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Vitamin-D insufficiency and sarcoidosis are more common and severe in African Americans (AA) than Caucasians. In sarcoidosis, substrate-dependent extrarenal 1,25-dihydroxyvitamin-D (1,25-(OH)2D) production is thought to contribute to hypercalciuria and hypercalcemia, and vitamin-D repletion is often avoided. However, the anti-inflammatory properties of vitamin-D may also be beneficial. We prospectively examined serum vitamin-D levels, calcium balance, and the effects of vitamin-D repletion in 86 AA and Caucasian patients with biopsy-proven active sarcoidosis from the USA (US) and Italy (IT) in university-affiliated outpatient clinics. Clinical features, pulmonary function, and calciotropic hormones were measured. 16 patients with vitamin-D deficiency and normal serum ionized calcium (Ca(2+)) were treated with oral ergocalciferol (50,000 IU/week) for 12 weeks. Baseline mineral parameters were similar in US (93% AA) and IT (95% Caucasian) patients irrespective of glucocorticoid treatment. Pulmonary dysfunction was less pronounced in IT patients. Nephrolithiasis (in 11% US, 17% IT patients) was associated with higher urinary calcium excretion. Vitamin-D deficiency was not more prevalent in patients compared to the respective general populations. As serum 25-hydroxyvitamin-D (25-OHD) rose postrepletion, serum 1,25-(OH)2D, γ-globulins, and the previously elevated angiotensin converting enzyme (ACE) levels declined. Asymptomatic reversible increases in Ca(2+) or urinary calcium/creatinine (Ca/Cr) developed in three patients during repletion. In conclusion, Caucasian and AA patients show similar calcium and vitamin D profiles. The higher prevalence of hypercalciuria and nephrolithiasis in sarcoidosis is unrelated to endogenous vitamin-D levels. Vitamin-D repletion in sarcoidosis is generally safe, although calcium balance should be monitored. A hypothesis that 25-OHD repletion suppresses granulomatous immune activity is provided., (Copyright © 2016 American Federation for Medical Research.)

This study investigated effects of xanthophylls (containing 40% lutein and 60% zeaxanthin) on gene expression of inflammatory mediators ( [] and []) and apoptosis ( [] and ) of breeding hens and chicks. In Exp. 1, 432 hens were divided into 3 groups and fed diets supplemented with 0 (as the control group), 20, or 40 mg/kg xanthophylls. The liver, duodenum, jejunum, and ileum were sampled after 35 d. Results showed that 40 mg/kg of xanthophyll addition decreased in the liver, in the liver and duodenum, and in the liver and jejunum while increasing level in the liver and jejunum. Experiment 2 was a 2 × 2 factorial design. Male chicks hatched from hens fed 0 or 40 mg/kg xanthophyll diets were fed diets containing either 0 or 40 mg/kg xanthophylls. The liver, duodenum, jejunum, and ileum were sampled at 0, 7, 14, and 21 d after hatching. Results showed that in ovo xanthophylls reduced inflammatory mediators and apoptosis in the liver, duodenum, and jejunum of chicks mainly within 1 wk after hatching, whereas dietary xanthophylls only decreased expression in the liver from 2 wk onward. These results underlined important anti-inflammatory and antiapoptotic effects of maternal but not progeny dietary xanthophylls. In conclusion, xanthophylls can suppress inflammatory mediators and apoptosis in different tissues of hens and chicks.

Unlabelled: In a retrospective analysis of 208 osteoporotic patients followed during a bisphosphonate holiday, lower body weight and risedronate use were associated with a more rapid decline in bone mineral density during the bisphosphonate holiday, while bone mineral density (BMD) trends were similar in patients who sustained vs. did not sustain a fracture., Introduction: A drug holiday has been suggested for some bisphosphonate-treated patients with osteoporosis to minimize potential side effects from prolonged use. However, there is limited information on the evolution of BMD during a bisphosphonate holiday. Our study analyzed the longitudinal course of BMD following bisphosphonate discontinuation and assessed its determinants., Methods: Retrospective single-center cohort study of osteoporosis patients treated with alendronate or risedronate for at least 2 years and then discontinued their bisphosphonate for a drug holiday. Patients were stratified by bisphosphonate type and by fracture occurrence during drug holiday., Results: A total of 208 patients were included in this analysis (87.5 % female). At the time of bisphosphonate cessation, mean ± SD age was 66.9 ± 8.9 years and BMI 24.5 ± 4.4 kg/m(2). Duration of bisphosphonate treatment was 5.2 ± 2.3 years, and follow-up during holiday was 3.3 ± 1.7 years. During the first 2 years of the holiday, BMD remained stable at the lumbar spine and femoral neck, but declined significantly at the total hip. BMD declined significantly at all sites thereafter. Significant predictors of BMD decline during bisphosphonate holiday included lower BMI at the start of the holiday and change in body weight during the holiday. BMD decline was more pronounced in former risedronate compared to former alendronate users. BMD trends were similar in patients who sustained vs. did not sustain a fracture during the holiday., Conclusions: BMD at the total hip declines significantly within 1 year of bisphosphonate discontinuation, particularly in lean patients. Additional studies are needed to identify predictors of fracture incidence during a bisphosphonate holiday.

Background: Rhizospheric fungi play an essential role in the plant-soil ecosystem, affecting plant growth and health. In this study, we evaluated the fungal diversity in the rhizosphere soil of 2-yr-old healthy Panax notoginseng cultivated in Wenshan, China., Methods: Culture-independent Illumina MiSeq and culture-dependent techniques, combining molecular and morphological characteristics, were used to analyze the rhizospheric fungal diversity. A diffusion test was used to challenge the phytopathogens of P. notoginseng., Results: A total of 16,130 paired-end reads of the nuclear ribosomal internal transcribed spacer 2 were generated and clustered into 860 operational taxonomic units at 97% sequence similarity. All the operational taxonomic units were assigned to five phyla and 79 genera. Zygomycota (46.2%) and Ascomycota (37.8%) were the dominant taxa; Mortierella and unclassified Mortierellales accounted for a large proportion (44.9%) at genus level. The relative abundance of Fusarium and Phoma sequences was high, accounting for 12.9% and 5.5%, respectively. In total, 113 fungal isolates were isolated from rhizosphere soil. They were assigned to five classes, eight orders (except for an Incertae sedis), 26 genera, and 43 species based on morphological characteristics and phylogenetic analysis of the internal transcribed spacer. Fusarium was the most isolated genus with six species (24 isolates, 21.2%). The abundance of Phoma was also relatively high (8.0%). Thirteen isolates displayed antimicrobial activity against at least one test fungus., Conclusion: Our results suggest that diverse fungi including potential pathogenic ones exist in the rhizosphere soil of 2-yr-old P. notoginseng and that antagonistic isolates may be useful for biological control of pathogens.

Background: Rhizobacteria play an important role in plant defense and could be promising sources of biocontrol agents. This study aimed to screen antagonistic bacteria and develop a biocontrol system for root rot complex of Panax notoginseng., Methods: Pure-culture methods were used to isolate bacteria from the rhizosphere soil of notoginseng plants. The identification of isolates was based on the analysis of 16S ribosomal RNA (rRNA) sequences., Results: A total of 279 bacteria were obtained from rhizosphere soils of healthy and root-rot notoginseng plants, and uncultivated soil. Among all the isolates, 88 showed antagonistic activity to at least one of three phytopathogenic fungi, Fusarium oxysporum, Fusarium solani, and Phoma herbarum mainly causing root rot disease of P. notoginseng. Based on the 16S rRNA sequencing, the antagonistic bacteria were characterized into four clusters, Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetesi. The genus Bacillus was the most frequently isolated, and Bacillus siamensis (Hs02), Bacillus atrophaeus (Hs09) showed strong antagonistic activity to the three pathogens. The distribution pattern differed in soil types, genera Achromobacter, Acidovorax, Brevibacterium, Brevundimonas, Flavimonas, and Streptomyces were only found in rhizosphere of healthy plants, while Delftia, Leclercia, Brevibacillus, Microbacterium, Pantoea, Rhizobium, and Stenotrophomonas only exist in soil of diseased plant, and Acinetobacter only exist in uncultivated soil., Conclusion: The results suggest that diverse bacteria exist in the P. notoginseng rhizosphere soil, with differences in community in the same field, and antagonistic isolates may be good potential biological control agent for the notoginseng root-rot diseases caused by F. oxysporum, Fusarium solani, and Panax herbarum.

Flexible organic light-emitting diodes (OLEDs) are emerging as a leading technology for rollable and foldable display applications. For the development of high-performance flexible OLEDs on plastic substrate, we report a transparent nanocomposite electrode with superior mechanical, electrical, and optical properties, which is realized by integrating the nanoimprinted quasi-random photonic structures into the ultrathin metal/dielectric stack to collectively optimize the electrical conduction and light outcoupling capabilities. The resulting flexible OLEDs with green emission yield the enhanced device efficiency, reaching the maximum external quantum efficiency of 43.7% and luminous efficiency of 154.9 cd/A, respectively.

Eight new fungal polyketides named koningiopisins A-H (1-8) and four previously known polyketides (9-12) were isolated from the endophytic fungus Trichoderma koningiopsis YIM PH 30002. Their structures were elucidated using extensive spectral data interpretation, and their antifungal and synergistic activities were also evaluated. Koningiopisin C (3) exhibited in vitro antifungal activity against the phytopathogenic fungus Plectosphaerella cucumerina with an MIC of 16 µg/mL. Although the antifungal activities of single compounds were not obvious, a mixture of six compounds (4-9) exhibited potent synergistic antifungal activity against P. cucumerina with an MIC of 16 µg/mL, and the antifungal activity of the mixture of any two compounds with a 1:1 ratio was better than that observed from the individual compound. The synergistic biological activity of the metabolites in YIM PH 30002 demonstrates the significant ecological function of the endophyte for its host plant, and provides additional insight into the search for and development of agents for biological control., (Georg Thieme Verlag KG Stuttgart · New York.)

This study investigated the effects of xanthophylls (containing 40% lutein and 60% zeaxanthin; Juyuan Biochemical Co., Ltd., GuangZhou, China) on gene expression associated with carotenoid cleavage enzymes (β-carotene 15, 15'-monooxygenase, BCMO1; and β-carotene 9', 10'-dioxygenase, BCDO2) and retinoid metabolism (lecithin:retinol acyl transferase (LRAT) and STRA6) of breeding hens and chicks. In experiment 1, 432 hens were divided into 3 groups and fed diets supplemented with zero (as the control group), 20, or 40 mg/kg xanthophyll. The liver, duodenum, jejunum, and ileum were sampled at d 35 of the trial. Results showed that 40 mg/kg xanthophyll supplementation increased BCDO2 mRNA in the liver, duodenum, and jejunum; LRAT mRNA in the jejunum; and STRA6 mRNA in the liver, while it decreased LRAT mRNA in the liver. Experiment 2 was a 2 × 2 factorial design. Male chicks hatched from a zero or 40 mg/kg xanthophyll diet of hens were fed a diet containing either zero or 40 mg/kg xanthophylls. The liver, duodenum, jejunum, and ileum were sampled at zero, 7, 14, and 21 d after hatching. Results showed that in ovo xanthophyll modulated carotenoid and retinoid metabolism mainly within one wk after hatching. The maternal effects gradually vanished and dietary effects began to work one to 2 wk after hatching. Dietary xanthophyll regulated carotenoid and retinoid metabolism mainly from 2 wk onward. The xanthophyll regulation of carotenoid and retinoid metabolism also revealed strong tissue specificity. In conclusion, xanthophyll supplementation could modulate carotenoid and retinoid metabolism in different tissues of hens and chicks., (© 2015 Poultry Science Association Inc.)

Background: Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. Although improvements in contemporary therapy and development of new treatment strategies have led to dramatic increases in the cure rate in children with ALL, the relapse rate remains high and the prognosis of relapsed childhood ALL is poor. Molecularly targeted therapies have emerged as the leading treatments in cancer therapy. Multi-cytotoxic drug regimens have achieved success, yet many studies addressing targeted therapies have focused on only one single agent. In this study, we attempted to investigate whether the effect of the mammalian target of rapamycin (mTOR) inhibitor rapamycin is synergistic with the effect of focal adhesion kinase (FAK) down-regulation in the treatment of ALL., Methods: The effect of rapamycin combined with FAK down-regulation on cell proliferation, the cell cycle, and apoptosis was investigated in the human precursor B acute lymphoblastic leukemia cells REH and on survival time and leukemia progression in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model., Results: When combined with FAK down-regulation, rapamycin-induced suppression of cell proliferation, G0/G1 cell cycle arrest, and apoptosis were significantly enhanced. In addition, REH cell-injected NOD/SCID mice treated with rapamycin and a short-hairpin RNA (shRNA) to down-regulate FAK had significantly longer survival times and slower leukemia progression compared with mice injected with REH-empty vector cells and treated with rapamycin. Moreover, the B-cell CLL/lymphoma-2 (BCL-2) gene family was shown to be involved in the enhancement, by combined treatment, of REH cell apoptosis., Conclusions: FAK down-regulation enhanced the in vitro and in vivo inhibitory effects of rapamycin on REH cell growth, indicating that the simultaneous targeting of mTOR- and FAK-related pathways might offer a novel and powerful strategy for treating ALL.

CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.

Amodiaquine (AQ) is routinely prescribed as an anti-malarial drug. Here, we evaluated AQ-induced toxicity in the male reproductive system. Eighty adult male Sprague-Dawley rats were randomly divided into four groups that received distilled water (control) or daily doses of 5 mg/kg body weight, 10 mg/kg, or 15 mg/kg AQ for 2 weeks. Testes morphology was analyzed using hematoxylin-and-eosin staining, terminal dUTP nicked-end labeling (TUNEL), and immunostaining whereas protein expression was determined by Western blotting. AQ dose-dependently led to abnormal spermatogenesis. Disruption of the blood-testis barrier and increased germ cell apoptosis were observed in all three AQ-treated groups. Interestingly, AQ-induced damage of spermatogenesis recovered over time, based on the survival of promyelocytic leukemia zinc-finger (PLZF)-positive, undifferentiated spermatogonia. Serum levels of luteinizing hormone and testosterone, as well as testicular testosterone levels, were not significantly altered in AQ-treated groups compared with controls. Collectively, our study suggests that AQ exerts substantial acute side effects on the reproductive systems of adult male rats by inducing the apoptosis of differentiating spermatogenic cells and disruption of blood-testis barrier function., (© 2015 Wiley Periodicals, Inc.)

Gossypol, a polyphenolic compound isolated from cottonseeds, has been reported to possess many pharmacological activities, but whether it can influence inflammasome activation remains unclear. In this study, we found that in mouse macrophages, gossypol induced cell death characterized by rapid membrane rupture and robust release of HMGB1 and pro-caspase-11 comparable to ATP treatment, suggesting an induction of pyroptotic cell death. Unlike ATP, gossypol induced much low levels of mature interleukin-1β (IL-1β) secretion from mouse peritoneal macrophages primed with LPS, although it caused pro-IL-1β release similar to that of ATP. Consistent with this, activated caspase-1 responsible for pro-IL-1β maturation was undetectable in gossypol-treated peritoneal macrophages. Besides, RAW 264.7 cells lacking ASC expression and caspase-1 activation also underwent pyroptotic cell death upon gossypol treatment. In further support of pyroptosis induction, both pan-caspase inhibitor and caspase-1 subfamily inhibitor, but not caspase-3 inhibitor, could sharply suppress gossypol-induced cell death. Other canonical pyroptotic inhibitors, including potassium chloride and N-acetyl-l-cysteine, could suppress ATP-induced pyroptosis but failed to inhibit or even enhanced gossypol-induced cell death, whereas nonspecific pore-formation inhibitor glycine could attenuate this process, suggesting involvement of a non-canonical pathway. Of note, gossypol treatment eliminated thioglycollate-induced macrophages in the peritoneal cavity with recruitment of other leukocytes. Moreover, gossypol administration markedly decreased the survival of mice in a bacterial sepsis model. Collectively, these results suggested that gossypol induced pyroptosis in mouse macrophages via a non-canonical inflammasome pathway, which raises a concern for its in vivo cytotoxicity to macrophages., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Flexible organic light-emitting diodes (OLEDs) hold great promise for future bendable display and curved lighting applications. One key challenge of high-performance flexible OLEDs is to develop new flexible transparent conductive electrodes with superior mechanical, electrical, and optical properties. Herein, an effective nanostructured metal/dielectric composite electrode on a plastic substrate is reported by combining a quasi-random outcoupling structure for broadband and angle-independent light outcoupling of white emission with an ultrathin metal alloy film for optimum optical transparency, electrical conduction, and mechanical flexibility. The microcavity effect and surface plasmonic loss can be remarkably reduced in white flexible OLEDs, resulting in a substantial increase in the external quantum efficiency and power efficiency to 47.2% and 112.4 lm W(-1).

Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. We recently developed in silico models to distinguish mTOR inhibitors and non-inhibitors. In this study, we developed an integrated strategy for identifying new mTOR inhibitors using cascaded in silico screening models. With this strategy, fifteen new mTOR kinase inhibitors including four compounds with IC50 values below 10 μM were discovered. In particular, compound 17 exhibited potent anticancer activities against four tumor cell lines, including MCF-7, HeLa, MGC-803, and C6, with IC50 values of 1.90, 2.74, 3.50 and 11.05 μM. Furthermore, cellular studies and western blot analyses revealed that 17 induces cell death via apoptosis by targeting both mTORC1 and mTORC2 within cells and arrests the cell cycle of HeLa at the G1/G0-phase. Finally, multi-nanosecond explicit solvent simulations and MM/GBSA analyses were carried out to study the inhibitory mechanisms of 13, 17, and 40 for mTOR. The potent compounds presented here are worthy of further investigation.

The abnormal fibrillation of human islet amyloid polypeptide (hIAPP) has been implicated in the development of type II diabetes. Aluminum is known to trigger the structural transformation of many amyloid proteins and induce the formation of toxic aggregate species. The (-)-epigallocatechin gallate (EGCG) is considered capable of binding both metal ions and amyloid proteins with inhibitory effect on the fibrillation of amyloid proteins. However, the effect of Al(III)/EGCG complex on hIAPP fibrillation is unclear. In the present work, we sought to view insight into the structures and properties of Al(III) and EGCG complex by using spectroscopic experiments and quantum chemical calculations and also investigated the influence of Al(III) and EGCG on hIAPP fibrillation and aggregation as well as their combined interference on this process. Our studies demonstrated that Al(III) could promote fibrillation and aggregation of hIAPP, while EGCG could inhibit the fibrillation of hIAPP and lead to the formation of hIAPP amorphous aggregates instead of the ordered fibrils. Furthermore, we proved that the Al(III)/EGCG complex in molar ratio of 1 : 1 as Al(EGCG)(H 2 O) 2 could inhibit the hIAPP fibrillation more effectively than EGCG alone. The results provide the invaluable reference for the new drug development to treat type II diabetes., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Scarring of the kidney directly promotes loss of kidney function. A thorough understanding of renal fibrosis at the molecular level is urgently needed. One prominent microRNA, miR-21, was previously reported to be up-regulated in renal fibrosis, but its mechanism is unclear. In the present study, an unbiased search for downstream messenger RNA targets of miR-21 using the HK-2 human tubular epithelial cell line was performed. Effects of the target gene in renal fibrosis and underlying mechanism were explored. Results show that forced expression of miR-21 significantly increased cell apoptosis, interstitial deposition, and decreased E-cadherin level of the HK-2 cells. Conversely, inhibition of miR-21 promoted the opposite effects. We identified that miR-21 directly interacted with the 3'-untranslated region of the suppressor of dimethylarginine dimethylaminohydrolase 1 (DDAH1) by dual-luciferase assay. Moreover, pcDNA3.1-DDAH1 pretreatment could effectively reduce α-SMA, collagen I, fibronectin expression, and promoted E-cadherin expression, as well as inhibiting HK-2 cell apoptosis, while all those effects can be attenuated by pretreatment with the Wnt/β-catenin signaling activator Licl. Taken together, our results suggest that miR-21 may regulate renal fibrosis by the Wnt pathway via directly targeting DDAH1. Therefore, this study may provide novel strategies for the development of renal fibrosis therapy.

Aims: Circulating microRNAs (miRNAs) as biomarkers for leukemia have been validated by emerging studies. This meta-analysis aims to estimate the overall diagnostic accuracy of blood-based circulating miRNAs for leukemia., Methods: We searched multiple databases (PubMed, EMBASE, Cochrane Library, CNKI, Wan Fang Data and CQVIP) up to June 18, 2015., Results: 32 studies from 10 publications were included in this meta-analysis. Diagnostic capacity was evaluated by pooled sensitivity, specifIcity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) through random-effects model. Sensitivity analyses were sequentially performed to find potential sources of heterogeneity. The quality of included studies was assessed by QUADAS (quality assessment for studies of diagnostic accuracy). Meta-Disc 1.4 and Stata 12.0 software were used to perform the meta-analysis. A high diagnostic accuracy was displayed, with a sensitivity of 0.84, a specificity of 0.88, a PLR of 7.20, a NLR of 0.18, a DOR of 52, and an AUC of 0.94. Subgroup analyses revealed better performance for combined miRNAs, acute myeloid leukemia patients and Asian population than other subgroups., Conclusion: Our analyses suggested that blood-based circulating miRNAs are promising diagnostic biomarkers for leukemia, especially combined miRNAs. Its clinical application awaits further study., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs' characteristics.

Background: Arginine vasopressin (AVP) is considered to be an etiologic hormone in motion sickness (MS). The present study was designed to investigate whether individual differences in AVP expression in the paraventricular nucleus (PVN) and in modulation on the vestibular nucleus (VN) are involved in MS. Systemic application or microinjection of AVP into rat VN and rotatory stimulus were used to induce conditioned taste aversion (CTA) to 0.15 % saccharin sodium solution as a model of MS., Results: Intra-VN use of SSR149415, an antagonist of V1b receptors (V1bRs), blunted CTA. AVP inhibited Ca(2+) influxes through L-type Ca(2+) channels and NMDA receptor channels in cultured VN neurones, but antagonised by SSR149415. More AVP and V1bRs were expressed respectively in the PVN and VN after rotatory stimulus, especially in rats susceptible to MS. In the VN, AVP content was low, the AVP mRNA was less expressed, a few AVP-positive fibres were sparsely distributed, and fewer AVP/synaptophysin-positive terminals were identified. Almost no fluoro-ruby-labelled AVP-positive neurones in the PVN were found with retrograde tracing from the VN. SNP analysis of the reported 9 sites of the AVP gene showed significant difference between the groups susceptible and insusceptible to MS at the site rs105235842 in the allele frequencies and genotypes. However, there was not any difference between these two groups in the SNP of the reported 38 sites of V1bR gene., Conclusions: AVP, through its modulatory, possibly humoral action on the VN neurones via the mediation of V1bR, may contribute to the development of motion sickness in rats; AVP gene polymorphisms may contribute to the individual difference in the responsive expression of AVP in the PVN; and higher expressions of AVP in the PVN and V1bRs in the VN may contribute to the development of motion sickness in rats after vestibular stimulation.

Objective: Acute myeloid leukemia (AML) is the second leading leukemia in children. There is growing evidence that microRNAs (miRNAs) are crucial regulators involved in leukemogenesis. This study aimed to investigate the role of miR-155 in Chinese pediatric AML by evaluating its diagnostic and prognostic significance., Patients and Methods: The expression of miR-155 and miR-25 in bone marrow specimens from 83 AML and 29 non-malignancies children were analyzed by TaqMan probe-based real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR)., Results: The expression level of miR-155 was significantly higher in AML patients than in controls. Besides, a lowest miR-155 level was found in favorable prognosis group and t (15; 17)/M3 subgroup compared to the rest, while a higher level in C-Kit/FLT3-ITD mutation and relatively lower level existed in "Negative" mutation group. Moreover, miR-155 level was positively associated with the white blood cell (WBC) count, serum lactate dehydrogenase (LDH) and C-reaction protein (CRP) value in peripheral blood (PB), as well as miR-25/miR-196b expression levels. Survival analysis showed a statistically negative association with overall survival (OS) in the expression of miR-155 in chemotherapy group., Conclusions: These finding suggested that miR-155 expression cannot only be promising biomarker for the early detection of pediatric AML but also predict poor outcome. MiR-155 would be a novel biomarker for diagnosis, prognosis and therapy in pediatric AML.

Previously we reported that valproic acid (VPA) acts in synergy with GOS to enhance cell death in human DU145 cells. However, the underlying mechanism remains elusive. In this study, we observed that such synergistic cytotoxicity of GOS and VPA could be extended to human A375, HeLa, and PC-3 cancer cells. GOS and VPA co-treatment induced robust apoptosis as evidenced by caspase-8/-9/-3 activation, PARP cleavage, and nuclear fragmentation. GOS and VPA also markedly decreased cyclin A2 protein expression. Owing to the reduction of cyclin A2, Akt signaling was suppressed, leading to dephosphorylation of FOXO3a. Consequently, FOXO3a was activated and the expression of its target genes, including pro-apoptotic FasL and Bim, was upregulated. Supporting this, FOXO3a knockdown attenuated FasL and Bim upregulation and apoptosis induction in GOS+VPA-treated cells. Furthermore, blocking proteasome activity by MG132 prevented the downregulation of cyclin A2, dephosphorylation of Akt and FOXO3a, and induction of apoptosis in cells co-treated with GOS and VPA. In mouse model, GOS and VPA combination significantly inhibited the growth of A375 melanoma xenografts. Our findings indicate that GOS and VPA co-treatment induces apoptosis in human cancer cells by suppressing the cyclin-A2/Akt/FOXO3a pathway.

Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMΦs) is correlated with enhanced production of IL-6 and TNF-α upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMΦs from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection.

Objective: We conducted a meta-analysis of case-controlled prospective or retrospective studies to assess the effect of MTHFR polymorphisms on the risk of developing endometrial cancer., Materials and Methods: PubMed, Cochrane, EMBASE, and ISI Web of Knowledge were searched (up to March 2014) for prospective or retrospective case-controlled studies that investigated the association of three MTHFR polymorphisms (rs180113 [C677T], rs1801131 [A1289C], and rs2274976 [G1793A]) with endometrial cancer., Results: The patient population included subjects from three separate countries: China, Spain, and the USA. Only one study reported quantitative findings for MTHFR G1793A and, consequently, this polymorphism was not evaluated in our analysis. There were no significant associations of any MTHFR C677T or MTHFR A1298C alleles or genotypes with endometrial cancer (all p > 0.300)., Conclusion: This meta-analysis does not support the association of endometrial cancer with two common MTHFR polymorphisms from this patient population., (Copyright © 2015. Published by Elsevier B.V.)

Aims: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits., Results: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA., Innovation and Conclusion: These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment.

We selected the grid of 5 m x 5 m in a dynamic monitoring plot (340 m x 300 m) as the sampling unites and chose 5 structural characteristics (density, average crown breadth, coverage, conspicuousness and average height) to study the spatial heterogeneity of community structure of Picea crassifolia forest in Dayekou Basin of Qilian Mountains by the fractal geometry and geostatistics methods. The results showed that the order of spatial variation in these characteristics was: density > average crown breadth > conspicuousness > coverage > average height, with the variation coefficient ranging from 43.7% to 79.6%. Moran's I index indicated that the structural variables had different degrees of spatial autocorrelation, and the order of autocorrelation was density > average height> coverage > average crown breadth > conspicuousness, with the range of -0.047-0.382. The exponential semivariation model well fitted the spatial variability in different structural features, and the range was 24.6-68.1 m. The variables displayed moderate spatial autocorrelation except for coverage, while the other variables had strong spatial autocorrelation, and the fractal dimension of the variables was close to 2, indicating a low spatial dependence among variables. The variables presented a superposing characteristic of zonal and patchy structures except for density and coverage, while the other variables presented strong patchiness property. Density and coverage had a certain spatial dependence on average crown breadth, conspicuousness and average height. Density and coverage for the spatial heterogeneity of community structural of P. crassifolia forests were 10 m and 0.5 hm2, respectively.

This study was designed to evaluate the neuroprotective effect of l-serine and the underlying mechanisms in mice after traumatic brain injury (TBI) induced using a weight drop model. The mice were intraperitoneally injected with l-serine 3 h after TBI and then injected twice each day for 7 days or until the end of the experiment. The neurological severity score, brain water content, lesion volume, and neurone loss were determined. The levels of TNF-α, IL-1β, IL-6, and IL-10 and the number of GFAP- and Iba-1-positive cells and activated caspase-3-positive neurones in the brain tissue ipsilateral to TBI were also measured. Simultaneously, the influences of l-serine on these variables were observed. In addition, the expression of glycine receptors and l-serine-induced currents were measured. We found l-serine treatment: 1) decreased the neurological deficit score, brain water content, lesion volume, and neurone loss; 2) inhibited activated caspase-3; and 3) reduced the levels of TNF-α, IL-1β and IL-6 and the number of GFAP- and Iba-1-positive cells. The effects of l-serine were antagonised by the administration of strychnine, an antagonist of glycine receptors. In addition, we found that glycine receptors were expressed mainly in the cortical neurones but less in the astrocytes or microglial cells, and l-serine activated these receptors and induced strychnine-sensitive currents in these neurones. In conclusion, l-serine induces the activation of glycine receptors, which alleviates neuronal excitotoxicity, a secondary brain injury process, thereby reduces the activation of astrocytes and microglial cells and secretion of proinflammatory cytokines and inhibits neuronal apoptosis. Thus, l-serine treatment leads to neuroprotection of brain tissue through reducing inflammatory responses and improves recovery of the neurological functions in mice after traumatic brain injury., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Acute lymphoblastic leukaemia (ALL) is a common paediatric cancer and is among the most curable cancers. However, the acquisition of drug resistance is a significant obstacle to the achievement of favourable outcomes, and autophagy is regarded as a mechanism that underlies chemoresistance. In this study, RT-qPCR was used to measure the expression of HMGB1 and Beclin1 in bone marrow mononuclear cells. A CCK-8 test was conducted to assess cell viability. Western blot, immunofluorescence and transmission electron microscopic analyses were performed to evaluate the autophagy levels. Immunoprecipitation analysis was performed to detect protein-protein interactions in the autophagy complexes. We found that HMGB1 expression correlated with the clinical status of ALL. In vitro, anticancer agent-induced cytotoxic effects were associated with autophagy-related drug resistance, and these effects were ameliorated by FIP200 depletion or the application of autophagy inhibitors. Moreover, the Ulk1‑Atg13-FIP200 complex, which promotes HMGB1 trafficking, acted upstream of the HMGB1-Beclin1 and PI3KC3-Beclin1 complexes and played a critical role in autophagy. Targeting the transformation of autophagic complexes or HMGB1 translocation may suppress autophagy and consequently overcome chemoresistance in leukaemia.

The ribonucleotide reductase M2 subunit (RRM2) modulates the enzymatic activity of ribonucleotide reductase, and is involved in tumor progression. Recently, high levels of RRM2 expression were reported to correlate with poor survival outcomes in patients with colorectal and bladder cancer. However, changes in RRM2 expression in nasopharyngeal carcinoma (NPC), and its effect on the prognosis of this disease remain unknown. The aim of the present study was to analyze the expression of RRM2 in NPC cell lines, and to identify whether RRM2 may serve as a biomarker with which to assess the prognosis of NPC. The present study found that RRM2 expression was higher in NPC cell lines and tissue samples than in noncancerous nasopharyngeal epithelial cell lines and noncancerous tissues, as shown by reverse transcription-quantitative polymerase chain reaction analysis, western blotting and immunohistochemistry staining. Kaplan-Meier survival analysis demonstrated that patients with higher RRM2 expression levels had poorer disease-free survival outcomes than those with lower expression levels of RRM2. Univariate analysis showed that a lower survival rate was significantly associated with high RRM2 expression levels [hazard ratio (HR), 6.424; 95% confidence interval (CI), 2.381-17.333; P<0.001]. Multivariate analysis indicated that RRM2 expression is an independent prognostic factor for patients with NPC (HR, 3.461; 95 % CI, 1.204-9.949; P=0.021). Overexpression of RRM2 led to increased cell proliferation, colony formation, migration and invasion in vivo. These results suggest that high levels of RRM2 expression may be a useful predictor for survival in patients with NPC and may serve as a novel prognostic indicator for these individuals.

Objective: To observe the protection of Qingyuan Shenghua Decoction (QSD) on multiple organs of sepsis patients after bone trauma, and to preliminarily explore its mechanism., Methods: Totally 60 sepsis patients after bone trauma were randomly assigned to the treatment group and the control group according to random digit table, 30 in each group. All patients received routine Western medical treatment. Patients in the treatment group additionally took QSD or were nasally fed with QSD, one dose per day for 1 week. Changes of WBC, oxygenation index (PaO2/FiO2), serum creatinine (SCr), total bilirubin (TBIL), aspartate aminotransferase (AST), fibrinogen (FIB), D-dimer (DD), activated partial thromboplastin time (APTT), pro-calcitonin (PCT), C-reactive protein (CRP), heart rate (HR), mean arterial pressure (MAP), intra-abdominal pressure, scores for Acute Physiology and Chronic Health Evaluation II (APACHE II), sequential organ failure assessment (SOFA) scores were observed before treatment and on day 1, 3 and 7 after treatment., Results: Compared with the control group at the same time point, MAP increased at post-treatment day 1 and 3; CRP, APTT, HR, SCr, TBIL, AST, intra-abdominal pressure at post-treatment day 3 obviously decreased in the treatment group (P < 0.05, P < 0.01). WBC, SOFA scores, PCT, CRP, APACHE II, APTT, D-D, HR, SCr, TBIL, AST and intra-abdominal pressure significantly decreased; FIB, MAP and PaO2/FiO2 obviously increased at post-treatment day 7 (P < 0.05, P < 0.01)., Conclusion: QSD had good protective effect on multiple organ function in sepsis patients after bone trauma, and its mechanism might be related with effectively clearing endotoxin, alleviating inflammatory reactions, and fighting against coagulation dysfunction.

Acute and chronic lead (Pb) exposure might cause hypertension and cardiovascular diseases. The purpose of this study was to evaluate the effects of early acute exposure to Pb on the cellular morphology, apoptosis, and proliferation in rats and to elucidate the early mechanisms involved in the development of Pb-induced hypertension. Very young Sprague-Dawley rats were allowed to drink 1% Pb acetate for 12 and 40 days. Western blot analysis indicated that the expression of proliferating cell nuclear antigen (PCNA) decreased in the tissues of the abdominal and thoracic aortas and increased in the cardiac tissue after 12 and 40 days of Pb exposure, respectively. Bax was upregulated and Bcl-2 was downregulated in vascular and cardiac tissues after 40 days of Pb exposure. In addition, an increase in caspase-3 activity was observed after 40 days of exposure to Pb. In terms of morphology, we found that the internal elastic lamina (IEL) of aorta lost the original curve and the diameter of cardiac cell was enlarged after 40 days. Furthermore, the exposure led to a marked increase in acetylated histone H3 levels in the aortas and cardiac tissue after 12 and 40 days, than that in the control group. These findings indicate that Pb might increase the level of histone acetylation and induce apoptosis in vascular and cardiac tissues. However, the mechanism involved need to be further investigated.

A novel endophytic actinobacterium, designated strain YIM 64602T, was isolated from healthy stems of Tripterygium wilfordii. It grew at 15-40 °C, pH 6.0-9.0 and in the presence of 0-3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YIM 64602T belongs to the genus Stackebrandtia. Whole-cell hydrolysates of strain YIM 64602T contained the amino acid meso-diaminopimelic acid with the sugars mannose, rhamnose and glucose, and a trace of ribose. The major polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine and phosphatidylethanolamine. MK-10(H6), MK-10(H4) and MK-11(H4) were the predominant components in the quinone system. The fatty-acid pattern was mainly composed of the saturated branched-chain acids iso-C16 : 0, anteiso-C17 : 0, iso-C15 : 0 and iso-C17 : 0. The DNA G+C content was 72.4 mol%. 16S rRNA gene sequence analysis showed the highest pairwise sequence identity (96.0-98.5 %) with the members of the genus Stackebrandtia. Strain YIM 64602T displayed a DNA-DNA relatedness of 43.9±0.4 % with the type strain Stackebrandtia albiflava YIM 45751T. Based on evidence from this polyphasic study, strain YIM 64602T ( = BCRC 16954T = DSM 45928T) is considered to represent a novel species of the genus Stackebrandtia, for which the name Stackebrandtia endophytica is proposed.

Cucurbitacins, the natural triterpenoids possessing many biological activities, have been reported to suppress the mTORC1/p70S6K pathway and to induce autophagy. However, the correlation between such activities is largely unknown. In this study, we addressed this issue in human cancer cells in response to cucurbitacin E (CuE) treatment. Our results showed that CuE induced autophagy as evidenced by the formation of LC3-II and colocalization of punctate LC3 with the lysosomal marker LAMP2 in HeLa and MCF7 cells. However, CuE induced much lower levels of autophagy in ATG5-knocked down cells and failed to induce autophagy in DU145 cells lacking functional ATG5 expression, suggesting the dependence of CuE-induced autophagy on ATG5. Consistent with autophagy induction, mTORC1 activity (as reflected by p70S6K and ULK1S758 phosphorylation) was inhibited by CuE treatment. The suppression of mTORC1 activity was further confirmed by reduced recruitment of mTOR to the lysosome, which is the activation site of mTORC1. In contrast, CuE rapidly activated AMPK leading to increased phosphorylation of its substrates. AMPK activation contributed to CuE-induced suppression of mTORC1/p70S6K signaling and autophagy induction, since AMPK knockdown diminished these effects. Collectively, our data suggested that CuE induced autophagy in human cancer cells at least partly via downregulation of mTORC1 signaling and upregulation of AMPK activity.

The anti-inflammatory property of chloroquine (CQ) has long been recognized. This study aimed to investigate the effect of CQ on proinflammatory cytokine expression in RAW 264.7 macrophages stimulated with heat-inactivated Staphylococcus aureus cells (SAC). The results showed that CQ treatment reduced the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and CC chemokine ligand 2 (CCL2) in culture medium but increased intracellular protein expression of TNF-α and CCL2 in SAC-activated cells. However, CQ showed differential effects on their messenger RNA (mRNA) levels: it reduced IL-6 mRNA expression, increased CCL2 mRNA levels, but had no effect on TNF-α mRNA. The SAC-activated inflammatory signaling pathways were slightly or minimally affected by CQ treatment. Additionally, CQ increased the accumulation of pro-TNF-α proteins within cells, suggesting an inhibition of pro-TNF-α processing and secretion. Collectively, CQ differentially modulated proinflammatory cytokine expression in Gram-positive bacterium-activated macrophages at multiple regulatory layers in the course of their biosynthesis.

Diclofenac is a nonsteroidal anti-inflammatory drug. It undergoes hydroxylation by mammalian cytochrome P450 enzymes at 4'- and/or 5'-positions. A bacterial P450 enzyme, CYP105D7 from Streptomyces avermitilis, has been shown to catalyze hydroxylation of 1-deoxypentalenic acid and an isoflavone daidzein. Here, we demonstrated that CYP105D7 also catalyzes hydroxylation of diclofenac at the C4'-position. A spectroscopic analysis showed that CYP105D7 binds diclofenac in a slightly cooperative manner with an affinity of 65 μM and a Hill coefficient of 1.16. The crystal structure of CYP105D7 in complex with diclofenac was determined at 2.2 Å resolution. The distal pocket of CYP105D7 contains two diclofenac molecules, illustrating drug recognition with a double-ligand-binding mode. The C3' and C4' atoms of the dichlorophenyl ring of one diclofenac molecule are positioned near the heme iron, suggesting that it is positioned appropriately for aromatic hydroxylation to yield the 4'-hydroxylated product. However, recognition of diclofenac by CYP105D7 was completely different from that of rabbit CYP2C5, which binds one diclofenac molecule with a cluster of water molecules. The distal pocket of CYP105D7 contains four arginine residues, forming a wall of the substrate-binding pocket, and the arginine residues are conserved in bacterial P450s in the CYP105 family.

Puerarin is shown to exert a variety of pharmacological effects including neuroprotective properties. However, mechanisms of the action are not fully understood. This study was designed to explore the mechanism of puerarin in treatment of acute spinal ischemia-reperfusion injury in rats. Acute spinal ischemia-reperfusion injury was conducted by aortic occlusion in twenty-eight male Sprague-Dawley rats, weighting 230-250 g. The animals were randomly divided into four groups. In the animals with puerarin treatment, 50 mg/kg of puerarin was injected intraperitoneally after reperfusion, and followed by the same dose of injection every 24h for 2 days. In the animals with roscovitine pre-treatment, 30 mg/kg roscovitine was intravenously administrated 60 min before spinal ischemia started. After spinal ischemia for 60 min followed by 48 h of reperfusion, the motor function, spinal infarction volume, apoptosis indices and the activities of Cdk5 and p25 were examined. Acute spinal ischemia-reperfusion resulted in an injury of the spines associated with motor deficit, elevation of Cdk5 and p25 activities, and increase in the spinal apoptosis number and spinal infarction volume. Puerarin improved motor function associated with the decreased apoptosis number, spinal infarction volume, and Cdk5 and p25 activities. The present study indicated that reduction of spinal injury was associated with inhibition of Cdk5 and p25, and that inhibition of Cdk5 and p25 was one of the neuroprotective mechanisms in the puerarin treatment of acute ischemia/reperfusion-induced spinal injury in rats., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the efficacy of intraoperative three-dimensional (3D) Iso-C C-arm-navigated percutaneous radiofrequency ablation (RFA) of osteoid osteomas., Methods: 35 patients (20 males and 15 females) with osteoid osteomas underwent treatment with intraoperative 3D Iso-C C-arm navigation-guided RFA. The tumour was first biopsied for pathological examination, the core needle was removed and the RFA needle was inserted into the nidus. Post-operative X-rays and CT scans were performed to evaluate the degree of ablation and to assess for recurrence at 3-month follow-up. Patients also completed a visual analogue scale (VAS) both pre-operatively and 3 days post-operatively to subjectively assess pain., Results: Pathological diagnosis confirmed osteoid osteoma in 19 cases. The other 16 cases were not pathologically diagnosed owing to inadequate biopsy specimens. In all cases, localized pain was immediately relieved following RFA. Patients reported significantly decreased pain, with mean pre-operative VAS scores of 3.4 reducing to 0.80 at 3 days post-operatively and further to 0.06 at 3-month follow-up (p < 0.05). The mean follow-up time was 15.5 months (range: 3-38 months)., Conclusion: 3D Iso-C C-arm navigation-guided RFA is a safe and effective option for the treatment of osteoid osteomas and may be considered in place of intraoperative CT-guided and open resection., Advances in Knowledge: C-arm image-guided percutaneous RFA mitigates the need for pre-operative CT as well as intraoperative scintigraphy, provides real-time imaging of the anatomy, facilitates accurate resection of the tumour and enables immediate confirmation of excision.

The hydrotalcite with the properties of flame-retardant, eliminating smoke, filling and thermostability is a new kind of inorganic flame retardant. In the work, the MgAl hydrotalcite as flame retardant with Mg/Al molar ratio of 4 (MgAl-LDH) was prepared by using urea as the precipitating agent. The thermolysis behavior of the MgAl-LDH flame retardant was investigated by X-ray diffraction (XRD), fourier transform infrared spectroscopy (FT-IR) and thermogravimetry-differential scanning calorimetry (TG-DSC) as well as self deconvolution and curve-fitting analyses. Thermal phase transition of the MgAl-LDH was clarified, especially the characteristics of the hydroxyl groups (-OH) in the brucite-like layers and the changes in coordinate of the carbonate (CO3(2-)) from the interlayers. Based on thermodynamic data, thermal decomposition process was discussed. By.XRD analysis; it was found that the phase change took place when the decomposition temperature increased. The MgAl-LDH was decarbonated basically to MgAl mixed metal oxides (Mg-Al-O) at 500 °C, and impurity MgAl204 phase formed at 600 °C. According to the analyses of FT-IR, TG-DSC and curve-fitting technique, the hydroxyl groups (-OH) in the brucite-like layers possessed three the ligands such as [Al-OH-Al], [Al-OH-Mg] and [Mg-OH-Mg] modes. Dehydroxylation of the brucite-like layers based on the binding forces, where the [Mg-OH-Mg] among the three modes was the most difficult to be re- moved during the pyrolysis process. In the same way, the CO3(2-) ligands also possessed three modes such as H2O-bridged CO3(2-), monodentate and bidentate coordination modes. Based on the thermodynamic analysis, the thermodynamic properties of the hydrotalcite as flame retardant were evaluated, and the expressions of the Gibbs free energy, (ΔrGθT), as a function of temperature, were derived for the Mg8Al2 (OH)20CO3 crystal. Thermodynamic analysis showed that the removal of -OH from the brucite-like layers was spontaneous process, when the Gibbs free energy (ΔrGθT) was under zero at the temperature (T) above 228. 65 °C. The result and datum were close to the experimental result from the TG-DSC analyses, indicating that the relationship between the Gibbs free energy (ΔrGθT) and temperature (T) from thermodynamic analysis was reliable.

The anti-inflammatory effect of piperine has been largely investigated in macrophages, but its activity on epithelial cells in inflammatory settings is unclear. The present study aimed to investigate the effect of piperine on the expression of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated human epithelial-like SW480 and HT-29 cells. Our data showed that although piperine inhibited the proliferation of SW480 and HT-29 cells in a dose-dependent manner, it had low cytotoxicity on these cell lines with 50 % inhibiting concentration (IC50) values greater than 100 μM. As epithelial-like cells, SW480 and HT-29 cells secreted high levels of the chemokine CXCL8 upon LPS stimulation. Importantly, piperine dose-dependently suppressed LPS-induced secretion of CXCL8 and the expression of CXCL8 messenger RNA (mRNA). Although piperine failed to affect the critical inflammatory nuclear factor-κB pathway, it attenuated the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling. Consistent with previous reports, p38 signaling seemed to play a more pronounced role on the CXCL8 expression than JNK signaling since inhibition of p38, instead of JNK, greatly suppressed LPS-induced CXCL8 expression. Collectively, our results indicated that piperine could attenuate the inflammatory response in epithelial cells via downregulating the MAPK signaling and thus the expression of CXCL8, suggesting its potential application in anti-inflammation therapy.

Previously, we have reported alterations to HSP27 during Microcystin-LR (MC-LR)-induced cytoskeletal reorganization in the human liver cell line HL7702. To further elucidate the detailed mechanism of MC-LR-induced cytoskeletal assembly, we focused on two cytoskeletal-related proteins, Tau and VASP. These two proteins phosphorylated status influences their ability to bind and stabilize cytoskeleton. We found that MC-LR markedly increased the level of Tau phosphorylation with the dissociation of phosphorylated Tau from the cytoskeleton. Furthermore, the phosphorylation of Tau induced by MC-LR was suppressed by an activator of PP2A and by an inhibitor of p38 MAPK. VASP was also hyperphosphorylated upon MC-LR exposure; however, its phosphorylation appeared to regulate its cellular localization rather than cytoskeletal dynamics, and its phosphorylation was unaffected by the PP2A activator. These data suggest that phosphorylated Tau is regulated by p38 MAPK, possibly as a consequence of PP2A inhibition. Tau hyperphosphorylation is likely an important factor leading to the cytoskeletal destabilization triggered by MC-LR and the role of VASP alteration upon MC-LR exposure needs to be studied further. To our knowledge, the finding that Tau is implicated in cytoskeletal destabilization in MC-LR-treated hepatocytes and MC-LR-induced VASP's alteration has not been reported previously., (© 2013 Wiley Periodicals, Inc.)

Background: Thyroid carcinoma is the most common malignancy of the endocrine organs. Although the majority of thyroid cancer patients experience positive outcomes, anaplastic thyroid carcinoma is considered one of the most aggressive malignancies. Current therapeutic regimens do not confer a significant survival benefit, and new therapies are urgently needed. Oncolytic herpes simplex virus (oHSV) may represent a promising therapy for cancer. In the present study, we investigated the therapeutic effects of a third-generation HSV vector, G47Δ, on various human thyroid carcinoma cell lines in vitro. Two subcutaneous (s.c.) models of anaplastic thyroid carcinoma were also established to evaluate the in vivo anti-tumor efficacy of G47Δ., Materials and Methods: The human thyroid carcinoma cell line ARO, FRO, WRO, and KAT-5, were infected with G47Δat different multiplicities of infection (MOIs) in vitro. The survival rates of infected cells were calculated each day. Two s.c. tumor models were established using ARO and FRO cells in Balb/c nude mice, which were intratumorally (i.t.) treated with either G47Δor mock. Tumor volumes and mouse survival times were documented., Results: G47Δ was highly cytotoxic to different types of thyroid carcinomas. For ARO, FRO, and KAT-5, greater than 30% and 80% of cells were killed at MOI=0.01 and MOI=0.1, respectively on day 5. WRO cells displayed modest sensitivity to G47Δ, with only 21% and 38% of cells killed. In the s.c. tumor model, both of the anaplastic thyroid carcinoma cell lines (ARO and FRO) were highly sensitive to G47Δ G47Δ significantly inhibited tumor growth and prolonged the survival of mice bearing s.c. ARO and FRO tumors., Conclusions: The oHSV G47Δ can effectively kill different types of human thyroid carcinomas in vitro. G47Δ significantly inhibited growth of anaplastic thyroid carcinoma in vivo and prolonged animal survival. Therefore, G47Δ may hold great promise for thyroid cancer patients.

Background: Acute kidney injury (AKI) is traditionally described as a condition leading to rapid damage to kidney function, eventually becoming a significant healthcare concern with a high mortality rate. Autophagy deficiency in the tubular epithelial cells is the main cause of AKI; however, the underlying molecular mechanism remains to be defined. MicroRNAs (miRNAs) are related to autophagy in many diseases. This study was aimed at investigating the relationship between miRNA expression and autophagic activity in the pathogenesis of AKI., Methods: A mouse model of AKI was produced by ischemia reperfusion (I/R). The expressions of microRNA-34a (miR-34a) and the autophagy-related protein LC3 II/I and p62 were determined in renal tissues and the tubular epithelial cells (RTECs). Moreover, the autophagic activity was investigated after miR-34a overexpression and inhibition. Additionally, the effect of miR-34a on its target gene in regulating autophagic activity in RTECs was also investigated., Results: I/R suppressed the autophagic activity and increased the expression of miR-34a in renal tissues. The in vitro data showed that the upregulation of miR-34a suppressed, whereas the inhibition of miR-34a promoted, autophagy in RTECs. Moreover, miR-34a could directly bind to Atg4B 3'-untranslated region. In addition, the knockdown of Atg4B expression inhibited the autophagic activity in RTECs., Conclusion: This study indicated that miR-34a might regulate the autophagic activity and can cause injury in I/R RTECs via targeting Atg4B., (© 2015 S. Karger AG, Basel.)

A new C3-symmetric Schiff-base fluorescent probe (L) based on 8-hydroxy-2-methylquinoline has been developed. As expected, the probe L can display high fluorescent selectivity for Cd(2+) over Zn(2+) and most other common ions in neutral ethanol aqueous medium. Moreover, the mechanism of the L-Cd(2+) complex has been confirmed by X-ray crystallography and density functional theory calculation results. More importantly, L could be used to image Cd(2+) within living cells.

Ginsenoside Rg1 is one of the major active components of ginseng, which has been shown to regulate the immune response of hosts. However, the mechanism underlying the immunomodulatory effect of Rg1 is incompletely understood. In this study, we aimed to explore whether and how Rg1 regulates the innate immune response in macrophages. The results showed that Rg1 treatment significantly increased tumor necrosis factor (TNF)-α but decreased interleukin-6 (IL-6) protein expression in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and mouse peritoneal macrophages. However, Rg1 reduced the mRNA levels of both cytokines in LPS-activated macrophages, which might be a consequence of decreased activation of IκB and nuclear factor-κB (NF-κB). Importantly, Rg1 treatment further promoted LPS-induced activation of the Akt/mechanistic target of rapamycin (mTOR) pathway, which is critical for controlling protein translation. The elevated Akt/mTOR signaling was likely responsible for increased production of TNF-α protein at the translational level, as suppression of this pathway by LY294002, an inhibitor of the upstream phosphatidylinositol 3-kinase (PI3K), abrogated such an enhancement of TNF-α protein expression even though its mRNA levels were conversely increased. These findings highlight a novel mechanism for Rg1 to regulate the innate immune response in macrophages through differentially modulating the NF-κB and PI3K/Akt/mTOR pathways., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aims: Our previous studies indicate that glycine can inhibit N-methyl-D-aspartate receptor (NMDAR) responses induced by high concentrations of NMDA in rat hippocampal neurons. The present study was designed to observe whether D-serine induces inactivation of NMDARs in cultured rat hippocampal neurons and to investigate the underlying mechanisms of this effect., Methods: Cell culture, whole-cell patch-clamp electrophysiology, Ca(2+) imaging, immunohistochemistry, and Western blot analysis were used., Results: We found that the peak current and Ca(2+) influx evoked by 30 μM NMDA were increased by co-application of D-serine, but those evoked by 300 μM NMDA were reduced dose-dependently by co-application of D-serine. However, the inhibitory effect of D-serine on NMDAR responses was reversed by ZnCl2 (30 nM), an inhibitor of the NR2A subunit, but was less influenced by ifenprodil (10 μM), an NR2B inhibitor. In addition, the inhibitory effect of D-serine was not detected in young hippocampal neurons that expressed less of the NR2A subunits and reversed in the presence of 10 mM BAPTA., Conclusions: D-serine can also induce inactivation of NMDARs, the NR2A subunit is required for the induction of this effect, and this inactivation is Ca(2+)-dependent in nature. This action of D-serine is hypothesized to play a neuroprotective role upon a sustained large glutamate insult to the brain., (© 2014 John Wiley & Sons Ltd.)

Microcystin-LR (MC-LR) is a potent inhibitor of protein phosphatases 1 and 2A, and has potent hepatotoxicity and tumor promotion activity. Numerous studies on MC-LR toxicity have been conducted in rat hepatocytes, but few studies of the effects of microcystins on human hepatocytes have been done. In this study, HL7702 cells (a human normal liver cell line) were incubated in MC-LR for 24 h. The existence of MC-LR in HL7702 cells was confirmed. Furthermore, PP2A activity and the alteration of PP2A subunits were assessed. The results show that PP2A activity decreased from the concentration of 1 μM MC-LR, showing a concentration-dependent decline, to about 34% at 10 μM MC-LR. This activity undergone opposite change with alternations of phosphorylated Y307-PP2A/C and PP2A/C subunit but showed same change with the alteration of the ratio of methylated L309-PP2A/C to PP2A/C. B55α, a regulatory subunit of PP2A, was slightly increases in cells treated with the highest concentration of MC-LR (10 μM), and colocalized increasedly with rearranged-microtubules after 1 μM MC-LR exposure. However, the proportion of early apoptotic cells did not show any change at various concentration of MC-LR for 24 h. To our knowledge, this is the first report showing MC-LR-induced alteration of PP2A phosphatase in human cultured hepatocytes, and the mechanism of action seems to be similar as described before in vitro. The alteration of PP2A and microtubule seems to be the early event induced by MC-LR exposure., (Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.)

Urban forest is one of the positive factors that increase urban carbon sequestration, which makes great contribution to the global carbon cycle. Based on the high spatial resolution imagery of QuickBird in the study area within the ring road in Yiwu, Zhejiang, the forests in the area were divided into four types, i. e., park-forest, shelter-forest, company-forest and others. With the carbon stock from sample plot as dependent variable, at the significance level of 0.01, the stepwise linear regression method was used to select independent variables from 50 factors such as band grayscale values, vegetation index, texture information and so on. Finally, the remote sensing based forest carbon stock estimation models for the four types of forest were established. The estimation accuracies for all the models were around 70%, with the total carbon reserve of each forest type in the area being estimated as 3623. 80, 5245.78, 5284.84, 5343.65 t, respectively. From the carbon density map, it was found that the carbon reserves were mainly in the range of 25-35 t · hm(-2). In the future, urban forest planners could further improve the ability of forest carbon sequestration through afforestation and interplanting of trees and low shrubs.

Ethnopharmacological Relevance: Ginseng, the root of Panax ginseng C.A. Meyer, is a traditional medicinal herb that has been widely used in Asia for the treatment of many diseases through its effects of reinforcing vitality, strengthening the bodily resistance to pathogenic factors, engendering body liquids and allaying thirst, relieving uneasiness of the body and mind and benefiting intelligence, reducing body weight and prolonging life. Ginsenosides are the most important biologically active substances in ginseng. Many reports have suggested that ginsenosides could exert prominent neuroprotective and neurotrophic effects, promote neural stem/progenitor cell (NSC) proliferation and promote neurite outgrowth and neuronal network formation. The present study aimed to investigate whether treatment with ginsenosides could facilitate NSC proliferation in the hippocampal formation after traumatic brain injury (TBI) and contribute to the recovery of neurological functions including learning and memory., Materials and Methods: The modified Feeney׳s method was used to induce a TBI in rats. Ginseng total saponins (GTS) were treated intraperitoneally twice a day for 1 week after the TBI. The neurological functions, morphology of the hippocampus, expression of nerve growth-related factors and number of NSCs in the hippocampal formation ipsilateral to the trauma were determined., Results: We determined 1) GTS (5-80 mg/kg) treatment after a TBI improved the recovery of neurological functions, including learning and memory, and reduced cell loss in the hippocampal area. The effects of GTS at 20, 40, 60, and 80 mg/kg were better than the effects of GTS at 5 and 10 mg/kg. 2) GTS treatment (20 mg/kg) after a TBI increased the expression of NGF, GDNF and NCAM, inhibited the expression of Nogo-A, Nogo-B, TN-C, and increased the number of BrdU/nestin positive NSCs in the hippocampal formation., Conclusions: GTS treatment in rats after a TBI alleviated the secondary brain injury and ameliorated the neurological functions with an effective dose limit of 5-80 mg/kg. GTS regulated the expression of nerve growth-related factors and improved the proliferation of neural stem/progenitor cells, which might facilitate neural regeneration and tissue repair, and might contribute to the recovery of neurological functions, including learning and memory. These effects of GTS might provide a foundation for the use of ginseng as a medicinal herb to enhance intelligence, reduce the aging process and prolong life in the traditional medicine., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A comprehensive understanding of the energy-level alignment at the organic heterojunction interfaces is of paramount importance to optimize the performance of organic solar cells (OSCs). Here, the detailed electronic structures of organic interconnectors, consisting of cesium fluoride-doped 4,7-diphenyl-1,10-phenanthroline and hexaazatriphenylene-hexacarbonitrile (HATCN), have been investigated via in situ photoemission spectroscopy, and their impact on the charge recombination process in tandem OSCs has been identified. The experimental determination shows that the HATCN interlayer plays a significant role in the interface energetics with a dramatic decrease in the reverse built-in potential for electrons and holes from stacked subcells, which is beneficial to the charge recombination between HATCN and the adjacent layer. In accordance with the energy-level alignments, the open-circuit voltage of tandem OSC incorporating a HATCN-based interconnector is almost 2 times that of a single-cell OSC, revealing the effectiveness of the HATCN-based interconnectors in tandem organic devices.

Objective: Humoral immunity has been clearly implicated in solid organ transplantation, but little is known about the relationship between humoral immunity and hematopoietic stem cell transplantation. This study was designed to investigate that relationship., Materials and Methods: Sensitized serum was obtained from a sensitized murine model established by allogeneic splenocyte transfusion. Sensitized serum was incubated with allogeneic bone marrow cells (BMCs) in vitro and the cytotoxicity was evaluated by the complement-dependent cytotoxicity method. Mice were transplanted with allogeneic BMCs incubated with sensitized serum after lethal irradiation. The engraftment was assayed by hematopoietic recovery and chimera analysis. Moreover, mice received passive transfer of sensitized serum 1 day prior to transplantation. Mortality was scored daily after bone marrow transplantation., Results: The in vitro experiments showed that sensitized serum was capable of impairing allogeneic BMCs through the complement-dependent cytotoxicity pathway. The animal studies showed that BMCs incubated with sensitized serum failed to rescue mice from lethal irradiation. The engraftment assay showed that the allogeneic BMCs incubated with sensitized serum were rejected with time in the recipients. Furthermore, the mice died of marrow graft rejection by transfer of sensitized serum prior to transplantation., Conclusion: Taken together, our results indicated that sensitized serum played a critical role in graft rejection during hematopoietic stem cell transplantation.