GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert β-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced β-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.     

HIV envelope-CXCR4 signaling activates cofilin to overcome cortical actin restriction in resting CD4 T cells

Binding of the HIV envelope to the chemokine coreceptors triggers membrane fusion and signal transduction. The fusion process has been well characterized, yet the role of coreceptor signaling remains elusive. Here, we describe a critical function of the chemokine coreceptor signaling in facilitating HIV infection of resting CD4 T cells. We find that static cortical actin in resting T cells represents a restriction and that HIV utilizes the Galphai-dependent signaling from the chemokine coreceptor CXCR4 to activate a cellular actin-depolymerizing factor, cofilin, to overcome this restriction. HIV envelope-mediated cofilin activation and actin dynamics are important for a postentry process that leads to viral nuclear localization. Inhibition of HIV-mediated actin rearrangement markedly diminishes viral latent infection of resting T cells. Conversely, induction of active cofilin greatly facilitates it. These findings shed light on viral exploitation of cellular machinery in resting T cells, where chemokine receptor signaling becomes obligatory.     

Modulating effects of hesperidin on circadian pattern indices of rotenone induced redox homeostasis in clock mutant (cryb) of Drosophila melanogaster

The circadian timing system controls drug metabolism and cellular processes over the 24 h period in every cell. Impaired redox homeostasis is a casual factor for a number of diseases and it is desirable to understand the orchestration of circadian clock under oxidative stress in the model organism, Drosophila melanogaster. This study evaluates the effect of hesperidin on the circadian rhythms of lipid peroxidation products and antioxidants during rotenone-induced oxidative stress in fruit fly. The characteristics of temporal rhythms (acrophase, amplitude, and mesor) of glutathione peroxides (GPx), reduced glutathione (GSH)), were markedly declined in rotenone-treated flies when compared to other groups. Treatment of hesperidin to rotenone-treated flies significantly increased the mesor and modified the amplitudes of antioxidants. Further, delays in acrophase in rotenone-induced flies were reversed by hesperidin treatment. Thus, treatment of hesperidin results in normalization of the altered rhythms of these indices plausibly by its cytoprotective and antioxidant effects. Impairment of 24 h rhythms in oxidative stress markers and antioxidants were observed during rotenone treatment and the impairment is severe in circadian clock mutant cry^b flies. A reversibility of rhythms was prominent consequent to hesperidin treatment in wild-type flies than cry^b flies. These findings revealed a role of circadian clock in redox homeostasis and the use of Drosophila model in screening putative antioxidative phytomedicines earlier to their use in mammalian systems.     

Prevalence of Dyslipidemia in Urban and Rural India: The ICMR–INDIAB Study

Aim

To study the pattern and prevalence of dyslipidemia in a large representative sample of four selected regions in India.

Methods

Phase I of the Indian Council of Medical Research–India Diabetes (ICMR-INDIAB) study was conducted in a representative population of three states of India [Tamil Nadu, Maharashtra and Jharkhand] and one Union Territory [Chandigarh], and covered a population of 213 million people using stratified multistage sampling design to recruit individuals ≥20 years of age. All the study subjects (n = 16,607) underwent anthropometric measurements and oral glucose tolerance tests were done using capillary blood (except in self-reported diabetes). In addition, in every 5th subject (n = 2042), a fasting venous sample was collected and assayed for lipids. Dyslipidemia was diagnosed using National Cholesterol Education Programme (NCEP) guidelines.

Results

Of the subjects studied, 13.9% had hypercholesterolemia, 29.5% had hypertriglyceridemia, 72.3% had low HDL-C, 11.8% had high LDL-C levels and 79% had abnormalities in one of the lipid parameters. Regional disparity exists with the highest rates of hypercholesterolemia observed in Tamilnadu (18.3%), highest rates of hypertriglyceridemia in Chandigarh (38.6%), highest rates of low HDL-C in Jharkhand (76.8%) and highest rates of high LDL-C in Tamilnadu (15.8%). Except for low HDL-C and in the state of Maharashtra, in all other states, urban residents had the highest prevalence of lipid abnormalities compared to rural residents. Low HDL-C was the most common lipid abnormality (72.3%) in all the four regions studied; in 44.9% of subjects, it was present as an isolated abnormality. Common significant risk factors for dyslipidemia included obesity, diabetes, and dysglycemia.

Conclusion

The prevalence of dyslipidemia is very high in India, which calls for urgent lifestyle intervention strategies to prevent and manage this important cardiovascular risk factor.     

Molecular dynamics simulation of drug uptake by polymer

Drug uptake by polymer was modeled using a molecular dynamics (MD) simulation technique. Three drugs—doxorubicin (water soluble), silymarin (sparingly water soluble) and gliclazide (water insoluble)—and six polymers with varied functional groups—alginic acid, sodium alginate, chitosan, Gantrez AN119 (methyl-vinyl–ether-co-malic acid based), Eudragit L100 and Eudragit RSPO (both acrylic acid based)—were selected for the study. The structures were modeled and minimized using molecular mechanics force field (MM+). MD simulation (Gromacs-forcefield, 300 ps, 300 K) of the drug in the vicinity of the polymer molecule in the presence of water molecules was performed, and the interaction energy (IE) between them was calculated. This energy was evaluated with respect to electric-dipole, van der Waals and hydrogen bond forces. A good linear correlation was observed between IE and our own previous data on drug uptake^* [R ² = 0.65, R_adj² = 0.65,R_pre² = 0.56, {\hbox{R}}_{\rm{adj}}^2 = 0.65,{\hbox{R}}_{\rm{pre}}^2 = 0.56, and a F ratio of 30.25, P < 0.001; Devarajan et al. (2005) J Biomed Nanotechnol 1:1–9]. Maximum drug uptake by the polymeric nanoparticles (NP) was achieved in water as the solvent environment. Hydrophilic interaction between NP and water was inversely correlated with drug uptake. The MD simulation method provides a reasonable approximation of drug uptake that will be useful in developing polymer-based drug delivery systems.     

Anti-ESBL activity of silver nanoparticles biosynthesized using soil Streptomyces species

Emergence of antibiotic resistance by bacteria has become a serious threat for public health worldwide. In this study, Streptomyces isolated from fertile soil sample was tested for biosynthesis of silver nanoparticles (AgNps) using cell-free supernatant and synthesized AgNps were screened for anti-ESBL (extended spectrum β-lactamase) activity against multi-drug resistant (MDR) ESBL-producing strain Klebsiella pneumoniae (ATCC 700603) and other medically important pathogens. Synthesis of AgNps was confirmed by change in pale yellow color to dark brown color and characteristic absorption spectra at 420 nm. The XRD spectrum displayed typical peaks of crystalline silver and EDAX analysis showed a major signal for silver. FTIR spectra revealed prominent peaks at 3,294 cm^?1 (NH stretching due to amide group), 2,952 cm^?1 (aldehydic C–H stretching) 1,658 cm^?1 indicating the presence of carbonyl group. AgNps were spherical in shape with size ranging from 20 to 70 nm. The synthesized AgNps showed significant antimicrobial activity against standard ESBL pathogen K. pneumoniae (22 mm), 21 mm against clinical ESBL isolate E. coli and 16 mm against clinical ESBL isolates K. pneumoniae and Citrobacter species, respectively. The results of this study suggest that AgNps synthesized by Streptomyces sp. VITSJK10 can be used as a potential alternative to control MDR ESBL pathogens. The present study aimed for green synthesis of AgNps using Streptomyces species and to explore its anti-ESBL activity.     

Artificial leucine rich repeats as new scaffolds for protein design

The leucine rich repeat (LRR) motif that participates in many biomolecular recognition events in cells was suggested as a general scaffold for producing artificial receptors. We describe here the design and first total chemical synthesis of small LRR proteins, and their structural analysis. When evaluating the tertiary structure as a function of different number of repeating units (1-3), we were able to find that the 3-repeats sequence, containing 90 amino acids, folds into the expected structure.     

Large cryptic internal sequence repeats in protein structures from <Emphasis Type="Italic">Homo sapiens</Emphasis>

Amino acid sequences are known to constantly mutate and diverge unless there is a limiting condition that makes such a change deleterious. However, closer examination of the sequence and structure reveals that a few large, cryptic repeats are nevertheless sequentially conserved. This leads to the question of why only certain repeats are conserved at the sequence level. It would be interesting to find out if these sequences maintain their conservation at the three-dimensional structure level. They can play an active role in protein and nucleotide stability, thus not only ensuring proper functioning but also potentiating malfunction and disease. Therefore, insights into any aspect of the repeats — be it structure, function or evolution — would prove to be of some importance. This study aims to address the relationship between protein sequence and its three-dimensional structure, by examining if large cryptic sequence repeats have the same structure.     

A pilot study on the association between SLCO1B1 RS4363657 polymorphism and muscle adverse events in adults with newly diagnosed dyslipidaemia who were prescribed a statin: the Malaysian primary health care cohort

Abstract

Introduction: Statin, the first-line treatment for dyslipidaemia, may have suboptimal adherence due to its associated muscle adverse events. These data, however, remain limited.

Aim: To determine the association of serum creatine kinase (CK) and SLCO1B1 rs4363657 polymorphism with statin-associated muscle adverse events (SAMAE) among dyslipidaemia participants.

Methods: This was a prospective cohort study at government health clinics involving newly diagnosed adults with dyslipidaemia. SAMAE were recorded based on the patient’s complaint after a month on statin. CK was taken at baseline and follow-up. Genetic profiling was performed for SLCO1B1 rs4363657 polymorphism.

Results: Among 118 participants, majority were Malay (72%) males (61%) with a mean age of 49?±?12.2 years old and prescribed lovastatin (61.9). There was a significant association between statin types (lovastatin and simvastatin) and SAMAE (p?=?0.0327); no significant association noted between CK and SAMAE (p?=?0.5637). The SLCO1B1 rs4363657 polymorphism was significantly associated SAMAE (p?<?0.0001).

Conclusions: In this first pilot study of a multiethnic Malaysian population, the incidence of SAMAE was 18.6%. SAMAE were significantly higher in subjects on lovastatin compared to simvastatin. SLCO1B1 rs4363657 polymorphism was a significant risk factor for SAMAE.