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Background: Ethanol (EtOH) exposure during pregnancy may result in fetal alcohol spectrum disorders (FASD). One of the most deleterious consequences of EtOH exposure is neuronal loss in the developing brain. Previously, we showed that EtOH exposure induced neuroapoptosis in the brain of postnatal day 4 (PD4) mice but not PD12 mice. This differential susceptibility may result from an insufficient cellular stress response system such as unfolded protein response (also known as endoplasmic reticulum [ER] stress) in PD4 mice. In this study, we compared the effect of EtOH on ER stress in PD4 and PD12 mice and determined whether the inhibition of ER stress could protect the developing brain against EtOH damage. Methods: We used a third‐trimester equivalent mouse model of FASD. PD4 and PD12 C57BL/6 mice were subcutaneously injected with saline (control), EtOH, EtOH plus 4‐phenylbutyric acid (4‐PBA), a chemical chaperone known as ER stress inhibitor, and 4‐PBA alone. The expression of apoptosis marker, ER stress markers, and markers for glial cell activation was examined in the cerebral cortex. Results: EtOH induced neuroapoptosis and increased the expression of ER stress markers, such as activating transcription factor 6, 78‐kDa glucose‐regulated protein, inositol‐requiring enzyme 1α, mesencephalic astrocyte‐derived neurotrophic factor, and caspase‐12 in PD4 but not PD12 mice. EtOH exposure also activated microglia and astrocytes. Interestingly, treatment with 4‐PBA attenuated EtOH‐induced neuroapoptosis. Moreover, 4‐PBA inhibited the expression of the aforementioned ER stress markers and EtOH‐induced glial activation in PD4 mice. Conclusions: ER stress plays an important role in EtOH‐induced damage to the developing brain. Inhibition of ER stress is neuroprotective and may provide a new therapeutic strategy for treating FASD. [ABSTRACT FROM AUTHOR]

OY-TES-1 is a member of the CTA (cancer-testis antigen) group expressed in a variety of cancer and restrictedly expressed in adult normal tissues, except for testis. To determine whether MSCs (mesenchymal stem cells) express OY-TES-1 and its possible roles on MSCs, OY-TES-1 expression in MSCs isolated from human bone marrow was tested with RT (reverse transcription)-PCR, immunocytochemistry and Western blot. Using RNAi (RNA interference) technology, OY-TES-1 expression was knocked down followed by analysing cell viability, cell cycle, apoptosis and migration ability. MSCs expressed OY-TES-1 at both mRNA and protein levels. The down-regulation of OY-TES-1 expression in these MSCs caused cell growth inhibition, cell cycle arrest, apoptosis induction and migration ability attenuation. Through these primary results it was suggested that OY-TES-1 may influence the biological behaviour of MSCs. [ABSTRACT FROM AUTHOR]

Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound DPPA-1 could bind PD-L1 at an affinity of 0.51 μ M in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that DPPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Our previous studies showed that protein phosphatase 1 γ (PP1 γ) exacerbates cardiomyocyte apoptosis through promotion of Ca2+/calmodulin-dependent protein kinase δ (CaMKII δ) splicing. Here we determine the role of PP1 γ in abdominal aorta constriction-induced hypertrophy and remodelling in rat hearts. Systolic blood pressure and echocardiographic measurements were used to evaluate the model of cardiac hypertrophy. Sirius red staining and invasive haemodynamic/cardiac index measurements were used to evaluate the effects of PP1 γ or inhibitor 1 of PP1 transfection. Western blot, reverse transcription polymerase chain reaction and co-immunoprecipitation were applied to investigate the molecular mechanisms. Transfection of PP1 γ increased the value of the heart mass index, left ventricular mass index and cardiac fibrosis, and simultaneously decreased the value of maximal left ventricular pressure increase and decline rate, ejection fraction, fractional shortening, and left ventricular end-diastolic pressure, as well as left ventricular systolic pressure. Transfection of inhibitor 1 of PP1, however, showed opposite effects on the aforementioned indexes. Overexpression of PP1 γ potentiated CaMKII δC production and decreased CaMKII δB production in the hypertrophic heart. In contrast, inhibition of PP1 γ re-balanced the CaMKII δ splicing. Furthermore, CaMKII activity was found to be augmented or attenuated by PP1 γ overexpression or inhibition, respectively. Further mechanistic studies showed that abdominal aorta constriction stress specifically increased the association of alternative splicing factor with PP1 γ, but not with PP1 β. Overexpression of PP1 γ, but not inhibitor 1 of PP1, further potentiated this association. These results suggest that PP1 γ alters the cardiac hypertrophy and remodelling likely through promotion of the alternative splicing factor-mediated splicing of CaMKII δ. [ABSTRACT FROM AUTHOR]