Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

Bile acids (BAs) are amphipathic sterols primarily synthesized from cholesterol in the liver and released in the intestinal lumen upon food intake. BAs play important roles in micellination of dietary lipids, stimulating bile flow, promoting biliary phospholipid secretion, and regulating cholesterol synthesis and elimination. Emerging evidence, however, suggests that, aside from their conventional biological function, BAs are also important signaling molecules and therapeutic tools. In the last decade, the therapeutic applications of BAs in the treatment of ocular diseases have gained great interest. Despite the identification of BA synthesis, metabolism, and recycling in ocular tissues, much remains unknown with regards to their biological significance in the eye. Additionally, as gut microbiota directly affects the quality of circulating BAs, their analysis could derive important information on changes occurring in this microenvironment. This review aims at providing an overview of BA metabolism and biological function with a focus on their potential therapeutic and diagnostic use for retinal diseases.

Discovery of a redox-thiol switch regulating cellular energy metabolism

Previously, we reported that increased synthesis of the gas hydrogen sulfide (H2S) during the Integrated Stress Response (ISR) induced proteome-wide cysteine-sulfhydration with the predominant modified pathway being enzymes of cellular energy metabolism (Gao, et al. 2015). Using pancreatic beta cells and quantitative proteomics in this study, we identified a Redox Thiol Switch from S-glutathionylation to S-sulfhydration and we named it, RTSGS. About half of the identified proteins are involved in energy metabolism, and one novel target was the mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) whose catalytic Cys306was targeted by both modifications. The enzymatic activity of PCK2 was inhibited by S-glutathionylation, and this inhibition was largely reversed by S-sulfhydration. S-sulfhydration also reversed the S-glutathionylation-mediated inhibition of glucose flux, indicating a broad metabolic significance. We propose that a Redox Thiol Switch from S-glutathionylation to S-sulfhydration is a key mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.

Effect of Fluridone on Some Physiological and Qualitative Features of Ripening Tomato Fruit

In tomato fruits, chlorophyll, lycopene and ß-carotene are mostly responsible for the color. During ripening of tomato fruits, the color of the pericarp changes from green to red as chlorophyll is degraded and carotenoids accumulate. These changes are associated with an increase in respiration and ethylene production. Carotenoid biosynthesis pathway in plants can be disturbed by herbicide fluridone (1-methyl-3-phenyl-5-[3-trifluoromethyl(phenyl)]- 4(1H)-pyridinone), which inhibits the activity of phytoene desaturase, an enzyme responsible for conversion of phytoene to phytofluene. Fluridone is also used as an inhibitor of biosynthesis of abscisic acid (ABA) and strigolactones, and it reduces chlorophyll production in plants. In our research we studied the effect of fluridone on some physiological parameters, such as color, firmness, ethylene production, lycopene and chlorophyll content during ripening of the tomato fruit. Tomato plants cv. Altadena (Syngenta) were cultivated in a greenhouse in controlled temperature and both immature and mature fruits were used for the experiments, performed between August and November 2016. Fluridone at concentrations of 0.1% and 1.0% in lanolin paste was applied as a 2-3 mm stripe from the top to the base of tomato fruits, and as a control a stripe of lanolin was applied in the same way on the opposite side of the fruits. Fluridone at a concentration of 1.0% greatly inhibited lycopene accumulation in the pericarp of tomato fruits from the treated side. The measurements of fruit firmness have shown no significant differences between firmness of the part of the tomato fruits treated with fluridone, and the non-treated ones. Tomato fruits treated with fluridone produced amounts of ethylene similar to those found in control tissues on the opposite side of the same fruit. Fluridone delayed chlorophyll degradation in tomato fruits. The metabolic significance of these findings is discussed with the role of carotenogenesis inhibition in tomato fruit ripening.

Compounds from Terminalia mantaly L. (Combretaceae) Stem Bark Exhibit Potent Inhibition against some Pathogenic Yeasts and Enzymes of Metabolic Significance

The chemical investigation of the anti-yeast methanol extract from the stem bark of Terminalia mantaly led to the isolation of seven compounds: 3-O-methyl-4-O-α-rhamnopyranoside ellagic acid (1), 3-O-mehylellagic acid (2), arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid (3), arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside (4), 2α,3α,24-trihydroxyolean-11,13(18)-dien-28-oïc acid (5), stigmasterol (6), stigmasterol 3-O-β-D-glucopyranoside (7). Their structures were established by means of spectroscopic analysis and comparison with published data. Compounds 1-5 were tested in vitro for activity against three pathogenic yeast isolates, Candida albicans, Candida parapsilosis and Candida krusei. The activity of compounds 1, 2 and 4 were comparable to that of the reference compound fluconazole (MIC values below 32 µg/ml) against the three tested yeast isolates. They were also tested for inhibitory properties against four enzymes of metabolic significance: Glucose-6-Phosphate Deshydrogenase (G6PD), human erythrocyte Carbonic anhydrase I and II (hCA I and hCA II), Glutathione S-transferase (GST). Compound 4 showed highly potent inhibitory property against the four tested enzymes with overall IC50 values below 4 µM and inhibitory constant (Ki) <3 µM.

MECHANISMS IN ENDOCRINOLOGY: Brown adipose tissue in humans: regulation and metabolic significance

The recent discovery that functional brown adipose tissue (BAT) persists in adult humans has enkindled a renaissance in metabolic research, with a view of harnessing its thermogenic capacity to combat obesity. This review focuses on the advances in the regulation and the metabolic significance of BAT in humans. BAT activity in humans is stimulated by cold exposure and by several factors such as diet and metabolic hormones. BAT function is regulated at two levels: an acute process involving the stimulation of the intrinsic thermogenic activity of brown adipocytes and a chronic process of growth involving the proliferation of pre-existing brown adipocytes or differentiation to brown adipocytes of adipocytes from specific white adipose tissue depots. BAT activity is reduced in the obese, and its stimulation by cold exposure increases insulin sensitivity and reduces body fat. These observations provide strong evidence that BAT plays a significant role in energy balance in humans and has the potential to be harnessed as a therapeutic target for the management of obesity.