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Lipids in Health and Disease Aug 2023Obesity is often accompanied by metabolic disorder and insulin resistance, resulting in type 2 diabetes. Based on previous findings, FYGL, a natural hyperbranched...
Obesity is often accompanied by metabolic disorder and insulin resistance, resulting in type 2 diabetes. Based on previous findings, FYGL, a natural hyperbranched proteoglycan extracted from the G. lucidum fruiting body, can decrease blood glucose and reduce body weight in diabetic mice. In this article, the underlying mechanism of FYGL in ameliorating obesity-induced diabetes was further investigated both in vivo and in vitro. FYGL upregulated expression of metabolic genes related to fatty acid biosynthesis, fatty acid β-oxidation and thermogenesis; downregulated the expression of insulin resistance-related genes; and significantly increased the number of beige adipocytes in db/db mice. In addition, FYGL inhibited preadipocyte differentiation of 3T3-L1 cells by increasing the expression of FABP-4. FYGL not only promoted fatty acid synthesis but also more significantly promoted triglyceride degradation and metabolism by activating the AMPK signalling pathway, therefore preventing fat accumulation, balancing adipocyte production and lipid metabolism, and regulating metabolic disorders and unhealthy obesity. FYGL could be used as a promising pharmacological agent for the treatment of metabolic disorder-related obesity.
Topics: Mice; Animals; Reishi; Diabetes Mellitus, Type 2; Lipid Metabolism; Insulin Resistance; Diabetes Mellitus, Experimental; Proteoglycans; Adipocytes; Adipogenesis; Obesity; Fatty Acids; 3T3-L1 Cells
PubMed: 37553709
DOI: 10.1186/s12944-023-01880-6 -
Matrix Biology : Journal of the... Apr 2014The concept of "proteoglycans" as discrete molecules surfaced some 40 years ago, out of previously muddled notions of the extracellular matrix. Core proteins were... (Review)
Review
The concept of "proteoglycans" as discrete molecules surfaced some 40 years ago, out of previously muddled notions of the extracellular matrix. Core proteins were gradually recognized as molecular entities, distinct with regard to location, substitution with glycosaminoglycan (GAG) chains and biological function. This development is surveyed, with brief outline of methodological approaches, biosynthesis, and functional aspects. Special emphasis is given to the impact of genomics on the field. Some outstanding unresolved issues are emphasized, including regulation of GAG biosynthesis and the specificity of GAG-protein interactions.
Topics: Animals; Disease; Genomics; Glycosaminoglycans; Growth and Development; Humans; Mice; Proteoglycans
PubMed: 24463261
DOI: 10.1016/j.matbio.2014.01.001 -
Usurped SLRPs: novel arthritis biomarkers exposed by catabolism of small leucine-rich proteoglycans?Arthritis Research & Therapy 2006Proteolytic degradation of articular cartilage macromolecules, including the large aggregating cartilage proteoglycan (aggrecan) and small leucine-rich proteoglycans... (Review)
Review
Proteolytic degradation of articular cartilage macromolecules, including the large aggregating cartilage proteoglycan (aggrecan) and small leucine-rich proteoglycans (SLRPs), is a prominent pathophysiological feature of arthritic diseases such as osteoarthritis (OA). Molecular profiling and monitoring of soluble/circulating proteoglycan catabolites that may be released from the cartilage matrix therefore represents an attractive strategy for evaluating OA disease progression and intervention. The recent identification of discrete metalloproteinase-sensitive SLRP cleavage sites, and complementary neoepitope-bearing SLRP catabolites, extends decisive insight into the functional regulation of extracellular matrix integrity, and proffers poignant leads to assist in disclosing and appraising applicable biomarkers of cartilage degeneration during arthritis.
Topics: Animals; Arthritis; Biomarkers; Humans; Leucine; Proteoglycans
PubMed: 16563183
DOI: 10.1186/ar1925 -
Pigment Cell & Melanoma Research Dec 2011Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified as a highly immunogenic tumor antigen on the surface of melanoma cells, is... (Review)
Review
Chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane proteoglycan originally identified as a highly immunogenic tumor antigen on the surface of melanoma cells, is associated with melanoma tumor formation and poor prognosis in certain melanomas and several other tumor types. The complex mechanisms by which CSPG4 affects melanoma progression have started to be defined, in particular the association with other cell surface proteins and receptor tyrosine kinases (RTKs) and its central role in modulating the function of these proteins. CSPG4 is essential to the growth of melanoma tumors through its modulation of integrin function and enhanced growth factor receptor-regulated pathways including sustained activation of ERK 1,2. This activation of integrin, RTK, and ERK1,2 function by CSPG4 modulates numerous aspects of tumor progression. CSPG4 expression has further been correlated to resistance of melanoma to conventional chemotherapeutics. This review outlines recent advances in our understanding of CSPG4-associated cell signaling, describing the central role it plays in melanoma tumor cell growth, motility, and survival, and explores how modifying CSPG4 function and protein-protein interactions may provide us with novel combinatorial therapies for the treatment of advanced melanoma.
Topics: Animals; Antigens; Disease Progression; Humans; Melanoma; Molecular Targeted Therapy; Proteoglycans; Signal Transduction; Skin Neoplasms
PubMed: 22004131
DOI: 10.1111/j.1755-148X.2011.00929.x -
Biochemistry Oct 2008Perlecan is a ubiquitous pericellular proteoglycan ideally placed to mediate cell signaling events controlling migration, proliferation, and differentiation. Its control... (Review)
Review
Perlecan is a ubiquitous pericellular proteoglycan ideally placed to mediate cell signaling events controlling migration, proliferation, and differentiation. Its control of growth factor signaling usually involves interactions with the heparan sulfate chains covalently coupled to the protein core's N-terminus. However, this modular protein core also binds with relatively high affinity to a number of growth factors and surface receptors, thereby stabilizing cell-matrix links. This review will focus on perlecan-growth factor interactions and describe recent advances in our understanding of this highly conserved proteoglycan during development, cancer growth, and angiogenesis. The pro-angiogenic capacities of perlecan that involve proliferative and migratory signals in response to bound growth factors will be explored, as well as the anti-angiogenic signals resulting from interactions between the C-terminal domain known as endorepellin and integrins that control adhesion of cells to the extracellular matrix. These two somewhat diametrically opposed roles will be discussed in light of new data emerging from various fields which converge on perlecan as a key regulator of cell growth and angiogenesis.
Topics: Animals; Cell Physiological Phenomena; Heparan Sulfate Proteoglycans; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Neovascularization, Pathologic; Protein Binding; Protein Structure, Tertiary; Proteoglycans; Signal Transduction
PubMed: 18826258
DOI: 10.1021/bi8013938 -
Proceedings of the Japan Academy.... 2024Multifunctional molecules involved in tumor progression and metastasis have been identified as valuable targets for immunotherapy. Among these, chondroitin sulfate... (Review)
Review
Multifunctional molecules involved in tumor progression and metastasis have been identified as valuable targets for immunotherapy. Among these, chondroitin sulfate proteoglycan 4 (CSPG4), a significant tumor cell membrane-bound proteoglycan, has emerged as a promising target, especially in light of advances in chimeric antigen receptor (CAR) T-cell therapy. The profound bioactivity of CSPG4 and its role in pivotal processes such as tumor proliferation, migration, and neoangiogenesis underline its therapeutic potential. We reviewed the molecular intricacies of CSPG4, its functional attributes within tumor cells, and the latest clinical-translational advances targeting it. Strategies such as blocking monoclonal antibodies, conjugate therapies, bispecific antibodies, small-molecule inhibitors, CAR T-cell therapies, trispecific killer engagers, and ribonucleic acid vaccines against CSPG4 were assessed. CSPG4 overexpression in diverse tumors and its correlation with adverse prognostic outcomes emphasize its significance in cancer biology. These findings suggest that targeting CSPG4 offers a promising avenue for future cancer therapy, with potential synergistic effects when combined with existing treatments.
Topics: Humans; Immunotherapy; Neoplasms; Animals; Chondroitin Sulfate Proteoglycans; Proteoglycans; Molecular Targeted Therapy; Antibodies, Monoclonal; Antigens; Membrane Proteins
PubMed: 38735753
DOI: 10.2183/pjab.100.019 -
Developmental Biology Apr 1988Extracellular matrix and cell surface proteoglycans are thought to play important roles in neural development and regeneration. Central nervous system proteoglycans have...
Extracellular matrix and cell surface proteoglycans are thought to play important roles in neural development and regeneration. Central nervous system proteoglycans have been isolated and characterized from rat and sheep brain and from chick neural retina. An experimental advantage offered by the latter tissue is that it is avascular and can be isolated free of connective tissue and pigment epithelium. Therefore, proteoglycans synthesized by this tissue are derived exclusively from neural cells. However, it has not yet been determined whether neurons and photoreceptors contribute to proteoglycan synthesis or whether these molecules are largely glial in origin. In the present study we have addressed this question using cultures of chick neural retinal cells free of flat, glial-like cells. Proteoglycans synthesized by cultures of retinal neurons, photoreceptors, and undifferentiated, process-free round cells from 8-day embryonic chick neural retina were metabolically labeled in vitro using [35S]sulfate and [3H]glucosamine as precursors. Radiolabeled proteoglycans accumulated in the medium, and could also be extracted from the cell layer by sequential treatments with Triton X-100 and with guanidine HCl. The proteoglycans were isolated by ion-exchange chromatography, and characterized by gel filtration chromatography and by susceptibility to degradation by enzymatic and chemical treatments. Overall, heparan sulfate proteoglycans were the predominant type of proteoglycan synthesized in vitro by the cultured neural retinal cells at this developmental stage. The medium and the Triton extract contained different proportions of both chondroitin sulfate and heparan sulfate proteoglycans, while heparan sulfate was the only proteoglycan recovered from the guanidine extract. These studies demonstrate that heparan sulfate and chondroitin sulfate proteoglycans are actively synthesized by cultures of neural retinal cells free of flat, glial-like cells.
Topics: Animals; Cells, Cultured; Chick Embryo; Chondroitin Sulfate Proteoglycans; Chromatography, Gel; Chromatography, Ion Exchange; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Microscopy, Phase-Contrast; Neurons; Photoreceptor Cells; Proteoglycans; Retina
PubMed: 3280364
DOI: 10.1016/0012-1606(88)90140-6 -
The Journal of Biological Chemistry Jan 2018Chondroitin sulfate proteoglycans (CSPGs) are important structural components of connective tissues in essentially all metazoan organisms. In vertebrates, CSPGs are...
Chondroitin sulfate proteoglycans (CSPGs) are important structural components of connective tissues in essentially all metazoan organisms. In vertebrates, CSPGs are involved also in more specialized processes such as neurogenesis and growth factor signaling. In invertebrates, however, knowledge of CSPGs core proteins and proteoglycan-related functions is relatively limited, even for This nematode produces large amounts of non-sulfated chondroitin in addition to low-sulfated chondroitin sulfate chains. So far, only nine core proteins (CPGs) have been identified, some of which have been shown to be involved in extracellular matrix formation. We recently introduced a protocol to characterize proteoglycan core proteins by identifying CS-glycopeptides with a combination of biochemical enrichment, enzymatic digestion, and nano-scale liquid chromatography MS/MS analysis. Here, we have used this protocol to map the chondroitin glycoproteome in , resulting in the identification of 15 novel CPG proteins in addition to the nine previously established. Three of the newly identified CPGs displayed homology to vertebrate proteins. Bioinformatics analysis of the primary protein sequences revealed that the CPG proteins altogether contained 19 unique functional domains, including Kunitz and endostatin domains, suggesting direct involvement in protease inhibition and axonal migration, respectively. The analysis of the core protein domain organization revealed that all chondroitin attachment sites are located in unstructured regions. Our results suggest that CPGs display a much greater functional and structural heterogeneity than previously appreciated and indicate that specialized proteoglycan-mediated functions evolved early in metazoan evolution.
Topics: Amino Acid Sequence; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Chondroitin Sulfate Proteoglycans; Chondroitin Sulfates; Chromatography, Gel; Glycopeptides; Proteoglycans; Tandem Mass Spectrometry
PubMed: 29138239
DOI: 10.1074/jbc.M117.807800 -
Connective Tissue Research 2016The objectives of this study were to assess the cartilage boundary lubricating ability of (1) nonreduced (NR) disulfide-bonded proteoglycan 4 (PRG4) multimers versus...
PURPOSE
The objectives of this study were to assess the cartilage boundary lubricating ability of (1) nonreduced (NR) disulfide-bonded proteoglycan 4 (PRG4) multimers versus PRG4 monomers and (2) NR versus reduced and alkylated (R/A) PRG4 monomers and to assess (3) the ability of NR PRG4 multimers versus monomers to adsorb to an articular cartilage surface.
MATERIALS AND METHODS
PRG4 was separated into two preparations, PRG4 multimer enriched (PRG4Multi+) and PRG4 multimer deficient (PRG4Multi-), using size exclusion chromatography (SEC) and characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The cartilage boundary lubricating ability of PRG4Multi+ and PRG4Multi- was compared at a physiological concentration (450 μg/mL) and assessed over a range of concentrations (45, 150, and 450 μg/mL). R/A and NR PRG4Multi- were evaluated at 450 μg/mL. Immunohistochemistry with anti-PRG4 antibody 4D6 was performed to visualize the adsorption of PRG4 preparations to the surface of articular cartilage explants.
RESULTS
Separation into enriched populations of PRG4Multi+ and PRG4Multi- was achieved using SEC and was confirmed by SDS-PAGE. PRG4Multi+ and PRG4Multi- both functioned as effective friction-reducing cartilage boundary lubricants at 450 μg/mL, with PRG4Multi+ being more effective than PRG4Multi-. PRG4Multi+ lubricated in a dose-dependent manner, however, PRG4Multi- did not. R/A PRG4Multi- lubricated similar to NR PRG4Multi-. PRG4-containing solutions showed 4D6 immunoreactivity at the articular surface; the immunoreactive intensity of PRG4Multi+ appeared to be similar to SF, whereas PRG4Multi- appeared to have less intensity.
CONCLUSIONS
These results demonstrate that the intermolecular disulfide-bonded multimeric structure of PRG4 is important for its ability to adsorb to a cartilage surface and function as a boundary lubricant. These findings contribute to a greater understanding of the molecular basis of cartilage boundary lubrication of PRG4. Elucidating the PRG4 structure-lubrication function relationship will further contribute to the understanding of PRG4's role in diarthrodial joint homeostasis and disease.
Topics: Adsorption; Animals; Cartilage, Articular; Cattle; Chromatography, Gel; Disulfides; Electrophoresis, Polyacrylamide Gel; Friction; Immunohistochemistry; Kinetics; Lubrication; Protein Multimerization; Proteoglycans
PubMed: 26631309
DOI: 10.3109/03008207.2015.1113271 -
Expert Reviews in Molecular Medicine Feb 2010Many microbial pathogens subvert proteoglycans for their adhesion to host tissues, invasion of host cells, infection of neighbouring cells, dissemination into the... (Review)
Review
Many microbial pathogens subvert proteoglycans for their adhesion to host tissues, invasion of host cells, infection of neighbouring cells, dissemination into the systemic circulation, and evasion of host defence mechanisms. Where studied, specific virulence factors mediate these proteoglycan-pathogen interactions, which are thus thought to affect the onset, progression and outcome of infection. Proteoglycans are composites of glycosaminoglycan (GAG) chains attached covalently to specific core proteins. Proteoglycans are expressed ubiquitously on the cell surface, in intracellular compartments, and in the extracellular matrix. GAGs mediate the majority of ligand-binding activities of proteoglycans, and many microbial pathogens elaborate cell-surface and secreted factors that interact with GAGs. Some pathogens also modulate the expression and function of proteoglycans through known virulence factors. Several GAG-binding pathogens can no longer attach to and invade host cells whose GAG expression has been reduced by mutagenesis or enzymatic treatment. Furthermore, GAG antagonists have been shown to inhibit microbial attachment and host cell entry in vitro and reduce virulence in vivo. Together, these observations underscore the biological significance of proteoglycan-pathogen interactions in infectious diseases.
Topics: Animals; Anti-Bacterial Agents; Communicable Diseases; Host-Pathogen Interactions; Humans; Proteoglycans
PubMed: 20113533
DOI: 10.1017/S1462399409001367