Tissue needs for retinoids are believed to be satisfied through the delivery in the circulation of retinol by its specific plasma transport protein, retinol-binding protein (RBP), which circulates as a 1-to-1 protein complex with transthyretin (TTR). The binding of RBP to TTR is thought to prevent filtration of retinol-RBP in the kidney and to play a role in secretion of RBP from hepatocytes. Recently a strain of mice (TTR-) that totally lacks immunoreactive TTR was produced by targeted mutagenesis. We have explored the effects of TTR deficiency on retinol and RBP metabolism in this mutant strain. In pooled plasma from the TTR- mice retinol levels averaged 6% of those of wild type animals. Similarly, plasma RBP in the TTR- mice was found to be 5% of wild type levels. Hepatic retinol and retinyl ester levels were similar for mutant and wild type mice, suggesting that the mutation affects neither the uptake nor storage of dietary retinol. Levels of retinol and retinyl esters in testis, kidney, spleen, and eye cups from TTR- mice were normal. Plasma all-trans-retinoic acid levels for the TTR- mice were 2.3-fold higher than those of wild type (425 versus 190 ng/dl). Kidney RBP levels were similar for the mutant and wild type mice and we were unable to detect intact RBP in urine from TTR- mice. Hepatic RBP levels in the TTR- mice were 60% higher than those of wild type mice (39.8 versus 25.0 micrograms of RBP/g of tissue). These data may suggest that there is a partial blockage in RBP secretion from TTR- hepatocytes that leads to lessened plasma levels of retinol-RBP.

Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.

Abstract:Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, are a rich source of antioxidants. Boldine [(S)-2,9-dihydroxy-1,10-dimethoxy-aporphine], an aporphine alkaloid, is a potent antioxidant found in the leaves and bark of the Chilean boldo tree. Boldine has been extensively reported as a potent “natural” antioxidant and possesses several health-promoting properties like anti-inflammatory, antitumor promoting, antidiabetic, and cytoprotective. Boldine exhibited significant endothelial protective effect in animal models of hypertension and diabetes mellitus. In isolated thoracic aorta of spontaneously hypertensive rats, streptozotocin-induced diabetic rats, and db/db mice, repeated treatment of boldine significantly improved the attenuated acetylcholine-induced endothelium-dependent relaxations. The endothelial protective role of boldine correlated with increased nitric oxide levels and reduction of vascular reactive oxygen species via inhibition of the nicotinamide adenine dinucleotide phosphate oxidase subunits, p47phox and nicotinamide adenine dinucleotide phosphate oxidase 2, and angiotensin II–induced bone morphogenetic protein-4 oxidative stress cascade with downregulation of angiotensin II type 1 receptor and bone morphogenetic protein-4 expression. Taken together, it seems that boldine may exert protective effects on the endothelium via several mechanisms, including protecting nitric oxide from degradation by reactive oxygen species as in oxidative stress–related diseases. The present review supports a complimentary therapeutic role of the phytochemical, boldine, against endothelial dysfunctions associated with hypertension and diabetes mellitus by interfering with the oxidative stress–mediated signaling pathway.

Peptidylprolyl isomerase cyclophilins play critical roles in a variety of biological processes. Recent findings that cyclophilins are present at high levels in the CNS and that cyclosporin A may possess neuroprotective/neurotrophic effects have prompted us to search for nonimmunosuppressant small molecule cyclophilin ligands. To this end, we report the lead identification through "virtual screening" and the synthesis of our first series of non-peptidic cyclophilin ligands, along with the preliminary biological results.

Sodium nitrite (NaNO2) induces relaxation in isolated arteries partly through an endothelium-dependent mechanism involving NO-eNOS-sGC-cGMP pathway. The present study was designed to investigate the effect of chronic NaNO2 administration on arterial systolic blood pressure (SBP) and vascular function in hypertensive rats. NaNO2 (150 mg L−1) was given in drinking water for four weeks to spontaneously (SHR) and Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) treated hypertensive SD rats. Arterial SBP and vascular function in isolated aortae were studied. Total plasma nitrate/nitrite and vascular cyclic guanosine monophosphate (cGMP) levels were measured using commercially available assay kits. Vascular nitric oxide (NO) levels were evaluated by DAF-FM fluorescence while the proteins involved in endothelial nitric oxide synthase (eNOS) activation was determined by Western blotting. NaNO2 treatment reduced SBP, improved the impaired endothelium-dependent relaxation, increased plasma total nitrate/nitrite level and vascular tissue NO and cGMP levels in SHR. Furthermore, increased presence of phosphorylated eNOS and Hsp-90 was observed in NaNO2-treated SHR. The beneficial effect of nitrite treatment was not observed in L-NAME treated hypertensive SD rats. The present study provides evidence that chronic treatment of genetically hypertensive rats with NaNO2 improves endothelium-dependent relaxation in addition to its antihypertensive effect, partly through mechanisms involving activation of eNOS.