SIRT3 Modulates Endothelial Mitochondrial Redox State during Insulin Resistance

Emerging evidence indicates that defects in sirtuin signaling contribute to impaired glucose and lipid metabolism, resulting in insulin resistance (IR) and endothelial dysfunction. Here, we examined the effects of palmitic acid (PA) treatment on mitochondrial sirtuins (SIRT2, SIRT3, SIRT4, and SIRT5) and oxidative homeostasis in human endothelial cells (TeloHAEC). Results showed that treatment for 48 h with PA (0.5 mM) impaired cell viability, induced loss of insulin signaling, imbalanced the oxidative status (p < 0.001), and caused negative modulation of sirtuin protein and mRNA expression, with a predominant effect on SIRT3 (p < 0.001). Restoration of SIRT3 levels by mimic transfection (SIRT3+) suppressed the PA-induced autophagy (mimic NC+PA) (p < 0.01), inflammation, and pyroptosis (p < 0.01) mediated by the NLRP3/caspase-1 axis. Moreover, the unbalanced endothelial redox state induced by PA was counteracted by the antioxidant δ-valerobetaine (δVB), which was able to upregulate protein and mRNA expression of sirtuins, reduce reactive oxygen species (ROS) accumulation, and decrease cell death. Overall, results support the central role of SIRT3 in maintaining the endothelial redox homeostasis under IR and unveil the potential of the antioxidant δVB in enhancing the defense against IR-related injuries

Strategies to reduce embryonic mortality in buffalo cows

The aim of the present study was to examine whether treatment with a GnRH agonist, hCG or P4 on Day 25 after AI increased P4 concentrations and reduced the incidence of embryonic mortality (EM) in pregnant buffaloes mated in mid-winter in a Mediterranean environment. The trial was carried out in two farms characterized, in previous years, by low (LEM Group), 153 buffaloes (DIM=150±7 days), and high (HEM Group), 284 buffaloes (DIM=163±5 days), incidence of embryo mortality. Animals were synchronized by Ovsynch-TAI Program and artificially inseminated. On day 25, pregnant buffaloes were randomly assigned to four groups: Control (no treatment), GnRH agonist (buserelin acetate, 12.6 μg), hCG (1500 IU) and P4 (341 mg of P4 i.m. every 4 days for three times). Progesterone (pg/ml) was determined in milk whey on Days 10, 20 and 25 after AI in all buffaloes and in Days 30 and 45 only in buffaloes pregnant on day 25 and assigned to four groups of treatment. Pregnancy diagnosis was undertaken on Day 45 by ultrasound. All treatments increased P4 milk whey and reduced embryonic mortality in buffalo cows bred in the farm characterized by high EM

Synthesis and biological evaluation of phosphonated dihydroisoxazole nucleosides

Phosphonated isoxazolinyl nucleosides have been prepared via 1,3-dipolar cycloaddition reaction of nitrile oxides with corresponding vinyl or allyl nucleobases for antiviral studies. The cytotoxicity, the anti-HSV activity and the RT-inhibitory activity of the obtained compounds were evaluated and compared with those of AZT and diethyl{(10SR,40RS)-10-[[(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)]-30-methyl-20-oxa-30-azacyclopent-40-yl]}methylphosphonate, a saturated phosphonated dihydroisoxazole nucleoside analogue

Milk Metabolomics Reveals Potential Biomarkers for Early Prediction of Pregnancy in Buffaloes Having Undergone Artificial Insemination.

This study aimed to identify potential biomarkers for early pregnancy diagnosis in buffaloes subjected to artificial insemination (AI). The study was carried out on 10 pregnant and 10 non-pregnant buffaloes that were synchronized by Ovsynch-Timed Artificial Insemination Program and have undergone the first AI. Furthermore, milk samples were individually collected ten days before AI (the start of the synchronization treatment), on the day of AI, day 7 and 18 after AI, and were analyzed by LC–MS. Statistical analysis was carried out by using Mass Profile Professional (Agilent Technologies, Santa Clara, CA, USA). Metabolomic analysis revealed the presence of several metabolites differentially expressed between pregnant and non-pregnant buffaloes. Among these, a total of five metabolites were identified by comparison with an online database and a standard compound as acetylcarnitine (3-Acetoxy-4-(trimethylammonio)butanoate), argininesuccinic acid hydrate, 5’-O-{[3-({4-[(3aminopropyl)amino]butyl}amino)propyl]carbamoyl}-2’deoxyadenosine, N-(1-Hydroxy-2-hexadecanyl)pentadecanamide, and N-[2,3Bis(dodecyloxy)propyl]-L-lysinamide). Interestingly, acetylcarnitine was dominant in milk samples collected from non-pregnant buffaloes. The results obtained from milk metabolic profile and hierarchical clustering analysis revealed significant differences between pregnant and non-pregnant buffaloes, as well as in the metabolite expression. Overall, the findings indicate the potential of milk metabolomics as a powerful tool to identify biomarkers of early pregnancy in buffalo undergoing AI

Synergistic effect of dietary betaines on sirt1-mediated apoptosis in human oral squamous cell carcinoma cal 27

Betaines are food components widely distributed in plants, animals, microorganisms, and dietary sources. Among betaines, δ-valerobetaine (N,N,N-trimethyl-5-aminovaleric acid, δVB) shares a metabolic pathway common to γ-butyrobetaine (γBB). The biological properties of δVB are particularly attractive, as it possesses antioxidant, anti-inflammatory and anticancer activities. Here, we investigated the possible synergism between δVB and the structurally related γBB, to date unexplored, by testing the in vitro anticancer activity in head and neck squamous cell carcinoma cell lines, FaDu, UM-SCC-17A and Cal 27. Among cell lines tested, results indicated that betaines showed the highest effect in reducing Cal 27 cell proliferation up to 72 h (p < 0.01). This effect was enhanced when betaines were administered in combination (δVB plus γBB) (p < 0.001). Inhibition of cell growth by δVB plus γBB involved reactive oxygen species (ROS) accumulation, upregulation of sirtuin 1 (SIRT1), and apoptosis (p < 0.001). SIRT1 gene silencing by small interfering RNA decreased the apoptotic effect of δVB plus γBB by modulating downstream procaspase-3 and cyclin B1 (p < 0.05). These findings might have important implications for novel prevention strategies for tongue squamous cell carcinoma by targeting SIRT1 with naturally occurring betaines

Plasma cells in the carotid plaque: occurrence and significance

OBJECTIVE: Atherosclerosis is one of the leading causes of disability and mortality worldwide. Inflammation, including monocytes, T and B cells, plays a key role in its pathogenesis. Our purpose was to evaluate plasma cells’ presence in a large series of carotid artery plaques and the clinical association. PATIENTS AND METHODS: Forty-eight consecutive patients treated with carotid endarterectomy were retrospectively analyzed to assess plasma cells’ presence inside the plaque. A semiquantitative grading score was applied, ranging from absence, scattered, clusters of 5-10, and sheets of >10 plasma cells. Plasma cell’s location, as intraplaque, subendothelial or peri-adventitial, was also defined. RESULTS: In 75% of plaques analyzed, plasma cells were detected: scattered in 63.9%, in clusters in 22.2%, and in sheets in 13.9% of cases. In all cases, plasma cells were observed only inside the plaque. In 13.9% and in 11.1% of cases, plasma cells showed, respectively, a concomitant subendothelial or peri-adventitial distribution. In 5.6% of plaques, there was a simultaneous distribution in subendothelial, peri-adventitial layer, and intraplaque. Association between the presence of symptoms and plasma cells infiltrate was found. CONCLUSIONS: Our results suggest that plasma cells could be a key parameter linked to plaque instability. Some types of configurations are significantly associated with the occurrence of cerebrovascular symptoms

Phosphonated Carbocyclic 2'-Oxa-3'-azanucleosides as New Antiretroviral Agents

Phosphonated carbocyclic 2¢-oxa-3¢-azanucleosides have been synthesized and tested for their antiretroviral activity. The obtained results have shown that some of the compounds were as powerful as azydothymidine in inhibiting the reverse transcriptase activity of the human retrovirus T-cell leukemia/lymphotropic virus type 1 and in protecting human peripheral blood mononuclear cells against human retrovirus T-cell leukemia/ lymphotropic virus type 1 transmission in vitro. These data indicate that phosphonated carbocyclic 2¢-oxa- 3¢-azanucleosides possess the necessary requirements to efficiently counteract infections caused by human retroviruses