Role of glutathionylation in infection and inflammation

Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by dierent cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses

Glutathione increase by the n-butanoyl glutathione derivative (GSH-C4) inhibits viral replication and induces a predominant Th1 immune profile in old mice infected with influenza virus

During aging, glutathione (GSH) content declines and the immune system undergoes a deficiency in the induction of Th1 response. Reduced secretion of Th1 cytokines, which is associated with GSH depletion, could weaken the host defenses against viral infections. We first evaluated the concentration of GSH and cysteine in organs of old mice; then, the effect of the administration of the N-butanoyl GSH derivative (GSH-C4) on the response of aged mice infected with influenza A PR8/H1N1 virus was studied through the determination of GSH concentration in organs, lung viral titer, IgA and IgG1/IgG2a production and Th1/Th2 cytokine profile. Old mice had lower GSH than young mice in organs. Also the gene expression of endoplasmic reticulum (ER) stress markers involved in GSH metabolism and folding of proteins, i.e. Nrf2 and PDI, was reduced. Following infection, GSH content remained low and neither infection nor GSH-C4 treatment affected Nrf2 expression. In contrast, PDI expression was upregulated during infection and appeared counterbalanced by GSH-C4. Moreover, the treatment with GSH-C4 increased GSH content in organs, reduced viral replication and induced a predominant Th1 response. In conclusion, GSH-C4 treatment could be used in the elderly to contrast influenza virus infection by inducing immune response, in particular the Th1 profile

Growth inhibition of Friend erythroleukaemia cell tumours in vivo by a synthetic analogue of prostaglandin A: an action independent of natural killer-activity.

Prostaglandins of the A series (PGAs) have been previously shown to inhibit the growth and to stimulate the differentiation of Friend erythroleukaemic cells (FLC) in vitro. In the present report we analysed the effect of PGA treatment in vitro on FLC tumorigenicity, and in vivo on FLC proliferation and on natural killer (NK) activity. PGA1 pretreatment of FLC in vitro for 5 days before inoculation into syngeneic mice slightly delayed tumour appearance, but did not significantly alter the pattern of tumour growth or mice survival, indicating that PGA1, at least in the conditions studied, did not affect FLC tumorigenicity. Daily treatment of mice with a long-acting synthetic analogue of PGA2 (16, 16 dimethyl-PGA2-methyl ester, di-M-PGA2) delayed tumour appearance, inhibited tumour growth, as measured by tumour weight and diameter, and increased the median mice survival time by 15-35%, depending on the schedule of treatment. Daily treatment with di-M-PGA2 strongly suppressed NK activity in normal mice but had no significant effect in tumour-bearing immunodepressed mice. PGA treatment of effector or target cells in vitro, or PGA added during the NK assay, had no effect on NK activity. We suggest that the chemotherapeutic effect of PGA is due to a direct action on tumour cell replication rather than to a stimulation of the host NK activity

Skeletal Anomaly Monitoring in Rainbow Trout (Oncorhynchus mykiss, Walbaum 1792) Reared under Different Conditions

The incidence of skeletal anomalies could be used as an indicator of the "quality" of rearing conditions as these anomalies are thought to result from the inability of homeostatic mechanisms to compensate for environmentally-induced stress and/or altered genetic factors. Identification of rearing conditions that lower the rate of anomalies can be an important step toward profitable aquaculture as malformed market-size fish have to be discarded, thus reducing fish farmers' profits. In this study, the occurrence of skeletal anomalies in adult rainbow trout grown under intensive and organic conditions was monitored. As organic aquaculture animal production is in its early stages, organic broodstock is not available in sufficient quantities. Non-organic juveniles could, therefore, be used for on-growing purposes in organic aquaculture production cycle. Thus, the adult fish analysed in this study experienced intensive conditions during juvenile rearing. Significant differences in the pattern of anomalies were detected between organically and intensively-ongrown specimens, although the occurrence of severe, commercially important anomalies, affecting 2-12.5% of individuals, was comparable in the two systems. Thus, organic aquaculture needs to be improved in order to significantly reduce the incidence of severe anomalies in rainbow trout

Electrophysiology Model for a Human Heart with Ischemic Scar and Realistic Purkinje Network

The role of Purkinje fibres in the onset of arrhythmias is controversial and computer simulations may shed light on possible arrhythmic mechanisms involving the Purkinje fibres. However, few computational modelling studies currently include a detailed Purkinje network as part of the model. We present a coupled Purkinje-myocardium electrophysiology model that includes an explicit model for the ischemic scar plus a detailed Purkinje network, and compare simulated activation times to those obtained by electro-anatomical mapping in vivo during sinus rhythm pacing. The results illustrate the importance of using sufficiently dense Purkinje networks in patient-specific studies to capture correctly the myocardial early activation that may be influenced by surviving Purkinje fibres in the infarct region

The Clustering of Extremely Red Objects

We measure the clustering of Extremely Red Objects (EROs) in ~8 deg^2 of the NOAO Deep Wide Field Survey Bo\"otes field in order to establish robust links between ERO z~1.2 and local galaxy z<0.1 populations. Three different color selection criteria from the literature are analyzed to assess the consequences of using different criteria for selecting EROs. Specifically, our samples are (R-K_s)>5.0 (28,724 galaxies), (I-K_s)>4.0 (22,451 galaxies) and (I-[3.6])>5.0 (64,370 galaxies). Magnitude-limited samples show the correlation length (r_0) to increase for more luminous EROs, implying a correlation with stellar mass. We can separate star-forming and passive ERO populations using the (K_s-[24]) and ([3.6]-[24]) colors to K_s=18.4 and [3.6]=17.5, respectively. Star-forming and passive EROs in magnitude limited samples have different clustering properties and host dark halo masses, and cannot be simply understood as a single population. Based on the clustering, we find that bright passive EROs are the likely progenitors of >4L^* elliptical galaxies. Bright EROs with ongoing star formation were found to occupy denser environments than star-forming galaxies in the local Universe, making these the likely progenitors of >L^* local ellipticals. This suggests that the progenitors of massive >4L^* local ellipticals had stopped forming stars by z>1.2, but that the progenitors of less massive ellipticals (down to L^*) can still show significant star formation at this epoch.Comment: 19 pages, 16 figures, 4 tables, Accepted to ApJ 27th November 201

Non-B HIV type 1 subtypes among men who have sex with men in Rome, Italy

An increase in the circulation of HIV-1 non-B subtypes has been observed in recent years in Western European countries. Due to the lack of data on the circulation of HIV-1 non-B subtypes among European HIV-1-infected men who have sex with men (MSM), a biomolecular study was conducted in Rome, Italy. HIV-1 partial pol gene sequences from 111 MSM individuals (76 drug naive and 35 drug experienced) were collected during the years 2004-2006. All these sequences were analyzed using the REGA HIV-1 Subtyping Tool, and aligned using CLUSTAL X followed by manual editing using the Bioedit software. A BLAST search for non-B subtype sequences was also performed. Twenty-six (23.4%) MSM were not Italians. Eight individuals (7.2%) were diagnosed as HIV infected before 1991, 20 (18.0%) between 1991 and 1999, and 83 (74.8%) from 2000 to 2006. Fifteen (15/111, 13.5%) individuals were infected with the non-B subtype. The percentage of infection with HIV-1 non-B subtypes was 8.2% (7/85) among Italian MSM and 30.8% (8/26) among the non-Italians (OR = 4.95 95% IC: 1.40-17.87). Individuals infected with the non-B subtype were significantly younger than those infected with the HIV-1 B subtype (28 years vs. 34 years, p = 0.003). The CRFs were more prevalent (8.1%) than pure subtypes (5.4%), which were distributed as follows: subtype C (2.6%), subtype A1 (1.7%), and subtype F1 (0.9%). Major mutations conferring resistance to antiretroviral drugs (ARV) were not found among HIV-1 non-B subtype drug-naive patients but were found in two ARV-experienced individuals. The data show that viral diversity is likely increasing in a population group that had been previously characterized by the circulation of HIV-1 subtype B. © Copyright 2009, Mary Ann Liebert, Inc

Experimental data based machine learning classification models with predictive ability to select in vitro active antiviral and non-toxic essential oils

In the last decade essential oils have attracted scientists with a constant increase rate of more than 7% as witnessed by almost 5000 articles. Among the prominent studies essential oils are investigated as antibacterial agents alone or in combination with known drugs. Minor studies involved essential oil inspection as potential anticancer and antiviral natural remedies. In line with the authors previous reports the investigation of an in-house library of extracted essential oils as a potential blocker of HSV-1 infection is reported herein. A subset of essential oils was experimentally tested in an in vitro model of HSV-1 infection and the determined IC50s and CC50s values were used in conjunction with the results obtained by gas-chromatography/mass spectrometry chemical analysis to derive machine learning based classification models trained with the partial least square discriminant analysis algorithm. The internally validated models were thus applied on untested essential oils to assess their effective predictive ability in selecting both active and low toxic samples. Five essential oils were selected among a list of 52 and readily assayed for IC50 and CC50 determination. Interestingly, four out of the five selected samples, compared with the potencies of the training set, returned to be highly active and endowed with low toxicity. In particular, sample CJM1 from Calaminta nepeta was the most potent tested essential oil with the highest selectivity index (IC50 = 0.063 mg/mL, SI &gt; 47.5). In conclusion, it was herein demonstrated how multidisciplinary applications involving machine learning could represent a valuable tool in predicting the bioactivity of complex mixtures and in the near future to enable the design of blended essential oil possibly endowed with higher potency and lower toxicity