Anti-aging effect of DL-ß-hydroxybutyrate against hepatic cellular senescence induced by D-galactose or γ-irradiation via autophagic flux stimulation in male rats.

The present study aims to shed new light on anti-aging effect of DL-ß-hydroxybutyrate (ßOHB) against hepatic cellular senescence induced by d-galactose or γ-irradiation. The rats divided into 6 groups. Group 1, control, group 2, exposed to γ-ray (5 GY), group 3, injected by d-galactose (150 mg/kg) daily for consecutive 6 weeks, which regarded to induce the aging, group 4, injected intraperitoneal by ß-hydroxybutyrate (ßOHB) (72.8 mg/kg) daily for consecutive 14 days, group 5, exposed to γ-ray then treated with ßOHB daily for consecutive 14 days, group 6, injected daily with d-galactose for consecutive 6 weeks, then treated with ßOHB daily at the last two weeks of d-galactose. Aspartate amino transferase (AST), alanine amino transferase (ALT), Insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were estimated in serum. Moreover, protein expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) ratio, mechanistic target of rapamycin (mTOR), pAMPK, mRNA gene expression of 5' AMP-activated protein kinase (AMPK), Nucleoporin p62 (p62), cyclin-dependent kinase inhibitor 1(P21CIP1), cyclin-dependent kinase inhibitor 2A (p16INK4a) and DNA fragmentation percentage were measured in liver tissue as a biomarker of cellular senescence. The results confirmed that ßOHB modulated serum level of AST, ALT, insulin, IL-6 and TNF-α, protein expression of mTOR and LC3-II/LC3-I ratio, pAMPK and p62 in liver aging model induced by d-galactose or γ-irradiation. Histopathological examination results of liver tissue indicated coincidence with those recorded by molecular biochemical inspection. Taken together, these findings suggest that ßOHB may be useful in combating hepatic cellular senescence induced by d-galactose or γ-irradiation via autophagy dependent mechanisms.

Evaluation of the carbapenem inactivation method (CIM) for detecting carbapenemase activity in enterobacteria.

OBJECTIVES: The objective of this study was to evaluate the accuracy of the CIM test in the detection of carbapenemase activity in 124 strains of Enterobacteriaceae. METHODS: A panel of 124 previously characterized Enterobacteriaceae was tested: 77 strains producing the following carbapenemase families: KPC (n = 14), GES (n = 22), NDM (n = 19), VIM (n = 4), IMP (n = 4) and OXA-48 (n = 14) and 47 non-carbapenemase producers. For the CIM method, an active susceptibility meropenem disc was exposed to a bacterial suspension of a test strain; when a carbapenemase is produced, the antibiotic is inactivated allowing uninhibited growth of an indicator strain after overnight incubation. A clear inhibition zone (≥20 mm) was considered indicative of no-carbapenemase activity. RESULTS: All KPC, NDM, VIM, IMP or OXA-48 producing strains were unequivocally detected with the CIM test. CIM false negative results were obtained with eleven Enterobacter cloacae producing GES-6. Two other E. cloacae not producing carbapenemase (one with SHV-12, one hyperproducing AmpC) were positive by the test. The sensitivity and specificity of the assay compared to those of molecular methods were 85.7% and 95.7%, respectively. CONCLUSIONS: The CIM method proved to be inexpensive and easy to interpret. It provided less than optimal results in the detection of GES-6 activity.

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.

The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

Three-phase plasma arc atomic-emission spectrometric analysis of environmental samples using an ultrasonic nebulizer.

Combination of an ultrasonic nebulizer and plasma excitation sources for spectrochemical analysis offers desirable features of low detection limits, high sample throughput, wide dynamic range of operation, acceptable precision and accuracy, and simultaneous quantitative analytical capabilities. Moreover, the ultrasonic nebulizer does not require sample preconcentration. Recently we have developed a three-phase plasma arc (TPPA) for atomic emission spectrochemical analysis. In the present work, to increase the analytical utility of the three-phase plasma system, an ultrasonic nebulizer was used for sample introduction. The effects of the argon gas flow rate, current, excitation temperature have been studied. The analytical calibration curves are obtained for Ca, Cr, Fe, Mg and Mn, and detection limits have been calculated. The present technique is used to determine the concentration of the elements Ca, Cr, Fe, Mg and Mn in airborne samples.