Activation of PPAR-α attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis and mitochondrial injury via upregulating 14-3-3η.

This study aimed to explore the effects of peroxisome proliferator-activated receptor α (PPAR-α), a known inhibitor of ferroptosis, in Myocardial ischemia/reperfusion injury (MIRI) and its related mechanisms. In vivo and in vitro MIRI models were established. Our results showed that activation of PPAR-α decreased the size of the myocardial infarct, maintained cardiac function, and decreased the serum contents of creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and Fe2+ in ischemia/reperfusion (I/R)-treated mice. Additionally, the results of H&E staining, DHE staining, TUNEL staining, and transmission electron microscopy demonstrated that activation of PPAR-α inhibited MIRI-induced heart tissue and mitochondrial damage. It was also found that activation of PPAR-α attenuated MIRI-induced ferroptosis as shown by a reduction in malondialdehyde, total iron, and reactive oxygen species (ROS). In vitro experiments showed that intracellular contents of malondialdehyde, total iron, LDH, reactive oxygen species (ROS), lipid ROS, oxidized glutathione disulphide (GSSG), and Fe2+ were reduced by the activation of PPAR-α in H9c2 cells treated with anoxia/reoxygenation (A/R), while the cell viability and GSH were increased after PPAR-α activation. Additionally, changes in protein levels of the ferroptosis marker further confirmed the beneficial effects of PPAR-α activation on MIRI-induced ferroptosis. Moreover, the results of immunofluorescence and dual-luciferase reporter assay revealed that PPAR-α achieved its activity via binding to the 14-3-3η promoter, promoting its expression level. Moreover, the cardioprotective effects of PPAR-α could be canceled by pAd/14-3-3η-shRNA or Compound C11 (14-3-3η inhibitor). In conclusion, our results indicated that ferroptosis plays a key role in aggravating MIRI, and PPAR-α/14-3-3η pathway-mediated ferroptosis and mitochondrial injury might be an effective therapeutic target against MIRI.

Epigallocatechin-3-gallate confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis, apoptosis, and autophagy via modulation of 14-3-3η.

Previous studies have demonstrated that the underlying mechanisms of myocardial ischemia/reperfusion injury (MIRI) are complex and involve multiple types of regulatory cell death, including ferroptosis, apoptosis, and autophagy. Thus, we aimed to identify the mechanisms underlying MIRI and validate the protective role of epigallocatechin-3-gallate (EGCG) and its related mechanisms in MIRI. An in vivo and in vitro models of MIRI were constructed. The results showed that pretreatment with EGCG could attenuate MIRI, as indicated by increased cell viability, reduced lactate dehydrogenase (LDH) activity and apoptosis, inhibited iron overload, abnormal lipid metabolism, preserved mitochondrial function, decreased infarct size, maintained cardiac function, decreased reactive oxygen species (ROS) level, and reduced TUNEL-positive cells. Additionally, EGCG pretreatment could attenuate ferroptosis, apoptosis, and autophagy induced by MIRI via upregulating 14-3-3η protein levels. Furthermore, the protective effects of EGCG could be abolished with pAd/14-3-3η-shRNA or Compound C11 (a 14-3-3η inhibitor) but not pAd/NC-shRNA. In conclusion, EGCG pretreatment attenuated ferroptosis, apoptosis, and autophagy by mediating 14-3-3η and protected cardiomyocytes against MIRI.

Investigation of autophagy­related genes and immune infiltration in calcific aortic valve disease: A bioinformatics analysis and experimental validation.

The present study aimed to elucidate the role of autophagy-related genes (ARGs) in calcific aortic valve disease (CAVD) and their potential interactions with immune infiltration via experimental verification and bioinformatics analysis. A total of three microarray datasets (GSE12644, GSE51472 and GSE77287) were obtained from the Gene Expression Omnibus database, and gene set enrichment analysis was performed to identify the relationship between autophagy and CAVD. After differentially expressed genes and differentially expressed ARGs (DEARGs) were identified using CAVD samples and normal aortic valve samples, a functional analysis was performed, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, protein-protein interaction network construction, hub gene identification and validation, immune infiltration and drug prediction. The results of the present study indicated a significant relationship between autophagy and CAVD. A total of 46 DEARGs were identified. GO and pathway enrichment analyses revealed the complex roles of DEARGs in regulating CAVD, including multiple gene functions and pathways. A total of 10 hub genes were identified, with three (SPP1, CXCL12 and CXCR4) consistently upregulated in CAVD samples compared with normal aortic valve samples in multiple datasets and experimental validation. Immune infiltration analyses demonstrated significant differences in immune cell proportions between CAVD samples and normal aortic valve samples, thus showing the crucial role of immune infiltration in CAVD development. Furthermore, therapeutic drugs were predicted that could target the identified hub genes, including bisphenol A, resveratrol, progesterone and estradiol. In summary, the present study illuminated the crucial role of autophagy in CAVD development and identified key ARGs as potential therapeutic targets. In addition, the observed immune cell infiltration and predicted autophagy-related drugs suggest promising avenues for future research and novel CAVD treatments.

Genome-Wide Association Study Identifies IFIH1 and HLA-DQB1*05:02 Loci Associated With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a rare autoimmune neurologic disorder, the genetic etiology of which remains poorly understood. Our study aims to investigate the genetic basis of this disease in the Chinese Han population. METHODS: We performed a genome-wide association study and fine-mapping study within the major histocompatibility complex (MHC) region of 413 Chinese patients with anti-NMDAR encephalitis recruited from 6 large tertiary hospitals and 7,127 healthy controls. RESULTS: Our genome-wide association analysis identified a strong association at the IFIH1 locus on chromosome 2q24.2 (rs3747517, p = 1.06 × 10-8, OR = 1.55, 95% CI, 1.34-1.80), outside of the human leukocyte antigen (HLA) region. Furthermore, through a fine-mapping study of the MHC region, we discovered associations for 3 specific HLA class I and II alleles. Notably, HLA-DQB1*05:02 (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59) demonstrates the strongest association among classical HLA alleles, closely followed by HLA-A*11:01 (p = 4.36 × 10-7; OR, 1.52; 95% CI 1.29-1.79) and HLA-A*02:07 (p = 1.28 × 10-8; OR, 1.87; 95% CI 1.50-2.31). In addition, we uncovered 2 main HLA amino acid variation associated with anti-NMDAR encephalitis including HLA-DQß1-126H (p = 1.43 × 10-12; OR, 2.10; 95% CI 1.70-2.59), exhibiting a predisposing effect, and HLA-B-97R (p = 3.40 × 10-8; OR, 0.63; 95% CI 0.53-0.74), conferring a protective effect. Computational docking analysis suggested a close relationship between the NR1 subunit of NMDAR and DQB1*05:02. DISCUSSION: Our findings indicate that genetic variation in IFIH1, involved in the type I interferon signaling pathway and innate immunity, along with variations in the HLA class I and class II genes, has substantial implications for the susceptibility to anti-NMDAR encephalitis in the Chinese Han population.

Resveratrol protects cardiomyocytes against ischemia/reperfusion-induced ferroptosis via inhibition of the VDAC1/GPX4 pathway.

The present study aimed to explore how resveratrol (Res) confers myocardial protection by attenuating ferroptosis. In vivo and in vitro myocardial ischemia/reperfusion injury (MIRI) models were established, with or without Res pretreatment. The results showed that Res pretreatment effectively attenuated MIRI, as evidenced by increased cell viability, reduced lactate dehydrogenase activity, decreased infarct size, and maintained cardiac function. Moreover, Res pretreatment inhibited MIRI-induced ferroptosis, as shown by improved mitochondrial integrity, increased glutathione level, decreased prostaglandin-endoperoxide synthase 2 level, inhibited iron overload, and abnormal lipid peroxidation. Of note, Res pretreatment decreased or increased voltage-dependent anion channel 1/glutathione peroxidase 4 (VDAC1/GPX4) expression, which was increased or decreased via anoxia/reoxygenation (A/R) treatment, respectively. However, the overexpression of VDAC1 via pAd/VDAC1 and knockdown of GPX4 through Si-GPX4 reversed the protective effect of Res in A/R-induced H9c2 cells, whereas the inhibition of GPX4 with RSL3 abolished the protective effect of Res on mice treated with ischemia/reperfusion.Interestingly, knockdown of VDAC1 by Si-VDAC1 promoted the protective effect of Res on A/R-induced H9c2 cells and the regulation of GPX4. Finally, the direct interaction between VDAC1 and GPX4 was determined using co-immunoprecipitation. In conclusion, Res pretreatment could protect the myocardium against MIRI-induced ferroptosis via the VDAC1/GPX4 signaling pathway.

Data mining and safety analysis of traditional immunosuppressive drugs: a pharmacovigilance investigation based on the FAERS database.

OBJECTIVE: The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate mofetil(MMF), cyclophosphamide(CTX) and methotrexate(MTX), which have not been concerned. METHODS: The FAERS data from January 2016 and December 2022 were selected for disproportionality analysis to discover the potential risks of traditional immunosuppressive drugs. RESULTS: Compared with CsA, FK506 has more frequent transplant rejection, and is more related to renal impairment, COVID-19, cytomegalovirus infection and aspergillus infection. However, CsA has a high infection-related fatality rate. In addition, we also found some serious and rare AE in other drugs which were rarely reported in previous studies. For example, AZA is closely related to hepatosplenic T-cell lymphoma with high fatality rate and MTX is strongly related to hypofibrinogenemia. CONCLUSION: The AEs report on this study confirmed that the results were basically consistent with the previous studies, but there were also some important safety signals that were inconsistent with or not mentioned in previous published studies. EXPERT OPINION: The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to improve the safety of immunosuppressive drugs.

Role of dysregulated ferroptosis­related genes in cardiomyocyte ischemia­reperfusion injury: Experimental verification and bioinformatics analysis.

Acute myocardial infarction is a life-threatening condition with high mortality and complication rates. Although myocardial reperfusion can preserve ischemic myocardial tissue, it frequently exacerbates tissue injury, a phenomenon known as ischemia-reperfusion injury (IRI). However, the underlying pathological mechanisms of IRI remain to be completely understood. Ferroptosis is a novel type of regulated cell death that is associated with various pathological conditions, including angiocardiopathy. The purpose of this article was to elucidate the possible mechanistic role of ferroptosis in IRI through bioinformatics analysis and experimental validation. Healthy and IRI heart samples were screened for differentially expressed ferroptosis-related genes and functional enrichment analysis was performed to determine the potential crosstalk and pathways involved. A protein-protein interaction network was established for IRI, and 10 hub genes that regulate ferroptosis, including HIF1A, EGFR, HMOX1, and ATF3 were identified. In vitro, an anoxia/reoxygenation (A/R) injury model was established using H9c2 cardiomyoblasts to validate the bioinformatics analysis results, and extensive ferroptosis was detected. A total of 4 key hub genes and 3 key miRNAs were also validated. It was found that IRI was related to the aberrant infiltration of immune cells and the small-molecule drugs that may protect against IRI by preventing ferroptosis were identified. These results provide novel insights into the role of ferroptosis in IRI, which can help identify novel therapeutic targets.

Enhancing Char Formation and Flame Retardancy of Ethylene-Vinyl Acetate Copolymer (EVA)/Aluminum Hydroxide (ATH) Composites by Grafting Ladder Phenyl/Vinyl Polysilsesquioxane (PhVPOSS).

The ladder phenyl/vinyl polysilsesquioxane (PhVPOSS) was used to improve the flame-retardancy performances of ethylene-vinyl acetate copolymer (EVA)/aluminum hydroxide (ATH) composites due to the reactivity of its vinyl groups. FTIR, XPS, 1H NMR, and SEM-EDS data demonstrated the PhVPOSS grafting onto EVA molecular chains. The PhVPOSS improved the thermal stability of EVA/ATH composites, as shown by the thermogravimetric analysis (TGA). Furthermore, with the cone calorimeter (CONE) experiments, EVA/ATH/PhVPOSS showed better fire safety than the EVA/ATH composites, with the PHRR, PSPR, and PCOP reduced by 7.89%, 57.4%, and 90.9%, respectively. The mechanism investigations of flame retardancy revealed that the charring behaviors of the EVA/ATH/PhVPOSS composites were improved by the formation of Si-C bonds and Si-O bonds, and a more compact and denser char layer can contribute more to the barrier effect.

Preparation and Performances of Polyether Polytriazole Elastomers Based on Click Chemistry.

Since the polyurethane elastomer synthesis process is susceptible to moisture, polytriazole polyethylene oxide-tetrahydrofuran (PTPET) elastomer was used as a replacement owing to its mild production environment. In contrast to the conventional flask-synthesis method, the twin-screw reactor instrument could provide more meaningful data in the synthesis. In this study, PTPET elastomer was prepared by the MiniLab twin-screw reactor method for the first time, and the activation energy of the PTPET elastomer was calculated using the torque variation obtained from the MiniLab twin-screw reactor during the synthesis process at two different temperatures. The addition of flame retardants could endow the composites with more useful properties. The PTPET composites poly (phenylsilsesquioxane) (PTPET-PPSQ), octaphenyl polyhedral oligomeric silsesquioxane (PTPET-OPS) and PTPET-PhVPOSS (phenyl/vinyl polysilsesquioxane) were synthesized by using the MiniLab twin-screw reactor. The prepared PTPET elastomer and composites were fully characterized by FT-IR, TG, DSC, swelling test, mechanical test, SEM and combustion test. The characterization results show that the addition of the flame retardants has little influence on the original structure and properties of PTPET elastomer. The flame retardancy was characterized by the combustion test showing that all PTPET composites form a certain thickness of char layer during the burning process. These results indicate that the addition of flame retardants maintains the outstanding properties of PTPET elastomer and also endows the materials with a certain extent of flame retardancy; thus, it is believed to be a good engineering material that could be applied in many realms.

[Antibiotic Pollution Characteristics and Ecological Risk Assessment in Jinjiang River Basin, Jiangxi Province].

The concentration and distribution characteristics of 27 antibiotics, including 8 sulfonamides, 9 quinolones, 4 tetracyclines, 4 macrolides, and 2 nitroimidazoles, in the surface water, groundwater, and wastewater of the Jinjiang River basin in Jiangxi province were determined using solid-phase extraction combined with ultra-performance liquid chromatography-tandem triple quadrupole mass spectrometry. The results showed that there was antibiotic pollution in the waters of the Jinjiang River basin. A total of 20 antibiotics were detected in the surface water, with a concentration range of 32.3-280 ng·L-1. There were 15 types of antibiotics detected in the groundwater, and the concentration range was 28.4-55.8 ng·L-1. Twenty-one types of antibiotics were detected in the wastewater, with a concentration range of 231-8.71×104 ng·L-1. A comparison with the concentrations of eight common antibiotics in rivers and lakes in China and abroad showed that the pollution level in the Jinjiang River basin was at a medium level. By comparing the concentrations of sulfamethoxazole in groundwater from domestic and international samples, the groundwater pollution in the Jinjiang River basin was clearly in the middle and lower range. A comparison of the concentrations of the three antibiotics in the aquaculture wastewater from domestic and abroad samples indicated that the pollution level of sulfadiazine in the aquaculture wastewater from the Jinjiang River basin was relatively high. The ecological risk assessment results showed that there were nine medium- and high-risk antibiotics, which were clarithromycin, erythromycin, ciprofloxacin, sulfathiazole, roxithromycin, tetracycline, ofloxacin, enrofloxacin, and sulfamethoxazole; the rest were low-risk or no-risk antibiotics.

Transcriptome and Metabolome Comparison of Smooth and Rough Citrus limon L. Peels Grown on Same Trees and Harvested in Different Seasons.

Background: Farmers harvest two batches fruits of Lemons (Citrus limon L. Burm. f.) i.e., spring flowering fruit and autumn flowering fruit in dry-hot valley in Yunnan, China. Regular lemons harvested in autumn have smooth skin. However, lemons harvested in spring have rough skin, which makes them less attractive to customers. Furthermore, the rough skin causes a reduction in commodity value and economical losses to farmers. This is a preliminary study that investigates the key transcriptomic and metabolomic differences in peels of lemon fruits (variety Yuning no. 1) harvested 30, 60, 90, 120, and 150 days after flowering from the same trees in different seasons. Results: We identified 5,792, 4,001, 3,148, and 5,287 differentially expressed genes (DEGs) between smooth peel (C) and rough peel (D) 60, 90, 120, and 150 days after flowering, respectively. A total of 1,193 metabolites differentially accumulated (DAM) between D and C. The DEGs and DAMs were enriched in the mitogen-activated protein kinase (MAPK) and plant hormone signaling, terpenoid biosynthesis, flavonoid, and phenylalanine biosynthesis, and ribosome pathways. Predominantly, in the early stages, phytohormonal regulation and signaling were the main driving force for changes in peel surface. Changes in the expression of genes associated with asymmetric cell division were also an important observation. The biosynthesis of terpenoids was possibly reduced in rough peels, while the exclusive expression of cell wall synthesis-related genes could be a possible reason for the thick peel of the rough-skinned lemons. Additionally, cell division, cell number, hypocotyl growth, accumulation of fatty acids, lignans and coumarins- related gene expression, and metabolite accumulation changes were major observations. Conclusion: The rough peels fruit (autumn flowering fruit) and smooth peels fruit (spring flowering fruit) matured on the same trees are possibly due to the differential regulation of asymmetric cell division, cell number regulation, and randomization of hypocotyl growth related genes and the accumulation of terpenoids, flavonoids, fatty acids, lignans, and coumarins. The preliminary results of this study are important for increasing the understanding of peel roughness in lemon and other citrus species.

[Ecosystem service function of green manure and its application in dryland agriculture of China]. / ç»¿è‚¥åœ¨æˆ‘å›½æ—±åœ°å†œä¸šç”Ÿæ€ç³»ç»Ÿä¸­çš„æœåŠ¡åŠŸèƒ½åŠå ¶åº”ç”¨.

Dryland agriculture, with wide distribution and high yield potential, plays an important role in ensuring food security in China. It is currently limited by water scarcity, soil depletion, water and soil loss, and low non-renewable resource-use efficiency. Green manure has the potential to improve growth environment of crops and promote sustainable high-yield crops by increasing soil quality, balancing soil nutrients, and enhancing soil water-storage capacity. In addition, green manure has ecological benefits, including enhancing agroecosystem biodiversity, increasing soil surface cover degree, reducing ineffective nutrient loss to environment, improving air balance of farmland systems, and biological control of diseases, insect pests, and weeds. Under current scenario of intensified global climate change, environmental deterioration, and agricultural product demand changes, the traditional agronomic techniques of using green manure as a fertilizer cannot satisfy the requirements of agricultural development. Thus, it is necessary to strengthen the selection and bree-ding of green manure genetic resources for dryland agriculture, to develop a new regionalization of green manure, and to establish a cropping pattern based on green manure suitable for different regions. Furthermore, it is important to study and optimize the tillage and cultivation techniques to satisfy modern production and to establish an evaluation system for the comprehensive benefits of green manure. It is needed to establish a green manure application pattern that enables resource and ecological protection for improving ecological environment and economic efficiency of dryland agriculture and provides theoretical basis and technical support for exploiting green manure benefits.

[Emergy analysis, water-heat utilization, and carbon emission of typical cropping patterns in the oasis irrigation area.] / ç»¿æ´²çŒåŒºå ¸åž‹ç§æ¤æ¨¡å¼çš„æ°´çƒ­åˆ©ç”¨ä¸Žç¢³æŽ’æ”¾å’Œèƒ½å€¼åˆ†æž.

Reasonable cropping pattern can improve resource utilization efficiency, reduce environmental risks in agricultural production, and achieve the goal of resource saving coupled with high production and efficiency. We evaluated the production effects of typical cropping patterns in an arid irrigation region from several aspects, including resource utilization, carbon emissions, economic benefit, emergy self-sufficiency ratio and net emergy yield ratio, with the method of emergy theory, to provide theoretical and practical basis for the establishment of efficient cropping with lower resource investment and carbon emissions but higher yield and resource utilization efficiency combined with the sustainability of agricultural production. The results showed that, high-efficient wheat-maize intercropping production pattern (integration of no tillage with 25 to 30 cm height of wheat straw covering in the wheat strip and two-year plastic mulching in the maize strip, NTSI) had the best performance in grain yield boosting, with the yields 13.5% to 16.9% and 13.8% to 17.1% higher than that in local traditional production patterns (i.e., wheat-maize intercropping, CTI, and monoculture maize, CTM), respectively. Moreover, NTSI increased water use efficiency and solar energy use efficiency by 12.4% to 17.2% and 6.1% to 8.1%, compared to CTI, respectively. Compared to CTI and CTM, NTSI improved the effect on carbon emission reduction by decreasing total soil CO2 emission by 618 to 895 kg·hm-2 and 1804 to 2002 kg·hm-2 with the ratio of 12.1% to 16.4% and 28.6% to 31.0%, but increased carbon emission efficiency by 29.3% to 40.1% and 58.9 to 71.4%, respectively. Meanwhile, the NTSI pattern had obvious resources saving potential. Compared with CTI and CTM, NTSI reduced total input by 1424 to 1431 yuan·hm-2 and 501 to 1547 yuan·hm-2, with the proportional reduction being 12.6% to 13.6% and 4.9% to 14.6%; however, increased total output by 4309 to 4603 yuan·hm-2 and 8439 to 11057 yuan·hm-2, the increased ratio was 11.2% to 11.8% and 24.4% to 36.3%; also, increased net return by 5740 to 6027 yuan·hm-2 and 9544 to 11558 yuan·hm-2, and the improved percentage was 19.6% to 22.4% and 40.1% to 57.7%, respectively. Therefore, the high-efficient NTSI pattern had greater input-output ratio by 27.9% to 29.0% and 40.5% to 45.6% than CTI and CTM, respectively, similarly, greater benefit per cubic meter of water by 19.9% to 23.2% and 27.7% to 39.3%, respectively. The emergy self-sufficiency ratio of NTSI pattern was 57.2%, being 4.0% and 12.2% higher than CTI and CTM, respectively. NTSI pattern's net emergy yield ratio was 0.173, being 10.0% greater than CTI but 11.7% lower than CTM. With respect to resource utilization, carbon emission reduction, economic benefits and the sustainable development of high-efficient intercropping pattern, the integration of no tillage with straw covering and two-year plastic film mulching measures had higher economic activity, better function of agricultural system, greater production efficiency, and higher returns on energy value. We concluded that NTSI could be a high-efficiency farming system pattern on resources saving, carbon emission reduction, high yield and efficiency in arid oasis irrigation areas.

Selective CO2 Capture and High Proton Conductivity of a Functional Star-of-David Catenane Metal-Organic Framework.

Network structures based on Star-of-David catenanes with multiple superior functionalities have been so far elusive, although numerous topologically interesting networks are synthesized. Here, a metal-organic framework featuring fused Star-of-David catenanes is reported. Two triangular metallacycles with opposite handedness are triply intertwined forming a Star-of-David catenane. Each catenane fuses with its six neighbors to generate a porous twofold intercatenated gyroid framework. The compound possesses exceptional stability and exhibits multiple functionalities including highly selective CO2 capture, high proton conductivity, and coexistence of slow magnetic relaxation and long-range ordering.

HLA-A*24:02 as a common risk factor for antiepileptic drug-induced cutaneous adverse reactions.

OBJECTIVE: To investigate the involvement of human leukocyte antigen (HLA) loci in aromatic antiepileptic drug-induced cutaneous adverse reactions. METHODS: A case-control study was performed to detect HLA loci involved in aromatic antiepileptic drug-induced Stevens-Johnson syndrome in a southern Han Chinese population. Between January 1, 2006, and December 31, 2015, 91 cases of Stevens-Johnson syndrome induced by aromatic antiepileptic drugs and 322 matched drug-tolerant controls were enrolled from 8 centers. Important genotypes were replicated in cases with maculopapular eruption and in the meta-analyses of data from other populations. Sequence-based typing determined the HLA-A, HLA-B, HLA-C, and HLA-DRB1 genotypes. RESULTS: HLA-B*15:02 was confirmed as strongly associated with carbamazepine-induced Stevens-Johnson syndrome (p = 5.63 × 10-15). In addition, HLA-A*24:02 was associated significantly with Stevens-Johnson syndrome induced by the aromatic antiepileptic drugs as a group (p = 1.02 × 10-5) and by individual drugs (carbamazepine p = 0.015, lamotrigine p = 0.005, phenytoin p = 0.027). Logistic regression analysis revealed a multiplicative interaction between HLA-B*15:02 and HLA-A*24:02. Positivity for HLA-A*24:02 and/or HLA-B*15:02 showed a sensitivity of 72.5% and a specificity of 69.0%. The presence of HLA-A*24:02 in cases with maculopapular exanthema was also significantly higher than in controls (p = 0.023). Meta-analysis of data from Japan, Korea, Malaysia, Mexico, Norway, and China revealed a similar association. CONCLUSIONS: HLA-A*24:02 is a common genetic risk factor for cutaneous adverse reactions induced by aromatic antiepileptic drugs in the southern Han Chinese and possibly other ethnic populations. Pretreatment screening is recommended for people in southern China.

miR-124 modulates gefitinib resistance through SNAI2 and STAT3 in non-small cell lung cancer.

Gefitinib is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC). Unfortunately, most NSCLC patients inevitably develop gefitinib resistance during treatment. In addition to EGFR mutation status, the mechanisms involved are largely unknown. In this study, we showed that miR-124, a tumor suppressor, was significantly down-regulated in gefitinib-resistant NSCLC patients and cell lines compared with gefitinib-sensitive patients and cell lines. In addition, the miR-124 depletion induced gefitinib resistance, and miR-124 overexpression sensitized gefitinib-resistant cells to gefitinib. Mechanistic analysis revealed that miR-124 decreased SNAI2 and STAT3 expression by directly targeting their 3'UTRs and that knocking down SNAI2 or STAT3 partly reversed the gefitinib resistance induced by miR-124 depletion. Our data demonstrate that the miR-124 plays a new critical role in acquired resistance to gefitinib and that the manipulation of miR-124 might provide a therapeutic strategy for reversing acquired gefitinib resistance.

Anticancer Activity of a Hexapeptide from Skate (Raja porosa) Cartilage Protein Hydrolysate in HeLa Cells.

In this study, the hexapeptide Phe-Ile-Met-Gly-Pro-Tyr (FIMGPY), which has a molecular weight of 726.9 Da, was separated from skate (Raja porosa) cartilage protein hydrolysate using ultrafiltration and chromatographic methods, and its anticancer activity was evaluated in HeLa cells. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay indicated that FIMGPY exhibited high, dose-dependent anti-proliferation activities in HeLa cells with an IC50 of 4.81 mg/mL. Acridine orange/ethidium bromide (AO/EB) fluorescence staining and flow cytometry methods confirmed that FIMGPY could inhibit HeLa cell proliferation by inducing apoptosis. Western blot assay revealed that the Bax/Bcl-2 ratio and relative intensity of caspase-3 in HeLa cells treated with 7-mg/mL FIMGPY were 2.63 and 1.83, respectively, significantly higher than those of the blank control (p < 0.01). Thus, FIMGPY could induce apoptosis by upregulating the Bax/Bcl-2 ratio and caspase-3 activation. Using a DNA ladder method further confirmed that the anti-proliferation activity of FIMGPY was attributable to its role in inducing apoptosis. These results suggest that FIMGPY from skate cartilage protein hydrolysate may have applications as functional foods and nutraceuticals for the treatment and prevention of cancer.

Levetiracetam-induced cutaneous adverse drug reactions were not associated with HLA genes in a small sample of Chinese patients with epilepsy.

PURPOSE: This study aimed to evaluate the clinical characteristics of levetiracetam (LEV)-induced cutaneous adverse drug reactions (cADRs) and to explore its possible genetic association with the human leukocyte antigen (HLA) genes. METHODS: Nine cases with LEV-induced cADRs were recruited. Demographic and clinical information of these cases was summarized. Additionally, cases were matched with LEV-tolerant controls (1:4). High-resolution HLA class I and class II genotyping was performed for each participant. The allele frequencies between the cases and controls were compared. RESULTS: All LEV-induced cADRs were mild skin rashes which occurred within 28 days of LEV exposure. The mean latency from LEV exposure to skin rash was (15.67±5.41) days (ranging 6-27). The carrier rates of the two alleles, HLA-DRB1*0405 and HLA-DQB1*0401, were higher in cases compared with controls (the same P=0.036, OR=13.875, 95% CI: 1.273-151.230). The association between the HLA-C*0304 allele and LEV-induced cADRs was boundary (P=0.05, OR=5.2, 95% CI: 1.086-24.897). However, the above-mentioned HLA alleles didn't reach statistical significance after multiple comparisons. CONCLUSIONS: Safety monitoring was necessary within four weeks after the initiation of LEV treatment, although it has been regarded as a safe antiepileptic drug. Our study failed to show any potential link between HLA alleles and LEV-induced cADRs in Han Chinese. Further studies are needed to clarify the genetic and immunological mechanisms of LEV-induced cADRs.

Magnetic Properties of 3D Heptanuclear Lanthanide Frameworks Supported by Mixed Ligands.

Two 3D lanthanide frameworks, [Ln7(DPA)5(NA)3(µ3-OH)8(H2O)3]·2.5H2O [H2DPA = diphenic acid; HNA = nicotinic acid; Ln = Gd (1), Dy (2)], were synthesized and structurally characterized. They were rarely seen examples of 3D frameworks constructed from heptanuclear trigonal-antiprismatic lanthanide clusters with mixed H2DPA and HNA ligands. Both 1 and 2 show typical antiferromagnetic interactions. Additionally, complex 1 possesses a large magnetocaloric effect of 34.15 J kg(-1) K(-1).

Two novel antioxidant nonapeptides from protein hydrolysate of skate (Raja porosa) muscle.

In the current study, the preparation conditions of neutrase hydrolysate (SMH) from skate (Raja porosa) muscle protein were optimized using orthogonal L9(3)4 tests, and R values indicated that pH was the most important factor affecting HO· scavenging activity of SMH. Under the optimum conditions of pH 7.0, enzymolysis temperature 60 °C, enzyme/substrate ratio (E/S) 2%, and enzymolysis time 5 h, EC50 of SMH on HO· was 2.14 ± 0.17 mg/mL. Using ultrafiltration, gel filtration chromatography, and RP-HPLC, two novel antioxidant nonapeptides (SP-A and SP-B) were isolated from SMH and their amino acid sequences were found to be APPTAYAQS (SP-A) and NWDMEKIWD (SP-B) with calculated molecular masses of 904.98 Da and 1236.38 Da, respectively. Both showed strong antioxidant activities. SP-A and SP-B exhibited good scavenging activities on HO· (EC50 0.390 and 0.176 mg/mL), DPPH· (EC50 0.614 and 0.289 mg/mL), and O2-· (EC50 0.215 and 0.132 mg/mL) in a dose-dependent manner. SP-B was also effective against lipid peroxidation in the model system. The aromatic (2Trp), acidic (2Asp and Glu), and basic (Lys) amino acid residues within the sequences of SP-B might account for its pronounced antioxidant activity. The results of this study suggested that protein hydrolysate and peptides from skate muscle might be effective as food additives for retarding lipid peroxidation occurring in foodstuffs.