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Atherosclerosis commences with the trapping of low density lipoproteins (LDLs) in blood vessels by modified proteoglycans (PGs) with hyperelongated glycosaminoglycan (GAG) chains. GAG chain synthesis and growth factor mediated hyperelongation regulates the composition and size of PGs in a manner that would cause low density lipoprotein (LDLs) retention in vessel wall. Galactosaminoglycans are a class of GAGs, commonly observed on PGs. Multiple enzymes are involved in galactosaminoglycan biosynthesis. Galactosaminoglycan synthesis is regulated by various signalling pathways which are amenable to pharmacological manipulation to treat atherosclerosis. Receptor mediated signalling pathways including protein tyrosine kinase receptors (PTKRs), serine/threonine kinase receptors (S/TKRs) and G-protein coupled receptors (GPCRs) pathways regulate galactosaminoglycan synthesizing enzyme expression. Increased expression of these enzymes modify galactosaminoglycan chain structure by making them hyperelongated. This review focuses on the signalling pathways regulating the expression of genes involved in galactosaminoglycan synthesis and modification. Furthermore, there are multiple other processes for inhibiting the interactions between LDL and galactosaminoglycans such as peptide mimetics of ApoB100 and anti-galactosaminoglycan antibodies and the therapeutic potential of these strategies is also addressed. [ABSTRACT FROM AUTHOR]

Introduction Currently, there is increasing interest in the identification of natural sources of antioxidants that have minimal side effects and can be used as preventive medicine. In this study, the protective role of honey against oxidative damage and hepatotoxicity induced by sub-chronic exposure to chlorpyrifos (CPF) was investigated. Methods Female Wistar rats ( n = 24) were randomly divided into the following four groups: (1) control, (2) honey-treated (3.0 g/kg), (3) CPF-treated (5.4 mg/kg) and (4) honey (3.0 g/kg) + CPF (5.4 mg/kg) treatments. All of the doses were administered daily via oral gavage for 4 weeks. Results Oral exposure to CPF caused hepato- and nephrotoxicity as indicated by the marked elevation in the serum hepatic marker enzymes (the transaminases and alkaline phosphatase activities), the total bilirubin, total cholesterol, triglycerides, urea, creatinine and hepatic lipid peroxidation levels, whereas the serum total protein level was significantly lower compared with the control. A significant decrease in the body weight gain and an increase in the absolute and relative liver weights were observed in the CPF-treated animals compared with the control. The biochemical alterations observed were accompanied by histopathological changes marked by the appearance of degenerative necrosis, congestion, inflammation and edema in the liver section. However, co-treatment with honey ameliorated the changes in the investigated biochemical parameters and the changes in the body and liver weights as revealed by the inhibition of lipid peroxidation and the improvement observed histopathologically. Conclusions The present study suggests that honey has a protective potential for the alleviation of hepatic and renal toxicities induced by CPF. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a complex and heterogeneous disorder which in its most common manifestation arises from insulin resistance and later insulin insufficiency. Type 2 diabetes is characterised by impaired insulin sensitivity and diagnosed as hyperglycaemia. Because of its cardiovascular consequences, Type 2 diabetes represents one of the world’s leading causes of mortality and morbidity. Drug discovery and development are required to produce better ways to prevent, treat and manage diabetes and its complications. Diabetes is a human, not an animal disease, so animals do not get Type 2 diabetes. However there are animal models which are variously suitable for the investigation of new agents for the treatment of Type 2 diabetes. In this Review we have examined the various models that are available for the study of natural products with a focus on models (genetic, nutritional and spontaneous) for the metabolic abnormities of diabetes. These models are also relevant to the investigation of Western medicines for the treatment of diabetes. A suitable experimental model plays an important role in drug discovery for translational studies leading to increased understanding of the molecular basis and management of diabetes. [ABSTRACT FROM AUTHOR]

The di-2-pyridylketone thiosemicarbazones, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), demonstrate potent and selective anti-tumor activity. In fact, DpC entered Phase I clinical trials for advanced and resistant tumors. This investigation examined the activity of these thiosemicarbazones in five tumor cell-types compared to nine clinically used chemotherapeutics and also in combination with these drugs. Dp44mT and especially DpC demonstrated potent anti-proliferative activity that was significantly greater than a range of standard anti-cancer therapeutics. As most anti-cancer drugs are given in combination, further studies were performed to examine the synergistic activity of DpC or Dp44mT with these chemotherapeutics. Combination experiments revealed broad synergy between Dp44mT or DpC upon addition of these drugs, with a sequential protocol of treating first with standard chemotherapies followed by incubation with the thiosemicarbazones being optimal. However, combining DpC and Dp44mT resulted in a pronounced antagonistic drug interaction. To dissect the mechanism of this latter effect, custom-prepared 14C-DpC was implemented and examined for its uptake by cells. The avid uptake of 14C-DpC by tumor cells observed at 37 °C was suppressed at 4 °C and by the metabolic inhibitor, sodium fluoride, suggesting a temperature- and energy-dependent mechanism. Furthermore, competition studies using an excess of unlabeled Dp44mT or DpC inhibited 14C-DpC or 14C-Dp44mT uptake, respectively, suggesting these ligands utilize the same carrier/receptor, antagonizing the internalization of each other. These studies demonstrate the potent and broad anti-proliferative activity of Dp44mT and particularly DpC, and are important for establishing optimized combinations with standard chemotherapies. • DpC was the most active anti-tumor agent examined from 9 therapeutics and Dp44mT. • Synergism between DpC and other drugs was the most common interaction observed. • Like Dp44mT, DpC uses a carrier/receptor for uptake into tumor cells. • Combination studies with Dp44mT and DpC demonstrated strong antagonism. • Antagonism between Dp44mT and DpC may be due to competition for the same receptor. [ABSTRACT FROM AUTHOR]

Widely used NAPDH oxidase (Nox) inhibitor, apocynin is a prodrug that needs to be converted to its pharmacologically active form by myeloperoxidase. In myeloperoxidase deficient non phagocytic cells such as vascular smooth muscle cells (VSMCs) apocynin stimulates the production of ROS. ROS is generated by the activation of many signalling pathways, thus we have used apocynin as a pharmacological tool to characterise the role of endogenous ROS in activating the transforming growth factor beta receptor (TGFBR1) without the activation of other pathways. The in vitro study utilized human VSMCs. Western blotting and quantitative real time PCR were performed to assess signalling pathways and gene expression, respectively. Intracellular ROS levels was measured using fluorescence detection assay. Treatment with apocynin of human VSMCs stimulated ROS production and the phosphorylation of TGFBR1 and subsequent activation of TGFBR1 signalling leading to the formation of phosphorylated Smad2 which consequently upregulates the mRNA expression of glycosaminoglycan synthesizing enzyme. These findings outline a specific involvement of ROS production in TGFBR1 activation. Furthermore, because apocynin stimulates Nox and ROS production, apocynin must be used with considerable care in vitro as its actions clearly extend beyond the stimulation of Nox enzymes and it has consequences for cellular signalling. Apocynin can stimulate Nox leading to the production of ROS and the outcome is completely dependent upon the redox properties of the cell. Unlabelled Image • Apocynin stimulates ROS generation in human vascular smooth muscle cells • ROS stimulates phosphorylation of transforming growth factor receptor type 1 • Apocynin mediated phosphorylation of Smad2 at carboxy terminal is ROS/Nox dependent • Apocynin mediated ROS production stimulates the mRNA expression of CHST11 [ABSTRACT FROM AUTHOR]

Increases in the incidence of cardiovascular disease (CVD) have aroused strong interest in identifying antioxidants from natural sources for use in preventive medicine. Citrus macroptera ( C. macroptera ), commonly known as “Satkara”, is an important herbal and medicinal plant reputed for its antioxidant, nutritious and therapeutic uses. The aim of the present study was to investigate the cardio-protective effects of ethanol extracts of C. macroptera peel and pulp against isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Male albino Wistar rats (n = 36) were pre-treated with peel and pulp extracts (500 mg/kg) for 45 days. They received a challenge with ISO (85 mg/kg) on the 44th and 45th days. Our findings indicated that subcutaneous injection of ISO induced severe myocardial injuries associated with oxidative stress, as confirmed by elevated lipid peroxidation (LPO) and decreased cellular reduced glutathione (GSH) and anti-peroxidative enzymes, including glutathione peroxidase, glutathione reductase and glutathione-S-transferase, compared with levels observed in control animals. Pre-treatment with C. macroptera peel and pulp extracts prior to ISO administration however, significantly improved many of the investigated biochemical parameters, i.e., cardiac troponin I, cardiac marker enzymes, lipid profile and oxidative stress markers. The fruit peel extract showed stronger cardio-protective effects than the pulp extract. The biochemical findings were further confirmed by histopathological examinations. Overall, the increased endogenous antioxidant enzyme activity against heightened oxidative stress in the myocardium is strongly suggestive of the cardio-protective potential of C. macroptera . [ABSTRACT FROM AUTHOR]