Schwarzinicine A inhibits transient receptor potential canonical channels and exhibits overt vasorelaxation effects

This study investigated the vasorelaxant effects of schwarzinicine A, an alkaloid recently reported from Ficus schwarzii Koord. Regulation of calcium homeostasis in vascular smooth muscle cells (VSMC) is viewed as one of the main mechanisms for controlling blood pressure. L-type voltage-gated calcium channel (VGCC) blockers are commonly used for controlling hypertension. Recently, the transient receptor potential canonical (TRPC) channels were found in blood vessels of different animal species with evidence of their roles in the regulation of vascular contractility. In this study, we studied the mechanism of actions of schwarzinicine A focusing on its regulation of L-type VGCC and TRPC channels. Schwarzinicine A exhibited the highest vasorelaxant effect (123.1%) compared to other calcium channel blockers. It also overtly attenuated calcium-induced contractions of the rat isolated aortae in a calcium-free environment showing its mechanism to inhibit calcium influx. Fluorometric intracellular calcium recordings confirmed its inhibition of hTRPC3-, hTRPC4-, hTRPC5- and hTRPC6-mediated calcium influx into HEK cells with IC50 values of 3, 17, 19 and 7 μM, respectively. The evidence gathered in this study suggests that schwarzinicine A blocks multiple TRPC channels and L-type VGCC to exert a significant vascular relaxation response

Non-Japanese Residents and the Earthquake : Reflections on our work thus far (Research Group on Non-Japanese Residents and the Earthquake)

BACKGROUND: Renal tubular epithelial cells (TECs) are one of the main targets of inflammatory insults during interstitial nephritis and kidney transplant rejection. While Th1 cells are know to be essential in the pathogenesis of rejection, the role of Th17 is still under debate. We hypothesize that TECs modulate the outcome of rejection process by production of distinct chemokines and cytokines that determine the attraction of different T-cell subsets. Therefore, we studied differential effects of activated human renal epithelial cells on T-cell migration. METHODS: Human primary TECs were stimulated by IFN-γ and TNF-α in vitro. Chemokines and cytokines produced by activated TECs were measured using Luminex or ELISA. Chemotaxis assay was performed using activated peripheral blood mononuclear cells composed of CD4+CXCR3+ and CD4+CCR6+ T cells migrating towards stimulated and unstimulated TECs. RESULTS: While activated TECs secreted abundant amounts of the pro-inflammatory cytokines IL-6 and IL-8, the T helper cell differentiation cytokines IL-1β, IL-12p70, IL-23 or TGF-β1 were not produced. The production of Th1 chemokines CXCL9, CXCL10 and CCL5 were significantly upregulated after TEC stimulation. In contrast, Th17 chemokine CCL20 could not be detected. Finally, activated TECs attracted significantly higher numbers of CD4+CXCR3+ T cells as compared to unstimulated TECs. No migration of CD4+CCR6+ T cells could be observed. CONCLUSION: Activated primary renal tubular epithelial cells do not attract Th17 cells nor produce cytokines promoting Th17 cell differentiation in our experimental system mimicking the proinflammatory microenvironment of rejection

Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: A single center experience of 10 years

Background: Data on mature T-cell and natural killer (NK)-cell lymphomas diagnosed with the World Health Organization (WHO) classification scheme are scarce. They are regarded to be more common in Asian populations. Methods: Consecutive T-cell and NK-cell lymphomas classified according to the WHO scheme within 10 years in a Chinese population were reviewed. Results: There were 148 cases, constituting 16.6% (T-cell, n = 90, 10.1%, NK-cell, n = 58, 6.5%) of all non-Hodgkin lymphomas in this period. There was a male predominance (male:female = 2.5), young age at diagnosis (median age 50 years, range 8-86) and frequent extranodal presentation. Commonest T-cell lymphomas included anaplastic large cell lymphoma (ALCL, n = 25, median age 35 years, nodal 60%, stage I/II 60%), peripheral T-cell lymphoma, unspecified (PTCL, n = 24, median age 54 years, nodal 42%, stage I/II 42%), and angioimmunoblastic T-cell lymphoma (AILT, n = 19, median age 67 years, nodal 95%, stage I/II 26%). Overall frequencies of T-cell lymphomas were comparable to Western patients. AILT, PTCL and ALCL were aggressive with a poor outcome. NK-cell lymphomas were predominantly extranodal (96%) and aggressive, with a frequency much higher than Western patients. Conclusions: The apparent high prevalence of T-cell and NK-cell lymphomas in the Chinese was due to more frequent NK-cell but not T-cell lymphomas. © 2005 European Society for Medical Oncology.link_to_OA_fulltex

Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes

AIM: Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM. METHODS AND RESULTS: We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence. CONCLUSION: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients

CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation

Using inverse polymerase chain reaction, we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (DLBCL). Notably, these translocations involving IGHSμ were detected in follicular lymphomas and exclusively in germinal center B cell - like (GCB) - DLBCLs. CD44 is not expressed in reactive GC B cells. The IGHSμ/CD44 translocations substitute Sμ for the CD44 promoter and remove exon 1 of CD44, resulting in the overexpression of Iμ-CD44 hybrid mRNA transcripts activated from derivative 11 that encode a new CD44 variant lacking the leader peptide and with a unique C-terminus (CD44ΔEx1). When overexpressed in vitro in the CD44 - GCB-DLBCL cell line BJAB, CD44ΔEx1 - green fluorescent protein localized to the cytoplasm and nucleus, whereas CD44s - green fluorescent protein (standard form) localized to the plasma membrane. The ectopic expression of CD44ΔEx1 in BJAB cells enhanced their proliferation rate and clonogenic ability, indicating a possible pathogenic role of the translocation. © 2010 by The American Society of Hematology.link_to_OA_fulltex