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Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have important implications for treatment of heart diseases. Here, we showed that PSEN1 was downregulated in ischemia-induced failing hearts. Functionally, cardiovascular specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy. At the age of 11 months, the ratio of the heart weight/body weight was slightly lower in the Sm22a-PSEN1-KO mice compared with that of the WT mice. Echocardiography showed that the percentage of ejection fraction and fractional shortening was significantly reduced in the Sm22a-PSEN1-KO group compared with the percent of these measures in the WT group, indicating that PSEN1-KO resulted in heart failure. The abnormally regulated genes resulted from PSEN1-KO were detected to be enriched in muscle development and dilated cardiomyopathy. Among them, several genes encode Ca

BACKGROUND The longitudinal association between persistent moderate to severe pain and subsequent long-term cognitive decline remains inconclusive. METHODS Study population came from the English Longitudinal Study of Ageing, an ongoing prospective and nationally representative cohort of community-dwelling adults aged ≥50 years in England. At waves 1 (2002/2003) and 2 (2004/2005) of the study, pain severity was measured based on pain intensity scores ranged from 0 to 10. We defined moderate to severe pain as pain intensity scores ≥5 points. Persistent moderate to severe pain was defined as participants reported moderate to severe pain at both waves 1 and 2. Standardized global cognitive Z scores derived from verbal memory, temporal orientation and semantic fluency were used as the primary outcome. RESULTS A total of 6,869 individuals (3,896 women; mean age: 63.9 ± 9.5 years) who have accepted twice measurements of pain at waves 1 and 2 (baseline), and at least one reassessment of cognitive function at waves 3 (2006/2007) to 8 (2016/2017), were included in this study. Each 5-point increase in the sum of pain intensity scores was associated with a faster rate of -0.009 (95% CI: -0.013 to -0.006, p

Thoracic aortic aneurysm (TAA) is progressive fatal aortic pathological dilation, which is characterized by increased proteoglycans and loss of elastic fibers. Recent advances in long non-coding RNAs (lncRNAs), an important regulator in many biological processes, suggested the close correlation between expression patterns and disease progression. In the present study, the ascending aortic tissues were collected from ascending TAA patients (n = 33) and organ donors (n = 16). Microarray analysis and real-time PCR were then applied to detect the lncRNA expression profiles. A total of 147 differentially expressed lncRNAs were determined, including 104 upregulated and 43 downregulated lncRNAs. Bioinformatics analysis showed 51.7% of differentially expressed lncRNAs were sense-overlapping, and most of the down-regulated lncRNAs were located on chromosome 1, 7, and 12. Subgroup analysis of TAA patients indicated that the expression of lnc-HLTF-5 was significantly higher in hypertension group than non-hypertension group (P

Sorbus commixta is a traditional oriental medicinal plant that grows in East Asian countries such as Korea, Japan and China. The twig of S. commixta has been considered valuable for centuries to treat diseases including asthma, cough and other bronchial disorders. However, the effect of S. commixta twig extract on human skin has not been investigated well. The present study aimed at assessing the antiphotoaging effect of S. commixta twig ethanol extract (STE) on ultraviolet B (UVB)-induced matrix metalloproteinase (MMP) levels and its underlying mechanism in human dermal fibroblasts. In this study, we found that STE (12.5-50 μg mL-1 ) treatment significantly inhibited UVB-induced MMP-1, MMP-2 and MMP-3 expression, concomitant with a downregulation of intracellular ROS generation. These effects might be associated with a STE-induced inhibition of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, STE also downregulated UVB-induced c-Fos expression in a concentration-dependent manner, but had no inhibitory effect on c-Jun phosphorylation. Taken together, these results indicate that STE may be an antiphotoaging agent and that its effect may occur via its inhibition of MMPs expression and MAPK pathway activation.

Recently, PSEN1 has been reported to have mutations in dilated cardiomyopathy pedigrees. However, the function and mechanism of PSEN1 in cardiomyopathy remains unresolved. Here, we established four types of genetically modified mice to determine the function of PSEN1 in cardiac development and pathology. PSEN1 null mutation resulted in perinatal death, retardation of heart growth, ventricular dilatation, septum defects, and valvular thickening. PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and reduced lengths of sarcomeres in cardiomyocytes. Cardiovascular loss of function of PSEN1 induced by Sm22a-Cre or Myh6-Cre/ER/tamoxifen also resulted in severe ultrastructural abnormalities, such as relaxed gap junctions between neighboring cardiomyocytes. Functionally, cardiovascular deletion of PSEN1 caused spontaneous mortality from birth to adulthood and led to diastolic heart dysfunction, including decreased volume of the left ventricle at the end-systolic and end-diastolic stages. Additionally, in a myocardial ischemia model, deletion of PSEN1 in the cardiovascular system first protected mice by inducing adaptive hypertrophy but ultimately resulted in severe heart failure. Furthermore, a collection of genes was abnormally expressed in the hearts of cardiac-specific PSEN1 knockout mice. They were enriched in cell proliferation, calcium regulation, and so on. Taken together, dynamic regulation and abnormal function of PSEN1 underlie the pathogenesis of cardiovascular diseases due to ultrastructural abnormality of cardiomyocytes.

OBJECTIVE To evaluate the effects of surgery and rehabilitation on patients undergoing total knee arthroplasty (TKA). METHODS Twelve patients and 12 healthy controls were enrolled and their clinical scores evaluated by a doctor. Gait data, including walking velocity, stride length, single support time, foot fall and swing power, were collected using a portable gait analyzer from 12 patients before and 6 weeks and 6 months after surgery and from 12 healthy controls. The gait data and clinical scores at selected time points were compared and correlations between gait characteristics and clinical scores assessed. RESULTS Clinical knee and knee function scores increased significantly from before surgery to 6 weeks to 6 months after surgery (P < 0.001). The only significant differences identified were for single support time on the diseased side between before surgery and 6 months after surgery (P = 0.031) and for foot fall with the diseased side between 6 weeks and 6 months after surgery (P = 0.016). Foot fall and speed of the healthy or diseased sides were significantly different in patients at all time points from those of the healthy subjects (P < 0.05). Single support time on the diseased side was significantly different 6 months after surgery (P = 0.035) in patients than in healthy controls. Single support time on the healthy side before surgery was significantly different from that of healthy controls (P = 0.048) and 6 weeks after surgery (P = 0.042). Stride lengths differed significantly between patients and healthy subjects before surgery (healthy side: P = 0.007; diseased side: P = 0.008) and 6 weeks after surgery (healthy side: P = 0.001; diseased side: P = 0.001), but were not different at 6 months after surgery (healthy side: P = 0.088; diseased side: P = 0.077). The only significant correlations identified were between single support time with the diseased side of patients and their knee (r = 0.43, P = 0.032) and knee function scores (r = 0.493, P = 0.012). CONCLUSIONS A portable gait analyzer appears to be suitable for evaluating the effects of TKA. Single support time on the diseased side may be a sensitive quantitative index for determining the effect of TKA and rehabilitation.

Astaxanthin is an extremely common antioxidant scavenging reactive oxygen species (ROS) and blocking lipid peroxidation. This study was conducted to investigate the effects of astaxanthin supplementation on oocyte maturation, and development of bovine somatic cell nuclear transfer (SCNT) embryos. Cumulus-oocyte complexes were cultured in maturation medium with astaxanthin (0, 0.5, 1.0, or 1.5 mg/l), respectively. We found that 0.5 mg/l astaxanthin supplementation significantly increased the proportion of oocyte maturation. Oocytes cultured in 0.5 mg/l astaxanthin supplementation were used to construct SCNT embryos and further cultured with 0, 0.5, 1.0 or 1.5 mg/l astaxanthin. The results showed that the supplementation of 0.5 mg/l astaxanthin significantly improved the proportions of cleavage and blastulation, as well as the total cell number in blastocysts compared with the control group, yet this influence was not concentration dependent. Chromosomal analyses revealed that more blastomeres showed a normal chromosomal complement in 0.5 mg/l astaxanthin treatment group, which was similar to that in IVF embryos. The methylation levels located on the exon 1 of the imprinted gene H19 and IGF2, pluripotent gene OCT4 were normalized, and global DNA methylation, H3K9 and H4K12 acetylation were also improved significantly, which was comparable to that in vitro fertilization (IVF) embryos. Moreover, we also found that astaxanthin supplementation significantly decreased the level of lipid peroxidation. Our findings showed that the supplementation of 0.5 mg/l astaxanthin to oocyte maturation medium and embryo culture medium improved oocyte maturation, SCNT embryo development, increased chromosomal stability and normalized the epigenetic modifications, as well as inhibited overproduction of lipid peroxidation.

The objective of this study was to evaluate the therapeutic effects of thymopentin (TP-5) injections on subclinical intramammary infection (IMI) in lactating cows. In Experiment I, 40 cows were randomly divided into four groups. The cows in groups 1, 2, and 3 received subcutaneous injections of TP-5 in the region of the supramammary lymph node at doses of 1, 2, and 4 mg, respectively, for 3 days. In Experiment II, 20 cows were randomly divided into two groups. The cows in group 1 were treated with injections of TP-5 (4 mg) for 3 days in the same area as in Experiment I. Group 4 in Experiment I and group 2 in Experiment II were not treated and served as control groups. Milk samples were collected before and after treatment for bacteriological examination and analysis of the somatic cell count and level of N-acetyl-β-d-glucosaminidase (NAGase). The results showed that treatment with TP-5 significantly reduced the somatic cell count (SCC) and NAGase activity of the milk and numerically reduced IMI. A dose of 4 mg was found to be optimal for the reduction of SCC and NAGase in milk. Therefore, further study of the use of TP-5 in the treatment of bovine mastitis is warranted.

A simple ultrahigh-performance liquid chromatography (UHPLC) tandem mass spectrometric method for the identification and quantification of two photoinitiators 4-methylbenzophenone and 2-ethylhexyl-4-dimethylaminobenzoate; nine plasticizers including di(2-ethylhexyl) adipate and diisobutyl adipate; three primary aromatic amines 4-aminobiphenyl, 4-amino-2′,3-dimethylazobenzene and bis-(4-aminophenyl) methane and six bisphenols bisphenol F diglycidyl ether, bisphenol A diglycidyl ether, bisphenol A (BPA), bisphenol B (BPB), bisphenol E (BPE) and bisphenol F (BPF) in food contact materials has been developed. The chromatographic conditions, pre-treatment methods and matrix effects were studied and optimized. For the determination of the four bisphenols, BPA, BPB, BPE and BPF, the UHPLC method employed a mobile phase of aqueous ammonia and methanol in binary gradient mode, and measurement was based on a triple quadrupole mass spectrometer equipped with an electrospray ionization (ESI) source operating in negative ion mode. The remaining chemicals were determined using the ESI source in positive ion mode and using the [M + NH4]+ or [M + H]+ adducts as precursor ions for tandem mass spectrometry. The calibration graphs were linear with correlation coefficients of above 0.995. Detection limits for the method were in the range of 1–16 µg/kg. Analyte recovery values were in the range of 70–114%, and relative standard deviations were 1–14%. Under optimized conditions, the chromatographic separation was performed in 12 min. The validation data indicated that the method was effective for the determination of the four classes of hazardous chemicals in plastic packaging materials or in can lacquers. The optimized method was successfully applied to trace analysis of commercially available food contact materials. Copyright © 2014 John Wiley & Sons, Ltd.

SUMMARY The goal of this study was to improve the development of bovine somatic-cell nuclear transfer (SCNT) embryos by optimizing the combination of DNA methyltransferases inhibitor S-adenosylhomocysteine (SAH) and histone deacetylase inhibitor Scriptaid (SPD). A. 4 × 4-factor design of different drug combinations (0, 0.75, 1.0, and 1.5 mM SAH and 0, 5, 250, and 500 nM SPD) was used to identify an optimal combination of 0.75 mM SAH and 250 nM SPD that improved the developmental competence of bovine SCNT embryos. Further experiments using this combination revealed that methylation levels of CpG islands near exon 1 of the pluripotent gene SOX2; the epigenetic-related gene HDAC3 and DNMT3a; imprinted genes XIST and PEG3; as well as apoptosis-related genes BCL2 and BAX were returned to levels similar to those of in vitro fertilized (IVF) embryo after treatment, which also normalized transcript levels for these genes. This combination also returned global DNA methylation to a normal level, correcting H4K12ac levels while enhancing H3K9ac levels. Thus, the combined application of 0.75 mM SAH and 250 nM SPD can significantly improve the reprogramming of bovine SCNT embryos by stabilizing how embryos utilize their genomes. Mol. Reprod. Dev. 81: 87–97, 2014. © 2013 Wiley Periodicals, Inc.

Summary Cholesterol catabolism is widespread in actinobacteria and is critical for Mycobacterium tuberculosis (Mtb) virulence. Catabolism of steroid nucleus rings C and D is poorly understood: it is initiated by the CoA thioesterification of 3aα-H-4α(3′-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP) by FadD3, whose gene is part of the KstR2 regulon. In Mtb, genes of this regulon were upregulated up to 30- and 22-fold during growth on cholesterol and HIP, respectively, versus another minimal medium. In contrast, genes involved in degrading the cholesterol side-chain and nucleus rings A and B were only upregulated during growth on cholesterol. Similar results were obtained in Rhodococcus jostii RHA1. Moreover, the regulon was not upregulated in a ΔfadD3 mutant unable to produce HIP-CoA. In electrophoretic mobility shift assays, HIP-CoA relieved the binding of KstR2Mtb to each of three KstR2 boxes: CoASH, HIP and a related CoA thioester did not. Inspection of the structure of KstR2RHA1 revealed no obvious HIP-CoA binding pocket. The results establish that Mtb can catabolize the entire cholesterol molecule and that HIP-CoA is an effector of KstR2. They further indicate that KstR2 specifically represses the expression of the HIP degradation genes in actinobacteria, which encode a lower pathway involved in the catabolism of multiple steroids.

The objective of this study was to compare the effect of two culture media: modified synthetic oviductal fluid (mSOF) and G1.2/G2.2, on the developmental competence of bovine somatic cell-cloned embryos. Cloned embryos were produced by transferring adult skin fibroblasts into enucleated MII oocytes. After activation, the reconstructed embryos were randomly allotted to either mSOF or G1.2/G2.2 for culture (the embryos were transferred from G1.2 to G2.2 on days 3 of culture). The development competence of cloned embryos in these two culture systems was compared in terms of cleavage rate, blastocyst formation rate and apoptosis cell number in day 7 blastocyts. To investigate the in vivo developmental competence of cloned embryos in the two culture systems, a total of 87 and 104 blastocysts derived from mSOF and G1.2/G2.2 medium groups were transferred individually to recipient Angus cows, respectively. No differences were observed in terms of cleavage rate, day 7 blastocyst rate and blastocyst cell number between these two culture systems. However, the day 6 blastocyst formation rate was significantly higher in G1.2/G2.2 than that in mSOF. In addition, blastocysts cultured in mSOF have a higher percentage of apoptotic blastomeres compared to those in G1.2/G2.2 (8.5 ± 1.2 vs 16.8 ± 1.5, p

The LI818 proteins and their Lhcx homologs in diatoms are a subgroup of the light-harvesting (LHC) antenna family, suspected of being involved in photoprotection and stress resistance. In this work, we report that the transcription of three LI818–like genes in Thalassiosira pseudonana Hasle et Heimdal (Lhcx1, Lhcx5, and Lhcx6) was down-regulated under iron or copper deprivation and when both trace metals were limiting, as was the case for Lhcf4, one of the standard light-harvesting genes. By contrast, the protein encoded by Lhcx1 was clearly up-regulated under iron limitation, suggesting that this gene is independently regulated at transcriptional and translational levels. In general, copper starvation had less effect on the expression of light-harvesting protein genes than iron deprivation, reflecting the different roles of iron and copper in photosynthetic function, that is, as an essential part of the electron transport chain versus as a cofactor for enzymes required to deal with the reactive oxygen species that result from inhibition of electron flow. Our results suggest that the Lhcx1 protein may be involved in stabilizing the photosynthetic apparatus when decreased nonphotochemical quenching (NPQ) results from Fe deficiency.

To cite this article: Mo J-H, Kang E-K, Quan S-H, Rhee C-S, Lee CH, Kim D-Y. Anti-tumor necrosis factor-alpha treatment reduces allergic responses in an allergic rhinitis mouse model. Allergy 2011; 66: 279–286. Abstract Background: Tumor necrosis factor (TNF)-α is a principal mediator of the acute inflammatory response, including allergic rhinitis. TNF-α inhibitors are widely used for the treatment of inflammatory conditions such as rheumatoid arthritis and inflammatory bowel diseases; however, the effects of TNF-α inhibitors on allergic rhinitis are not well established. We aimed to investigate the effects of infliximab, a TNF-α inhibitor, on allergic rhinitis in a mouse model. Methods: BALB/c mice were sensitized with ovalbumin (OVA) and alum, and challenged intranasally with OVA. The TNF-α inhibitor, infliximab was administered intraperitoneally, and multiple parameters of allergic responses were evaluated to determine the effects of infliximab. Results: Infliximab reduced allergic symptoms and eosinophilic infiltration into the nasal mucosa. It also suppressed total and OVA-specific IgE levels, and inhibited local Th2 cytokine transcription in the nasal mucosa and systemic Th2 cytokine production by splenocytes. Furthermore, the expression of E-selectin, neither intercellular adhesion molecule 1 (ICAM-1) nor vascular cell adhesion molecule 1 (VCAM-1), in the nasal mucosa was suppressed in the infliximab-treated group when compared to the nontreated group. Conclusion: This study shows that the TNF-α inhibitor infliximab induces anti-allergic effects by decreasing local and systemic Th2 cytokine (IL-4) production, total and OVA-specific IgE levels, adhesion molecule (E-selectin) expression, and eosinophil infiltration into the nasal mucosa in an allergic rhinitis model. Therefore, infliximab should be considered as a potential agent in treating allergic rhinitis.

With the enhancement of copper (Cu) stress, the germination percentage of wheat seeds decreased gradually. Pretreatment with sodium hydrosulfide (NaHS), hydrogen sulfide (H(2)S) donor alleviated the inhibitory effect of Cu stress in a dose-dependent manner; whereas little visible symptom was observed in germinating seeds and radicle tips cultured in NaHS solutions. It was verified that H(2)S or HS(-) rather than other sulfur-containing components derived from NaHS attribute to the potential role in promoting seed germination against Cu stress. Further studies showed that NaHS could promote amylase and esterase activities, reduce Cu-induced disturbance of plasma membrane integrity in the radicle tips, and sustain lower levels of malondialdehyde and H(2)O(2) in germinating seeds. Furthermore, NaHS pretreatment increased activities of superoxide dismutase and catalase and decreased that of lipoxygenase, but showed no significant effect on ascorbate peroxidase. Alternatively, NaHS prevented uptake of Cu and promoted the accumulation of free amino acids in seeds exposed to Cu. In addition, a rapid accumulation of endogenous H(2)S in seeds was observed at the early stage of germination, and higher level of H(2)S in NaHS-pretreated seeds. These data indicated that H(2)S was involved in the mechanism of germinating seeds' responses to Cu stress.