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Febrile seizures (FS) are the most common neurological disease in infancy and early childhood, it can lead to metabolic changes and have long-term health implications. Aim of this study was to investigate the long-term effects of FS on metabolism.We measured certain metabolic parameters in hyperthermia-prone (HP) rats, which were developed using a selective breeding process and showed a lower seizure threshold than wild-type (WT) rats. Body weight, body length, abdominal circumference and the levels of fasting blood glucose, serum triglyceride, and total cholesterol concentrations were analyzed. The mRNA expression of genes involved in glucose and lipid metabolism was determined by qPCR and the histone methylation level in the liver was determined by western blot.We found that the body weight of the HP rats was significantly lower than that of the WT rats. Similarly, the fasting blood glucose and serum triglyceride levels were lower in the HP group compared with the WT group. These changes were accompanied by increased mRNA expression of genes such as phosphoenolpyruvate carboxykinase (PEPCK) and carnitine palmitoyl transferase-1 (CPT-1), but not peroxisome proliferator-activated receptor α (PPARα). We also found tri-methylation of histone 3 at Lys9 and Lys27 was decreased in the HP group.These data may suggest an underlying mechanism by which FS have a long-term effect on energy metabolism via histone methylation.

Autoimmune diseases are usually accompanied by tissue injury caused by autoantigen-specific T-cells. KV1.3 channels participate in modulating calcium signaling to induce T-cell proliferation, immune activation and cytokine production. Effector memory T (TEM)-cells, which play major roles in many autoimmune diseases, are controlled by blocking KV1.3 channels on the membrane. Toxins derived from animal venoms have been found to selectively target a variety of ion channels, including KV1.3. By blocking the KV1.3 channel, these toxins are able to suppress the activation and proliferation of TEM cells and may improve TEM cell-mediated autoimmune diseases, such as multiple sclerosis and type I diabetes mellitus.

Evidence has shown that gastrin-releasing peptide receptor (GRPR) is involved in responses to stress and anxiety. The primary role of GRPR is to stimulate corticotrophin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH) secretion. Thus, the mechanisms of GRPR signaling should be elucidated to discover novel therapeutic targets for treating depression. This study aimed to investigate GRPR alterations in the C57 mouse hypothalamus after the animals were subjected to stress and fluoxetine treatments. Specifically, we subjected the mice to isolation and chronic unpredictable mild stress (CUMS) for three weeks to establish an experimental model of depression. These mice were subsequently treated with fluoxetine for three weeks. Then, we performed the sucrose preference test and the open field test and measured food intake and body weight to explore the effects of stress and fluoxetine on activity and anhedonia. After fluoxetine treatment, we also assessed changes in the levels of GRPR expression in the hypothalamus using immunohistochemistry, western blotting, and real-time quantitative PCR (RT-PCR). We found that stressed mice showed significant reductions in locomotion, food intake/body weight, and sucrose preference; these reduced parameters indicated a state of anhedonia. Marked increases in mRNA and protein expression of GRPR in the hypothalamus of CUMS-exposed mice were also observed, although treatment with fluoxetine reversed these stress-induced changes. Our results also demonstrated the feasibility and effectiveness of the C57 mouse model of depression established by CUMS and isolation. After fluoxetine treatment was administered, the animals’ depression symptoms were alleviated, and these behavioral alterations were accompanied by specific changes in mRNA and protein expression of GRPR in the hypothalamus. These results suggest that GRPR may be implicated in depression; therefore, new therapeutic targets of depression focused on GRPR signaling should be explored.

The dysregulation of the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis system is one of the major neuroendocrine abnormalities in major depression (MD). Many pieces of evidence supported that corticotropin-releasing hormone (CRH) play a role in the pathophysiology of major depression. In this article, whether genetic variations in the corticotropin-releasing hormone receptor1 (CRHR1) gene might be associated with increased susceptibility to major depression was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Three SNPs were identified in CRHR1 gene and genotyped in the samples of patients diagnosed with major depression and matched controls. We observed significant allele (P = 0.0008) and genotype (P = 0.0002) association with rs242939, and the haplotype defined by alleles G-G-T for the represent rs1876828, rs242939 and rs242941 was significantly over-represented in major depression patients compared to controls. These results support the idea that the CRHR1 gene is likely to be involved in the genetic vulnerability for major depression.

Autophagy is an important homeostatic process for the degradation of cytosolic proteins and organelles and has been reported to play an important role in cellular responses to pathogens and virus replication. However, the role of autophagy in Coxsackievirus A16 (CA16) infection and pathogenesis remains unknown. Here, we demonstrated that CA16 infection enhanced autophagosome formation, resulting in increased extracellular virus production. Moreover, expression of CA16 nonstructural proteins 2C and 3C was sufficient to trigger autophagosome accumulation by blocking the fusion of autophagosomes with lysosomes. Interestingly, we found that Immunity-related GTPase family M (IRGM) was crucial for the activation of CA16 infection-induced autophagy; in turn, reducing IRGM expression suppressed autophagy. Expression of viral protein 2C enhanced IRGM promoter activation, thereby increasing IRGM expression and inducing autophagy. CA16 infection inhibited Akt/mTOR signaling and activated extracellular signal-regulated kinase (ERK) signaling, both of which are necessary for autophagy induction. In summary, CA16 can use autophagy to enhance its own replication. These results raise the possibility of targeting the autophagic pathway for the treatment of hand, foot, and mouth disease (HFMD).

RNA interference has shown great potential for the treatment of HIV-1. Vectors derived from prototype foamy viruses (PFVs) with a nonpathogenic nature are very promising gene transfer vehicles in anti-HIV gene therapy. In this article, three short hairpin RNAs (shRNAs) targeting the conserved regions of the HIV-1NL4-3 5' long terminal repeat (LTR) were first designed. We then constructed novel recombinant PFV vector plasmids, p▵Φ-H1-shRNAs, expressing these shRNAs under the control of the H1 RNA promoter. To detect the efficacy of these ▵Φ-H1-shRNAs for the inhibition of HIV-1 replication, we performed a dual-luciferase reporter assay, RT-qPCR, ELISA, western blotting, and a lactate dehydrogenase (LDH) assay by transient transfection in 293T cells. The results suggest that these novel shRNAs driven by PFV vectors inhibit HIV-1 replication efficiently without cytotoxicity, with shRNA3 being the most effective. In addition, we analyzed the shRNA target sites in the 5' LTR of HIV-1 strains other than HIV-1NL4-3 and found that these shRNAs may possibly inhibit other HIV-1 strains.

Febrile seizure (FS) is the most common seizure disorder in children, and children with FS are regarded as a high risk for the eventual development of epilepsy. Brain inflammation may be implicated in the mechanism of FS. Transient receptor potential vanilloid 1 (TRPV1) is believed to act as a monitor and regulator of body temperature. The role of inflammation in synaptic plasticity mediation indicates that TRPV1 is relevant to several nervous system diseases, such as epilepsy. Here, we report a critical role for TRPV1 in a febrile seizure mouse model and reveal increased levels of pro-inflammatory factors in the immature brain. Animals were subjected to hyperthermia for 30 min, which generates seizures lasting approximately 20 min, and then were used for experiments. To invoke frequently repetitive febrile seizures, mice are exposed to hyperthermia for three times daily at an interval of 4h between every time induced seizure, and a total of 4 days to induce. Behavioral testing for febrile seizures revealed that a TRPV1 knock-out mouse model demonstrated a prolonged onset latency and a shortened duration and seizure grade of febrile seizure when compared with wild type (WT) mice. The expression levels of both TRPV1 mRNA and protein increased after a hyperthermia-induced febrile seizure in WT mice. Notably, TRPV1 activation resulted in a significant elevation in the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and HMGB1) in the hippocampus and cortex. These data indicate that the reduction of TRPV1 expression parallels a decreased susceptibility to febrile seizures. Thus, preventative strategies might be developed for use during febrile seizures.

Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, has broken out several times and was accompanied by neurological disease. microRNAs, a class of small non-coding RNAs that are approximately 20 nucleotides long, play important roles in the regulation of various biological processes, including antiviral defense. However, the roles of miRNAs in EV71 replication and pathogenesis are not well understood. In this study, we found that the expression of miR-27a was significantly decreased in EV71-infected cells. Interestingly, the over-expression of miR-27a could inhibit EV71 replication, as measured by virus titration, qPCR, and Western blotting. We identified EGFR mRNA is a bona fide target of miR-27a by computational analysis and luciferase reporter assays. Furthermore, miR-27a could decrease EGFR expression, as measured by qPCR and Western blotting. Moreover, the inhibition of EGFR expression by miR-27a decreased the phosphorylation of Akt and ERK, which facilitate EV71 replication. These results suggest that miR-27a may have antiviral activity against EV71 by inhibiting EGFR.

Artemisinin, a natural product from the Chinese medicinal plant, Artemisia annua L., is commonly used in the treatment of malaria, and has recently been reported to have potent anticancer activity in various types of human tumors. Yet, the effect of artemisinin on neuroblastoma is still unclear. In the present study, we aimed to investigate the effects of artemisinin on neuroblastoma cells. We observed that artemisinin significantly inhibited cell growth and proliferation, and caused cell cycle arrest in the G1 phase in neuroblastoma cell lines. Annexin V-FITC/PI staining assay revealed that artemisinin markedly induced apoptosis. Soft agar assays revealed that artemisinin suppressed the ability of clonogenic formation of neuroblastoma cells and a xenograft study in NOD/SCID mice showed that artemisinin inhibited tumor growth and development in vivo. Therefore, our results suggest that the Chinese medicine artemisinin could serve as a novel potential therapeutic agent in the treatment of neuroblastoma.

Artemisinic aldehyde Δ11 (13) reductase (DBR2) is the checkpoint enzyme catalyzing artemisinic aldehyde to form dihydroartemisinic aldehyde directly involved in artemisinin biosynthetic pathway. In the present study, DBR2 was employed to engineer the biosynthetic pathway of artemisinin in transgenic plants of Artemisia annua L. Seven independent transgenic plants of A. annua with DBR2 overexpression driven by the cauliflower mosaic virus 35S promoter were obtained by Agrobacterium-mediated genetic transformation and confirmed by genomic PCR. The results of real-time qPCR analysis showed that the expression levels of DBR2 gene in all the seven transgenic lines were significantly higher than in nontransgenic control. The high-performance liquid chromatography analysis of artemisinin and its relative metabolites demonstrated that the contents of artemisinin and its direct precursor dihydroartemisinic acid were remarkably increased in the transgenic plants of A. annua with DBR2 overexpression. Interestingly, it was also found that the contents of arteannuin B and its direct precursor artemisinic acid in the branch pathway competing against artemisinin biosynthesis were also improved in DBR2-overexpressed A. annua plants. The transgenic results in the present study indicated that DBR2 is a useful structural gene in engineering the artemisinin biosynthetic pathway to develop genetically modified A. annua with the higher yield of artemisinin.

Several investigations have suggested that PDLIM5 plays a key role in the pathophysiology of major depressive disorder (MDD), and that PDLIM5 might be a therapeutic target for the action of antidepressant. In this study, we sought to investigate whether variations of PDLIM5 gene sequence could predict response to antidepressants in MDD patients. We selected 3 SNPs (rs10008257, rs2433320, 2452600) of PDLIM5 gene, and performed an association analysis of PDLIM5 and the efficacy of fluoxetine treatment in 185 Han Chinese MDD patients. The results show that the rs2433320 of PDLIM5 gene are associated with fluoxetine therapeutic response in MDD patients (X(2) = 8.2960, df = 2, P = 0.0145) after correction with the Bonferroni multiple test, the HAMD score of the GG genotype group was significantly lower than that of the AA and AG genotype group at 1, 2, 4 and 6 weeks. The results support the idea that the PDLIM5 gene is likely to be involved in the antidepressant response in MDD.

Astragalus polysaccharide (APS) has been reported to increase insulin sensitization and to ameliorate diabetes in animal models, and studies have demonstrated that this effect may be correlated with its anti-inflammatory roles in vivo and in vitro. However, the potential pharmacological mechanisms of APS in anti-inflammatory regulation are still poorly understood. Herein, RAW264.7 cells treated with APS showed anti-inflammatory effects. Interleukin (IL)-10 protein levels and expression of most of the anti-inflammatory genes, including IL-10, macrophage mannose receptor (MMR), arginase, Dectin-1, YM-1 and YM-2, were significantly increased after treatment with APS for 24 h. Furthermore, to determine whether APS plays a potential role in RAW264.7 cell inflammation, we pretreated RAW264.7 cells with APS in the presence of palmitate. The results showed that APS markedly recovered the impairment of AMPK activity induced by palmitate. Furthermore, APS induced IL-10 protein production and anti-inflammatory gene expression of IL-10, MMR, Dectin-1, arginase, YM-1 and YM-2. Additionally, APS inhibited IL-1β protein production and expression of most of the pro-inflammatory genes, such as IL-1β, iNOS, MCP-1, IL-6 and CD11c but not tumor necrosis factor (TNF)-α. Notably, the effect of APS on inflammatory genes, except for TNF-α, was abrogated when AMPK activity was inhibited using a DN-AMPK plasmid. These results suggest that APS effectively ameliorates palmitate-induced pro-inflammatory responses through AMPK activity.

Febrile seizures (FS), as a multifactorial and genetic disease, are the most common type of convulsive event in infants and young children. Their genetic basis, however, remains elusive. To investigate the genetic mechanisms involved in FS and to identify novel susceptibility genes, we developed two new strains of rats that are hyperthermia-prone (HP, lower seizure threshold) and hyperthermia-resistant (HR, higher seizure threshold) using an established model of hyperthermia-induced seizures combined with selective breeding process. With each subsequent generation, the morbidity of the FS gradually increased in the HP group and gradually decreased in the HR group. Changes in seizure susceptibility between the two genotypes were investigated using kainic acid (KA)-induced seizures and electroencephalography (EEG). The HP rats had a greater seizure severity compared with the HR rats. Our findings may be a significant step toward discovering the genetic mechanisms involved in FS and may elucidate the pathogenesis of this disorder.

OBJECTIVE To study the relative expression of the genes involved in artemisinin biosynthesis in different tissues including roots, stems, leaves and flowers of Artemisia annua, and establish the relationship between gene expression and artemisinin accumulation, eventually leading to discover the mainly effective genes involved in artemisinin biosynthesis. METHOD The 7 functional genes involved in artemisinin biosynthesis were detected at the level of expression by using qRT-PCR, and simultaneously the content of artemisinin in the 4 investigated tissues was detected in parallel. RESULT The 3 genes including HMGR, DXR and FPS which were involved in the upstream pathway of artemisinin biosynthesis showed the highest expression levels in flowers, and the 4 functional genes including ADS, CYP71AV1, CPR and AAR which were involved in the artemisinin-specific biosynthetic pathway were found to be expressed in all the 4 detected tissues. The highest expression level of ADS was found in leaves, then followed by flowers, and the lowest expression level of ADS was found in roots and stems. CYP71AV1 had highest expression level in flowers and lowest in leaves. CPR showed highest expression level in flowers, and AAR had lower expression levels in the other 3 artemisinin-specific pathway genes in all the tissues. The highest content of artemisinin was found in leaves (0.343 mg x g(-1)), then followed by flowers (0.152 mg x g(-1)), roots (0.062 mg x g(-1)) and stems (0.060 mg x g(-1)). CONCLUSION In the biosynthesis of artemisinin, the upstream genes including HMGR from the MVA pathway, DXR from the MEP pathway and the checkpoint gene FPS were much more active in flowers, and this suggested that flowers might be the tissues of artemisinin precursor biosynthesis, and further DXR contributed more to artemisinin biosynthesis. The positive correlation of ADS expression and artemisinin content in tissues demonstrated that ADS played a very important role in artemisinin biosynthesis, which was the ideal target for engineering the artemisinin biosynthetic pathway. In summary, the functional genes involved in artemisinin biosynthesis do not express at the same level but synergistically.

Stroke is a major cause of death and disability throughout the world. Subtotal occlusion of the carotid artery is an important risk factor for stroke. Carotid artery stenting (CAS) is increasingly being used for treatment of carotid artery stenosis. There are many reports on treating carotid artery stenosis by CAS; however, there are few case reports on treating symptomatic carotid artery subtotal occlusion by CAS, especially in China. To test the clinical applicability, technical results, and morbidity of carotid artery stenting (CAS) in the treatment of symptomatic carotid artery subtotal occlusion. The clinical data of 27 symptomatic carotid artery subtotal occlusion patients treated with carotid stenting from January 2005 to December 2009 at the University Hospital of Hubei University for Nationalities and the West China Hospital of Sichuan University were systematically reviewed and analysed. Our results suggest that after balloon pre-dilation of the stenotic lesion, with the protection of a distal filter protection device, carotid stenting can be performed to treat symptomatic carotid artery subtotal occlusion patients with acceptable safety. However, the widespread use of this technique still requires large-scale clinical investigation.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially in China. Recent researches have shown that E3 ubiquitin ligases Pirh2 (p53-induced RING-H2 protein) is highly expressed in HCC cell lines and is correlated with poor survival and prognostic in patients with HCC; however, the function of Pirh2 in the genesis and the development of HCC remains unclear. Pirh2, a member of the RING finger family, can target p53 for degradation and thereby repress a diverse group of biological activities and involved in many signalling pathways related to the genesis and evolution of cancer. Up to now, four Pirh2 variants had been reported and named Pirh2A, Pirh2B, Pirh2C and Pirh2D. Here we report the existence of two additional isoforms from human hepatocellular liver carcinoma cell line (HepG2 cell) and named as Pirh2E and Pirh2F. Compared to full-length Pirh2A, Pirh2E lacks amino acids 235-261, while Pirh2F is missing C-terminal amino acids 227-261 and both isoforms harbor the RING domain; therefore, we speculate that ubiquitin ligase activity maybe reversed by them. Further studies are required to determine whether Pirh2E and Pirh2F functions in a manner similar to Pirh2A.

The voltage-gated Kv1.3 K(+) channel in effector memory T cells serves as a new therapeutic target for multiple sclerosis. In our previous studies, the novel peptide ADWX-1 was designed and synthesized as a specific Kv1.3 blocker. However, it is unclear if and how ADWX-1 alleviates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. In this study, the administration of ADWX-1 significantly ameliorated the rat experimental autoimmune encephalomyelitis model by selectively inhibiting CD4(+)CCR7(-) phenotype effector memory T cell activation. In contrast, the Kv1.3-specific peptide had little effect on CD4(+)CCR7(+) cells, thereby limiting side effects. Furthermore, we determined that ADWX-1 is involved in the regulation of NF-κB signaling through upstream protein kinase C-θ (PKCθ) in the IL-2 pathway of CD4(+)CCR7(-) cells. The elevated expression of Kv1.3 mRNA and protein in activated CD4(+)CCR7(-) cells was reduced by ADWX-1 engagement; however, an apparent alteration in CD4(+)CCR7(+) cells was not observed. Moreover, the selective regulation of the Kv1.3 channel gene expression pattern by ADWX-1 provided a further and sustained inhibition of the CD4(+)CCR7(-) phenotype, which depends on the activity of Kv1.3 to modulate its activation signal. In addition, ADWX-1 mediated the activation of differentiated Th17 cells through the CCR7(-) phenotype. The efficacy of ADWX-1 is supported by multiple functions, which are based on a Kv1.3(high) CD4(+)CCR7(-) T cell selectivity through two different pathways, including the classic channel activity-associated IL-2 pathway and the new Kv1.3 channel gene expression pathway.

Tryptophan decarboxylase (TDC) converts tryptophan into tryptamine that is the indole moiety of ajmalicine. The full-length cDNA of Rauvolfia verticillata (RvTDC) was 1,772 bps that contained a 1,500-bp ORF encoding a 499-amino-acid polypeptide. Recombinant 55.5 kDa RvTDC converted tryptophan into tryptamine. The K (m) of RvTDC for tryptophan was 2.89 mM, higher than those reported in other TIAs-producing plants. It demonstrated that RvTDC had lower affinity to tryptophan than other plant TDCs. The K (m) of RvTDC was also much higher than that of strictosidine synthase and strictosidine glucosidase in Rauvolfia. This suggested that TDC might be the committed-step enzyme involved in ajmalicine biosynthesis in R. verticillata. The expression of RvTDC was slightly upregulated by MeJA; the five MEP pathway genes and SGD showed no positive response to MeJA; and STR was sharply downregulated by MeJA. MeJA-treated hairy roots produced higher level of ajmalicine (0.270 mg g(-1) DW) than the EtOH control (0.183 mg g(-1) DW). Highest RvTDC expression level was detected in hairy root, about respectively 11, 19, 65, and 109-fold higher than in bark, young leaf, old leaf, and root. Highest ajmalicine content was also found in hairy root (0.249 mg g(-1) DW) followed by in bark (0.161 mg g(-1) DW) and young leaf (0.130 mg g(-1) DW), and least in root (0.014 mg g(-1) DW). Generally, the expression level of RvTDC was positively consistent with the accumulation of ajmalicine. Therefore, it could be deduced that TDC might be the key enzyme involved in ajmalicine biosynthesis in Rauvolfia.

This study was designed to evaluate composition, location, and severity of coronary atherosclerotic plaques with 64-slice computed tomography (CT) coronary angiography in Xingjiang Uygur and Han ethnic groups. 152 Uighur ethnic group confirmed coronary heart disease (CHD) and underwent 64-Slice CT coronary angiography were included consecutively from January 2007 to June 2010. 304 Han cases examined at the same time were enrolled as control. CT coronary angiography was used to assess plaques characteristics. There were significant differences in plaques characteristics between Uygur and Han ethnic groups, with a higher incidence, higher proportion of occurred in the left circumflex branch, severer luminal narrowing, higher proportion of obstructive plaque involved multi-branch, in Uygur ethnic group. Comparison of CHD risk factors, body mass index in Uighur was higher than that in Han. Non-invasive detection of coronary plaques using 64-Slice CT may constitute an important step in risk stratification of CHD in different ethnic groups.

Selective degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) can be modeled by the administration of the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+) ). Because abnormal mitochondrial dynamics are increasingly implicated in the pathogenesis of PD, in this study, we investigated the effect of MPP(+) on mitochondrial dynamics and assessed temporal and causal relationship with other toxic effects induced by MPP(+) in neuronal cells. In SH-SY5Y cells, MPP(+) causes a rapid increase in mitochondrial fragmentation followed by a second wave of increase in mitochondrial fragmentation, along with increased DLP1 expression and mitochondrial translocation. Genetic inactivation of DLP1 completely blocks MPP(+) -induced mitochondrial fragmentation. Notably, this approach partially rescues MPP(+) -induced decline in ATP levels and ATP/ADP ratio and increased [Ca(2+) ](i) and almost completely prevents increased reactive oxygen species production, loss of mitochondrial membrane potential, enhanced autophagy and cell death, suggesting that mitochondria fragmentation is an upstream event that mediates MPP(+) -induced toxicity. On the other hand, thiol antioxidant N-acetylcysteine or glutamate receptor antagonist D-AP5 also partially alleviates MPP(+) -induced mitochondrial fragmentation, suggesting a vicious spiral of events contributes to MPP(+) -induced toxicity. We further validated our findings in primary rat midbrain dopaminergic neurons that 0.5 μm MPP(+) induced mitochondrial fragmentation only in tyrosine hydroxylase (TH)-positive dopaminergic neurons in a similar pattern to that in SH-SY5Y cells but had no effects on these mitochondrial parameters in TH-negative neurons. Overall, these findings suggest that DLP1-dependent mitochondrial fragmentation plays a crucial role in mediating MPP(+) -induced mitochondria abnormalities and cellular dysfunction and may represent a novel therapeutic target for PD.

Activation of KCNQ-channels has been shown to decrease or reduce the propagation of neuronal excitation in the immature central nervous system, and KCNQ activators represent a new class of anticonvulsant compounds. Their effectiveness has been demonstrated in many seizure models but not in repetitive febrile seizures (RFS) models. This study aimed to test whether the KCNQ channel activator flupirtine is also effective for RFS in rats. RFS were induced in Sprague-Dawley (SD) rats at postnatal day 10 (P10) in a warm water bath for eight consecutive days with or without the pre-administration of flupirtine or phenobarbital. As results, both drugs significantly increased the latency and decreased the rate of febrile seizures. Furthermore, seizures in the flupirtine group had a significantly shorter duration and were less severe compared with the phenobarbital group. The flupirtine-treated group showed less impairment in learning and memory and less obvious pathological changes in the brain following RFS compared with the phenobarbital-treated group. In summary, flupirtine appears to be effective in RFS prophylaxis and may merit further study as a candidate for the treatment of RFS in infants and children.

Pirh2 (p53-induced RING-H2) is an E3 ubiquitin ligase that can target p53 for degradation and thereby repress a diverse group of biological activities regulated by p53. Notably, Pirh2, rather than MDM2, is the primary degrader of active p53 under conditions of DNA damage. Moreover, Pirh2 is highly expressed in multiple cancer cell lines regardless of p53 status. Recent research has shown that Pirh2 is involved in many signalling pathways related to the genesis and evolution of cancer. This review aims to summarize a comprehensive picture of the role of Pirh2 in cellular processes and its significance to tumorigenesis. Furthermore, this review focuses on its potential role as a cancer therapeutic target. (Cancer Sci 2011; 102: 909–917)

Background An important etiological hypothesis about depression is stress has neurotoxic effects that damage the hippocampal cells. Corticotropin-releasing hormone (CRH) regulates brain-derived neurotrophic factor (BDNF) expression through influencing cAMP and Ca2+ signaling pathways during the course. The aim of this study is to examine the single and combined effects of CRH receptor 1 (CRHR1) and BDNF genes in recurrent major depressive disorder (MDD). Methodology/Principal Finding The sample consists of 181 patients with recurrent MDD and 186 healthy controls. Whether genetic variations interaction between CRHR1 and BDNF genes might be associated with increased susceptibility to recurrent MDD was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). CRHR1 gene (rs1876828, rs242939 and rs242941) and BDNF gene (rs6265) were identified in the samples of patients diagnosed with recurrent MDD and matched controls. Allelic association between CRHR1 rs242939 and recurrent MDD was found in our sample (allelic: p = 0.018, genotypic: p = 0.022) with an Odds Ratio 0.454 (95% CI 0.266–0.775). A global test of these four haplotypes showed a significant difference between recurrent MDD group and control group (chi-2 = 13.117, df = 3, P = 0.016. Furthermore, BDNF and CRHR1 interactions were found in the significant 2-locus, gene–gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method. Conclusion Our results suggest that an interaction between CRHR1 and BDNF genes constitutes susceptibility to recurrent MDD.

Foamy viruses (FVs) are classified to a subfamily of retrovirus presented in a wide range of hosts. None of FVs has been found to associate with any diseases in their native hosts. Such a unique biological character of FVs makes it suitable for the development of vectors for gene transfer. However, it is still controversial whether foamy virus vectors (FV vectors) can be applied to the central nervous system (CNS). In this review, we summarize the studies of FV vectors, which have been used for transduction of neural cells and other nondividing cells. We further discuss the potential mechanisms underlying the infection and propose that FVs can be used to develop transfer vectors for gene therapy in neurological disorders.

A water environment security assessing system is constructed to respect the water environment security situation on pollution source, water quality, and ecology along Luan River to Tianjin Diversion Project. The model for assessment is proposed based on multi-hierarchy fuzzy theory. The corresponding assessment indexes, quantitative standards and weight functions are established. The system and method are applied to assess the water environment security status of Luan River-Tianjin Diversion Project. The result shows that the assessment system can reflect objective current status of water environment security. Therefore, it can provide technology support for securing water quality of Luan River-Tianjin Water diversion project.

Neuropathic pain is a long-lasting clinical problem that is often refractory to medical management. Gene transfer of specific genes for therapeutic benefit offers a novel approach to the treatment of neuropathic pain. In this study, we tested whether the transfer of the glutamic acid decarboxylase (GAD) gene to dorsal root ganglion (DRG) cells would attenuate below-injury level central neuropathic pain after spinal cord injury (SCI) by using a novel human foamy virus (HFV) vector to achieve release of gamma-aminobutyric acid (GABA). Subcutaneous inoculation of a replication-defective HFV vector, which expresses GAD (vector rdvGAD67) for 7 days after T13 spinal cord hemisection, reversed mechanical allodynia and thermal hyperalgesia evoked by SCI. The antiallodynic effect lasted 6 weeks and was reestablished by reinoculation. We also found that subcutaneous inoculation of rdvGAD67 resulted in enhanced production of GAD and tonical GABA release from transduced DRG neurons. These results suggest that HFV-mediated gene transfer to DRG could be employed to treat below-injury level central neuropathic pain after incomplete SCI.

Hypothalamic-pituitary-adrenal (HPA) axis appears to play a key role in the pathogenesis of major depressive disorders (MDD). Treatment of certain selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce the activity of corticotropin-releasing hormone (CRH) neurons and may contribute to their therapeutic action. It has been proposed that the downregulation of CRH activity is final and common step of antidepressant treatment. In this study, we tested whether the polymorphisms of three sites (rs1876828, rs242939 and rs242941) in corticotropin-releasing hormone receptor1 (CRHR1) gene are related to 6 weeks fluoxetine antidepressant effect in 127 Han Chinese patients with MDD. The results show that the rs242941 G/G genotype and homozygous GAG haplotype of the three single-nucleotide polymorphisms (SNPs) are associated with fluoxetine therapeutic response in MDD patients of high-anxiety (HA). The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD.

Temozolomide (TMZ) is an alkylating agent currently used as first-line therapy for gliomas treatment due to its DNA-damaging effect. However, drug resistance occurs, preventing multi-cycle use of this chemotherapeutic agent. One of the major mechanisms of cancer drug resistance is enhanced activity of a DNA repair enzyme, O(6)-methylguanine-DNA-methyltransferase (MGMT), which counteracts chemotherapy-induced DNA alkylation and is a key component of chemoresistance. MGMT repairs TMZ-induced DNA lesions, O(6)-meG, by transferring the alkyl group from guanine to a cysteine residue. This review provides an overview of recent advances in the field, with particular emphasis on the inhibitors of MGMT and underlying mechanisms. Literature search was performed through PubMed and all relevant articles were reviewed, with particular attention to MGMT, its role in TMZ-resistant gliomas, effects of MGMT inhibitors and the underlying mechanisms. Several strategies are currently being pursued to improve the therapeutic efficacy of TMZ via inhibition of MGMT to reduce chemoresistance and improve overall survival. MGMT may be a promising target for the treatment of TMZ-resistant gliomas.

To design a releasable PEGylated TNF-α (rPEG-TNF-α), a cathepsin B-sensitive dipeptide (Val-Cit moiety) was inserted into conventional PEG-modified TNF-α (PEG-TNF-α), facilitating its clinical use for anti-tumor therapy. Comparative pharmacokinetic and pharmacodynamic studies showed that the half-lives of both PEGylated forms of TNF-α were ∼60-fold greater than that of unmodified TNF-α. In addition, the in vitro bioactivity of rPEG-TNF-α was greater than that of PEG-TNF-α with the same degree of PEG modification. Release of TNF-α from rPEG-TNF-α in vitro was dependent on the presence of cathepsin B and was inhibited by a cathepsin B inhibitor. Despite the potent cytotoxicity of unmodified TNF-α against normal cells, its PEGylated forms at higher TNF-α concentrations showed low cytotoxic activity against these cells. In contrast, both forms of PEGylated TNF-α showed potent cytotoxic activity against the B16 and L929 cell lines, with rPEG-TNF-α being 5- and 9-fold more potent, respectively, than PEG-TNF-α. Moreover, rPEG-TNF-α was a more potent in vivo antitumor agent than PEG-TNF-α.

Background Prototype foamy virus (PFV) is a member of the Spumaretrovirinae subfamily of retroviruses, which maintains lifelong latent infection while being nonpathogenic to their natural hosts. Autophagy is a cell-programmed mechanism that plays a pivotal role in controlling homeostasis and defense against exotic pathogens. However, whether autophagy is the mechanism for host defense in PFV infection has not been investigated. Findings Our results revealed that PFV infection induced the accumulation of autophagosomes and triggered complete autophagic flux in BHK-21 cells. PFV infection also altered endoplasmic reticulum (ER) homeostasis. The PERK, IRE1 and ATF6 pathways, all of which are components of the ER stress-related unfolded protein response (UPR), were activated in PFV-infected cells. In addition, accelerating autophagy suppressed PFV replication, and inhibition of autophagy promoted viral replication. Conclusions Our data indicate that PFV infection can induce complete autophagy through activating the ER stress-related UPR pathway in BHK-21 cells. In turn, autophagy negatively regulates PFV replication. Electronic supplementary material The online version of this article (doi:10.1186/s12977-017-0341-x) contains supplementary material, which is available to authorized users.