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1.
Int J Chron Obstruct Pulmon Dis ; 14: 2291-2304, 2019.
Article in English | MEDLINE | ID: mdl-31631999

ABSTRACT

Purpose: Pulmonary rehabilitation (PR) is essential to manage patients with COPD. The aim of this study was to investigate the appropriate intensity of PR exercise training for patients with moderate-to-severe COPD. Patients and methods: A prospective multicenter randomized controlled trial was conducted from January 2014 to October 2018. The subjects were randomly assigned to three groups with different intensities of PR, according to their maximum oxygen uptake percentage determined by cardiopulmonary exercise testing. After 20 weeks of exercise training, the effects of low-, moderate-, and high-intensity exercise interventions on patients were compared to determine the most appropriate PR prescription. Results: For patients with moderate COPD, all the measured parameters were significantly improved in the moderate- and high-intensity PR groups (P<0.01), while there was no significant difference in the frequency of acute exacerbations and the mMRC questionnaire after 20 weeks of PR exercise in the low-intensity PR group. For patients with severe COPD, all variables were also improved in the high-intensity PR group (P<0.05), while the mean differences of pre- and post-PR were lower than those in patients with moderate COPD. Moreover, the Hamilton Anxiety Scale and body mass index showed no significant difference in low-intensity PR group (P>0.05). Conclusion: High-intensity PR exercise is helpful for patients with moderate to severe COPD. Moderate COPD patients need to receive intensive PR training; the improvement degrees from PR intervention were higher than those of the severe COPD patients. For patients with severe COPD, high-intensity PR exercise may be more beneficial if patients can tolerate it.


Subject(s)
Exercise Therapy , Pulmonary Disease, Chronic Obstructive/rehabilitation , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Single-Blind Method
2.
Neurourol Urodyn ; 37(4): 1272-1280, 2018 04.
Article in English | MEDLINE | ID: mdl-29160569

ABSTRACT

AIMS: To investigate the feasibility of restoring bladder function and prevention of renal deterioration by neurorrhaphy in rats with neurogenic bladder (NB). METHODS: Forty-two rats were assigned to the end-to-side nerve coaptation group (ECG, n = 16), no nerve coaptation group (NCG, n = 16), and control group (CG, n = 10). In the ECG, the left ventral root (VR) and dorsal root (DR) of L6 and S1 were transected, and the distal stump of L6VR was sutured to the lateral face of L4VR. In the NCG, the left VR and DR of L6 and S1 were transected, but coaptation was not performed. In the CG, no operation was performed. Nerve regeneration, bladder function, and renal function were evaluated by FluoroGold (FG) retrograde tract tracing, cystometry, electrical stimulation, MRI, histology and biochemical assays. RESULTS: In the ECG, FG-labeled neurons were observed in the left ventral horn of L4 spinal cord. There was a significant increase in intravesical pressure upon stimulation of the left L4VR proximal to the coaptation. Maximum cystometric capacity, post-void residual urine, bladder compliance and weight, serum creatinine, blood urea nitrogen, and fibrotic area of bladder and kidney were lower in the ECG than in the NCG, but higher than the CG. Hydronephrosis was noticed in ECG and NCG rats. Maximum detrusor voiding pressure was higher in the ECG and CG than in the NCG. CONCLUSIONS: End-to-side neurorrhaphy is a useful method for restoring bladder function and preventing renal injury in rats with NB.


Subject(s)
Kidney/physiopathology , Nerve Regeneration , Plastic Surgery Procedures/methods , Spinal Nerve Roots/physiopathology , Urinary Bladder, Neurogenic/surgery , Animals , Male , Rats , Rats, Sprague-Dawley , Spinal Cord Injuries/physiopathology , Urinary Bladder, Neurogenic/physiopathology , Urination/physiology
3.
Sci Rep ; 7(1): 3182, 2017 06 09.
Article in English | MEDLINE | ID: mdl-28600556

ABSTRACT

Anthracycline drugs such as doxorubicin (DOX) and daunorubicin remain some of the most active wide-spectrum and cost-effective drugs in cancer therapy. However, colorectal cancer (CRC) cells are inherently resistant to anthracyclines which at higher doses cause cardiotoxicity. Our recent studies indicate that aldose reductase (AR) inhibitors such as fidarestat inhibit CRC growth in vitro and in vivo. Here, we show that treatment of CRC cells with fidarestat increases the efficacy of DOX-induced death in HT-29 and SW480 cells and in nude mice xenografts. AR inhibition also results in higher intracellular accumulation of DOX and decreases the expression of drug transporter proteins MDR1, MRP1, and ABCG2. Further, fidarestat also inhibits DOX-induced increase in troponin-I and various inflammatory markers in the serum and heart and restores cardiac function in mice. These results suggest that fidarestat could be used as adjuvant therapy to enhance DOX sensitivity of CRC cells and to reduce DOX-associated cardiotoxicity.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Cardiotoxicity/drug therapy , Colonic Neoplasms/drug therapy , Doxorubicin/administration & dosage , Imidazolidines/administration & dosage , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Aldehyde Reductase/genetics , Animals , Cell Proliferation , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Doxorubicin/adverse effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , HT29 Cells , Humans , Mice , Multidrug Resistance-Associated Proteins/genetics , Neoplasm Proteins/genetics , Xenograft Model Antitumor Assays
4.
JACC Basic Transl Sci ; 1(4): 235-250, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27747306

ABSTRACT

BACKGROUND: Chagasic cardiomyopathy (CCM) caused by Trypanosoma cruzi (Tc) infection is prevalent in Latin America and recognized as an emerging infectious heart disease in the US. The NO-cGMP-PKG1α pathway maintains cardiac homeostasis and inotropy and may be disturbed due to phosphodiesterase (PDE5) mediated cGMP catabolism in CCM. METHODS AND RESULTS: C57BL/6 mice were infected with Tc, and at the end of acute parasitemia (i.e. 45 days post-infection), treated with sildenafil (SIL, 1 mg/kg) twice per week for 3 weeks. Mice were monitored at 150 days post-infection corresponding to chronic disease phase. The cGMP/PKG activity was decreased by 2-fold and PDE5 expression was increased by 1.4-fold and 100% at RNA and protein levels, respectively, in chagasic myocardium. Transthoracic echocardiography showed the left ventricular (LV) systolic function, i.e., stroke volume, cardiac output, and ejection fraction, were significantly decreased in chagasic mice. Sildenafil treatment resulted in normal levels of PDE5 and cGMP/PKG activity and preserved the LV function in chagasic mice. The cardioprotective effects of SIL were provided through inhibition of cardiac collagenosis and chronic inflammation that otherwise were pronounced in CCM. Further, mtDNA-encoded gene expression and ADP-coupled mitochondrial respiration were decreased and mitochondrial oxidative stress and cellular oxidative damage (lipid hydroperoxides and protein carbonyls) were increased in chagasic myocardium. SIL treatment restored the mtDNA-encoded gene expression and complex I (but not complex II) dependent ADP-coupled respiration, and established the oxidant/antioxidant balance in chagasic myocardium. In vitro studies in cardiomyocytes verified that SIL conserved the redox metabolic state and cellular health via maintaining the antioxidant status that otherwise was compromised in response to Tc infection. CONCLUSION: SIL therapy was useful in controlling the LV dysfunction and chronic pathology in CCM.

5.
PLoS Pathog ; 12(10): e1005954, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27764247

ABSTRACT

Chronic chagasic cardiomyopathy (CCM) is presented by increased oxidative/inflammatory stress and decreased mitochondrial bioenergetics. SIRT1 senses the redox changes and integrates mitochondrial metabolism and inflammation; and SIRT1 deficiency may be a major determinant in CCM. To test this, C57BL/6 mice were infected with Trypanosoma cruzi (Tc), treated with SIRT1 agonists (resveratrol or SRT1720), and monitored during chronic phase (~150 days post-infection). Resveratrol treatment was partially beneficial in controlling the pathologic processes in Chagas disease. The 3-weeks SRT1720 therapy provided significant benefits in restoring the left ventricular (LV) function (stroke volume, cardiac output, ejection fraction etc.) in chagasic mice, though cardiac hypertrophy presented by increased thickness of the interventricular septum and LV posterior wall, increased LV mass, and disproportionate synthesis of collagens was not controlled. SRT1720 treatment preserved the myocardial SIRT1 activity and PGC1α deacetylation (active-form) that were decreased by 53% and 9-fold respectively, in chagasic mice. Yet, SIRT1/PGC1α-dependent mitochondrial biogenesis (i.e., mitochondrial DNA content, and expression of subunits of the respiratory complexes and mtDNA replication machinery) was not improved in chronically-infected/SRT1720-treated mice. Instead, SRT1720 therapy resulted in 2-10-fold inhibition of Tc-induced oxidative (H2O2 and advanced oxidation protein products), nitrosative (inducible nitric oxide synthase, 4-hydroxynonenal, 3-nitrotyrosine), and inflammatory (IFNγ, IL1ß, IL6 and TNFα) stress and inflammatory infiltrate in chagasic myocardium. These benefits were delivered through SIRT1-dependent inhibition of NFκB transcriptional activity. We conclude that Tc inhibition of SIRT1/PGC1α activity was not a key mechanism in mitochondrial biogenesis defects during Chagas disease. SRT1720-dependent SIRT1 activation led to suppression of NFκB transcriptional activity, and subsequently, oxidative/nitrosative and inflammatory pathology were subdued, and antioxidant status and LV function were enhanced in chronic chagasic cardiomyopathy.


Subject(s)
Chagas Cardiomyopathy/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Oxidative Stress/drug effects , Sirtuin 1/metabolism , Stilbenes/pharmacology , Animals , Antioxidants/pharmacology , Blotting, Western , Disease Models, Animal , Heart/drug effects , Humans , Inflammation/metabolism , Mice , Mice, Inbred C57BL , NF-kappa B/drug effects , NF-kappa B/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Resveratrol , Signal Transduction/physiology , Sirtuin 1/drug effects , Transcriptome , Trypanosoma cruzi
6.
Parasitol Res ; 113(9): 3159-65, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24948102

ABSTRACT

The protozoan parasite Trypanosoma cruzi causes Chagas disease. Cardiac and adipose tissues are among the early targets of infection and are sites of persistent infection. In the heart and adipose tissue, T. cruzi infection results in an upregulation of pro-inflammatory mediators. In the heart, infection is associated with an increase in the markers of oxidative stress. To date, markers of oxidative stress have not been evaluated in adipose tissue in this infection. Brown and white adipose tissues were obtained from CD-1 mice infected with the Brazil strain of T. cruzi for 15, 30, and 130 days post infection. Protein carbonylation and lipid peroxidation assays were performed on these samples. There was an upregulation of these markers of oxidative stress at all time-points in both white and brown adipose tissue. Determinants of anti-oxidative stress were downregulated at similar time-points. This increase in oxidative stress during T. cruzi infection most likely has a deleterious effect on host metabolism and on the heart.


Subject(s)
Adipose Tissue/metabolism , Chagas Disease/metabolism , Oxidative Stress/physiology , Trypanosoma cruzi , Animals , Biomarkers , Chagas Disease/parasitology , Gene Expression Regulation , Male , Mice
7.
Urolithiasis ; 41(3): 265-6, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23549684

ABSTRACT

The melamine-contaminated milk powder incidence occurred in China in 2008. Many studies have been published regarding the epidemiology, clinical symptoms, diagnosis and treatment of melamine-related urinary stones. The objective of this study is to follow-up the effects of melamine-contaminated milk powder consumption on kidney and body growth in children with melamine-related urinary stones 4 years ago. One hundred and one children with melamine-related urinary stones were followed up by urinalysis, renal function tests and urinary ultrasonography. The data of body weight and height, clinical signs and complications were collected. Eighty normal children without the history of consuming melamine-contaminated milk powder were collected as controls. Eighty-one children with melamine-related urinary stones were successfully followed up. Of 45 cases with melamine-related urinary stones treated conservatively after discharge, 34 disappeared completely, 6 dissolved partially, 1 increased in size and 4 did not change at 4 years follow-up. The percentages of under-height and under-weight infants were significantly higher in melamine-related urinary stones group compared to the controls, respectively (p < 0.05). Routine blood, renal and bladder function tests as well as urinalysis were normal in all children. No urological tumors were detected. No noticeable impact of melamine-related urinary stones on kidney and bladder was found at 4 years follow-up. However, whether or not melamine-related urinary stones had effect on body growth needs follow-up in future.


Subject(s)
Food Contamination , Milk/toxicity , Triazines/toxicity , Urinary Calculi/etiology , Urinary Calculi/therapy , Animals , Case-Control Studies , Child , Child Development , Child, Preschool , China , Female , Follow-Up Studies , Humans , Infant , Infant Formula , Kidney/pathology , Male , Powders , Urinary Calculi/pathology
8.
J Dig Dis ; 13(12): 642-8, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23134554

ABSTRACT

OBJECTIVE: To investigate the success and recurrence rates and factors influencing the effect of endoscopic therapy for patients with biliary stricture after orthotopic liver transplantation (OLT). METHODS: Data of 56 patients who underwent endoscopic therapy for biliary stricture after OLT from 2006 to 2009 were reviewed in this study. Their clinical data, laboratory parameters and endoscopic features were recorded. RESULTS: Biliary stricture was treated successfully in 47 patients (83.9%). Compared with those with treatment failure, there was a longer duration from OLT to initial presentations (P = 0.02) in the successful group, fewer endoscopic retrograde cholangiopancreatography (ERCP) treatments (P < 0.01) and fewer stents inserted per patient (P < 0.01). Multivariate analysis showed that the number of ERCP treatments per patient was negatively related with treatment success. Of the 47 patients successfully treated, stricture recurred in 13 (27.7%) during follow-up. Compared with those without recurrence, the recurrence group had a shorter initial presentation time after OLT, higher serum alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase levels, higher numbers of ERCP treatments and stents used and a longer duration of treatment (P < 0.01 for all). Multivariate analysis showed that the treatment duration was a risk factor for recurrence (OR 2.33, 95% CI 1.34-4.05, P < 0.01). CONCLUSIONS: Endoscopic treatment is a safe and effective modality for biliary stricture after OLT. The number of ERCP treatments per patient is negatively related with treatment success and long treatment duration was a risk factor for stricture recurrence.


Subject(s)
Biliary Tract Diseases/surgery , Cholangiopancreatography, Endoscopic Retrograde/methods , Cholestasis/surgery , Liver Transplantation/adverse effects , Postoperative Complications/surgery , Aged , Biliary Tract Diseases/epidemiology , Cholestasis/epidemiology , Female , Humans , Liver Diseases/surgery , Male , Middle Aged , Postoperative Complications/epidemiology , Prognosis , Retrospective Studies , Risk Factors , Secondary Prevention , Treatment Outcome
9.
Mol Cell Proteomics ; 11(8): 435-52, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22543060

ABSTRACT

Chagas disease is initiated upon infection by Trypanosoma cruzi. Among the health consequences is a decline in heart function, and the pathophysiological mechanisms underlying this manifestation are not well understood. To explore the possible mechanisms, we employed IgY LC10 affinity chromatography in conjunction with ProteomeLab PF2D and two-dimensional gel electrophoresis to resolve the proteome signature of high and low abundance serum proteins in chagasic patients. MALDI-TOF MS/MS analysis yielded 80 and 14 differentially expressed proteins associated with cardiomyopathy of chagasic and other etiologies, respectively. The extent of oxidative stress-induced carbonyl modifications of the differentially expressed proteins (n = 26) was increased and coupled with a depression of antioxidant proteins. Functional annotation of the top networks developed by ingenuity pathway analysis of proteome database identified dysregulation of inflammation/acute phase response signaling and lipid metabolism relevant to production of prostaglandins and arachidonic acid in chagasic patients. Overlay of the major networks identified prothrombin and plasminogen at a nodal position with connectivity to proteome signature indicative of heart disease (i.e., thrombosis, angiogenesis, vasodilatation of blood vessels or the aorta, and increased permeability of blood vessel and endothelial tubes), and inflammatory responses (e.g., platelet aggregation, complement activation, and phagocyte activation and migration). The detection of cardiac proteins (myosin light chain 2 and myosin heavy chain 11) and increased levels of vinculin and plasminogen provided a comprehensive set of biomarkers of cardiac muscle injury and development of clinical Chagas disease in human patients. These results provide an impetus for biomarker validation in large cohorts of clinically characterized chagasic patients.


Subject(s)
Biomarkers/blood , Chagas Disease/blood , Proteome/analysis , Proteomics/methods , Adolescent , Adult , Aged , Biomarkers/metabolism , Chagas Cardiomyopathy/blood , Chagas Cardiomyopathy/metabolism , Chagas Disease/metabolism , Electrophoresis, Gel, Two-Dimensional , Female , Humans , Male , Middle Aged , Protein Carbonylation , Proteome/classification , Proteome/metabolism , Signal Transduction , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Young Adult
10.
Mol Cell Proteomics ; 11(4): M111.010918, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22199233

ABSTRACT

Inflammation and oxidative stress, elicited by Trypanosoma cruzi infection, are important pathologic events during progressive Chagasic cardiomyopathy. In this study, we infected Sprague-Dawley rats with T. cruzi, and treated with phenyl-α-tert-butylnitrone (PBN-antioxidant) and/or benznidazole (BZ-anti-parasite). We employed two-dimensional gel electrophoresis/mass spectrometry to investigate (a) the plasma proteomic changes associated with infection and disease development, and (b) the beneficial effects of PBN and BZ in controlling the disease-associated plasma profile. Matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) tandem MS (MS/MS) analysis of differentially expressed (total 146) and oxidized (total 48) protein spots yielded 92 unique proteins. Our data showed that treatment with PBN and BZ restored the differential expression of 65% and 30% of the disease-associated proteins to normal level, respectively, and PBN prevented development of oxidative adducts on plasma proteins. Western blotting to detect dinitrophenyl-derivatized carbonyl-proteins revealed plasma proteins were maximally oxidized during acute infection. Functional and disease/disorder analyses allocated a majority of the differentially expressed and oxidized proteins into inflammation/immunity and lipid metabolism categories and to molecular pathways associated with heart disease (e.g. cardiac infarction, contractile dysfunction, hypertrophy, and hypertension) in chagasic rats, and to curative pathways (e.g. ROS scavenging capacity, immune regulation) in infected rats treated with PBN and/or BZ. We validated the two-dimensional gel electrophoresis results by Western blotting, and demonstrated that the disease-associated increased expression of gelsolin and vimentin and release of cardiac MYL2 in the plasma of chagasic rats was returned to control level by PBN/BZ treatment. Increased plasma levels of gelsolin, MYL2 and vimentin were directly correlated with the severity of cardiac disease in human chagasic patients. Together, these results demonstrate the plasma oxidative and inflammatory response profile, and plasma detection of cardiac proteins parallels the pathologic events contributing to Chagas disease development, and is of potential utility in diagnosing disease severity and designing suitable therapy for management of human chagasic patients.


Subject(s)
Blood Proteins/metabolism , Chagas Disease/metabolism , Proteome/metabolism , Animals , Biomarkers/blood , Cardiac Myosins/blood , Chagas Disease/drug therapy , Cyclic N-Oxides/pharmacology , Free Radical Scavengers/pharmacology , Gelsolin/blood , Myosin Light Chains/blood , Nitroimidazoles/therapeutic use , Protein Carbonylation , Rats , Rats, Sprague-Dawley , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi , Vimentin/blood
11.
Adv Parasitol ; 76: 153-70, 2011.
Article in English | MEDLINE | ID: mdl-21884891

ABSTRACT

Inflammation is a host defence activated by exogenous (e.g. pathogen-derived, pollutants) or endogenous (e.g. reactive oxygen species-ROS) danger signals. Mostly, endogenous molecules (or their derivatives) have well-defined intracellular function but become danger signal when released or exposed following stress or injury. In this review, we discuss the potential role of ROS in chronic evolution of inflammatory cardiovascular diseases, using our experiences working on chagasic cardiomyopathy as a focus-point.


Subject(s)
Chagas Cardiomyopathy/immunology , Cytokines/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction , Trypanosoma cruzi/immunology , Animals , Chagas Cardiomyopathy/pathology , Humans , Inflammation/immunology , Inflammation/pathology , Trypanosoma cruzi/pathogenicity
12.
Neurochem Res ; 36(10): 1863-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21607610

ABSTRACT

Prion diseases are conformational diseases, many factors are involved in altering the conformation of prion, such as RNA, DNA, pH, and copper etc. However the neurotoxic mechanism of prion diseases is not clear yet. The aim of this study is to investigate the effect of the nucleoprotein complex of RNA and recombinant ovine prion protein (OvPrP(C)) on the cultured rat cortical neurons in vitro. Our previous study revealed that the nucleoprotein complex (OvPrP(C)-RNA) is characterized with high ß sheet conformation and proteinase K resistance. Here we found that the OvPrP(C)-RNA induced marked neuronal cell death by the MTT (3-(4,5-dimethyl-thiazole -2-yl)-2,5-diphenyl -tetrazolium bromide) and TUNEL (TdT mediated biotin-dUTP nicked-end labeling) assay, and the neurotoxic effects were confirmed by testing the content of Bcl-2 Associated X protein (Bax) in the immunoprecipitation assay and Western blot assay. Compared to the control group, there is no significant difference of active Bax or total Bax after RNA alone treatment or OvPrP(C) alone treatment, but the OvPrP(C)-RNA induced significant increases of active Bax level, while the contents of total Bax had no obvious changes after OvPrP(C)-RNA treatment. The results suggested that OvPrP(C)-RNA is neurotoxic in vitro, which added further evidence to the current understanding of mechanism of cellular injury by RNA molecules for transformation of the PrP(C) to PrP(Sc).


Subject(s)
Cerebral Cortex/cytology , Neurons/drug effects , PrPC Proteins/toxicity , Prion Diseases/metabolism , RNA/toxicity , Sheep , Animals , Cell Death/drug effects , Cells, Cultured , Humans , In Situ Nick-End Labeling , Neurons/cytology , Neurons/metabolism , Neurotoxicity Syndromes/metabolism , PrPC Proteins/genetics , Rats , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , bcl-2-Associated X Protein/metabolism
13.
J Am Coll Cardiol ; 55(22): 2499-508, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20510218

ABSTRACT

OBJECTIVES: The purpose of this study was to determine the pathological importance of oxidative stress-induced injurious processes in chagasic heart dysfunction. BACKGROUND: Trypanosoma cruzi-induced inflammatory pathology and a feedback cycle of mitochondrial dysfunction and oxidative stress may contribute to Chagas disease. METHODS: Sprague-Dawley rats were infected with T. cruzi and treated with phenyl-alpha-tert-butylnitrone (PBN), an antioxidant, and/or benzonidazole (BZ), an antiparasitic agent. We monitored myocardial parasite burden, oxidative adducts, mitochondrial complex activities, respiration, and adenosine triphosphate synthesis rates, and inflammatory and cardiac remodeling responses during disease development. The cardiac hemodynamics was determined for all rats. RESULTS: Benzonidazole (not PBN) decreased the parasite persistence and immune adverse events (proinflammatory cytokine expression, beta-nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase activities, and inflammatory infiltrate) in chronically infected hearts. PBN +/- BZ (not BZ alone) decreased the mitochondrial reactive oxygen species level, oxidative adducts (malonyldialdehyde, 4-hydroxynonenal, carbonyls), hypertrophic gene expression (atrial natriuretic peptide, B-type natriuretic peptide, alpha-skeletal actin), and collagen deposition and preserved the respiratory chain efficiency and energy status in chronically infected hearts. Subsequently, LV dysfunction was prevented in PBN +/- BZ-treated chagasic rats. CONCLUSIONS: BZ treatment after the acute stage decreased the parasite persistence and inflammatory pathology. Yet, oxidative adducts, mitochondrial dysfunction, and remodeling responses persisted and contributed to declining cardiac function in chagasic rats. Combination treatment (PBN + BZ) was beneficial in arresting the T. cruzi-induced inflammatory and oxidative pathology and chronic heart failure in chagasic rats.


Subject(s)
Chagas Disease/drug therapy , Cyclic N-Oxides/pharmacology , Mitochondria, Heart/drug effects , Nitroimidazoles/pharmacology , Oxidative Stress/drug effects , Analysis of Variance , Animals , Chagas Cardiomyopathy/etiology , Chagas Cardiomyopathy/prevention & control , Chagas Disease/complications , Chagas Disease/physiopathology , Chronic Disease , Disease Models, Animal , Disease Progression , Heart Function Tests , Hemodynamics/physiology , Lipid Peroxidation , Mitochondria, Heart/parasitology , Probability , Random Allocation , Rats , Rats, Sprague-Dawley , Statistics, Nonparametric , Trypanosoma cruzi
14.
Antioxid Redox Signal ; 12(1): 27-37, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19624257

ABSTRACT

In this study, we conducted a thorough analysis of mitochondrial bioenergetic function as well as the biochemical and molecular factors that are deregulated and contribute to compromised adenosine triphosphate (ATP) production in the myocardium during Trypanosoma cruzi infection. We show that ADP-stimulated state 3 respiration and ATP synthesis supported by pyruvate/malate (provides electrons to complex I) and succinate (provides electrons to complex II) substrates were significantly decreased in left ventricular tissue and isolated cardiac mitochondria of infected mice. The decreased mitochondrial ATP synthesis in infected murine hearts was not a result of uncoupling between the electron-transport chain and oxidative phosphorylation and decreased availability of the intermediary metabolites (e.g., NADH). The observed decline in the activities of complex-I, -IV, and -V was not physiologically relevant and did not contribute to compromised respiration and ATP synthesis in infected myocardium. Instead, complex III activity was decreased above the threshold level and contributed to respiratory-chain inefficiency and the resulting decline in mitochondrial ATP synthesis in infected myocardium. The loss in complex III activity occurred as a consequence of cytochrome b depletion. Treatment of infected mice with phenyl-alpha-tert-butyl nitrone (PBN, antioxidant) was beneficial in preserving the mtDNA-encoded cytochrome b expression, and subsequently resulted in improved complex III activity, mitochondrial respiration, and ATP production in infected myocardium. Overall, we provide novel data on the mechanism(s) involved in cardiac bioenergetic inefficiency during T. cruzi infection.


Subject(s)
Adenosine Triphosphate/biosynthesis , Chagas Disease/metabolism , Electron Transport Complex III/metabolism , Myocardium/metabolism , Oxygen/metabolism , Trypanosoma cruzi/isolation & purification , Animals , Chagas Disease/enzymology , Cytochromes b/genetics , Cytochromes b/metabolism , Male , Mice , Mice, Inbred C3H
15.
Free Radic Biol Med ; 47(10): 1414-21, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19686837

ABSTRACT

In this study, we investigated the role of Trypanosoma cruzi invasion and inflammatory processes in reactive oxygen species (ROS) production in a mouse atrial cardiomyocyte line (HL-1) and primary adult rat ventricular cardiomyocytes. Cardiomyocytes were incubated with T. cruzi (Tc) trypomastigotes, Tc lysate (TcTL), or Tc secreted proteins (TcSP) for 0-72 h, and ROS were measured by amplex red assay. Cardiomyocytes infected by T. cruzi (but not those incubated with TcTL or TcSP) exhibited a linear increase in ROS production for 2-48 h postinfection (max 18-fold increase), which was further enhanced by recombinant cytokines (IL-1beta, TNF-alpha, and IFN-gamma). We observed no increase in NADPH oxidase, xanthine oxidase, or myeloperoxidase activity, and specific inhibitors of these enzymes did not block the increased rate of ROS production in infected cardiomyocytes. Instead, the mitochondrial membrane potential was perturbed and resulted in inefficient electron transport chain (ETC) activity and enhanced electron leakage and ROS formation in infected cardiomyocytes. HL-1 rho (rho) cardiomyocytes lacked a functional ETC and exhibited no increase in ROS formation in response to T. cruzi. Together, these results demonstrate that invasion by T. cruzi and an inflammatory milieu affect mitochondrial integrity and contribute to electron transport chain inefficiency and ROS production in cardiomyocytes.


Subject(s)
Mitochondrial Membranes/immunology , Myocytes, Cardiac/immunology , Reactive Oxygen Species/immunology , Trypanosoma cruzi/isolation & purification , Animals , Cells, Cultured , Fluorescent Dyes/chemistry , Mice , Mitochondrial Membranes/drug effects , Myocytes, Cardiac/drug effects , Rats , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/immunology
16.
Interdiscip Perspect Infect Dis ; 2009: 190354, 2009.
Article in English | MEDLINE | ID: mdl-19547716

ABSTRACT

There is growing evidence to suggest that chagasic myocardia are exposed to sustained oxidative stress induced injuries that may contribute to disease progression. Trypanosoma cruzi invasion- and replication-mediated cellular injuries and immune-mediated cytotoxic reactions are the common source of reactive oxygen species (ROS) during acute infection. Mitochondria are proposed to be the major source of ROS in chronic chagasic hearts. However, it has not been established yet, whether mitochondrial dysfunction is a causative factor in chagasic cardiomyopathy or a consequence of other pathological events. A better understanding of oxidative stress in relation to cardiac tissue damage would be useful in the evaluation of its true role in the pathogenesis of Chagas disease and other heart diseases. In this review, we discuss the evidence for increased oxidative stress in chagasic disease, with emphasis on mitochondrial abnormalities, and its role in sustaining oxidative stress in myocardium.

17.
Mol Cell Endocrinol ; 309(1-2): 32-8, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19422880

ABSTRACT

The red-spotted grouper, Epinephelus akaara, is a protogynous hermaphroditic fish that shows the characteristic of natural sex change. In this study, 2-year-old female groupers were successfully reversed to functional males by oral administration of 17alpha-methyltestosterone (MT) for 42 days. The protein inhibitor of the neuronal nitric oxide synthase (PIN) gene was cloned from sex-reversed male gonads using modern suppression subtractive hybridization (SSH), cDNA synthesis and rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR). The full-length cDNA of PIN is 499bp containing a 270bp open reading frame (ORF) that encodes 89 amino acids. Virtual Northern blotting and reverse transcription-PCR (RT-PCR) analysis revealed that PIN was specifically transcribed in sex-reversed male gonads. Tissue-specific expression analysis showed that PIN gene was expressed in the brain, heart, liver, spleen, and kidney but not in the muscle tissue. Analyses of the expression pattern by RT-PCR and Western blotting indicated that transcription and the level of expression of PIN in the gonads increased gradually during the transformation from female to male. The results showed that PIN is strongly expressed in the sex-reversed male gonad but scarcely in the female gonad, and that its expression is upregulated as the change of sex proceeds. Taken together, these findings demonstrate that PIN is associated with the MT-induced sex transition of the red-spotted grouper, but the precise role of the gene in this process remains to be further investigated.


Subject(s)
Fish Proteins/genetics , Gene Expression Profiling , Gonads/metabolism , Hermaphroditic Organisms , Perciformes/genetics , Sex Determination Processes , Amino Acid Sequence , Animals , Base Sequence , Blotting, Western , DNA, Complementary/genetics , Diet , Fish Proteins/chemistry , Fish Proteins/metabolism , Gene Expression Regulation , Gene Library , Immunohistochemistry , Male , Molecular Sequence Data , Phylogeny , Sequence Homology, Amino Acid , Testosterone/blood , Transcription, Genetic
18.
J Bioenerg Biomembr ; 40(6): 587-98, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19009337

ABSTRACT

In this study, we have characterized the cellular source and mechanism for the enhanced generation of reactive oxygen species (ROS) in the myocardium during Trypanosoma cruzi infection. Cardiac mitochondria of infected mice, as compared to normal controls, exhibited 63.3% and 30.8% increase in ROS-specific fluorescence of dihydroethidium (detects O(2) (*-)) and amplex red (detects H(2)O(2)), respectively. This increase in ROS level in cardiac mitochondria of infected mice was associated with a 59% and 114% increase in the rate of glutamate/malate- (complex I substrates) and succinate- (complex II substrate) supported ROS release, respectively, and up to a 74.9% increase in the rate of electron leakage from the respiratory chain when compared to normal controls. Inhibition studies with normal cardiac mitochondria showed that rotenone induced ROS generation at the Q(Nf)-ubisemiquinone site in complex I. In complex III, myxothiazol induced ROS generation from a site located at the Q(o) center that was different from the Q(i) center of O(2) (*-) generation by antimycin. In cardiac mitochondria of infected mice, the rate of electron leakage at complex I during forward (complex I-to-complex III) and reverse (complex II-to-complex I) electron flow was not enhanced, and complex I was not the main site of increased ROS production in infected myocardium. Instead, defects of complex III proximal to the Q(o) site resulted in enhanced electron leakage and ROS formation in cardiac mitochondria of infected mice. Treatment of infected mice with phenyl-alpha-tert-butyl-nitrone (PBN) improved the respiratory chain function, and, subsequently, decreased the extent of electron leakage and ROS release. In conclusion, we show that impairment of the Q(o) site of complex III resulted in increased electron leakage and O(2) (*-) formation in infected myocardium, and was controlled by PBN.


Subject(s)
Antioxidants/administration & dosage , Chagas Disease/drug therapy , Chagas Disease/metabolism , Electron Transport Complex III/metabolism , Mitochondria, Heart/metabolism , Mitochondria, Heart/parasitology , Reactive Oxygen Species/metabolism , Animals , Antifungal Agents/administration & dosage , Binding Sites , Chagas Disease/parasitology , Electron Transport Complex III/drug effects , Male , Mice , Mice, Inbred C3H , Mitochondria, Heart/drug effects , Protein Binding , Treatment Outcome
19.
Zhen Ci Yan Jiu ; 33(4): 255-7, 261, 2008 Aug.
Article in Chinese | MEDLINE | ID: mdl-18928118

ABSTRACT

OBJECTIVE: To explore the anti-aging effect of moxibustion of "Zusnali" (ST 36) and "Xuanzhong" (GB 39) in D-galactose induced aging mice. METHODS: Thirty-three female Kunming mice (3 months old) were randomly divided into model group (n=11), saline control group (n=10), and moxibustion group (n=11). In addition, another 10 female mice (16 months old) were used as the physio-senility control (PSC) group. Senescent mouse model was established by subcutaneous injection of D-galactose (120 mg/kg x d(-1)) for 42 days. From the 13th day on after the first injection, moxibustion (3 cones/acupoint) was applied to bilateral ST36 and GB39, once every other day for one month. At the end of the treatment, the mice were killed under anesthesia for collecting cerebral cortex and cerebellar cortex separately. NO content and NOS activity were assayed by using nitrate reductase method and chemico-chromatometry respectively after homogenate and centrifugalization. RESULTS: Compared with saline control group, cerebral NO contents and NOS activity in physio-senility group and model group, cerebellar NO content in model group, cerebellar NOS activity in physio-senility and model groups increased considerably (P < 0.05, < 0.01). In comparison with model group, cerebral and cerebellar NO contents and NOS activity of moxibustion group lowered significantly (P < 0.05, 0.01). CONCLUSION: Moxibustion of ST36 and GB39 can significantly suppress aging induced increase of both NO content and NOS activity in cerebral and cerebellar cortical tissues in aged mice, suggesting an effective anti-aging effect of moxibustion.


Subject(s)
Aging/metabolism , Cerebral Cortex/metabolism , Moxibustion , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide/metabolism , Animals , Female , Humans , Mice , Random Allocation
20.
Microbes Infect ; 10(10-11): 1201-9, 2008.
Article in English | MEDLINE | ID: mdl-18675934

ABSTRACT

In this study, we examined the tissue specificity of inflammatory and oxidative responses and mitochondrial dysfunction in mice infected by Trypanosoma cruzi. In acute mice, parasite burden and associated inflammatory infiltrate was detected in all tissues (skeletal muscle>heart>stomach>colon). The extent of oxidative damage and mitochondrial decay was in the order of heart>stomach>skeletal muscle>colon. In chronic mice, a low level of parasite burden and inflammation continued in all tissues; however, oxidant overload and mitochondrial inefficiency mainly persisted in the heart tissue (also detectable in stomach). Further, we noted an unvaryingly high degree of oxidative stress, compromised antioxidant status, and decreased mitochondrial respiratory complex activities in peripheral blood of infected mice. A pair-wise log analysis showed a strong positive correlation in the heart-versus-blood (but not other tissues) levels of oxidative stress markers (malonyldialdehyde, glutathione disulfide), antioxidants (superoxide dismutase, MnSOD, catalase), and mitochondrial inhibition of respiratory complexes (CI/CIII) in infected mice. T. cruzi-induced acute inflammatory and oxidative responses are widespread in different muscle tissues. Antioxidant/oxidant status and mitochondrial function are consistently attenuated in the heart, and reflected in the peripheral-blood of T. cruzi-infected mice. Our results provide an impetus to investigate the peripheral-blood oxidative responses in relation to clinical severity of heart disease in chagasic human patients.


Subject(s)
Chagas Disease/metabolism , Mitochondria/enzymology , Mitochondria/metabolism , Oxidative Stress , Trypanosoma cruzi/physiology , Animals , Catalase/metabolism , Chagas Disease/parasitology , Electron Transport Complex I/metabolism , Electron Transport Complex II/metabolism , Gastric Mucosa/metabolism , Glutathione Peroxidase/metabolism , Inflammation/immunology , Inflammation/metabolism , Lipid Peroxidation , Male , Mice , Muscle, Skeletal/metabolism , Myocardium/metabolism , Superoxide Dismutase/metabolism , Tyrosine/analogs & derivatives , Tyrosine/blood , Tyrosine/metabolism
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