Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT_1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT_1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT_1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT_1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT_1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder.     

Insulin-Producing Cells Derived from Human Embryonic Stem Cells: Comparison of Definitive Endoderm- and Nestin-Positive Progenitor-Based Differentiation Strategies

Human embryonic stem cells (hESCs) are pluripotent and capable of undergoing multilineage differentiation into highly specialized cells including pancreatic islet cells. Thus, they represent a novel alternative source for targeted therapies and regenerative medicine for diabetes. Significant progress has been made in differentiating hESCs toward pancreatic lineages. One approach is based on the similarities of pancreatic β cell and neuroepithelial development. Nestin-positive cells are selected as pancreatic β cell precursors and further differentiated to secrete insulin. The other approach is based on our knowledge of developmental biology in which the differentiation protocol sequentially reproduces the individual steps that are known in normal β cell ontogenesis during fetal pancreatic development. In the present study, the hESC cell line PKU1.1 was induced to differentiate into insulin-producing cells (IPCs) using both protocols. The differentiation process was dynamically investigated and the similarities and differences between both strategies were explored. Our results show that IPCs can be successfully induced with both differentiation strategies. The resulting IPCs from both protocols shared many similar features with pancreatic islet cells, but not mature, functional β cells. However, these differently-derived IPC cell types displayed specific morphologies and different expression levels of pancreatic islet development-related markers. These data not only broaden our outlook on hESC differentiation into IPCs, but also extend the full potential of these processes for regenerative medicine in diabetes.     

Protecting tobacco plants from O3 injury by Bacillus velezensis with production of acetoin

Plant growth-promoting rhizobacteria (PGPRs) confer benefits to crops by producing volatile organic compounds (VOCs) to trigger induced systemic tolerance (IST). Here we show that Bacillus velezensis GJ11, a kind of PGPRs, produce VOCs such as 2,3-butanediol and acetoin to trigger IST and cause stomatal closure against O₃ injury in tobacco plants. Compared to 2,3-butanediol, acetoin was more effective on triggering IST against O₃ injury. The bdh-knockout strain GJ11Δbdh with a blocked metabolic pathway from acetoin to 2,3-butanediol produced more acetoin triggering stronger IST against O₃ injury than GJ11. Both acetoin and GJ11Δbdh effectively enhance the antioxidant enzymes activity (e.g. superoxide dismutase and catalases) that is favorable for scavenging the reactive oxygen species like H₂O₂ in leaves after exposure to O₃. Consequently, less H₂O₂ accumulation was observed, and reasonably less chlorophylls and proteins were damaged by H₂O₂ in the tobacco leaves treated with acetoin or GJ11Δbdh. The field experiment also showed that both acetoin and GJ11Δbdh could protect tobacco plants from O₃ injury after application by root-drench. This study provides new insights into the role of rhizobacterial B. velezensis and its volatile component of acetoin in triggering defense responses against stresses such as O₃ in plants.     

Knockout of SlNPR1 enhances tomato plants resistance against Botrytis cinerea by modulating ROS homeostasis and JA/ET signaling pathways

Tomato is one of the most popular horticultural crops, and many commercial tomato cultivars are particularly susceptible to Botrytis cinerea. Non-expressor of pathogenesis-related gene 1 (NPR1) is a critical component of the plant defense mechanisms. However, our understanding of how SlNPR1 influences disease resistance in tomato is still limited. In this study, two independent slnpr1 mutants were used to study the role of SlNPR1 in tomato resistance against B. cinerea. Compared to (WT), slnpr1 leaves exhibited enhanced resistance against B. cinerea with smaller lesion sizes, higher activities of chitinase (CHI), β-1, 3-glucanases (GLU) and phenylalanine ammonia-lyase (PAL), and significantly increased expressions of pathogenesis-related genes (PRs). The increased activities of peroxidase (POD), ascorbate peroxidase (APX) and decreased catalase (CAT) activities collectively regulated reactive oxygen species (ROS) homeostasis in slnpr1 mutants. The integrity of the cell wall in slnpr1 mutants was maintained. Moreover, the enhanced resistance was further reflected by induction of defense genes involved in jasmonic acid (JA) and ethylene (ET) signaling pathways. Taken together, these findings revealed that knocking out SlNPR1 resulted in increased activities of defense enzymes, changes in ROS homeostasis and integrity of cell walls, and activation of JA and ET pathways, which confers resistance against B. cinerea in tomato plants.     

Trichophyton indotineae sp. nov.: A New Highly Terbinafine-Resistant Anthropophilic Dermatophyte Species

Mycopathologia - In this report, we describe the first isolation of two highly terbinafine (TRF)-resistant Trichophyton interdigitale-like strains from a Nepali patient and an Indian patient with...     

Targeting BAX ubiquitin-binding sites reveals that BAX activation is essential for its ubiquitin-dependent degradation

BAX is an important proapoptotic protein of the BCL-2 family, and its stability is essential for the regulation of the mitochondrial apoptotic pathway. A previous study revealed that BAX could undergo degradation through the ubiquitin-proteasome pathway. In this study, we identified two lysine sites, K21 and K123, that were critical ubiquitin-binding sites in BAX. Mutation of these two sites prolonged the half-life of BAX and also affected its proapoptotic ability. Intriguingly, we found that ABT-737, a BCL-2 inhibitor, significantly enhanced TRAIL-induced BAX degradation in HCT116 cells and increased TRAIL-induced apoptosis in the HCT116 only with the BAX K21R/K123R mutant, not other BAX mutants. In addition, overexpression of PARKIN, an E3 ubiquitin ligase targeting BAX, dramatically decreased BAX protein level when only treated with ABT-737 in HCT116 cells. Therefore, we speculated that BAX activation is essential for its ubiquitin-dependent degradation.     

Heat waves trigger swift changes in the diet and life-history of a freshwater snail

Hydrobiologia - Extreme climatic events, such as heat waves, may induce changes in nutrient acquisition by omnivorous ectotherms. Likely modulated by the intensity, frequency and duration of these...     

miR-222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/β-catenin-mediated endothelium to mesenchymal transition

miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of β-catenin, thus negatively regulating the Wnt/β-catenin pathway, which was confirmed by β-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/β-catenin-mediated EndMT.     

Ribosomal protein S7 regulates arsenite-induced GADD45α expression by attenuating MDM2-mediated GADD45α ubiquitination and degradation

The stress-responding protein, GADD45α, plays important roles in cell cycle checkpoint, DNA repair and apoptosis. In our recent study, we demonstrate that GADD45α undergoes a dynamic ubiquitination and degradation in vivo, which process can be blocked by the cytotoxic reagent, arsenite, resulting in GADD45α accumulation to activate JNKs cell death pathway, thereby revealing a novel mechanism for the cellular GADD45α functional regulation. But the factors involved in GADD45α stability modulations are unidentified. Here, we demonstrated that MDM2 was an E3 ubiquitin ligase for GADD45α. One of MDM2-binding partner, ribosomal protein S7, interacted with and stabilized GADD45α through preventing the ubiquitination and degradation of GADD45α mediated by MDM2. This novel function of S7 is unrelated to p53 but seems to depend on S7/MDM2 interaction, for the S7 mutant lacking MDM2-binding ability lost its function to stabilize GADD45α. Further investigations indicated that arsenite treatment enhanced S7–MDM2 interaction, resulting in attenuation of MDM2-dependent GADD45α ubiquitination and degradation, thereby leading to GADD45α-dependent cell death pathway activation. Silencing S7 expression suppressed GADD45α-dependent cytotoxicity induced by arsenite. Our findings thus identify a novel function of S7 in control of GADD45α stabilization under both basal and stress conditions and its significance in mediating arsenite-induced cellular stress.