Highlights • Cerebral SGLT-1 exacerbates the development of cerebral ischemic neuronal damage. • Cortical and striatal SGLT-1 significantly increase at 12 h after focal cerebral ischemia. • SGLT-1 ...expresses in neuron with and without cerebral ischemic stress. • Concomitant treatment of H2 O2 and glucose induces activation of AMPK and up-regulation of SGLT-1 in primary cortical neuron.
Background
Both early life stress and neuropathic pain induce morphological and functional abnormalities of the nervous system that are associated with emotional regulation. In our previous study, ...early life stress enhanced nerve injury‐induced hyperalgesia in adult male and female mice. In the present study, using phosphorylated extracellular signal‐regulated kinase (p‐ERK) as a marker of neuronal activation, we examined the effect of early life stress on neuronal function following partial sciatic nerve ligation (PSL).
Methods
Early life stress was induced by maternal separation from 2 to 3 weeks of age and by social isolation after weaning (MSSI). Neuropathic pain was induced by PSL at 9 weeks of age, and p‐ERK expression after light touch stimulation to the ipsilateral paw was measured using immunohistochemistry 1 week after nerve injury.
Results
Although MSSI increased p‐ERK expression in the paraventricular nucleus (PVN) and amygdala of male mice, PSL did not affect p‐ERK expression in control and MSSI mice. In female mice, increased p‐ERK expression was observed in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Furthermore, p‐ERK expression in the PVN and amygdala was increased in MSSI‐PSL mice.
Conclusions
The present data suggest that early life stress sex‐dependently and site‐specifically increases neuronal activity in the brain. In addition, increased neuronal activity in multiplebrain regions of mice subjected to early life stress may enhance hyperalgesia after nerve injury.
What does this study add?
Maternal separation and social isolation (MSSI) increased p‐ERK in the paraventricular nucleus (PVN) and amygdala of male mice. MSSI increased p‐ERK in the medial prefrontal cortex and nucleus accumbens of female mice. Neuropathic pain increased p‐ERK in the PVN and amygdala of female MSSI mice.
Background and Purpose
The ω‐3 polyunsaturated fatty acids exert antinociceptive effects in inflammatory and neuropathic pain; however, the underlying mechanisms remain unclear. Docosahexaenoic ...acid‐induced antinociception may be mediated by the orphan GPR40, now identified as the free fatty acid receptor 1 (FFA1 receptor). Here, we examined the involvement of supraspinal FFA1 receptor signalling in the regulation of inhibitory pain control systems consisting of serotonergic and noradrenergic neurons.
Experimental Approach
Formalin‐induced pain behaviours were measured in mice. Antinociception induced by FFA1 receptor agonists was examined by intrathecal injections of a catecholaminergic toxin, 5‐HT lowering drug or these antagonists. The expression of FFA1 receptor protein and c‐Fos was estimated by immunohistochemistry, and the levels of noradrenaline and 5‐HT in the spinal cord were measured by LC‐MS/MS.
Key Results
FFA1 receptors colocalized with NeuN (a neuron marker) in the medulla oblongata and with tryptophan hydroxylase (TPH; a serotonergic neuron marker) and dopamine β‐hydroxylase (DBH; a noradrenergic neuron marker). A single i.c.v. injection of GW9508, a FFA1 receptor agonist, increased the number of c‐Fos‐positive cells and the number of neurons double‐labelled for c‐Fos and TPH and/or DBH. It decreased formalin‐induced pain behaviour. This effect was inhibited by pretreatment with 6‐hydroxydopamine, DL‐p‐chlorophenylalanine, yohimbine or WAY100635. Furthermore, GW9508 facilitated the release of noradrenaline and 5‐HT in the spinal cord. In addition, GW1100, a FFA1 receptor antagonist, significantly increased formalin‐induced pain‐related behaviour.
Conclusion and Implications
Activation of the FFA1 receptor signalling pathway may play an important role in the regulation of the descending pain control system.
Highlights • Cerebral SGLT-3 was not affected inpost-ischemic hyperglycemia. • Cerebral SGLT-3 may suppress the developed ischemic neuronal damage. • SGLT-3 and choline acetyltransferase were ...co-localized in the cortex and striatum.
Abstract Vascular endothelial growth factors (VEGFs), a family of angiogenic factors, are upregulated by nerve injuries. To clarify the extracellular signals involved in VEGF production in the brain, ...the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/d Ala1,3,11,15 -ET-1, an ETB receptor agonist, increased the level of VEGF-A mRNA in the rat cerebrum, whereas those of VEGF-B, placental growth factor (PLGF), angiopoietin (ANG)-1, and ANG-2 mRNAs were not largely affected by Ala1,3,11,15 -ET. The ET-induced increases in cerebrum VEGF-A mRNA were reduced by coadministration of 1 nmol/d BQ788, an ETB antagonist. Ala1,3,11,15 -ET-1 also stimulated the production of VEGF-A proteins in the cerebrum. Immunohistochemical observations in the cerebrum of Ala1,3,11,15 -ET-1-infused rats showed that glial fibrillary acidic protein (GFAP)-positive astrocytes had VEGF-A immunoreactivity. Neurons, microglia, and brain capillary endothelial cells in the Ala1,3,11,15 -ET-1-infused rats did not show VEGF-A reactivity. The i.c.v. administration of Ala1,3,11,15 -ET-1 stimulated tyrosine phosphorylations of VEGF-R1 and R2 receptors in the rat cerebrum, whereas expression levels of total VEGF-R1 and R2 proteins were not largely changed. Immunoreactivity of tyrosine-phosphorylated VEGF-R1 was selectively shown in GFAP-positive astrocytes in the cerebrum of Ala1,3,11,15 -ET-1-infused rats. Tyrosine-phosphorylated VEGF-R2 proteins were present in astrocytes and brain capillary endothelial cells. These findings indicate that activation of brain ETB receptors increases production of VEGF-A and stimulates VEGF receptor signaling in the brain.
A serious problem for Paan-lime production in Thailand is a citrus canker disease caused by the bacterium Xanthomonas citri subsp. citri (Xcc). The use of antagonist against pathogenic Xcc is ...increasingly becoming popular. In this study, we investigated the effect of pathogenic Xcc and a bacterial antagonist on defense-related gene expression of Paan-lime. The ability of Xcc and the antagonist Pseudomonas aeruginosa SWUC02 to induce defense-related gene expression, including PR-1, Pt14, LRR8, and LOX gene, was assessed. We assured that all four defense-related genes are present in Paan-lime by analyzing the similarity of nucleotide sequences in parts of the genes against other citrus species. Using reverse-transcription PCR (RT-PCR), we showed that the antagonist is able to induce the expression of LRR8 gene at 24 hours post-inoculation, while Xcc induces PR-1 and LOX gene expression at the same time. Our results suggest that these defense-related genes alter their expressions in response to canker disease infection. Thus, we could use this group of genes as a biomarker for screening canker-resistance Paan-lime tree.
The Pirarubicin Monotherapy Study Group trial was a randomized Phase II study that evaluated the efficacy of intravesical instillation of pirarubicin in the prevention of bladder recurrence after ...nephroureterectomy for upper urinary tract urothelial carcinoma. This study conducted further analysis of the Pirarubicin Monotherapy Study Group cohort, focusing on intravesical seeding of cancer cells.
Using the data from the Pirarubicin Monotherapy Study Group trial, bladder recurrence-free survival rates and factors associated with bladder recurrence in the control group were analyzed.
Of 36 patients in the control group, 14 with positive urine cytology had more frequent recurrence when compared with the 22 patients with negative cytology (P = 0.004). Based on the multivariate analysis in the control group, voided urine cytology was an independent predictive factor of bladder recurrence (hazard ratio, 5.54; 95% confidence interval 1.12-27.5; P = 0.036). Of 72 patients in the Pirarubicin Monotherapy Study Group trial, 31 had positive urine cytology. Among the 31 patients, 17 patients who received pirarubicin instillation had fewer recurrences when compared with 14 patients who received control treatment (P = 0.0001). On multivariate analysis, pirarubicin instillation was an independent predictor of better recurrence-free survival rates in the patients with positive urine cytology (hazard ratio, 0.02; 95% confidence interval, 0.00-0.53; P = 0.018). Of 21 patients with bladder recurrence, 17 had recurrent tumor around cystotomy or in the bladder neck compromised by the urethral catheter, supporting the notion that tumor cells seeded in the injured urothelium.
Intravesical instillation of pirarubicin immediately after nephroureterectomy significantly reduced the bladder recurrence rate in patients with positive voided urine cytology. The results suggest that intravesical seeding of upper urinary tract urothelial carcinoma occurs during nephroureterectomy.
It is well known that opioid analgesics exert central antinociceptive actions. However, in vivo and in vitro studies have shown that some opioid analgesics given systemically have limited access to ...the central nervous system because of the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-dependent drug efflux transporter, is one component of the BBB. In this report, we assessed the antinociceptive effect of morphine, fentanyl, and meperidine in P-gp deficient (
mdr1a KO) mice, and compared these effects with those in wild type (WT) mice. The antinociceptive effects of morphine and fentanyl in
mdr1a KO mice were significantly greater than those in WT mice. However, there was no clear difference in the antinociceptive effects of meperidine in the two genotypes. In addition, we determined the effect of opioid analgesics on P-gp ATPase activity, which is requisite for drug transport, using mouse brain capillary endothelial cells. In our observations, morphine and fentanyl, but not meperidine, significantly increased P-gp ATPase activity, and the drugs' concentration-response curves were bell-shaped, reaching a peak at a concentration of 1 μM. These results suggest that P-gp ATPase activity may be, at least in part, involved in the antinociceptive potencies of those opioid analgesics that are substrates for P-gp.
The structural gene for phospholipase D (PLD) of an actinomycete, Streptoverticillium cinnamoneum, together with its promoter region was introduced into Streptomyces lividans using a shuttle ...vector--pUC702--for Escherichia coli and S. lividans. The transformant was found to secrete a large amount of PLD (about 2.0x10⁴ U/l, 42 mg/l) when cultured in a jar fermentor. Both an initial glucose concentration of 17.5 g/l and the feeding of carbon and nitrogen sources are effective for efficient secretion of PLD; under these culture conditions, the amount of PLD secreted reached a maximum level (about 5.5 x10⁴ U/l, 118 mg/l) after about 60 h. In contrast to the original producer, Stv. cinnamoneum, which secretes only a small amount of PLD (about 1.1x10³ U/l, 2 mg/l) along with other extracellular proteins, this heterologous expression system is markedly more efficient in production of secretory PLD.
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