Toll-like receptors (TLRs) have a crucial role not only in triggering innate responses against microbes but in orchestrating an appropriate adaptive immunity. However, deregulated activation of TLR signaling leads to chronic inflammatory conditions such as inflammatory bowel disease (IBD). In this study, we evaluated the immunomodulatory potential of a TLR inhibitor in the form of a cell-penetrating peptide using an ulcerative colitis animal model. A peptide derived from the TIR domain of the TLR adaptor molecule TIRAP that was conjugated with a cell-penetrating sequence (cpTLR-i) suppressed the induction of pro-inflammatory cytokines such as TNF-α and IL-1β in macrophages. In DSS-induced colitis mice, cpTLR-i treatment ameliorated colitis symptoms, colonic tissue damage, and mucosal inflammation. Intriguingly, cpTLR-i attenuated the induction of TNF-α-expressing proinflammatory macrophages while promoting that of regulatory macrophages expressing arginase-1 and reduced type 17 helper T cell (Th17) responses in the inflamed colonic lamina propria. An in vitro study validated that cpTLR-i enhanced the differentiation of monocyte-driven macrophages into mature macrophages with a regulatory phenotype in a microbial TLR ligand-independent manner. Furthermore, the cocultivation of CD4 T cells with macrophages revealed that cpTLR-i suppressed the activation of Th17 cells through the functional modulation of macrophages. Taken together, our data show the immunomodulatory potential of the TLR inhibitor peptide and suggest cpTLR-i as a novel therapeutic candidate for the treatment of IBD.
Background: Massive increases in glutamate concentration in the spinal cord have been known to cause neurologic injury after spinal ischemia.However, changes in glutamate receptor subtype mRNA expression have not been evaluated.The purpose of this study was to elucidate changes of glutamate receptor subtype mRNA expressions after 15 minutes of transient spinal ischemia in the rat.Methods: Rats were anesthetized with enflurane, and divided into 7 groups: Sham operation (S group), 1 hour reperfusion (H1 group), 3 hours reperfusion (H3 group), 1 day reperfusion (D1 group), 2 days reperfusion (D2 group), 1 week reperfusion (W1 group), and 2 weeks reperfusion (W2 group).Spinal ischemia was produced by inducing hypotension and by clamping the thoracic aorta.After spinal ischemia, neurologic scores were assessed and spinal cords were removed for glutamate receptor mRNA RT-PCR after various reperfusion times.Results: No significant differences in the group were observed in physiologic variables and neurologic scores.mGluR2 and mGluR6 were up-regulated 1 day after ischemia and returned to baseline at 2 weeks.mGluR3 was up-regulated 1 week after reperfusion and returned at 2 week, and mGluR1 and mGluR4 were downregulated 3 hours after reperfusion and returned to the control level at 1-2 weeks.NMDAR1 and 2A were down-regulated after reperfusion, but NMDAR2B was up-regulated 1 day after reperfusion and returned to the control level at 1 week.The GluR1, 2, 3, 4-flip were down-regulated 3 hours after reperfusion and returned to control level at 1 week.However, the GluR1, 2, 3-flop were up-regulated 2 days after reperfusion and returned to control level at 2 weeks.Conclusions: Changes in spinal cord glutamate receptor subtype mRNA expression after transient spinal ischemia were different for the receptor types and reperfusion times.The changes in glutamate receptor subtypes in the spinal cord differed from those in the brain.(
Abstract Objective To investigate the molecular mechanisms of the antiarthritic effects of bee venom (BV) and melittin (a major component of BV) in a murine macrophage cell line (Raw 264.7) and in synoviocytes obtained from patients with rheumatoid arthritis. Methods We evaluated the antiarthritic effects of BV in a rat model of carrageenan‐induced acute edema in the paw and in a rat model of chronic adjuvant‐induced arthritis. The inhibitory effects of BV and melittin on inflammatory gene expression were measured by Western blotting, and the generation of prostaglandin E 2 (PGE 2 ) and nitric oxide (NO) and the intracellular calcium level were assayed. NF‐κB DNA binding and transcriptional activity were determined by gel mobility shift assay or by luciferase assay. Direct binding of BV and melittin to the p50 subunit of NF‐κB was determined with a surface plasmon resonance analyzer. Results BV (0.8 and 1.6 μg/kg) reduced the effects of carrageenan‐ and adjuvant‐induced arthritis. This reducing effect was consistent with the inhibitory effects of BV (0.5, 1, and 5 μg/ml) and melittin (5 and 10 μg/ml) on lipopolysaccharide (LPS; 1 μg/ml)–induced expression of cyclooxygenase 2, cytosolic phospholipase A 2 , inducible NO synthase, generation of PGE 2 and NO, and the intracellular calcium level. BV and melittin prevented LPS‐induced transcriptional and DNA binding activity of NF‐κB via the inhibition of IκB release and p50 translocation. BV (affinity [ K d ] = 4.6 × 10 −6 M ) and melittin ( K d = 1.2 × 10 −8 M ) bound directly to p50. Conclusion Target inactivation of NF‐κB by directly binding to the p50 subunit is an important mechanism of the antiarthritic effects of BV.
The ultrastructure of Sertoli cell in the testes of Korean native goats was investigated by scanning and transmission electron microscopy to elucidate the relationship between germ cell and Sertoli cell processes in the spermiogenetic cycle. Type-A Sertoli cells at stage V of the spermiogenetic cycle and type-B Sertoli cells at stage VII of the spermiogenetic cycle were used for analysis. Morphologically, the Sertoli cell processes were classified into sheet-like and slender cord-like processes. The sheet-like process originated solely from the Sertoli cell column while the slender cord-like process projected either from the Sertoli cell column or the sheet-like process. Periodic acid (PA)-thiocarbohydrazide (TCH)-silver protein (SP)-physical development (PD)-positive granules were found diffusively both in the sheet-like and slender cord-like processes near the round spermatid, whereas they had accumulated near the head of the elongated spermatid. The morphological variation and glucoconjugate histochemical reaction of the Sertoli cell processes reflect nourishment, movement and transformation of the spermatogenic cells in accordance with spermiogenesis.
Cancer is the second leading cause of death in the United States and a leading cause of morbidity and mortality worldwide. A promising area of cancer research is focused on chemoprevention by nutritional compounds. Epidemiological studies have shown a strong negative correlation between fruit, vegetable and spice intake and rates of cancer. Although individual active compounds have demonstrated significant anti‐cancer activity, an emerging area of research is focusing on the combination of multiple dietary compounds on cancer that act synergistically to exert greater effects. In the current study, we evaluated potential synergistic effects of capsaicin, an active compound from red chili peppers, in combination with 3,3'‐Diindolylmethane (DIM), from cruciferous vegetables. A synergistic induction of apoptosis and inhibition of cell proliferation was observed in the human colorectal cancer cells treated with combination of capsaicin and DIM. We also observed that these two compounds activated transcriptional activity of NF‐kB and p53 synergistically. Combination treatment stabilized nuclear p53 and up‐ or down‐regulated expression of several target genes that are downstream of NF‐kB and p53. The present study suggests capsaicin and DIM work synergistically to inhibit cell proliferation and induce apoptosis in colorectal cancer through modulating transcriptional activity of NF‐κB, p53 and target genes associated with apoptosis. Grant Funding Source : American Cancer Society, University of Maryland
Lymphangioma is a benign tumor resulted from abnormal communication between large dermal lymphatic channels and central lymphatic system. The tumor is encountered more often in the neck and axilla and less often in mediastinum, omentum, retroperitoneum, and scrotum. It rarely developes at urogenital system, and there has been no previous description of lymphangioma involving the bladder wall in Korea. We report a case of 35-year-old female with infected huge lymphagioma ansing from pelvic cavity and involving bladder wall.
Partial bladder outlet obstruction (pBOO) causes considerable remodeling of the urinary bladder resulting in bladder organ hypertrophy. The serine/threonine protein kinase Akt serves as a convergent point in signaling networks and plays a critical role in cellular survival and growth. At 2 weeks after surgically induction of pBOO in rat, the phosphorylation (activation) level of the Akt isoform Akt1 was significantly increased in the urinary bladder, whereas the activity of Akt2 was not changed. In the urinary bladder with pBOO, excessive collagen deposition played a significant role in bladder hypertrophy, however, real‐time PCR showed that collagen mRNA level was not changed when compared to control. This was consistent to that the phosphorylation (activation) level of mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), and 4E‐BP1, a protein synthesis pathway downstream of Akt1, were increased in pBOO bladder. The increases in protein synthesis also resulted in detrusor smooth muscle cellular hypertrophy examined by an increase in the relative level of α‐smooth muscle actin against nuclear protein histone H3. These results suggest that an increased protein synthesis regulated by Akt1‐mediated translational machinery may underlie pBOO‐induced bladder hypertrophy resulting from excessive collagen deposition and detrusor smooth muscle cellular hypertrophy. Grant Funding Source : DK077917
'%3e%3cg id='b'%3e%3cpath id='a' stroke='%23000' stroke-width='2' d='M-6-25H6m-12 3H6m-12 3H6'/%3e%3cuse xlink:href='%23a' y='44'/%3e%3c/g%3e%3cpath stroke='%23fff' d='M0 17v10'/%3e%3ccircle r='12' fill='%23cd2e3a'/%3e%3cpath fill='%230047a0' d='M0-12A6 6 0 0 0 0 0a6 6 0 0 1 0 12 12 12 0 0 1 0-24z'/%3e%3c/g%3e%3cg transform='rotate(-123.69)'%3e%3cuse xlink:href='%23b'/%3e%3cpath stroke='%23fff' d='M0-23.5v3M0 17v3.5m0 3v3'/%3e%3c/g%3e%3c/svg%3e)