Ondansetron attenuates hepatic injury via p38 MAPK-dependent pathway in a rat haemorrhagic shock model

Background

Ondansetron is a 5-HT3 receptor antagonist with potent antiemetic, analgesic, and antiphlogistic effects. Recent evidence suggests that the co-existence of 5-HT3 receptors in various cell types is involved in inflammation. However, the effects that 5-HT3 antagonists produce in haemorrhagic shock and resuscitation remain unknown. In this study, we hypothesized that ondansetron administration in male rats, after haemorrhagic shock, decreases cytokine production and protects against hepatic injury through a p38 mitogen-activated protein kinase (MAPK) pathway.

Methods

Male Sprague-Dawley rats underwent haemorrhagic shock (mean arterial blood pressure 40 mmHg for 90 min), followed by resuscitation. Various doses of ondansetron (0.1, 0.3, 1, 3 mg kg⁻¹) or a single dose of ondansetron (1 mg kg⁻¹) with or without a p38 MAPK inhibitor (SB-203580, 2 mg kg⁻¹) or vehicle were administered intravenously during resuscitation. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations and various liver proinflammatory parameters were measured at 24 h after resuscitation.

Results

Results show that haemorrhagic shock increases plasma AST and ALT concentrations, hepatic myeloperoxidase activity, cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) levels. These parameters were significantly improved in the ondansetron-treated rats subjected to haemorrhagic shock. Ondansetron treatment restored phos-p38 MAPK expression as compared with vehicle-treated haemorrhaged rats. Coadministration of SB-203580 prevented the beneficial effects of ondansetron on postresuscitation proinflammatory responses and hepatic injury.

Conclusion

Ondansetron attenuates hepatic injury following haemorrhagic shock, which is, at least in part, to be due to its anti-inflammatory effect via p38 MAPK signal pathway.     

IL-22、IL-27、VEGF、TF及TFPI鉴别良恶性胸腔积液的应用价值研究

目的探讨白细胞介素(IL)-2、IL-27、血管内皮生长因子(VEGF)、组织因子(TF)及组织因子途径抑制物(TFPI)鉴别良恶性胸腔积液的应用价值。方法采用酶联免疫吸附测定(ELISA)法检测67例良性胸腔积液及73例恶性胸腔积液的IL-22、IL-27、VEGF、TF及TFPI 5种分子标志物的水平。结果恶性胸腔积液组的IL-22、IL-27、VEGF、TF及TFPI水平均显著高于良性胸腔积液组,差异有统计学意义(P0.05)。多因素Logistic回归分析显示,只有VEGF是胸腔积液良恶性鉴别的独立影响因素。结论胸腔积液IL-22、IL-27、VEGF、TF及TFPI的检测有助于临床诊治良恶性胸腔积液患者,其中VEGF可做为胸腔积液良恶性鉴别的独立影响因素。     

The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus‐specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4‐SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en‐passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.     

The Brazilian Founder Mutation TP53 p.R337H is Uncommon in Portuguese Women Diagnosed with Breast Cancer

Since the first studies reporting the TP53 p.R337H mutation as founder mutation in Southern and Southeastern Brazil, there has been controversy on its origin. Preliminary analysis of a small subset of Brazilian mutation carriers revealed that the haplotype incided on a Caucasian background. The vast majority of carriers identified today reside in Brazil or, if identified in other countries, are Brazilian immigrants. To our knowledge, the only two exceptions of carriers without a recognizable link with Brazil are two European families, from Portugal and Germany. Haplotype analysis in the Portuguese family revealed the same haplotype identified in Brazilian individuals, but in the German family, a distinct haplotype was found. Knowing that a significant proportion of women with breast cancer (BC) in Southern Brazil are p.R337H carriers, we analyzed p.R337H in a Portuguese cohort of women diagnosed with this disease. Median age at diagnosis among the first 573 patients tested was 60 years and 100 (17.4%) patients had been diagnosed at or under the age of 45 years. Mutation screening failed to identify the mutation in the 573 patients tested. These results are in contrast with the mutation frequency observed in a study including 815 BC‐affected women from Brazil, in which carrier frequencies of 12.1 and 5.1% in pre‐ and postmenopausal women were observed, respectively. These findings suggest that the Brazilian founder mutation p.R337H, the most frequent germline TP53 mutation reported to date, is not a common germline alteration in Portuguese women diagnosed with BC.