scholarly journals The Effect of the GH/IGF-1 Axis During Trypanosoma Cruzi Infection

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A492-A493
Author(s):  
Patricia Mora-Criollo ◽  
Reetobrata Basu ◽  
Yanrong Qian ◽  
Jaime A Costales ◽  
Jaime Guevara-Aguirre ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cell Lines ◽  
Chronic Phase ◽  
Mouse Fibroblast ◽  
Host Cells ◽  
Cervical Cancer Cell Line ◽  
Cell Line Hela ◽  
Vitro Effect ◽  
Cruzi Infection

Abstract Trypanosoma cruzi is the parasite responsible for Chagas disease (CD), that affects 6-8 million people worldwide. CD treatment is limited to two drugs (benznidazole and nifurtimox). Treatment is mostly effective during the acute phase of the disease (initial two months post-infection), while their efficacy during the chronic phase is controversial. In the absence of treatment, 30% of infected individuals suffer irreversible chronic cardiac and digestive damages, which lead to inability and, in some instances, death. Patients with Laron Syndrome (LS, a form of congenital GH insensitivity) are short in stature with low levels of IGF-1, elevated levels of GH and, surprisingly, are resistant to cancer and diabetes. A cohort of LS patients living in southern Ecuador, where CD is endemic, has been studied by Dr. Jaime Guevara for over 25 years (1). Few, if any, cases of CD have been reported among these patients (Dr. Guevara, personal communications). T. cruzi infection has been shown to directly modulate pituitary hormones such as GH, PRL and glucocorticoids (stress related hormones), leading to immunosuppression and thymic atrophy by depletion of CD4+ CD8+ cells. Previously, rats infected with T. cruzi and treated with GH showed reduced parasitism and less tissue damage compared to controls (2). The purpose of this research is to investigate the in vitro effect of GH during T. cruzi infection, simulating conditions of GH insensitivity. First, we separately treated T. cruzi and the host cells [human cervical cancer cell line (HeLa) and male mouse fibroblast (L-cells)] with relatively low or high levels of GH, IGF-1, PRL, and EGF. Next, we treated the parasite and host cells simultaneously with these hormones. When the parasites were treated alone, T. cruzi responded to exogenous GH (5ng/ml-50ng/ml) by significantly increasing the percentage of amastigotes (less infective form of the parasite). Also, when GH (50ng/ml) were administered to the host cells, T. cruzi infectivity was significantly reduced by 12% (percentage of infection) compared to 20% from untreated conditions. Similarly, both parasite and host cells treated with GH significantly reduced T. cruzi infectivity (10%) compared to untreated conditions (18%). We further treated both cell lines with a combination of GH/IGF-1. Conditions used were as follows: control (no-treatment), moderate levels (5ng/ml GH+150 ng/ml IGF-1), relatively high levels (50ng/ml GH+600ng/ml IGF-1), or levels that would simulate those found in patients with LS(50ng/ml GH+20 ng/ml IGF-1). Of these, the LS concentrations significantly reduced infection in both cell lines (11%) compared to control (16%). Together these results indicate that GH can influence T. cruzi infectivity and that GH, not IGF-1, is mediating the decreased infectivity. Finally, the results suggest that high concentrations of GH, as seen in LS patients, could be protective during T. cruzi infection. 1)Guevara-Aguirre et al., 2011 2) Frare et al., 2010

Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence

Parasitology ◽  
2019 ◽  
Vol 146 (07) ◽  
pp. 914-927 ◽  
Author(s):  
Thaiany G. Souza-Silva ◽  
Lívia F. Diniz ◽  
Ana Lia Mazzeti ◽  
Andrea A. S. Mendonça ◽  
Reggiani V. Gonçalves ◽  
...  
Keyword(s):  
Systematic Review ◽  
Trypanosoma Cruzi ◽  
Clinical Evidence ◽  
Renin Angiotensin System ◽  
Risk Of Bias ◽  
Host Cells ◽  
Angiotensin System ◽  
Preclinical And Clinical Studies ◽  
Cruzi Infection

AbstractAlthough leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact onTrypanosoma cruziinfection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs onT. cruziinfections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The mainin vitrofindings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γby T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed inT. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas’ disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.

In vitro Study on the Effect of Nanoparticles and Transfersomes as Targeted Drug Carrier for Cancer

2019 ◽  
Vol 9 (4) ◽  
pp. 512-518
Author(s):  
Karthikeyan Muthu ◽  
Blessy Vijayakumar ◽  
Thirumurugan Alagu
Keyword(s):  
Gold Nanoparticles ◽  
Drug Carrier ◽  
Cancer Cell Line ◽  
Sem Analysis ◽  
Cervical Cancer Cell Line ◽  
Hela Cell Lines ◽  
Cell Line Hela ◽  
Uv Visible ◽  
Vitro Effect

Introduction: Cancer is one of the current leading cause of death all over the world. Among the various emerging technologies, nanotechnology plays a prominent role in delivering the drug to the target region. Materials and Methods: In this study, the In vitro effect of doxorubicin adsorbed gold nanoparticles synthesized by Azadirachta Indica leaves extract as reducing agent and the doxorubicin entrapped modified liposomes called transfersomes was compared over the cervical cancer cell line (HeLa cell lines). The synthesized gold nanoparticles were characterized using a UV-visible spectrophotometer, SEM analysis. Results: The UV-Visible spectrum showed the peak at 537nm and the incorporation of drug over the nanoparticles was conformed using FTIR and SEM analysis. The drug entrapment onto transfersomes was also characterized using FTIR and SEM analysis. When compared, the drug entrapped transfersomes shows significant effect with the lowest concentration of drug (0.25 µg/mL) than the drug adsorbed nanoparticles. Conclusion: Hence, the transfersomes may also become the promising drug carrier in the future.

scholarly journals A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Roberto I. Cuevas-Hernández ◽  
Richard M. B. M. Girard ◽  
Sarai Martínez-Cerón ◽  
Marcelo Santos da Silva ◽  
Maria Carolina Elias ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Structural Characteristics ◽  
Chronic Phase ◽  
Human Infection ◽  
Host Cells ◽  
Mammalian Host ◽  
Content Type ◽  
Trypanocidal Drugs

ABSTRACT Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes [IC50(Epi) = 23.1 ± 1.75 μM] and intracellular forms of trypomastigotes [IC50(Tryp) = 8.5 ± 2.9 μM] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenylbenzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs.

scholarly journals Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

2021 ◽  
Vol 9 (2) ◽  
pp. 406
Author(s):  
Nieves Martinez-Peinado ◽  
Nuria Cortes-Serra ◽  
Julian Sherman ◽  
Ana Rodriguez ◽  
Juan M. Bustamante ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Specific Activity ◽  
Low Cost ◽  
Chronic Phase ◽  
Vero Cells ◽  
Host Cells ◽  
Vitro Assay ◽  
Specific Selectivity

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), affects more than six million people worldwide, with its greatest burden in Latin America. Available treatments present frequent toxicity and variable efficacy at the chronic phase of the infection, when the disease is usually diagnosed. Hence, development of new therapeutic strategies is urgent. Repositioning of licensed drugs stands as an attractive fast-track low-cost approach for the identification of safer and more effective chemotherapies. With this purpose we screened 32 licensed drugs for different indications against T. cruzi. We used a primary in vitro assay of Vero cells infection by T. cruzi. Five drugs showed potent activity rates against it (IC50 < 4 µmol L−1), which were also specific (selectivity index >15) with respect to host cells. T. cruzi inhibitory activity of four of them was confirmed by a secondary anti-parasitic assay based on NIH-3T3 cells. Then, we assessed toxicity to human HepG2 cells and anti-amastigote specific activity of those drugs progressed. Ultimately, atovaquone-proguanil, miltefosine, and verapamil were tested in a mouse model of acute T. cruzi infection. Miltefosine performance in vitro and in vivo encourages further investigating its use against T. cruzi.

Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi

Parasitology ◽  
2019 ◽  
Vol 146 (8) ◽  
pp. 1006-1012 ◽  
Author(s):  
M. R. Simões-Silva ◽  
J. S. De Araújo ◽  
R. B. Peres ◽  
P. B. Da Silva ◽  
M. M. Batista ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Kinase Inhibitor ◽  
Fixed Ratio ◽  
Chronic Phase ◽  
Host Cells ◽  
Public Health Issue ◽  
Mammalian Host ◽  
Neglected Diseases

AbstractChagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

scholarly journals Synthesis of 3-(2-(subsituted-(trifluoromethyl)phenylamino)acetyl)-2H-chromen-2-one derivatives as new anticancer agents

2022 ◽  
Vol 11 (1) ◽  
pp. 105-112 ◽  
Author(s):  
Anees Pangal ◽  
Yusufi Mujahid ◽  
Bajarang Desai ◽  
Javed A. Shaikh ◽  
Khursheed Ahmed
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Line ◽  
Cervical Cancer Cell Line ◽  
Solvent Free Conditions ◽  
Cell Line Hela ◽  
Mcf 7

Under solvent free conditions and in presence of a base 3-(2-(subsituted-(trifluoromethyl)phenylamino)acetyl)-2H-chromen-2-one derivatives were synthesized by grinding technique. Structural investigations were carried out with IR studies, HRMS, 1HNMR and 13CNMR. The compounds were checked for their in vitro anticancer activities against three different human cancer cell lines viz human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human oral squamous cell carcinoma (SCC-40) using SRB method. All the title compounds showed low toxicity towards non-malignant PBMC cells indicating their tumour selectivity. The compounds exhibited good in vitro anti-proliferative potency at lower concentrations against HeLa and MCF-7 cell lines and remain moderately active against SCC-40.

scholarly journals Phenothiazinium Dyes Are Active against Trypanosoma cruzi In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Gisele Bulhões Portapilla ◽  
Luiz Miguel Pereira ◽  
Cássia Mariana Bronzon da Costa ◽  
Maiara Voltarelli Providello ◽  
Pedro Alexandre Sampaio Oliveira ◽  
...  
Keyword(s):  
Methylene Blue ◽  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Low Cost ◽  
Chronic Phase ◽  
Host Cells ◽  
Migration Process ◽  
Mitochondrial Potential ◽  
Low Toxicity

Chagas disease is a tropical illness caused by the protozoan Trypanosoma cruzi. The disease affects populations of the Americas and has been spread to other continents due to the migration process. The disease is partially controlled by two drugs, Benznidazole and Nifurtimox. These molecules are active in the acute phase of the infection but are usually ineffective during the symptomatic chronic phase. Several research groups have developed novel candidates to control Chagas disease; however, no novel commercial formulation is available. In this article, we described the anti-T. cruzi effects of phenothiazinium dyes in amastigote and trypomastigote forms of the parasite. Methylene Blue, New Methylene Blue, Toluidine Blue O, and 1,9-Dimethyl Methylene Blue inhibited the parasite proliferation at nanomolar concentrations and also demonstrated low toxicity in host cells. Moreover, combinations of phenothiazinium dyes indicated a synergic pattern against amastigotes compared to the Benznidazole counterparts. Phenothiazinium dyes levels of reactive oxygen species (ROS) and decreased the mitochondrial potential in trypomastigotes, indicating the mechanism of action of the dyes in T. cruzi. Our article offers a basis for future strategies for the control of Chagas disease using low-cost formulations, an important point for endemic underdeveloped regions.

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.

Sign in / Sign up

Export Citation Format

Share Document