The posttranslational modification of HDAC4 in cell biology: Mechanisms and potential targets

Histone deacetylase 4 (HDAC4) is a member of the HDACs family, its expression is closely related to the cell development. The cell is an independent living entity that undergoes proliferation, differentiation, senescence, apoptosis, and pathology, and each process has a strict and complex regulatory system. With deepening of its research, the expression of HDAC4 is critical in the life process. This review focuses on the posttranslational modification of HDAC4 in cell biology, providing an important target for future disease treatment.     

CircDHDDS/miR-361-3p/WNT3A Axis Promotes the Development of Retinoblastoma by Regulating Proliferation,Cell Cycle,Migration, and Invasion of Retinoblastoma Cells

Neurochemical Research - Retinoblastoma (RB) is a common intraocular malignant tumor. The growing evidence has reported that circular RNAs (circRNAs) play critical roles in RB development....     

Chromoblastomycosis in Mainland China: A Systematic Review on Clinical Characteristics

Chromoblastomycosis is one of the most frequent chronic infections caused by melanized fungi. In order to evaluate the clinical characteristics of chromoblastomycosis in Mainland China, we performed an evidence-based review of published literature. PubMed and Chinese-language database of CNKI, VIP and Wanfang data during January 1990–August 2011 were searched. Epidemiology, clinical features, laboratory findings, therapy and prognosis were analyzed. Cladophialophora carrionii was the most common causative agent in the north of the Mainland China, and Fonsecaea monophora and F. pedrosoi were the most common agents in the southern part of the Mainland China. Infection commonly initiated after the etiologic agents gain entrance through puncture wounds and more common involved extremities of the males. Skin lesions were found in different sites, like the extremities, buttocks, trunk and face, and presented diversity morphology. There were about seven different clinical types found in Mainland China: plaque type, tumoral type, cicatricial type, verrucous type, pseudo-vacuole type, eczymatous type and mixed type of lesions. The success of treatment for chromoblastomycosis was related to the causative agent, the clinical form and severity of the lesions. Most of the patients could be treated successfully with the physical treatment, chemotherapy and/or combination therapy. The itraconazole, terbinafine or a combination of both were commonly medication for these mycosis patients. Physical methods were usually indicated to support chemotherapy with some severe forms and long-lasting cases. Photodynamic therapy has been extended from the oncological field to that of antimicrobial chemotherapy in these years. We applied it on some recalcitrant cases of chromoblastomycosis and found its good clinical response, and hopeful it could be a promising therapy in near future.     

Establishment of a Captive All‐male Group of Proboscis Monkey (Nasalis larvatus) at the Singapore Zoo

Surplus male proboscis monkeys at the Singapore Zoo pose a considerable problem for maintenance and maximizing of exhibition potential. In 2008, a new exhibit was constructed to house and display a group of six proboscis monkey males born in Singapore Zoo. To document and monitor the all‐male group establishment in the new exhibit, we conducted observations on intragroup interactions between the monkeys, spatial use of their new exhibit, and visitor effects on their behavior. We found contact aggressive interactions between the monkeys to be consistently lower than noncontact aggressive interactions and by week six of introduction to the new exhibit, contact aggression was almost nonevident. Affiliative interactions also developed between individuals in the group, with an interface of aggressive and socioreconcilatory behavior influenced by food competition and a dominance hierarchy. This was evident from significantly higher overall aggression and affiliation during feeding times compared to nonfeeding times, and this was reduced when food competition was mitigated by modifying the feeding regime. We measured the groups’ spatial use of the exhibit and the relation to behavior, crowd size, and density. Our results showed that the proboscis monkeys utilized the available exhibit space, were largely unaffected by visitor crowd size and density, and were able to exhibit a variety of natural behaviors, including swimming. Our accomplishment in maintaining and displaying an all‐male group of proboscis monkeys in captivity provides viable options for more comprehensive captive management and breeding programs for this endangered species. Zoo Biol. 32:281‐290, 2013. © 2012 Wiley Periodicals, Inc.     

The kinetic properties of a human PPIP5K reveal that its kinase activities are protected against the consequences of a deteriorating cellular bioenergetic environment

We obtained detailed kinetic characteristics–stoichiometry, reaction rates, substrate affinities and equilibrium conditions–of human PPIP5K2 (diphosphoinositol pentakisphosphate kinase 2). This enzyme synthesizes ‘high-energy’ PP-InsPs (diphosphoinositol polyphosphates) by metabolizing InsP₆ (inositol hexakisphosphate) and 5-InsP₇ (5-diphosphoinositol 1,2,3,4,6-pentakisphosphate) to 1-InsP₇ (1-diphosphoinositol 2,3,4,5,6-pentakisphosphate) and InsP₈ (1,5-bis-diphosphoinositol 2,3,4,6-tetrakisphosphate), respectively. These data increase our insight into the PPIP5K2 reaction mechanism and clarify the interface between PPIP5K catalytic activities and cellular bioenergetic status. For example, stochiometric analysis uncovered non-productive, substrate-stimulated ATPase activity (thus, approximately 2 and 1.2 ATP molecules are utilized to synthesize each molecule of 1-InsP₇ and InsP₈, respectively). Impaired ATPase activity of a PPIP5K2-K248A mutant increased atomic-level insight into the enzyme''s reaction mechanism. We found PPIP5K2 to be fully reversible as an ATP-synthase in vitro, but our new data contradict previous perceptions that significant ‘reversibility’ occurs in vivo. PPIP5K2 was insensitive to physiological changes in either [AMP] or [ATP]/[ADP] ratios. Those data, together with adenine nucleotide kinetics (ATP K_m=20–40 μM), reveal how insulated PPIP5K2 is from cellular bioenergetic challenges. Finally, the specificity constants for PPIP5K2 revise upwards by one-to-two orders of magnitude the inherent catalytic activities of this enzyme, and we show its equilibrium point favours 80–90% depletion of InsP₆/5-InsP₇.     

Quantifying Salmonella Population Dynamics in Water and Biofilms

Members of the bacterial genus Salmonella are recognized worldwide as major zoonotic pathogens often found to persist in non-enteric environments including heterogeneous aquatic biofilms. In this study, Salmonella isolates that had been detected repeatedly over time in aquatic biofilms at different sites in Spring Lake, San Marcos, Texas, were identified as serovars Give, Thompson, Newport and -:z10:z39. Pathogenicity results from feeding studies with the nematode Caenorhabditis elegans as host confirmed that these strains were pathogenic, with Salmonella-fed C. elegans dying faster (mean survival time between 3 and 4 days) than controls, i.e., Escherichia coli-fed C. elegans (mean survival time of 9.5 days). Cells of these isolates inoculated into water at a density of up to 10⁶?ml^?1 water declined numerically by 3 orders of magnitude within 2 days, reaching the detection limit of our quantitative polymerase chain reaction (qPCR)-based quantification technique (i.e., 10³ cells ml^?1). Similar patterns were obtained for cells in heterogeneous aquatic biofilms developed on tiles and originally free of Salmonella that were kept in the inoculated water. Cell numbers increased during the first days to more than 10⁷ cells cm^?2, and then declined over time. Ten-fold higher cell numbers of Salmonella inoculated into water or into biofilm resulted in similar patterns of population dynamics, though cells in biofilms remained detectable with numbers around 10⁴ cells cm^?2 after 4 weeks. Independent of detectability by qPCR, samples of all treatments harbored viable salmonellae that resembled the inoculated isolates after 4 weeks of incubation. These results demonstrate that pathogenic salmonellae were isolated from heterogeneous aquatic biofilms and that they could persist and stay viable in such biofilms in high numbers for some time.     

Protective effects of EphB2 on Aβ1–42 oligomer-induced neurotoxicity and synaptic NMDA receptor signaling in hippocampal neurons

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized pathologically by the abnormal deposition of extracellular amyloid-β (Aβ) oligomers. However, the nature and precise mechanism of the toxicity of Aβ oligomers are not clearly understood. Aβ oligomers have been previously shown to cause a major loss of EphB2, a member of the EphB family of receptor tyrosine kinases. To determine the effect of EphB2 on Aβ oligomer-induced neurotoxicity and the underlying molecular mechanisms, we examined the EphB2 gene in cultured hippocampal neurons. Using a cellular model of AD, Aβ_1–42 oligomers were confirmed to induce neurotoxicity in a time-dependent manner and result in a major decrease of EphB2. EphB2 overexpression could prevent the neurotoxicity of hippocampal neurons from exposure to Aβ_1–42 oligomers for 1 h. Further analysis revealed that EphB2 overexpression increased synaptic NR1 and NR2B expression in Aβ_1–42 oligomer-treated neurons. Moreover, EphB2 overexpression prevented Aβ_1–42 oligomer-induced downregulation of dephosphorylated p38 MAPK and phosphorylated CREB. Together, these results suggest that EphB2 is a factor which protects hippocampal neurons against the toxicity of Aβ_1–42 oligomers, and we infer that the protection of EphB2 is achieved by increasing the synaptic NMDA receptor level and downstream p38 MAPK and CREB signaling in hippocampal neurons. This study provides new molecular insights into the neuroprotective effect of EphB2 and highlights its potential therapeutic role in the management of AD.     

Calcium-mediated enhancement of copper tolerance in Elodea canadensis

The alleviative effects of exogenous calcium on copper phytotoxicity were investigated in Elodea canadensis plants. There was a significant accumulation of Cu in the plants after their exposure to 0.01 mM Cu accompanied by many symptoms of toxicity. Increased uptake of Cu severely reduced content of photosynthetic pigments, soluble proteins, and free proline. The total antioxidant capacity (T-AOC), reduced glutathione (GSH), and non-protein thiol (NP-SH) were severely suppressed in Cu-stressed plants resulting in a rapid increase in content of superoxide anion (O₂ ^·?), hydrogen peroxide, lipid peroxidation, and cell death. Simultaneous application of Ca markedly increased the content of photosynthetic pigments, soluble proteins, free proline, T-AOC, GSH, and NP-SH, and reduced oxidative damage as indicated by lowered content of MDA, O₂ ^·?, and H₂O₂; and decreased cell death. Furthermore, application of Ca reduced Cu uptake and effectively reversed the Cu-induced nutrient imbalance.     

川芎嗪对Aβ25-35诱导体外大鼠海马神经元细胞凋亡的影响

本文通过Aβ25-35诱导体外原代培养的SD乳大鼠海马神经元,建立Aβ毒性损伤细胞模型,结合AnnexinV-FITC/PI荧光双染法流式细胞术、MTT比色法、实时荧光定量PCR及Western blot方法检测川芎嗪(tetrameth-ylpyrazine,TMP)对原代培养的海马神经元细胞活性、早期凋亡率和Bax、Bcl-2基因表达的影响。结果显示川芎嗪高、中剂量可明显增强细胞活性,增加神经元细胞的存活率(P<0.01),可显著抑制海马神经元细胞早期凋亡(P<0.01),抑制凋亡蛋白Bax的表达(P<0.01),增强抗凋亡蛋白bcl-2的表达(P<0.01)。川芎嗪可通过调节Bax/Bcl-2平衡抵抗Aβ25-35诱导的海马神经元凋亡,降低Aβ的神经元毒性,对海马神经元损伤有明显的保护作用。     

Increasing βB1-crystallin sensitivity to proteolysis caused by the congenital cataract-microcornea syndrome mutation S129R

Congenital hereditary cataract, which is mainly caused by the deposition of crystallins in light-scattering particles, is one of the leading causes of newborn blindness in human beings. Recently, an autosomal dominant congenital cataract-microcornea syndrome in a Chinese family has been associated with the S129R mutation in βB1-crystallin. To investigate the underlying molecular mechanism, we examined the effect of the mutation on βB1-crystallin structure and thermal stability. Biophysical experiments indicated that the mutation impaired the oligomerization of βB1-crystallin and shifted the dimer–monomer equilibrium to monomer. Molecular dynamic simulations revealed that the mutation altered the hydrogen-bonding network and hydrophobic interactions in the subunit interface of the dimeric protein, which resulted in the opening of the tightly associated interacting sites to allow the infiltration of the solvent molecules into the interface. Despite the disruption of βB1-crystallin assembly, the thermal stability of βB1-crystallin was increased by the mutation accompanied by the reduction of thermal aggregation at high temperatures. Further analysis indicated that the mutation significantly increased the sensitivity of βB1-crystallin to trypsin hydrolysis. The digested fragments of the mutant were prone to aggregate and unable to protect βA3-crystallin against aggregation. These results indicated that the thermal stability-beneficial mutation S129R in βB1-crystallin provided an excellent model for discovering molecular mechanisms apart from solubility and stability. Our results also highlighted that the increased sensitivity of mutated crystallins towards proteases might play a crucial role in the pathogenesis of congenital hereditary cataract and associated syndrome.