BackgroundPreterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury.MethodsC57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining.ResultsHI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model.ConclusionsWe have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury.

Although necrosis is recognized as the main mode of cell death induced by acetaminophen (APAP) overdose in animals and humans, more recently an increasing number of publications, especially in the herbal medicine and dietary supplement field, claim an important contribution of apoptotic cell death in the pathophysiology. However, most of these conclusions are based on parameters that are not specific for apoptosis. Therefore, the objective of this review was to re-visit the key signaling events of receptor-mediated apoptosis and APAP-induced programmed necrosis and critically analyze the parameters that are being used as evidence for apoptotic cell death. Both qualitative and quantitative comparisons of parameters such as Bax, Bcl-2, caspase processing and DNA fragmentation in both modes of cell death clearly show fundamental differences between apoptosis and cell death induced by APAP. These observations together with the lack of efficacy of pan-caspase inhibitors in the APAP model strongly supports the conclusion that APAP hepatotoxicity is dominated by necrosis or programmed necrosis and does not involve relevant apoptosis. In order not to create a new controversy, it is important to understand how to use these "apoptosis" parameters and properly interpret the data. These issues are discussed in this review.

Background. Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.Methods. Wild-type and TLR2-deficient (TLR2−/−) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.Results. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2−/− mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.Conclusions. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.