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Cancers Feb 2022Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the... (Review)
Review
Proteoglycans are emerging as critical regulators of intracellular catabolism. This rise in prominence has transformed our basic understanding and alerted us to the existence of non-canonical pathways, independent of nutrient deprivation, that potently control the autophagy downstream of a cell surface receptor. As a member of the small leucine-rich proteoglycan gene family, decorin has single-handedly pioneered the connection between extracellular matrix signaling and autophagy regulation. Soluble decorin evokes protracted endothelial cell autophagy via Peg3 and breast carcinoma cell mitophagy via mitostatin by interacting with VEGFR2 or the MET receptor tyrosine kinase, respectively. In this paper, we give a mechanistic perspective of the vital factors underlying the nutrient-independent, SLRP-dependent programs utilized for autophagic and/or mitophagic progression in breast cancer. Future protein therapies based on decorin (or fellow proteoglycan members) will represent a quantum leap forward in transforming autophagic progression into a powerful tool to control intracellular cell catabolism from the outside.
PubMed: 35159071
DOI: 10.3390/cancers14030804 -
Frontiers in Oncology 2021The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has... (Review)
Review
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
PubMed: 34917515
DOI: 10.3389/fonc.2021.801801 -
Annals of Gastroenterology 2023Sarcopenia is a syndrome characterized by a decline in skeletal muscle quantity and/or quality, strength and performance, leading to unfortunate events, such as... (Review)
Review
Sarcopenia is a syndrome characterized by a decline in skeletal muscle quantity and/or quality, strength and performance, leading to unfortunate events, such as injurious falls or even death. It is not identical to frailty and malnutrition, even though there is a significant overlap among these syndromes. In patients with liver cirrhosis (LC), sarcopenia is classified as secondary and has been associated with increased morbidity and mortality during the pre- and post-transplantation period. It can be a result of malnutrition, hyperammonemia, low physical activity, endocrine abnormalities, accelerated starvation, metabolic disturbances, altered gut function leading to chronic inflammation, and alcohol abuse. Myokines are peptides mainly synthesized by contracting muscle and adipose tissue cells and may play a key role in the pathophysiology of sarcopenia. More than a hundred myokines have been recognized, but only a few have been investigated. They can be classified as negative regulators, such as myostatin, tumor growth factor-β, activins, growth differentiation factor-11, and positive regulators of muscle growth including follistatin, bone morphogenic proteins, and irisin. So far, only myostatin, follistatin, irisin and decorin have been studied in LC-associated sarcopenia. In this review, we focused on the mechanisms of cirrhosis-related sarcopenia and the role of myokines that have already been studied in the literature, either as markers helping in the diagnostic evaluation of sarcopenia, or as prognostic factors of survival. Standard therapeutic options to prevent or treat sarcopenia in LC are also being reported, as well as the possible therapeutic implication of myokines.
PubMed: 37396001
DOI: 10.20524/aog.2023.0804 -
Matrix Biology : Journal of the... Feb 2021In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal...
In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal mechanosensitive activities of chondrocytes. Thus, it is imperative to discern the micromechanobiological functions of the pericellular matrix, the ~ 2-4 µm-thick domain that is in immediate contact with chondrocytes. In this study, we discovered that decorin, a small leucine-rich proteoglycan, is a key determinant of cartilage pericellular matrix micromechanics and chondrocyte mechanotransduction in vivo. The pericellular matrix of decorin-null murine cartilage developed reduced content of aggrecan, the major chondroitin sulfate proteoglycan of cartilage and a mild increase in collagen II fibril diameter vis-à-vis wild-type controls. As a result, decorin-null pericellular matrix showed a significant reduction in micromodulus, which became progressively more pronounced with maturation. In alignment with the defects of pericellular matrix, decorin-null chondrocytes exhibited decreased intracellular calcium activities, [Ca], in both physiologic and osmotically evoked fluidic environments in situ, illustrating impaired chondrocyte mechanotransduction. Next, we compared [Ca] activities of wild-type and decorin-null chondrocytes following enzymatic removal of chondroitin sulfate glycosaminoglycans. The results showed that decorin mediates chondrocyte mechanotransduction primarily through regulating the integrity of aggrecan network, and thus, aggrecan-endowed negative charge microenvironment in the pericellular matrix. Collectively, our results provide robust genetic and biomechanical evidence that decorin is an essential constituent of the native cartilage matrix, and suggest that modulating decorin activities could improve cartilage regeneration.
Topics: Aggrecans; Animals; Biomechanical Phenomena; Calcium Signaling; Cartilage, Articular; Decorin; Extracellular Matrix; Female; Loss of Function Mutation; Male; Mechanotransduction, Cellular; Mice; Regeneration
PubMed: 33246102
DOI: 10.1016/j.matbio.2020.11.002 -
Journal of the College of Physicians... Nov 2021To evaluate immunohistochemical (IHC) staining of decorin and vascular endothelial growth factor (VEGF) of ovarian and endometrial tissues in patients with and without...
OBJECTIVE
To evaluate immunohistochemical (IHC) staining of decorin and vascular endothelial growth factor (VEGF) of ovarian and endometrial tissues in patients with and without endometriosis. Study Design: Descriptive study.
PLACE AND DURATION OF STUDY
Department of Obstetrics and Gynecology, ZeynepKamil Training and Research Hospital, Istanbul, Turkey, between Istanbul, TurkeyJanuary 2018 and June 2019.
METHODOLOGY
Thirty patients, who underwent total abdominal hysterectomy (TAH) + bilateral salpingo-oophorectomy (BSO)/unilateral salpingo-oophorectomy (USO) and were in the proliferative phase of menstrual cycle,were included. The study population consisted of 20 patients (patient group) with an endometriomaand the control group consisted of 10 patients who were operated for benign gynecological pathologies.The ovarian and endometrial tissue specimens were collected from the archives. IHC staining was performed using decorin and VEGF.
RESULTS
Decorin analysis showed a significantly higher intensity of staining in both endometrial and ovarian tissues in control group than patient group. Patients with endometriosis had a lower intensity of staining of decorin and a higher intensity of staining of VEGF compared to control group. There was a negative, statistically significant concordance between VEGF and decorin staining of endometrial tissues of both groups (concordance rate -0.560, p=0.001). Therewas a negative, statistically significant concordance between VEGF and decorin staining of ovarian tissues of both groups (concordance rate -0.564, p<0.001).
CONCLUSION
Angiogenesis plays a critical role in endometriosisand interaction between decorin and VEGF,which suggests that decorin may be a promising molecule for the treatment of endometriosis. Key Words: Decorin, Endometriosis, Immunohistochemical staining, Vascular endothelial Growth factor.
Topics: Decorin; Endometriosis; Endometrium; Female; Humans; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 34689484
DOI: 10.29271/jcpsp.2021.11.1285 -
Clinical Kidney Journal Aug 2023Endothelial damage and cardiovascular disease complicate chronic kidney disease (CKD). The increased atherogenicity observed in patients with CKD can be linked to...
BACKGROUND
Endothelial damage and cardiovascular disease complicate chronic kidney disease (CKD). The increased atherogenicity observed in patients with CKD can be linked to microinflammation and endothelial damage. Circulating endothelial glycocalyx degradation products, such as perlecan and decorin, tend to be elevated in CKD. We aimed to explore the association between the plasma perlecan and decorin levels and this pro-inflammatory and atherogenic state by studying monocyte subpopulations and intracellular adhesion molecule (ICAM)-1 expression in patients with CKD.
METHODS
We studied 17 healthy controls, 23 patients with advanced CKD, 25 patients on haemodialysis, 23 patients on peritoneal dialysis and 20 patients who underwent kidney transplantation. Perlecan and decorin levels were evaluated using enzyme-linked immunosorbent assays, and the monocyte phenotype was analysed using direct immunofluorescence and flow cytometry.
RESULTS
The plasma perlecan levels were higher in patients with CKD than in the healthy controls. These levels were associated with a higher prevalence of ICAM-1+ monocytes. Conversely, patients with advanced CKD (pre-dialysis) had higher plasma decorin levels, which were associated with a reduced ICAM-1 expression per monocyte.
CONCLUSIONS
Elevated perlecan levels in CKD may be associated with a higher prevalence of ICAM-1+ monocytes and a pro-inflammatory phenotype. Elevated decorin levels may act as a negative regulator of ICAM-1 expression in monocytes. Therefore, perlecan and decorin may be related to inflammation and monocyte activation in CKD and may act as potential markers of endothelial damage.
PubMed: 37529650
DOI: 10.1093/ckj/sfad051 -
Cells Oct 2023Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype...
Adiponectin (adipoq), the most abundant hormone in circulation, has many beneficial effects on the cardiovascular system, in part by preserving the contractile phenotype of vascular smooth muscle cells (VSMCs). However, the lack of adiponectin or its receptor and treatment with recombinant adiponectin have shown contradictory effects on plaque in mice. RNA sequence of and VSMCs from male aortas identified a critical role for adiponectin in AKT signaling, the extracellular matrix (ECM), and TGF-β signaling. Upregulation of AKT activity mediated proliferation and migration of cells. Activation of AMPK with metformin or AdipoRon reduced AKT-dependent proliferation and migration of cells but did not improve the expression of contractile genes. Adiponectin deficiency impaired oxidative phosphorylation (OXPHOS), increased expression of glycolytic enzymes, and elevated mitochondrial reactive oxygen species (ROS) (superoxide, and hydrogen peroxide). Anti-atherogenic mechanisms targeted the ECM in cells, downregulating MMP2 and 9 and upregulating decorin (DCN) and elastin (ELN). In vivo, the main sex differences in protein expression in aortas involved a more robust upregulation of MMP3 in females than males. Females also showed a reduction in DCN, which was not affected in males. Our study uncovered the AKT/MAPK/TGF-β network as a central regulator of VSMC phenotype.
Topics: Male; Mice; Female; Animals; Adiponectin; Proto-Oncogene Proteins c-akt; Muscle, Smooth, Vascular; Phenotype; Transforming Growth Factor beta
PubMed: 37887338
DOI: 10.3390/cells12202493 -
Cell & Bioscience 2019Autophagy is a catabolic process for degradation of intracellular components. Damaged proteins and organelles are engulfed in double-membrane vesicles ultimately fused... (Review)
Review
BACKGROUND
Autophagy is a catabolic process for degradation of intracellular components. Damaged proteins and organelles are engulfed in double-membrane vesicles ultimately fused with lysosomes. These vesicles, known as phagophores, develop to form autophagosomes. Encapsulated components are degraded after autophagosomes and lysosomes are fused. Autophagy clears denatured proteins and damaged organelles to produce macromolecules further reused by cells. This process is vital to cell homeostasis under both physiologic and pathologic conditions.
MAIN BODY
While the role of autophagy in cancer is quite controversial, the majority of studies introduce it as an anti-tumorigenesis mechanism. There are evidences confirming this role of autophagy in cancer. Mutations and monoallelic deletions have been demonstrated in autophagy-related genes correlating with cancer promotion. Another pathway through which autophagy suppresses tumorigenesis is cell cycle. On the other hand, under hypoxia and starvation condition, tumors use angiogenesis to provide nutrients. Also, autophagy flux is highlighted in vessel cell biology and vasoactive substances secretion from endothelial cells. The matrix proteoglycans such as Decorin and Perlecan could also interfere with angiogenesis and autophagy signaling pathway in endothelial cells (ECs). It seems that the connection between autophagy and angiogenesis in the tumor microenvironment is very important in determining the fate of cancer cells.
CONCLUSION
Matrix glycoproteins can regulate autophagy and angiogenesis linkage in tumor microenvironment. Also, finding details of how autophagy and angiogenesis correlate in cancer will help adopt more effective therapeutic approaches.
PubMed: 31428311
DOI: 10.1186/s13578-019-0327-6 -
International Journal of Molecular... Jul 2021Retinal diseases such as age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and diabetic retinopathy (DR) are the leading causes of visual... (Review)
Review
Retinal diseases such as age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and diabetic retinopathy (DR) are the leading causes of visual impairment worldwide. There is a critical need to understand the structural and cellular components that play a vital role in the pathophysiology of retinal diseases. One potential component is the family of structural proteins called small leucine-rich proteoglycans (SLRPs). SLRPs are crucial in many fundamental biological processes involved in the maintenance of retinal homeostasis. They are present within the extracellular matrix (ECM) of connective and vascular tissues and contribute to tissue organization and modulation of cell growth. They play a vital role in cell-matrix interactions in many upstream signaling pathways involved in fibrillogenesis and angiogenesis. In this comprehensive review, we describe the expression patterns and function of SLRPs in the retina, including Biglycan and Decorin from class I; Fibromodulin, Lumican, and a Proline/arginine-rich end leucine-rich repeat protein (PRELP) from class II; Opticin and Osteoglycin/Mimecan from class III; and Chondroadherin (CHAD), Tsukushi and Nyctalopin from class IV.
Topics: Animals; Chondroitin Sulfate Proteoglycans; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Leucine; Retina; Small Leucine-Rich Proteoglycans
PubMed: 34298915
DOI: 10.3390/ijms22147293 -
Advances in Experimental Medicine and... 2021Proteoglycans consist of protein cores to which at least one glycosaminoglycan chain is attached. They play important roles in the physiology and biomechanical function...
Proteoglycans consist of protein cores to which at least one glycosaminoglycan chain is attached. They play important roles in the physiology and biomechanical function of tendons, ligaments, cardiovascular system, and other systems through their involvement in regulation of assembly and maintenance of extracellular matrix, and through their participation in cell proliferation together with growth factors. They can be divided into two main groups, small and large proteoglycans. The small proteoglycans are also known as small leucine-rich proteoglycans (SLRPs) which are encoded by 18 genes and are further subclassified into Classes I-V. Several members of Class I and II, such as decorin and biglycan from Class I, and Class II fibromodulin and lumican, are known to regulate collagen fibrillogenesis. Decorin limits the diameter of collagen fibrils during fibrillogenesis. The function of biglycan in fibrillogenesis is similar to that of decorin. Though biomechanical function of tendon is compromised in decorin-deficient mice, decorin can substitute for lack of biglycan in biglycan-deficient mice. New data also indicate an important role for biglycan in disorders of the cardiovascular system, including aortic valve stenosis and aortic dissection. Two members of the Class II of SLRPs, fibromodulin and lumican bind to the same site within the collagen molecule and can substitute for each other in fibromodulin- or lumican-deficient mice.Aggrecan and versican are the major representatives of the large proteoglycans. Though they are mainly found in the cartilage where they provide resilience and toughness, they are present also in tensile portions of tendons and, in slightly different biochemical form in fibrocartilage. Degradation by aggrecanase is responsible for the appearance of different forms of aggrecan and versican in different parts of the tendon where these cleaved forms play different roles. In addition, they are important components of the ventricularis of cardiac valves. Mutations in the gene for versican or in the gene for elastin (which binds to versican ) lead to severe disruptions of normal developmental of the heart at least in mice.
Topics: Animals; Collagen; Decorin; Extracellular Matrix; Keratan Sulfate; Mice; Versicans
PubMed: 34807417
DOI: 10.1007/978-3-030-80614-9_5