Graft-versus-host disease (GVHD) is a severe adverse effect that results from bone marrow or peripheral blood cells transplantation and has a high rate of mortality. About 50% of the patients are accompanied with acute Graft-versus-Host Disease (aGVHD) after bone marrow cell transplantation and need systematic treatment. It has an important clinical significance to evaluate the prevention and treatment effects of GVHD. The stable and reliable approaches of humanized animal models are crucial for advancing on the study the biology of GVHD. Relative models transplanting the human immune cells into the mouse body can trigger immunoreaction similar to the humans. As it is a disease triggered by human immune cells, any intervention research prior to clinical treatment has more clinical interrelations compared with the general animal models. In this review, we update the current understanding on humanized animal disease models on studying Graft-versus-host disease and expect to provide more theoretical basis to further study on Graft-versus-host disease.
The key regulators of endothelial differentiation induced by shear stress (SS) are mostly unclear. Human atonal homolog 6 (Hath6) was identified as an endothelial-selective and SS-responsive transcription factor. In this study, we sought to elucidate the role of Hath6 in the endothelial specification of embryonic stem cells. In a stepwise human embryonic stem cell-endothelial cell (hESC-EC) induction system, Hath6 was upregulated synchronously with endothelial determination. Subsequently, gain-of-function and loss-of-function studies of Hath6 were performed using the hESC-EC induction model and endothelial cell lines. The overexpression of Hath6, which mimics SS treatment, resulted in an increased CD45−CD31+KDR+ population, a higher tubular-structure-formation capacity, and increased endothelial-specific gene expression. In contrast, the knockdown of the Hath6 gene markedly decreased endothelial differentiation. Hath6 also facilitates the maturation of ECs in terms of endothelial gene expression, tubular structure formation, and cell migration. We further demonstrated that eNOS is a direct target of Hath6 through a reporter system assay and western blot analysis and that the inhibition of eNOS diminishes hESC-EC differentiation. These results suggest that eNOS plays a key role in linking Hath6 to the endothelial phenotype. Further in situ hybridization studies in zebrafish and mouse embryos indicated that homologues of Hath6 are involved in vasculogenesis and angiogenesis. This study provides the first confirmation of the positive impact of Hath6 on human embryonic endothelial differentiation and function. Moreover, we present a potential signaling pathway through which SS stimulates endothelial differentiation.
The increased incidence of systemic lupus erythematosus (SLE) in recent decades might be related to changes in modern dietary habits. Since sodium chloride (NaCl) promotes pathogenic T cell responses, we hypothesize that excessive salt intake contributes to the increased incidence of autoimmune diseases, including SLE. Given the importance of dendritic cells (DCs) in the pathogenesis of SLE, we explored the influence of an excessive sodium chloride diet on DCs in a murine SLE model. We used an induced lupus model in which bone marrow-derived dendritic cells (BMDCs) were incubated with activated lymphocyte-derived DNA (ALD-DNA) and transferred into C57BL/6 recipient mice. We observed that a high-salt diet (HSD) markedly exacerbated lupus progression, which was accompanied by increased DC activation. NaCl treatment also stimulated the maturation, activation and antigen-presenting ability of DCs in vitro. Pretreatment of BMDCs with NaCl also exacerbated BMDC-ALD-DNA-induced lupus. These mice had increased production of autoantibodies and proinflammatory cytokines, more pronounced splenomegaly and lymphadenopathy, and enhanced pathological renal lesions. The p38 MAPK-STAT1 pathway played an important role in NaCl-induced DC immune activities. Taken together, our results demonstrate that HSD intake promotes immune activation of DCs through the p38 MAPK-STAT1 signaling pathway and exacerbates the features of SLE. Thus, changes in diet may provide a novel strategy for the prevention or amelioration of lupus or other autoimmune diseases.
// Qian Qian Wang 1, 2, * , Xin Yi Zhou 1, 2, * , Yan Fang Zhang 1, 2 , Na Bu 2 , Jin Zhou 3 , Feng Lin Cao 3 , Hua Naranmandura 1, 2 1 Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China 2 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China 3 Department of Hematology and Oncology, The First Clinical College of Harbin Medical University, Harbin 150086, China * These authors have contributed equally to this work Correspondence to: Hua Naranmandura, e-mail: narenman@zju.edu.cn Keywords: acute promyelocytic leukemia, arsenic trioxide, trivalent arsenicals, arsenic binding proteins, monomethylarsonous acid Received: June 02, 2015 Accepted: July 06, 2015 Published: July 15, 2015 ABSTRACT Arsenic trioxide (As 2 O 3 ) is one of the most effective therapeutic agents used for patients with acute promyelocytic leukemia (APL). The probable explanation for As 2 O 3 -induced cell differentiation is the direct targeting of PML-RARα oncoprotein by As 2 O 3 , which results in initiation of PML-RARα degradation. However, after injection, As 2 O 3 is rapidly methylated in body to different intermediate metabolites such as trivalent monomethylarsonous acid (MMA III ) and dimethylarsinous acid (DMA III ), therefore, it remains unknown that which arsenic specie is actually responsible for the therapeutic effects against APL. Here we have shown the role of As 2 O 3 (as iAs III ) and its intermediate metabolites (i.e., MMA III /DMA III ) in NB4 cells. Inorganic iAs III predominantly showed induction of cell differentiation, while MMA III and DMA III specifically showed to induce mitochondria and endoplasmic reticulum-mediated apoptosis, respectively. On the other hand, in contrast to iAs III , MMA III showed stronger binding affinity for ring domain of PML recombinant protein, however, could not induce PML protein SUMOylation and ubiquitin/proteasome degradation. In summary, our results suggest that the binding of arsenicals to the ring domain of PML proteins is not associated with the degradation of PML-RARα fusion protein. Moreover, methylated arsenicals can efficiently lead to cellular apoptosis, however, they are incapable of inducing NB4 cell differentiation.
Osteoarthritis (OA) is a chronic joint disease characterized by cartilage imbalance and disruption of cartilage extracellular matrix secretion. Identifying key genes that regulate cartilage differentiation and developing effective therapeutic strategies to restore their expression is crucial. In a previous study, we observed a significant correlation between the expression of the gene encoding casein kinase-2 interacting protein-1 (CKIP-1) in the cartilage of OA patients and OA severity scores, suggesting its potential involvement in OA development. To test this hypothesis, we synthesized a chondrocyte affinity plasmid, liposomes CKIP-1, to enhance CKIP-1 expression in chondrocytes. Our results demonstrated that injection of CAP-Lipos-CKIP-1 plasmid significantly improved OA joint destruction and restored joint motor function by enhancing cartilage extracellular matrix (ECM) secretion. Histological and cytological analyses confirmed that CKIP-1 maintains altered the phosphorylation of the signal transduction molecule SMAD2/3 of the transforming growth factor-β (TGF-β) pathway by promoting the phosphorylation of the 8T, 416S sit. Taken together, this work highlights a novel approach for the precise modulation of chondrocyte phenotype from an inflammatory to a noninflammatory state for the treatment of OA and may be broadly applicable to patients suffering from other arthritic diseases.
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