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Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder emerging in early life characterized by impairments in social interaction, poor verbal and non-verbal communication, and repetitive patterns of behaviors. Among the best-known genetic risk factors for ASD, there are mutations causing the loss of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) leading to Fragile X syndrome (FXS), a common form of inherited intellectual disability and the leading monogenic cause of ASD. Being a pivotal regulator of motor activity, motivation, attention, and reward processing, dopaminergic neurotransmission has a key role in several neuropsychiatric disorders, including ASD. Fmr1Δexon 8 rats have been validated as a genetic model of ASD based on FMR1 deletion, and they are also a rat model of FXS. Here, we performed behavioral, biochemical and in vivo SPECT neuroimaging experiments to investigate whether Fmr1Δexon 8 rats display ASD-like repetitive behaviors associated with changes in striatal dopamine transporter (DAT) availability assessed through in vivo SPECT neuroimaging. At the behavioral level, Fmr1Δexon 8 rats displayed hyperactivity in the open field test in the absence of repetitive behaviors in the hole board test. However, these behavioral alterations were not associated with changes in striatal DAT availability as assessed by non-invasive in vivo SPECT and Western blot analyses. [ABSTRACT FROM AUTHOR]

The article focuses on the crosstalk between bone marrow stromal cells (BMSCs) and acute myeloid leukemia (AML) cells in response to proteotoxic stress-induced AML cell death, highlighting the role of BMSCs in AML therapy resistance and the potential use of ascorbic acid.

Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase, which catalyzes the conjugation between glutathione and platinum( II)-containing drugs. Therefore, we evaluated the effect of the strong glutathione S-transferase inhibitor NBDHEX on human mesothelioma cell lines ( MSTO-211H, MPP89, MM- B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC50 values in the low micromolar range ( IC50 between 1 and 4 μ M). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy. [ABSTRACT FROM AUTHOR]

The cannabinoid receptor type 2 (CB2) is the peripheral receptor for cannabinoids, involved in the homeostatic control of several physiological functions. Male mitotic germ cells express a high level of CB2, whose activation promotes their differentiation in both in vitro and in vivo experiments, controlling the correct progression of spermatogenesis. However, it remains elusive if CB2 activation in spermatogonia could affect reproductive success in terms of fertility and healthy pregnancy outcomes. In this study, we explored the effects of male CB2 activation on sperm number and quality and its influence on next generation health. We show that exposure of male mice to JWH-133, a selective CB2 agonist, decreased sperm count, impaired placental development and reduced offspring growth. These defects were associated with altered DNA methylation/hydroxymethylation levels at imprinted genes in sperm and conserved in placenta. Our findings reveal that paternal selective activation of CB2 alters the sperm epigenome and compromises offspring growth. This study demonstrates, for the first time, a new role of CB2 signaling in male gametes in causing epigenetic alterations that can be transmitted to the next generation by sperm, highlighting potential risks induced by recreational cannabinoid exposure. [ABSTRACT FROM AUTHOR]

Background: This pilot study aimed to ascertain whether the local application of ascorbic acid (AA), of T3, and of rat (r) bone marrow mesenchymal stem cells (BMSCs), alone or in all possible combinations, promoted healing after an Achilles tendon injury in a rat model. Methods: An Achilles tendon defect was produced in 24 6–8-week-old male inbred Lewis rats. The animals were then randomly divided into eight groups of three rats each. The tendon defect was filled with 50 μL of phosphate-buffered saline (PBS) containing (1) 50 μg/mL AA (AA group), (2) 10−7 M T3 (T3 group), (3) 4 × 106 rBMSCs (rBMSC group), (4) 50 μg/mL AA + 10−7 M T3 (AA + T3 group), (5) 4 × 106 rBMSCs + 50 μg/mL AA (rBMSC + AA group), (6) 4 × 106 rBMSCs + 10−7 M T3 (rBMSC + T3 group), (7) 4 × 106 rBMSCS + 50 μg/mL AA + 10−7 M T3 (rBMSC + AA + T3 group), and (8) PBS only (control group: CTRL). All treatments were administered by local injection immediately after the tendons had been damaged; additionally, AA was injected also on the second and fourth day from the first injection (for groups 1, 4, 5, and 7), and T3 was injected again every day for 4 days (for groups 2, 4, 6, and 7). At 30 days from initial treatment, tendon samples were harvested, and the quality of tendon repair was evaluated using histological and histomorphological analysis. The structure and morphology of the injured Achilles tendons were evaluated using the modified Svensson, Soslowsky, and Cook score, and the collagen type I and III ratio was calculated. Results: The group treated with AA combined with T3 displayed the lowest Svensson, Soslowsky, and Cook total score value of all tissue sections at histopathological examination, with fiber structure close to regular orientation, normal-like tendon vasculature, and no cartilage formation. AA + T3 also showed the highest collagen I and the lowest collagen III values compared to all other treatments including the CTRL. Conclusion: There are potential benefits using a combination of AA and T3 to accelerate tendon healing. [ABSTRACT FROM AUTHOR]

Examines the elevation of circulating tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in HIV type-1 infection. Contribution of the overproduction of cytokines to AIDS pathogenesis; Expression of TNF-alpha and IL-6 in human macrophages; Response of TNF-alpha and IL-6 to lipopolysaccharide stimulation.

Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound extracted from honey, plants and propolis. It possesses anti-inflammatory activity, anti-oxidant properties and promotes cell death by perturbing cell cycle progression. In this study, our attention focused on the possible role that chrysin may have as a potential anti-cancer agent, and we tested its biological activity in murine and human melanoma cell lines (B16-F1 and A375). This study demonstrated that chrysin reduced melanoma cell proliferation and induced cell differentiation in both human and murine melanoma cells through synthesis increase and intracellular accumulation of protoporphirin IX (PpIX). Furthermore, following treatments with chrysin an increase in the expression of porphobilinogen deaminase (PBG-D) was noted. This study demontrated also that chrysin induces cell death in human and murine melanoma cells through caspase-dependent mechanisms, involving down-regulation of ERK 1/2, and activation of p38 MAP kinases. Induction of cell death may be a promising therapeutic approach in cancer therapy. Our results suggest that chrysin may be considered a potential candidate for both cancer prevention and treatment.

Honey has long been used in medicine for different purposes. Only recently, however, its antioxidant property and preventive effects against different diseases, such as cancer, have been highlighted. Chrysin (5,7-dihydroxyflavone) is a natural flavone commonly found in acacia honey. It has previously been shown to be an anti-tumor agent. In this study, we investigated the antiproliferative role of honey or chrysin on human (A375) and murine (B16-F1) melanoma cell lines. The results of the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and the trypan blue exclusion test showed that both the tested compounds were able to induce an antiproliferative effect on melanoma cells in a dose- and time-dependent manner. Flow cytometry analysis indicated that cytotoxicity induced by honey or chrysin was mediated by G(0)/G(1) cell cycle arrest and induction of hyperploid progression. Our results suggest that the anti-proliferative effects of honey are due mainly to the presence of chrysin. Chrysin may therefore be considered a potential candidate for both cancer prevention and treatment. Further investigation is needed to validate the contribution of chrysin in tumor therapy in vivo.

HIV-1 infection causes a severe T-cell impairment with alteration of immune response. However, in children the natural decline of lymphocytes and CD4 cells in early life makes it more difficult to monitor immunocompetence and progression of HIV-infection. Aim of this study was to characterize the CD8 response in non-vertically HIV-infected children exposed persistently to viremia and in HIV-infected children controlling efficiently viremia by ART, by analysing the effect of persistent viremia on CD4 and CD8 T-cells count, HIV-specific immune-response and naive/memory pattern of CD8 T-cell. Whereas, no differences of CD4 count between viremic patients and viral controllers were observed (1046.9 +/- 472.1 cells/microl vs 1101.3 +/- 415.4 cells/microl; p > 0.05), CD8 count was higher in the viremic patients (1080.6 +/- 652.1 cells/microl vs 747.5 +/- 389.9 cells/microl, p < 0.05). In viremic patients, HIV-specific CD8 T-cells correlated with viral load. However, in this group a loss of HIV-specific CD8 response was associated with a 7 fold decrease of naïve and increase of pre-effector CD8 T-cells (62.8% +/- 10.21% vs 10.37% +/- 7.91%, p < 0.03). Persistent exposure to viremia alters HIV-specific CD8 response possibly through a persistent immune activation process leading to exhaustion of naive CD8 T-cells and skewed maturation of memory subset. Therefore, memory CD8 T-cells might lose the ability to respond correctly and efficiently to HIV-antigen exposure.

In this study, the processes of differentiation and melanogenesis induced by 5,7-dimethoxycoumarin in murine (B16) and human (A375) melanoma cells were investigated. Taking into account the previously demonstrated antiproliferative and differentiation activities of this compound, we examined Ras/Raf/Mek/Erk mitogen-activated protein kinase activity following treatment; inhibition of Mek 1/2 kinase activity and subsequent reduction in Erk 1/2 activation were detected in both cell types. We observed melanogenesis induction associated to an increase in cAMP-response element-binding protein (CREB) and microphthalmia-associated transcription factor (Mitf) expression, both involved in its regulation. Mitf is fundamental for development, survival and differentiation of melanocyte and melanoma, since it regulates transcription of genes encoding for proteins involved in cell cycle progression or in melanogenesis, such as the enzyme tyrosinase. A significant increase of tyrosinase activity was revealed following treatment in B16 but not in A375 cells, although a strong synthesis of melanin was induced by 5,7-dimethoxycoumarin in both cell lines. The treatment induced protoporphyrine IX accumulation involved in melanogenesis since it promotes stability of cAMP. Finally, the Mek 1/2 inhibitor U0126 significantly potentiated growth inhibition of B16 cells triggered by 5,7-dimethoxycoumarin, suggesting that down-regulation of Raf/Mek/Erk pathway sensitizes melanoma cells to 5,7-dimethoxycoumarin treatment.