Long-Term Stabilization Effects of Leptin on Brain Functions in a Leptin-Deficient Patient

Context

Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy. In a previous study, we were able to show changes in homeostatic (hypothalamus) and reward-related brain areas (striatum, orbitofrontal cortex (OFC), substantia nigra/ventral tegmental area, amygdala) 3 days and 6 months after therapy start in a leptin-deficient adolescent girl. To further access the time course of functional brain activation changes, we followed the patient for 2 years after initiation of the therapy.

Design, Patient

Functional magnetic resonance imaging during visual stimulation with food (high- and low-caloric) and non-food pictures was performed 1 and 2 years after therapy start in the previously described patient.

Results

The comparison of ‘food vs. non-food’ pictures showed a stabilization of the long-term effects in the amygdala and in the OFC. Therefore, no significant differences were observed between 6 months compared to 12 and 24 months in these regions. Additionally, a reduction of the frontopolar cortex activity over the whole time span was observed. For the comparison of high- and low-caloric pictures, long-term effects in the hypothalamus showed an assimilating pattern for the response to the food categories whereas only acute effects after 3 months were observed in hedonic brain regions.

Conclusion

This follow-up study shows that the long lasting benefit of metreleptin therapy is also associated with activation changes in homeostatic, hedonic and frontal control regions in congenital leptin deficiency.     

Studying Food Reward and Motivation in Humans

A key challenge in studying reward processing in humans is to go beyond subjective self-report measures and quantify different aspects of reward such as hedonics, motivation, and goal value in more objective ways. This is particularly relevant for the understanding of overeating and obesity as well as their potential treatments. In this paper are described a set of measures of food-related motivation using handgrip force as a motivational measure. These methods can be used to examine changes in food related motivation with metabolic (satiety) and pharmacological manipulations and can be used to evaluate interventions targeted at overeating and obesity. However to understand food-related decision making in the complex food environment it is essential to be able to ascertain the reward goal values that guide the decisions and behavioral choices that people make. These values are hidden but it is possible to ascertain them more objectively using metrics such as the willingness to pay and a method for this is described. Both these sets of methods provide quantitative measures of motivation and goal value that can be compared within and between individuals.     

Exosome biogenesis,bioactivities and functions as new delivery systems of natural compounds

A rapidly growing body of experimental evidence has begun to shed light on the wide ranging molecular mechanisms which modulate intra- and inter-cellular communications. A substantial quantity of the available knowledge has only been uncovered in recent years, and we are learning that donor cells release nanovesicles, known as exosomes, which regulate the cellular behavior of recipient cells following uptake. Based on the impressive capacity of exosomes in delivering their “payload”, different therapeutic agents, are currently being tested using this delivery method for more effective therapy. This review summarizes the most recent developments in exosome bioactivities and discusses the biochemical nature of exosomes and their biogenesis. It also summarizes the use of exosomes as delivery vehicles for drugs and natural compounds to the targeted site.     

Effect of ethrel,chlormequat chloride and paclobutrazol on growth and pyrethrins accumulation in <Emphasis Type="Italic">Chrysanthemum cinerariaefolium</Emphasis> Vis.

Pyrethrins and flower yield of pyrethrum (Chrysanthemum cinerariaefolium Viz.) plants were determined after application of ethrel, chlormequat chloride and paclobutrazol. Ethrel at 50, 100, 250 and 500 mg l^−l produced a significant positive effect on pyrethrins level, decreased plant height, while 50 and 100 mg l^−l significantly increased fresh and dry flower yield. Chlormequat chloride at 1000 and 2000 mg l^−l and paclobutrazol (80 and 160 mg l^−l) increased pyrethrins level, single flower weight and decreased plant height and flower yield. ¹⁴C-acetate incorporation studies further substantiated positive effect of growth retardants on pyrethrins biosynthesis. The effect of growth retardants on pyrethrins seems to be mediated through its effect on biosynthesis.     

Radioprotection by caffeine pre- and post-treatment in the bone marrow chromosomes of mice given whole-body gamma-irradiation.

The effect of caffeine given as pre- and post-treatment in mice exposed to whole-body gamma-irradiation (1.5 Gy 60Co gamma-rays) was studied. The pre-treatment was either acute or chronic. The acute dose (5 mg/kg and 15 mg/kg body weight) was in the form of an injection given intraperitoneally, 30 min before irradiation. The chronic administration was in the form of caffeine solution (4.208 x 10(-3) M and 7.72 x 10(-4) M) contained in the drinking water that mice had had ad libitum access to instead of plain drinking water for 5 weeks prior to radiation exposure. The acute pre-treatment with caffeine reduced the radiation-induced frequency of chromosomal aberrations discernibly, whereas the chronic pre-treatment afforded a much more significant degree of radioprotection. The caffeine post-treatment (5 mg/kg and 15 mg body weight) was given in the form of an intraperitoneal injection to the mice immediately following whole-body gamma-irradiation. It is noted that both post-treatment concentrations of caffeine also significantly reduced the frequency of chromosomal aberrations induced by gamma-rays. These data are briefly discussed in terms of possible mechanistic considerations.     

Relationship between gibberellin and cytokinin activity and flowering in Rosa damascena Mill.

Kinetin at 10 mg l^–1 increased the number of flowers produced on Rosa damascena plants while GA₃ inhibited flowering. In the leaves of non-flowering plants GA-like activity was high while specific cytokinin activity (fraction-II) was significantly higher in flowering plants. A novel compound 10- methyldihydrozeatin riboside and isopentenyl-adenine were identified from TLC fraction-II while TLC fraction-I yielded zeatin and 2-hydroxy-6-methylaminopurine.Abbreviations TLC thin layer chromatography - BA N⁶-benzyladenine - GA₃ gibberellic acid CIMAP communication No. 92-40J     

Enantiomeric Separation and Simulation Studies of Pheniramine,Oxybutynin, Cetirizine,and Brinzolamide Chiral Drugs on Amylose‐Based Columns

Solid phase extraction ( SPE)‐chiral separation of the important drugs pheniramine, oxybutynin, cetirizine, and brinzolamide was achieved on the C₁₈ cartridge and AmyCoat (150 x 46 mm) and Chiralpak AD (25 cm x 0.46 cm id) chiral columns in human plasma. Pheniramine, oxybutynin, cetirizine, and brinzolamide were resolved using n‐hexane‐2‐PrOH‐DEA (85:15:0.1, v/v), n‐hexane‐2‐PrOH‐DEA (80:20:0.1, v/v), n‐hexane‐2‐PrOH‐DEA (70:30:0.2, v/v), and n‐hexane‐2‐propanol (90:10, v/v) as mobile phases. The separation was carried out at 25 ± 1 ºC temperature with detection at 225 nm for cetirizine and oxybutynin and 220 nm for pheniramine and brinzolamide. The flow rates of the mobile phases were 0.5 mLmin^‐1. The retention factors of pheniramine, oxybutynin, cetirizine and brinzolamide were 3.25 and 4.34, 4.76 and 5.64, 6.10 and 6.60, and 1.64 and 2.01, respectively. The separation factors of these drugs were 1.33, 1.18, 1.09 and 1.20 while their resolutions factors were 1.09, 1.45, 1.63 and 1.25, and 1.15, respectively. The absolute configurations of the eluted enantiomers of the reported drugs were determined by simulation studies. It was observed that the order of enantiomers elution of the reported drugs was S‐pheniramine > R‐pheniramine; R‐oxybutynin > S‐oxybutynin; S‐cetirizine > R‐cetirizine; and S‐brinzolamide > R‐brinzolamide. The mechanism of separation was also determined at the supramolecular level by considering interactions and modeling results. The reported SPE‐chiral high‐performance liquid chromatography ( HPLC) methods are suitable for the enantiomeric analyses of these drugs in any biological sample. In addition, simulation studies may be used to determine the absolute configuration of the first and second eluted enantiomers. Chirality 26:136–143, 2014. © 2014 Wiley Periodicals, Inc.