Roles of Proteoglycans and Glycosaminoglycans in Wound Healing and Fibrosis

A wound is a type of injury that damages living tissues. In this review, we will be referring mainly to healing responses in the organs including skin and the lungs. Fibrosis is a process of dysregulated extracellular matrix (ECM) production that leads to a dense and functionally abnormal connective tissue compartment (dermis). In tissues such as the skin, the repair of the dermis after wounding requires not only the fibroblasts that produce the ECM molecules, but also the overlying epithelial layer (keratinocytes), the endothelial cells, and smooth muscle cells of the blood vessel and white blood cells such as neutrophils and macrophages, which together orchestrate the cytokine-mediated signaling and paracrine interactions that are required to regulate the proper extent and timing of the repair process. This review will focus on the importance of extracellular molecules in the microenvironment, primarily the proteoglycans and glycosaminoglycan hyaluronan, and their roles in wound healing. First, we will briefly summarize the physiological, cellular, and biochemical elements of wound healing, including the importance of cytokine cross-talk between cell types. Second, we will discuss the role of proteoglycans and hyaluronan in regulating these processes. Finally, approaches that utilize these concepts as potential therapies for fibrosis are discussed

Lipid changes Of goat sperm plasma membrane during epididymal maturation

Highly purified plasma membranes of maturing goat caput-, corpus- and cauda-epididymal spermatozoa were isolated by aqueous two-phase polymer methods and their lipid constituents were analysed, Phospholipid (app~'ox. 75% w/w), neutral lipid (approx. 15% w/w) and glycolipid (approx. 10% w/w) were the major sperm membrane lipids. "l'here was a significant decrease in the total lipids (approx. 25% w/w), phospholipid {approx. 30% w/w) and glycotipid (approx. 80% w/w) contents of sperm membrane during epididymal maturation. On the contrary, the mature cauda-sperrn membrane showed greater (approx. 50% w/w) neutral lipid content than that of the immature caput sperm. Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and sphingomyelin were the phospholipids of the sperm membrane, the former two being the major lipids. Both PC and PE fractions consisted of three species - diacyl, alkylacyl and alkenylacyl forms, the last one being lhe dominant species in both PC and PIE. Of all the phospholipids, diacyl PE decreased most strikingly (approx. 65% w/w) during sperm maturation. The neutral lipid fraction contained sterols, wax esters,l-O alkyl-2,3-diacylglycerol, triacylglycerol and fail?, acids. Sterols represented nearly 75% w/w of the neutral lipids and cholesterol was the major component (approx. 95% w/w) of the sterol fraction. The sperm maturity was associated with marked increase of sterol {approx. 60% w/w) and steryl ester (approx. 200% w/w) and decrease (approx. 50-65% w/w) of the other membrane-bound neutral iipids, The glyeolipid was identified as monogalaetosyldiacylglycerol. The fatty acid profile of the various membrane lipids underwent marked alteration during the epididymal transit of the male gametes. Cholesterol/phospbolipid and saturated/unsaturated fatty acid ratios increased greatly in the maturing sperm membrane. The altered lipid profile of ',he ma~nre sperm membrane leads to changes in its fluidity that play an important role in determining the structure and functions of the biomembrane

FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells

Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs

FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells

Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs

Phospholipid Asymmetry of goat Sperm Plasma-Membrane during Epididymal Maturation

The p~s~~oI~p~d~ and their fatty acids of the inner and outer plasma membrane feaBets of the rn~i~in~ goat cap&-, corpusand caud~-cp~~~rna~ ~~er~~ozoa were ana&zed by treating the intact s~e~~to~a with phospbo~pas~ C and ~K~~~oben~~ne sulphonate, The inner and outer membrane showed marked differences in the pho~pholipjd corn~s~t~o~ at all stages of cp~didymal sperm ma~ra~o~. The outer memlxm~ was rich in ~~lospbat~~ic~o~~~ (PC> and sp~~~~~e~o fSPf_f) whereas the inner leaflet was dominated by phosphatidylecb~olamine (FE& ~tbougb the ratio of FE/ PC in the inner rnembr~~ was similar in both the mature cauda sperm and the ~rnrna~~rec ap& sperm, it decreased s~~~~~c~t~~in sperm ~~dcrgoi~ mat~lration in the corpus-epididymis. The dis~~~b~tio~o f the saturated and ~sat~~ated fatty acids in the phospbo~~p~df ractions of both the membrane Leaflets undereat profound allocations during the ~~idid~~l ~~~t~~ation. The data demonstrate as~rne~ of phosphol~~ids and their fatty acids in the sperm inner and outer plasma rnernb~a~~s and this lipid asymmetry is greatly altered during ~~idid~a~ maturity of the male gamete

Utilization of Glycosaminoglycans/Proteoglycans as Carriers for Targeted Therapy Delivery

The outcome of patients with cancer has improved significantly in the past decade with the incorporation of drugs targeting cell surface adhesive receptors, receptor tyrosine kinases, and modulation of several molecules of extracellular matrices (ECMs), the complex composite of collagens, glycoproteins, proteoglycans, and glycosaminoglycans that dictates tissue architecture. Cancer tissue invasive processes progress by various oncogenic strategies, including interfering with ECM molecules and their interactions with invasive cells. In this review, we describe how the ECM components, proteoglycans and glycosaminoglycans, influence tumor cell signaling. In particular this review describes how the glycosaminoglycan hyaluronan (HA) and its major receptor CD44 impact invasive behavior of tumor cells, and provides useful insight when designing new therapeutic strategies in the treatment of cancer

Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer

Synthesis, deposition, and interactions of hyaluronan (HA) with its cellular receptor CD44 are crucial events that regulate the onset and progression of tumors. The intracellular signaling pathways initiated by HA interactions with CD44 leading to tumorigenic responses are complex. Moreover, HA molecules may perform dual functions depending on their concentration and size. Overexpression of variant isoforms of CD44 (CD44v) is most commonly linked to cancer progression, whereas their loss is associated with inhibition of tumor growth. In this review, we highlight that the regulation of HA synthases (HASes) by post-translational modifications, such as O-GlcNAcylation and ubiquitination, environmental factors and the action of microRNAs is important for HA synthesis and secretion in the tumor microenvironment. Moreover, we focus on the roles and interactions of CD44 with various proteins that reside extra- and intracellularly, as well as on cellular membranes with particular reference to the CD44-HA axis in cancer stem cell functions, and the importance of CD44/CD44v6 targeting to inhibit tumorigenesis