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Chemical structures of Benznidazole (BZN) and Nifurtimox (NFX). Benznidazole, (IUPAC name: N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide) and Nifurtimox (IUPAC name: 3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dione) are pro-drug compounds and in the cells can be activated to act as a drug, which can react with several cellular molecular targets.
Source publication
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-infecte...
Context in source publication
Context 1
... the 1970s, a new class of drugs were used to treat Chagas disease, however, only two drugs are currently available for its treatment [13]. Both drugs belong to the same class of nitroheterocycles and they are named benznidazole (BZN) and nifurtimox (NFX), and their chemical structures are shown in Figure 1. The mechanism of action of NFX is not completely understood yet, since initially it was believed that this drug acts by oxidative stress generating free radicals with trypanocide effects [14]. ...
Citations
... This process is coordinated by the transcription coactivator PGC-1, and PGC-1α is the main regulator that regulates mitochondrial biogenesis by binding to the nuclear receptor in the promoter region of the target gene and specific sequences [69]. PGC-1α regulates the transcription of TFAM after coactivating Nrf1 and 2 [70]. TFAM translocates to the mitochondrial matrix and stimulates mtDNA replication and mitochondrial gene expression [71]. ...
Background
Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic differentiation and vascular formation in human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) by the long-chain noncoding RNA small nucleolar RNA host gene 1 (SNHG1) during cartilage tissue regeneration.
Methods
JBMMSCs were isolated from the jaws via the adherent method. The effects of lncRNA SNHG1 on the chondrogenic differentiation of JBMMSCs in vitro were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), Pellet experiment, Alcian blue staining, Masson’s trichrome staining, and modified Sirius red staining. RT-qPCR, matrix gel tube formation, and coculture experiments were used to determine the effect of lncRNA SNHG1 on the angiogenesis in JBMMSCs in vitro. A model of knee cartilage defects in New Zealand rabbits and a model of subcutaneous matrix rubber suppositories in nude mice were constructed for in vivo experiments. Changes in mitochondrial function were detected via RT-qPCR, dihydroethidium (DHE) staining, MitoSOX staining, tetramethyl rhodamine methyl ester (TMRM) staining, and adenosine triphosphate (ATP) detection. Western blotting was used to detect the phosphorylation level of signal transducer and activator of transcription 3 (STAT3).
Results
Alcian blue staining, Masson’s trichrome staining, and modified Sirius Red staining showed that lncRNA SNHG1 promoted chondrogenic differentiation. The lncRNA SNHG1 promoted angiogenesis in vitro and the formation of microvessels in vivo. The lncRNA SNHG1 promoted the repair and regeneration of rabbit knee cartilage tissue. Western blot and alcian blue staining showed that the JAK inhibitor reduced the increase of STAT3 phosphorylation level and staining deepening caused by SNHG1. Mitochondrial correlation analysis revealed that the lncRNA SNHG1 led to a decrease in reactive oxygen species (ROS) levels, an increase in mitochondrial membrane potential and an increase in ATP levels. Alcian blue staining showed that the ROS inhibitor significantly alleviated the decrease in blue fluorescence caused by SNHG1 knockdown.
Conclusions
The lncRNA SNHG1 promotes chondrogenic differentiation and angiogenesis of JBMMSCs. The lncRNA SNHG1 regulates the phosphorylation of STAT3, reduces the level of ROS, regulates mitochondrial energy metabolism, and ultimately promotes cartilage regeneration.
... factors NRF-1 and NRF-2. This enhances the uncoupling ability of the oxidative phosphorylation electron transport chain [7] . These factors, in turn, interact with peroxisome proliferator-activated receptor-γ coactivator (PGC-1), increasing mitochondrial numbers and promoting the expression of oxidative phosphorylation complexes. ...
Cold stimulation has been linked to acute myocardial infarction and other cardiovascular diseases. Residents in the frigid zones, such Heilongjiang Province, experience a higher incidence of adverse cardiovascular events during winter, posing a significant health threat and increasing the overall medical burden. Cold stimulation serves as an detrimental stressor, inducing inflammation in the body. Therefore, understanding the role of inflammatory responses induced by cold stimulation in the occurrence and development of cardiovascular diseases is of paramount importance. Given the impact of cold on inflammation in cardiovascular diseases and the expanding array of anti-inflammatory methods for the treatment of cardiovascular diseases, delving into the inflammatory responses mediated by can significantly complement cardiovascular disease management. This review explorest the synergistic relationship between cold stimulation and inflammation induction, elucidating how this interplay influences the occurrence and progression of cardiovascular diseases.
... ROS plays a vital role as a signaling molecule regulating innate and adaptive immune responses via producing proinflammatory cytokines such as TNF-α, IL-1β, and IFN-γ, released by dendritic cells and macrophages [50]. NOX2/ROS axis was reported as the key mediator of cytokine production during T. cruzi infection and a genetic deficiency of a subunit of NOX2 are associated with the increased vulnerability against T. cruzi, indicating the pivotal role of oxidative stress metabolism in the immune system activation and controlling of CD [51,52]. On the other hand, trypanosomes, including T. cruzi have developed an antioxidant system to escape ROSmediated killing by utilizing trypanothione (T(SH) 2 ) which is a small molecular weight thiol [53]. ...
Purpose of Review
The global COVID-19 pandemic has become a major public health problem since December 2019, affecting millions of people, especially individuals with comorbidities including cancer, diabetes, hypertension, cardiovascular disease, obesity, and hematological disorders. People are still infected and die despite vaccination since the virus mutates quickly. Enzyme deficiencies, neglected conditions, and arboviral infections are currently discussed as potential contributors to COVID-19 vulnerability. Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi, affecting 6–8 million people worldwide, and CD is endemic in most of Latin America. Since people with CD have been found in the USA, Canada, Japan, and Europe because of the increased immigration, the spread and implications of CD have drawn attention since the disease shares similar pathogenesis with COVID-19.
Recent Findings
Enhanced oxidative stress and inflammation are the common features of CD and COVID-19 infection, leading to thrombosis, cardiomyopathy, thrombosis, cytokine storm, and heart failure associated with mortality and disease severity; therefore, it is still debated whether COVID-19 activates CD disease. On the other hand, CD patients can be more vulnerable to COVID-19 and show severe symptoms during the acute or chronic phase. Inflammation and oxidative stress are the first responses to COVID-19 or T. cruzi infections, where the vicious cycle between them is the key to infection pathogenesis. Therefore, this review discussed the importance of the oxidative stress-inflammation axis in disease pathogenesis, including thrombosis, immune response, cardiomyopathy, and heart failure. Additionally, antioxidant and anticoagulant therapies showed promising outcomes in the CD and COVID-19 patients addressing the importance of the oxidative stress-inflammation axis on the disease pathogenesis.
Summary
CD patients can be considered and treated as a risk group for COVID-19 infection even if the disease is in the silent phase to prevent mortality and severe symptoms. Antioxidant therapy should be considered a supportive treatment in CD patients infected with COVID-19.
... For Sánchez-Villamil et al. [31], a balance between ROS levels and the antioxidant response is fundamental in maintaining a safe environment for cells. The use of antioxidants as adjuvant compounds can reduce oxidative damage to host cells, becoming a potential in the treatment of Chagas disease [31,32]. Antioxidant properties of genus Terminalia have already been reported in the literature [22,33,34]. ...
Chagas disease is a severe infectious and parasitic disease caused by the protozoan Trypanosoma cruzi and considered a public health problem. Chemotherapeutics are still the main means of control and treatment of the disease, however with some limitations. As an alternative treatment, plants have been pointed out due to their proven pharmacological properties. Many studies carried out with Terminalia catappa have shown several biological activities, but its effect against T. cruzi is still unknown. The objective of this work is to evaluate the therapeutic potential of extracts and fractions obtained from T. catappa on the parasite T. cruzi, in addition to analyzing its antioxidant activity. T. catappa ethyl acetate fraction were produced and submitted the chemical characterization by Liquid Chromatography Coupled to Mass Spectrometry (LC-MS). From all T. catappa extracts and fractions evaluated, the ethyl acetate and the aqueous fraction displayed the best antioxidant activity by the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) radical scavenging method (IC 50 of 7.77 ± 1.61 and 5.26 ± 1.26 µg/mL respectively), and by ferric ion reducing (FRAP) method (687.61 ± 0.26 and 1009.32 ± 0.13 µM of Trolox equivalent/mg extract, respectively). The ethyl acetate fraction showed remarkable T. cruzi inhibitory activity with IC 50 of 8.86 ± 1.13, 24.91 ± 1.15 and 85.01 ± 1.21 µg/mL against epimastigotes, trypomastigotes and intracellular amastigotes, respectively, and showed no cytotoxicity for Vero cells (CC 50 > 1000 µg/mL). The treatment of epimastigotes with the ethyl acetate fraction led to drastic ultrastructural changes such as the loss of cytoplasm organelles, cell disorganization, nucleus damage and the loss of integrity of the parasite. This effect could be due to secondary compounds present in this extract, such as luteolin, kaempferol, quercetin, ellagic acid and derivatives. The ethyl acetate fraction obtained from T. catappa leaves can be an effective alternative in the treatment and control of Chagas disease, and material for further investigations.
... They are mainly associated with dermatological side-effects, fever, and lymphadenopathy [22,124]. Rarely, such conditions as gastrointestinal disorders, weight loss as well as more severe paresthesia, polyneuropathy, peripheral-nerve inflammation, bone-marrow dysfunction, and heart failure were reported [125][126][127][128][129]. The use of nanotechnology can have a significant impact on improving biopharmaceutical properties of the above-mentioned drugs. ...
The usage of nanotechnology in the fight against parasitic diseases is in the early stages of development, but it brings hopes that this new field will provide a solution to target the early stages of parasitosis, compensate for the lack of vaccines for most parasitic diseases, and also provide new treatment options for diseases in which parasites show increased resistance to current drugs. The huge physicochemical diversity of nanomaterials developed so far, mainly for antibacterial and anti-cancer therapies, requires additional studies to determine their antiparasitic potential. When designing metallic nanoparticles (MeNPs) and specific nanosystems, such as complexes of MeNPs, with the shell of attached drugs, several physicochemical properties need to be considered. The most important are: size, shape, surface charge, type of surfactants that control their dispersion, and shell molecules that should assure specific molecular interaction with targeted molecules of parasites’ cells. Therefore, it can be expected that the development of antiparasitic drugs using strategies provided by nanotechnology and the use of nanomaterials for diagnostic purposes will soon provide new and effective methods of antiparasitic therapy and effective diagnostic tools that will improve the prevention and reduce the morbidity and mortality caused by these diseases.
... The production of nitric oxide induced by the CNZ and CN miniemulsions offers interesting results, since reactive oxygen intermediates have a great influence on immune responses by activating or inhibiting the action of certain transcription factors or cytokines and by modifying pathways of programmed cell death (Arruda et al., 2004). The antioxidant total production capacity was studied, determining that both miniemulsions have the capacity to induce higher levels of antioxidants, that can be correlated with the promotion of mitochondrial biogenesis increasing antioxidant enzymes production, decreasing the exacerbation of proinflammatory cytokine response, and blocking or scavenging the excessive response of ROS and RSN, that in higher amounts can affect a healthy immune response (Maldonado et al., 2021). Is important to mention that cottonseed oil contain antioxidants that can act as exogenous antioxidant sources, however, is possible that antioxidants could be synthesized through different intracellular mechanisms. ...
Background
Emulsions have been widely used as immunological adjuvants. But the use of materials derived from plants such as cottonseed oil, alpha-tocopherol, or minerals such as zinc, as well as their use at the nanometric scale has been little explored. In this study, we develop a new miniemulsion and evaluated its antioxidant and phagocytic capacity, as well as parameters related to immune response stimulation by cytokine expression and antibodies production in a mice model.
Methods
Formulated CN (cottonseed oil miniemulsion) and CNZ (cottonseed oil miniemulsion whit zinc oxide nanoparticles) miniemulsions were characterized by scanning electronic microscopy SEM, DLS and FT-IR. In murine macrophages, splenocytes and thymocytes primary cultures safety and cytotoxicity were determined by MTT. In macrophages the antioxidant and phagocytic capacity was evaluated. In BALB/c mice, the stimulation of the immune system was determined by the expression of cytokines and the production of antibodies.
Results
The CN and CNZ presented stability for 90 days. Immediately after preparation, the CN presented a higher particle size (543.1 nm) than CNZ (320 nm). FT-IR demonstrated the correct nanoparticle synthesis by the absence of sulfate groups. CN and CNZ (1.25 to 10 µL/mL) had no toxic effect on macrophages ( p = 0.108), splenocytes ( p = 0.413), and thymocytes ( p = 0.923). All CN and CNZ doses tested induced nitric oxide and antioxidants production in dose dependent manner when compared with control. CN-ovalbumin and CNZ-ovalbumin treatments in femoral subcutaneous tissue area showed inflammation with higher leukocyte infiltration compared with FCA. The intraperitoneal administration with CN, CNZ, and FCA showed a higher total intraperitoneal cells recruitment (CD14 ⁺ ) after 24 h of inoculation than control ( p = 0.0001). CN and CNZ increased the phagocyte capacity with respect to untreated macrophages in the Candida albicans -phagocytosis assay. The evaluation of residual CFU indicated that only CN significantly decreased ( p = 0.004) this value at 3 h. By other side, only CN increased ( p = 0.002) the nitric oxide production. CNZ stimulated a major INFγ secretion compared with FCA at day 7. A major IL-2 secretion was observed at days 7 and 14, stimulated with CN and CNZ. Both miniemulsions did not affect the antibody isotypes production (IgG1, IgG2a, IgG3, IgA and IgM) at days 7, 14, 28, and 42. CN induced a significant IgG production against OVA, but lesser than FCA.
Conclusions
The two new miniemulsions with adjuvant and antioxidant capacity, were capable of generating leukocyte infiltration and increased cytokines and antibodies production.
... Several evidences have indicated that, during progression of Chagas disease, the host antioxidant response is exhausted (Perez-Fuentes et al., 2003;Wen et al., 2008Wen et al., , 2017, supporting the association of the consequent oxidative stress with parasite persistence in host tissues (Paiva et al., 2012) and with the development of cardiac alterations due to mitochondrial dysfunction and chronic inflammation (Lopez et al., 2018;Bonney et al., 2019). As a consequence, some approaches for Chagas disease treatment are focused on reducing the oxidative damage in the host by using an adjuvant therapy with antioxidants (Macao et al., 2007;Budni et al., 2013;Maldonado et al., 2021). Also, Benznidazole, one of the drugs used to treat T. cruzi infection, can induce increased reactive oxygen species (ROS) and DNA damage in host tissues, and antioxidant supplementation has been found to be able to attenuate this effect (Ribeiro et al., 2010;Barbosa et al., 2016). ...
Chagas’ disease or American trypanosomiasis, caused by Trypanosoma cruzi infection, is an endemic disease in
Latin America, which has spread worldwide in the past years. The drugs presently used for treatment have shown
limited efficacy due to the appearance of resistant parasites and severe side effects. Some of the most recent
studies on anti-parasitic drugs have been focused on protein acetylation, a reversible reaction modulated by
Acetyl Transferases (KATs) and Deacetylases (KDACs). We have previously reported the anti-parasite activity of
resveratrol (RSV), an activator of KDACs type III (or sirtuins), and showed that this drug can reduce the growth of
T. cruzi epimastigotes and the infectivity of trypomastigotes. Since RSV is now widely used in humans due to its
beneficial effects as an antioxidant, it has become an attractive candidate as a repurposing drug. In this context,
the aim of the present study was to evaluate the ability of this drug to protect three different types of host cells
from parasite infection. RSV treatment before parasite infection reduced the percentage of infected cells by
50–70% depending on the cell type. Although the mammalian cell lines tested showed different sensitivity to
RSV, apoptosis was not significantly affected, showing that RSV was able to protect cells from infection without
the activation of this process. Since autophagy has been described as a key process in parasite invasion, we also
monitored this process on host cells pretreated with RSV. The results showed that, at the concentrations and
incubation times tested, autophagy was not induced in any of the cell types evaluated. Our results show a partial
protective effect of RSV in vitro, which justifies extending studies to an in vivo model to elucidate the mechanism
by which this effect occurs.
... Moreover, proteins present in mitochondria are essential for most biosynthetic pathways. 52,53 In the present work, the mass spectra of T. cruzi proteins were obtained by the MicroFlex MALDI-TOF/MS, a system used for microorganism classification. Applying a machine learning model, the protein profile of BMA-treated parasites was compared to naive parasites (untreated group) and those treated with the standard drug benznidazole. ...
Chagas disease, caused by Trypanosoma cruzi, affects seven million people worldwide and lacks effective treatments. Using bioactivity-guided fractionation, NMR, and electrospray ionization-high resolution mass spectrometry (ESI-HRMS) spectral analysis, the indole alkaloid 6-bromo-2'-de-N-methylaplysinopsin (BMA) was isolated and chemically characterized from the marine coral Tubastraea tagusensis. BMA was tested against trypomastigotes and intracellular amastigotes of T. cruzi, resulting in IC50 values of 62 and 5.7 μM, respectively, with no mammalian cytotoxicity. The mechanism of action studies showed that BMA induced no alterations in the plasma membrane permeability but caused depolarization of the mitochondrial membrane potential, reducing ATP levels. Intracellular calcium levels were also reduced after the treatment, which was associated with pH alteration of acidocalcisomes. Using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)/MS analysis, alterations of mass spectral signals were observed after treatment with BMA, suggesting a different mechanism from benznidazole. In silico pharmacokinetic-pharmacodynamic (PKPD) parameters suggested a drug-likeness property, supporting the promising usefulness of this compound as a new hit for optimizations.
... Nuclear factor E2-related factor 2 (Nrf2) is a master endogenous antioxidant transcription factor that has been increasingly reported to play crucial roles in protecting cells against oxidative stress 18 . Physiologically, Nrf2 is critical for the expression of antioxidative genes, cytoprotective enzymes, and export transporters, which constitute an antioxidant defense system that maintains intracellular redox homeostasis 19 . The activation of Nrf2 signaling is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1), which functions as a redox sensor for ROS and electrophiles 20,21 . ...
Intervertebral disc degeneration (IDD) is a common degenerative musculoskeletal disorder and is recognized as a major contributor to discogenic lower back pain. However, the molecular mechanisms underlying IDD remain unclear, and therapeutic strategies for IDD are currently limited. Oxidative stress plays pivotal roles in the pathogenesis and progression of many age-related diseases in humans, including IDD. Nuclear factor E2-related factor 2 (Nrf2) is a master antioxidant transcription factor that protects cells against oxidative stress damage. Nrf2 is negatively modulated by Kelch-like ECH-associated protein 1 (Keap1) and exerts important effects on IDD progression. Accumulating evidence has revealed that Nrf2 can facilitate the transcription of downstream antioxidant genes in disc cells by binding to antioxidant response elements (AREs) in promoter regions, including heme oxygenase-1 (HO-1), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and NADPH quinone dehydrogenase 1 (NQO1). The Nrf2 antioxidant defense system regulates cell apoptosis, senescence, extracellular matrix (ECM) metabolism, the inflammatory response of the nucleus pulposus (NP), and calcification of the cartilaginous endplates (EP) in IDD. In this review, we aim to discuss the current knowledge on the roles of Nrf2 in IDD systematically.
... It is noteworthy that SIRT3, 4, and 5 are found in the mitochondrial matrix [174]. As cardiomyocyte mitochondrial dysfunction plays a central role in chagasic myocarditis (vide supra), the activation of sirtuins such as SIRT1 by agonists including resveratrol may enhance antioxidant defenses [181,182], therefore comprise promising coadjuvant therapies for CD [183][184][185], although selenium was previously reported to increase tissue parasitism [186]. ...
Chagas disease, caused by the protozoan Trypanosoma cruzi, is a major neglected disease endemic to Latin America, associated to significant morbimortality comprising a remarkable socioeconomic problem mainly for low-income tropical populations. The present chapter focuses translational research on Chagas disease, approaching drug combinations and repositioning, particularly exploiting the parasite oxidative stress by prospecting prooxidant compounds combined with antagonists of antioxi-dant systems, for developing low-cost and safe therapies for this infection. The pertinent literature on protozoal parasitic diseases is reviewed as well as on repurposing disulfiram aiming the combination with the Chagas disease drug of choice benznida-zole. Both disulfiram and its first derivative sodium diethyldithiocarbamate (DETC) are able not only to inhibit p-glycoprotein, possibly reverting resistance phenotypes, but also to reduce toxicity of numerous other drugs, heavy metals, etc. Therefore, this innovation, presently in clinical research, may furnish a novel therapeutic for T. cruzi infections overcoming the adverse effects and refractory cases that impair the effectiveness of Chagas disease treatment.
