Increasing epidemiological evidence has indicated that inherited variations of mitochondrial DNA (mtDNA) copy number affect the genetic susceptibility of many malignancies in a tumour-specific manner and that DNA methylation also plays an important role in controlling gene expression during the differentiation and development of hepatocellular carcinoma (HCC). Our previous study demonstrated that HCC tissues showed a lower 5-hydroxymethylcytosine (5-hmC) content when compared to tumour-adjacent tissues, but the relationship among 5-hmC, 5-methylcytosine (5-mC) and mtDNA content in HCC patients is still unknown. This study aimed to clarify the correlation among mtDNA content, 5-mC and 5-hmC by quantitative real-time PCR and liquid chromatography tandem mass spectrometry analysis. We demonstrated that 5-hmC correlated with tumour size [odds ratio (OR) 0.847, 95% confidence interval (CI) 0.746–0.962, P = 0.011], and HCC patients with a tumour size ≥5.0 cm showed a lower 5-hmC content and higher levels of fasting plasma aspartate aminotransferase, the ratio of alanine amiotransferase to aspartate aminotransferase, γ-glutamyltransferase, alpha-fetoprotein than those with a tumour size <5 cm (all P<0.05). We further revealed that the mtDNA content of HCC tumour tissues was 225.97(105.42, 430.54) [median (25th Percentile, 75th Percentile)] and was negatively correlated with 5-mC content (P = 0.035), but not 5-hmC content, in genomic DNA from HCC tumour tissues.
Antifouling magnetic iron oxide nanoparticles (IONPs) coated with block copolymer poly(ethylene oxide)-block-poly(γ-methacryloxypropyltrimethoxysilane) (PEO-b-PγMPS) were investigated for improving cell targeting by reducing nonspecific uptake. Conjugation of a HER2 antibody, Herceptin®, or a single chain fragment (ScFv) of antibody against epidermal growth factor receptor (ScFvEGFR) to PEO-b-PγMPS-coated IONPs resulted in HER2-targeted or EGFR-targeted IONPs (anti-HER2-IONPs or ScFvEGFR-IONPs). The anti-HER2-IONPs bound specifically to SK-BR-3, a HER2-overexpressing breast cancer cell line, but not to MDA-MB-231, a HER2-underexpressing cell line. On the other hand, the ScFvEGFR-IONPs showed strong reactivity with MDA-MB-231, an EGFR-positive human breast cancer cell line, but not with MDA-MB-453, an EGFR-negative human breast cancer cell line. Transmission electron microscopy revealed internalization of the receptor-targeted nanoparticles by the targeted cancer cells. In addition, both antibody-conjugated and non-antibody-conjugated IONPs showed reduced nonspecific uptake by RAW264.7 mouse macrophages in vitro. The developed IONPs showed a long blood circulation time (serum half-life 11.6 hours) in mice and low accumulation in both the liver and spleen. At 24 hours after systemic administration of ScFvEGFR-IONPs into mice bearing EGFR-positive breast cancer 4T1 mouse mammary tumors, magnetic resonance imaging revealed signal reduction in the tumor as a result of the accumulation of the targeted IONPs.
magnetic nanoparticles; active targeting; antifouling; breast cancer; magnetic resonance imaging
Age-related loss of muscle mass and function, sarcopenia, has a major impact on the quality of life in the elderly. Among the proposed causes of sarcopenia are mitochondrial dysfunction and accumulated oxidative damage during aging. Dietary restriction (DR), a robust dietary intervention that extends lifespan and modulates age-related pathology in a variety of species has been shown to protect from sarcopenia in rodents. Although the mechanism(s) by which DR modulates aging are still not defined, one potential mechanism is through modulation of oxidative stress and mitochondrial dysfunction. To directly test the protective effect of DR against oxidative stress induced muscle atrophy in vivo, we subjected mice lacking a key antioxidant enzyme, CuZnSOD (Sod1) to DR (40% of ad libitum fed diet). We have previously shown that the Sod1−/− mice exhibit an acceleration of sarcopenia associated with high oxidative stress, mitochondrial dysfunction, and severe neuromuscular innervation defects. Despite the dramatic atrophy phenotype in the Sod1−/− mice, DR led to a reversal or attenuation of reduced muscle function, loss of innervation and muscle atrophy in these mice. DR improves mitochondrial function as evidenced by enhanced Ca2+ regulation and reduction of mitochondrial reactive oxygen species (ROS). Furthermore, we show upregulation of SIRT3 and MnSOD in DR animals, consistent with reduced mitochondrial oxidative stress and reduced oxidative damage in muscle tissue measured as F2- isoprostanes. Collectively, our results demonstrate that DR is a powerful mediator of mitochondrial function, mitochondrial ROS production, and oxidative damage, providing a solid protection against oxidative stress induced neuromuscular defects and muscle atrophy in vivo even under conditions of high oxidative stress.
The objective of this study was to investigate the tempo-spatial distribution of paddy rice in Northeast China using moderate resolution imaging spectroradiometer (MODIS) data. We developed an algorithm for detection and estimation of the transplanting and flooding periods of paddy rice with a combination of enhanced vegetation index (EVI) and land surface water index with a central wavelength at 2 130 nm (LSWI2130). In two intensive sites in Northeast China, fine resolution satellite imagery was used to validate the performance of the algorithm at pixel and 3×3 pixel window levels, respectively. The commission and omission errors in both of the intensive sites were approximately less than 20%. Based on the algorithm, annual distribution of paddy rice in Northeast China from 2001 to 2009 was mapped and analyzed. The results demonstrated that the MODIS-derived area was highly correlated with published agricultural statistical data with a coefficient of determination (R
2) value of 0.847. It also revealed a sharp decline in 2003, especially in the Sanjiang Plain located in the northeast of Heilongjiang Province, due to the oversupply and price decline of rice in 2002. These results suggest that the approaches are available for accurate and reliable monitoring of rice cultivated areas and variation on a large scale.
Paddy rice; Moderate resolution imaging spectroradiometer (MODIS); Northeast China; Enhanced vegetation index; Land surface water index
Radiation dose has raised significant concerns to patients and operators in modern x-ray computed tomography (CT) examinations. A simple and cost-effective means to perform a low-dose CT scan is to lower the milliampere-seconds (mAs) as low as reasonably achievable in data acquisition. However, the associated image quality with lower-mAs scans (or low-dose scans) will be unavoidably degraded due to the excessive data noise, if no adequate noise control is applied during image reconstruction. For image reconstruction with low-dose scans, sinogram restoration algorithms based on modeling the noise properties of measurement can produce an image with noise-induced artifact suppression, but they often suffer noticeable resolution loss. As an alternative method, the noise-reduction algorithms via edge-preserving image filtering can yield an image without noticeable resolution loss, but they often do not completely eliminate the noise-induced artifacts. With above observations, in this paper, we present a sinogram restoration induced non-local means (SR-NLM) image filtering algorithm to retain the CT image quality by fully considering the advantages of the sinogram restoration and image filtering algorithms in low-dose image reconstruction. Extensive experimental results show that the present SR-NLM algorithm outperforms the existing methods in terms of visual inspection, noise reduction, contrast-to-ratio measure, noise-resolution tradeoff and receiver operating characteristic (ROC) curves.
CT; low-dose; sinogram restoration; non-local means; image filtering
Degradation of certain proteins through the ubiquitin-proteasome pathway is a common strategy taken by the key modulators responsible for stress responses. Kelch-like ECH-associated protein-1(Keap1), a substrate adaptor component of the Cullin3 (Cul3)-based ubiquitin E3 ligase complex, mediates the ubiquitination of two key modulators, NF-E2-related factor 2 (Nrf2) and IκB kinase β (IKKβ), which are involved in the redox control of gene transcription. However, compared to the Keap1-Nrf2 protein-protein interaction (PPI), the intermolecular recognition mechanism of Keap1 and IKKβ has been poorly investigated. In order to explore the binding pattern between Keap1 and IKKβ, the PPI model of Keap1 and IKKβ was investigated. The structure of human IKKβ was constructed by means of the homology modeling method and using reported crystal structure of Xenopus laevis IKKβ as the template. A protein-protein docking method was applied to develop the Keap1-IKKβ complex model. After the refinement and visual analysis of docked proteins, the chosen pose was further optimized through molecular dynamics simulations. The resulting structure was utilized to conduct the virtual alanine mutation for the exploration of hot-spots significant for the intermolecular interaction. Overall, our results provided structural insights into the PPI model of Keap1-IKKβ and suggest that the substrate specificity of Keap1 depend on the interaction with the key tyrosines, namely Tyr525, Tyr574 and Tyr334. The study presented in the current project may be useful to design molecules that selectively modulate Keap1. The selective recognition mechanism of Keap1 with IKKβ or Nrf2 will be helpful to further know the crosstalk between NF-κB and Nrf2 signaling.
The purpose of this study was to synthesize, characterize and tailor the surface properties of magnetic nanoparticles with biocompatible copolymer coatings and to evaluate the efficiency of the resulting nanoconjugates as magnetic resonance imaging (MRI) contrast agents for liver imaging.
Magnetic nanoparticles with core diameters of 10 and 30 nm were synthesized by pyrolysis and were subsequently coated with a copolymer containing either carboxyl (SHP) or methoxy groups (SMG) as termini. All four formulas, and ferumoxides (Feridex I.V.®), were individually injected intravenously into separate, normal Balb/C mice (at 2.5, 1.0, and 0.56 mg Fe/kg), and the animals underwent T2-weighted MRI at multiple time points post injection (p.i.) to evaluate the hepatic uptake and clearance. Furthermore, we compared the abilities of the new formulas and Feridex to detect tumors in an orthotropic Huh7 tumor model.
TEM revealed a narrow size distribution of both the 10 nm and 30 nm nanoparticles, in contrast to a wide size distribution of Feridex. MTT, apoptosis and Cyclin/DNA flow cytometry assays showed that the polymer coated nanoparticles had no adverse effect on cell growth. Among all the tested formulas, including Feridex, SHP-30 showed the highest macrophage uptake at the in vitro level. In vivo MRI studies on normal mice confirmed the superiority of SHP-30 in inducing hypointensities in the liver tissue, especially at clinical dose (0.56 mg Fe/kg) and 3T field. SHP-30 showed better contrast-to-noise ratio (CNR) than Feridex on the orthotropic Huh7 tumor model.
SHP-30 was found to be an efficient contrast agent for liver MR imaging. The success of this study suggests that by improving the synthetic approach and by tuning the surface properties of IONPs, one can arrive at better formulas than Feridex for clinical practice.
Iron oxide nanoparticle (IONP); hepatocarcinoma (HCC); magnetic resonance imaging (MRI); liver contrast agent
Mixed lineage leukemia (MLL) fusion protein (FP)-induced acute leukemia is highly aggressive and often refractory to therapy. Recent progress in the field has unraveled novel mechanisms and targets to combat this disease. Menin, a nuclear protein, interacts with wild-type (WT) MLL, MLL-FPs and other partners such as the chromatin-associated protein LEDGF and the transcription factor c-myb to promote leukemogenesis. The newly solved co-crystal structure illustrating the menin-MLL interaction, coupled with the role of menin in recruiting both WT MLL and MLL-FPs to target genes, highlights menin as a scaffold protein and a central hub controlling this type of leukemia. The menin/WT MLL/MLL-FP hub may also cooperate with several signaling pathways, including Wnt, GSK3, and bromodomain-containing Brd4-related pathways to sustain MLL-FP-induced leukemogenesis, revealing new therapeutic targets to improve the treatment of MLL-FP leukemias.
Menin; MLL; Chromatin; Leukemia; Therapy
To examine the association of anthropometry indices with gout and to compare the performance of indices to predict gout in Taiwanese men.
There were 1443 male subjects aged more than 20 years who participated in the Nutrition and Health Survey in Taiwan (NAHSIT, 1993–1996). Anthropometric evaluation consisted of weight, height, hip and waist circumference (WC) with later body mass index (BMI), waist to height (WHtR) and waist to hip (WHR) estimations. We conducted 4 logistic models to determine the relationships between anthropometric indices and gout. Receiver operating characteristic (ROC) curve were used to compare the predictive performance and to identify the optimal cut-off points, sensitivity and specificity of these indices for gout in men.
After controlling for other covariables, the adjusted odds ratios for the mid and top tertiles of WHtR were 2.55 (95% CI: 1.16, 5.59) and 3.01 (95% CI: 1.13, 7.99), respectively, but no linear association was found for BMI, WHR and WC. In ROC curve, the greatest area under curve was 0.684 for WHtR and the cut-off point of WHtR was 0.57.
WHtR had a significant linear association with gout in Taiwanese men and was superior to BMI, WHR and WC.
Gout; Anthropometry; Waist to height ratio
Between January 2012 and March 2012, the infection rates of porcine epidemic diarrhea virus (PEDV) increased substantially in vaccinated swine herds in many porcine farms in Gansu Province, China. The spike (S) glycoprotein is an important determinant for PEDV biological properties. To determine the distribution profile of PEDV outbreak strains, we sequenced the full-length S gene of five samples from two farms where animals exhibited severe diarrhea and high mortality rates. Five new PEDV variants were identified, and the molecular diversity, phylogenetic relationships, and antigenicity analysis of Gansu field samples with other PEDV reference strains were investigated. A series of insertions, deletions, and mutations in the S gene was found in five PEDV variants compared with classical and vaccine strains. These mutations may provide stronger pathogenicity and antigenicity to the new PEDV variants that influenced the effectiveness of the CV777-based vaccine. Our results suggest that these new PEDV variant strains in Gansu Province might be from South Korean or South China, and the effectiveness of the CV777-based vaccine needs to be evaluated.
molecular characterization; spike glycoprotein gene; phylogenetic analysis; porcine epidemic diarrhea virus (PEDV)
Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1).
A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression.
Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression.
SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance.
Non-small cell lung cancer; SHP1; Radiosensitivity; Cell cycle
The tumor suppressor p53 is arguably the most important transcription factor that safeguards the genome. Although it is clear that the transcriptional activity of p53 is required for its tumor suppressive function, the underlying mechanisms are still largely unknown. In the past several years, genome-wide approaches have provided novel insights into the tumor suppressive functions of p53. This mini-review summarizes recent progress in studying these functions using genome-wide approaches, and offers some perspectives on this rapidly expanding field.
Intra-hepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver that shares histological features with the hepatic bile ducts from which it is thought to arise. The incidence of this disease is increasing, possibly related to increased inflammatory liver diseases such as viral hepatitis and steatohepatitis (commonly called “fatty liver”), induced by obesity, diabetes, and other metabolic derangements. Its prognosis is generally poor with early metastasis and presently there are limited effective treatments. A basic understanding of the disease has long been hampered by limited tumor cell lines and good model systems. Similarly, such limitations have obstructed new therapeutic inroads.
cholangiocarcinoma; KRAS; biliary tract cancer; mouse model
The aim of this study was to investigate whether genetic variations at positions -1082, -819, and -592 in the interleukin (IL)-10 promoter affect IL-10 production in children with irritable bowel syndrome (IBS).
Ninety-four children with IBS and 102 children as healthy controls (HCs) were enrolled. Genomic DNA was extracted, and IL-10 -1082, -819, and -592 polymorphisms were detected by direct sequencing from all participants. Peripheral blood mononuclear cells (PBMCs) from 46 IBS children and 38 HCs were isolated and cultured with and without 5 ng/mL Escherichia coli lipopolysaccharide (LPS). IL-10 levels in the culture supernatants were measured by enzyme-linked immunosorbent assay.
There were no significant differences in the distribution of IL-10 -1082, -819, and -592 polymorphisms or in the allele and haplotype frequencies between IBS children and HCs. PBMCs from children with IBS had significantly lower IL-10 levels after LPS stimulation than PBMCs from HCs (p=0.011); however, LPS-induced IL-10 levels in PBMCs with different genotypes of -819 and -592 polymorphisms were not significantly different between IBS patients and HCs.
Although significantly lower LPS-induced IL-10 production by PBMCs was noted, it is unlikely that IL-10 production was fully genetically determined in our IBS children. ClinicalTrials.gov identifier: NCT01131442.
Irritable bowel syndrome; Child; Interleukin-10; Interleukin-10 gene polymorphisms
Hypertension is considered as one of the major risk factors of atherosclerosis, especially for carotid artery plaque, which is a sign for cardiovascular incapacity and cerebral infarction. As adult age, systolic blood pressure (SBP or S) tends to rise and diastolic blood pressure (DBP or D) tends to fall, thus the pulse pressure (PP) will increase. The vascular injury was directly proportional to the level of SBP, and inversely proportional to DBP. But so far, studies of the vascular injury based on SBP and DBP measurement were mostly qualitative. The exact contribution of each parameter to the vascular injury has not been quantitatively identified. In this study, we employed a mathematical model to predict the risk for plaques of carotid arteries in aged people and combined the SBP, DBP and heart rate (HR) to perform a quantitative analysis. We analyzed 1672 males who were over 60-year-old and hospitalized due to atherosclerosis-related diseases and received a 24-h arterial blood pressure monitoring (ABPM) examination. These patients were divided into 19 subgroups using the ABPM data, 24-h average SBP, DBP and HR as variables based on the ascending order of the magnitude of each element. We developed a new index, namely the dynamic level (DL) which correlated best with the plaque formation of carotid arteries among all the well-established indexes for blood pressure. We demonstrated that index DL has better correlation to plaques incidence tendency (p < 0.0001) when compared to either SBP (P < 0.05) or PP (P < 0.001) alone. The risk on incidence of the plaques of carotid arteries has positive correlation with first power of SBP and -0.8 power of DBP. This model can be used clinically to predict the occurrence of plaque formation.
Blood pressure parameters; the plaques of carotid arteries; mathematical method; vascular injury
One common sign of human cytomegalovirus infection is altered liver function. Murine cytomegalovirus strain v70 induces a rapid and severe hepatitis in immunocompetent mice that requires the presence of T cells in order to develop. v70 exhibits approximately 10-fold-greater virulence than the commonly used strain K181, resulting in a more severe, sustained, and lethal hepatitis but not dramatically higher viral replication levels. Hepatitis and death are markedly delayed in immunodeficient SCID compared to immunocompetent BALB/c mice. Transfer of BALB/c splenocytes to SCID mice conferred rapid disease following infection, and depletion of either CD4 or CD8 T cells in BALB/c mice reduced virus-induced hepatitis. The frequency of CD8 T cells producing gamma interferon and tumor necrosis factor in response to viral antigen was higher in settings where more severe disease occurred. Thus, virus-specific effector CD8 T cells appear to contribute to lethal virus-induced hepatitis, contrasting their protective role during sublethal infection. This study reveals how protection and disease during cytomegalovirus infection depend on viral strain and dose, as well as the quality of the T cell response.
We report a controllable wet method for effective decoration of 2-dimensional (2D) molybdenum disulfide (MoS2) layers with Au nanoparticles (NPs). Au NPs can be selectively formed on the edge sites or defective sites of MoS2 layers. The Au-MoS2 nano-composites are formed by non-covalent bond. The size distribution, morphology and density of the metal nanoparticles can be tuned by changing the defect density in MoS2 layers. Field effect transistors were directly fabricated by placing ion gel gate dielectrics on Au-decorated MoS2 layers without the need to transfer these MoS2 layers to SiO2/Si substrates for bottom gate devices. The ion gel method allows probing the intrinsic electrical properties of the as-grown and Au-decorated MoS2 layers. This study shows that Au NPs impose remarkable p-doping effects to the MoS2 transistors without degrading their electrical characteristics.
We report in this Communication a facile, two-step surface modification strategy to achieve manganese oxide nanoparticles with prominent MRI T1 contrast. In a U87MG glioblastoma xenograft model, we confirmed that the particles can accumulate efficiently in tumor area to induce effective T1 signal alteration.
p53 is critical in regulating the differentiation of ES and induced pluripotent stem (iPS) cells. Here, we report a whole-genome study of p53-mediated DNA damage signaling in mouse ES cells. Systems analyses reveal that binding of p53 at promoter region significantly correlates with gene activation but not with repression. Unexpectedly, we identify a regulatory mode for p53-mediated repression through interfering with distal enhancer activity. Importantly, many ES cell-enriched core transcription factors are p53-repressed genes. Further analyses demonstrate that p53-repressed genes are functionally associated with ES/iPS cell status while p53-activated genes are linked to differentiation. p53-activated genes and -repressed genes also display distinguishable features of expression levels and epigenetic markers. Upon DNA damage, p53 regulates the self-renewal and pluripotency of ES cells. Together, these results support a model that, in response to DNA damage, p53 affects the status of ES cells through activating differentiation-associated genes and repressing ES cell-enriched genes.
embryonic stem cells; p53; genomics; epigenetics; transcription
A novel dopamine-plus-HSA (human serum albumin) approach was developed to functionalize iron oxide nanoparticles (IONPs), yielding nanoconjugates that are highly efficient in labeling various types of cell lines, which was demonstrated by in vivo MR imaging on xenograft and focal cerebral ischemia models.
Type III IFNs (IFN-λs) constitute a new subfamily with antiviral activities by signaling through a unique receptor complex composed of IFN-λs receptor 1 (IFNλR1) and interleukin-10 receptor 2 (IL10R2). As tree shrews (Tupaia belangeri) have shown susceptiblility to several human viruses, they are a potentially important model for analyzing viral infection. However, little is known about their IFN-λs system. We used the tree shrew genome to retrieve IFN-λs and their receptor contig sequences by BLASTN and BLASTZ algorithms, and GenScan was used to scan transcripts from the putative contig sequences. RT-PCR and bioinformatic methods were then used to clone and characterize the IFN-λs system. Due to its highest identity with human IFN-λ3, we opted to define one intact IFN-λ gene, tsIFN-λ3, as well as its two receptor subunits, tsIFNλR1 and tsIL10R2. Additionally, our results showed that tsIFN-λ3 contained many features conserved in IFN-λ3 genes from other mammals, including conserved signal peptide cleavage and glycosylation sites, and several residues responsible for binding to the type III IFNR. We also found six transcript variants in the receptors: three in tsIFNλR1, wherein different extracellular regions exist in three transmembrane proteins, resulting in different affinities with IFN-λs; and three more variants in tsIL10R2, encoding one transmembrane and two soluble proteins. Based on tissue distribution in the liver, heart, brain, lung, intestine, kidney, spleen, and stomach, we found that IFN-λs receptor complex was expressed in a variety of organs although the expression level differed markedly between them. As the first study to find transcript variants in IL-10R2, our study offers novel insights that may have important implications for the role of IFN-λs in tree shrews’ susceptibility with a variety of human viruses, bolstering the arguments for using tree shrews as an animal model in the study of human viral infections.
NBM-T-L-BMX-OS01 (BMX) was derived from the semisynthesis of osthole, isolated from Cnidium monnieri (L.) Cuss., and was identified to be a potent inhibitor of HDAC8. This study shows that HDAC8 is highly expressed in the pancreas and the brain. The function of HDAC8 in the brain has not been adequately studied. Because BMX enhances neurite outgrowth and cAMP response element-binding protein (CREB) activation, the effect of BMX on neural plasticity such as learning and memory is examined. To examine declarative and nondeclarative memory, a water maze, a passive one-way avoidance task, and a novel object recognition task were performed. Results from the water maze revealed that BMX and suberoylanilide-hydroxamic-acid-(SAHA-) treated rats showed shorter escape latency in finding the hidden platform. The BMX-treated animals spent more time in the target quadrant in the probe trial performance. An analysis of the passive one-way avoidance results showed that the BMX-treated animals stayed longer in the illuminated chamber by 1 day and 7 days after footshock. The novel object recognition task revealed that the BMX-treated animals showed a marked increase in the time spent exploring novel objects. Furthermore, BMX ameliorates scopolamine-(Sco-) induced learning and memory impairment in animals, indicating a novel role of BMX in learning and memory.
Antagonism of the histamine H4 receptor (H4R) has been shown to be anti-inflammatory in a number of preclinical disease models, however the exact mechanisms behind this are still being uncovered. In vitro, the receptor interacts with TLR and impacts inflammatory mediator production from a number of different cell types. Here it is shown that this interaction also occurs in vivo.
Materials and methods
Wild-type and H4R deficient BALB/c mice received an i.p. injection of LPS in PBS in conjunction with p.o. JNJ 7777120 or JNJ 28307474 (H4R antagonists). Two hours later blood was collected and TNF was measured.
Two different H4R antagonists inhibited LPS-induced TNF production in mice and this production was also reduced in H4R-deficient mice. The TNF mRNA analysis showed that the major source of the cytokine was the liver and not blood, and that the H4R antagonist only reduced the expression levels in the liver. Depletion or inactivation of macrophages reduced the TNF levels and eliminated the H4R sensitivity. Treatment with an H4R antagonist also reduced LPS-induced liver injury and blocked LPS-enhanced lung inflammation in mice.
The data support an interaction between H4R and TLR activation in vivo that can drive inflammatory responses.
Electronic supplementary material
The online version of this article (doi:10.1007/s00011-013-0612-5) contains supplementary material, which is available to authorized users.
Histamine; Macrophages; Kupffer cells; Toll-like receptors
Mouthparts are closely associated with the feeding behavior and feeding habits of insects. The features of mouthparts frequently provide important traits for evolutionary biologists and systematists. The short-faced scorpionflies (Panorpodidae) are distinctly different from other families of Mecoptera by their extremely short rostrum. However, their feeding habits are largely unknown so far. In this study, the mouthpart morphology of Panorpodes kuandianensis Zhong et al., 2011 was investigated using scanning electron microscopy and histological techniques. The mandibulate mouthparts are situated at the tip of the short rostrum. The clypeus and labrum are short and lack distinct demarcation between them. The epipharynx is furnished with sublateral and median sensilla patches. The blade-shaped mandibles are sclerotized and symmetrical, bearing apical teeth and serrate inner margins. The maxilla and labium retain the structures of the typical pattern of biting insects. The hirsute galea, triangular pyramid-shaped lacinia, and labial palps are described in detail at ultrastructural level for the first time. Abundant sensilla are distributed on the surface of maxillary and labial palps. The sexual dimorphism of mouthparts is found in Panorpodes for the first time, mainly exhibiting on the emargination of the labrum and apical teeth of mandibles. Based on the features of mouthparts, the potential feeding strategy and feeding mechanism are briefly discussed in Panorpodes.