128 research outputs found
Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4
Background: The transcription factor interferon regulatory factor 4 (IRF4) was identified to be involved in human pigmentation by genome-wide association studies (GWASs). The rs12203592-[T/C], which is located in intron 4 of IRF4, shows the strongest link to these pigmentation phenotypes including freckling, sun sensitivity, eye and hair color. Previous studies indicated a functional cooperation of IRF4 with Microphthalmia-associated transcription factor (MITF), a causing gene of Waardenburg syndrome (WS), to synergistically trans-activate Tyrosinase (TYR). However, the underlying mechanism is still unknown. Methods: To investigate the importance of DNA binding in the synergic effect of IRF4. Reporter plasmids with mutant TYR promoters was generated to locate the IRF4 DNA binding sites in the Tyrosinase minimal promoter. By building MITF and IRF4 truncated mutations plasmids, the necessary regions of the synergy functions of these two proteins were also located. Results: The cooperative effect between MITF and IRF4 was specific for TYR promoter. The DNA-binding of IRF4 was critical for the synergic function. IRF4 DNA binding sites in TYR promoter were identified. The Trans-activation domains in IRF4 (aa134-207, aa300-420) were both important for the synergic function, whereas the auto-mask domain (aa207-300) appeared to mask the synergic effect. Mutational analysis in MITF indicated that both DNA-binding and transcriptional activation domains were both required for this synergic effect. Conclusions: Here we showed that IRF4 potently synergized with MITF to activate the TYR promoter, which was dependent on DNA binding of IRF4. The synergic domains in both IRF4 and MITF were identified by mutational analysis. This identification of IRF4 as a partner for MITF in regulation of TYR may provide an important molecular function for IRF4 in the genesis of melanocytes and the pathogenic mechanism in WS
Effect of Spatholobus suberectus (Fabaceae) extract on second-degree burns in rats
Purpose: To evaluate the wound-healing effect of Spatholobus suberectus (Fabaceae) on seconddegree burns in a rat model.Methods: The animals were divided into normal, negative control, as well as 10 % Spatholobus suberectus (SS) (SS10), 20 % SS (SS20) and standard (STD) groups. Second-degree burns were inflicted by exposing a 3 × 3 cm sterile area of skin to boiling water for 10 min. The animals were treated topically twice daily for 2 weeks. Wound contraction (%) was measured after 2 weeks, while wound tissue histopathology was assessed by hematoxylin & eosin and Masson’s trichrome staining. In addition, lipid peroxidation (malondialdehyde kit) and cytokine secretion (ELISA) were measured in liver and plasma, respectively.Results: The results of this study suggest that topical application of SS for 2 weeks significantly increases wound closure compared with the negative control. Moreover, treatment with SS significantly improved the pathological status of the wound throughout the protocol. There was also a significant decrease in malondialdehyde activity and increase in cytokine release in SS-treated rats compared with control rats.Conclusions: The results show that topical application of SS after inflicting second-degree burns in rats results in increased wound healing and decreased cytokine release and oxidative stress.Keyword: Spatholobus suberectus, Burns, Wound, Lipid peroxidation, Cytokine
Identification and Characterization of Key Chemical Constituents in Processed Gastrodia elata Using UHPLC-MS/MS and Chemometric Methods
© The Author(s) 2019. Background. Obesity is a major medical issue nationally, with rates continually increasing. In obese patients, minimal data exist for appropriate dosing of acyclovir to decrease the rates of nephrotoxicity. The purpose of this study was to determine the prevalence of and risk factors associated with acyclovir-induced nephrotoxicity. Methods. A retrospective case-control of patients who received intravenous acyclovir for \u3e48 hours at University of Mississippi Medical Center over a 4-year period were evaluated to elucidate the prevalence of acyclovir-induced nephrotoxicity. Additionally, risk factors for the development of nephrotoxicity, including the effect of obesity and dosing strategy, were assessed. Results. One hundred fifteen patients were included in the study. A total of 24 (21%) patients developed nephrotoxicity after acyclovir exposure and were in the Risk (9.6%), Injury (4.3%), and Failure (7%) categories, defined by the RIFLE criteria. Neither acyclovir dosage, fluid status, nor baseline characteristics, other than obesity, varied between those who developed nephrotoxicity vs those who did not. Independent predictors of nephrotoxicity were obesity (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.19-8.67) and receipt of vancomycin (OR, 4.73; 95% CI, 1.57-14.25). No differences in vancomycin dosing or concentrations were observed between the patients who developed nephrotoxicity and those who did not. Conclusions. In this study, nephrotoxicity occurred in 21% of patients receiving acyclovir. Concomitant vancomycin receipt and obesity led to higher rates of toxicity. Efforts should be made to target obese patients on acyclovir plus vancomycin and discontinue therapy in patients not warranting antiviral coverage to minimize chances of toxicity
Short-term effects of intravenous batroxobin in treatment of sudden sensorineural hearing loss: a propensity score-matched study
BackgroundSudden sensorineural hearing loss (SSNHL) can cause great panic in patients. Whether it is advantageous to add intravenous batroxobin in the treatment of SSNHL remains to be determined. This study aimed to compare the short-term efficacy of therapy combined with intravenous batroxobin and that without intravenous batroxobin in SSNHL patients.MethodsThis retrospective study harvested the data of SSNHL patients hospitalized in our department from January 2008 to April 2021. The hearing levels on the admitted day (before treatment) and the discharge day were considered pre-treatment hearing and post-treatment hearing, respectively. The hearing gain was the difference value of pre-treatment hearing and post-treatment hearing. We used Siegel's criteria and the Chinese Medical Association of Otolaryngology (CMAO) criteria to evaluate hearing recovery. The complete recovery rate, overall effective rate, and hearing gain at each frequency were considered outcomes. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the batroxobin group and the non-batroxobin group. Sensitivity analysis was carried out in flat-type and total-deafness SSNHL patients.ResultsDuring the study period, 657 patients with SSNHL were admitted to our department. Among them, a total of 274 patients met the enrolled criteria of our study. After PSM, 162 patients (81 in each group) were included in the analysis. Once the hospitalized treatment was completed, the patients would be discharged the next day. Logistic regression analysis of the propensity score-matched cohort indicated that both the complete recovery rates [Siegel's criteria, OR: 0.734, 95% CI: 0.368–1.466, p = 0.381; CMAO criteria, OR: 0.879, 95% CI: 0.435–1.777, p = 0.720] and the overall effective rates [Siegel's criteria and CMAO criteria, OR: 0.741, 95% CI: 0.399–1.378, p = 0.344] were not significantly different between the two treatment groups. Sensitivity analysis has shown similar results. For flat-type and total-deafness SSNHL patients, no significant difference was found in post-treatment hearing gain at each frequency between the two groups after PSM.ConclusionThere was no significant difference in short-term hearing outcomes between treatment with batroxobin and treatment without batroxobin in SSNHL patients by Siegel's and CMAO criteria after PSM. Future studies for better therapy regimens of SSNHL are still needed
Stage-Specific Deletion of Olig2 Conveys Opposing Functions on Differentiation and Maturation of Oligodendrocytes
The temporal and spatial patterning involved in the specification, differentiation, and myelination by oligodendroglia is coordinated in part by the activation and repression of various transcriptional programs. Olig2 is a basic helix-loop-helix transcription factor necessary for oligodendroglial development and expressed continuously throughout the lineage. Despite evidence for the critical role of Olig2 in oligodendroglial specification and differentiation, the function for Olig2 during later stages of oligodendroglial development, namely, the transition into mature oligodendrocytes (OLs) and the formation of the myelin sheath, remains unclear. To address the possibility for a stage-specific role, we deleted Olig2 in oligodendrocyte precursor cells (OPCs) under the control of the CNPase-promoter or in immature OLs under the inducible proteolipid protein promoter. As expected, ablation of Olig2 in OPCs significantly inhibits differentiation, resulting in hypomyelination. However, deletion of the Olig2 gene in immature OLs significantly enhances the maturation process and accelerates the kinetics of myelination/remyelination. Underlying the stage-specific roles for Olig2 is the compensatory expression and function of Olig1, a transcription factor that promotes OL maturation and (re)myelination. Olig1 expression is significantly reduced upon Olig2 deletion in OPCs but is dramatically increased by nearly threefold when deleted in immature OLs. By enforcing expression of Olig1 into OPCs in a null Olig2 background, we demonstrate that overexpression of Olig1 is sufficient to rescue the differentiation phenotype and partially compensates for the Olig2 deletion in vitro. Our results suggest a stage-specific regulatory role for Olig2, mediated by Olig1 that conveys opposing functions on the differentiation and maturation of oligodendrocytes
Mitochondrial Superoxide Contributes to Blood Flow and Axonal Transport Deficits in the Tg2576 Mouse Model of Alzheimer's Disease
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid beta (Abeta) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.In the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.These findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology
Hydrophilic interaction chromatography combined with tandem mass spectrometry method for the quantification of tobramycin in human plasma and its application in a pharmacokinetic study
Unified Brake Service by a Hierarchical Controller for Active Deceleration Control in an Electric and Automated Vehicle
Unified brake service is a universal service for generating certain brake force to meet the demand deceleration and is essential for an automated driving system. However, it is rather difficult to control the pressure in the wheel cylinders to reach the target deceleration of the automated vehicle, which is the key issue of the active deceleration control system (ADC). This paper proposes a hierarchical control method to actively control vehicle deceleration with active-brake actuators. In the upper hierarchical, the target pressure of wheel cylinders is obtained by dynamic equations of a pure electric vehicle. In the lower hierarchical, the solenoid valve instructions and the pump speed of hydraulic control unit (HCU) are determined to satisfy the desired pressure with the feedback of measured wheel cylinder pressure by pressure sensors. Results of road experiments of a pure electric and automated vehicle indicate that the proposed method realizes the target deceleration accurately and efficiently
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