It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a ...risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment.
Chronic inflammatory events appear to play a fundamental role in Alzheimer's disease (AD)-related neuropathological changes, and to result in neuronal dysfunction and death. The inflammatory ...responses observed in the AD brain include activation and proliferation of glial cells, together with up-regulation of inflammatory mediators and of free radicals. Along with glial cells, neurons themselves can also react and contribute to neuroinflammatory changes in the AD brain, by serving as sources of inflammatory mediators. Because excess cholesterol cannot be degraded in the brain, it must be excreted from that organ as cholesterol oxidation products (oxysterols), in order to prevent its accumulation. Among risk factors for this neurodegenerative disease, a mechanistic link between altered cholesterol metabolism and AD has been suggested; oxysterols appear to be the missing linkers between the two, because of their neurotoxic effects. This study shows that 24-hydroxycholesterol, 27-hydroxycholesterol, and 7β-hydroxycholesterol, the three oxysterols potentially implicated in AD pathogenesis, induce some pro-inflammatory mediator expression in human neuroblastoma SH-SY5Y cells, via Toll-like receptor-4/cyclooxygenase-2/membrane bound prostaglandin E synthase (TLR4/COX-2/mPGES-1); this clearly indicates that oxysterols may promote neuroinflammatory changes in AD. To confirm this evidence, cells were incubated with the anti-inflammatory flavonoid quercetin; remarkably, its anti-inflammatory effects in SH-SY5Y cells were enhanced when it was loaded into β-cyclodextrin-dodecylcarbonate nanoparticles, versus cells pretreated with free quercetin. The goal of loading quercetin into nanoparticles was to improve its permeation across the blood-brain barrier into the brain, and its bioavailability to reach target cells. The findings show that this drug delivery system might be a new therapeutic strategy for preventing or reducing AD progression.
Regular consumption of moderate doses of wine is an integral part of the Mediterranean diet, which has long been considered to provide remarkable health benefits. Wine's beneficial effect has been ...attributed principally to its non-alcoholic portion, which has antioxidant properties, and contains a wide variety of phenolics, generally called polyphenols. Wine phenolics may prevent or delay the progression of intestinal diseases characterized by oxidative stress and inflammation, especially because they reach higher concentrations in the gut than in other tissues. They act as both free radical scavengers and modulators of specific inflammation-related genes involved in cellular redox signaling. In addition, the importance of wine polyphenols has recently been stressed for their ability to act as prebiotics and antimicrobial agents. Wine components have been proposed as an alternative natural approach to prevent or treat inflammatory bowel diseases. The difficulty remains to distinguish whether these positive properties are due only to polyphenols in wine or also to the alcohol intake, since many studies have reported ethanol to possess various beneficial effects. Our knowledge of the use of wine components in managing human intestinal inflammatory diseases is still quite limited, and further clinical studies may afford more solid evidence of their beneficial effects.
The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled "Advancing Animal Models for Antibacterial Drug Development" on 5 March 2020. The workshop mainly focused on models of ...pneumonia caused by
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The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.
The Francisella tularensis live vaccine strain (LVS), in contrast to its iglC mutant, replicates in the cytoplasm of macrophages. We studied the outcome of infection of the murine macrophagelike cell ...line J774A.1 with LVS and with iglC, iglD, and mglA mutants, the latter of which is deficient in a global regulator. Compared to LVS, all of the mutants showed impaired intracellular replication up to 72 h, and the number of the mglA mutant bacteria even decreased. Colocalization with LAMP-1 was significantly increased for all mutants compared to LVS, indicating an impaired ability to escape into the cytoplasm. A lysosomal acidity-dependent dye accumulated in approximately 40% of the vacuoles containing mutant bacteria but not at all in vacuoles containing LVS. Preactivation of the macrophages with gamma interferon inhibited the intracellular growth of all strains and significantly increased acidification of phagosomes containing the mutants, but it only slightly increased the LAMP-1 colocalization. The intracellular replication and phagosomal escape of the iglC and iglD mutants were restored by complementation in trans. In conclusion, the IglC, IglD, and MglA proteins each directly or indirectly critically contribute to the virulence of F. tularensis LVS, including its intracellular replication, cytoplasmic escape, and inhibition of acidification of the phagosomes.
Influenza hemagglutinin (HA) is considered a major protective antigen of seasonal influenza vaccine but antigenic drift of HA necessitates annual immunizations using new circulating HA versions. Low ...variation found within conserved non-HA influenza virus (INFV) antigens may maintain protection with less frequent immunizations. Conserved antigens of influenza A virus (INFV A) that can generate cross protection against multiple INFV strains were evaluated in BALB/c mice using modified Vaccinia virus Ankara (MVA)-vectored vaccines that expressed INFV A antigens hemagglutinin (HA), matrix protein 1 (M1), nucleoprotein (NP), matrix protein 2 (M2), repeats of the external portion of M2 (M2e) or as tandem repeats (METR), and M2e with transmembrane region and cytoplasmic loop (M2eTML). Protection by combinations of non-HA antigens was equivalent to that of subtype-matched HA. Combinations of NP and forms of M2e generated serum antibody responses and protected mice against lethal INFV A challenge using PR8, pandemic H1N1 A/Mexico/4108/2009 (pH1N1) or H5N1 A/Vietnam/1203/2004 (H5N1) viruses, as demonstrated by reduced lung viral burden and protection against weight loss. The highest levels of protection were obtained with NP and M2e antigens delivered as MVA inserts, resulting in broadly protective immunity in mice and enhancement of previous natural immunity to INFV A.
Summary
Francisella tularensis are the causative agent of the zoonotic disease, tularaemia. Among four F. tularensis subspecies, ssp. novicida (F. novicida) is pathogenic only for immunocompromised ...individuals, while all four subspecies are pathogenic for mice. This study utilized proteomic and bioinformatic approaches to identify seven F. novicida secreted proteins and the corresponding Type IV pilus (T4P) secretion system. The secreted proteins were predicted to encode two chitinases, a chitin binding protein, a protease (PepO), and a β‐glucosidase (BglX). The transcription of F. novicida pepO and bglX was regulated by the virulence regulator MglA. Intradermal infection of mice with F. novicida mutants defective in T4P secretion system or PepO resulted in enhanced F. novicida spread to systemic sites. Infection with F. novicida pepO mutants also resulted in increased neutrophil infiltration into the mouse airways. PepO is a zinc protease that is homologous to mammalian endothelin‐converting enzyme ECE‐1. Therefore, secretion of PepO likely results in increased production of endothelin and increased vasoconstriction at the infection site in skin that limits the F. novicida spread. Francisella human pathogenic strains contain a mutation in pepO predicted to abolish its secretion. Loss of PepO function may have contributed to evolution of highly virulent Francisellae.
Inflammatory reactions, known to promote tumor growth and invasion, have been found associated with colorectal carcinoma (CRC). Macrophages are the chief component of the inflammatory infiltration ...that occurs early in the progression from non-invasive to malignant tumor, with a switch from the pro-inflammatory phenotype to the tumor-promoting phenotype. Tumor and stroma are additional sources of inflammation-related molecules. The study aimed to evaluate, during colorectal carcinogenesis from benign to malignant phases: i) the trend of serum levels of IL-8, IL-6, TGFβ1, VEGF and MMPs; ii) the parallel trend of CRP serum levels; iii) derangement of the principal TGFβ1 receptors (TGFβ1RI/RII) in tumor tissues.
96 patients with colon adenomas or CRC at different stages of progression, and 17 controls, were recruited. Serum IL-8, IL-6, TGFβ1, VEGF, MMPs and CRP levels were analyzed before endoscopy or surgery. TGFβ1 receptors were evaluated in adenoma biopsies and surgically-removed colorectal adenocarcinomas. Serum levels of IL-8 in adenocarcinoma patients were increased from stage II, when also the enzymatic activity of MMP-9 increased. Of note, the increasing trend of the two serum markers was found significantly correlated. Trend of serum CRP was also very similar to that of IL-8 and MMP-9, but just below statistical significance. TGFβ1 levels were lower at stage III CRC, while IL-6 and VEGF levels had no significant variations. In tissue specimens, TGFβ1 receptors were already absent in about 50% of adenomas, and this percentage of missing receptors markedly increased in CRC stages III and IV.
Combined quantification of serum IL-8, MMP-9 and CRP, appears a reliable and advanced index of inflammation-related processes during malignant phase of colorectal carcinogenesis, since these molecules remain within normal range in colorectal adenoma bearing patients, while consistently increase in the blood of CRC patients, even if from stage II only.
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