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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 -
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 -
International Journal of Molecular... Jan 2021Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and...
Proteoglycan (PG) is a glycosaminoglycan (GAG)-conjugated protein essential for maintaining tissue strength and elasticity. The most abundant skin PGs, biglycan and decorin, have been reported to decrease as skin ages. Insulin-like growth factor-1 (IGF-1) is important in various physiological functions such as cell survival, growth, and apoptosis. It is well known that the serum level of IGF-1 decreases with age. Therefore, we investigated whether and how IGF-1 affects biglycan and decorin. When primary cultured normal human dermal fibroblasts (NHDFs) were treated with IGF-1, protein levels of biglycan and decorin increased, despite no difference in mRNA expression. This increase was not inhibited by transcription blockade using actinomycin D, suggesting that it is mediated by IGF-1-induced enhanced translation. Additionally, both mRNA and protein expression of ADAMTS5, a PG-degrading enzyme, were decreased in IGF-1-treated NHDFs. Knockdown of ADAMTS5 via RNA interference increased protein expression of biglycan and decorin. Moreover, mRNA and protein expression of ADAMTS5 increased in aged human skin tissues compared to young tissue. Overall, IGF-1 increases biglycan and decorin, which is achieved by improving protein translation to increase synthesis and preventing ADAMTS5-mediated degradation. This suggests a new role of IGF-1 as a regulator for biglycan and decorin in skin aging process.
Topics: ADAMTS5 Protein; Adolescent; Adult; Aged; Aged, 80 and over; Biglycan; Cells, Cultured; Child; Decorin; Down-Regulation; Female; Fibroblasts; Gene Expression Profiling; Gene Knockdown Techniques; Healthy Volunteers; Humans; Insulin-Like Growth Factor I; Male; Primary Cell Culture; Protein Biosynthesis; Proteolysis; Skin; Skin Aging; Up-Regulation; Young Adult
PubMed: 33573338
DOI: 10.3390/ijms22031403 -
Analytical and Bioanalytical Chemistry Apr 2022Extracellular matrix (ECM) proteins, collectively known as the matrisome, include collagens, glycoproteins, and proteoglycans. Alterations in the matrisome have been...
Extracellular matrix (ECM) proteins, collectively known as the matrisome, include collagens, glycoproteins, and proteoglycans. Alterations in the matrisome have been implicated in the neurodegenerative pathologies including Parkinson's disease (PD). In this work, we utilized our previously published PD and control proteomics data from human prefrontal cortex and focused our analysis on the matrisome. Among matrisome proteins, we observed a significant enrichment in the expression of type I collagen in PD vs. control samples. We then performed histological analysis on the same samples used for proteomics study, and examined collagen expression using picrosirius red staining. Interestingly, we observed similar trends in collagen abundance in PD vs. control as in our matrisome analysis; thus, this and other histological analyses will be useful as a complementary technique in the future to study the matrisome in PD with a larger cohort, and it may aid in choosing regions of interest for proteomic analysis. Additionally, collagen hydroxyprolination was less variable in PD compared to controls. Glycoproteomic changes in matrisome molecules were also observed in PD relative to aged individuals, especially related to type VI collagen and versican. We further examined the list of differentially expressed matrisome molecules using network topology-based analysis and found that angiogenesis indicated by alterations in decorin and several members of the collagen family was affected in PD. These findings collectively identified matrisome changes associated with PD; further studies with a larger cohort are required to validate the current results.
Topics: Aged; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Parkinson Disease; Proteoglycans; Proteomics
PubMed: 35112150
DOI: 10.1007/s00216-022-03929-4 -
Autophagy Sep 2022Ferroptosis is a form of inflammatory cell death for which key mediators remain obscure. Here, we report that the proteoglycan decorin (DCN) is released by cells that...
Ferroptosis is a form of inflammatory cell death for which key mediators remain obscure. Here, we report that the proteoglycan decorin (DCN) is released by cells that are dying from ferroptosis and then acts as an alarm signal to trigger innate and adaptive immune responses. The early release of DCN during ferroptosis is an active process that involves secretory macroautophagy/autophagy and lysosomal exocytosis. Once released, extracellular DCN binds to the receptor advanced glycosylation end-product-specific receptor (AGER) on macrophages to trigger the production of pro-inflammatory cytokines in an NFKB/NF-κB-dependent manner. Pharmacological and genetic inhibition of the DCN-AGER axis protects against ferroptotic death-related acute pancreatitis and limits the capacity of ferroptotic cancer cells to induce a tumor-protective immune response. Thus, DCN is an essential mediator of the inflammatory and immune consequences of ferroptosis.
Topics: Acute Disease; Autophagy; Cell Death; Decorin; Humans; Immunity; Pancreatitis
PubMed: 34964698
DOI: 10.1080/15548627.2021.2008692 -
NPJ Regenerative Medicine Oct 2023Heart failure (HF) remains a global public health burden and often results following myocardial infarction (MI). Following injury, cardiac fibrosis forms in the...
Heart failure (HF) remains a global public health burden and often results following myocardial infarction (MI). Following injury, cardiac fibrosis forms in the myocardium which greatly hinders cellular function, survival, and recruitment, thus severely limits tissue regeneration. Here, we leverage biophysical microstructural cues made of hyaluronic acid (HA) loaded with the anti-fibrotic proteoglycan decorin to more robustly attenuate cardiac fibrosis after acute myocardial injury. Microrods showed decorin incorporation throughout the entirety of the hydrogel structures and exhibited first-order release kinetics in vitro. Intramyocardial injections of saline (n = 5), microrods (n = 7), decorin microrods (n = 10), and free decorin (n = 4) were performed in male rat models of ischemia-reperfusion MI to evaluate therapeutic effects on cardiac remodeling and function. Echocardiographic analysis demonstrated that rats treated with decorin microrods (5.21% ± 4.29%) exhibited significantly increased change in ejection fraction (EF) at 8 weeks post-MI compared to rats treated with saline (-4.18% ± 2.78%, p < 0.001) and free decorin (-3.42% ± 1.86%, p < 0.01). Trends in reduced end diastolic volume were also identified in decorin microrod-treated groups compared to those treated with saline, microrods, and free decorin, indicating favorable ventricular remodeling. Quantitative analysis of histology and immunofluorescence staining showed that treatment with decorin microrods reduced cardiac fibrosis (p < 0.05) and cardiomyocyte hypertrophy (p < 0.05) at 8 weeks post-MI compared to saline control. Together, this work aims to contribute important knowledge to guide rationally designed biomaterial development that may be used to successfully treat cardiovascular diseases.
PubMed: 37872196
DOI: 10.1038/s41536-023-00336-w