Garlic improves insulin sensitivity and associated metabolic syndromes in fructose fed rats

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes mellitus, characterized by peripheral insulin resistance, is a major lifestyle disorder of the 21^stCentury. Raw garlic homogenate has been reported to reduce plasma glucose levels in animal models of type 1 diabetes mellitus. However, no specific studies have been conducted to evaluate the effect of raw garlic on insulin resistance or type 2 diabetes mellitus. This study was designed to investigate the effect of raw garlic on fructose induced insulin resistance, associated metabolic syndrome and oxidative stress in diabetic rats.</p> <p>Methods</p> <p>Male Sprague Dawley rats weighing 200-250 gm body weight were divided into 3 groups (n = 7 per group) and fed diet containing 65% cornstarch (Control group) and 65% fructose (Diabetic group) for 8 weeks. The third group (Dia+Garl group) was fed both 65% fructose and raw garlic homogenate (250 mg/kg/day) for 8 weeks. Whole garlic cloves were homogenized with water to make a fresh paste each day.</p> <p>Results</p> <p>At the end of 8 weeks, serum glucose, insulin, triglyceride and uric acid levels, as well as insulin resistance, as measured by glucose tolerance test, were significantly (p < 0.01) increased in fructose fed rats (Diabetic group) when compared to the cornstarch fed (Control) rats. Administration of raw garlic to fructose fed rats (Dia+Garl group) significantly (p < 0.05) reduced serum glucose, insulin, triglyceride and uric acid levels, as well as insulin resistance when compared with fructose fed rats. Garlic also normalised the increased serum levels of nitric oxide (NO) and decreased levels of hydrogen sulphide (H₂S) after fructose feeding. Although body weight gain and serum glycated haemoglobin levels of fructose fed rats (Diabetic group) were not significantly different from control rats, significant (p < 0.05) reduction of these parameters was observed in fructose fed rats after garlic administration (Dia+Garl group). Significant (p < 0.05) increase in TBARS and decrease in GSH was observed in diabetic liver. Catalase was not significantly affected in any of the groups. Administration of raw garlic homogenate normalised both hepatic TBARS and GSH levels.</p> <p>Conclusions</p> <p>Our study demonstrates that raw garlic homogenate is effective in improving insulin sensitivity while attenuating metabolic syndrome and oxidative stress in fructose-fed rats.</p

Simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by LCâESI-MS/MS and its application to pharmacokinetics in rats

Polypill is a fixed-dose combination that contains three or more active ingredients used as a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. A novel and accurate liquid chromatography tandem mass spectrometry method using electrospray ionization mode has been developed and validated for the simultaneous determination of amlodipine (AMD), valsartan (VAL) using losartan (LOS) as an internal standard (IS), and hydrochlorothiazide (HCT) using furosemide (FSD) as an IS. The separation was carried on Aquasil C18 (50 mmÃ2.1 mm, 5 µm) reversed phase column using acetonitrile and water containing 0.1% formic acid (50:50, v/v) as the mobile phase. The method was validated in terms of linearity, accuracy and precision over the concentration range of 1â1000 ng/mL. The intra and inter-day precision and accuracy, stability and extraction recoveries of all the analytes were in the acceptable range. This method can be successfully applied to the pharmacokinetic study of AMD, VAL and HCT when given as a polypill. Keywords: Amlodipine, Valsartan, Hydrochlorothiazide, Exforge HCT, Polypil

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem

Bombesin-conjugated nanoparticles improve the cytotoxic efficacy of docetaxel against gastrin-releasing but androgen-independent prostate cancer

Aim: Bombesin (BBN)-conjugated polymeric nanoparticles to target docetaxel (DTX) to prostate cancer cells that overexpress gastrin-releasing peptides receptors. Materials & methods: In vitro cytotoxicity, uptake of nanoparticles and inhibition of cell migration were assessed against human prostate cancer cells. Preclinical pharmacokinetic and tissue-distribution studies of nanoparticles were performed in Balb/c mice and results compared with the marketed formulation Taxotere®. Results: BBN-conjugated DTX-loaded nanoparticles exhibited higher cytotoxicity, inhibition of cell migration and colony formation than non-targeted nanoparticles or DTX alone. More BBN-conjugated nanoparticles were taken up at a faster rate than unconjugated nanoparticles. In vivo, this drug delivery improved pharmacokinetics of DTX by increasing mean residence time and decreasing clearance. Conclusion: This study provides an alternate approach for polysorbate-free delivery of DTX, with improved in vivo performance

Synthesis and bio-evaluation of novel acyl derivatives of karanjin

115-120Different lipidic moieties such as 10-undecenoic, oleic, lipoic, caproic, caprylic and lauric acids have been acylated to demethylated karanjin to prepare six lipoconjugated karanjin. All the derivatives have been evaluated for antimicrobial, anticancer and antiinflammatory activities and compared with karanjin and its demethylated analog. Lipoconjugation does not seem to improve the activity of karanjin against studied bacterial and fungal strains. However, karanjin, demethylated karanjin and six lipoconjugated karanjin show moderate to good anticancer activity against prostate and breast cancer cell lines. Mild antiinflammatory response has also been observed in case of karanjin and lipoic acid-conjugated karanjin

Improving efficacy, oral bioavailability, and delivery of paclitaxel using protein-grafted solid lipid nanoparticles

Oral delivery of anticancer drugs remains challenging despite the most convenient route of drug administration. Hydrophobicity and nonspecific toxicities of anticancer agents are major impediments in the development of oral formulation. In this study, we developed wheat germ agglutinin (WGA)-conjugated, solid lipid nanoparticles to improve the oral delivery of the hydrophobic anticancer drug, paclitaxel (PTX). This study was focused to improve the PTX loading in biocompatible lipid matrix with high bioconjugation efficiency. WGA-conjugated, PTX-loaded solid lipid nanoparticles (LPSN) exhibited enhanced anticancer activity against A549 lung cancer cells after internalization through lectin receptors than free PTX. Biodistribution studies in rats revealed that LPSN significantly improved the oral bioavailability and lung targetability of PTX, which could be due to cumulative bioadhesive property of the nanocarrier system and the targeting ligand WGA

Large Amino Acid Transporter 1 Selective Liposomes of l-DOPA Functionalized Amphiphile for Combating Glioblastoma

Despite significant progress in neurosurgery and radiation therapy during the past decade, overall survivability (OS) of glioblastoma patients continues to be less than 2 years. The scope of systemic chemotherapy is greatly limited by poor drug transport across the blood brain barrier (BBB) and, thereby, suboptimal drug accumulation in glioma tissue. To this end, use of large amino acid transporter-1 (LAT1) overexpressed both on brain capillary endothelial cells (BCECs) and glioma cells has begun. Prior reports on the use of LAT1 mediated delivery of model drugs showed their brain accumulations. However, in depth in vivo glioblastoma regression studies aimed at examining the therapeutic potential of LAT1 mediated delivery of potent chemotherapeutics to brain tumor tissues have not yet been undertaken. Herein, we report on the development of a nanometric (100-135 nm) promising LAT1 selective liposomal drug carrier prepared from a novel l-3,4-dihydroxyphenylalanine (l-DOPA) functionalized amphiphile (Amphi-DOPA). In vitro studies using Rh-PE labeled liposomes of Amphi-DOPA both in untreated glioma (GL261) cells and in GL261cells preincubated with LAT1 antibody revealed LAT1 mediated cellular uptake. Intravenously administered NIR-dye labeled liposomes of Amphi-DOPA in glioblastoma-bearing mice showed preferential accumulation of the dye in brain tissue. Notably iv administration of WP1066-loaded liposomes of Amphi-DOPA enhanced the overall survivability of C57BL/6J mice bearing orthotopically established mouse glioblastoma by ∼60% compared to that for the untreated mouse group. Furthermore, we show that the OS of established glioblastoma-bearing mice can be significantly enhanced (by >300% compared to that for the untreated mouse group) when the presently described LAT1 mediated targeted chemotherapy with WP1066-loaded liposomes of Amphi-DOPA is combined with in vivo DC-targeted DNA vaccination using a survivin (a glioblastoma antigen) encoded DNA vaccine. The present findings open a new door for LAT1 mediated systemic chemotherapy of glioblastoma

Synthesis of some novel orsellinates and lecanoric acid related depsides as <i>α</i>-glucosidase inhibitors

<p>Sixteen novel orsellinic esters (<b>6a-l, 7a-d</b>) along with four lecanoric acid related depsides (3<b>a-c, 4</b>) were synthesized and confirmed their structures by spectroscopic data (¹H, ¹³C & HRMS). The synthesized compounds were evaluated for their <i>in vitro α</i>-glucosidase (<i>Saccharomyces cerevisiae</i>) inhibitory potential. Among the tested compounds, <b>3c</b> (IC₅₀: 140.9 μM) and <b>6c</b> (IC₅₀: 203.9 μM) displayed potent α-glucosidase inhibitory activity and found more active than the standard drug acarbose (IC₅₀: 686.6 μM). Both the test compounds were subjected to <i>in vivo</i> antihyperglycemic activity using sucrose loaded model in Wistar rats and found compound <b>3c</b> exhibited significant reduction in glucose levels.</p

<em>Diospyros melanoxylon</em> (Roxb.): A tribal fruit that maintains euglycemic state after consumption and cools oxidative stress

194-203Tendu, Diospyros melanoxylon Roxb. (Family: Ebenaceae) fruit is indigenous to the Indian subcontinent. The ripe fruit of tendu is eaten by tribal people. Both, unripe, as well as ripe fruits, have been used in folk-medicine by tribal communities. Aqueous methanol extract of unripe fruit displayed potent free radicals scavenging properties and also mitigated free radicals induced DNA damage. Furthermore, this extract also alleviated the development of oxidative stress induced due to a hyper physiological concentration of H2O2 and glucose in NIH 3T3 cells. FACS analysis revealed that extracts significantly (p 2O2. Total polyphenols, flavonoids, and anthocyanins were present in unripe fruit were observed radically decreased when the fruit ripened. Presence of pancreatic α-amylase, intestinal α-glucosidase, and pancreatic lipase inhibitory activities in fruit extracts were also recorded. Postprandial glycemic excursion of unripe as well as ripe fruits pulp were significantly (p D. melanoxylon may become an economic beverage fully equipped to counter free radicals and resultant oxidative stress. Furthermore, fruit may serve as a true euglycemic sweetener against sucrose