Identification and Functional Analysis of a Protein Disulfide Isomerase (AtPDI1) in Arabidopsis thaliana

Protein disulfide isomerase (PDI) catalyzes the conversion of thiol-disulfide and plays an important role in various physiological events in animals. A PDI (OaPDI) from a tropical plant was detailed studied and it was found to be involved in response of biotic stress (Gruber et al., 2007). However, the activities of PDI related to physiological functions in plants are poorly understood. In the present study, a homolog of human PDI in Arabidopsis (AtPDI1), encoded by the gene (At3g54960), was characterized. The recombinant AtPDI1 protein had disulfide isomerase activity in vitro and two pairs of conservative cysteines in catalytic domains play a crucial role in the PDI activities. Expression of AtPDI1 in Escherichia coli significantly enhanced stress tolerance of cells and the mutations of critical cysteines almost lose this function. In plants, AtPDI1 was strongly induced by abiotic stresses and exogenous abscisic acid. An ArabidopsisAtPDI1 knockdown mutant (pdi1) and overexpression lines of transgenic plants obtained by this investigation were used to further examine the function of AtPDI1. The mutant line was more sensitive to stresses than the wild-type, while overexpressing AtPDI1 increased tolerance of seedlings to abiotic stresses, with a higher germination ratio and longer length of roots than the wild-type. Our results suggested AtPDI1 played roles in anti-stresses in Arabidopsis, which relate to the activities of PDI

Synthesis and biological evaluation of tetrahydropyridinepyrazoles ('PFPs') as inhibitors of STAT3 phosphorylation

The transcription factor STAT3 is constitutively overexpressed in many human tumors and hence represents a putative target for anticancer drug design. In this work, we describe the synthesis and biological evaluation of a novel chemotype, pyridine-fused pyrazoles ('PFPs') as inhibitors of STAT3 phosphorylation. The effect of the compounds synthesized was evaluated in cell proliferation assays of MCF-7 and HepG2 cancer cell lines and two of the compounds tested (12g and 12k) were found to show significant activity. Both compounds were also found to inhibit the proliferation of Hep3B, HUH-7 and PLC/PRF5 HCC cells in a dose-and time-dependent manner. Furthermore, we established in a DNA binding assay that one of the compounds (12g) was able to significantly inhibit the DNA binding ability of STAT3. Cytotoxicity of 12g against PC3 cells, which do not constitutively phosphorylate STAT3, was found to be minimal, hence lending further support for our mode-of-action hypothesis of this compound. We established for this structure a complete inhibition of CXCL12-induced cell invasion and associated wound healing in HCCLM3 cells, corroborating the proposed modulation of the STAT3 axis by 12g. Finally, molecular modeling was employed to evaluate the hypothesis of PFPs to bind to the SH2 domain of STAT3. Given the efficacy of PFPs in the biological systems studied here we propose their further evaluation in the context of STAT3-mediated cancer therapy

Coexistence of Histologically Confirmed Hashimoto's Thyroiditis with Different Stages of Papillary Thyroid Carcinoma in a Consecutive Chinese Cohort

Purpose. To determine the relationship between Hashimoto's thyroiditis (HT) and all stages of papillary thyroid carcinoma (PTC) with or without local lymph node metastasis (LNM). Methods:. We conducted a retrospective study of thyroidectomies from 2008–2013 in First Affiliated Hospital of Nanjing Medical University. We categorized patients according to the presence of histopathologically proven HT. The prevalence of mPTC (maximum diameter ≤ 10 mm) and crPTC (clinical relevant PTC) and local LNM rates were compared. Results:. We evaluated 6,432 consecutive thyroidectomies. In total, 1,328 specimens were confirmed as HT. The prevalence of PTC in this HT cohort was 43.8%, significantly higher than non-HT group. After adjustment of gender and age, the prevalence of PTC was still higher in HT group. HT was a risk factor for PTC in multivariate analysis with odds ratio 2.725 (95% CI, 2.390–3.109) (P < 0.001). However, no correlation was found between HT and LNM of PTC. Conclusion:. HT was associated with an increased prevalence of all stages of PTC, independent of tumor size, gender, and age. In contrast, locally advanced disease defined by LNM was unrelated to HT. These data suggest an association of HT with low risk PTC and a potential protective immunologic effect from further disease progression

Surface mediated ligands addressing bottleneck of room-temperature synthesized inorganic perovskite nanocrystals toward efficient light-emitting diodes

Cesium lead halide perovskites (CsPbX3) have become superior candidates for perspective optoelectronic applications. However, room temperature synthesized CsPbX3 nanocrystals (NCs) suffer from serious lattice/surface traps, mostly induced by nonequilibrium reactions and polar solvent systems. Thus, direct assembly of such poor crystals cannot be available toward high efficiency light emitting diodes (LEDs). To address this issue, differing from the general post-treatment works, here we propose a double-terminal diamine bromide salt to in situ passivate the surface traps of room temperature synthesized CsPbBr3 NCs. High-quality NC solutions with photoluminescence quantum yield (PLQY) beyond 90% are obtained owing to the renovated surface bromide vacancies. Meanwhile, instead of longer oleylamine (OLA) ligand, the abridged diamine bromine ligand could significantly enhance charge transport throughout the NC film. In addition, the NC based LED performance is found related to chain length of the ligand, where the optimal luminance of 14021 Cd m(-2) and current efficiency of 25.5 Cd A(-1) are achieved by 1, 4-butanediamine bromide passivated NC devices. This work provides a direct efficient approach to meet the device application of room temperature synthesized perovskite NCs, underlines the significance of selective ligands to address the challenges of NC emitters in future displays and solid-state lighting

HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression