scholarly journals A Nonazole CYP51 Inhibitor Cures Chagas’ Disease in a Mouse Model of Acute Infection

2010 ◽  
Vol 54 (6) ◽  
pp. 2480-2488 ◽  
Author(s):  
Patricia S. Doyle ◽  
Chiung-Kuang Chen ◽  
Jonathan B. Johnston ◽  
Stephanie D. Hopkins ◽  
Siegfried S. F. Leung ◽  
...  
Keyword(s):  
Mouse Model ◽  
Chagas Disease ◽  
Rational Design ◽  
Fungal Infections ◽  
Acute Infection ◽  
Sterol Composition ◽  
Gas Chromatography Mass Spectrometry ◽  
Promising Alternative ◽  
Morphological Alterations ◽  
Normal Tissues

ABSTRACT Chagas’ disease, the leading cause of heart failure in Latin America, is caused by the kinetoplastid protozoan Trypanosoma cruzi. The sterols of T. cruzi resemble those of fungi, both in composition and in biosynthesis. Azole inhibitors of sterol 14α-demethylase (CYP51) successfully treat fungal infections in humans, and efforts to adapt the success of antifungal azoles posaconazole and ravuconazole as second-use agents for Chagas’ disease are under way. However, to address concerns about the use of azoles for Chagas’ disease, including drug resistance and cost, the rational design of nonazole CYP51 inhibitors can provide promising alternative drug chemotypes. We report the curative effect of the nonazole CYP51 inhibitor LP10 in an acute mouse model of T. cruzi infection. Mice treated with an oral dose of 40 mg LP10/kg of body weight twice a day (BID) for 30 days, initiated 24 h postinfection, showed no signs of acute disease and had histologically normal tissues after 6 months. A very stringent test of cure showed that 4/5 mice had negative PCR results for T. cruzi, and parasites were amplified by hemoculture in only two treated mice. These results compare favorably with those reported for posaconazole. Electron microscopy and gas chromatography-mass spectrometry (GC-MS) analysis of sterol composition confirmed that treatment with LP10 blocked the 14α-demethylation step and induced breakdown of parasite cell membranes, culminating in severe ultrastructural and morphological alterations and death of the clinically relevant amastigote stage of the parasite.

Assessing the effectiveness of AS-48 in experimental mice models of Chagas’ disease

2020 ◽  
Vol 75 (6) ◽  
pp. 1537-1545 ◽  
Author(s):  
Rubén Martín-Escolano ◽  
Rubén Cebrián ◽  
Mercedes Maqueda ◽  
Desirée Romero ◽  
Maria José Rosales ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Enterococcus Faecalis ◽  
Chagas Disease ◽  
Chronic Infection ◽  
Acute Infection ◽  
Chronic Phase ◽  
Aetiological Agent ◽  
Promising Alternative ◽  
Parasitic Load

Abstract Objectives We report the in vivo trypanocidal activity of the bacteriocin AS-48 (lacking toxicity), which is produced by Enterococcus faecalis, against the flagellated protozoan Trypanosoma cruzi, the aetiological agent of Chagas’ disease. Methods We determined the in vivo activity of AS-48 against the T. cruzi Arequipa strain in BALB/c mice (in both acute and chronic phases of Chagas’ disease). We evaluated the parasitaemia, the reactivation of parasitaemia after immunosuppression and the nested parasites in the chronic phase by PCR in target tissues. Results AS-48 reduced the parasitaemia profile in acute infection and showed a noteworthy reduction in the parasitic load in chronic infection after immunosuppression according to the results obtained by PCR (double-checking to demonstrate cure). Conclusions AS-48 is a promising alternative that provides a step forward in the development of a new therapy against Chagas’ disease.

Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

2019 ◽  
Vol 26 (36) ◽  
pp. 6519-6543 ◽  
Author(s):  
Adriana Egui ◽  
Paola Lasso ◽  
Elena Pérez-Antón ◽  
M. Carmen Thomas ◽  
Manuel Carlos López
Keyword(s):  
Immune Response ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Cardiac Tissue ◽  
Acute Infection ◽  
Clinical Status ◽  
Chronic Phase ◽  
Parasite Load ◽  
Chronic Patients ◽  
Cruzi Infection

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

scholarly journals Nanocarriers of Miconazole or Fluconazole: Effects on Three-Species Candida Biofilms and Cytotoxic Effects In Vitro

2021 ◽  
Vol 7 (7) ◽  
pp. 500
Author(s):  
Anne Caroline Morais Caldeirão ◽  
Heitor Ceolin Araujo ◽  
Laís Salomão Arias ◽  
Wilmer Ramírez Carmona ◽  
Gustavo Porangaba Miranda ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Artificial Saliva ◽  
Cytotoxic Effects ◽  
Promising Alternative ◽  
Colony Forming Units ◽  
Mtt Reduction ◽  
Diphenyl Tetrazolium Bromide ◽  
Negative Controls ◽  
Positive Controls

The contribution of different Candida species in oral fungal infections has stimulated the search for more effective therapies. This study assessed the antibiofilm effects of nanocarriers of miconazole (MCZ) or fluconazole (FLZ) on Candida biofilms, and their cytotoxic effects on murine fibroblasts. Three-species biofilms (Candida albicans/Candida glabrata/Candida tropicalis) were formed on 96-well plates, and they were treated with nanocarriers (iron oxide nanoparticles coated with chitosan—“IONPs-CS”) of MCZ or FLZ at 39/78/156 µg/mL; antifungals alone at 156 µg/mL and artificial saliva were tested as positive and negative controls, respectively. Biofilms were analyzed by colony forming units (CFU), biomass, metabolic activity, and structure/viability. The cytotoxicity (L929 cells) of all treatments was determined via 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction assay. Data were submitted to one- or two-way ANOVA, followed by Tukey’s or Fisher LSD’s tests (p < 0.05). IONPs-CS-MCZ at 78 µg/mL promoted similar antibiofilm and cytotoxic effects compared with MCZ at 156 µg/mL. In turn, IONPs-CS-FLZ at 156 µg/mL was overall the most effective FLZ antibiofilm treatment, surpassing the effects of FLZ alone; this nanocarrier was also less cytotoxic compared with FLZ alone. It can be concluded that both nanocarriers are more effective alternatives to fight Candida biofilms compared with their respective positive controls in vitro, being a promising alternative for the treatment of oral fungal infections.

scholarly journals 24(S)-Saringosterol Prevents Cognitive Decline in a Mouse Model for Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. 190
Author(s):  
Nikita Martens ◽  
Melissa Schepers ◽  
Na Zhan ◽  
Frank Leijten ◽  
Gardi Voortman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Inflammatory Marker ◽  
Amyloid Β ◽  
Liver Fat ◽  
Gas Chromatography Mass Spectrometry ◽  
Memory Decline ◽  
Plaque Load

We recently found that dietary supplementation with the seaweed Sargassum fusiforme, containing the preferential LXRβ-agonist 24(S)-saringosterol, prevented memory decline and reduced amyloid-β (Aβ) deposition in an Alzheimer’s disease (AD) mouse model without inducing hepatic steatosis. Here, we examined the effects of 24(S)-saringosterol as a food additive on cognition and neuropathology in AD mice. Six-month-old male APPswePS1ΔE9 mice and wildtype C57BL/6J littermates received 24(S)-saringosterol (0.5 mg/25 g body weight/day) (APPswePS1ΔE9 n = 20; C57BL/6J n = 19) or vehicle (APPswePS1ΔE9 n = 17; C57BL/6J n = 19) for 10 weeks. Cognition was assessed using object recognition and object location tasks. Sterols were analyzed by gas chromatography/mass spectrometry, Aβ and inflammatory markers by immunohistochemistry, and gene expression by quantitative real-time PCR. Hepatic lipids were quantified after Oil-Red-O staining. Administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice without affecting the Aβ plaque load. Moreover, 24(S)-saringosterol prevented the increase in the inflammatory marker Iba1 in the cortex of APPswePS1ΔE9 mice (p < 0.001). Furthermore, 24(S)-saringosterol did not affect the expression of lipid metabolism-related LXR-response genes in the hippocampus nor the hepatic neutral lipid content. Thus, administration of 24(S)-saringosterol prevented cognitive decline in APPswePS1ΔE9 mice independent of effects on Aβ load and without adverse effects on liver fat content. The anti-inflammatory effects of 24(S)-saringosterol may contribute to the prevention of cognitive decline.

scholarly journals Identifying Current and Missing Knowledge in the Control of Pyrethroid-Resistant Triatoma infestans, Vector of Chagas Disease

2017 ◽  
Vol 9 (7) ◽  
pp. 47
Author(s):  
Gonzalo Roca Acevedo ◽  
María Inés Picollo
Keyword(s):  
Chagas Disease ◽  
Chemical Control ◽  
Rational Design ◽  
Pyrethroid Resistance ◽  
Triatoma Infestans ◽  
Vector Transmission ◽  
Pyrethroid Insecticides ◽  
Blood Sucking ◽  
Deltamethrin Resistance ◽  
Metabolic Detoxification

Triatomines are blood-sucking bugs that occur mainly in Latin America. They are vectors of Trypanosoma cruzi, the parasite that causes Chagas disease. Chemical control of Chagas disease´s vectors by using pyrethroid insecticides has been highly successful for the elimination of domestic infestation and consequently the reduction of the vector transmission. However, at the beginning of the 2000s a decrease in the effectiveness of the chemical control of triatomines was detected in several areas from Argentina and Bolivia, particularly in the Gran Chaco eco-region.During the last 15 years, several studies demonstrated the evolution of insecticide resistance in Triatoma infestans and established the presence of different toxicological profiles, the autosomal inherence of resistance, the biological costs of deltamethrin resistance, the expression of deltamethrin resistance thorough the embryonic development, and the main mechanisms of resistance (target-site insensitivity and metabolic detoxification of insecticides).The emergence of pyrethroid resistance coupled with the usual difficulties in sustaining adequate rates of insecticide applications emphasize the need of incorporating other tools for integrated vector and disease control, such as the proposal of the organo-phosphorus insecticide fenitrothion as an alternative chemical strategy for the management of the resistance because it was effective against pyrethroid-resistant populations in laboratory and semi-field trials.New studies on the current situation of presence and spread of resistant populations of triatomines and the acceptance of the use of alternative insecticides are critical requirements in the implementation of strategies for the management of resistance and for the rational design of campaigns oriented to reducing the vector transmission of Chagas’ disease.

scholarly journals Fusogenics

2010 ◽  
Vol 16 (1) ◽  
pp. 90-100 ◽  
Author(s):  
Jeannick Cizeau ◽  
Marianne G. P. Torres ◽  
Sharla G. Cowling ◽  
Stacy Stibbard ◽  
Arjune Premsukh ◽  
...  
Keyword(s):  
Specific Antibody ◽  
Screening Method ◽  
Antibody Fragment ◽  
Vital Role ◽  
Single Step ◽  
Functional Assay ◽  
Plant Toxin ◽  
Promising Alternative ◽  
Pseudomonas Exotoxin A ◽  
Normal Tissues

Antibody-based therapeutics play a vital role in the treatment of certain cancers; however, despite commercial success, various strategies are being pursued to increase their potency and hence improve patient outcomes. The use of antibodies to deliver a cytotoxic payload offers a promising alternative for more efficacious therapies. Immunotoxins are composed of an internalizing antibody fragment linked to a bacterial or plant toxin. Once internalized, the payload, such as Pseudomonas exotoxin A (PE), blocks protein synthesis and induces apoptosis. Typically, immunotoxins are developed by first isolating a tumor-specific antibody, which is then either chemically linked to a toxin or reengineered as a fusion protein. Here, the authors describe the development of Fusogenics, an immunotoxin-based screening method that selects internalizing tumor-specific antibodies using a functional assay. Selected immune library clones were characterized and shown to be selective against normal tissues and specific to tumor tissues. In summary, the Fusogenics immunotoxin platform represents a unique, single-step selection approach combining specificity and functionality to isolate novel internalizing tumor-specific antibody fragments with potential for direct clinical application in the treatment of cancer.

scholarly journals Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Gregory T. Robertson ◽  
Victoria A. Ektnitphong ◽  
Michael S. Scherman ◽  
Matthew B. McNeil ◽  
Devon Dennison ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
Promising Alternative ◽  
Lung Lesions ◽  
Content Type ◽  
Drug Levels ◽  
Lower Resistance ◽  
Inha Inhibitor

ABSTRACT AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis. In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline antituberculosis agent isoniazid.

scholarly journals Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) Rendle Essential Oils in the Endotoxin-induced Acute Airway Inflammation Mouse Model

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3553
Author(s):  
Eszter Csikós ◽  
Kata Csekő ◽  
Amir Reza Ashraf ◽  
Ágnes Kemény ◽  
László Kereskai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Essential Oils ◽  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Whole Body ◽  
Gas Chromatography Mass Spectrometry ◽  
Thymus Vulgaris ◽  
Inflammatory Conditions ◽  
Inflammatory Parameters

Thyme (TO), cinnamon (CO), and Ceylon type lemongrass (LO) essential oils (EOs) are commonly used for inhalation. However, their effects and mechanisms on inflammatory processes are not well-documented, and the number of in vivo data that would be important to determine their potential benefits or risks is low. Therefore, we analyzed the chemical composition and investigated the activity of TO, CO, and LO on airway functions and inflammatory parameters in an acute pneumonitis mouse model. The components of commercially available EOs were measured by gas chromatography–mass spectrometry. Airway inflammation was induced by intratracheal endotoxin administration in mice. EOs were inhaled during the experiments. Airway function and hyperresponsiveness were determined by unrestrained whole-body plethysmography on conscious animals. Myeloperoxidase (MPO) activity was measured by spectrophotometry from lung tissue homogenates, from which semiquantitative histopathological scores were assessed. The main components of TO, CO, and LO were thymol, cinnamaldehyde, and citronellal, respectively. We provide here the first evidence that TO and CO reduce inflammatory airway hyperresponsiveness and certain cellular inflammatory parameters, so they can potentially be considered as adjuvant treatments in respiratory inflammatory conditions. In contrast, Ceylon type LO inhalation might have an irritant effect (e.g., increased airway hyperresponsiveness and MPO activity) on the inflamed airways, and therefore should be avoided.

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