scholarly journals The Use of Antioxidants as Potential Co-Adjuvants to Treat Chronic Chagas Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1022
Author(s):  
Edio Maldonado ◽  
Diego A. Rojas ◽  
Fabiola Urbina ◽  
Aldo Solari
Keyword(s):  
Gene Expression ◽  
Adjuvant Therapy ◽  
Chagas Disease ◽  
Latin American ◽  
Mitochondrial Biogenesis ◽  
Antioxidant Defenses ◽  
Myocardial Inflammation ◽  
Nuclear Respiratory Factor ◽  
Mitochondrial Functions ◽  
Activate Gene

Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosome cruzi. This illness affects to almost 8–12 million people worldwide, however, is endemic to Latin American countries. It is mainly vectorially transmitted by insects of the Triatominae family, although other transmission routes also exist. T. cruzi-infected cardiomyocytes at the chronic stage of the disease display severe mitochondrial dysfunction and high ROS production, leading to chronic myocardial inflammation and heart failure. Under cellular stress, cells usually can launch mitochondrial biogenesis in order to restore energy loss. Key players to begin mitochondrial biogenesis are the PGC-1 (PPARγ coactivator 1) family of transcriptional coactivators, which are activated in response to several stimuli, either by deacetylation or dephosphorylation, and in turn can serve as coactivators for the NRF (nuclear respiratory factor) family of transcription factors. The NRF family of transcriptional activators, namely NRF1 and NRF2, can activate gene expression of oxidative phosphorylation (OXPHOS) components, mitochondrial transcriptional factor (Tfam) and nuclear encoded mitochondrial proteins, leading to mitochondrial biogenesis. On the other hand, NRF2 can activate gene expression of antioxidant enzymes in response to antioxidants, oxidants, electrophile compounds, pharmaceutical and dietary compounds in a mechanism dependent on KEAP1 (Kelch-like ECH-associated protein 1). Since a definitive cure to treat Chagas disease has not been found yet; the use of antioxidants a co-adjuvant therapy has been proposed in an effort to improve mitochondrial functions, biogenesis, and the antioxidant defenses response. Those antioxidants could activate different pathways to begin mitochondrial biogenesis and/or cytoprotective antioxidant defenses. In this review we discuss the main mechanisms of mitochondrial biogenesis and the NRF2-KEAP1 activation pathway. We also reviewed the antioxidants used as co-adjuvant therapy to treat experimental Chagas disease and their action mechanisms and finish with the discussion of antioxidant therapy used in Chagas disease patients.

Growth restriction in the rat alters expression of metabolic genes during postnatal cardiac development in a sex-specific manner

2013 ◽  
Vol 45 (3) ◽  
pp. 99-105 ◽  
Author(s):  
Glenn D. Wadley ◽  
Glenn K. McConell ◽  
Craig A. Goodman ◽  
Andrew L. Siebel ◽  
Kerryn T. Westcott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucose Transport ◽  
Mitochondrial Biogenesis ◽  
Cardiac Development ◽  
Growth Restriction ◽  
Antioxidant Defenses ◽  
Postnatal Life ◽  
Male And Female ◽  
Glut 1 ◽  
The Impact

This study investigated the impact of uteroplacental insufficiency and growth restriction on the expression of genes related to mitochondrial biogenesis, glucose transport, and antioxidant defenses in cardiac tissue at embryonic day 20 (E20) and postnatal days 1, 7, and 35 in male and female Wistar rats (8–10 per group). Bilateral uterine vessel ligation to induce growth restriction (Restricted) or sham surgery was performed at pregnancy day 18. In male and female Controls, expression of most cardiac genes decreased during postnatal life, including genes involved in mitochondrial biogenesis regulation such as PGC-1α, NRF-2, and mtTFA and the glucose transporter GLUT-1 ( P < 0.05). However, the pattern of gene expression during cardiac development differed in male and female Restricted rats compared with their respective Controls. These effects of restriction were observed at postnatal day 1, with female Restricted rats having delayed reductions in PGC-1α and GLUT-1, whereas males had exacerbated reductions in PGC-1α and mtTFA ( P < 0.05). By day 35, cardiac gene expression in Restricted hearts was similar to Controls, except for expression of the antioxidant enzyme MnSOD, which was significantly lower in both sexes. In summary, during postnatal life male and female Control rats have similar patterns of expression for genes involved in mitochondrial biogenesis and glucose transport. However, following uteroplacental insufficiency these gene expression patterns diverge in males and females during early postnatal life, with MnSOD gene expression reduced in later postnatal life.

scholarly journals The role of mitochondria in physical activity and its adaptation on aging

2015 ◽  
Vol 32 (04) ◽  
pp. 257-263
Author(s):  
M. Ferro ◽  
G. Rodrigues ◽  
R. De Souza
Keyword(s):  
Physical Activity ◽  
Muscle Tissue ◽  
Mitochondrial Biogenesis ◽  
Oxidative Capacity ◽  
Mitochondrial Activity ◽  
Nutritional Interventions ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 1 ◽  
Body Tissues ◽  
Mitochondrial Functions

Abstract Introduction: The mitochondria are essential in numerous physiological processes, including energy production, redox potential, modulation of calcium and several metabolic pathways. When the number or mitochondrial activity is insufficient, the human body quickly goes into fatigue due to ATP deficiency. Methods: The principal data base were used: PubMed, Medline, Scielo and Lilacs. Keywords used were: mitochondrial biogenesis, aging, organic acids, enzyme changes and respiratory chain. Groups considered: young and aged. Types of training: aerobic and anaerobic. Papers dealing with pathogies were not considered. The oxidative capacity of muscle tissue and the preservation of mitochondria depends on the mitochondrial biogenesis that occurs through the transcription factor proliferator-activator receptor-γ coactivatorlα (PGC-1α). The oxidative process and the progressive change in the biogenesis of mitochondria have direct influence on the aging of muscle tissue. The regulation of the biogenesis occurs through the PGC-1α combined with nuclear respiratory factor 1 (NRF1). Abnormalities in mitochondria and mutagenesis in mitochondrial DNA (mtDNA) are tied to multi-system degeneration, as well as intolerance to stress, and decreased energy in aging in humans, rats and monkeys. The mitochondrial functions are dramatically altered in heart disease, demonstrating a decrease in expression of PGC-1α, which plays a key role in the coordination of energy metabolism. This process can be reversed by the PGC-1α itself. The identification of compounds capable of activating the transcription of PGC-1α could be part of future therapies to reverse pathologies associated with the decline of this organelle. Morpho-physiological and biochemical changes of these organelles directly reflect the physiological performance of all body tissues. Conclusion: evidence demonstrated that physical activity, both in young and aged is a major ally in mitochondrial biogenesis by activating the transcription of PGC - 1α and that future nutritional interventions may be of great aid in the health and performance of mitochondria. However, further studies are needed in order to understand and clarify this operation, since currently these mechanisms are only partially known.

scholarly journals Ontogeny of Carbon Monoxide-Related Gene Expression in a Deep-Diving Marine Mammal

2021 ◽  
Vol 12 ◽  
Author(s):  
Elizabeth R. Piotrowski ◽  
Michael S. Tift ◽  
Daniel E. Crocker ◽  
Anna B. Pearson ◽  
José P. Vázquez-Medina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Lipid Peroxidation ◽  
Carbon Monoxide ◽  
Mitochondrial Biogenesis ◽  
Oxygen Storage ◽  
Antioxidant Defenses ◽  
Deep Diving ◽  
Immune System Activation ◽  
Expression Of Genes

Marine mammals such as northern elephant seals (NES) routinely experience hypoxemia and ischemia-reperfusion events to many tissues during deep dives with no apparent adverse effects. Adaptations to diving include increased antioxidants and elevated oxygen storage capacity associated with high hemoprotein content in blood and muscle. The natural turnover of heme by heme oxygenase enzymes (encoded by HMOX1 and HMOX2) produces endogenous carbon monoxide (CO), which is present at high levels in NES blood and has been shown to have cytoprotective effects in laboratory systems exposed to hypoxia. To understand how pathways associated with endogenous CO production and signaling change across ontogeny in diving mammals, we measured muscle CO and baseline expression of 17 CO-related genes in skeletal muscle and whole blood of three age classes of NES. Muscle CO levels approached those of animals exposed to high exogenous CO, increased with age, and were significantly correlated with gene expression levels. Muscle expression of genes associated with CO production and antioxidant defenses (HMOX1, BVR, GPX3, PRDX1) increased with age and was highest in adult females, while that of genes associated with protection from lipid peroxidation (GPX4, PRDX6, PRDX1, SIRT1) was highest in adult males. In contrast, muscle expression of mitochondrial biogenesis regulators (PGC1A, ESRRA, ESRRG) was highest in pups, while genes associated with inflammation (HMOX2, NRF2, IL1B) did not vary with age or sex. Blood expression of genes involved in regulation of inflammation (IL1B, NRF2, BVR, IL10) was highest in pups, while HMOX1, HMOX2 and pro-inflammatory markers (TLR4, CCL4, PRDX1, TNFA) did not vary with age. We propose that ontogenetic upregulation of baseline HMOX1 expression in skeletal muscle of NES may, in part, underlie increases in CO levels and expression of genes encoding antioxidant enzymes. HMOX2, in turn, may play a role in regulating inflammation related to ischemia and reperfusion in muscle and circulating immune cells. Our data suggest putative ontogenetic mechanisms that may enable phocid pups to transition to a deep-diving lifestyle, including high baseline expression of genes associated with mitochondrial biogenesis and immune system activation during postnatal development and increased expression of genes associated with protection from lipid peroxidation in adulthood.

Major Kinds of Drug Targets in Chagas Disease or American Trypanosomiasis

2019 ◽  
Vol 20 (11) ◽  
pp. 1203-1216 ◽  
Author(s):  
Vilma G. Duschak
Keyword(s):  
Chagas Disease ◽  
Latin American ◽  
Drug Targets ◽  
Defense Mechanisms ◽  
Cysteine Proteinase ◽  
Parasitic Infection ◽  
Etiologic Agent ◽  
World Health ◽  
American Trypanosomiasis ◽  
Group I

American Trypanosomiasis, a parasitic infection commonly named Chagas disease, affects millions of people all over Latin American countries. Presently, the World Health Organization (WHO) predicts that the number of international infected individuals extends to 7 to 8 million, assuming that more than 10,000 deaths occur annually. The transmission of the etiologic agent, Trypanosoma cruzi, through people migrating to non-endemic world nations makes it an emergent disease. The best promising targets for trypanocidal drugs may be classified into three main groups: Group I includes the main molecular targets that are considered among specific enzymes involved in the essential processes for parasite survival, principally Cruzipain, the major antigenic parasite cysteine proteinase. Group II involves biological pathways and their key specific enzymes, such as Sterol biosynthesis pathway, among others, specific antioxidant defense mechanisms, and bioenergetics ones. Group III includes the atypical organelles /structures present in the parasite relevant clinical forms, which are absent or considerably different from those present in mammals and biological processes related to them. These can be considered potential targets to develop drugs with extra effectiveness and fewer secondary effects than the currently used therapeutics. An improved distinction between the host and the parasite targets will help fight against this neglected disease.

Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Zhongyuan Piao ◽  
Lin Song ◽  
Lifen Yao ◽  
Limei Zhang ◽  
Yichan Lu
Keyword(s):  
Energy Metabolism ◽  
Cytochrome C ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Citrate Synthase ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Mitochondrial Functions ◽  
Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

scholarly journals Current knowledge of Chagas-related heart disease among pediatric cardiologists in the United States

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sanchi Malhotra ◽  
Imran Masood ◽  
Noberto Giglio ◽  
Jay D. Pruetz ◽  
Pia S. Pannaraj
Keyword(s):  
United States ◽  
Differential Diagnosis ◽  
Heart Disease ◽  
Chagas Disease ◽  
Latin American ◽  
Current Knowledge ◽  
Parasitic Infection ◽  
The United States ◽  
Cardiac Complications ◽  
The U.S

Abstract Background Chagas disease is a pathogenic parasitic infection with approximately 8 million cases worldwide and greater than 300,000 cases in the United States (U.S.). Chagas disease can lead to chronic cardiomyopathy and cardiac complications, with variable cardiac presentations in pediatrics making it difficult to recognize. The purpose of our study is to better understand current knowledge and experience with Chagas related heart disease among pediatric cardiologists in the U.S. Methods We prospectively disseminated a 19-question survey to pediatric cardiologists via 3 pediatric cardiology listservs. The survey included questions about demographics, Chagas disease presentation and experience. Results Of 139 responses, 119 cardiologists treat pediatric patients in the U.S. and were included. Most providers (87%) had not seen a case of Chagas disease in their practice; however, 72% also had never tested for it. The majority of knowledge-based questions about Chagas disease cardiac presentations were answered incorrectly, and 85% of providers expressed discomfort with recognizing cardiac presentations in children. Most respondents selected that they would not include Chagas disease on their differential diagnosis for presentations such as conduction anomalies, myocarditis and/or apical aneurysms, but would be more likely to include it if found in a Latin American immigrant. Of respondents, 87% agreed that they would be likely to attend a Chagas disease-related lecture. Conclusions Pediatric cardiologists in the U.S. have seen very few cases of Chagas disease, albeit most have not sent testing or included it in their differential diagnosis. Most individuals agreed that education on Chagas disease would be worth-while.

scholarly journals Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model

2018 ◽  
Author(s):  
Janeesh A. Plakkal ◽  
Kezia Lizardo ◽  
Sean Wang ◽  
Edward Yurkow ◽  
Jyothi F. Nagajyothi
Keyword(s):  
Er Stress ◽  
Chagas Disease ◽  
Disease Model ◽  
Chronic Inflammatory Disease ◽  
Initiation Factor ◽  
Mortality And Morbidity ◽  
Downstream Signaling ◽  
Mitochondrial Functions ◽  
Metabolic Dysfunctions ◽  
Cruzi Infection

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2&alpha;) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

METHYLTRANSFERASE SMYD5 EXAGGERATES INFLAMMATORY BOWEL DISEASE BY REGULATING PPAR-γ COACTIVATOR 1-α STABILITY

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S27-S27
Author(s):  
Yuning Hou ◽  
Xiaonan Sun ◽  
Pooneh Gheinani ◽  
Xiaoqing Guan ◽  
Shaligram Sharma ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Experimental Colitis ◽  
Conditional Knockout ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Lysine Methylation ◽  
Promising Therapeutic Approach ◽  
Mitochondrial Functions ◽  
Inflammatory Bowel

Abstract Background and Aims The expression and role of methyltransferase SET and MYND domain-containing protein 5 (SMYD5) in inflammatory bowel diseases (IBD) is completely unknown. Here, we investigated the role and the underlying mechanism of epithelial SMYD5 in IBD pathogenesis and progression. Methods The expression and subcellular localization of SMYD5 and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were examined by Western blot analysis, immunofluorescence staining, and immunohistochemistry in intestinal epithelial cells (IECs) and in colon tissues from human IBD patients and mice with experimental colitis. Mice with Smyd5 conditional knockout in IECs and littermate controls were subjected to DSS-induced experimental colitis and the disease severity and inflammation were assessed. SMYD5-regulated mitochondrial biogenesis was examined by RT-qPCR and transmission electron microscopy and mitochondrial oxygen consumption rate was measured in a Seahorse Analyzer system. The interaction between SMYD5 and PGC-1α was determined by co-immunoprecipitation assay. PGC-1α degradation and turnover (half-life) were analyzed by cycloheximide chase assay. SMYD5-mediated PGC-1α methylation was measured via in vitro methylation followed by mass spectrometry to identify the specific lysine residues that were methylated. Results Up-regulated SMYD5 and down-regulated PGC-1α were observed in IECs from IBD patients and mice with experimental colitis. However, Smyd5 depletion in IECs protected mice from DSS-induced colitis. SMYD5 was critically involved in regulating mitochondrial biology such as mitochondrial biogenesis, respiration, and apoptosis. Mechanistically, SMYD5 regulated mitochondrial functions in a PGC-1α dependent manner. Further, SMYD5 mediated lysine methylation of PGC-1α and facilitated its ubiquitination and proteasomal degradation. Conclusion SMYD5 attenuates mitochondrial functions in IECs and promotes IBD progression by enhancing the proteasome-mediated degradation of PGC-1α protein in a methylation-dependent manner. Strategies to decrease SMYD5 expression and/or increase PGC-1α expression in IECs might be a promising therapeutic approach to treat patients with IBD.

NUSAP1 and KIAA0101 downregulation by neo-adjuvant therapy is associated with better outcome and survival in breast cancer.

2020 ◽  
Author(s):  
Gerardo I. Magallanes-Garza ◽  
Sandra K. Santuario-Facio ◽  
Arlina F. Varela-Varela ◽  
Servando Cardona-Huerta ◽  
Pablo Ruiz-Flores ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Adjuvant Therapy ◽  
Expression Profiles ◽  
Pathological Response ◽  
Primary Tumors ◽  
Before And After ◽  
Neo Adjuvant Chemotherapy

Abstract Background: Studies of molecular changes occurring before and after neo-adjuvant chemotherapy (NCT) for breast cancer may unveil genetic biomarkers to predict therapy response. This study aimed at identifying genomic changes in breast primary tumors of patients under NCT. Gene expression changes were correlated with pathological response and survival.Methods: Gene expression profiles in tissue samples from pre and post NCT were obtained by a non-supervised classification analysis. Thirty-nine patients were classified according to their response to the chemotherapy as pathologic complete responders or non-responders (pCR and no-pCR, respectively). Overall survival was assessed by comparing gene expression values before NCT using the Log-rank (Mantel-Cox) test. Results: A signature constituted by 43 genes was obtained to stratify pCR and no-pCR patients after NCT (FC = + 3, FDR p -value < 0.0298). These genes were involved in regulation of the mitotic nuclear division and the anaphase-promoting complex-dependent catabolic process. Remarkably, over-expression of NUSAP1 and KIAA0101 were associated to poor overall survival. Conclusions: A new expression signature evaluating response for the neo-adjuvant chemotherapy stratified pathological response. The expression levels of NUSAP1 and KIAA0101 before and after the neo-adjuvant therapy may be useful to predict overall survival.

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