**3. Therapy: GAGs as Targets and Novel Therapy Agents**

GAGs are essential ECMs and cell membrane components and are extensively altered under various pathological conditions, including cancer. Indeed, during disease progression, the fine GAG structure and expression change in a manner that is associated with disease evolution. Furthermore, pathological conditions are characterized by the extent of GAG remodeling that is either due to the increased expression of glycosidases or to a chemical reaction with elevated, radical oxygen species. Specific disease-dependent GAG alterations have been identified as druggable entities, with industry and academic research efforts examining their potential in drug development. Berdiaki et al. [9] discuss the up-todate developments of implementing GAG disease-dependent changes in two directions: (i) utilizing GAGs as the targets of therapeutic strategies and (ii) employing GAG specificity and excellent physicochemical properties for the targeted delivery of cancer therapeutics.

Faria-Ramos et al. [10] specifically focus on the role of HS in carcinogenesis. Due to HS's well-established regulation of critical cellular receptors and respective downstream signaling pathways and the aberrant expression of HS in tumor tissue, these GAGs have been characterized as modulators of malignant features. This review article highlights the significant clinical potential of HS to improve both the diagnosis and prognosis of cancer, either as HS-based biomarkers or as therapeutic targets [10].

GAG functions are implicated in inflammatory processes. Notably, cardiovascular disease propagation and the inflammatory status of tissues are closely correlated. The treatment of endothelial cells with the cytokine TNF-α, which is known to be increased in obese patients and has been reported to induce cardiometabolic diseases, strongly affects the expression patterns of hyaluronan and the HS-containing proteoglycans known as syndecans [11]. These changes seem to facilitate the onset of a pathological state by altering (i) the endothelial barrier properties, (ii) increasing HA in the pericellular coat and the possibility of consequent monocyte recruitment from the blood; or (iii) altering the sulfation pattern of membrane-bound HS, which can cause modifications to the endothelium response to growth factors and cytokines. Therefore, the authors confirm the critical role of ECM components such as GAGs in disease progression.

Matrix metalloproteinases (MMPs) are endopeptidases that are able to cleave both matrix and non-matrix proteins. MMPs activity and the resulting extracellular matrix remodeling are increased in acute and chronic diseases and are correlated with disease pathogenesis. Thus, the enhanced activity of MMP-8 facilitates the progression of various pathologies, including atherosclerosis, pulmonary fibrosis, and sepsis. Since natural GAGs are known to modulate the functions of various MMPs, the synthetic non-sugar mimetics of GAGs have been hypothesized to inhibit MMP-8 activity. The strategy of Moria and Desai [12], upon screening a library of 58 synthetic, sulfated mimetics consisting of a dozen scaffolds, led to the identification of sulfated benzofurans and sulfated quinazolinones as promising inhibitors of MMP-8. Interestingly, this work provides the first proof that the sulfated mimetics of GAGs could lead to potent, selective, and catalytic activity-tunable, small molecular inhibitors of MMP-8.

Due to the lack of blood vessels and the consequently limited bioavailability of oxygen and nutrients, articular cartilage has restricted regenerative capacity, resulting in frequent degenerative disease in older individuals. Therefore, therapeutic strategies limiting or halting the progression of cartilage destruction are an unmet health need. Perlecan, a multifunctional HS proteoglycan, promotes embryonic cartilage development and stabilizes mature tissue. Using immunohistochemistry, Garcia et al. [13] showed a pericellular and diffuse matrix staining pattern for perlecan in both natural and cell-therapy-repaired cartilage. This observation was related to whether the morphology of the newly formed tissue was hyaline cartilage or fibrocartilage. In addition, immunostaining was significantly more enhanced in these repair tissues for perlecan than it was for normal age-matched controls and was sensitive to heparanase treatment. Thus, the modulation of HS could be helpful in the treatment of degenerative cartilage disease.

A novel, interesting therapeutic function of heparin has been shown by Lantero et al. [14]. Indeed, these authors report an antimalarial activity of heparin. Innovative antimalarial strategies are urgently needed as plasmodium parasites continue to express increased resistance to the available drugs that have been developed against plasmodium parasites. Heparin delivered in membrane feeding assays together with *Plasmodium berghei*-infected blood of *Anopheles stephensi* mosquitoes was shown to inhibit the parasite's ookinete–oocyst transition by binding the ookinetes. The inhibition of the parasite life-cycle by heparin might represent a new antimalarial strategy for rapid implementation and is an excellent example of the ubiquitous use of these multifaceted molecules.
