Asphorodin,a potent lipoxygenase inhibitory triterpene diglycoside from Asphodelus tenuifolius

Asphorodin (1), a new diglycoside, has been isolated from the ethyl acetate-soluble fraction of Asphodelus tenuifolius. It showed significant inhibitory activity against the enzyme lipoxygenase in a concentration-dependent manner. The Lineweaver–Burk and Dixon plots indicated that the nature of inhibition was non-competitive.     

Gestational and lactational exposure to the polychlorinated biphenyl mixture Aroclor 1254 modulates retinoid homeostasis in rat offspring

Polychlorinated biphenyls (PCBs) induce a broad spectrum of biochemical and toxic effects in mammals including alterations of the vital retinoid (vitamin A) system. The aim of this study was to characterize alterations of tissue retinoid levels in rat offspring and their dams following gestational and lactational exposure to the PCB mixture Aroclor 1254 (A1254) and to assess the interrelationship of these changes with other established sensitive biochemical and toxicological endpoints. Sprague-Dawley rat dams were exposed orally to 0 or 15 mg/kg body weight/day of A1254 from gestational day 1 to postnatal day (PND) 23. Livers, kidneys and serum were collected from the offspring on PNDs 35, 77 and 350. Tissue and serum retinoid levels, hepatic cytochrome P450 (CYP) enzymes and serum thyroid hormones were analyzed. A multivariate regression between A1254 treatment, hepatic retinoid levels, hepatic CYP enzymes activities, thyroid hormone levels and body/liver weights was performed using an orthogonal partial least-squares (PLS) analysis. The contribution of dioxin-like (DL) components of A1254 to the observed effects was also estimated using the toxic equivalency (TEQ) concept. In both male and female offspring short-term alterations in tissue retinoid levels occurred at PND35, i.e. decreased levels of hepatic retinol and retinoic acid (RA) metabolite 9-cis-4-oxo-13,14-dihydro-RA with concurrent increases in hepatic and renal all-trans-RA levels. Long-term changes consisted of decreased hepatic retinyl palmitate and increased renal retinol levels that were apparent until PND350. Retinoid system alterations were associated with altered CYP enzyme activities and serum thyroid hormone levels as well as body and liver weights in both offspring and dams. The estimated DL activity was within an order of magnitude of the theoretical TEQ for different endpoints, indicating significant involvement of DL congeners in the observed effects. This study shows that tissue retinoid levels are affected both short- and long-term by developmental A1254 exposure and are associated with alterations of other established endpoints of toxicological concern.     

Prevention and management of periodontal diseases and dental caries in the older adults

As a result of aging populations, in the future, dental practitioners will be caring for more older adults than ever before. These older adults, especially in developed countries, will demand a greater number of dental services, driven by increased tooth retention and an expectation of excellent oral healthcare throughout the life course. Further, the global rise in the prevalence and incidence of chronic diseases will increase the risk and/or severity of oral diseases and add a layer of complexity to the management of oral diseases in older adults. More older adults will be at a higher risk of periodontal disease and root caries as a result of reduced tooth loss and edentulism. This article reviews information on periodontitis and root caries, oral diseases which reflect the cumulative risk of the individual, and which are best addressed through prevention. Oral healthcare providers must embrace the concept of lifelong emphasis on prevention, as well as participation as active members of a healthcare team which provides healthcare for older adults in various settings (eg, hospital/clinic-based care, community-based settings, and long-term care facilities). National guidelines that address oral health are being considered by some countries, and if these are implemented they will increase the accessibility to oral health for older adults. In parallel to this, revisions of existing older adult insurance schemes (eg, the inclusion of routine oral healthcare in the US Medicare program) would promote the maintenance of a functional dentition that is pain-free and conducive to general health. The opportunity exists to implement a holistic approach to oral health that will align oral health with general health and emphasize that true health can only be achieved with the inclusion of oral health.     

Application of PBPK modeling to predict monoclonal antibody disposition in plasma and tissues in mouse models of human colorectal cancer

This investigation evaluated the utility of a physiologically based pharmacokinetic (PBPK) model, which incorporates model parameters representing key determinants of monoclonal antibody (mAb) target-mediated disposition, to predict, a priori, mAb disposition in plasma and in tissues, including tumors that express target antigens. Monte Carlo simulation techniques were employed to predict the disposition of two mAbs, 8C2 (as a non-binding control mouse IgG1 mAb) and T84.66 (a high-affinity murine IgG1 anti-carcinoembryonic antigen mAb), in mice bearing no tumors, or bearing colorectal HT29 or LS174T xenografts. Model parameters were obtained or derived from the literature. ¹²⁵I-T84.66 and ¹²⁵I-8C2 were administered to groups of SCID mice, and plasma and tissue concentrations were determined via gamma counting. The PBPK model well-predicted the experimental data. Comparisons of the population predicted versus observed areas under the plasma concentration versus time curve (AUC) for T84.66 were 95.4?±?67.8 versus 84.0?±?3.0, 1,859?±?682 versus 2,370?±?154, and 5,930?±?1,375 versus 5,960?±?317 (nM?×?day) at 1, 10, and 25?mg/kg in LS174T xenograft-bearing SCID mice; and 215?±?72 versus 233?±?30, 3,070?±?346 versus 3,120?±?180, and 7,884?±?714 versus 7,440?±?626 in HT29 xenograft-bearing mice. Model predicted versus observed 8C2 plasma AUCs were 312.4?±?30 versus 182?±?7.6 and 7,619?±?738 versus 7,840?±?24.3 (nM?×?day) at 1 and 25?mg/kg. High correlations were observed between the predicted median plasma concentrations and observed median plasma concentrations (r ²?=?0.927, for all combinations of treatment, dose, and tumor model), highlighting the utility of the PBPK model for the a priori prediction of in vivo data.