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Endocrine Oct 2023Emerging evidence revealed that brain-derived neurotrophic factor (BDNF), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21(FGF-21) and... (Observational Study)
Observational Study
PURPOSE
Emerging evidence revealed that brain-derived neurotrophic factor (BDNF), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21(FGF-21) and growth differentiation factor 15 (GDF-15) are involved in energy metabolism and body weight regulation. Our study aimed at examining their association with BMI, their alterations after anti-obesity treatments, and their association with 1-year weight loss.
METHODS
A prospective observational study of 171 participants with overweight and obesity and 46 lean controls was established. All participants received lifestyle educational intervention (LEI) with or without anti-obesity treatments (LEI + bariatric/metabolic surgery, n = 41; LEI + topiramate, n = 46; LEI + liraglutide, n = 31; LEI + orlistat, n = 12; and LEI alone, n = 41). Anthropometric and metabolic parameters, insulin sensitivity, C-reactive protein (CRP), fasting plasma levels of BDNF, SPARC, GDF-15, and FGF-21 were measured at baseline and 1 year.
RESULTS
Multiple linear regression showed that fasting levels of SPARC, FGF-21, and GDF-15 were significantly associated with baseline BMI after adjustment for age and sex. At 1 year, the average weight loss was 4.8% in the entire cohort with a significant improvement in glycemia, insulin sensitivity, and CRP. Multiple linear regression adjusted for age, sex, baseline BMI, type of treatment, and presence of T2DM revealed that the decrease in logFGF-21 and logGDF-15 at 1 year from baseline was significantly associated with a greater percentage of weight loss at 1 year.
CONCLUSIONS
This study highlights the association of SPARC, FGF-21, and GDF-15 levels with BMI. Decreased circulating levels of GDF-15 and FGF-21 were associated with greater weight loss at 1 year, regardless of the types of anti-obesity modalities.
Topics: Humans; Brain-Derived Neurotrophic Factor; Insulin Resistance; Growth Differentiation Factor 15; Osteonectin; Obesity; Weight Loss
PubMed: 37436597
DOI: 10.1007/s12020-023-03435-2 -
Biochemical Pharmacology May 2024The enzyme tryptophan 2,3-dioxygenase (TDO2) has been implicated in the dysregulation across a variety of human cancers. Despite this association, the implications of...
The enzyme tryptophan 2,3-dioxygenase (TDO2) has been implicated in the dysregulation across a variety of human cancers. Despite this association, the implications of TDO2 in the progression of bladder cancer have eluded thorough understanding. In this study, we demonstrate that TDO2 expression is notably elevated in bladder cancer tissues and serves as an unfavorable prognostic factor for overall survival. Through a series of biological functional assays, we have determined that TDO2 essentially enhances cell proliferation, metastatic potential, and imparts a decreased sensitivity to the chemotherapeutic agent cisplatin. Our mechanistic investigations reveal that TDO2 augments aryl hydrocarbon receptor (AhR) signaling pathways and subsequently upregulates the expression of SPARC and FILIP1L. Importantly, we have identified a positive correlation between TDO2 levels and the basal/squamous subtype of bladder cancer, and we provide evidence to suggest that TDO2 expression is modulated by the tumor suppressors RB1 and TP53. From a therapeutic perspective, we demonstrate that the targeted inhibition of TDO2 with the molecular inhibitor 680C91 markedly attenuates tumor growth and metastasis while concurrently enhancing the efficacy of cisplatin. These findings open a new therapeutic avenue for the management of bladder cancer.
Topics: Humans; Tryptophan Oxygenase; Cisplatin; Receptors, Aryl Hydrocarbon; Tryptophan; Urinary Bladder Neoplasms; Intracellular Signaling Peptides and Proteins; Osteonectin
PubMed: 38552852
DOI: 10.1016/j.bcp.2024.116172 -
JBMR Plus Oct 2023The regulation of bone mineral density (BMD) is highly influenced by genetics and age. Although genome-wide association studies (GWAS) for BMD have uncovered many genes...
The regulation of bone mineral density (BMD) is highly influenced by genetics and age. Although genome-wide association studies (GWAS) for BMD have uncovered many genes through their proximity to associated variants (variant nearest-neighbor [VNN] genes), the cell-specific mechanisms of each VNN gene remain unclear. This is primarily due to the inability to prioritize these genes by cell type and age-related expression. Using age-related transcriptomics, we found that the expression of many VNN genes was upregulated in the bone and marrow from aged mice. Candidate genes from GWAS were investigated using single-cell RNA-sequencing (scRNA-seq) datasets to enrich for cell-specific expression signatures. VNN candidate genes are highly enriched in osteo-lineage cells, osteocytes, hypertrophic chondrocytes, and Lepr+ mesenchymal stem cells. These data were used to generate a "blueprint" for Cre-loxp mouse line selection for functional validation of candidate genes and further investigation of their role in BMD maintenance throughout aging. In VNN-gene-enriched cells, , encoding the extracellular matrix (ECM) protein osteonectin, was robustly expressed. This, along with expression of numerous other ECM genes, indicates that many VNN genes likely have roles in ECM deposition by osteoblasts. Overall, we provide data supporting streamlined translation of GWAS candidate genes to potential novel therapeutic targets for the treatment of osteoporosis. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
PubMed: 37808401
DOI: 10.1002/jbm4.10795 -
International Journal of Molecular... Jul 2023The matricellular secreted protein acidic and rich in cysteine (SPARC; also known as osteonectin), is involved in the regulation of extracellular matrix (ECM) synthesis,...
The matricellular secreted protein acidic and rich in cysteine (SPARC; also known as osteonectin), is involved in the regulation of extracellular matrix (ECM) synthesis, cell-ECM interactions, and bone mineralization. We found decreased SPARC expression in aged skin. Incubating foreskin fibroblasts with recombinant human SPARC led to increased type I collagen production and decreased matrix metalloproteinase-1 (MMP-1) secretion at the protein and mRNA levels. In a three-dimensional culture of foreskin fibroblasts mimicking the dermis, SPARC significantly increased the synthesis of type I collagen and decreased its degradation. In addition, SPARC also induced receptor-regulated SMAD (R-SMAD) phosphorylation. An inhibitor of transforming growth factor-beta (TGF-β) receptor type 1 reversed the SPARC-induced increase in type I collagen and decrease in MMP-1, and decreased SPARC-induced R-SMAD phosphorylation. Transcriptome analysis revealed that SPARC modulated expression of genes involved in ECM synthesis and regulation in fibroblasts. RT-qPCR confirmed that a subset of differentially expressed genes is induced by SPARC. These results indicated that SPARC enhanced ECM integrity by activating the TGF-β signaling pathway in fibroblasts. We inferred that the decline in SPARC expression in aged skin contributes to process of skin aging by negatively affecting ECM integrity in fibroblasts.
Topics: Humans; Aged; Osteonectin; Collagen Type I; Matrix Metalloproteinase 1; Cells, Cultured; Extracellular Matrix; Transforming Growth Factor beta; Signal Transduction; Fibroblasts
PubMed: 37569556
DOI: 10.3390/ijms241512179 -
Tzu Chi Medical Journal 2024Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This... (Review)
Review
Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to β-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.
PubMed: 38406573
DOI: 10.4103/tcmj.tcmj_212_23 -
Nutrients Mar 2024Childhood obesity is one of the major challenges of public health policies. The problem of fatty liver in childhood, known as MAFLD (metabolic dysfunction-associated...
BACKGROUND
Childhood obesity is one of the major challenges of public health policies. The problem of fatty liver in childhood, known as MAFLD (metabolic dysfunction-associated fatty liver disease), is of particular interest as the gold standard diagnosis technique is invasive (liver biopsy). Hence, efforts are made to discover more specific biomarkers for the MAFLD signature. Therefore, the aim of the study was to evaluate Osteonectin and Hsp27 as biomarkers for MAFLD diagnosis and to assess their links with auxological and biochemical profiles of overweight and obese pediatric subjects.
METHODS
A cross-sectional study in which we (re)analyzed data from the MR PONy cohort comprising 71 pediatric subjects. Auxological data, liver ultrasonography and biochemical serum profile were recorded. Lipid-derived indices and body composition indices were calculated. Nevertheless, serum Osteonectin and Hsp27 levels were assessed using an ELISA approach.
RESULTS
MAFLD prevalence was 40.8%. Higher Osteonectin levels were noted in MAFLD subjects versus non-MAFLD subjects and in dyslipidemic children regardless of their liver function status. Lipid-derived indices had good diagnostic capacity for MAFLD.
CONCLUSIONS
We confirm Osteonectin as a MAFLD diagnosis biomarker in children. Also, lipid-derived indices are useful as metabolic-associated organ impairment markers in children even before the onset of obesity.
Topics: Humans; Child; Animals; Horses; Osteonectin; Cross-Sectional Studies; Pediatric Obesity; HSP27 Heat-Shock Proteins; Non-alcoholic Fatty Liver Disease; Biomarkers; Cardiovascular Diseases; Lipids
PubMed: 38542777
DOI: 10.3390/nu16060866 -
Platelets Dec 2023Many roles of human platelets in health and disease are linked to their ability to transport and secrete a variety of small molecules and proteins carried in dense (δ-)...
Many roles of human platelets in health and disease are linked to their ability to transport and secrete a variety of small molecules and proteins carried in dense (δ-) and α-granules. Determination of granule number and content is important for diagnosis of platelet disorders and for studies of platelet structure, function, and development. We have optimized methods for detection and localization of platelet proteins via antibody and lectin staining, imaging via structured illumination laser fluorescence microscopy (SIM), and three-dimension (3D) image analysis. The methods were validated via comparison with published studies based on electron microscopy and high-resolution fluorescence microscopy. The α-granule cargo proteins thrombospondin-1 (TSP1), osteonectin (SPARC), fibrinogen (FGN), and Von Willebrand factor (VWF) were localized within the granule lumen, as was the proteoglycan serglycin (SRGN). Colocalization analysis indicates that staining with fluorescently labeled wheat germ agglutinin (WGA) allows detection of α-granules as effectively as immunostaining for cargo proteins, with the advantage of not requiring antibodies. RAB27B was observed to be concentrated at dense granules, allowing them to be counted via visual scoring and object analysis. We present a workflow for counting dense and α-granules via object analysis of 3D SIM images of platelets stained for RAB27B and with WGA. SIM: structured illumination microscopy; WGA: wheat germ agglutinin; FGN: fibrinogen; TSP1: thrombospondin 1; ER: endoplasmic reticulum.
Topics: Humans; Lighting; Blood Platelets; Microscopy, Electron; Microscopy, Fluorescence; Fibrinogen; Antibodies; Lasers; Cytoplasmic Granules
PubMed: 36572649
DOI: 10.1080/09537104.2022.2157808 -
Journal of Ayurveda and Integrative... 2023In traditional medicine, Xanthium strumarium is used as an anti-inflammatory and anti-arthritic plant-based medicine. Human Dental Pulp Stem Cells (hDPSCs) are an ideal...
BACKGROUND
In traditional medicine, Xanthium strumarium is used as an anti-inflammatory and anti-arthritic plant-based medicine. Human Dental Pulp Stem Cells (hDPSCs) are an ideal in vitro model for drug and bioactive compound screening. This study assessed the potential of X. strumarium aqueous extract on hDPSCs differentiation towards the osteogenic lineage.
MATERIALS AND METHODS
HDPSCs were isolated and cultured by explant method and characterized by surface marker expression, Colony Forming units fibroblasts (CFU-F), Population Doubling time (PDT), and tri-lineage differentiation. X. strumarium aqueous seed extract (XSE) was prepared and its cytotoxic effect on hDPSCs was examined by MTT assay. The effect of XSE on hDPSC differentiation into osteocytes was investigated by biochemical staining and gene expression.
RESULTS
The hDPSCs were positive for CD73, CD90, and CD105 and negative for CD34, CD45, and HLA-DR surface markers. The cells had a colony-forming ability with a PDT of 44.91 h. The hDPSCs differentiated into osteocytes, chondrocytes, and adipocytes. The XSE concentration of 15 μg/ml had a significant increase in hDPSC viability. Alizarin Red S staining revealed that XSE treatment enhanced calcium accumulation and matrix mineralization in hDPSCs. XSE treatment also increased osteonectin and IL-6 transcript expression in osteogenesis-induced hDPSCs.
CONCLUSION
X. strumarium aqueous extract is a suitable candidate for bone repair because it promotes osteogenic differentiation in hDPSCs. Therefore this could be explored further in the treatment of bone disorders.
PubMed: 38061199
DOI: 10.1016/j.jaim.2023.100811 -
International Immunopharmacology May 2024Inflammation and atherosclerosis (AS) are closely associated to Secreted Protein Acidic and Rich in Cysteine (SPARC) and its related factors. This study attempted to...
BACKGROUND AND AIMS
Inflammation and atherosclerosis (AS) are closely associated to Secreted Protein Acidic and Rich in Cysteine (SPARC) and its related factors. This study attempted to define the role and the potential mechanism of SPARC and its related factors in ameliorating hyperlipidemia and AS by aerobic exercise intervention.
METHODS
The AS rat model was established with a high-fat diet plus vitamin D3 intraperitoneal injection. Treadmill exercises training (5 days/week at 14 m/min for 60 min/day) for 6 weeks was carried out for AS rat intervention method. Western blotting and qRT-PCR were used to analyze the mRNA and protein expression of SPARC and its related factors, respectively. H&E staining was applied to evaluate the morphological changes and inflammation damage. Von Kossa staining was used to measure the degree of vascular calcification. Fluorescence immunohistochemistry staining was used to detect the expression and distribution of SPARC signal molecules.
RESULTS
SPARC was highly expressed and co-localization with the smooth muscle marker α-SMC in the AS rat. And its downstream factors, NF-κB, Caspase-1, IL-1β and IL-18 were upregulated (P < 0.05 or P < 0.01), FNDC5 expression was downregulated in AS rat model. However, slight declined body weight, delayed AS progression, decreased hyperlipidemia and favorable morphology of skeletal muscle and blood vessels have been detected in AS rat with aerobic exercise intervention. Moreover, the expression of SPARC and its downstream factors were decreased (P < 0.05 or P < 0.01), while elevated the expression of FNDC5 (P < 0.01) was observed after aerobic exercise intervention.
CONCLUSIONS
This study suggested that aerobic exercise ameliorated hyperlipidemia and AS by effectively inhibiting SPARC signal, and vascular smooth muscle cells may contribute greatly to the protection of AS.
Topics: Animals; Osteonectin; Atherosclerosis; Male; Physical Conditioning, Animal; Diet, High-Fat; Rats; Rats, Sprague-Dawley; Signal Transduction; Disease Models, Animal; Hyperlipidemias; Cholecalciferol
PubMed: 38537537
DOI: 10.1016/j.intimp.2024.111856 -
International Dental Journal Apr 2024The present study aimed to (1) investigate biocompatibility and cytotoxicity of pulp-capping materials on viability of human dental pulp stem cells (hDPSCs); (2)...
OBJECTIVES
The present study aimed to (1) investigate biocompatibility and cytotoxicity of pulp-capping materials on viability of human dental pulp stem cells (hDPSCs); (2) determine angiogenic, odontogenic, and osteogenic marker mRNA expressions; and (3) observe changes in surface morphology of the hDPSCs using scanning electron microscopy (SEM).
METHODS
Impacted third molars were used to isolate the hDPSCs, which were treated with extract-release fluids of the pulp-capping materials (Harvard BioCal-Cap, NeoPUTTY MTA, TheraCal LC, and Dycal). Effects of the capping materials on cell viability were assessed using 3-(4,5-di-methyl-thiazol-2-yl)-5-(3-carboxy-methoxy-phenyl)-2-(4-sulfo-phenyl)-2H-tetrazolium (MTS) assay and the apoptotic/necrotic cell ratios and reactive oxygen species (ROS) levels from flow cytometry. Marker expressions (alkaline phosphatase [ALP], osteocalcin [OCN], collagen type I alpha 1 [Col1A], secreted protein acidic and rich in cysteine [SPARC], osteonectin [ON], and vascular endothelial growth factor [VEGF]) were determined by quantitative reverse-transcription polymerase chain reaction. Changes in surface morphology of the hDPSCs were visualised by SEM.
RESULTS
The MTS assay results at days 1, 3, 5, and 7 indicated that Harvard BioCal-Cap, NeoPUTTY MTA, and TheraCal LC did not adversely affect cell viability when compared with the control group. According to the MTS assay results at day 14, no significant difference was found amongst Dycal, Harvard BioCal-Cap, NeoPUTTY MTA, and TheraCal LC affecting cell viability. Dycal was the only capping material that increased ROS level. High levels of VEGF expression were observed with Harvard BioCal-Cap, TheraCal LC, and NeoPUTTY MTA. NeoPUTTY MTA, and Dycal upregulated OCN expression, whereas TheraCal LC upregulated Col1A and SPARC expression. Only Dycal increased ALP expression. HDSCs were visualized in characteristic spindle morphology on SEM when treated with TheraCal LC and Harvard BioCal-Cap.
CONCLUSIONS
NeoPUTTY MTA and Harvard BioCal-Cap showed suitable biocompatibility values; in particular, these pulp-capping materials were observed to support the angiogenic marker.
PubMed: 38692961
DOI: 10.1016/j.identj.2024.04.006