Bisphenol A exacerbates anxiety-like behavior and neuroinflammation in prefrontal cortex of adult obese mice.

AIMS: Bisphenol A (BPA) is an endocrine-disrupting chemical inducing several damages such as neurotoxicity, immunotoxicity, and metabolic disorders. Obesity is the main risk factor for the increased occurrence of metabolic alterations as well as mood disorders. Here, we investigated in obese mice the effects of BPA on anxiety-like behavior, associated with neuroinflammation and immune activation. MAIN METHODS: Male C57Bl/6J mice were divided into 4 groups: control group (STD) receiving chow diet and BPA vehicle; STD group treated with BPA (50 µg/kg/die); high-fat diet (HFD) group receiving BPA vehicle; HFD group treated with BPA. BPA treatment started 12 weeks after HFD feeding and lasted 3 weeks. KEY FINDINGS: The open field and elevated plus-maze tests showed in HFD + BPA group the worsening of HFD-induced anxiety-like behavior. The anxiogenic effects of BPA also emerged from hyperactivation of the hypothalamus-pituitary-adrenal gland axis, determined by the increased transcription of Crh and its receptor in the prefrontal cortex (PFC). Furthermore, BPA activated NLRP3 inflammasome and exacerbated the neuroinflammation induced by HFD, increasing IL-1ß, TNF-α and monocyte chemoattractant protein (MCP)-1 in PFC. Furthermore, it induced inflammation and monocyte recruitment in hypothalamus and amygdala. Contextually, BPA significantly amplified the immune activation caused by lipid overload as evidenced by the increased expression of TLR-4 and MCP-1 in the PFC and triggered mastocytosis in the hypothalamus rather than STD mice. SIGNIFICANCE: All these data show that sub-chronic BPA exposure represents an additional risk factor for mood disorders strictly related to obesity, enhancing neuroinflammation and immune activation triggered by HFD feeding.

Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: a randomized clinical trial.

BACKGROUND AND AIMS: In patients with chronic kidney disease (CKD), alterations in gut microbiome are posited to be responsible for gastrointestinal symptoms and generation of p-cresol, a uremic toxin that has been associated with CKD progression and cardiovascular mortality. This pilot study investigated whether Probinul-neutro®, a synbiotic that normalizes intestinal microflora, may lower plasma p-cresol concentrations and reduce gastrointestinal symptoms in non-dialyzed CKD patients. METHODS AND RESULTS: This was a double-blind, randomized placebo-controlled trial. Thirty patients on 3-4 CKD stages were randomized to receive either Probinul neutro® or placebo for 4 weeks. Total plasma p-cresol concentration was assessed at baseline, and 15 and 30 days after treatment start. At the same study times, ease and frequency of defecation, upper and lower abdominal pain, stool shape, borborygmi, and flatus were quantified by subjective assessment questionnaires. Compared to baseline total plasma p-cresol median concentrations on 15th and 30th day were significantly lower in patients receiving Probinul-neutro® (2.31 and 0.78 vs. 3.05 µg/ml, p < 0.05; n = 18); no changes of plasma p-cresol concentrations were recorded in placebo-treated patients. No significant changes in gastrointestinal symptoms were observed during the study both in Probinul-neutro®-treated and placebo-treated patients. CONCLUSION: Probinul-neutro® lowered total plasma p-cresol concentrations but did not ameliorate gastrointestinal symptoms in non-dialyzed CKD patients. Because high plasma concentrations of p-cresol in early phases of CKD are predictive of progression to end-stage renal disease, the results of our study suggest that synbiotics deserve attention as possible tools to delay CKD progression towards end-stage renal disease (ESRD). CLINICALTRIALSGOV IDENTIFIER: NCT02008331.

Prediction of drug-membrane interactions by IAM-HPLC: effects of different phospholipid stationary phases on the partition of bases.

The chromatographic capacity factors of 39 neutral and basic compounds were measured on an immobilized artificial membrane-phosphatidylcholine-drug discovery (IAM-PC-DD) HPLC column, and the values compared with both octanol/water partition coefficients and capacity factors previously obtained on an IAM-PC-MG column. These two columns differ in their lipidic phase, since the IAM-PC-MG phase is made of phosphatidylcholine as found in biomembranes, whereas the glycerol linker is absent in the IAM-PC-DD phase. We found that the two phases interact differently with basic compounds at different degrees of ionization. On the IAM-PC-MG column, ionized compounds are as strongly or more strongly retained than isolipophilic neutral compounds. In contrast, their retention on the IAM-PC-DD column is less strong than, or at most as strong as, that of isolipophilic neutral compounds. The IAM-PC-MG data appear as better predictors of the interactions between drugs and biological membranes. Indeed, they correlate better than the IAM-PC-DD data with partitioning in both biological membrane and liposomes; moreover, they are better correlated with biological activities from the literature. These results suggest that even modest modifications in the structure of IAM phospholipids can have a major effect on the retention of basic compounds. We conclude that an acceptable IAM-HPLC estimate of the interactions between biomembranes and basic compounds should rely on stationary phases that reproduce the structure of natural phospholipids.

Non-specific currents at fertilisation in sea urchin oocytes.

Using the whole-cell voltage-clamp technique to clamp sea urchin oocytes we show that the fertilising spermatozoon triggers an inward current of -521 +/- 56.7 pA (n = 8) at activation. Simultaneously, the plasma membrane depolarises and the conductance increases from 23.4 +/- 1.4 to 40.6 +/- 1.2 nS (n = 8). The I/V curve for the peak activation current is linear and the current reverses between 0 and +20 mV, suggesting a non-specific ion current. Since injection of inositol triphosphate induced an inward current of -1062 +/- 314 pA (n = 4), and the current was inhibited by preloading oocytes with the calcium chelator BAPTA, the non-specific activation current in sea urchin appears to be calcium dependent.

Nitric oxide gates fertilization channels in ascidian oocytes through nicotinamide nucleotide metabolism.

In this paper we use the nitric oxide (NO) donor sodium nitroprusside to examine the response of the unfertilised oocyte of the ascidian Ciona intestinalis to nitric oxide. We show that the release of NO triggers an inward current that displays similar properties to the ascidian fertilisation current. Furthermore, the production of NO causes the release of intracellular calcium through a ruthenium-red sensitive mechanism. Our data suggest that these effects are due to the stimulation of nicotinamide nucleotide metabolism, but the active second messenger is not cyclic adenosine diphosphate ribose (cADPr). Finally, we show that NO production increases at fertilisation. The results suggest that ascidian sperm trigger the release of NO and this second messenger causes the breakdown of nicotinamide nucleotides leading to the production of a second messenger which induces the fertilisation current and may assist in the production of the increase in calcium.

Analysis of calcium channel blocking dihydropyridines and their degradation products by gas chromatography.

Seven dihydropyridine calcium blockers have been analyzed by GC. Simultaneous analysis has been performed both by an isothermal and a gradient method. Moreover, the proposed methods have been performed on the analysis of daylight exposed methanolic solutions of considered compounds; the ability of the systems in separate original compounds from daylight degradation products has been studied. The GC-MC spectra of photodegradation products are discussed.

Mechanism of action of indomethacin in tubular defects.

Indomethacin, a potent prostaglandin synthesis inhibitor, has been proven to be effective in a number of tubular defects characterized by enhanced prostaglandin (namely, prostaglandin E2 (PGE2) production, but its mechanism of action is poorly understood. To elucidate further the mechanism(s) by which indomethacin reverses the abnormal tubular functions, five children with different tubular defects (nephrogenic diabetes insipidus, three cases; Fanconi syndrome, one case; and pseudohypoaldosteronism, one case) were treated with indomethacin. Indomethacin, 1 mg/kg every eight hours, was given for 1 week to all children and then was given chronically to four of the children who responded to the drug. Its use was suspended in a 10 year-old-boy with nephrogenic diabetes insipidus because it proved ineffective. To assess the site along the nephron where indomethacin affects the solute and water excretion, an acute water load study was performed in three responsive children before and during the treatment. Indomethacin did not significantly alter the glomerular filtration rate but was effective in reducing diuresis and levels of urinary sodium and potassium excretion. In the child with Fanconi syndrome, indomethacin was also effective in controlling the urinary loss of phosphate, urate, glucose, and bicarbonate. Results of the water load studies show that indomethacin decreases the delivery of solute from the proximal tubule, reduces the fractional free water clearance, and increases the urine-plasma osmolar ratio.(ABSTRACT TRUNCATED AT 250 WORDS)