Increased remodeling of the extracellular matrix in malignant tumors has been shown to correlate with tumor aggressiveness and a poor prognosis. This remodeling involves degradation of the original extracellular matrix (ECM) and deposition of a new tumor-supporting ECM. The main constituent of the ECM is collagen and collagen turnover mainly occurs in a sequential manner, where initial proteolytic cleavage of the insoluble fibers is followed by cellular internalization of large well-defined collagen fragments for lysosomal degradation. However, despite extensive research in the field, a lack of consensus on which cell types within the tumor microenvironment express the involved proteases still exists. Furthermore, the relative contribution of different cell types to collagen internalization is not well-established. Here, we developed quantitative ex vivo collagen degradation assays and show that the proteases responsible for the initial collagen cleavage in two murine syngeneic tumor models are matrix metalloproteinases produced by cancer-associated fibroblasts and that collagen degradation fragments are endocytosed primarily by tumor-associated macrophages and cancer-associated fibroblasts from the tumor stroma. Using tumors from mannose receptor-deficient mice, we show that this receptor is essential for collagen-internalization by tumor-associated macrophages. Together, these findings identify the cell types responsible for the entire collagen degradation pathway, from initial cleavage to endocytosis of fragments for intracellular degradation.

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

New strategies for immune modulation have shown real promise in regenerative medicine as well as the fight against autoimmune diseases, allergies, and cancer. Dendritic cells (DCs) are gatekeepers of the immune system and their ability in shaping the adaptive immune responses makes DCs ideal targets for immune modulation. Carbohydrates are abundant in different biological systems and are known to modulate DC phenotype and function. However, how simple monosaccharides instruct DC function is less well understood. In this study, we used a combinatorial array of immobilized monosaccharides to investigate how they modulate DC phenotype and function and crucially the impact of such changes on downstream adaptive immune responses. Our data show that a selection of monosaccharides significantly suppress lipopolysaccharide-induced DC activation as evidenced by a reduction in CD40 expression, IL-12 production, and indoleamine 2,3-dioxygenase activity, while inducing a significant increase in IL-10 production. These changes are indicative of the induction of an anti-inflammatory or regulatory phenotype in DCs, which was further confirmed in DC-T cell co-cultures where DCs cultured on the \'regulatory\' monosaccharide-coated surfaces were shown to induce naïve T cell polarization toward regulatory phenotype. Our data also highlighted a selection of monosaccharides that are able to promote mixed Treg and Th17 cell differentiation, a T cell phenotype expected to be highly immune suppressive. These data show the potential immunomodulatory effects of immobilized monosaccharides in priming DCs and skewing T cell differentiation toward an immune-regulatory phenotype. The ability to fine-tune immune responses using these simple carbohydrate combinations (e.g. as coatings for existing materials) can be utilized as novel tools for immune modulation with potential applications in regenerative medicine, implantable medical devices, and wound healing where reduction of inflammatory responses and maintaining immune homeostasis are desirable.

Apart from its role as a digestive and absorptive organ, the gastrointestinal (GI) tract is a vital immune organ that encompasses roughly 70 % of the total immune cells of the body. As such, the physical, chemical and nutrient composition of the diet influences overall GI function, effectively as an immune organ. With the improvement in feed technology, agro-industrial co-products that are high in fibre have been widely used as a feed ingredient in the diets of pigs and poultry. Arabinoxylan (AX) and mannan are the most abundant hemicellulosic polysaccharides present in cereal grain and co-product ingredients used in the livestock industry. When monogastric animals consume diets containing high amounts of AX and mannans, stimulation of GI immune cells may occur. This involves the activation of several cellular and molecular pathways of the immune system and requires a considerable amount of energy and nutrients to be expended by the animal, which may ultimately influence overall health and growth performance of animals. Therefore, a better understanding of the role of AX and mannan in immune modulation will be helpful in modulating untoward GI immune responses, thereby minimising nutrient and energy expenditure toward this effort. This review will summarise pertinent research on the role of oligosaccharides and polysaccharides containing AX and mannans in immune modulation in order to preserve gut integrity.

Myocardial infarction and ischemic stroke are the most frequent causes of death or disability worldwide. Due to their ability to dissolve blood clots, the thrombolytics are frequently used for their treatment. Improving the effectiveness of thrombolytics for clinical uses is of great interest. The knowledge of the multiple roles of the endogenous thrombolytics and the fibrinolytic system grows continuously. The effects of thrombolytics on the alteration of the nervous system and the regulation of the cell migration offer promising novel uses for treating neurodegenerative disorders or targeting cancer metastasis. However, secondary activities of thrombolytics may lead to life-threatening side-effects such as intracranial bleeding and neurotoxicity. Here we provide a structural biology perspective on various thrombolytic enzymes and their key properties: (i) effectiveness of clot lysis, (ii) affinity and specificity towards fibrin, (iii) biological half-life, (iv) mechanisms of activation/inhibition, and (v) risks of side effects. This information needs to be carefully considered while establishing protein engineering strategies aiming at the development of novel thrombolytics. Current trends and perspectives are discussed, including the screening for novel enzymes and small molecules, the enhancement of fibrin specificity by protein engineering, the suppression of interactions with native receptors, liposomal encapsulation and targeted release, the application of adjuvants, and the development of improved production systems.

BACKGROUND: Patients with cirrhotic ascites (PCA) are susceptible to spontaneous bacterial peritonitis (SBP) which has increased morbidity and mortality. Since some host defense aspects of peritoneal macrophages (PMф) from PCA are altered this study examined factors related to receptor-mediated phagocytosis.
METHODS: Twelve PCA were studied. PMɸ were isolated from ascitic fluid (AF) samples removed from these patients. Uptake of mannose receptor (MR)-specific ligand, fluorescein isothiocyanate-mannosylated-bovine serum albumin (FITC-man-BSA), by patients\' PMɸ and controls, a human monocytic cell line, was measured pre- and post-IL-4 treatment. Phagocytosis of FITC-labeled yeast particles by patients\' PMɸ was measured pre- and post-IL-4 treatment. Fluorescence values were obtained using a spectrofuorometer. MRC1 gene was analyzed in blood samples from PCA and controls, healthy donors, using standard polymerase chain reaction (PCR) technique.
RESULTS: Past SBP episode(s) were reported in 58.3% of patients. Mean AF volume analyzed per patient was 1.3L. PMɸ ratio in cell yield was 53.73% (SD 18.1). Mean uptake absorbance of patients\' PMф was 0.0841 (SD 0.077) compared to 0.338 (SD 0.34) of controls, P = 0.023. Following IL-4 treatment absorbance increased to 0.297 (SD 0.28) in patients\' PMф (P = 0.018 on paired sample t-test), and to 0.532 (SD 0.398 in controls (P = 0.053 on independent sample t-test). Mean phagocytosis absorbance of patients\' PMф was 0.1250 (SD 0.032) before IL-4 treatment compared to 0.2300 (SD 0.104) after (P = 0.026). PCR analysis for MRC1 gene was negative in all PCA samples compared to positive results in all controls.
CONCLUSIONS: Since decreased phagocytosis and MR uptake were enhanced post-IL-4 treatment MR downregulation pre-treatment is plausible. Negative PCR results for MRC1 might suggest an anomaly, but this awaits further ellucidation. These altered host defense findings are relevant to infection pathophysiology, and their relevance to SBP susceptibility in PCA is worth verifying.