Therapeutic potential of CKD-506, a novel selective histone deacetylase 6 inhibitor, in a murine model of rheumatoid arthritis

Abstract Objectives Histone deacetylase (HDAC) 6 promotes inflammation. We investigated the anti-arthritic effects of CKD-506, a novel HDAC6 inhibitor, in vitro and in a murine model of arthritis as a novel treatment option for rheumatoid arthritis (RA). Methods HDAC6 was overexpressed in mouse peritoneal macrophages and RAW 264.7 cells, and the effects of a HDAC6 inhibitor CKD-506 on cytokine production and activity of NF-κB and AP-1 signaling were examined. Peripheral blood mononuclear cells (PBMCs) from RA patients and fibroblast-like synoviocytes (FLS) were activated in the presence of CKD-506. Next, regulatory T cells (Tregs) were induced from RA patients and co-cultured with healthy effector T cells (Teffs) and cell proliferation was analyzed by flow cytometry. Finally, the effects of the inhibitor on the severity of arthritis were assessed in a murine model of adjuvant-induced arthritis (AIA). Results Overexpression of HDAC6 induced macrophages to produce TNF-α and IL-6. The inhibitory effect of CKD-506 was mediated via blockade of NF-κB and AP-1 activation. HDAC6 inhibition reduced TNF-α and IL-6 production by activated RA PBMCs. CKD-506 inhibited production of MMP-1, MMP-3, IL-6, and IL-8 by activated FLS. In addition, CKD-506 inhibited proliferation of Teffs directly and indirectly by improving iTreg function. In AIA rats, oral CKD-506 improved clinical arthritis in a dose-dependent manner. A combination of sub-therapeutic CKD-506 and methotrexate exerted a synergistic effect. Conclusion The novel HDAC6 inhibitor CKD-506 suppresses inflammatoryresponses by monocytes/macrophages, improves Treg function, and ameliorates arthritis severity in a murine model of RA. Thus, CKD-506 might be a novel and effective treatment option for RA

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol

Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+)Gr-1(+) MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/-)) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Phylogenetic Relationships of Russian Far-East Apis cerana with Other North Asian Populations

Apis cerana Fabricius, 1793 is the eastern honeybee species distributed throughout Asia from the tropical climate in the southern part to the temperate climate in the northern part. We sequenced and annotated the complete mitochondrial DNA (mtDNA) of A. cerana from Vladivostok, Primorsky Krai of the Russian Far East and uploaded it to the database GenBank (AP018450). MtDNA sequence has 15,919 bp length, AT-content 84% and GC-content 16% and contains 22 tRNA genes, 13 protein-coding genes, two ribosomal RNA genes, one AT-rich region and four non-coding intergenic regions (NC1-4). All proteincoding genes start with ATT and ATG codons, except for ATC, the start codon of the ATP8 gene, which and stop with the common stop codons TAA and TAG. A comparative analysis of complete mtDNA of A. cerana from China, Indonesia, Korea, Malaysia, Russia, Taiwan, Thailand, Vietnam, and Japan found that the Russian Far East Apis cerana differed from others on the subspecies level. Based on the comparative analysis of complete mtDNA (~16,000 bp), nuclear DNA (nDNA) gene Vitellogenin (VG) (~4,100 bp) and morphological measurements (six parameters), we assumed that the Russian Far-East A. cerana can be a distinct northern Asia population and can be described as a separate unique subspecies of A. c. ussuriensis subsp. nov. A. c. koreana subsp. nov. is also validated and described as a new subspecies

The Potential Roles of Radionanomedicine and Radioexosomics in Prostate Cancer Research and Treatment

The artificial nanostructures such as nanoparticles and natural nanostructures such as secreted nanosized extracellular vesicles known as exosomes are promising tools for the realization of personalized medicine. Radionanomedicine is a recently coined term for the simultaneous application of either radiation technology or nuclear medicine with nanomedicine. In addition, radioexosomics is our suggested term for the study of exosomes functions, cytotoxicity, cancerogenicity, and biodistribution using radiation technology and nuclear medicine tracing technology. Prostate cancer (PCa) is the most commonly diagnosed cancer in males and a big majority of patients with PC progress to castration-resistant prostate cancer (CRPC) mostly. The mechanisms leading to development of CRPC remain poorly understood and there is still a need to improve the therapeutic options available for PCa. In this review, a wide variety of nanostructure-based prostate cancer research using radiation technology and nuclear medicine is discussed. In addition, we will present what is currently known about the function of exosomes in PCa. The review concludes by summarizing the current status and future perspectives of radionanomedicine and radioexosomics for understanding PCa biology, as well as PCa enhancement of targeting strategies, drug delivery, molecular imaging and therapy