Curcumin ameliorates hepatic chronic inflammation induced by bile duct obstruction in mice through the activation of heme oxygenase-1

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In Vitro-In Vivo Extrapolation and Hepatic Clearance-Dependent Underprediction

Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field.     

Novel phenotype of mouse spermatozoa following deletion of nine β-defensin genes

β-defensin peptides are a large family of antimicrobial peptides. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. Despite their inducible presence at mucosal surfaces, their main site of expression is the epididymis. Recent evidence suggests that a major function of these peptides is in sperm maturation. In addition to previous work suggesting this, work at the MRC Human Genetics Unit, Edinburgh, has shown that homozygous deletion of a cluster of nine β-defensin genes in the mouse results in profound male sterility. The spermatozoa derived from the mutants had reduced motility and increased fragility. Epididymal spermatozoa isolated from the cauda region of the homozygous mutants demonstrated precocious capacitation and increased spontaneous acrosome reactions compared with those from wild-types. Despite this, these mutant spermatozoa had reduced ability to bind to the zona pellucida of oocytes. Ultrastructural examination revealed a disintegration of the microtubule structure of mutant-derived spermatozoa isolated from the epididymal cauda region, but not from the caput. Consistent with premature acrosome reaction and hyperactivation, spermatozoa from mutant animals had significantly increased intracellular calcium content. This work demonstrates that in vivo β-defensins are essential for successful sperm maturation, and that their disruption alters intracellular calcium levels, which most likely leads to premature activation and spontaneous acrosome reactions that result in hyperactivation and loss of microtubule structure of the axoneme. Determining which of the nine genes are responsible for the phenotype and the relevance to human sperm function is important for future work on male infertility.     

超脉冲CO2点阵激光联合PRP治疗面部痤疮凹陷性瘢痕疗效分析

目的:探究超脉冲CO2点阵激光联合富血小板血浆(PRP)治疗面部痤疮凹陷性瘢痕的疗效。方法:72例面部痤疮凹陷性瘢痕患者,随机分为观察组(36例)和对照组(36例)。对照组采用超脉冲CO2点阵激光治疗,观察组采用超脉冲CO2点阵激光联合PRP治疗。比较两组患者的灰度差异、时间指标、瘢痕程度、疼痛、不良反应及视觉评估。结果:观察组的并发症发生率为11.11%,低于对照组的36.11%,差异具有统计学意义(P<0.05)。治疗后,两组患者的灰度差异率均减小,且观察组患者的灰度差异率显著低于对照组,差异具有统计学意义(P<0.05)。治疗后,观察组的炎性渗出时间、红肿时间、愈合时间、停工时间及瘢痕程度评分均低于对照组,差异均具有统计学意义(P<0.05);但疼痛度评分组间比较,差异无统计学意义(P>0.05)。结论:超脉冲CO2点阵激光联合PRP治疗面部痤疮凹陷性瘢痕效果较好,可有效降低瘢痕程度,减少治疗时间及并发症的发生,帮助患者迅速回归正常工作与生活,值得临床推广使用。     

Regulated expression of virulence gene mviN provides protective immunity and colonization control of Salmonella in poultry

Current live attenuated vaccines for control of Salmonella in poultry persist in the ceca and may persist in the environment. In this paper we report the construction and characterization of the vaccine efficacy of a Salmonella mutant strain with inducible mviN expression and rapid clearance from the host. The mutant was effective in oral immunization of the broiler chicken host against a virulent Salmonella oral challenge strain, having a mean 7 × 10⁶ CFU/g in the ceca of unvaccinated controls compared to a mean 2 × 10³ CFU/g in the ceca of vaccinated chickens at 4 weeks post-challenge (6 weeks of age). The mutant strain also demonstrated immunogenicity, reduced organ colonization, and rapid clearance in broiler chickens within 3 weeks of inoculation.