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Angiotensin II, the main effector of renin angiotensin system, plays an important role in the inflammatory process and most of its effects are mediated through the AT1 receptor activation. However, the knowledge about the AT2 receptor involvement in this process is still evolving. We previously found that in an experimental model of colitis, AT2 receptor activation can contribute to the impairment of the muscle contractility in vitro in the course of inflammation. Here, we investigated the potential alleviating effects of the in vivo treatment of PD123319 (1-[[4-(Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate), AT2 receptor antagonist, in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat model of colitis. The effects of i.p PD123319 (0.3, 3 and 10 mg/kg) administration to rats subjected to intra-rectal DNBS instillation were investigated. The study revealed that the colon injury and the inflammatory signs were ameliorated by PD123319 when visualized by the histopathological examination. The colon shortening, myeloperoxidase activity, and colonic expression of IL-1β, IL-6 and iNOS were downregulated in a dose-dependent manner in DNBS-induced colitis rats treated with PD123319 and the anti-oxidant defense machinery was also improved. The mechanism of these beneficial effects was found in the ability of PD123319 to inhibit NF-κB activation induced by DNBS. The colonic contractility in inflamed tissues was also improved by PD123319 treatment. In conclusion, our data have demonstrated previously that undescribed proinflammatory effects for the AT2 receptors in DNBS-induced colitis in rats in which they are mediated likely by NF-κB activation and reactive oxygen species generation. Moreover, when the inflammatory process is mitigated by the AT2 receptor antagonist treatment, the smooth muscle is able to recover its functionality.

Background: Guanosine, a guanine-based purine, is an extracellular signaling molecule exerting anti-inflammatory and antioxidative effects in several in vivo and in vitro injury models. We aimed to investigate its protective effects on 2, 4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in rat., Methods: Rats were divided into five groups and colitis was induced by intracolonic instillation of DNBS (15 mg/rat). Guanosine (4 or 8 mg/kg) was administered for 6 days i.p. starting the day of the colitis induction. Body weight loss, stool consistency, colon weight/length, histological analysis, myeloperoxidase activity (MPO) and pro-inflammatory cytokine levels were assessed. Immunoblotting of nuclear factor-κB (NF-κB) p65 protein levels and detection of oxidative and nitrosative stress markers were also performed., Results: Guanosine, in a dose-dependent manner, significantly ameliorated the severity of DNBS-induced colitis, reducing body weight loss and diarrhea incidence, preventing the DNBS-induced macroscopic and microscopic damage to the colonic mucosa, and the MPO increase. Guanosine treatment also lowered interleukin-1β, interleukin-6, and tumor necrosis factor-α mRNA levels. Importantly, guanosine in DNBS rats down-regulated the expression of NF-κB p65 and the levels of reactive oxygen species and nitrite., Conclusions: In conclusion, guanosine exerts beneficial effects in DNBS-induced colitis in rats, through modulation of colonic inflammation, downregulating of NFκB-mediated signaling.

Background: Aβ 1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. Suppression of neuroinflammation may then represent a suitable therapeutic target in AD. We evaluated the efficacy of IFNβ1a in attenuating cognitive impairment and inflammation in an animal model of AD., Methods: A rat model of AD was obtained by intra-hippocampal injection of Aβ 1-42 peptide (23 μg/2 μl). After 6 days, 3.6 μg of IFNβ1a was given subcutaneously (s.c.) for 12 days. Using the novel object recognition (NOR) test, we evaluated changes in cognitive function. Measurement of pro-inflammatory or anti-inflammatory cytokines, reactive oxygen species (ROS), and SOD activity levels was performed in the hippocampus. Data were evaluated by one-way ANOVA with Fisher's Protected Least Significant Difference (PLSD) test., Results: We showed that treatment with IFNβ1a was able to reverse memory impairment and to counteract microglia activation and upregulation of pro-inflammatory cytokines (IL-6, IL-1β) in the hippocampus of Aβ 1-42 -injected rats. The anti-inflammatory cytokine IL-10, significantly reduced in the Aβ 1-42 animals, recovered to control levels following IFNβ1a treatment. IFNβ1a also reduced ROS and lipids peroxidation and increased SOD1 protein levels in the hippocampus of Aβ 1-42 -injected rats., Conclusion: This study shows that IFNβ1a is able to reverse the inflammatory and cognitive effects of intra-hippocampal Aβ 1-42 in the rat. Given the role played by inflammation in AD pathogenesis and the established efficacy of IFNβ1a in the treatment of inflammatory diseases of the central nervous system such as multiple sclerosis, its use may be a viable strategy to inhibit the pro-inflammatory cytokine and oxidative stress cascade associated with Aβ deposition in the hippocampus of AD patients.

Ageing is a complex process that negatively impacts the development of the different systems and its ability to function. On the other hand, the rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, seems to be different in every individual. Therefore, attempts have been made to analyse this individual age, the so-called biological age, in comparison to chronological age. Age-related changes in body function or composition that could serve as a measure of biological age and predict the onset of age-related diseases and/or residual lifetime are termed biomarkers of ageing. Such biomarkers of ageing should help on the one hand to characterise this biological age and, as age is a major risk factor in many degenerative diseases, could be subsequently used on the other hand to identify individuals at high risk of developing age-associated diseases or disabilities. Unfortunately, most of the markers under discussion are related to age-related diseases rather than to age, so none of these markers discussed in literature is a true biomarker of ageing. Hence, we discuss some disease-related biomarkers useful for a better understanding of ageing and the development of new strategies to counteract it, essential for improving the quality of life of the elderly population. Biomarkers discussed are based on immunosenescence, inflammatory responses and oxidative stress, since the review is based on data from author laboratories rather than on an extensive review of the literature. However, this kind of knowledge is useful to anti-ageing strategies aimed to slow ageing and to postpone death by preventing infectious diseases and delaying the onset of age-related diseases.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) and/or genetic factors (pro-inflammatory genotype) have been described. At the biochemical level metals such as zinc are known to accelerate the aggregation of the amyloid peptide and play a role in the control of inflammatory responses. In particular, zinc availability may regulate mRNA cytokine expression, so influencing inflammatory network phenotypic expression.

Life-long antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and proinflammatory cytokine production. A large number of studies have documented changes in zinc metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory conditions. In particular, modification of zinc plasma concentration, as well as intracellular disturbance of antioxidant intracellular pathways, has been found in aging and in some age-related diseases. Zinc deficiency is diffused in aged individuals in order to avoid meat and other high zinc content foods due to fear of cholesterol. Rather, they increase the consumption of refined wheat products that lack zinc and other critical nutrients as a consequence of the refining process. On the other hand, plasma zinc concentration is influenced by proinflammatory cytokines (IL-6 and TNF-alpha) and by metallothioneins (MT) homeostasis, which is in turn affected by proinflammatory cytokines. MT increase in aging and chronic inflammation allowing a continuous sequestration of intracellular zinc with subsequent low zinc ion availability against stressor agents and inflammation. This phenomenon leads to an impaired inflammatory/immune response in the elderly. A major target of zinc is NF-kappaB, a transcription factor critical for the expression of proinflammatory cytokines whose production is regulated by extra- and intracellular activating and inhibiting factors interacting with the regulatory elements on cytokine genes. Effects of zinc on translocation of NF-kappaB have been attributed to the suppression of phosphorylation and degradation of the inhibitory proteins (A20) that normally sequester it in the cytoplasm. Moreover, this factor and A20 are regulated by specific genes involved in inflammation and by intracellular zinc ion availability. So, it is not so surprising that zinc deficiency is constantly observed in chronic inflammation, such as in old individuals. On the other hand, cytokine genes are highly polymorphic and some of these polymorphisms are associated with atherosclerosis and diabetes type 2. Therefore, zinc turnover, via MT homeostasis, in individuals genetically predisposed to a dysregulation of the inflammatory/immune response may play a crucial role in causing possible adverse events with the appearance of age-related diseases.

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progressive activation of macrophages and related cells. This pro-inflammatory status, interacting with the genetic background, potentially triggers the onset of age-related inflammatory diseases as atherosclerosis. Thus, the analysis of polymorphisms of the genes that are key nodes of the natural immunity response might clarify the patho-physiology of age-related inflammatory diseases as atherosclerosis. On the other hand, centenarians are characterized by marked delay or escape from age-associated diseases that, on average, cause mortality at earlier ages. In addition, centenarian offspring have increased likelihood of surviving to 100 years and show a reduced prevalence of age-associated diseases, as cardiovascular disease (CVD) and less prevalence of cardiovascular risk factors. So, genes involved in CVD may play an opposite role in human longevity. Thus, the model of centenarians can be used to understand the role of these genes in successful and unsuccessful ageing. Accordingly, we report the results of several studies in which the frequencies of pro-inflammatory alleles were significantly higher in patients affected by infarction and lower in centenarians whereas age-related controls displayed intermediate values. These findings point to a strong relationship between the genetics of inflammation, successful ageing and the control of cardiovascular disease at least in men, in which these studies were performed. These data are also briefly discussed in the light of antagonistic pleiotropy theory and in order to pursuit a pharmacogenomics approach.

The present study evaluated the ability of KlamExtra®, an Aphanizomenon flos aquae (AFA) extract, to counteract metabolic dysfunctions due to a high fat diet (HFD) or to accelerate their reversion induced by switching an HFD to a normocaloric diet in mice with diet-induced obesity. A group of HFD mice was fed with an HFD supplemented with AFA (HFD-AFA) and another one was fed with regular chow (standard diet—STD) alone or supplemented with AFA (STD-AFA). AFA was able to significantly reduce body weight, hypertriglyceridemia, liver fat accumulation and adipocyte size in HFD mice. AFA also reduced hyperglycaemia, insulinaemia, HOMA-IR and ameliorated the glucose tolerance and the insulin response of obese mice. Furthermore, in obese mice AFA normalised the gene and the protein expression of factors involved in lipid metabolism (FAS, PPAR-γ, SREBP-1c and FAT-P mRNA), inflammation (TNF-α and IL-6 mRNA, NFkB and IL-10 proteins) and oxidative stress (ROS levels and SOD activity). Interestingly, AFA accelerated the STD-induced reversion of glucose dysmetabolism, hepatic and VAT inflammation and oxidative stress. In conclusion, AFA supplementation prevents HFD-induced dysmetabolism and accelerates the STD-dependent recovery of glucose dysmetabolism by positively modulating oxidative stress, inflammation and the expression of the genes linked to lipid metabolism. [ABSTRACT FROM AUTHOR]

Abstract Growing evidence suggests a link between obesity and neurodegeneration. The purpose of the present study was to explore the neuroprotective potential of glucagon-like peptide-2 (GLP-2) in the brain of high fat diet (HFD)-fed mice. Markers of inflammation and oxidative stress were analysed in the brains of obese mice chronically treated with [Gly2]-GLP-2 (teduglutide), the stable analogue of the GLP-2, and they were compared to age-matched untreated obese and lean animals. Neurodegeneration was examined by TUNEL assay. HFD feeding increased the expression of pro-inflammatory mediators (NF-kB, IL-8, TNF-α, IL-1β and IL-6), glial fibrillary acidic protein (GFAP), index of gliosis and neurodegeneration, stress marker proteins (p-ERK, Hsp60 and i-NOS), amyloid-β precursor protein (APP). [Gly2]-GLP-2 treatment significantly attenuated the HFD-induced increased expression of the various markers, as well as the higher levels of reactive oxygen species found in brains of untreated-HFD mice. Immunofluorescence confirmed that the increase of GFAP or APP in the brain cortex of HFD mice were less prominent in the [Gly2]-GLP-2 treated group. TUNEL-positive cell number in brain sections of [Gly2]-GLP-2-treated HFD-fed mice was significantly lesser in comparison with untreated-HFD animals and similar to STD fed mice. In conclusion, the results of the present study suggest that GLP-2 stable analogue improves the obesity-associated neuroinflammation and the central stress conditions, it reduces the neuronal apoptotic death, providing evidence for a neuroprotective role of the peptide. Highlights • [Gly2]-GLP-2 prevents the increased expression of inflammatory mediators and GFAP in brains of mice with diet-induced obesity. • The peptide reduces the increase in the expression of stress marker proteins) and amyloid-β precursor protein. • TUNEL-positive cell number in brain sections of [Gly2]-GLP-2-treated obese mice is lesser than untreated obese animals. • GLP-2 stable analogue improves the obesity-associated neuroinflammation and the central stress conditions and apoptosis. • GLP-2 could play a neuroprotective role. [ABSTRACT FROM AUTHOR]

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as "Cardiometabolic Disease" (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus. One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD. The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19. • There is a bidirectional impact of COVID-19 and CMD • The pathogenesis of COVID-19 dysregulates the immune response and triggeres a "cytokine storm" • Proinflammatory response is already present in CMD patients significantly affecting their health during SARS-CoV2 infection. • Targeting of inflammatory biomarkers could be promising for early identification of patients at risk of adverse outcomes [ABSTRACT FROM AUTHOR]

Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic background favoring longevity. Hence, genotypes of natural immunity should play an opposite role in atherosclerosis and longevity. Metalloproteinase (MMPs) are involved in tissue remodeling and therefore play a remarkable role in inflammation-based disease. MMPs are a family of Zn2+-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans, and elastin, which appear to play important roles in the development and progression of the atherosclerotic lesion. There is evidence indicating a role played by the MMPs in the weakening of atherosclerotic plaque which predisposes to lesion disruption. In this study we performed a genetic study on −1562C/T MMP-9 single nucleotide polymorphism (SNP) in order to discern a possible role in AMI. We analyzed the distribution of this SNP in 115 AMI patients, 123 controls, and 34 centenarians from Sicily. We found no significant differences in the genetic distribution and allelic frequency of −1562C/T MMP-9 SNP between the studied groups. The present results are not in agreement with our previous findings, strengthening our hypothesis that genetic background protection against cardiovascular disease is a relevant component of the longevity trait, at least in the generation of Italian male centenarians under study. However, present results do not exclude that differential expression of MMP-9 playing an opposite role in AMI and longevity because other kinds of regulation might be more relevant than those linked to the SNP under study. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the Central Nervous System, characterized by an inflammatory process leading to the destruction of myelin with neuronal death and neurodegeneration. In MS, lymphocytes cross the blood-brain barrier, creating inflammatory demyelinated plaques located primarily in the white matter. MS potential treatments involve various mechanisms of action on immune cells, immunosuppression, inhibition of the passage through the blood-brain barrier, and immunotolerance. Bio-nanotechnology represents a promising approach to improve the treatment of autoimmune diseases by its ability to affect the immune responses. The use of nanotechnology has been actively investigated for the development of new MS therapies. In this review, we summarize the results of the studies on natural and artificial vesicles and nanoparticles, and take a look to the future clinical perspectives for their application in the MS therapy. [ABSTRACT FROM AUTHOR]

Background: Aphanizomenon flos-aquae (AFA) is a unicellular cyanobacterium considered to be a "superfood" for its complete nutritional profile and beneficial properties. We investigated possible beneficial effects of an AFA extract, commercialized as AphaMax®, containing concentrated amount of phycocyanins and phytochrome, in 2,4 dinitrobenzensulfonic acid(DNBS)-induced colitis in rats. Methods: Effects of preventive oral treatment of AphaMax® (20, 50 or 100 mg/kg/day) in colitic rats were assessed and then macroscopic and microscopic analyses were performed to evaluate the inflammation degree. Myeloperoxidase (MPO) activity and NF-κB, pro-inflammatory citockines, cycloxygenase-2 (COX-2), and inducible NOS (iNOS) levels of expression were determined, as Reactive Oxygen Species (ROS) and nitrite levels. Results: AphaMax® treatment attenuated the severity of colitis ameliorating clinical signs. AphaMax® reduced the histological colonic damage and decreased MPO activity, NF-κB activation, as well as iNOS and COX-2 expression. AphaMax® treatment improved the altered immune response associated with colonic inflammation reducing IL-1β, IL-6 expression. Lastly, AphaMax® reduced oxidative stress, decreasing ROS and nitrite levels. Conclusions: Preventive treatment with AphaMax® attenuates the severity of the inflammation in DNBS colitis rats involving decrease of the NF-kB activation, reduction of iNOS and COX-2 expression, and inhibition of oxidative stress. Due its anti-inflammatory and antioxidant proprieties AphaMax® could be a good candidate as a complementary drug in inflammatory bowel disease (IBD) treatment. [ABSTRACT FROM AUTHOR]