The extracellular matrix (ECM) is a dynamic set of molecules produced by the cellular component of normal and pathological tissues of the embryo and adult. ECM acts as critical regulator in various biological processes such as differentiation, cell proliferation, angiogenesis, and immune control. The most frequent primary brain tumors are gliomas and by far the majority are adult astrocytic tumors (AATs). The prognosis for patients with these neoplasms is poor and the treatments modestly improves survival. In the literature, there is a fair number of studies concerning the composition of the ECM in AATs, while the number of studies relating the composition of the ECM with the immune regulation is smaller. Circulating ECM proteins have emerged as a promising biomarker that reflect the general immune landscape of tumor microenvironment and may represent a useful tool in assessing disease activity. Given the importance it can have for therapeutic and prognostic purposes, the aim of our study is to summarize the biological properties of ECM components and their effects on the tumor microenvironment and to provide an overview of the interactions between major ECM proteins and immune cells in AATs. As the field of immunotherapy in glioma is quickly expanding, we retain that current data together with future studies on ECM organization and functions in glioma will provide important insights into the tuning of immunotherapeutic approaches.

Tumor angiogenesis, the formation of new blood vessels within the tumor microenvironment, is considered a hallmark of cancer progression and represents a crucial target for therapeutic intervention. The tumor microenvironment is characterized by a complex interplay between proangiogenic and antiangiogenic factors, regulating the vascularization necessary for tumor growth and metastasis. The study of angiogenesis involves a spectrum of techniques, spanning from biomarker assessment to advanced imaging modalities. This comprehensive review aims to provide insights into the molecular intricacies, regulatory dynamics, and clinical implications of tumor angiogenesis. By delving into these aspects, we gain a deeper understanding of the processes driving vascularization in tumors, paving the way for the development of novel and effective antiangiogenic therapies in the fight against cancer.

Like most phosphinic acids, the potent and selective RXP03 inhibitor of different MMPs exhibited moderate absorption and low bioavailability, which impaired its use. In an unprecedented attempt, we present an interesting synthetic approach to a new class of phosphinate prodrug, glycosyl ester of RXP03, to provide a potentially improved blood-brain barrier (BBB) behavior compared to the former lead compound RXP03. To validate this speculation, a predictive study for permeability enhancer of glycosyl ester of RXP03 showed encouraging insights to improve drug delivery across biological barriers.

Abdominal aortic aneurysm (AAA) is a critical, multifactorial cardiovascular disorder marked by localized dilatation of the abdominal aorta. A major challenge to countering the pathophysiology of AAAs lies in the naturally irreversible breakdown of elastic fibers in the aorta wall, which is linked to the poor elastogenicity of adult and diseased vascular smooth muscle cells (SMCs) and their impaired ability to assemble mature elastic fibers in a chronic proteolytic tissue milieu. We have previously shown that these are downstream effects of neutrophil elastase-induced activation of the epidermal growth factor receptor (EGFR) activity in aneurysmal SMCs. The novelty of this study lies in investigating the benefits of an EGFR inhibitor drug, afatinib (used to treat nonsmall cell lung cancer), for proelastogenic and antiproteolytic stimulation of aneurysmal SMCs. In in vitro cell cultures, we have shown that safe doses of 0.5 and 1 nM afatinib inhibit EGFR and p-extracellular signal-regulated kinases 1/2 protein expression by 50-70% and downstream elastolytic matrix metalloprotease 2 (MMP2) versus untreated control cultures. In addition, elastin production on a per cell basis was significantly upregulated by afatinib doses within the 0.1-1 nM dose range, which was further validated through transmission electron microscopy showing significantly increased presence of tropoelastin coacervates and maturing elastic fibers upon afatinib treatment at the above doses. Therefore, our studies for the first time demonstrate the therapeutic benefits of afatinib toward use for elastic matrix repair in small AAAs.

[This corrects the article DOI: 10.3389/fimmu.2023.1089001.].

The ectodomain of the transmembrane protein E-cadherin can be cleaved and released in a soluble form referred to as soluble E-cadherin, or sE-cad, accounting for decreased E-cadherin levels at the cell surface. Among the proteases implicated in this cleavage are matrix metalloproteases (MMP), including MMP9. Opposite functions have been reported for full-length E-cadherin and sE-cad. In this study, we found increased MMP9 levels in the media of two non-small cell lung cancer (NSCLC) cell lines, A549 and H1299, treated with BDNF, nicotine, or epinephrine that were decreased upon cell treatment with the β-adrenergic receptor blocker propranolol. Increased MMP9 levels correlated with increased sE-cad levels in A549 cell media, and knockdown of MMP9 in A549 cells led to downregulation of sE-cad levels in the media. Previously, we reported that A549 and H1299 cell viability increased with nicotine and/or BDNF treatment and decreased upon treatment with propranolol. In investigating the function of sE-cad, we found that immunodepletion of sE-cad from the media of A549 cells untreated or treated with BDNF, nicotine, or epinephrine reduced activation of EGFR and IGF-1R, decreased PI3K and ERK1/2 activities, increased p53 activation, decreased cell viability, and increased apoptosis, while no effects were found using H1299 cells under all conditions tested.

Matrix metalloproteinase-9 (MMP-9) is an endopeptidase that remodels the extracellular matrix. MMP-9 has been implicated in several diseases including neurodegeneration, arthritis, cardiovascular diseases, fibrosis and several types of cancer, resulting in a high demand for MMP-9 inhibitors for therapeutic purposes. For such drug design efforts, large amounts of MMP-9 are required. Yet, the catalytic domain of MMP-9 (MMP-9Cat) is an intrinsically unstable enzyme that tends to auto-cleave within minutes, making it difficult to use in drug design experiments and other biophysical studies. We set our goal to design MMP-9Cat variant that is active but stable to auto-cleavage. For this purpose, we first identified potential auto-cleavage sites on MMP-9Cat using mass spectroscopy and then eliminated the auto-cleavage site by predicting mutations that minimize auto-cleavage potential without reducing enzyme stability. Four computationally designed MMP-9Cat variants were experimentally constructed and evaluated for auto-cleavage and enzyme activity. Our best variant, Des2, with 2 mutations, was as active as the wild-type enzyme but did not exhibit auto-cleavage after 7 days of incubation at 37°C. This MMP-9Cat variant, with an identical with MMP-9Cat WT active site, is an ideal candidate for drug design experiments targeting MMP-9 and enzyme crystallization experiments. The developed strategy for MMP-9CAT stabilization could be applied to redesign other proteases to improve their stability for various biotechnological applications.

Chronic wounds (CWs) are a growing issue for the health care system. Their treatment requires a synergic approach to reduce both inflammation and the bacterial burden. In this work, a promising system for treating CWs was developed, comprising cobalt-lignin nanoparticles (NPs) embedded in a supramolecular (SM) hydrogel. First, NPs were obtained through cobalt reduction with phenolated lignin, and their antibacterial properties were tested against both Gram-negative and Gram-positive strains. The anti-inflammatory capacity of the NPs was proven through their ability to inhibit myeloperoxidase (MPO) and matrix metalloproteases (MMPs), which are enzymes involved in the inflammatory process and wound chronicity. Then, the NPs were loaded in an SM hydrogel based on a blend of α-cyclodextrin and custom-made poly(ether urethane)s. The nano-enabled hydrogel showed injectability, self-healing properties, and linear release of the loaded cargo. Moreover, the SM hydrogel\'s characteristics were optimized to absorb proteins when in contact with liquid, suggesting its capacity to uptake harmful enzymes from the wound exudate. These results render the developed multifunctional SM material an interesting candidate for the management of CWs.

UNASSIGNED: In this study, we investigated the therapeutic potential of vitamin D (VITD) in OA Wistar rats induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT + MMx). In ACLT + MMx-induced OA rats, pain severity, cartilage destruction, inflammatory cytokines, and MMPs were all measured.
UNASSIGNED: ACLT + MMx methods were used to induce OA, and pain behavioral studies such as the weight bearing test and paw withdrawal test were performed while the knee width and body weights were also measured. Furthermore, Hematoxylin and Eosin (H&E) staining was used to determine knee histopathological studies, as well as OARSI scoring, cartilage thickness, cartilage width, and cartilage degradation scores. The enzyme-linked immunosorbent assay (ELISA) studies were used to check the serum levels of VITD, C-telopeptide of Type II collagen (CTX-II), and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and anti-inflammatory cytokines interleukin-10 (IL-10), and MMPs (MMP-3, MMP-9, and MMP-13). Finally, the reverse transcription polymerase chain reaction (RT-PCR) test was used to determine the levels of MMPs, nuclear factor-kappa B (NF-κB), TNF-α, IL-6, and IL-10 in IL-1β stimulated chondrocytes.
UNASSIGNED: The oral VITD supplement significantly reduced OA pain, inflammation, cartilage destruction, and MMPs levels. Furthermore, serum VITD levels increased while CTX-II levels decreased, indicating that VITD reduced cartilage degradation effectively. Moreover, VITD supplementation reduced the expression of pro-inflammatory TNF-α, IL-1β, and IL-6 cytokines while increasing the expression of anti-inflammatory IL-10. The elevation of MMPs after ACLT + MMx surgery contributed to articular cartilage destruction, which was reduced by VITD supplementation. Finally, VITD supplementation significantly reduces serum levels of MMPs, IL-1β, TNF-α, and IL-6 while increasing IL-10 levels. Then, using the in-vitro cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) MTT assay, examine the cytotoxicity profile of VITD in rat chondrocytes after stimulated with IL-1β, which shows no toxicity in the dose range of VITD 0-500 IU. Finally, RT-PCR studies in IL-1β stimulated rat chondrocytes revealed that VITD (50, 100, and 500 IU) significantly reduced the mRNA levels of MMPs, NF-κB, TNF-α, and IL-6, while increasing IL-10 levels, indicating that VITD reduced chondrocyte destruction and overcame harsh conditions in a dose-dependent manner.
UNASSIGNED: Overall, the in vivo and in vitro findings show that VITD effectively reduces OA pain, inflammation, and chondrocyte destruction by lowering MMPs levels specifically.

The extracellular matrix (ECM) is a ubiquitous member of the body and is key to the maintenance of tissue and organ integrity. Initially thought to be a bystander in many cellular processes, the extracellular matrix has been shown to have diverse components that regulate and activate many cellular processes and ultimately influence cell phenotype. Importantly, the ECM\'s composition, architecture, and stiffness/elasticity influence cellular phenotypes. Under normal conditions and during development, the synthesized ECM constantly undergoes degradation and remodeling processes via the action of matrix proteases that maintain tissue homeostasis. In many pathological conditions including fibrosis and cancer, ECM synthesis, remodeling, and degradation is dysregulated, causing its integrity to be altered. Both physical and chemical cues from the ECM are sensed via receptors including integrins and play key roles in driving cellular proliferation and differentiation and in the progression of various diseases such as cancers. Advances in \'omics\' technologies have seen an increase in studies focusing on bidirectional cell-matrix interactions, and here, we highlight the emerging knowledge on the role played by the ECM during normal development and in pathological conditions. This review summarizes current ECM-targeted therapies that can modify ECM tumors to overcome drug resistance and better cancer treatment.