Effect of Colchicine on Myocardial Injury Induced by Trypanosoma cruzi in Experimental Chagas Disease

Background: The hallmark of Chagas disease (CD) is multifocal myocarditis and extensive fibrosis. We investigated the potential effect of colchicine on myocardial remodeling in experimental CD. Methods and Results: One hundred Syrian hamsters were randomly divided into noninfected untreated control (CG), noninfected control treated with colchicine (COLG 0.4 mg kg(-1) d(-1) by gavage), infected (IG), and infected treated with colchicine (ICOLG, 0.4 mg kg(-1) d(-1)) groups. The interstitial collagen volume fraction (ICVF) was evaluated by videomorphometry with picrosirius red staining. The gelatinolytic activities of matrix metalloproteinase (MMP) 2 were examined with the use of zymography. Myocarditis was described according to the Dallas criteria. Statistical comparisons were performed with parametric analysis of variance and Tukey test. ICVF (%) accumulation was attenuated in infected colchicine-treated animals in the left (CG 0.81 +/- 0.13, COLG 0.85 +/- 0.13, IG: 1.35 +/- 0.31,* ICOLG 1.06 +/- 0.19; *P < .05 compared with ICOLG) and right ventricles (CG 1.4 +/- 0.36, COLG 1.26 +/- 0.14, IG 1.97 +/- 0.058,* ICOLG: 1.52 +/- 0.23; *P < .05 compared with ICOLG). A significant increase in MMP-2 enzymatic activity (UA) was observed in ICOLG (17,432.8*) compared with GC (3731.6), COLG (2,792.6), and IG (4,286.3; *P < .001). In IG, 66% of animals had myocarditis compared with only 49% in ICOLG. Conclusions: Colchicine had a protective effect on myocardium, indicated by decreased interstitial myocardial fibrosis, increased intensity of MMP-2, and attenuated myocardial inflammation. (J Cardiac Fail 2012;18:654-659)

Aerobic exercise attenuates pulmonary injury induced by exposure to cigarette smoke

It has recently been suggested that regular exercise reduces lung function decline and risk of chronic obstructive pulmonary disease (COPD) among active smokers; however, the mechanisms involved in this effect remain poorly understood. The present study evaluated the effects of regular exercise training in an experimental mouse model of chronic cigarette smoke exposure. Male C57BL/6 mice were divided into four groups (control, exercise, smoke and smoke+exercise). For 24 weeks, we measured respiratory mechanics, mean linear intercept, inflammatory cells and reactive oxygen species (ROS) in bronchoalveolar lavage (BAL) fluid, collagen deposition in alveolar walls, and the expression of antioxidant enzymes, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase (TIMP) 1, interleukin (IL)-10 and 8-isoprostane in alveolar walls. Exercise attenuated the decrease in pulmonary elastance (p<0.01) and the increase in mean linear intercept (p=0.003) induced by cigarette smoke exposure. Exercise substantially inhibited the increase in ROS in BAL fluid and 8-isoprostane expression in lung tissue induced by cigarette smoke. In addition, exercise significantly inhibited the decreases in IL-10, TIMP1 and CuZn superoxide dismutase induced by exposure to cigarette smoke. Exercise also increased the number of cells expressing glutathione peroxidase. Our results suggest that regular aerobic physical training of moderate intensity attenuates the development of pulmonary disease induced by cigarette smoke exposure.

Coffee and Caffeine Protect against Liver Injury Induced by Thioacetamide in Male Wistar Rats

Coffee intake has been inversely related to the incidence of liver diseases, although there are controversies on whether these beneficial effects on human health are because of caffeine or other specific components in this popular beverage. Thus, this study evaluated the protective effects of coffee or caffeine intake on liver injury induced by repeated thioacetamide (TAA) administration in male Wistar rats. Rats were randomized into five groups: one untreated group (G1) and four groups (G2G5) treated with the hepatotoxicant TAA (200 similar to mg/kg b.w., i.p.) twice a week for 8 similar to weeks. Concomitantly, rats received tap water (G1 and G2), conventional coffee (G3), decaffeinated coffee (G4) or 0.1% caffeine (G5). After 8 similar to weeks of treatment, rats were killed and blood and liver samples were collected. Conventional and decaffeinated coffee and caffeine intake significantly reduced serum levels of alanine aminotransferase (ALT) (p similar to<similar to 0.001) and oxidized glutathione (p similar to<similar to 0.05), fibrosis/inflammation scores (p similar to<similar to 0.001), collagen volume fraction (p similar to<similar to 0.01) and transforming growth factor beta-1 (TGF-beta 1) protein expression (p similar to=similar to 0.001) in the liver from TAA-treated groups. In addition, conventional coffee and caffeine intake significantly reduced proliferating cellular nuclear antigen (PCNA) S-phase indexes (p similar to<similar to 0.001), but only conventional coffee reduced cleaved caspase-3 indexes (p similar to<similar to 0.001), active metalloproteinase 2 (p similar to=similar to 0.004) and the number of glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions (p similar to<similar to 0.05) in the liver from TAA-treated groups. In conclusion, conventional coffee and 0.1% caffeine intake presented better beneficial effects than decaffeinated coffee against liver injury induced by TAA in male Wistar rats.

Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline-and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J approximate to C57BL/6J approximate to C3H/HeJ < 129S1/SvImJ approximate to CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor alpha (PPAR alpha)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPAR alpha-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.-Tryndyak, V., de Conti, A., Kobets, T., Kutanzi, K., Koturbash, I., Han, T., Fuscoe, J. C., Latendresse, J. R., Melnyk, S., Shymonyak, S., Collins, L., Ross, S. A., Rusyn, I., Beland, F. A., Pogribny, I. P. Interstrain differences in the severity of liver injury induced by a choline-and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism. FASEB J. 26, 4592-4602 (2012). www.fasebj.org

Immunohistochemical evidence for myofibroblastlike cells associated with liver injury induced by Aflatoxin B1 in rainbow trout (Oncorhynchus mykiss)

In mammalian species, profibrogenic cells are activated to become myofibroblasts in response to liver damage. Few studies have examined hepatic myofibroblasts and their role in liver damage in teleosts. The aim of the present study was to investigate the involvement of myofibroblast-like cells in rainbow trout (Oncorhynchus mykiss) with hepatic damage induced by aflatoxin B1 (AFB1). Histopathological and immunohistochemical analyses characterized alterations in the liver stroma during the carcinogenic process. Anti-human a-smoothmuscle actin (SMA) and anti-human desmin primary antibodies were used in immunohistochemistry. Only the anti-SMA reagent labelled cells in trout liver. In the livers of control fish, only smooth muscle in blood vessels and around bile ducts was labelled. In the livers from AFB1-treated fish, SMA-positive cells were present in the stroma surrounding neoplastic lesions and in areas of desmoplastic reaction. These observations indicate that in teleosts, as in mammals, the myofibroblast-like cell is involved in fibrosis associated with liver injury. Chronic liver injury induced in trout by aflatoxin may provide a useful model system for study of the evolution of such mechanisms.

Protective effects of aerobic exercise on acute lung injury induced by LPS in mice

Abstract Introduction The regular practice of physical exercise has been associated with beneficial effects on various pulmonary conditions. We investigated the mechanisms involved in the protective effect of exercise in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Methods Mice were divided into four groups: Control (CTR), Exercise (Exe), LPS, and Exercise + LPS (Exe + LPS). Exercised mice were trained using low intensity daily exercise for five weeks. LPS and Exe + LPS mice received 200 µg of LPS intratracheally 48 hours after the last physical test. We measured exhaled nitric oxide (eNO); respiratory mechanics; neutrophil density in lung tissue; protein leakage; bronchoalveolar lavage fluid (BALF) cell counts; cytokine levels in BALF, plasma and lung tissue; antioxidant activity in lung tissue; and tissue expression of glucocorticoid receptors (Gre). Results LPS instillation resulted in increased eNO, neutrophils in BALF and tissue, pulmonary resistance and elastance, protein leakage, TNF-alpha in lung tissue, plasma levels of IL-6 and IL-10, and IL-1beta, IL-6 and KC levels in BALF compared to CTR (P ≤0.02). Aerobic exercise resulted in decreases in eNO levels, neutrophil density and TNF-alpha expression in lung tissue, pulmonary resistance and elastance, and increased the levels of IL-6, IL-10, superoxide dismutase (SOD-2) and Gre in lung tissue and IL-1beta in BALF compared to the LPS group (P ≤0.04). Conclusions Aerobic exercise plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of exercise are mainly mediated by the expression of anti-inflammatory cytokines and antioxidants, suggesting that exercise can modulate the inflammatory-anti-inflammatory and the oxidative-antioxidative balance in the early phase of ALI.

Effect of endogenous hydrogen sulfide inhibition on structural and functional renal disturbances induced by gentamicin

Animal models of gentamicin nephrotoxicity present acute tubular necrosis associated with inflammation, which can contribute to intensify the renal damage. Hydrogen sulfide (H2S) is a signaling molecule involved in inflammation. We evaluated the effect of DL-propargylglycine (PAG), an inhibitor of endogenous H2S formation, on the renal damage induced by gentamicin. Male Wistar rats (N = 8) were injected with 40 mg/kg gentamicin (im) twice a day for 9 days, some of them also received PAG (N = 8, 10 mg·kg-1·day-1, ip). Control rats (N = 6) were treated with saline or PAG only (N = 4). Twenty-four-hour urine samples were collected one day after the end of these treatments, blood samples were collected, the animals were sacrificed, and the kidneys were removed for quantification of H2S formation and histological and immunohistochemical studies. Gentamicin-treated rats presented higher sodium and potassium fractional excretion, increased plasma creatinine [4.06 (3.00; 5.87) mg%] and urea levels, a greater number of macrophages/monocytes, and a higher score for tubular interstitial lesions [3.50 (3.00; 4.00)] in the renal cortex. These changes were associated with increased H2S formation in the kidneys from gentamicin-treated rats (230.60 ± 38.62 µg·mg protein-1·h-1) compared to control (21.12 ± 1.63) and PAG (11.44 ± 3.08). Treatment with PAG reduced this increase (171.60 ± 18.34), the disturbances in plasma creatinine levels [2.20 (1.92; 4.60) mg%], macrophage infiltration, and score for tubular interstitial lesions [2.00 (2.00; 3.00)]. However, PAG did not interfere with the increase in fractional sodium excretion provoked by gentamicin. The protective effect of PAG on gentamicin nephrotoxicity was related, at least in part, to decreased H2S formation.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) phosphorylation by protein kinase Cδ (PKCδ) inhibits mitochondria elimination by lysosomal-like structures following ischemia and reoxygenation-induced injury

Background: How damaged mitochondria are removed by mitophagy is not fully described. Results: Ischemia and reoxygenation (I/R)-induced injury triggers mitochondria association of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and mitophagy, and protein kinase Cδ (PKCδ) activation inhibits it. Conclusion: PKCδ-mediated phosphorylation of GAPDH inhibits mitophagy. Significance: GAPDH/PKCδ is a signaling switch, which is activated during ischemic injury to regulate the balance between cell survival by mitophagy and cell death by apoptosis.

Impact of arterial injury on neointimal hyperplasia after implantation of drug-eluting stents in coronary arteries: an intravascular ultrasound study

Aims: We investigated the impact of arterial injury on neointimal hyperplasia following implantation of drug-eluting stents (DES). Methods and results: A total of 196 patients with 223 segments (sirolimus-eluting stents [SES]: 104, paclitaxel-eluting stents [PES]: 119) underwent intravascular ultrasound eight months after DES implantation. Arterial injury was defined as the balloon-to-artery ratio (BAR). Segments were categorised into two groups: high BAR defined as BAR>1.1 (120 segments), and low BAR defined as BAR ≤1.1 (103 segments). Baseline clinical characteristics were similar for both groups. Although reference vessel diameter was smaller, stent diameter, maximal balloon pressure and balloon diameter were higher in the high BAR compared with the low BAR group. Lumen (7.10±1.91 vs. 6.25±1.69, p=0.001), stent (7.31±1.95 vs. 6.41±1.80, p=0.001), and external elastic membrane (17.1±4.9 vs. 14.8±4.0, p<0.0001) areas (mm2) were higher, but neointimal hyperplasia (0.21±0.36 vs. 0.16±0.48, p=0.42) area (mm2) was similar in the high BAR compared with the low BAR group. Arterial injury as assessed by BAR was not associated with the amount of neointimal hyperplasia (R2=0.003, p=0.40). Conclusions: Arterial injury does not correlate with the amount of neointimal hyperplasia following DES implantation. Conventionally aggressive DES implantation techniques do not adversely affect long-term outcome with respect to restenosis. - See more at: http://www.pcronline.com/eurointervention/30th_issue/79/#sthash.1do4X31G.dpuf

Inflammatory myopathy and severe rhabdomyolysis induced by leuprolide acetate therapy for prostate cancer: a case report

Introduction Leuprolide acetate is a synthetic analog of gonadotropin-releasing hormone used for the treatment of prostate cancer. Its side effects are hot flashes, nausea, and fatigue. We report a case of a patient with proximal inflammatory myopathy accompanied by severe rhabdomyolysis and renal failure following the second application of leuprolide acetate. Drug withdrawal and steroid therapy resulted in remission within six weeks of the diagnosis. To the best of our knowledge, our case report describes the second case of leuprolide acetate-induced inflammatory myopathy and the first case of severe leuprolide acetate-induced rhabdomyolysis and renal failure in the literature. Case presentation A 64-year-old Swiss Caucasian man was admitted to the hospital because of progressive proximal muscle weakness, dyspnea, and oliguria. He had been treated twice with leuprolide acetate in monthly doses. We performed a muscle biopsy, which excluded other causes of myopathy. The patient's renal failure and rhabdomyolysis were treated with rehydration and steroid therapy. Conclusion The aim of our case report is to highlight the rare but severe side effects associated with leuprolide acetate therapy used to treat patients with inflammatory myopathy: severe rhabdomyolysis and renal failure.

Sphingosylphosphorylcholine acts in an anti-inflammatory manner in renal mesangial cells by reducing interleukin-1beta-induced prostaglandin E2 formation

Sphingosylphosphorylcholine (SPC) is a bioactive lipid that binds to G protein-coupled-receptors and activates various signaling cascades. Here, we show that in renal mesangial cells, SPC not only activates various protein kinase cascades but also activates Smad proteins, which are classical members of the transforming growth factor-beta (TGFbeta) signaling pathway. Consequently, SPC is able to mimic TGFbeta-mediated cell responses, such as an anti-inflammatory and a profibrotic response. Interleukin-1beta-stimulated prostaglandin E(2) formation is dose-dependently suppressed by SPC, which is paralleled by reduced secretory phospholipase A(2) (sPLA(2)) protein expression and activity. This effect is due to a reduction of sPLA(2) mRNA expression caused by inhibited sPLA(2) promoter activity. Furthermore, SPC upregulates the profibrotic connective tissue growth factor (CTGF) protein and mRNA expression. Blocking TGFbeta signaling by a TGFbeta receptor kinase inhibitor causes an inhibition of SPC-stimulated Smad activation and reverses both the negative effect of SPC on sPLA(2) expression and the positive effect on CTGF expression. In summary, our data show that SPC, by mimicking TGFbeta, leads to a suppression of proinflammatory mediator production and stimulates a profibrotic cell response that is often the end point of an anti-inflammatory reaction. Thus, targeting SPC receptors may represent a novel therapeutic strategy to cope with inflammatory diseases.

FTY720 suppresses interleukin-1beta-induced secretory phospholipase A2 expression in renal mesangial cells by a transcriptional mechanism

BACKGROUND AND PURPOSE: FTY720 is a potent immunomodulatory prodrug that is converted to its active phosphorylated form by a sphingosine kinase. Here we have studied whether FTY720 mimicked the action of sphingosine-1-phosphate (S1P) and exerted an anti-inflammatory potential in renal mesangial cells. EXPERIMENTAL APPROACH: Prostaglandin E(2) (PGE(2)) was quantified by an enzyme-linked immunosorbent-assay. Secretory phospholipase A(2) (sPLA(2)) protein was detected by Western blot analyses. mRNA expression was determined by Northern blot analysis and sPLA(2)-promoter activity was measured by a luciferase-reporter-gene assay. KEY RESULTS: Stimulation of cells for 24 h with interleukin-1beta (IL-1beta) is known to trigger increased PGE(2) formation which coincides with an induction of the mRNA for group-IIA-sPLA(2) and protein expression. FTY720 dose-dependently suppressed IL-1beta-induced IIA-sPLA(2) protein secretion and activity in the supernatant. This effect is due to a suppression of cytokine-induced sPLA(2) mRNA expression which results from a reduced promoter activity. As a consequence of suppressed sPLA(2) activity, PGE(2) formation is also reduced by FTY720. Mechanistically, the FTY720-suppressed sPLA(2) expression results from an activation of the TGFbeta/Smad signalling cascade since inhibition of the TGFbeta receptor type I by a specific kinase inhibitor reverses the FTY720-mediated decrease of sPLA(2) protein expression and sPLA(2) promoter activity. CONCLUSIONS AND IMPLICATIONS: In summary, our data show that FTY720 was able to mimic the anti-inflammatory activity of TGFbeta and blocked cytokine-triggered sPLA(2) expression and subsequent PGE(2) formation. Thus, FTY720 may exert additional in vivo effects besides the well reported immunomodulation and its anti-inflammatory potential should be considered.

Systemic hypertension and proteinuria in childhood chronic renal parenchymal disease: role of antihypertensive drug management

A variety of chronic kidney diseases tend to progress towards end-stage kidney disease. Progression is largely due to factors unrelated to the initial disease, including systemic hypertension and proteinuria. Drugs that block the renin-angiotensin II-aldosterone system, either ACE inhibitors or angiotensin II receptor antagonists, reduce both BP and proteinuria and appear superior to a more conventional antihypertensive treatment regimen in preventing progression to end-stage kidney disease. The most recent recommendations state that the BP goal in children with chronic kidney disease is the corresponding 90th centile for body height, age, and gender.Since satisfactory BP control is often not achieved, the mnemonic acronym DELTAREPROSI was generated to recall the following tips for the practical management of hypertension and proteinuria in childhood chronic renal parenchymal disease: DEfinition of hypertension and Low blood pressure TArget in REnal disease (90th centile calculated by means of simple formulas), potential of drugs inhibiting the REnin-angiotensin II-aldosterone system in hypertension and PROteinuria, advantages of SImplified treatment regimens and escalating the doses every SIx weeks.

[Drug therapy of type-II diabetes: tablets, insulin or a combination of these]

Optimal therapy of diabetes has to be based on the known pathophysiology of metabolic disturbances and should eventually alleviate reduced secretion of insulin as well as reduce the usually present resistance to insulin in order to normalize the average blood glucose levels. In less than 30% of patients with type-II diabetes, dietetic measures combined with increased physical activity alone, are sufficient for metabolic control, thus increasing the importance of pharmacologic treatment immensely. Biguanides are the therapeutic choice in patients with massive overweight, because they usually do not induce weight gain; however, specific contraindications (renal failure in particular) have to be taken into consideration. The effect of blood glucose lowering by biguanides is not due to increased secretion of insulin, thus neither hypoglycemias nor hyperinsulinism are induced or increased, respectively. Patients with normal or slightly increased body weight should profit best from sulfonylureas that stimulate insulin production. Combinations of sulfonylurea and biguanides or of insulin and oral antidiabetics or insulin alone have to be taken into account when monotherapy with oral antidiabetics is too inefficient; however, clear and generally accepted guidelines for correct indications of these therapeutic modalities are lacking. Particularly in long-lasting diabetes and for patients with distinct overweight an adequate therapeutic success is often not obtained with the currently available therapeutic means. Possibly, future developments will provide new therapeutic ways with drugs that increase insulin sensitivity or reduce gluconeogenesis.