Selective intracellular vaporisation of antibody-conjugated phase-change nano-droplets in vitro.

While chemotherapy is a major mode of cancer therapeutics, its efficacy is limited by systemic toxicities and drug resistance. Recent advances in nanomedicine provide the opportunity to reduce systemic toxicities. However, drug resistance remains a major challenge in cancer treatment research. Here we developed a nanomedicine composed of a phase-change nano-droplet (PCND) and an anti-cancer antibody (9E5), proposing the concept of ultrasound cancer therapy with intracellular vaporisation. PCND is a liquid perfluorocarbon nanoparticle with a liquid-gas phase that is transformable upon exposure to ultrasound. 9E5 is a monoclonal antibody targeting epiregulin (EREG). We found that 9E5-conjugated PCNDs are selectively internalised into targeted cancer cells and kill the cells dynamically by ultrasound-induced intracellular vaporisation. In vitro experiments show that 9E5-conjugated PCND targets 97.8% of high-EREG-expressing cancer cells and kills 57% of those targeted upon exposure to ultrasound. Furthermore, direct observation of the intracellular vaporisation process revealed the significant morphological alterations of cells and the release of intracellular contents.

Lactobacillus pentosus strain b240 suppresses pneumonia induced by Streptococcus pneumoniae in mice.

AIMS: Oral administration of probiotics has been known to improve inflammatory responses against infectious diseases. Here, we describe the inhibitory effect of oral intake of heat-killed Lactobacillus pentosus strain b240 (b240) on pneumococcal pneumonia in a murine experimental model. METHOD AND RESULTS: The mice treated with oral b240 for 21 days before Streptococcus pneumoniae infection exhibited prolonged survival time and less body weight loss, compared with saline-treated control mice. Mild pneumonia with significantly reduced secretion of inflammatory cytokines/chemokines according to related mitogen-activated protein kinase signalling molecules (phosphorylated c-Jun N-terminal kinase) was found in b240-treated mice, whereas severe pneumonia with hypercytokinemia was evident in control mice. Prominent reduction in the number of pneumococci and elevated expression of Toll-like receptor 2 and 4 in the lung tissues was concomitantly noted in b240-treated mice. CONCLUSIONS: These findings indicate that b240 has inhibitory effects on pneumococcal pneumonia induced by Strep. pneumoniae infection and improves inflammatory tissue responses, resulting in reduced damages to the respiratory tissues. SIGNIFICANCE AND IMPACT OF THE STUDY: These results demonstrate that oral administration of b240 might protect host animals from Strep. pneumoniae infection by augmentation of innate immune response.

Effects of ammonium chloride-induced acidosis on oxidative metabolism in liver mitochondria of chicks.

The present studies were undertaken to characterise oxidative metabolism with diverse substrates in hepatic mitochondria of acidotic chicks. Metabolic acidosis was experimentally induced by replacement of drinking water with ammonium chloride solution (15 g/l) for 5 d. State 3 oxidation rates in liver mitochondria were significantly reduced in acidotic chicks only for pyruvate and glutamate as substrates requiring complex I, III and IV of the electron transport chain, while they were not changed for either succinate-requiring complexes II, III and IV, ascorbate+TMPD-requiring complex IV, or alpha-ketoglutarate requiring complexes I, III and IV. It can be concluded that the impairment of oxidation rate was substrate-specific in liver mitochondria of acidotic animals and not associated with functional damage of the respiratory chain in mitochondria. Possible reasons for the reductions in oxidation rate with pyruvate and glutamate are discussed.

Metabolic acidosis inhibits pyruvate oxidation in chick liver by decreasing activity of pyruvate dehydrogenase complex.

Replacement of drinking water with NH4Cl (1.5%) solution significantly reduced blood pH on the 2nd d in chicks and thereafter. Concomitant with this reduction, oxidation rate of state 3 with pyruvate in liver mitochondria was also decreased in acidotic animals when compared with control animals. No significant differences between the two groups were observed in the state 4 oxidation at any feeding period. The ADP/O ratio did not appear to be affected by the treatment. The successive experiments of gavage-feeding for 4 d were also employed to ensure an equivalent intake of diet and the amount of NH4Cl given. As a result, the higher the NH4Cl provided, the lower the oxidation rate of state 3 with pyruvate in liver mitochondria, and the actual activity of pyruvate dehydrogenase complex, as expressed as units of produced CO2 per g wet weight of liver, which were accompanied by the lower pH in blood. This study provides the first evidence for a critical role of pyruvate dehydrogenase complex in the regulation of pyruvate catabolism in the liver from acidotic chicks induced by NH4Cl.