Background
Reports show that stressful events before injury exacerbates post-injury pain. The mechanism underlying stress-induced heightened thermal pain is unclear. Here, we examined the effects of chronic intermittent stress (CIS) on nociceptive behaviors and brain-derived nerve growth factor (BDNF) system in the prefrontal cortex (PFC) and hypothalamus of rats with and without thermal injury.
Results
Unstressed rats showed transient mechanical allodynia during stress exposure. Stressed rats with thermal injury displayed persistent exacerbated mechanical allodynia (
P
< 0.001). Increased expression of BDNF mRNA in the PFC (
P
< 0.05), and elevated TrkB and p-TrkB (
P
< 0.05) protein levels in the hypothalamus were observed in stressed rats with thermal injury but not in stressed or thermally injured rats alone. Furthermore, administration of CTX-B significantly reduced stress-induced exacerbated mechanical allodynia in thermally injured rats (
P
< 0.001).
Conclusion
These results indicate that BDNF-TrkB signaling in PFC and hypothalamus contributes to CIS-induced exacerbated mechanical allodynia in thermal injury state.
Electronic supplementary material
The online version of this article (10.1186/s12868-019-0500-1) contains supplementary material, which is available to authorized users.
Primary high-risk Human Papillomavirus (hrHPV) screening has recently become an accepted standalone or co-test with conventional cytology. Unfortunately, hrHPV singularly lacks specificity for cytopathological grade. However, mechanisms and markers of evolving virus-host interactions at the epigenome level may be harnessed as a better predictor of carcinogenesis. This study aimed to validate and expand the clinical performance of a multiparametric biomarker panel, referred to as the “Molecular Pap smear” based, on HPV genotype and
ADCY8
,
CDH8
and
ZNF582
CpG-methylation as a predictive classifier of cervical cytology. This prospective, cross-sectional study used an independent cohort of residual liquid-based cytology for HPV genotyping and epigenetic analysis. Extracted DNA underwent parallel PCR using 3 primer sets for HPV DNA amplification. HPV-infected samples were genotyped by Sanger sequencing. Promoter methylation levels of 3 tumor suppressor genes were quantified by bisulfite-pyrosequencing of genomic DNA on the newest high-resolution PyroMark Q48 platform. Logistic model performance was compared, and model parameters were used to predict and classify binary cytological outcomes. A total of 883 samples were analyzed. HPV DNA positivity correlated with worsening grade: 125/237 (53%) NILM; 136/235 (58%) ASCUS; 222/229 (97%) LSIL; and 157/182 (86%) HSIL samples. The proportion of carcinogenic HPV-types in PCR-positive sequenceable samples correlated with worsening grade: NILM 34/98 (35%); ASCUS 50/113 (44%); LSIL 92/214 (43%); HSIL 129/152 (85%). Additionally,
ADCY8
,
CDH8
, and
ZNF582
methylation levels increased in direct correlation with worsening grade. Overall, the multi-marker modeling parameters predicted binarized cytological outcomes better than HPV-type alone with significantly higher area under the receiver operator curve (AUC)s, respectively: NILM vs. > NILM (AUC 0.728 vs. 0.709); NILM/ASCUS vs. LSIL/HSIL (AUC 0.805 vs. 0.776); and
E2 attenuates inflammatory responses by suppressing expression of pro-inflammatory genes. Given that inflammation is increasingly being associated with neurodegenerative and psychiatric processes, we sought to elucidate mechanisms by which E2 down-regulates a component of an inflammatory response, cyclooxygenase– 2 (COX-2) expression. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, we found that the COX-2 gene (cox-2) was expressed in a neuronal context, specifically in an amygdalar cell line (AR-5). Given that COX-2 has been reported to be in neurons in the brain, and that the amygdala is a site involved in neurodegenerative and neuropsychiatric processes, we investigated mechanisms by which E2 could down-regulate cox-2 expression in the AR-5 line. These cells express estrogen receptors alpha (ERα) and beta (ERβ), and as shown here cox-2. At the level of RNA, E2 and the ERβ selective ligand diarylpropionitrile (DPN) both attenuated gene expression, whereas the ERα selective ligand propyl pyrazole triol (PPT) had no effect. Neither ligand increased ERβ at the cox-2 promoter. Rather, DPN decreased promoter occupancy of NF-κB p65 and histone 4 (H4) acetylation. Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the TSA effect, E2 and DPN increased histone deacetylase one (HDAC1) and switch-independent 3A (Sin3A) promoter occupancy. Lastly, even though E2 increased CpG methylation, DPN did not. Taken together, the pharmacological data indicate that ERβ contributes to neuronal cox-2 expression, as measured by RNA levels. Furthermore, ER ligands lead to increased recruitment of HDAC1, Sin3A and a concomitant reduction of p65 occupancy and Ac-H4 levels. None of the events, however, are associated with a significant recruitment of ERβ at the promoter. Thus, ERβ directs recruitment to the cox-2 promoter, but does so in the absence of being recruited itself.
Acute kidney injury (AKI) is associated with high mortality in burn patients. Urinary biomarkers can aid in the prediction of AKI and its consequences, such as death and the need for renal replacement therapy (RRT). The purpose of this study was to investigate a novel methodology for detecting urinary biomarkers, the NephroCheck® Test System, and assess its ability to predict death or the need for RRT in burn patients. Burn patients admitted to the United States Army Institute of Surgical Research (USAISR) burn intensive care unit were prospectively enrolled between March 2016 and April 2018. A urine sample was obtained from all study participants using the NephroCheck® system. Patient and injury characteristics were gathered, and descriptive statistics were calculated and multivariable logistic regression analyses were performed using these data. Of the 69 patients in this study, 15 patients (21.7%) attained the composite outcome of death or needing RRT within 30 days of urine collection. NephroCheck® scores were higher for patients with the composite outcome, with P = 0.06 for centrifuged scores and P = 0.04 for noncentrifuged scores. Centrifuged and noncentrifuged scores were in high agreement and correlation (R2 = 0.97, P < 0.0001). Noncentrifuged scores were significant in the unadjusted analysis, but they were not significant in the adjusted analysis. Although these scores had a lower sensitivity and negative predictive value compared with other parameters, they had the second highest specificity and positive predictive value. NephroCheck® scores were higher in burn patients with the composite outcome of death or needing RRT, and they demonstrated comparable sensitivity and specificity to creatinine and TBSA.
will lay the foundation for understanding dysfunctional signaling processes during cutaneous inflammatory pain and disease and potentially reveal novel drug targets for topical therapeutics. Work supported by NS040538.
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