Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis.

BackgroundIn multiple sclerosis (MS) and its widely used animal model, experimental autoimmune encephalomyelitis (EAE), autoreactive T cells contribute importantly to central nervous system (CNS) tissue damage and disease progression. Promoting apoptosis of autoreactive T cells may help eliminate cells responsible for inflammation and may delay disease progression and decrease the frequency and severity of relapse. Programmed cell death 5 (PDCD5) is a protein known to accelerate apoptosis in response to various stimuli. However, the effects of recombinant human PDCD5 (rhPDCD5) on encephalitogenic T cell-mediated inflammation remain unknown.MethodsWe examined the effects of intraperitoneal injection of rhPDCD5 (10 mg/kg) on EAE both prophylactically (started on day 0 post-EAE induction) and therapeutically (started on the onset of EAE disease at day 8), with both of the treatment paradigms being given every other day until day 25. Repeated measures two-way analysis of variance was used for statistical analysis.ResultsWe showed that the anti-inflammatory effects of rhPDCD5 were due to a decrease in Th1/Th17 cell frequency, accompanied by a reduction of proinflammatory cytokines, including IFN-γ and IL-17A, and were observed in both prophylactic and therapeutic regimens of rhPDCD5 treatment in EAE mice. Moreover, rhPDCD5-induced apoptosis of myelin-reactive CD4+ T cells, along with the upregulation of Bax and downregulation of Bcl-2, and with activated caspase 3.ConclusionsOur data demonstrate that rhPDCD5 ameliorates the autoimmune CNS disease by inhibiting Th1/Th17 differentiation and inducing apoptosis of predominantly pathogenic T cells. This study provides a novel mechanism to explain the effects of rhPDCD5 on neural inflammation. The work represents a translational demonstration that rhPDCD5 has prophylactic and therapeutic properties in a model of multiple sclerosis

Kirenol attenuates experimental autoimmune encephalomyelitis by inhibiting differentiation of Th1 and th17 cells and inducing apoptosis of effector T cells.

Experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is characterized by CNS demyelination mediated by autoreactive T cells. Kirenol, a biologically active substance isolated from Herba Siegesbeckiae, has potent anti-inflammatory activities. Here we investigated effects of kirenol on EAE. Kirenol treatment markedly delayed onset of disease and reduced clinical scores in EAE mice. Kirenol treatment reduced expression of IFN-γ and IL-17A in the serum and proportion of Th1 and Th17 cells in draining lymph nodes. Priming of lymphocytes was reduced and apoptosis of MOG-activated CD4+ T cells was increased in kirenol treated EAE mice. Kirenol treatment of healthy animals did not affect the lymphocytes in these non-immunized mice. Further in vitro studies showed that kirenol inhibited viability of MOG-specific lymphocytes and induced apoptosis of MOG-specific CD4+ T cells in a dose- and time-dependent manner. Kirenol treatment upregulated Bax,downregulated Bcl-2,and increased activation of caspase-3 and release of cytochrome c, indicating that a mitochondrial pathway was involved in kirenol induced apoptosis. Moreover, pretreatment with either a pan-caspase inhibitor z-VAD-fmk or a more specific caspase 3 inhibitor Ac-DEVD-CHO in lymphocytes reduced kirenol induced apoptosis. Our findings implicate kirenol as a useful agent for the treatment of MS

Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis.

Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS

Weak and Strong Convergence Theorems for Finite Families of Asymptotically Quasi-Nonexpansive Mappings in Banach Spaces

A finite-step iteration sequence for two finite families of asymptotically nonexpansive mappings is introduced and the weak and strong convergence theorems are proved in Banach space. The results presented in the paper generalize and unify some important known results of relevant scholars

5-(1H-Inden-2-yl)-1,3-benzodioxole

In the title compound, C16H12O2, the non-H atoms are coplanar with a mean r.m.s. deviation of 0.0260 (2) Å. The deviations of the bond angles from normal values at the indenyl junction C atom and the indenyl bridgehead C atom nearest the junction are imposed by the five-membered ring geometry. Due to conjugation, the single bond linking the two ring systems [1.455 (3) Å] is significantly shorter than the formal single bonds in the five-membered carbocyclic ring [1.500 (3) and 1.489 (3) Å]

The strong decay patterns of ZcZ_c and ZbZ_b states in the relativized quark model

Employing the relativized quark model and the quark-interchange model, we investigate the decay of the charged heavy quarkonium-like states $Z_c(3900)$, $Z_c(4020)$, $Z_c(4430)$, $Z_b(10610)$ and $Z_b(10650)$ into the ground and radially excited heavy quarkonia via emitting a pion meson. The $Z_c$ and $Z_b$ states are assumed to be hadronic molecules composed of open-flavor heavy mesons. The calculated decay ratios can be compared with the experimental data, which are useful in judging whether the molecule state assignment for the corresponding $Z_c$ or $Z_b$ state is reasonable or not. The theoretical framework constructed in this work will be helpful in revealing the underlying structures of some exotic hadrons.Comment: 19 pages, 4 figures, version published in EPJ

Gene Expression Divergence and Evolutionary Analysis of the Drosomycin Gene Family in Drosophila melanogaster

Drosomycin (Drs) encoding an inducible 44-residue antifungal peptide is clustered with six additional genes, Dro1, Dro2, Dro3, Dro4, Dro5, and Dro6, forming a multigene family on the 3L chromosome arm in Drosophila melanogaster. To get further insight into the regulation of each member of the drosomycin gene family, here we investigated gene expression patterns of this family by either microbe-free injury or microbial challenges using real time RT-PCR. The results indicated that among the seven drosomycin genes, Drs, Dro2, Dro3, Dro4, and Dro5 showed constitutive expressions. Three out of five, Dro2, Dro3, and Dro5, were able to be upregulated by simple injury. Interestingly, Drs is an only gene strongly upregulated when Drosophila was infected with microbes. In contrast to these five genes, Dro1 and Dro6 were not transcribed at all in either noninfected or infected flies. Furthermore, by 5′ rapid amplification of cDNA ends, two transcription start sites were identified in Drs and Dro2, and one in Dro3, Dro4, and Dro5. In addition, NF-κB binding sites were found in promoter regions of Drs, Dro2, Dro3, and Dro5, indicating the importance of NF-κB binding sites for the inducibility of drosomycin genes. Based on the analyses of flanking sequences of each gene in D. melanogaster and phylogenetic relationship of drosomycins in D. melanogaster species-group, we concluded that gene duplications were involved in the formation of the drosomycin gene family. The possible evolutionary fates of drosomycin genes were discussed according to the combining analysis of gene expression pattern, gene structure, and functional divergence of these genes

Systematic cloning and analysis of autophagy-related genes from the silkworm Bombyx mori

<p>Abstract</p> <p>Background</p> <p>Through the whole life of eukaryotes, autophagy plays an important role in various biological events including development, differentiation and determination of lifespan. A full set of genes and their encoded proteins of this evolutionarily conserved pathway have been identified in many eukaryotic organisms from yeast to mammals. However, this pathway in the insect model organism, the silkworm <it>Bombyx mori</it>, remains poorly investigated.</p> <p>Results</p> <p>Based on the autophagy pathway in several model organisms and a series of bioinformatic analyses, we have found more than 20 autophagy-related genes from the current database of the silkworm <it>Bombyx mori</it>. These genes could be further classified into the signal transduction pathway and two ubiquitin-like pathways. Using the mRNA extracted from the silkgland, we cloned the full length cDNA fragments of some key genes via reverse transcription PCR and 3' rapid amplification of cDNA ends (RACE). In addition, we found that the transcription levels of two indicator genes <it>BmATG8 </it>and <it>BmATG12 </it>in the silkgland tend to be increased from 1^stto 8^thday of the fifth instar larvae.</p> <p>Conclusion</p> <p>Bioinformatics in combination with RT-PCR enable us to remodel a preliminary pathway of autophagy in the silkworm. Amplification and cloning of most autophagy-related genes from the silkgland indicated autophagy is indeed an activated process. Furthermore, the time-course transcriptional profiles of <it>BmATG8 </it>and <it>BmATG12 </it>revealed that both genes are up-regulated along the maturation of the silkgland during the fifth instar. These findings suggest that the autophagy should play an important role in <it>Bombyx mori </it>silkgland.</p

Molecular Mechanisms of Hepatocellular Carcinoma Related to Aflatoxins: An Update

Hepatocellular carcinoma (hepatocarcinoma) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Aflatoxins are I-type chemical carcinogen for hepatocarcinoma. Increasing evidence has shown that hepatocarcinoma induced by aflatoxins is the result of interaction between aflatoxins and hereditary factor. Aflatoxins can induce DNA damage including DNA strand break, adducts formation, oxidative DNA damage, and gene mutation and determine which susceptible individuals feature cancer. Inheritance such as alterations may result in the activation of proto-oncogenes and the inactivation of tumor suppressor genes and determine individual susceptibility to cancer. Interaction between aflatoxins and genetic susceptible factors commonly involve in almost all pathologic sequence of hepatocarcinoma: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and hepatocarcinoma of early stages. In this review, we discuss the biogenesis, toxification, and epidemiology of aflatoxins and signal pathways of aflatoxin-induced hepatocarcinoma. We also discuss the roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis related to aflatoxins

Prevalence and treatment gap of active convulsive epilepsy: A large community-based survey in rural West China

AbstractPurposeActive convulsive epilepsy (ACE) impacts patients greatly, especially in low-income countries where patients do not receive appropriate treatment. In the present study, we measured the prevalence and treatment gap (TG) of ACE in rural West China.MethodsSix rural areas in West China that have a total population of 3,541,319 were selected to conduct prevalence and TG estimates of ACE via a clue survey from 2007 to 2009. Clue survey here is a community-based screening strategy among defined population which requires employed well-trained local physicians//health workers to collect all clues available to discover/identify/recruit patients within a study period. Questionnaire-based interviews were used for the identification of ACE patients, and information was obtained during the survey. Prevalence and TG of ACE were calculated.ResultsA total of 6547 patients with ACE were identified. The estimated prevalence of ACE was 1.8 per 1000 in the general population, with the prevalences in males and females determined to be 2.0 and 1.7, respectively (p<0.001). The TG in the general population was 66.3%, and it was 66.6% and 66.0% in males and females, respectively (p>0.05). The TG figures dropped with advancing age and increased above 30 years of age. Patients aged 60 years or older had the largest TG (77.8%); those with disease course less than 10 years showed a larger TG and those who experienced two to five seizures annually had a significantly larger TG (70.6%). Additionally, only 63.9% of the ACE patients included in the study were aware of the disease and had consulted a doctor.ConclusionsThere exists a large TG of ACE in West China rural areas. Majority of those ever consulted a doctor but failed to receive or adhere to an appropriate treatment program. Management including public education as well as training of local physicians were necessary to fill that gap