Adenosine negatively regulates duodenal motility in mice: role of A1 and A2a receptors .

BACKGROUND AND PURPOSE: Adenosine is considered to be an important modulator of intestinal motility. This study was undertaken to investigate the role of adenosine in the modulation of contractility in the mouse duodenum and to characterize the adenosine receptor subtypes involved. EXPERIMENTAL APPROACH: RT-PCR was used to investigate the expression of mRNA encoding for A(1), A(2A), A(2B) and A(3) receptors. Contractile activity was examined in vitro as changes in isometric tension. KEY RESULTS: In mouse duodenum, all four classes of adenosine receptors were expressed, with the A(2B) receptor subtype being confined to the mucosal layer. Adenosine caused relaxation of mouse longitudinal duodenal muscle; this was antagonized by the A(1) receptor antagonist and mimicked by N(6)-cyclopentyladenosine (CPA), selective A(1) agonist. The relaxation induced by A(1) receptor activation was insensitive to tetrodotoxin (TTX) or N(ω)-nitro-l-arginine methyl ester (l-NAME). Adenosine also inhibited cholinergic contractions evoked by neural stimulation, effect reversed by the A(1) receptor antagonist, but not myogenic contractions induced by carbachol. CPA and 2-p-(2-carboxyethyl) phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680), A(2A) receptor agonist, both inhibited the nerve-evoked cholinergic contractions. l-NAME prevented only the CGS-21680-induced effects. S-(4-Nitrobenzyl)-6-thioinosine, a nucleoside uptake inhibitor, reduced the amplitude of nerve-evoked cholinergic contractions, an effect reversed by an A(2A) receptor antagonist or l-NAME. CONCLUSIONS AND IMPLICATIONS: Adenosine can negatively regulate mouse duodenal motility either by activating A(1) inhibitory receptors located post-junctionally or controlling neurotransmitter release via A(1) or A(2A) receptors. Both receptors are available for pharmacological recruitment, even if only A(2A) receptors appear to be preferentially stimulated by endogenous adenosine. LINKED ARTICLE: This article is commented on by Antonioli et al., pp. 1577–1579 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01529.

Challenges and opportunities of light-emitting diode (Led) as key to modulate antioxidant compounds in plants. a review

Plant antioxidants are important compounds involved in plant defense, signaling, growth, and development. The quantity and quality of such compounds is genetically driven; nonetheless, light is one of the factors that strongly influence their synthesis and accumulation in plant tissues. Indeed, light quality affects the fitness of the plant, modulating its antioxidative profile, a key element to counteract the biotic and abiotic stresses. With this regard, light-emitting diodes (LEDs) are emerging as a powerful technology which allows the selection of specific wavelengths and intensities, and therefore the targeted accumulation of plant antioxidant compounds. Despite the unique advantages of such technology, LED application in the horticultural field is still at its early days and several aspects still need to be investigated. This review focused on the most recent outcomes of LED application to modulate the antioxidant compounds of plants, with particular regard to vitamin C, phenols, chlorophyll, carotenoids, and glucosinolates. Additionally, future challenges and opportunities in the use of LED technology in the growth and postharvest storage of fruits and vegetables were also addressed to give a comprehensive overview of the future applications and trends of research

Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon.

Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1\u2013 300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na+-channel blocker. GLP-2 inhibitory effect was not affected by Nomega-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca2+-dependent K+ channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP7\u201328 (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a Gi/o protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by Gi protein

CONTROLLO GLICOMETABOLICO E ABITUDINI ALIMENTARI IN ADOLESCENTI CON DIABETE MELLITO TIPO 1

Background: Gli studi che hanno valutato le abitudini alimentari dei bambini e adolescenti con diabete, hanno riportato una percentuale di assunzione di carboidrati più bassa di quella minima raccomandata spesso associata ad un maggiore consumo di grassi e ad una ridotta assunzione di fibre . Alcuni studi che hanno valutato il rapporto tra composizione della dieta e controllo glicometabolico in soggetti con diabete tipo 1, hanno evidenziato che una dieta ricca di grassi e povera di fibre è associata ad un peggior controllo glicometabolico. Obiettivo: Valutare in adolescenti affetti da diabete mellito tipo 1, con diverso grado di controllo metabolico, la frequenza di consumo settimanale dei vari gruppi di alimenti e l’eventuale correlazione di questa con i valori di emoglobina glicosilata ( HbA1c). Metodo: In 43 soggetti (M/F :22/21; età 11-14 anni) suddivisi in due gruppi in rapporto al valore mediano di HbA1c ( 8,45%), sono stati raccolti i dati relativi ai consumi alimentari degli ultimi tre mesi attraverso un questionario di frequenza di consumo ed è stata considerata la frequenza di scelte alimentari settimanali per gruppo di alimenti. Risultati I soggetti con miglior controllo glicometabolico (HbA1c< 8,45%) presentavano una maggiore frequenza di consumo settimanale dei seguenti gruppi di alimenti: frutta( p<0,0001) , ortaggi (p=0,017) e legumi ( p=0,03). I soggetti con peggior controllo glicometabolico ( HbA1c > 8,45%) consumavano con maggiore frequenza alimenti appartenenti al gruppo di salumi (p=0,007), formaggi (p=0,02) e dolci /bevande zuccherate (p=0,0065). I valori di HbA1c erano inversamente correlati alla frequenza di consumo settimanale di frutta ((r – 0,65 p< 0,0001) e a quello di ortaggi( r – 0,32 p < 0,017) e direttamente correlati alla frequenza settimanale di consumo di alimenti appartenenti ai gruppi di salumi ( r 0,37 p< 0,007). Conclusioni: Il controllo glicometabolico in adolescenti con diabete tipo 1 è influenzato dalla frequenza di consumo settimanale di alimenti ricchi di fibre e di grassi animali. I principi di una san

Enniatin and Beauvericin Biosynthesis in Fusarium Species: Production Profiles and Structural Determinant Prediction

Citation: Liuzzi, V. C., Mirabelli, V., Cimmarusti, M. T., Haidukowski, M., Leslie, J. F., Logrieco, A. F., . . . Mule, G. (2017). Enniatin and Beauvericin Biosynthesis in Fusarium Species: Production Profiles and Structural Determinant Prediction. Toxins, 9(2), 17. doi:10.3390/toxins9020045Members of the fungal genus Fusarium can produce numerous secondary metabolites, including the nonribosomal mycotoxins beauvericin (BEA) and enniatins (ENNs). Both mycotoxins are synthesized by the multifunctional enzyme enniatin synthetase (ESYN1) that contains both peptide synthetase and S-adenosyl-L-methionine-dependent N-methyltransferase activities. Several Fusarium species can produce ENNs, BEA or both, but the mechanism(s) enabling these differential metabolic profiles is unknown. In this study, we analyzed the primary structure of ESYN1 by sequencing esyn1 transcripts from different Fusarium species. We measured ENNs and BEA production by ultra-performance liquid chromatography coupled with photodiode array and Acquity QDa mass detector (UPLC-PDA-QDa) analyses. We predicted protein structures, compared the predictions by multivariate analysis methods and found a striking correlation between BEA/ENN-producing profiles and ESYN1 three-dimensional structures. Structural differences in the beta strand's Asn789-Ala793 and His797-Asp802 portions of the amino acid adenylation domain can be used to distinguish BEA/ENN-producing Fusarium isolates from those that produce only ENN

A Quantitative Estimate of the Expected Shortening of the Median Isolation Period of Patients With COVID-19 After the Adoption of a Symptom-Based Strategy

A long period of isolation was observed in patients hospitalized for COVID-19 in Milan over March-September 2020 (45; IQR: 37–54 days). A significantly shorter period would have been observed by the application of May-WHO (22, IQR: 17–30 days, P < 0.001) and October-Italian (26, IQR: 21–34 days, P < 0.001) Guidelines. The adoption of the new symptom-based criteria is likely to lead to a significant reduction in the length of the isolation period with potential social, economic and psychological benefits, particularly in the younger population with mild/moderate disease and no comorbidities. In our opinion, the release from isolation after 21 days from symptoms onset, even without a PCR diagnostic test, in most cases seems the most adequate strategy that could balance precautions to prevent SARS CoV-2 transmission and unnecessary prolonged isolation or overuse of diagnostic testing

Identification of a minimum number of genes to predict triple-negative breast cancer subgroups from gene expression profiles

Background: Triple-negative breast cancer (TNBC) is a very heterogeneous disease. Several gene expression and mutation profiling approaches were used to classify it, and all converged to the identification of distinct molecular subtypes, with some overlapping across different approaches. However, a standardised tool to routinely classify TNBC in the clinics and guide personalised treatment is lacking. We aimed at defining a specific gene signature for each of the six TNBC subtypes proposed by Lehman et al. in 2011 (basal-like 1 (BL1); basal-like 2 (BL2); mesenchymal (M); immunomodulatory (IM); mesenchymal stem-like (MSL); and luminal androgen receptor (LAR)), to be able to accurately predict them. Methods: Lehman’s TNBCtype subtyping tool was applied to RNA-sequencing data from 482 TNBC (GSE164458), and a minimal subtype-specific gene signature was defined by combining two class comparison techniques with seven attribute selection methods. Several machine learning algorithms for subtype prediction were used, and the best classifier was applied on microarray data from 72 Italian TNBC and on the TNBC subset of the BRCA-TCGA data set. Results: We identified two signatures with the 120 and 81 top up- and downregulated genes that define the six TNBC subtypes, with prediction accuracy ranging from 88.6 to 89.4%, and even improving after removal of the least important genes. Network analysis was used to identify highly interconnected genes within each subgroup. Two druggable matrix metalloproteinases were found in the BL1 and BL2 subsets, and several druggable targets were complementary to androgen receptor or aromatase in the LAR subset. Several secondary drug–target interactions were found among the upregulated genes in the M, IM and MSL subsets. Conclusions: Our study took full advantage of available TNBC data sets to stratify samples and genes into distinct subtypes, according to gene expression profiles. The development of a data mining approach to acquire a large amount of information from several data sets has allowed us to identify a well-determined minimal number of genes that may help in the recognition of TNBC subtypes. These genes, most of which have been previously found to be associated with breast cancer, have the potential to become novel diagnostic markers and/or therapeutic targets for specific TNBC subsets

Diagnostic and Therapeutic Approach to Sleep Disorders, High Blood Pressure and Cardiovascular Diseases: A Consensus Document by the Italian Society of Hypertension (SIIA)

Hypertension is a major contributor to fatal/nonfatal cardiovascular diseases, and timely identification and appropriate management of factors affecting hypertension and its control are mandatory public health issues. By inducing neurohormonal alterations and metabolic impairment, sleep disorders have an impact on a variety of cardiovascular risk factors, including hypertension, and ultimately increase the risk of cardiovascular events. There is evidence that qualitative and quantitative sleep disorders are associated with resistant hypertension and with impaired circadian blood pressure variations. However, sleep disturbances are often unrecognized, or heterogeneity exists in their management by non-specialists in the field. This document by the Italian Society of Hypertension summarizes the updated evidence linking sleep disorders to hypertension and cardiovascular diseases, the major underlying mechanisms, and the possible management strategies. A simplified, evidence-based diagnostic and therapeutic algorithm for comorbid hypertension and common sleep disorders, namely obstructive sleep apnoea and insomnia, is proposed

Effectiveness of Golimumab as Second Anti-TNFα Drug in Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Axial Spondyloarthritis in Italy: GO-BEYOND, a Prospective Real-World Observational Study

In this prospective observational study, data were collected from 34 rheumatology clinics in Italy in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) who started golimumab (GLM) as a second anti-TNFα drug. The primary objective was to evaluate the effectiveness of GLM after 6 months. Changes in quality of life using the EQ-5D-5L were also assessed. A total of 194 patients aged 53.2 ± 12 years started GLM as a second anti-TNF drug: 39 (20.1%) with RA, 91 (46.9%) with PsA and 64 (32.9%) with axSpA. After 6 months of GLM treatment, 68% of RA patients achieved low disease activity (LDA; DAS28-CRP ≤ 3.2), 31.9% of PsA patients achieved minimal disease activity and 32.5% of axSpA patients achieved LDA (ASDAS-CRP &lt; 2.1). Good/moderate EULAR response was achieved in 61.9% and 73.8% of patients with RA and PsA, respectively, and 16% of axSpA patients achieved a 50% improvement in BASDAI. Across all indications, improvements in disease activity measures and EQ-5D-5L domains were observed over 6 months. The main reasons for GLM interruption were lack/loss of efficacy (7.2%) or adverse events (2%). This study confirms the effectiveness of GLM as a second-line anti-TNF for the treatment of RA, PsA and axSpA in a real-world setting in Italy