10.1152/ajpcell.00260.2021 -
Experimental Cell Research Aug 2023Fibrotic scar is a severe side effect of trabeculectomy, resulting in unsatisfactory outcomes for glaucoma surgery. Accumulating evidence showed human Tenon's...
BACKGROUND
Fibrotic scar is a severe side effect of trabeculectomy, resulting in unsatisfactory outcomes for glaucoma surgery. Accumulating evidence showed human Tenon's fibroblasts (HTFs) play an important role in fibrosis formation. We previously reported that the aqueous level of secreted protein acidic and rich in cysteine (SPARC) was higher in the patients with primary angle closure glaucoma, which was associated with the failure of trabeculectomy. In this study, the potential effect and mechanism of SPARC in promoting fibrosis were explored by using HTFs.
METHODS
HTFs were employed in this study and examined under a phase-contrast microscope. Cell viability was determined by CCK-8. The expressions of SPARC-YAP/TAZ signaling and the fibrosis-related markers were examined with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence, subcellular fractionation was conducted to further determined the variation of YAP and phosphorylated YAP. The differential gene expressions were analyzed with RNA sequencing (RNAseq), followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses.
RESULTS
Exogenous SPARC induced HTFs-myofibroblast transformation, as evidenced by the increased expression of α-SMA, collagen I and fibronectin in both protein and mRNA levels. SPARC knockdown decreased the expressions of the above genes in TGF-β2-treated HTFs. KEGG analysis showed that the Hippo signaling pathway was mostly enriched. SPARC treatment increased the expressions of YAP, TAZ, CTGF and CYR61 as well as enhanced YAP translocation from cytoplasm to nucleus, and decreased the phosphorylation of YAP and LAST1/2, which was reversed by SPARC knockdown. Knockdown of YAP1 decreased the fibrosis-related markers, such as α-SMA, collagen I and Fibronectin, in SPARC-treated HTFs.
CONCLUSIONS
SPARC induced HTFs-myofibroblast transformation via activating YAP/TAZ signaling. Targeting SPARC-YAP/TAZ axis in HTFs might provide a novel strategy for inhibiting fibrosis formation after trabeculectomy.
Topics: Humans; Myofibroblasts; Fibronectins; Osteonectin; Fibroblasts; Collagen Type I; Fibrosis; Cells, Cultured
PubMed: 37225012
DOI: 10.1016/j.yexcr.2023.113649 -
Sleep Sep 2022Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified...
STUDY OBJECTIVES
Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls.
METHODS
SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs.
RESULTS
Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases.
CONCLUSIONS
Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.
Topics: Biomarkers; Cognitive Dysfunction; Disorders of Excessive Somnolence; Humans; Kleine-Levin Syndrome; Proteomics
PubMed: 35859339
DOI: 10.1093/sleep/zsac097 -
International Journal of Molecular... Oct 2020In thyroid cancer, calcification is mainly present in classical papillary thyroid carcinoma (PTC) and in medullary thyroid carcinoma (MTC), despite being described in... (Review)
Review
In thyroid cancer, calcification is mainly present in classical papillary thyroid carcinoma (PTC) and in medullary thyroid carcinoma (MTC), despite being described in benign lesions and in other subtypes of thyroid carcinomas. Thyroid calcifications are classified according to their diameter and location. At ultrasonography, microcalcifications appear as hyperechoic spots ≤ 1 mm in diameter and can be named as stromal calcification, bone formation, or psammoma bodies (PBs), whereas calcifications > 1 mm are macrocalcifications. The mechanism of their formation is still poorly understood. Microcalcifications are generally accepted as a reliable indicator of malignancy as they mostly represent PBs. In order to progress in terms of the understanding of the mechanisms behind calcification occurring in thyroid tumors in general, and in PTC in particular, we decided to use histopathology as the basis of the possible cellular and molecular mechanisms of calcification formation in thyroid cancer. We explored the involvement of molecules such as runt-related transcription factor-2 (Runx-2), osteonectin/secreted protein acidic and rich in cysteine (SPARC), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteopontin (OPN) in the formation of calcification. The present review offers a novel insight into the mechanisms underlying the development of calcification in thyroid cancer.
Topics: Animals; Calcification, Physiologic; Calcinosis; Humans; Models, Biological; Osteopontin; Thyroid Gland; Thyroid Neoplasms
PubMed: 33086487
DOI: 10.3390/ijms21207718