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Previous studies suggest that regulatory microRNAs (miRs) may modulate neuro-inflammatory processes. The purpose of the present study was to examine the role of miR-17 following intervertebral disc herniation.
Learn More >We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.
Learn More >Critical for diverse biological processes, proteases represent one of the largest families of pharmaceutical targets. To inhibit pathogenic proteases with desired selectivity, monoclonal antibodies (mAbs) hold great promise as research tools and therapeutic agents. However, identification of mAbs with inhibitory functions is challenging because current antibody discovery methods rely on binding rather than inhibition. This study developed a highly efficient selection method for protease inhibitory mAbs by coexpressing 3 recombinant proteins in the periplasmic space of -an antibody clone, a protease of interest, and a β-lactamase modified by insertion of a protease cleavable peptide sequence. During functional selection, inhibitory antibodies prevent the protease from cleaving the modified β-lactamase, thereby allowing the cell to survive in the presence of ampicillin. Using this method to select from synthetic human antibody libraries, we isolated panels of mAbs inhibiting 5 targets of 4 main protease classes: matrix metalloproteinases (MMP-14, a predominant target in metastasis; MMP-9, in neuropathic pain), β-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), cathepsin B (a cysteine protease in cancer), and Alp2 (a serine protease in aspergillosis). Notably, 37 of 41 identified binders were inhibitory. Isolated mAb inhibitors exhibited nanomolar potency, exclusive selectivity, excellent proteolytic stability, and desired biological functions. Particularly, anti-Alp2 Fab A4A1 had a binding affinity of 11 nM and inhibition potency of 14 nM, anti-BACE1 IgG B2B2 reduced amyloid beta (Aβ) production by 80% in cellular assays, and IgG L13 inhibited MMP-9 but not MMP-2/-12/-14 and significantly relieved neuropathic pain development in mice.
Learn More >We used magnetization transfer imaging to assess white matter tissue integrity in migraine, to explore whether white matter microstructure was more diffusely affected beyond visible white matter hyperintensities (WMHs), and to explore whether focal invisible microstructural changes precede visible focal WMHs in migraineurs.
Learn More >Accumulating evidence indicates that phosphorylated serum- and glucocorticoid-regulated kinase 1 (SGK1) is associated with spinal nociceptive sensitization by modulating glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined whether spinal SGK1 signaling contributes to the development of morphine analgesic tolerance. Chronic morphine administration markedly induced phosphorylation of SGK1 in the spinal dorsal horn neurons. Intrathecal injection of SGK1 inhibitor GSK-650394 reduced the development of morphine tolerance with a significant leftward shift in morphine dose-effect curve. Furthermore, spinal inhibition of SGK1 suppressed morphine-induced phosphorylation of nuclear factor kappa B (NF-κB) p65 and upregulation of NMDAR NR1 and NR2B expression in the spinal dorsal horn. In contrast, intrathecal administration of NMDAR antagonist MK-801 had no effect on the phosphorylation of SGK1 in morphine-treated rats. In addition, morphine-induced upregulation of NR2B, but not NR1, was significantly abolished by intrathecal pretreatment with PDTC, a specific NF-κB activation inhibitor. Finally, spinal delivery of SGK1 small interfering RNA exhibited similar inhibitory effects on morphine-induced tolerance, phosphorylation of NF-κB p65, as well as upregulation of NR1 and NR2B expression. Our findings demonstrate that spinal SGK1 contributes to the development of morphine tolerance by enhancing NF-κB p65/NMDAR signaling. Interfering spinal SGK1 signaling pathway could be a potential strategy for prevention of morphine tolerance in chronic pain management.
Learn More >We previously demonstrated that sodium channel 1.7 (Nav1.7) in trigeminal ganglion (TG) was a critical factor in temporomandibular joint (TMJ) inflammation-induced hypernociception, but the mechanism underlying inflammation-induced upregulation of Nav1.7 remained unclear. Glial-neuron interaction plays a critical role in pain process and connexin 43 (Cx43), a gap junction protein expressed in satellite glial cells (SGCs) has been shown to play an important role in several pain models. In the present study, we investigate the role of Cx43 in TMJ inflammation-induced hypernociception and its possible impact on neuronal Nav1.7. We induced TMJ inflammation in rats by injecting complete Freund's adjuvant (CFA) into TMJ and observed a decrease in head withdraw threshold after 24 hours. Electron microscopy showed morphological alterations of SGCs in TMJ-inflamed rats. The expression of Cx43, glial fibrillary acidic protein (GFAP), and Nav1.7 increased greatly compared with controls. In addition, pretreatment with Cx43 blockers in TMJ-inflamed rats could alleviate mechanical hypernociception, inhibit SGCs activation and IL-1βrelease, and thus block the upregulation of Nav1.7. These findings indicate that the propagation of SGCs activation via Cx43 plays a critical role in Nav1.7-involved mechanical hypernociception induced by TMJ inflammation.
Learn More >Prognostic screening of people with low back pain (LBP) improves utilisation of primary healthcare resources. Whether this also applies to secondary healthcare remains unclear. Therefore, this study aims to develop prognostic models to determine at baseline which patients with persistent LBP are likely to have a good and poor outcome to a 5-week programme of combined education and exercise ('UPLIFT') delivered in a secondary healthcare setting.
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