Anti-Inflammatory activity of a polyphenolic extract from Arabidopsis thaliana in in vitro and in vivo models of Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the primary form of dementia in the elderly. One of the main features of AD is the increase in amyloid-beta (Aβ) peptide production and aggregation, leading to oxidative stress, neuroinflammation and neurodegeneration. Polyphenols are well known for their antioxidant, anti-inflammatory and neuroprotective effects and have been proposed as possible therapeutic agents against AD. Here, we investigated the effects of a polyphenolic extract of Arabidopsis thaliana (a plant belonging to the Brassicaceae family) on inflammatory response induced by Aβ. BV2 murine microglia cells treated with both Aβ25⁻35 peptide and extract showed a lower pro-inflammatory (IL-6, IL-1β, TNF-α) and a higher anti-inflammatory (IL-4, IL-10, IL-13) cytokine production compared to cells treated with Aβ only. The activation of the Nrf2-antioxidant response element signaling pathway in treated cells resulted in the upregulation of heme oxygenase-1 mRNA and in an increase of NAD(P)H:quinone oxidoreductase 1 activity. To establish whether the extract is also effective against Aβ-induced neurotoxicity in vivo, we evaluated its effect on the impaired climbing ability of AD Drosophila flies expressing human Aβ1⁻42. Arabidopsis extract significantly restored the locomotor activity of these flies, thus confirming its neuroprotective effects also in vivo. These results point to a protective effect of the Arabidopsis extract in AD, and prompt its use as a model in studying the impact of complex mixtures derived from plant-based food on neurodegenerative diseases

Hyperexpression of CDRs and HWP1 genes negatively impacts on Candida albicans virulence

C. albicans is a commensal organism present in the human microbiome of more than 60% of the healthy population. Transition from commensalism to invasive candidiasis may occur after a local or a general failure of host's immune system. This transition to a more virulent phenotype may reside either on the capacity to form hyphae or on an acquired resistance to antifungal drugs. Indeed, overexpression of genes coding drug efflux pumps or adhesins, cell wall proteins facilitating the contact between the fungus and the host, usually marks the virulence profile of invasive Candida spp. In this paper, we compare virulence of two clinical isolates of C. albicans with that of laboratory-induced resistant strains by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of drug efflux pumps genes CDR1, CDR2, MDR1 and the adhesin genes ALS1 and HWP1. Although both clinical isolates were found resistant to both fluconazole and micafungin they were found less virulent than laboratory-induced resistant strains. An unexpected behavior emerged for the former clinical isolate in which three genes, CDR1, CDR2 and HWP1, usually correlated with virulence, although hyperexpressed, conferred a less aggressive phenotype. On the contrary, in the other isolate, we observed a decreased expression of CDR1, CDR2 and HWP1as well as of MDR1 and ALS1 that may be consistent with the less aggressive performance observed in this strain. These altered gene expressions might directly influence Candida virulence or they might be an epiphenomenon of a vaster rearrangement occurred in these strains during the challenge with the host's environment. An in-deepth comprehension of this scenario could be crucial for developing interventions able to counteract C. albicans invasiveness and lethality.C. albicans is a commensal organism present in the human microbiome of more than 60% of the healthy population. Transition from commensalism to invasive candidiasis may occur after a local or a general failure of host's immune system. This transition to a more virulent phenotype may reside either on the capacity to form hyphae or on an acquired resistance to antifungal drugs. Indeed, overexpression of genes coding drug efflux pumps or adhesins, cell wall proteins facilitating the contact between the fungus and the host, usually marks the virulence profile of invasive Candida spp. In this paper, we compare virulence of two clinical isolates of C. albicans with that of laboratory-induced resistant strains by challenging G. mellonella larvae with these pathogens along with monitoring transcriptional profiles of drug efflux pumps genes CDR1, CDR2, MDR1 and the adhesin genes ALS1 and HWP1. Although both clinical isolates were found resistant to both fluconazole and micafungin they were found less virulent than laboratory-induced resistant strains. An unexpected behavior emerged for the former clinical isolate in which three genes, CDR1, CDR2 and HWP1, usually correlated with virulence, although hyperexpressed, conferred a less aggressive phenotype. On the contrary, in the other isolate, we observed a decreased expression of CDR1, CDR2 and HWP1as well as of MDR1 and ALS1 that may be consistent with the less aggressive performance observed in this strain. These altered gene expressions might directly influence Candida virulence or they might be an epiphenomenon of a vaster rearrangement occurred in these strains during the challenge with the host's environment. An in-deepth comprehension of this scenario could be crucial for developing interventions able to counteract C. albicans invasiveness and lethality

Failure and multiple failure for disease modifying antirheumatic drugs in rheumatoid arthritis: Real-life evidence from a tertiary referral center in Italy

Background rheumatoid arthritis (RA) is a chronic inflammatory disease with a heterogeneous treatments' clinical response. goals of treatment are remission and low disease activity, which are not achieved in all patients despite the introduction of early treatment and the treat to target strategy. ObjectiveTo investigate the causes of disease-modifying antirheumatic drugs (DMARDs) discontinuation and treatment failure and multiple failure for inefficacy, and to identify possible failure predictors' according to RA patient characteristics in a real-world setting. methods718 RA patients were retrospectively evaluated. Conventional synthetic (cs) and biologic (b)DMARDs treatments line/s, effectiveness, and reasons of discontinuations were evaluated. patients failing to at least two csDMARDs or bDMARDs' drug for inefficacy were defined "csDMARDs multifailure" and "bDMARDs multifailure", respectively. Discontinuation of at least two cs- and bDMARDs was termed "global multifailure". ResultsIn total, 1422 csDMARDs and 714 bDMARDs treatment were analysed. Causes of csDMARDs discontinuation were intolerance (21.8%), inefficacy (20.2%), acute adverse reactions (5.3%) and severe infections (0.6%) while csDMARDs multifailure for inefficacy was observed in 5.7% of cases. reasons of bDMARDs withdrawal were inefficacy (29%), intolerance (10.0%), acute adverse reaction (6.3%) and severe infections (1.5%). Altogether, 8.4% of patients were bDMARDs multifailure for inefficacy while 16.6% were global multifailure. longstanding disease (>= 12 months) and smoke habit, resulted as positive predictor of csDMARDs failure (OR 2.6 and OR 2.7, respectively). thyreopathy was associated with both csDMARDs failure and global multifailure (OR 2.4 and OR 1.8, respectively). Higher prevalence of failure to at least one bDMARDs and global multifailure was detected in female than male (OR 2.3 and OR 2, respectively). conclusionsdifferent causes of drug discontinuation were observed on DMARDs treatments. demographic and clinical features were identified as possible predictors of both cs- and bDMARDs treatment failure and multiple failure, underlining the need of a more personalized therapeutic approach to achieve treatment targets

Inhibition of Poly(ADP-ribose)polymerase impairs Epstein Barr Virus lytic cycle progression

<p>Abstract</p> <p>Background</p> <p>Poly(ADP-ribosylation) is a post-translational modification of nuclear proteins involved in several cellular events as well as in processes that characterize the infective cycle of some viruses. In the present study, we investigated the role of poly(ADP-ribosylation) on Epstein-Barr Virus (EBV) lytic cycle activation.</p> <p>Results</p> <p>Inhibition of PARP-1 by 3-aminobenzamide (3-ABA) during EBV induction, diminished cell damage and apoptosis in the non-productive Raji cell line while markedly reducing the release of viral particles in the productive Jijoye cells. Furthermore, incubation with 3-ABA up-regulated the levels of LMP1 and EBNA2 latent viral proteins. At the same time, it slightly affected the expression of the immediate early BZLF1 gene, but largely down-regulated the levels of the early BFRF1 protein. The modulation of the expression of both latent and lytic EBV genes appeared to be post-transcriptionally regulated.</p> <p>Conclusion</p> <p>Taken together the data indicate that PARP-1 plays a role in the progression of EBV lytic cycle and therefore, PARP inhibitors might represent suitable pharmacological adjuncts to control viral spread in EBV productive infection.</p

PARP-1 involvement in neurodegeneration: A focus on Alzheimer’s and Parkinson’s diseases

DNA damage is the prime activator of the enzyme poly(ADP-ribose)polymerase1 (PARP-1) whose overactivation has been proven to be associated with the pathogenesis of numerous central nervous system disorders, such as ischemia, neuroinflammation, and neurodegenerative diseases. Under oxidative stress conditions PARP-1 activity increases, leading to an accumulation of ADP-ribose polymers and NAD+ depletion, that induces energy crisis and finally cell death. This review aims to explain the contribution of PARP-1 in neurodegenerative diseases, focusing on Alzheimer’s and Parkinson’s disease, to stimulate further studies on this issue and thereby engage a new perspective regarding the design of possible therapeutic agents or the identification of biomarkers

Interactions of Epstein-Barr virus origins of replication with nuclear matrix in the latent and in the lytic phases of viral infection

Eukaryotic DNA is organized into domains or loops generated by the attachment of chromatin fibers to the nuclear matrix via specific regions called scaffold or matrix attachment regions. The role of these regions in DNA replication is currently under investigation since they have been found in close association with origins of replication. Also, viral DNA sequences, containing the origins of replication, have been found attached to the nuclear matrix. To investigate the functional role of this binding we have studied, in Raji cells, the interaction between Epstein-Barr virus (EBV) origins of replication and the nuclear matrix in relation to the viral cycle of infection. We report here that both the latent (ori P) and the lytic (ori Lyt) EBV origins of replication are attached to the nuclear matrix, the first during the latent cycle of infection and the second after induction of the lytic cycle. These findings suggest that the binding of the origins of replication with the nuclear matrix modulates viral replication and expression in the two different phases of infection

Co-operative interactions of oligonucleosomal DNA with the H1e histone variants and its poly (ADP-ribosyl)ated isoforms

H1 histone somatic variants from L929 mouse fibroblasts were purified by reverse-phase HPLC. We analysed the ability of each H1 histone variant to allow the H1–H1 interactions that are essential for the formation of the higher levels of chromatin structure, and we investigated the role played by the poly(ADP-ribosyl)ation process. Cross-linking analysis showed that H1e is the only somatic variant which, when bound to DNA, is able to produce H1–H1 polymers; the size of polymers was decreased when H1e was enriched in its poly(ADP-ribosyl)ated isoform. Measurement of the methyl-accepting ability in native nuclei compared with nuclei in which poly(ADP-ribosyl)ation was induced showed that the poly(ADP-ribosyl)ated H1 histone had not been removed from linker regions, in spite of its different interaction with DNA