Here, we show that radicicol, a fungal antibiotic, resulted in marked inhibition of inducible nitric oxide synthase (iNOS) transcription by the pancreatic beta cell line MIN6N8a in response to cytokine mixture (CM: TNF-α, IFN-γ, and IL-1β). Treatment of MIN6N8a cells with radicicol inhibited CM-stimulated activation of NF-κB/Rel, which plays a critical role in iNOS transcription, in a dose-related manner. Nitrite production in the presence of PD98059, a specific inhibitor of the extracellular signal-regulated protein kinase-1 and 2 (ERK1/2) pathway, was dramatically diminished, suggesting that the ERK1/2 pathway is involved in CM-induced iNOS expression. In contrast, SB203580, a specific inhibitor of p38, had no effect on nitrite generation. Collectively, this series of experiments indicates that radicicol inhibits iNOS gene expression by blocking ERK1/2 signaling. Due to the critical role that NO release plays in mediating destruction of pancreatic beta cells, the inhibitory effects of radicicol on iNOS expression suggest that radicicol may represent a useful anti-diabetic activity.
A Schmorl's node is defined as a simple endplate intravertebral herniation resulting from trauma or idiopathic causes. Although Schmorl's nodes have been considered clinically insignificant, they might indicate an active symptomatic process or cause serious complications. In this study, we report an interesting case of complete separation of a vertebral body caused by an untreated Schmorl's node accompanying severe osteoporosis. To our knowledge, this is the first clinical report in the published literature to evaluate the complete separation of a vertebral body associated with a Schmorl's node.
We demonstrate herein that silibinin, a polyphenolic flavonoid compound isolated from milk thistle (Silybum marianum), inhibits LPS-induced activation of macrophages and production of nitric oxide (NO) in RAW 264.7 cells. Western blot analysis showed silibinin inhibits iNOS gene expression. RT-PCR showed that silibinin inhibits iNOS, TNF-α, and IL1β. We also showed that silibinin strongly inhibits p38 MAPK phosphorylation, whereas the ERK1/2 and JNK pathways are not inhibited. The p38 MAPK inhibitor abrogated the LPS-induced nitrite production, whereas the MEK-1 inhibitor did not affect the nitrite production. A molecular modeling study proposed a binding pose for silibinin targeting the ATP binding site of p38 MAPK (1OUK). Collectively, this series of experiments indicates that silibinin inhibits macrophage activation by blocking p38 MAPK signaling.
The aim of this prospective study was to evaluate the efficacy of bone cement-augmented percutaneous short segment fixation for treating Kummell's disease accompanied by severe osteoporosis.From 2009 to 2013, ten patients with single-level Kummell's disease accompanied by severe osteoporosis were enrolled in this study. After postural reduction for 1-2 days, bone cement-augmented percutaneous short segment fixation was performed at one level above, one level below, and at the collapsed vertebra. Clinical results, radiological parameters, and related complications were assessed preoperatively and at 1 month and 12 months after surgery.Prior to surgery, the mean pain score on the visual analogue scale was 8.5±1.5. One month after the procedure, this score improved to 2.2±2.0 and the improvement was maintained at 12 months after surgery. The mean preoperative vertebral height loss was 48.2±10.5%, and the surgical procedure reduced this loss to 22.5±12.4%. In spite of some recurrent height loss, significant improvement was achieved at 12 months after surgery compared to preoperative values. The kyphotic angle improved significantly from 22.4±4.9° before the procedure to 10.1±3.8° after surgery and the improved angle was maintained at 12 months after surgery despite a slight correction loss. No patient sustained adjacent fractures after bone cement-augmented percutaneous short segment fixation during the follow-up period. Asymptomatic cement leakage into the paravertebral area was observed in one patient, but no major complications were seen.Bone cement-augmented percutaneous short segment fixation can be an effective and safe procedure for Kummell's disease.
The purpose of this study was to evaluate the efficacy of the anterior approach following intraoperative reduction under general anesthesia in patients with cervical facet fracture and dislocation.Twenty-three patients with single level cervical facet fracture and dislocation who were subjected to the anterior approach alone following immediate intraoperative reduction under general anesthesia from March 2013 to December 2017 were enrolled in this study. Neurological status, clinical outcome, and radiological studies were evaluated preoperatively, postoperatively, and during the follow-up period.The cohort comprised 15 men and eight women with a mean age of 57 years (from 24 to 81). All patients were operated on within the first 8 hours following the injury. After gentle manual reduction or closed reduction with Gardner-Wells traction, under general anesthesia monitored by somatosensory-evoked potentials, all operations were successfully completed using the anterior approach alone except in two patients, who had a risk of over-distraction. In them, a satisfactory gentle manual reduction or closed reduction was not possible, and required open posterior reduction of the locked facets followed by anterior cervical discectomy and fusion. In one patient, screw retropulsion was observed in 1 month after surgery. There were no reduction-related complications or neurological aggravations after surgery. All patients showed evidence of stability at the instrumented level at the final follow-up (mean follow-up, 12 months).Anterior approach following intraoperative reduction monitored by somatosensory-evoked potentials under general anesthesia for cervical dislocation and locked facets is a relatively safe and effective alternative when cervical alignment is achieved by intraoperative reduction.
BB, a member of the TNF receptor superfamily, functions mainly as a costimulatory molecule in T cells. Since signaling through 4-1BB provides T cells with costimulation independently of CD28, it has been postulated that 4-1BB plays an important role in allograft rejection. In this study, we demon- strated the critical role of 4-1BB in heart allograft rejection using 4-1BB-deficient mice. When 4-1BB- deficient C57BL/6 mice received MHC-mis- matched cardiac transplant of Balb/c origin, there was a markedly-delayed graft rejection as com- pared with the wild type. The delayed graft rejec- tion in the mutant mice correlated with less severe lymphocytic infiltration and vasculitis in the donor hearts. The cardiac grafts were harvested on days 1,3, 5, and 7, and the transcription level of various T cell cytokines and antigens were analyzed by RT- PCR. Furthermore, T cells of 4-1BB-deficient mice showed lower proliferation and cytokine produc- tion when challenged with allostimulatory den- dritic cells. We found that the mRNA levels of FasL and T cell activation cytokines such as IL-2, IFN-y, iNOS were decreased in 4-1BB-/- mice compared to wild type mice. Whereas, transcription of B7-2 antigen, CD28 related costimulatory molecule, was increased in 4-1BB/- mice. These findings have a clinical implication that the blockade of 4-BB sig- naling may prolong the survival of solid organ transplants.
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