Joo-Yong Kim

Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis.

Abstract Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti‐fibrotic agents is urgently needed. Although histone deacetylases (HDACs) have been reported to be involved in renal fibrosis, current HDAC inhibitors are unsatisfactory anti‐fibrosis drugs. Therefore, more potentially relevant anti‐renal fibrosis HDAC inhibitors are needed. We initially found that non‐cytotoxic concentrations of SB939 (pracinostat) had strong anti‐fibrotic activity, drastically decreasing TGF‐&bgr;1‐induced alpha smooth muscle actin (&agr;‐SMA) expression in the NRK renal fibroblast cell line. Similar anti‐fibrotic activity of SB939 on epithelial‐to‐mesenchymal transition (EMT) was confirmed using the HK‐2 human renal proximal tubular epithelial cell line. SB939 inhibited Smad‐independent TGF‐&bgr; signaling involving the MAPK and PI3K/AKT pathways. To evaluate in vivo anti‐fibrotic activity, we administered SB939 in a unilateral ureteric obstruction (UUO) model. SB939 treatment markedly inhibited the accumulation of &agr;‐SMA and tissue injury. Inflammatory and pro‐fibrotic cytokines in the obstructed kidney were also significantly decreased by SB939 treatment. Our results suggest that SB939 might be a promising therapeutic drug for preventing renal fibrosis. HighlightsPan‐HDAC inhibitor SB939 was investigated on renal fibrosis.SB939 inhibits TGF‐&bgr;1‐induced myofibroblast generation.SB939 inhibits Smad‐independent pathways in TGF‐&bgr; signaling.Administration of SB939 into UUO model reduces renal fibrosis and inflammation.

Effect of upregulated TLR2 expression from G-CSF-mobilized donor grafts on acute graft-versus-host disease.

Our previous study demonstrated that G-CSF treatment increased the expression of TLR2 in donor grafts; this contributed to rapid engraftment after allogeneic hematopoietic stem cell transplantation (HSCT) in mice. In the current study, we investigated the effects of upregulated TLR2 expression in G-CSF-mobilized donor grafts on acute graft-versus-host disease (GVHD). We found that TLR2 was highly expressed on myeloid cell populations but not T and B cells from the spleens of G-CSF-treated donor mice. After transplantation, the mortality and disease severity in recipients were not significantly different between G-CSF-treated TLR2-/- and wt donor grafts. Although endogenous TLR2 ligand was detected in the serum of both recipients, T cells from TLR2-/- and wt donors have the same ability regarding alloreactivity. Moreover, the blockade of TLR2 signaling in recipients by administering anti-TLR2 blocking antibody after BMT did not lead to a significant difference in acute GVHD compared with control IgG treatment. However, the hematopoietic ability of G-CSF-mobilized lin−c-kit+ HSCs from TLR2-/- donor grafts was lower than that from wt donor grafts. Our results demonstrate that upregulated TLR2 expression in G-CSF-mobilized donor grafts has no effect on acute GVHD, suggesting that TLR2 is a valuable target for increasing HSCT efficiency in order to enhance engraftment without exacerbating acute GVHD.

Stress radiography for clinical evaluation of anterior shoulder instability

BACKGROUND The purpose of this study was to examine the validity of stress radiography using the Telos GA-IIE as a clinical methodology to evaluate shoulder instability. METHODS On 36 anterior shoulder dislocators and 23 uninjured volunteers, 4 types of stress radiographs were captured while applying 15 daN of force anteriorly (AER0 and AER60) and posteriorly (PER0 and PER60) at 2 different positions: (1) 90° of abduction combined with 0° external rotation and (2) 90° of abduction combined with 60° external rotation. The results of the anterior drawer test and of the same test under anesthesia were correlated. RESULTS AER0 and AER60 from the affected shoulder revealed significantly larger displacement than on the normal side (P < .05), and all 4 radiographs from the affected joints demonstrated significantly larger displacement (P < .05) than in the volunteers. Among the 4 types of radiographs, AER0 and AER60 showed significantly higher displacement in the patients (P < .001), whereas there were no differences in the volunteers (P = .167). The results of the anterior drawer test positively correlated to AER60 (Pearson correlation coefficient [PCC] = 0.453; P = .005) and AER0 (PCC = 0.529; P = .001), and those of examination under anesthesia weakly correlated to AER60 (PCC = 0.287; P = .264) but highly correlated to AER0 (PCC = 0.695; P = .002). CONCLUSION Stress radiographs on the affected shoulder frequently correlated with physical examinations, and the displacement of >3 mm on AER0 suggests anterior instability.