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In present investigation, self-assembled nanomicelles of amphiphilic clotrimazole glycyl-glycine (CLT-GG-SANMs) analogue were customized for augmenting drug delivery, permeability and apoptosis in B16F1 mouse melanoma cancer cells both in vitro and in vivo following intratumoral ( i.t. ) route of administration. The mean particle size of CLT-GG-SANMs was measured to be 35.9 ± 3.4 nm in addition to zeta-potential of −17.1 ± 3.5 mV. The shape of CLT-GG-SANMs was visualized to be smooth and spherical as like nanoparticles. The critical micellar concentration (CMC) of CLT-GG-SANMs was estimated to be 17 μg/ml using DPH (1,6-diphenyl-1,3,5-hexatriene) as a UV probe. Modification of CLT to CLT-GG-SANMs induced the amorphization in therapeutic moiety. Next, CLT suspension released only 9.7% of the drug within 1 h under dissolution testing and further analysis up to 48 h did not display any remarkable effect on the drug release. On the other hand, CLT-GG-SANMs released 46.2% of the drug significantly (P < 0.01) higher than CLT suspension at 4 h. The IC 50 of CLT-GG-SANMs was measured to be 15.1-μM significantly (P < 0.05) lower than CLT suspension (IC 50  > 20 μM) in B16F1 cells. Western blotting and histopathological analysis also supported the superior therapeutic efficacy of CLT-GG-SANMs in terms of higher extent of apoptosis, tumour regression and exhibition of strong antioxidant potential against B16F1 cells induced tumour in C57BL6J mice. In conclusion, in vitro and in vivo therapeutic efficacy analysis indicated that CLT-GG-SANMs may be a potential candidate for translating in to a clinically viable product. [ABSTRACT FROM AUTHOR]

Purpose The aim of this research work was to explore the possibility of providing multifunctional oral insulin delivery system by conjugating several types of dipeptides on chitosan and trimethyl chitosan to be used as drug carriers. Method Conjugates of Glycyl-glycine and alanyl-alanine of chitosan and trimethyl chitosan (on primary alcohol group of polymer located on carbon 6) were synthesized and nanoparticles containing insulin were prepared for oral delivery. Preparation conditions of nanoparticles were optimized and their performance to enhance the permeability of insulin as well as cytotoxicity of nanoparticles in Caco-2 cell line was evaluated. To evaluate the efficacy of orally administered nanoparticles, nanoparticles with the most permeability enhancing ability were studied in male Wistar rats as animal model by measuring insulin and glucose Serum levels. Result Structural study of all the conjugates by infrared spectroscopy and nuclear magnetic resonance confirmed the successful formation of the conjugates with the desirable substitution degree. By optimizing preparation conditions, nanoparticles with expected size (157.3–197.7 nm), Zeta potential (24.35–34.37 mV), polydispersity index (0.365–0.512), entrapment efficiency (70.60–86.52%) and loading capacity (30.92–56.81%), proper morphology and desirable release pattern were obtained. Glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan showed 2.5–3.3 folds more effective insulin permeability in Caco-2 cell line than their chitosan counterparts. In animal model, oral administration of glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan demonstrated reasonable increase in Serum insulin level with relative bioavailability of 17.19% and 15.46% for glycyl-glycine and alanyl-alanine conjugate nanoparticles, respectively, and reduction in Serum glucose level compared with trimethyl chitosan nanoparticles ( p  < 0.05). Conclusion It seems that glycyl-glycine and alanyl-alanine conjugate nanoparticles of trimethyl chitosan have met the aim of this research work and have been able to orally deliver insulin with more than one mechanism in animal model. Hence, they are promising candidates for further research studies. [ABSTRACT FROM AUTHOR]

Glycylation and glutamylation, the posttranslational addition of glycines and glutamates to genetically encoded glutamates in the intrinsically disordered tubulin C-terminal tails, are crucial for the biogenesis and stability of cilia and flagella and play important roles in metazoan development. Members of the diverse family of tubulin tyrosine ligase-like (TTLL) enzymes catalyze these modifications, which are part of an evolutionarily conserved and complex tubulin code that regulates microtubule interactions with cellular effectors. The site specificity of TTLL enzymes and their biochemical interplay remain largely unknown. Here, we report an in vitro characterization of a tubulin glycylase. We show that TTLL3 glycylates the β-tubulin tail at four sites in a hierarchical order and that TTLL3 and the glutamylase TTLL7 compete for overlapping sites on the tubulin tail, providing a molecular basis for the anticorrelation between glutamylation and glycylation observed in axonemes. This anticorrelation demonstrates how a combinatorial tubulin code written in two different posttranslational modifications can arise through the activities of related but distinct TTLL enzymes. To elucidatewhat structural elements differentiate TTLL glycylases from glutamylases, with which they share the common TTL scaffold, we determined the TTLL3 X-ray structure at 2.3-Å resolution. This structure reveals two architectural elements unique to glycyl initiases and critical for their activity. Thus, our work sheds light on the structural and functional diversification of TTLL enzymes, and constitutes an initial important step toward understanding how the tubulin code is written through the intersection of activities of multiple TTLL enzymes. [ABSTRACT FROM AUTHOR]

The effect of cationic micelles of cetyltrimethylammonium bromide (CTAB) and dodecyltrimethylammonium bromide (DTAB) on interactions of glycyl dipeptide in aqueous medium have been studied in varying concentrations (0.001, 0.005 and 0.010 mol·kg –1 ) at different temperatures (293.15 K to 293.15 K). The conductivity method has been employed to determine critical micelle concentration, CMC i.e. point of aggregation and the results have been discussed in terms of glycylglycine–CTAB/DTAB hydrophobic and electrostatic interactions in aqueous medium. The obtained CMC values reveal the fact that the micellization tendency of the surfactant increases in the presence of glycyl dipeptide. The CMC ’s of CTAB and DTAB have been found to decrease from 0.87 to 0.66 mmol·kg –1 and 14.2–13.7 mmol·kg –1 respectively as the [Glycyl dipeptide] increased from 0.001 to 0.010 mol·kg –1 . The temperature dependence of the CMC values has been established in terms of ion–ion, ion–polar and hydrophobic–hydrophobic group interactions around the hydrophobic part of surfactants. Furthermore, the standard thermodynamic parameters of micellization have been evaluated and interpreted which enable to grasp fully the ion–ion/ion–hydrophilic interactions existing in the present ternary (surfactant–dipeptide–water) system. In addition, the pyrene fluorescence technique has been used to study the change of micropolarity produced by the interactions of surfactants with glycyl dipeptide and the aggregation behaviour ( CMC determination) of surfactants. [ABSTRACT FROM AUTHOR]

The article presents findings of a research conducted on the kinetic analysis involving degradation of glycyl-l-leucine and L-leucyl-glycine in subcritical water. Under the research, two dipeptides were studied to understand the phenomena occurring during treatment. It mentions that treatment was administered in a stainless steel tubular reacter connected to an high-pressure liquid chromatograph (HPLC) pump and immersed in an oil bath. It estimates constant reaction rate related to degradation.

The objectives of this study were to determine the effects of dietary glycyl-glutamine (Gly-Gln) on postweaning growth, small intestinal morphology, and immune response of stressed or nonstressed piglets. Pigs (n = 144; initially 4.49 kg and 14 d of age) were randomly allocated to 24 pens (6 pigs/pen) in an environmentally controlled nursery and assigned to Escherichia eoli lipopolysaccharide (LPS) challenge (PBS vs. LPS) and Gly-Gln supplementation (0 vs. 0.15%) in a 2 × 2 factorial arrangement of treatments with 6 pens/treatment. The LPS was the stress-inducing agent, and it was injected on d 7 and 14 of the 21-d experiment. Inflammatory challenge with LPS reduced ADG (P < 0.05) and tended to reduce ADFI (P = 0.06) of piglets from d 7 to 21 of the experiment. Supplementation of Gly-Gln increased ADG and G:F from d 0 to 21 (P < 0.05). On d 21 (1 wk after the second LPS injection), there was an LPS challenge × diet Gly-Gln interaction for ADFI (P < 0.05), but it was difficult to ascertain whether Gly-Gln increased ADFI. A trend for an LPS challenge × diet Gly-Gln interaction was observed for ADG (P = 0.07). There were no differences in lymphocyte proliferation among treatments. The LPS challenge increased crypt depth (CD) of the duodenum and decreased the ratio of villus height (VH) to CD of the ileum (P < 0.05) on d 14 (1 wk after the first LPS injection), whereas dietary supplementation of Gly-Gln increased VH of the ileum and VH:CD of the duodenum (P < 0.05). The concentration of peripheral blood IL-1ß was increased by injection of LPS (P < 0.05) and was decreased by dietary Gly-Gln supplementation during the experimental period (P < 0.05); however, there was no interaction of LPS challenge × Gly-Gln addition for IL-1ß concentration. Concentrations of peripheral blood IL-2 tended to increase at d 14 (P = 0.09) and soluble IL-2 receptor tended to decrease at d 7 (P = 0.06) in piglets supplemented with Gly-Gln; therefore, the peripheral blood IL-2/soluble IL-2 receptor system tended to favor the secretion of IL-2 during the first 2 wk of the experiment. In conclusion, considerable suppression of growth and immune function occurred in early weaning piglets challenged with LPS, and such depression could be alleviated by dietary Gly-Gln supplementation independent of the LPS challenge. [ABSTRACT FROM AUTHOR]

Abstract: Peptide inhibitors of ethanol consumption have shown promise. The purpose of this study was to test the cyclized form of the opioid-derived dipeptide, glycyl-l-glutamine to reduce ethanol consumption after either peripheral injections or site-specific injections into the nucleus accumbens (NAC) of high drinking and low drinking rats. Following I.P. cyclo-glycyl-glutamine (c-GQ), the data show a mean decrease in ethanol intake of 34.4% in P rats, and 39.4% in Sprague–Dawley rats at doses between 5 and 25mg/kg. The data show that peripherally administered c-GQ is effective in reducing ethanol consumption in both high (P) and low (SD) drinking strains of rats and suggests a therapeutic potential. [Copyright &y& Elsevier]

Abstract: β-endorphin, implicated in modulation of ethyl alcohol reward, has neuron terminals in several reward sites. Alcohol consumption was reduced after ventricular or site-specific injections into the nucleus accumbens of an opioid-derived dipeptide, glycyl-glutamine. The current study examined the effects of this dipeptide after site-specific injections into additional reward sites. Alcohol-preferring (P) rats, stereotaxically implanted with bilateral guide cannulae into the nucleus accumbens, ventral tegmental area, and the central nucleus of the amygdala were given 30% alcohol and water in a 24h voluntary two-bottle choice paradigm. Upon achieving stable baseline intakes, glycyl-glutamine (GQ) doses were injected bilaterally, and the alcohol and water intakes and body weight recorded for the response and recovery. The data show reduced alcohol intake by 32–49.5% after 100-pmol glycyl-glutamine into reward sites (nucleus accumbens, ventral tegmental area, and central nucleus of the amygdala), but not after injections into control sites dorsal to reward sites. The order of sensitivity to the 1-fmol dose was amygdala ≥ ventral tegmental area > accumbens. GQ was effective in reducing ethanol intake at reported β-endorphin terminal regions in each of the three reward sites tested. The effective doses were similar to reported endogenous GQ levels, consistent with the notion that it may function as part of an endogenous counter regulatory mechanism and represent a “stop drinking” signal in the high drinking, P rats at these three reward sites. [Copyright &y& Elsevier]

Summary 1. Severe blood loss initially lowers arterial pressure through a central mechanism that is thought to involve opioid and cholinergic neurons. The present study tested the hypothesis that simultaneous administration of a cholinergic agonist and an opioid receptor antagonist would produce a synergistic effect in the treatment of haemorrhage. Specifically, we tested whether choline, a precursor of acetylcholine, potentiates the pressor effect of the β-endorphin derived peptide glycyl-glutamine (Gly-Gln) or the opioid receptor antagonist naloxone following acute haemorrhage. 2. Conscious rats were treated intracerebroventricularly (i.c.v.) with choline chloride (180 nmol) alone or combined with Gly-Gln (10 nmol) or naloxone (10 nmol) 2 min after blood withdrawal (2.5 mL/100 g bodyweight over 20 min) was completed; mean arterial pressure and heart rate were monitored for 30 min. 3. Combined treatment with choline and Gly-Gln elevated mean arterial pressure but did not affect heart rate significantly. Choline and Gly-Gln had no effect on cardiovascular function when administered alone to haemorrhaged rats or when given together to normotensive animals. Choline also potentiated the pressor and tachycardic effect of naloxone in haemorrhaged rats. 4. These data show that choline potentiates the pressor effect of Gly-Gln and naloxone in haemorrhaged rats. [ABSTRACT FROM AUTHOR]