Variable sulfation of dietary polyphenols by recombinant human sulfotransferase (SULT) 1A1 genetic variants and SULT1E1.

Human cytosolic sulfotransferases (SULTs) catalyze the sulfate conjugation of several important endo- and xenobiotics. Among the superfamily of SULT enzymes, SULT1A1 catalyzes the sulfation of small planar phenolic compounds, whereas SULT1E1 has a major role in estrogen conjugation. The human SULT1A1 gene has common single nucleotide polymorphisms that define three allozymes, SULT1A1*1, *2, and *3. The enzyme kinetics of SULT1A1 allozymes and SULT1E1 were characterized for the polyphenolic substrates apigenin, chrysin, epicatechin, quercetin, and resveratrol. Purified recombinant SULT proteins were generated in a baculoviral-insect cell system, and incubated in vitro with each substrate to determine catalytic activity. The effect of polyphenol sulfation was examined in mammalian cell lines stably expressing SULT1E1. For all polyphenols investigated, "normal-activity" SULT1A1*1 allozyme had significantly greater Vmax estimates than SULT1E1, and allele-specific differences in SULT1A1-mediated sulfation were observed. The polymorphic SULT1A1*2 allozyme exhibited low activity toward apigenin, epicatechin, and resveratrol. SULT1A1*1 and *3 acted as normal-activity allozymes for these substrates. Altered cellular proliferation was observed in MCF-7 cells stably expressing SULT1E1 upon treatment with chrysin, quercetin, or resveratrol, thus suggesting inactivation of these compounds by SULT1E1. These results suggest an important role for SULT isozymes and their pharmacogenetics in polyphenol disposition.     

Impact of epinephrine volume on further bleeding due to high-risk peptic ulcer disease in the combination therapy era

BACKGROUNDIn monotherapy studies for bleeding peptic ulcers, large volumes of epinephrine were associated with a reduction in rebleeding. However, the impact of epinephrine volume in patients treated with combination endoscopic therapy remains unclear. AIMTo assess whether epinephrine volume was associated with bleeding outcomes in individuals who also received endoscopic thermal therapy and/or clipping.METHODSData from 132 patients with Forrest class Ia, Ib, and IIa peptic ulcers were reviewed. The primary outcome was further bleeding at 7 d; secondary outcomes included further bleeding at 30 d, need for additional therapeutic interventions, post-endoscopy blood transfusions, and 30-day mortality. Logistic and linear regression and Cox proportional hazards analyses were performed.RESULTSThere was no association between epinephrine volume and all primary and secondary outcomes in multivariable analyses. Increased odds for further bleeding at 7 d occurred in patients with elevated creatinine values (aOR 1.96, 95%CI 1.30-3.20; P < 0.01) or hypotension requiring vasopressors (aOR 6.34, 95%CI 1.87-25.52; P < 0.01). Both factors were also associated with all secondary outcomes.CONCLUSIONEpinephrine maintains an important role in the management of bleeding ulcers, but large volumes up to a range of 10-20 mL are not associated with improved bleeding outcomes among individuals receiving combination endoscopic therapy. Further bleeding is primarily associated with patient factors that likely cannot be overcome by increased volumes of epinephrine. However, in carefully-selected cases where ulcer location or size pose therapeutic challenges or when additional modalities are unavailable, it is conceivable that increased volumes of epinephrine may still be beneficial.     

The association between dental status and temporomandibular osseous changes: a morphological study on Roman–Byzantine skeletons

The aim of this study was to evaluate the association between dental status and the prevalence and severity of osseous changes in the temporomandibular joints of human skulls from the Roman–Byzantine period. Fifty‐eight skulls from 36 men and 22 women between the ages of 19 and 63 years were studied, and the following parameters were evaluated: morphological osseous changes in the articular surface of the condyles, tooth wear and molar support. A significant correlation between age and dental wear or loss of molar support was observed, although no correlation was noted between age and morphological osseous changes in the condyles. The loss of molar support was significantly correlated with morphological osseous changes of the condyles, whereas no significant correlation was found between dental wear and condylar changes. This study demonstrates that the loss of molar support can serve as a predictor of osseous changes in the condyle. Reduced molar support may be one of the aetiologies associated with morphological osseous changes in temporomandibular joints. Further studies should to be performed to investigate this potential correlation.     

Odanacatib Restores Trabecular Bone of Skeletally Mature Female Rabbits With Osteopenia but Induces Brittleness of Cortical Bone: A Comparative Study of the Investigational Drug With PTH,Estrogen, and Alendronate

Cathepsin K (CK), a lysosomal cysteine protease, is highly expressed in mature osteoclasts and degrades type 1 collagen. Odanacatib (ODN) is a selective and reversible CK inhibitor that inhibits bone loss in preclinical and clinical studies. Although an antiresorptive, ODN does not suppress bone formation, which led us to hypothesize that ODN may display restorative effect on the osteopenic bones. In a curative study, skeletally mature New Zealand rabbits were ovarectomized (OVX) and after induction of bone loss were given a steady‐state exposure of ODN (9 mM/d) for 14 weeks. Sham‐operated and OVX rabbits treated with alendronate (ALD), 17b‐estradiol (E2), or parathyroid hormone (PTH) served as various controls. Efficacy was evaluated by assessing bone mineral density (BMD), bone microarchitecture (using micro‐computed tomography), fluorescent labeling of bone, and biomechanical strength. Skeletal Ca/P ratio was measured by scanning electron microscopy (SEM) with X‐ray microanalysis, crystallinity by X‐ray diffraction, and bone mineral density distribution (tissue mineralization) by backscattered SEM. Between the sham and ODN‐treated osteopenic groups, lumbar and femur metaphyseal BMD, Ca/P ratio, trabecular microstructure and geometric indices, vertebral compressive strength, trabecular lining cells, cortical parameters (femoral area and thickness and periosteal deposition), and serum P1NP were largely comparable. Skeletal improvements in ALD‐treated or E2‐treated groups fell significantly short of the sham/ODN/PTH group. However, the ODN group displayed reduced ductility and enhanced brittleness of central femur, which might have been contributed by higher crytallinity and tissue mineralization. Rabbit bone marrow stromal cells expressed CK and when treated with ODN displayed increased formation of mineralized nodules and decreased apoptosis in serum‐deficient medium compared with control. In vivo, ODN did not suppress remodeling but inhibited osteoclast activity more than ALD. Taken together, we show that ODN reverses BMD, skeletal architecture, and compressive strength in osteopenic rabbits; however, it increases crystallinity and tissue mineralization, thus leading to increased cortical bone brittleness. © 2015 American Society for Bone and Mineral Research.     

Trachyspermum ammi L. (Carom) Oil Induces Alterations in SOD-3, GST-4 Expression and Prolongs Lifespan in Caenorhabditis elegans

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - The use of herbs in the form of dietary supplements and medicine is fascinating the world, owing to their...     

Immunological diseases of the pancreatico-hepatobiliary system: update on etiopathogenesis and cross-sectional imaging findings

Immunological diseases of the hepatobiliary system and the pancreas include a broad spectrum of disorders that manifest characteristic histopathology/serology and variable clinical features and imaging findings. Recent studies have thrown fresh light on the complex role of genetics and autoimmunity in the pathogenesis and natural history of these diverse disorders that include autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, IgG4-related cholangitis, overlap/outlier syndromes, and autoimmune pancreatitis.