Serum IL-17 and IL-23 levels were significantly higher in AS patients than in healthy controls and the levels correlate to disease activity measured by BASDAI scores, but not parameters of functional ability and spinal mobility. These results suggest the existence of a role of IL-17 and IL-23 in the pathogenesis of inflammation in AS.
Summary
Posttranslational modifications of histones play fundamental roles in many biological functions. Specifically, histone H4-K20 methylation is critical in DNA synthesis and repair. However, little is known about how these functions are regulated by the upstream stimuli. Here, we identify a tyrosine phosphorylation site at Y72 of histone H4, which facilitates recruitment of histone methyltransferases (HMTases), SET8 and SUV4-20H, to enhance its K20 methylation, thereby promoting DNA synthesis and repair. Phosphorylation-defective histone H4 mutant is deficient in K20 methylation, leading to reduced DNA synthesis, delayed cell cycle progression, and decreased DNA repair ability. Disrupting the interaction between epidermal growth factor receptor (EGFR) and histone H4 by Y72 peptide significantly reduced tumor growth. Furthermore, EGFR expression clinically correlates with histone H4-Y72 phosphorylation, H4-K20 mono-methylation, and the Ki-67 proliferation marker. These findings uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and repair.
Objective. To analyze the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome (PRES), the risk factors of PRES-related intracranial hemorrhage (ICH), and all-cause mortality in patients with systemic lupus erythematosus (SLE). Methods. Twenty-six episodes of PRES were identified in 23 SLE patients, using an electronic medical records database of 3,746 SLE patients.
Melatonin (MLT; N-acetyl-5-methoxytryptamine) exhibits analgesic properties in chronic pain conditions. While researches linking MLT to epigenetic mechanisms have grown exponentially over recent years, very few studies have investigated the contribution of MLT-associated epigenetic modification to pain states. Here, we report that together with behavioral allodynia, spinal nerve ligation (SNL) induced a decrease in the expression of catalytic subunit of phosphatase 2A (PP2Ac) and enhanced histone deacetylase 4 (HDAC4) phosphorylation and cytoplasmic accumulation, which epigenetically alleviated HDAC4-suppressed hmgb1 gene transcription, resulting in increased high-mobility group protein B1 (HMGB1) expression selectively in the ipsilateral dorsal horn of rats. Focal knock-down of spinal PP2Ac expression also resulted in behavioral allodynia in association with similar protein expression as observed with SNL. Notably, intrathecal administration with MLT increased PP2Ac expression, HDAC4 dephosphorylation and nuclear accumulation, restored HDAC4-mediated hmgb1 suppression and relieved SNL-sensitized behavioral pain; these effects were all inhibited by spinal injection of 4P-PDOT (a MT2 receptor antagonist, 30 minutes before MLT) and okadaic acid (OA, a PP2A inhibitor, 3 hr after MLT). Our findings demonstrate a novel mechanism by which MLT ameliorates neuropathic allodynia via epigenetic modification. This MLT-exhibited anti-allodynia is mediated by MT2-enhanced PP2Ac expression that couples PP2Ac with HDAC4 to induce HDAC4 dephosphorylation and nuclear import, herein increases HDAC4 binding to the promoter of hmgb1 gene and upregulates HMGB1 expression in dorsal horn neurons.
Emerging evidence has indicated that the pathogenesis of neuropathic pain is mediated by spinal neural plasticity in the dorsal horn, which provides insight for analgesic therapy. Here, we report that the abundance of tumor necrosis factor receptor-associated factor 2 and NcK-interacting kinase (TNIK), a kinase that is presumed to regulate neural plasticity, was specifically enhanced in ipsilateral dorsal horn neurons after spinal nerve ligation (SNL; left L5 and L6). Spinal TNIK-associated allodynia is mediated by downstream TNIK-GluR1 coupling and the subsequent phosphorylation-dependent trafficking of GluR1 toward the plasma membrane in dorsal horn neurons. Tumor necrosis factor receptor-associated factor 2 (TRAF2), which is regulated by spinal F-box protein 3 (Fbxo3)-dependent F-box and leucine-rich repeat protein 2 (Fbxl2) ubiquitination, contributes to SNL-induced allodynia by modifying TNIK/GluR1 phosphorylationassociated GluR1 trafficking. Although exhibiting no effect on
Significance StatementTNF-␣ participates in neuropathic pain development by facilitating the spinal TRAF2-dependent TNIK-GluR1 association, which drives GluR1-containing AMPA receptor trafficking toward the plasma membrane. In addition, F-box protein 3 modifies this pathway by inhibiting F-box and leucine-rich repeat protein 2-mediated TRAF2 ubiquitination, suggesting that protein ubiquitination contributes crucially to the development of neuropathic pain. These results provide a novel therapeutic strategy for pain relief.
We investigated the participation of cyclin-dependent kinase-5 (Cdk5)-mediated N-methyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation in cross-organ reflex sensitization caused by colon irritation. The external urethral sphincter electromyogram (EUSE) reflex activity evoked by the pelvic afferent nerve test stimulation (TS, 1 stimulation/30s) and protein expression in the spinal cord and dorsal root ganglion tissue (T13-L2 and L6-S2 ipsilateral to the stimulation) in response to colon mustard oil (MO) instillation were tested in anesthetized rats. When compared with a baseline reflex activity with a single action potential evoked by the TS before the administration of test agents, MO instillation into the descending colon sensitized the evoked activity characterized by elongated firing in the reflex activity in association with increased protein levels of Cdk5, PSD95, and phosphorylated NR2B (pNR2B) but not of total NR2B (tNR2B) in the spinal cord tissue. Both cross-organ reflex sensitization and increments in protein expression were reversed by intra-colonic pretreatments with ruthenium red (a non-selective transient receptor potential vanilloid, TRPV, antagonist), capsaizepine (a TRPV1-selective antagonist), lidocaine (a nerve conduction blocker) as well as by the intra-thecal pretreatment with APV (a NRMDR antagonist) Co-101244 (a NR2B-selective antagonist) and roscovitine (a Cdk5 antagonist). Moreover, compared with the control group, both the increase in pNR2B and the cross-organ reflex sensitization were attenuated in the si-RNA of NR2B rats. All these results suggested that Cdk-dependent NMDAR NR2B subunit phosphorylation mediates the development of cross-organ pelvic-urethra reflex sensitization caused by acute colon irritation which could possibly underlie the high concurrence of pelvic pain syndrome with irritable bowel syndrome.
Objective. A relatively common occurrence of spontaneous subarachnoid hemorrhage (SAH) in patients with systemic lupus erythematosus (SLE) has been noted; however, the subsequent studies were conflicting. This nationwide populationbased study aimed to evaluate the risk of SAH in patients with SLE. Methods. We identified 16,967 SLE patients from the Taiwan National Health Insurance (NHI) database between 2000 and 2006, and compared the incidence rate of SAH with 16,967 randomly selected age-and sex-matched non-SLE subjects. A Cox multivariable proportional hazards model was used to evaluate the risk factors of SAH in the SLE cohort. Results. The SLE cohort had a higher risk of SAH, with an incidence rate ratio of 4.84 (P < 0.001). Despite a younger age, the mortality rate after SAH was significantly higher in the SLE cohort compared to all of the non-SLE SAH patients identified from the 1 million NHI beneficiaries (60.0% versus 38.9%; P ؍ 0. Conclusion. This study demonstrated that SAH is a rare but associated complication of SLE with a high mortality rate. Other than age, higher mean daily steroid use and a history of platelet or red blood cell transfusion were associated with the occurrence of SAH in patients with SLE.
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