Ochratoxin A as a potential etiologic factor in endemic nephropathy: lessons from toxicity studies in rats.

Various reports suggest that chronic dietary exposure to ochratoxin A (OTA), a mycotoxin frequently detected in various food items may be linked to the pathogenesis of endemic nephropathy, a chronic tubulointerstitial kidney disease which occurs in geographically limited areas of the Balkan region. OTA is a potent nephrotoxin and renal carcinogen. However, the pathological lesions observed in kidneys of rats treated with OTA appear be rather different from the clinical and pathological characteristics of endemic nephropathy. Moreover, increasing evidence suggests that OTA does not bind to DNA but induces tumors by an epigenetic, thresholded mechanism. This implies that there is a dose below which no adverse health effects are expected to occur. Based on food consumption data and OTA serum concentrations, it appears that human exposure - even in areas with relatively high dietary exposure to OTA such as endemic villages - is several orders of magnitude below doses known to cause nephrotoxicity and tumor formation in laboratory animals. While it is undoubtedly important to encourage prevention of food contamination by OTA and other mycotoxins, these observations suggest that OTA is not likely to be an etiological factor involved in BEN and indicate a need to search for new clues for the etiology of this endemic kidney disease.     

Relevance of a rat model of papillary necrosis and upper urothelial carcinoma in understanding the role of ochratoxin A in Balkan endemic nephropathy and its associated carcinoma.

Ochratoxin A is nephrotoxic and has been implicated in the genesis of Balkan endemic nephropathy (BEN), a condition that leads to end-stage renal disease and upper urothelial tumours. This compound induces renal parenchymal carcinoma in male mice only, and is not considered to be a potent carcinogen nor is there experimental evidence of its propensity to cause upper urothelial carcinoma. There is, however, evidence that exposure to more than one mycotoxin may be an important factor in the clinical spectrum of BEN. Analgesic nephropathy is clinically different, but is also associated with an upper urothelial carcinoma. The combination of urothelial initiation and an acute papillary necrosis in rats produces upper urothelial carcinoma. This two-stage experimental model offers the potential to assess the role of ochratoxin A in BEN-associated upper urothelial carcinoma under experimental conditions.     

The transport of organic cations in the small intestine: Current knowledge and emerging concepts

A wide variety of drugs and endogenous bioactive amines are organic cations (OCs). Approximately 40% of all conventional drugs on the market are OCs. Thus, the transport of xenobiotics or endogenous OCs in the body has been a subject of considerable interest, since the discovery and cloning of a family of OC transporters, referred to as organic cation transporter (OCTs), and a new subfamily of OCTs, OCTNs, leading to the functional characterization of these transporters in various systems including oocytes and some cell lines. Organic cation transporters are critical in drug absorption, targeting, and disposition of a drug. In this review, the recent advances in the characterization of organic cation transporters and their distribution in the small intestine are discussed. The results of the in vitro transport studies of various OCs in the small intestine using techniques such as isolated brush-border membrane vesicles, Ussing chamber systems and Caco-2 cells are discussed, and in vivo knock-out animal studies are summarized. Such information is essential for predicting pharmacokinetics and pharmacodynamics and in the design and development of new cationic drugs. An understanding of the mechanisms that control the intestinal transport of OCs will clearly aid achieving desirable clinical outcomes.     

Coixlachryside B: a new benzoxazinoid glycoside from the roots of Coix lachryma-jobi var. ma-yuen (Gramineae)

Coix lachryma-jobi L. var. ma-yuen has been a source of food and traditional folk medicine in some parts of Asia for thousands of years; however, the roots of this plant have not been phytochemically investigated. Herein, we report the isolation of a new benzoxazinoid glycoside, coixlachryside B (1), along with ten known compounds (2–11), from the roots of C. lachryma-jobi var. ma-yuen using a variety of chromatographic methods. Among the known compounds, the absolute configuration of compound 4 was determined. The structures of all compounds were elucidated by interpreting NMR spectroscopic data, and experimental and calculated electronic circular dichroism spectra.     

Perspectives for the use of biotechnology in green chemistry applied to biopolymers,fuels and organic synthesis: from concepts to a critical point of view

Since the eighteenth century, after the first industrial revolution, humans have been exploiting the planet's natural resources in an unsustainable manner. This has caused some irreversible impacts on the environment. Because of this, we are facing a change of philosophy within the scientific community about chemical and industrial processes. During the 1990s, the concepts of green chemistry began to solidify, while in parallel some major advances in biotechnology were achieved through developments of genomic sciences and genetic and metabolic engineering. This work will discuss some new insights into the use of biotechnology as an important tool in green chemistry, showing new applications to biopolymers, biofuels and as a new alternative to traditional organic synthesis, making chemical processes more sustainable and less damaging to the planet.     

The role of CYP1A1/2 in cholesterol ester accumulation provides a new perspective for the treatment of hypercholesterolemia

Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases.CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout(KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-densi...     

Inhibition of protein denaturation by fatty acids, bile salts and other natural substances: a new hypothesis for the mechanism of action of fish oil in rheumatic diseases

Natural hydrophobic substances like bile salts (cholate, deoxycholate, chenodeoxycholate, lithocholate and their conjugates with glycine and taurine), fatty acids (caprylic, capric, lauric, myristic, palmitic, stearic, oleic, linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acid) were much more active (EC50 approximately 10(-4)-10(-5) M) than selected amino acids (EC50 > 10(-2) M) and inorganic salts (EC50 approximately 10(-1) M) in inhibiting heat-induced denaturation of human serum albumin in vitro. Fish oil, rich in n-3-polyunsaturated acids such as eicosapentaenoic acid and docosahexaenoic acid, administered p.o. (1 ml/kg) in the rat, protected ex vivo (after 2 hr) serum against heat-induced denaturation more than bendazac, a known antidenaturant drug. Thus, we speculated that the antidenaturant activity of fish oil may be partly (in addition to the known effect on endogenous eicosanoid composition) responsible for its beneficial effects in rheumatoid arthritis and other rheumatic conditions. In this connection, it is of note that the in vitro antidenaturant activity of fish oil fatty acids was higher than that of known antidenaturant drugs such as bendazac and bindarit and nonsteroidal anti-inflammatory drugs like phenylbutazone and indomethacin which could exert beneficial effects in chronic inflammatory conditions by stabilizing endogenous proteins.     

Interactions between enkephalin and dopamine in the control of locomotor activity in the rat: a new hypothesis

D-ala2-met5-enkephalinamide (DALA) was found to be without effect on motility when injected in doses from 10 to 40 micrograms. When ICV injection of DALA was combined with IP injection of amphetamine, DALA markedly enhanced the stimulatory effect of amphetamine. The effects of DALA + amphetamine could be partially antagonized by naloxone. The locomotion-reducing effect of the dopamine antagonist pimozide was not affected by concurrent administration of DALA. These data suggest a complex interaction between opiates and dopamine. It is suggested that the effects of DALA are best explained assuming that the opiate inhibits GABAergic neurotransmission.     

Disruption of sequential priming in organic and pharmacological amnesia: a role for the medial temporal lobes in implicit contextual learning.

We examined learning and expression of contextual implicit learning of a sequence of targets in a speeded target-detection task in amnesic and control participants. Amnesia was of organic origin in one participant group and induced psychopharmacologically (diazepam 7.5 or 15 mg) in another. Although the amnesic groups were able to learn the target sequence normally, their expression of sequence knowledge (priming) was attenuated when contextual support was limited. This was evaluated by studying response latencies for targets primed by between 0 and 5 preceding context locations. Whereas control participants showed priming when the current target location was primed by only two previous locations, priming was eliminated with two (but not four) previous locations by a low dose of diazepam and was eliminated even with four elements of context under a high dose of diazepam and in amnesia of organic origin. The results suggest that a function of the hippocampal memory system is to support contextual learning and performance, even when that learning is nondeclarative.     

Effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of organic cations (OCS): Selective inhibition of sinusoidal OCs uptake without influencing glucose uptake and canalicular OCs excretion

The effect of a new hepatoprotective agent, YH-439, on the hepatobiliary transport of a model organic cation (OC), TBuMA (tributylmethylammonium), was investigated. The area under the plasma concentration-time curve (AUC) from time zero to 4 h following iv administration of TBuMA (6.6 micromol/kg) was increased significantly when YH-439 in corn oil (300 mg/kg) was orally administered to rats 24 h prior to the experiment. Nevertheless, the cumulative biliary excretion of TBuMA remained unchanged. As a consequence, the apparent biliary clearance (CLb) of TBuMA was decreased significantly as a result of YH-439 pretreatment, consistent with the fact that the in vivo excretion clearance of TBuMA across the canalicular membrane (CLexc) was not changed by the pretreatment. The in vitro uptake of TBuMA into isolated hepatocytes was decreased by one half by the pretreatment, owing to a decrease in the apparent Vmax and CLlinear, but the Km for the process remained constant. Most interestingly, however, the sinusoidal uptake of glucose, a nutrient, into hepatocytes was not influenced by the pretreatment, suggesting the YH-439 pretreatment specifically impaired the sinusoidal uptake of OCs. Thus, the OC-specific inhibition of hepatic uptake, without influencing the uptake of glucose, a nutrient, appeared to be associated with the hepatoprotective activity of YH-439.     

Life (and death) in Pink: The dangerous rise of synthetic opioids in the new psychoactive substances panorama

Novel psychoactive substances represent a recent and unprecedented challenge in the global health panorama. Recently, among these, synthetic opioids are growing in number and prevalence of use, leaving behind them severe intoxications and victims, and fuelling the illicit drug market, particularly on the Dark Net. Further attention should be drawn to this alarming phenomenon, from both clinicians and policymakers.     

Postulated human sperm count decline may involve historic elimination of juvenile iodine deficiency: a new hypothesis with experimental evidence in the rat.

Human sperm count studies, historic dietary iodination, and an animal model where neonatal goitrogen administration causes unprecedented testis enlargement, together suggest an hypothesis relevant to the postulated fall in human sperm counts. We present the hypothesis with a supporting study extending the model to include iodine deficiency. In a one-generation rat reproduction study, dams were fed an iodine sufficient (control, 200 ppb I) or deficient (low iodine diet [LID], <20 ppb I) diet from prebreeding through weaning, when male offspring were divided into three groups: 1) controls from iodine sufficient dams, 2) neonatal LID (NLID) from the LID dams, fed control diet postweaning, and 3) chronic LID (CLID) from LID dams, fed a moderate LID (40 ppb I) postweaning. F1 males were euthanized on postnatal day (PND) 133+/-1. Each of the three diet groups comprised two subgroups in which testicular parameters were evaluated: 1) daily sperm production (DSP), sperm motility, morphology, and histopathology, and 2) Sertoli cell and round spermatid morphometry. In the first subgroup, NLID and CLID testes weights were 8.5% and 14.0% heavier than their unusually heavy controls (3.921 g; historical control mean approximately 3.5 g), with proportional DSP increases. Sperm motility, morphology, and testis histopathology were unaffected. In the morphometry subgroup, respective increases in NLID and CLID rats included testes weights (+28.6% and +20.3%), Sertoli cells (+24.8% and +23.9%), and round spermatids (+20.4% and +15.8%). The results indicate that neonatal iodine deficiency can significantly increase spermatogenic function in rats, and support our hypothesis concerning human sperm counts.     

Intracellular mechanisms mediating the inhibition of apoB-containing lipoprotein synthesis and secretion in HepG2 cells by avasimibe (CI-1011), a novel acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor

We have studied the cellular and molecular mechanisms involved in the suppression of apoB secretion from HepG2 cells following incubation with avasimibe (CI-1011), a novel inhibitor of acyl-coenzyme A: cholesterol acyltransferase (ACAT). Cellular lipid analysis revealed that avasimibe significantly decreased the synthesis of cholesterol and cholesteryl ester, and, at higher doses, of triglyceride. Time-course trypsin protection assays revealed that avasimibe induced the accumulation of translocationally arrested apoB intracellularly. Pulse-chase studies showed that the treatment with avasimibe induced a >75% decrease in apoB secretion relative to control, but initially enhanced the protein stability and cellular accumulation of apoB. Subcellular fractionation of microsomes further confirmed the accumulation of secretion-incompetent apoB-lipoproteins in the endoplasmic reticulum (ER) and Golgi compartments of avasimibe-treated HepG2 cells. Although incubation of drug-treated cells with carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a potent proteasome inhibitor, increased cellular apoB (70%), it failed to increase apoB secretion. Drug treatment induced an accumulation of secretion-incompetent apoB-containing lipoprotein particles, the majority of which demonstrated a density in a range similar to that of high-density lipoprotein. However, studies in permeabilized cells demonstrated that, at longer chase times, intracellularly accumulated apoB was eventually degraded, indicating that the inhibition of degradation may be transient. Oleate treatment of avasimibe-treated cells partially restored apoB secretion but not to the levels seen in control cells. In summary, we hypothesize that avasimibe acutely blocks the secretion of apoB and its associated lipoproteins from HepG2 cells, transiently enhancing its membrane association and cellular accumulation with eventual intracellular degradation of accumulated apoB.     

The role of organic anion‐transporting polypeptides and formulation in the clearance and distribution of a novel Nav1.7 channel blocker

PF‐06456384 is an extremely potent and selective blocker of the Na_v1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Na_v1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion‐transporting polypeptide mediated hepatic uptake and subsequent biliary excretion. However, the physicochemical properties of the i.v. lead matter were substantially different, moving from acidic, amphiphilic chemical space to zwitterions as well as substantially increasing molecular weight. This report describes the continued relevance of organic anion‐transporting polypeptide driven hepatic uptake in this physicochemical space and highlights an apparent impact of the formulation excipient Solutol on the clearance and distribution of PF‐06456384.     

The pitfalls of urine surveillance: the role of research in evaluation and remedy.

Millions of dollars and a great deal of staff time in methadone programs are spent on urine screening, but the difficulties inherent in such testing are rarely documented. An evaluation of the accuracy of the urine screening procedure used for a methadone maintenance clinic revealed the unusually high danger of inaccuracy in laboratory results. Feedback of this information to the laboratory resulted in significant decrease in the frequency of erroneous reports. Two subsequent evaluations were carried out, each leading to improved precision and accuracy in the reports received subsequently. The importance of this improvement in the level of accuracy of the reports to the operation of the clinic are discussed.     

The health encounter as a treatable moment for homeless substance-using adults: the role of homelessness, health seeking behavior, readiness for behavior change and motivation for treatment

Substance-using homeless persons frequent emergency departments and hospitals often. However, little is known about how homelessness affects when they seek care and their motivation for substance abuse treatment (SAT). We surveyed homeless (N=266) and non-homeless (N=104) substance-using adults sequentially admitted to an urban hospital medicine service, comparing demographics, readiness for change (URICA), and motivating reasons for SAT. Homeless respondents were more likely to be younger, uninsured, have hepatitis B/C, and <12th grade education. The majority in both groups were in either a precontemplative or contemplative stage of change, although more homeless respondents were in an action stage. They also had similar motivating reasons for wanting SAT, although being homeless was an additional motivator for the majority of homeless respondents. Almost half reported that being homeless caused them to delay seeking health care; paradoxically those citing physical health as a SAT motivator were 3.4 times more likely to have delayed care. While acutely ill homeless persons were at least as motivated for SAT, these data suggest the challenge is getting them to care in a timely manner and tailoring interventions during the care episode to avail of this motivation.     

The role of acetaldehyde outside ethanol metabolism in the carcinogenicity of alcoholic beverages: Evidence from a large chemical survey

Acetaldehyde is a volatile compound naturally found in alcoholic beverages, and it is regarded as possibly being carcinogenic to humans (IARC Group 2B). Acetaldehyde formed during ethanol metabolism is generally considered as a source of carcinogenicity in alcoholic beverages. However, no systematic data is available about its occurrence in alcoholic beverages and the carcinogenic potential of human exposure to this directly ingested form of acetaldehyde outside ethanol metabolism. In this study, we have analysed and evaluated a large sample collective of different alcoholic beverages (n=1,555). Beer (9+/-7 mg/l, range 0-63 mg/l) had significantly lower acetaldehyde contents than wine (34+/-34 mg/l, range 0-211 mg/l), or spirits (66+/-101 mg/l, range 0-1,159 mg/l). The highest acetaldehyde concentrations were generally found in fortified wines (118+/-120 mg/l, range 12-800 mg/l). Assuming an equal distribution between the beverage and saliva, the residual acetaldehyde concentrations in the saliva after swallowing could be on average 195 microM for beer, 734 microM for wine, 1,387 microM for spirits, or 2,417 microM for fortified wine, which are above levels previously regarded as potentially carcinogenic. Further research is needed to confirm the carcinogenic potential of directly ingested acetaldehyde. Until then, some possible preliminary interventions include the reduction of acetaldehyde in the beverages by improvement in production technology or the use of acetaldehyde binding additives. A re-evaluation of the 'generally recognized as safe' status of acetaldehyde is also required, which does not appear to be in agreement with its toxicity and carcinogenicity.