Metabolites of Purine Nucleoside Phosphorylase (NP) in Serum Have the Potential to Delineate Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC

The Efficacy of Exercise in Reducing Depressive Symptoms among Cancer Survivors: A Meta-Analysis

INTRODUCTION: The purpose of this meta-analysis was to examine the efficacy of exercise to reduce depressive symptoms among cancer survivors. In addition, we examined the extent to which exercise dose and clinical characteristics of cancer survivors influence the relationship between exercise and reductions in depressive symptoms. METHODS: We conducted a systematic search identifying randomized controlled trials of exercise interventions among adult cancer survivors, examining depressive symptoms as an outcome. We calculated effect sizes for each study and performed weighted multiple regression moderator analysis. RESULTS: We identified 40 exercise interventions including 2,929 cancer survivors. Diverse groups of cancer survivors were examined in seven exercise interventions; breast cancer survivors were examined in 26; prostate cancer, leukemia, and lymphoma were examined in two; and colorectal cancer in one. Cancer survivors who completed an exercise intervention reduced depression more than controls, d(+) = -0.13 (95% CI: -0.26, -0.01). Increases in weekly volume of aerobic exercise reduced depressive symptoms in dose-response fashion (β = -0.24, p = 0.03), a pattern evident only in higher quality trials. Exercise reduced depressive symptoms most when exercise sessions were supervised (β = -0.26, p = 0.01) and when cancer survivors were between 47-62 yr (β = 0.27, p = 0.01). CONCLUSION: Exercise training provides a small overall reduction in depressive symptoms among cancer survivors but one that increased in dose-response fashion with weekly volume of aerobic exercise in high quality trials. Depressive symptoms were reduced to the greatest degree among breast cancer survivors, among cancer survivors aged between 47-62 yr, or when exercise sessions were supervised

Scavenging of peroxynitrite by phycocyanin and phycocyanobilin from spirulina platensis: protection against oxidative damage to DNA

Peroxynitrite (ONOO- is known to inactivate important cellular targets and also mediate oxidative damage in DNA. The present study has demonstrated that phycocyanin, a biliprotein from spirulina platensis and its chromophore, phycocyanobilin (PCB), efficiently scavenge ONOO-, a potent physiological inorganic toxin. Scavenging of ONOO- by phycocyanin and PCB was established by studying their interaction with ONOO- and quantified by using competition kinetics of pyrogallol red bleaching assay. The relative antioxidant ratio and IC50 value clearly indicate that phycocyanin is a more efficient ONOO- scavenger than PCB. The present study has also shown that PCB significantly inhibits the ONOO--mediated single-strand breaks in supercoiled plasmid DNA in a dose-dependent manner with an IC50 value of 2.9 ± 0.6 μM. These results suggest that phycocyanin, has the ability to inhibit the ONOO--mediated deleterious biological effects and hence has the potential to be used as a therapeutic agent

Antioxidant and radical scavenging properties of 8-oxo derivatives of xanthine drugs pentoxifylline and lisofylline

The antioxidant and radical scavenging properties of 8-oxo derivatives of pentoxifylline, lisofylline, enprofylline (3-propyl xanthine), and 1,7-dimethyl enprofylline were studied in vitro. The results show that 8-oxopentoxifylline and 8-oxolisofylline are significantly better hydroxyl and peroxyl radical scavengers and more potent inhibitors of t-butylhydroperoxide-induced lipid peroxidation in human erythrocyte membranes than the parent drugs. The hydroxyl radical scavenging property of 8-oxoenprofylline and its analogue 1,7-dimethyl-8-oxoenprofylline is marginally better than their corresponding xanthines. Interestingly, 1,7-dimethyl-8-oxoenprofylline is an effective inhibitor of lipid peroxidation whereas enprofylline, 1,7-dimethylenprofylline, and 8-oxoenprofylline exhibit significantly less activity. All the 8-oxo derivatives tested are better hydroxyl radical scavengers than uric acid, a natural antioxidant and a free radical scavenger in humans. The rate constant for the reaction between 8-oxopentoxifylline and hydroxyl radical is 1.6-4.2 × 1010 M-1 s-1 which is comparable to that of dimethyl sulfoxide (1.4-1.6 × 1010 M-1 s-1) and better than that of mannitol (1.9-2.5 × 109 M-1 s-1), the known hydroxyl radical scavengers. Both 8-oxo pentoxifylline (IC50, 1.8 ± 0.08 μM) and 8-oxolisofylline (IC50, 2.2 ± 0.13 μM) are as efficient peroxyl radical scavengers as uric acid (IC50, 1.9 ± 0.05 μM). The results presented clearly indicate that the anti-inflammatory property of pentoxifylline and lisofylline is exerted more through their 8-oxo derivatives than through the parent drugs

Efficient scavenging of hydroxyl radicals and inhibition of lipid peroxidation by novel analogues of 1,3,7-trimethyluric acid

New water-soluble analogues of 1,3,7-trimethyluric acid with N-1 methyl replaced by various groups were prepared and evaluated for their ability to scavenge hydroxyl radicals as well as their protective potential against lipid peroxidation in erythrocyte membranes. The deoxyribose degradation method indicates that all the analogues tested effectively scavenge hydroxyl radicals and some of them show better activity than uric acid and methyluric acids. These effects are shown to be concentration dependent and are more potent at low concentrations (10-50 μM). Among the analogues tested, 1-butenyl-, 1-propargyl- and 1-benzyl-3,7-dimethyluric acids show high hydroxyl radical scavenging property with a reaction rate constant (Ks) of 3.2-6.7 × 1010 M-1 S-1, 2.3-3.7 × 1010 M-1 S-1 and 2.4-3.7 × 1010 M-1 S-1, respectively. The effectiveness of these analogues as hydroxyl radical scavengers appears to be better than mannitol (Ks, 1.9-2.5 × 109 M-1 S-1). With the exception of 1-pentyl- and 1-(2'-oxopropyl)-3,7-dimethyluric acids, all other analogues tested are effective inhibitors of tert-butylhydroperoxide-induced lipid peroxidation in human erythrocyte membranes. All the analogues tested are susceptible to peroxidation in the presence of hemoprotein and hydrogen peroxide. The present study has pointed out that it is possible to significantly enhance the antioxidant property of 1,3,7-trimethyluric acid by structural modification at N-1 position. Such compounds may be useful as antioxidants in vivo

Hepatoprotective effect of C-phycocyanin: protection for carbon tetrachloride and R-(+)-pulegone-mediated hepatotoxicty in rats

Effect of C-phycocyanin (fromSpirulina platensis) pretreatment on carbontetrachloride and R-(+)-pulegone-induced hepatotoxicity in rats was studied. Intraperitoneal (i.p.) administration (200 mg/kg) of a single dose of phycocyanin to rats, one or three hours prior to R-(+)-pulegone (250 mg/kg) or carbontetrachloride (0.6 ml/kg) challenge, significantly reduced the hepatotoxicity caused by these chemicals. For instance, serum glutamate pyruvate transaminase (SGPT) activity was almost equal to control values. The losses of microsomal cytochrome P450, glucose-6-phosphatase and aminopyrine-N-demethylase were significantly reduced, suggesting that phycocyanin provides protection to liver enzymes. It was noticed that the level of menthofuran, the proximate toxin of R-(+)-pulegone was nearly 70% more in the urine samples collected from rats treated with R-(+)-pulegone alone than rats treated with the combination of phycocyanin and R-(+)-pulegone. The possible mechanism involved in the hepatoprotection is discussed

Serum phosphodiesterase levels in oral cancer

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies recognized nowadays. Its early detection is the better alternative to provide a good quality of life for the patients. During the last years, several studies have identified potential biomarkers of OSCC progression and prognosis. The phosphodiesterases (PDEs) are responsible for the hydrolysis of the second messengers with a fundamental role in the transduction of the intracellular signals. Variations in PDE activity have been correlated to different pathological mechanisms, such as cellular differentiation, apoptosis, and tumor invasivity. PDEs are also known to play a role in tumor growth by influencing angiogenesis. Aim: To estimate and compare serum PDE levels in healthy controls and biopsy-proven oral cancer patients before definitive therapy. Materials and Methods: Institutional Ethics Committee gave us the permission to conduct this study. After obtaining consent from biopsy-proven oral cancer patients (n = 39) (before onset of any definitive treatment) and age- and sex-matched healthy controls (n = 20), 2 ml of blood was collected in plain vacutainers. After clot formation, samples were centrifuged and serum was collected for estimation of PDE. Statistical Analysis: Kruskal-Wallis test; Mann-Whitney Test Results and Discussion: Pretreatment PDE levels were significantly elevated in oral cancer patients (P<0.0001) as compared with the controls and also there was a significant increase in PDE levels (P<0.001) with advancing stage in oral cancer patients. This may implicate a role for serum PDE in pathophysiology of oral cancer

Serum phosphodiesterase levels in oral cancer

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies recognized nowadays. Its early detection is the better alternative to provide a good quality of life for the patients. During the last years, several studies have identified potential biomarkers of OSCC progression and prognosis. The phosphodiesterases (PDEs) are responsible for the hydrolysis of the second messengers with a fundamental role in the transduction of the intracellular signals. Variations in PDE activity have been correlated to different pathological mechanisms, such as cellular differentiation, apoptosis, and tumor invasivity. PDEs are also known to play a role in tumor growth by influencing angiogenesis. Aim: To estimate and compare serum PDE levels in healthy controls and biopsy-proven oral cancer patients before definitive therapy. Materials and Methods: Institutional Ethics Committee gave us the permission to conduct this study. After obtaining consent from biopsy-proven oral cancer patients (n = 39) (before onset of any definitive treatment) and age- and sex-matched healthy controls (n = 20), 2 ml of blood was collected in plain vacutainers. After clot formation, samples were centrifuged and serum was collected for estimation of PDE. Statistical Analysis: Kruskal-Wallis test; Mann-Whitney Test Results and Discussion: Pretreatment PDE levels were significantly elevated in oral cancer patients (P&lt;0.0001) as compared with the controls and also there was a significant increase in PDE levels (P&lt;0.001) with advancing stage in oral cancer patients. This may implicate a role for serum PDE in pathophysiology of oral cancer

High-Glucose-Induced Regulation of Intracellular ANG II Synthesis and Nuclear Redistribution in Cardiac Myocytes

The prevailing paradigm is that cardiac ANG II is synthesized in the extracellular space from components of the circulating and/or local renin-angiotensin system. The recent discovery of intracrine effects of ANG II led us to determine whether ANG II is synthesized intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent angiotensin type 1 (AT1) receptor-mediated internalization of ANG II. ANG II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized ANG II, respectively. Isoproterenol increased ANG II concentration in cell lysates and medium of NRVM in the absence or presence of candesartan. High glucose markedly increased ANG II synthesis only in cell lysates in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin, and chymase in high-glucose-exposed cells. Confocal immunofluorocytometry confirmed the presence of ANG II in the cytoplasm and nucleus of high-glucose-exposed NRVM and along the actin filaments in isoproterenol-exposed cells. ANG II synthesis was dependent on renin and chymase in high-glucose-exposed cells and on renin and angiotensin-converting enzyme in isoproterenol-exposed cells. In summary, the site of ANG II synthesis, intracellular localization, and the synthetic pathway in NRVM are stimulus dependent. Significantly, NRVM synthesized and retained ANG II intracellularly, which redistributed to the nucleus under high-glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions