The Modulation of Phase II Drug-Metabolizing Enzymes in Proliferating and Differentiated CaCo-2 Cells by Hop-Derived Prenylflavonoids.

Prenylflavonoids in the human organism exhibit various health-beneficial activities, although they may interfere with drugs via the modulation of the expression and/or activity of drug-metabolizing enzymes. As intestinal cells are exposed to the highest concentrations of prenylflavonoids, we decided to study the cytotoxicity and modulatory effects of the four main hop-derived prenylflavonoids on the activities and mRNA expression of the main drug-conjugating enzymes in human CaCo-2 cells. Proliferating CaCo-2 cells were used for these purposes as a model of colorectal cancer cells, and differentiated CaCo-2 cells were used as an enterocyte-like model. All the tested prenylflavonoids inhibited the CaCo-2 cells proliferation, with xanthohumol proving the most effective (IC50 8.5 µM). The prenylflavonoids modulated the activities and expressions of the studied enzymes to a greater extent in the differentiated, as opposed to the proliferating, CaCo-2 cells. In the differentiated cells, all the prenylflavonoids caused a marked increase in glutathione S-transferase and catechol-O-methyltransferase activities, while the activity of sulfotransferase was significantly inhibited. Moreover, the prenylflavonoids upregulated the mRNA expression of uridine diphosphate (UDP)-glucuronosyl transferase 1A6 and downregulated that of glutathione S-transferase 1A1/2.

Structure Elucidation of Prenyl- and Geranyl-Substituted Coumarins in Gerbera piloselloides by NMR Spectroscopy, Electronic Circular Dichroism Calculations, and Single Crystal X-ray Crystallography.

Crude ethyl acetate extract of Gerbera piloselloides (L.) Cass. was investigated by dual high-resolution PTP1B/α-glucosidase inhibition profiling and LC-PDA-HRMS. This indicated the presence of a series of unprecedented prenyl- and geranyl-substituted coumarin derivatives correlated with both α-glucosidase and PTP1B inhibitory activity. Repeated chromatographic separation targeting these compounds led to the isolation of 13 new compounds, of which ten could be isolated as both enantiomers after chiral separation. The structures of all isolated compounds were characterized by HRMS and extensive 1D and 2D NMR analysis. The absolute configurations of the isolated compounds were determined by comparison of experimental and calculated electronic circular dichroism spectra. Compound 6 features a rare furan-oxepane 5/7 ring system, possibly formed through addition of a geranyl unit to C-3 of 5-methylcoumarin, representing a new type of geranyl-substituted coumarin skeleton. Compounds 19 and 24 are the first examples of dimeric natural products consisting of both coumarin and chromone moieties.

Permanent Pancreatic Duct Occlusion With Neoprene-based Glue Injection After Pancreatoduodenectomy at High Risk of Pancreatic Fistula: A Prospective Clinical Study.

OBJECTIVE: The aim of this study was to assess safety and efficacy of pancreatic duct occlusion (PDO) with neoprene-based glue in selected patients undergoing pancreatoduodenectomy (PD) at high risk of postoperative pancreatic fistula (POPF). BACKGROUND DATA: PD is the reference standard approach for tumors of the pancreaticoduodenal region. POPF is the most relevant complication after PD. PDO has been proposed as an alternative to anastomosis to manage the pancreatic stump. METHODS: A single-center, prospective, nonrandomized trial enrolled 100 consecutive PD for cancer. Patients at high risk for POPF according to Fistula Risk Score (FRS) >15% (≥6 points) were treated with PDO using neoprene glue (study cohort); patients with FRS ≤15% (≤5 points) received pancreaticojejunal anastomosis (PJA: control cohort). Primary endpoint was complication rate grade ≥3 according to Dindo-Clavien Classification (DCC). Other postoperative outcomes were monitored (ClinicalTrials.gov NCT03738787). RESULTS: Fifty-one patients underwent PDO and 49 PJA. DCC ≥3, postoperative mortality, and POPF grade B-C were 25.5% versus 24.5% (P = 0.91), 5.9% versus 2% (P = 0.62), and 11.8% versus 16.3% (P = 0.51) in the study versus control cohort, respectively. At 1 and 3 years, new-onset diabetes was diagnosed in 13.7% and 36.7% of the study cohort versu 4.2% and 12.2% in controls (P = 0.007). CONCLUSIONS: PDO with neoprene-based glue is a safe technique that equalizes early outcome of selected patients at high risk of POPF to those at low risk undergoing PJA. Neoprene-based PDO, however, triples the risk of diabetes at 1 and 3 years.

The antioxidant activity of a prenyl flavonoid alters its antifungal toxicity on Candida albicans biofilms.

The antioxidant effect of 8PP, a prenylflavonoid from Dalea elegans on Candida albicans biofilms, was investigated. We previously reported that sensitive (SCa) and resistant C. albicans (RCa) biofilms were strongly inhibited by this compound, in a dose-depending manner (50 µM-100 µM), with a prooxidant effect leading to accumulation of endogenous oxidative metabolites and increased antioxidant defenses. In this work, the antifungal activity of high concentrations of 8PP (200-1000 µM), the cellular stress imbalance and the architecture of biofilms were evaluated. Biofilms were studied by crystal violet and confocal scanning laser microscopy (CSLM) with COMSTAT analysis. Superoxide anion radical, the activity of the superoxide dismutase and the total antioxidant capacity were measured. Intracellular ROS were detected by a DCFH-DA and visualized by CSLM; reactive nitrogen intermediates by Griess. An antioxidant effect was detected at 1000 µM and levels of oxidant metabolites remained low, with major changes in the SCa. COMSTAT analysis showed that biofilms treated with higher concentrations exhibited different diffusion distances with altered topographic surface architectures, voids, channels and pores that could change the flow inside the matrix of biofilms. We demonstrate for first time, a concentration-dependent antioxidant action of 8PP, which can alter its antifungal activity on biofilms.

A randomized-clinical trial examining a neoprene abdominal binder in gynecologic surgery patients.

PURPOSE OF INVESTIGATION: Pain control and early ambulation are two important postoperative goals. Strategies that decrease morphine use while increasing ambulation have the potential to decrease postoperative complications. In this study the authors sought to determine the effect of an abdominopelvic binder on postoperative morphine use, pain, and ambulation in the first day after surgery. MATERIALS AND METHODS: The authors randomly assigned 75 patients undergoing abdominal gynecologic surgery to either binder or not after surgery. Demographic data and surgical characteristics were collected. Outcome variables included morphine use, pain score, time to ambulation, and number of ambulations. RESULTS: A group at high risk for decreased mobility was identified and the binder increased the number of ambulatory events by 300%, 260%, and 240% in patients with vertical incisions, age over 50 years, and complex surgeries, respectively. Morphine use and pain scores were not significantly different. CONCLUSION: The binder increased ambulations in the subset of patients at the highest risk for postoperative complications: elderly, cancer patients, and vertical incisions. Routine use of the binder may benefit particularly high-risk gynecologic surgical patients.

Anatomy of the foot venous pump: physiology and influence on chronic venous disease.

The aim of this paper is to demonstrate the location of the venous foot pump using an anatomical study. Four hundred cadaveric feet were injected with green neoprene latex followed by a dissection. A coloured segmentation of the venous system was achieved. The Lejars' concept of the venous sole of the foot is incorrect: the true blood venous reservoir of the foot is located deeply in the plantar veins, between the plantar muscles. The medial and mostly lateral plantar veins converge into the plexus shaped calcaneal crossroad, where the blood is ejected upwards into the two posterior tibial veins. In addition, the several medial perforators of the foot directly connect the deep system (medial plantar veins) to the superficial venous system (medial marginal vein). This forms a true 'medial functional unit' which is unique in the limb given its directional flow is from deep to superficial. In conclusion, the plantar veins play an important role in the physiology of the venous return since a venous reservoir of 25 mL of blood is mobilized upwards with each step during walking. Therefore, the impairment of the foot pump by a static foot disorder should be considered as an important risk factor for chronic venous disease, and should be evaluated and corrected in any patient with venous insufficiency.

Chemical constituents of malagasy liverworts, part V: prenyl bibenzyls and clerodane diterpenoids with nitric oxide inhibitory activity from Radula appressa and Thysananthus spathulistipus.

3Beta,4beta:15,16-diepoxy-13(16),14-clerodadiene (1) and a new clerodane diterpenoid designated thysaspathone (2) were isolated from the liverwort Thysananthus spathulistipus, while Radula appressa produced radulannin A (3), radulannin L (4), 2-geranyl-3,5-dihydroxybibenzyl (5), 2(S)-2-methyl-2-(4-methyl-3-pentenyl)-7-hydroxy-5-(2-phenylethyl) chromene (o-cannabichromene) (6), 6-hydroxy-4-(2-phenylethyl) benzofuran (7), and o-cannabicyclol (8). All of the isolated compounds inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the greatest inhibition was attributed to compound 5, with an IC50 value of 4.5 microM.

Prenylflavones from Psoralea corylifolia inhibit nitric oxide synthase expression through the inhibition of I-kappaB-alpha degradation in activated microglial cells.

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) switches the function of NO from a physiological neuromodulator to a neurotoxic effector in central nervous system (CNS) after brain injury. From the methanol extracts of Psoralea corylifolia, we purified two inhibitors of NO production in lipopolysaccharide (LPS)-activated microglia by activity guided purification along with two inactive compounds. The active compounds were identified as a chromenoflavanone [7,8-dihydro-8-(4-hydroxyphenyl)-2,2-dimethyl-2H,6H-benzo-(1,2-b:5,4-b')dipyran-6-one] (1) and 4-hydroxylonchocarpin (2). And the inactive two compounds were identified as bavachinin (3) and bavachalcone (4) by spectral analysis. The compound 2 was isolated first time from this plant. Compounds 1 and 2 inhibited the production of NO in LPS-activated microglia in a dose dependent manner (IC(50)'s were 11.4, 10.2 microM, respectively). They also suppressed the expression of protein and mRNA of iNOS in LPS-activated microglial cells at 10 muM as observed in Western blot analysis and RT-PCR experiment. Furthermore they inhibited the degradation of I-kappaB-alpha in activated microglia. These results imply that compounds 1 and 2 can be lead compounds for the development of neuroprotective drug with the inhibitory activity of NO overproduction by activated microglial cells.

Artelastocarpin and carpelastofuran, two new flavones, and cytotoxicities of prenyl flavonoids from Artocarpus elasticus against three cancer cell lines.

Further study of one of the fractions from the wood of Artocarpus elasticus furnished two new prenylated flavonoids artelastocarpin and carpelastofuran as well as ethyl 2,4-dihydroxybenzoate. The two flavonoids and the prenylated flavonoids artelastin, artelastochromene, artelasticin, artocarpesin, and cyclocommunin isolated earlier from this species were tested for cytotoxicity in vitro against three human cell lines. All seven flavonoids were active, the cytotoxic effect varying from strong to moderate and with artelastin showing the most potent activity.

1,1-Dimethylallylcoumarins potently suppress both lipopolysaccharide- and interferon-gamma-induced nitric oxide generation in mouse macrophage RAW 264.7 cells.

We investigated the suppressive effects of 16 coumarin-related compounds on both lipopolysaccharide (LPS)- and interferon (IFN)-gamma-induced nitric oxide (NO) generation in a mouse macrophage cell line, RAW 264.7. Notably, coumarins possessing prenyl unit(s) were found to be highly active, a tendency consistent with our previous study. Among the coumarins tested, 1,1-dimethylallylcoumarins showed the highest inhibitory activity. Western blotting analysis revealed that they inhibited NO generation by suppressing inducible NO synthase (iNOS) protein expression. Our ongoing studies suggest that coumarins are prominent natural compounds that attenuate excessive and prolonged NO generation at inflammatory sites.

In vivo and in vitro testing of gloves for protection against UV-curable acrylate resin systems.

In vitro data demonstrated that the permeation of a UV-curable urethane acrylate resin system through glove materials was greatest for latex and neoprene gloves and less for two nitrile gloves. Permeation in vitro for the resin system took longer than 480 min. Individual components of the resin permeated faster when tested separately than when in the formulated system. In vivo 48-h patch test data suggested that neither nitrile glove would be adequate for worker protection, but the in vivo test exaggerated the duration of contact between resin, glove, and skin. Both nitrile gloves provide adequate protection under use conditions, provided the gloves were not re-used within 8 h.

The effect of duct obliteration on the histology and endocrine function of the canine pancreas.

Although duct obliteration is a safe and effective method for ablation of exocrine secretion in segmental pancreas transplantation, it remains to be clarified whether its effects are restricted to the exocrine tissue. In 20 dogs (beagles 9-15 kg) the right lobe of the pancreas was removed and the ductal system of the left lobe was injected with the duct-obliterants neoprene (6 dogs), polyisoprene (6 dogs), or prolamine (8 dogs). In this study, i.v. glucose tolerance tests (the results of which are expressed in K values) and relaparotomies for taking biopsies were performed at 1, 3, and 12 months after duct obliteration. Biopsies were studied histologically and immunohistochemically in a qualitative and semiquantitative fashion. Three prolamine-injected dogs developed diabetes. All other dogs maintained normal fasting blood glucose levels but showed reduced K values at 1 month after duct obliteration. Further deterioration of glucose tolerance was not observed up to 12 months. Differences in K values depending on the type of obliterant were insignificant at all intervals. The exocrine tissue was completely replaced by fibrosis at 3 months after duct obliteration, and the architecture of the islets was disrupted. Morphometrical analysis of relative numbers of different endocrine cell types showed transient changes at 1 month after duct obliteration, but did not differ from unmodified controls at 12 months. We conclude that the effects of duct obliteration are not restricted to the exocrine pancreatic tissue, but that the endocrine pancreas is interfered with as well. Changes in islet function and histology are brought about during the first month after duct obliteration and stabilize thereafter.

Chemical protective clothing: a comparison of chemical permeation test cells and direct-reading instruments.

Chemical permeation of acetone through unsupported Neoprene using the ASTM cell and another commercially-available, but smaller, test cell was compared. Also, different portable direct-reading instruments were used to determine breakthrough time and steady-state permeation. The breakthrough times between the two permeation cells and among different portable direct-reading instruments were not statistically different. However, steady-state permeation rates between the two cells using the same direct-reading instrument were statistically different. Chemical permeation test methods suitable for field evaluation of chemical protective clothing are discussed.

Pathology of the pancreas after intraductal neoprene injection in dogs and diabetic patients treated by pancreatic transplantation.

The injection of neoprene into the pancreatic ducts of dogs has been used to destroy exocrine function prior to pancreatic transplantation. The subsequent histological changes and the evolution of lesions over a period of 3-36 months are described. Animals were sacrificed or biopsied at various intervals (3, 15 and 36 months) and the pancreases showed the disappearance of exocrine acini and changes of chronic pancreatitis. An immunoperoxidase procedure with insulin, glucagon, somatostatin and pancreatic polypeptide antisera was used to show the persistence of pancreatic endocrine cells. After the injections, sclerosis progressively increased and secondary lesions of the islets were seen, although functional islets persisted. This technique was then applied to pancreas transplantation in man. Eight transplants from seven diabetic patients were available for examination. In four cases, there were early technical failures, but four pancreatic transplants continued to function for 28-889 days until suppuration destroyed one of the grafts and the three other patients died. The persistence of endocrine cells in sclerotic tissue was observed in histological and immunopathological examinations.

[A new method of pancreatic transplantation. 1 - Effects on the dog pancreas of the intraduct injection of neoprene (author's transl)]. / Une nouvelle méthode de transplantation pancréatique. I. Effet sur le pancréas du chien de l'injection intracanalaire de néoprène.

Injection into the pancreatic ducts of a synthetic liquid gum (neoprene), which polymerises when it comes into contact with the fluid secreted by the gland, would appear to be a simple and effective means of suppressing exocrine secretion of the pancreas in the dog. Endocrine secretion was remained in the short and mid-term. The therapeutic implications of this new technique in the preparation of pancreatic transplants are discussed.