Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes

Rat liver microsomes were irradiated with gamma-rays at a dose rate of 1.31 Gys-1. The extent of lipid peroxidation, measured in terms of malondialdehyde (MDA) formed, increased with radiation dose. The presence of calmodulin antagonists during irradiation decreased lipid peroxidation. The order of their protective efficiency was: chlorpromazine (CPZ) greater than promethazine (PMZ) greater than trimeprazine (TMZ). Their protective effect was diminished in the presence of ferrous (Fe2+) ions and was restored on addition of EDTA. However, calmodulin antagonists considerably inhibited radiation-induced lipid peroxidation in the presence of ferric (Fe3+) ions. Calmodulin antagonists also decreased the cytochrome P-450 content of microsomes. These results are discussed with respect to their applicability to radiotherapy. A possible mechanism for the inhibition of radiation-induced lipid peroxidation is suggested.     

Atrial paroxysmal tachycardia in dogs and its management with homeopathic Digitalis--two case reports

Homeopathic Digitalis 6c was evaluated in two clinical cases of atrial paroxysmal tachycardia in dogs. Tachycardias are common cardiac problems in dogs, and atrial paroxysmal tachycardia is a serious cardiac arrhythmia that may lead to syncope. Both adult dogs (Labrador and German Shepherd) were treated with Digitalis 6c, 4 drops orally four times daily for 7 days. Following treatment with Digitalis 6c heart rate stabilised and synchronized atrial and ventricular electrical activity was restored in 7 days.     

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire

PurposeThis paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib).MethodsThis is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe.ResultsClinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction–related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals.ConclusionEmpagliflozin has a favorable effect on neutropenia/neutrophil dysfunction–related symptoms and safety profile in individuals with GSD Ib.     

Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism

Stromal cell-derived factor 1 (SDF-1) plays a major role in the migration, recruitment, and retention of endothelial progenitor cells to sites of ischemic injury and contributes to neovascularization. We provide direct evidence demonstrating an important role for heme oxygenase 1 (HO-1) in mediating the proangiogenic effects of SDF-1. Nanomolar concentrations of SDF-1 induced HO-1 in endothelial cells through a protein kinase C zeta-dependent and vascular endothelial growth factor-independent mechanism. SDF-1-induced endothelial tube formation and migration was impaired in HO-1-deficient cells. Aortic rings from HO-1(-/-) mice were unable to form capillary sprouts in response to SDF-1, a defect reversed by CO, a byproduct of the HO-1 reaction. Phosphorylation of vasodilator-stimulated phosphoprotein was impaired in HO-1(-/-) cells, an event that was restored by CO. The functional significance of HO-1 in the proangiogenic effects of SDF-1 was confirmed in Matrigel plug, wound healing, and retinal ischemia models in vivo. The absence of HO-1 was associated with impaired wound healing. Intravitreal adoptive transfer of HO-1-deficient endothelial precursors showed defective homing and reendothelialization of the retinal vasculature compared with HO-1 wild-type cells following ischemia. These findings demonstrate a mechanistic role for HO-1 in SDF-1-mediated angiogenesis and provide new avenues for therapeutic approaches in vascular repair.     

Resveratrol and liver disease: from bench to bedside and community

Liver diseases incorporate several maladies, which can range from benign histological changes to serious life‐threatening conditions. These may include inborn metabolic disease, primary and metastatic cancers, alcoholic cirrhosis, viral hepatitis and drug‐induced hepatotoxicity. Liver disease remains a major cause of morbidity and mortality with significant economic and social costs. Several novel approaches are currently being studied which may provide a better therapeutic outcome. The use of naturally occurring phytochemicals, some of them obtained from dietary sources, in the amelioration of illness have recently gained considerable popularity. These agents, having anti‐oxidant and anti‐inflammatory properties, provide a safe and effective means of ameliorating chronic disease. Resveratrol, a grape polyphenol, has shown considerable promise as a therapeutic agent in the treatment of the aforementioned liver ailments. Several studies have highlighted the hepatoprotective properties of resveratrol. Resveratrol has been shown to prevent hepatic damage because of free radicals and inflammatory cytokines, induce anti‐oxidant enzymes and elevate glutathione content. Resveratrol has also been shown to modulate varied signal transduction pathways implicated in liver diseases. This review critically examines the current preclinical in vitro and in vivo studies on the preventive and therapeutic effects of resveratrol in liver diseases. The review highlights the pharmacological mechanisms involved in mediating the aforementioned effects. Toxicity, pharmacokinetics and clinical bioavailability of resveratrol are also reviewed in this article. The challenges involved, future directions and novel approaches such as site‐specific drug delivery in the use of resveratrol for the prevention and treatment of liver disease are also discussed.     

Prevention of benzene-induced genotoxicity in bone marrow and lung cells: superiority of polyphenolic acetates to polyphenols

Previous investigations carried out in our laboratory have highlighted that 7,8-diacetoxy-4-methylcoumarin demonstrates a mechanism-based inhibition of cytochrome P450 (Cyt-P450) activities such as microsome-mediated aflatoxin B₁ (AFB₁) epoxidation, dealkylation of alkylated resorufin, and toxicokinetics of benzene. 7,8-Diacetoxy-4-methylcoumarin, quercetin pentaacetate, and ellagic acid peracetate were also found to be effective in giving the protection of AFB₁-induced genotoxicity in rat’s bone marrow and lung cells possibly due to acetylation of Cyt-P450 apoprotein mediated by acetoxy drug: protein transacetylase. Later, this transacetylase was identified as calreticulin, and the acetyltransferase function of calreticulin was appropriately termed calreticulin transacetylase. In this communication, we have focused on the superiority of several classes of polyphenolic acetates to polyphenols in the modification of Cyt-P450-linked mixed function oxidases (MFOs) such as 7-ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-dealkylase (PROD). Special attention has also been focused on benzene-induced genotoxicity in bone marrow and lung cells. Results clearly indicated that polyphenolic acetates demonstrated time-dependent inhibition of Cyt-P450-linked MFOs, while parent polyphenols failed to demonstrate the same. Polyphenolic acetates were found to be more superior to polyphenols in preventing benzene-induced micronuclei formation. The pattern of inhibition of Cyt-P450-dependent MFOs and benzene-induced micronuclei formation by polyphenolic acetates was found in tune with their specificities to calreticulin transacetylase. These results further substantiated that inhibition of Cyt-P450-linked MFOs and benzene-induced genotoxicity in bone marrow and lung cells by polyphenolic acetates are mediated by the action of calreticulin transacetylase that catalyzes the acetylation of concerned proteins.     

Synthesis,radiolabeling and evaluation of a new positively charged 99mTc‐labeled fatty acid derivative for myocardial imaging

¹²³I‐labeled fatty acids and ¹⁸F‐FDG are used as metabolic markers for detecting myocardial abnormalities. However, a ^99mTc‐based molecule may find wider application. In the present work, a new ^99mTc‐labeled, uni‐positively charged, 16‐carbon fatty acid has been prepared and evaluated in normal Swiss mice. The results are then compared with the neutral analogue reported earlier. A 16‐cysteinyl hexadecanoic acid conjugate was synthesized in a six‐step synthetic procedure starting with 16‐bromohexadecanoic acid. The ligand upon incubation with [^99mTcN(PNP6)]²⁺ core formed the required positively charged complex in ～85% yield. The complex, which was obtained as a mixture of syn‐anti isomers, was purified by HPLC and the major fraction was used for in vivo studies in Swiss mice. The biodistribution studies in Swiss mice showed initial uptake similar to ¹²⁵I‐IPPA followed by rapid clearance from the myocardium till 10 min p.i. Thereafter, the rate of clearance was significantly decreased, an observation reported earlier for positively charged fatty acid complexes. In terms of absolute uptake, the positively charged complex performed better than the neutral analogue reported earlier. The positively charged fatty acid complexes, prepared using [^99mTcN(PNP)]²⁺ core, seems to be better candidates for the development of myocardial metabolic tracers than their neutral counterparts. Copyright © 2010 John Wiley & Sons, Ltd.     

Leiomyomatosis of the Esophagus: Experience over a Decade

Purpose  To assess the clinical, radiological findings, and treatment strategies in patients with esophageal leiomyomatosis. Background  Esophageal leiomyomatosis is a rare hamartomatous disorder with varied presentation. It is described mostly in children and is associated with Alport’s syndrome. Methods  A retrospective analysis of three cases managed in the Department of General Surgery at Chandigarh over a period of 10 years. Results  The study involves three female patients of different generations within the same family with age range of 10–58 years. All presented with dysphagia of 2–7 years duration. Barium swallow revealed a long-segment stricture in two patients. Computed tomography (CT) demonstrated a circumferential mass lesion in the lower esophagus in all the patients. Esophageal resection was carried out in all the patients. All patients made an uneventful recovery. Conclusions  Esophageal leiomyomatosis should be suspected in patients with long-standing dysphagia. Barium findings are suggestive but can mimic achalasia. CT scan shows a circumferential esophageal wall thickening. Surgical resection and reconstruction of the digestive passage is the optimal treatment.     

Vasoprotective endothelial effects of a standardized grape product in humans

The pathogenesis of coronary lesion development is a multi-factorial process involving a number of different cell types and covariates, and injury and dysfunction of the vascular endothelium is an important marker and likely participant in the initiation and/or progression of most forms of heart disease. In addition to chronic dysfunction of endothelial responses in patients with established heart disease, there is evidence that 'acute insults' can cause measurable dysfunction in vascular response in humans (drug toxicities, hypoxia, high fat meal). Such repeated acute insults may contribute to disease risk in otherwise healthy individuals or promote disease progression in established patients. Consumption of grape products, especially wine, has been linked to lower cardiovascular risk but the vascular endothelial effects of grape products in healthy normal subjects, in the absence of ethanol, have not been evaluated. We therefore tested the hypotheses that 1) a standardized product derived from fresh grapes (GP, acute and chronic consumption) improves endothelial performance in healthy normal young subjects, and 2) that concomitant grape consumption affects the 'acute endothelial insult' caused by a single standardized high fat meal (HF). Acute consumption of GP equivalent to 1.25 cups of fresh grapes caused significant improvement in brachial artery flow mediated dilation (FMD) within 3 h of consumption, when compared to control consumption of sugar solution (p<0.05). No acute changes in heart rate, hemodynamics, or lipid profiles were observed. When this 'dose' was then consumed twice daily for 3 weeks FMD was further improved and total antioxidant capacity in plasma was slightly increased (p<0.05), with no change in heart rate, hemodynamics, or lipid profiles. A single HF meal (900 cal, 49 g total fat) caused a 50% reduction in FMD response when consumed alone, and this effect coincided with increased blood triglyceride levels within 3 h post-consumption. In contrast the concomitant consumption of GP with the HF meal completely prevented this HF-induced vascular endothelial dysfunction (p<0.05), but had no effect on rising triglycerides. These data demonstrate that a modest intake of fresh grapes can have acute favorable effects on vascular endothelial function in normal healthy subjects, that chronic intake can further improve performance and concomitant intake can blunt the 'acute insult' to endothelium caused by a typical western HF meal. This effect is likely to be related to antioxidant effects at the endothelium, rather than changes in blood lipids. These data support epidemiological data of the health benefits of grapes, and demonstrate that 'favorable' food consumption can apparently reduce some toxicities induced by 'unfavorable' food consumption.