scholarly journals PARA UMA DOENÇA TÃO ANTIGA, O VISLUMBRE DE NOVOS TRATAMENTOS PROMISSORES NA DOENÇA DE CHAGAS

2021 ◽  
Vol 58 (1) ◽  
pp. eUJ4087
Author(s):  
Sabrina Sehn Hilgert ◽  
◽  
Sofia Comássio de Paula Lima ◽  
Sofia Ferreira Salviano ◽  
Cristiane Tefé-Silva ◽  
...  
Keyword(s):  
Treatment Time ◽  
Parasite Load ◽  
New Drugs ◽  
In Vivo Models ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Production And Distribution ◽  
Synthase Inhibitor

It has been more than 100 years since the discovery of Chagas Disease (CD). However, the repertoire indicated for its treatment is still limited. Thus, this article aims to present a review of the new pharmacological strategies being studied for CD. This literature review, consisting of 68 articles, from 1957 to 2021, was carried out on several scientific platforms. Positive effects from benznidazole have been described in the acute and chronic phases, in addition to its association with itraconazole in the acute phase. Among the cruzain inhibitors, the compound K777 presented trypanocidal effects, although demonstrating major adverse effects, while its analogue WRR-483 demonstrated great beneficial effects in vivo and in vitro. As for the nitroheterocyclics, fexinidazole showed high rates of cure in animal model, in addition to low toxicity. Nifurtimox, in early chronic stages, was able to delay the progression of tissue damage and reduce the parasite load. The compound WC-9, a squalene synthase inhibitor, showed potential inhibition of T. cruzi replication. Regarding aromatic diamidines, many compounds were able to stop the trypanosome, both in vitro and in vivo models. It was concluded that there are favorable findings to improve the treatment of CD. However, the development of effective new drugs does not only depend on their effective action, but also on numerous variables that must be circumvented, such as the reduction of side effects, treatment time and adherence to the current medication of choice, as well as the investment in production and distribution to the population.

scholarly journals Biological Relevance of Extra Virgin Olive Oil Polyphenols Metabolites

Antioxidants ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 170 ◽  
Author(s):  
Gabriele Serreli ◽  
Monica Deiana
Keyword(s):  
Olive Oil ◽  
Intracellular Signaling ◽  
Cellular Response ◽  
Virgin Olive Oil ◽  
Extra Virgin Olive Oil ◽  
Main Concern ◽  
Beneficial Effects ◽  
Positive Effects

Extra virgin olive oil (EVOO) polyphenols beneficial effects have widely been debated throughout the last three decades, with greater attention to hydroxytyrosol and tyrosol, which are by far the most studied. The main concern about the evaluation of EVOO phenols activities in vitro and in vivo is that the absorption and metabolism of these compounds once ingested lead to the production of different metabolites in the human body. EVOO phenols in the ingested forms are less concentrated in human tissues than their glucuronide, sulfate and methyl metabolites; on the other hand, metabolites may undergo deconjugation before entering the cells and thus act as free forms or may be reformed inside the cells so acting as conjugated forms. In most in vitro studies the presence of methyl/sulfate/glucuronide functional groups does not seem to inhibit biological activity. Parent compounds and metabolites have been shown to reach tissue concentrations useful to exert beneficial effects others than antioxidant and scavenging properties, by modulating intracellular signaling and improving cellular response to oxidative stress and pro-inflammatory stimuli. This review aims to give an overview on the reported evidence of the positive effects exerted by the main EVOO polyphenols metabolites in comparison with the parent compounds.

scholarly journals The Role of DPP4 Activity in Cardiovascular Districts: In Vivo and In Vitro Evidence

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
L. Pala ◽  
C. M. Rotella
Keyword(s):  
Minimal Risk ◽  
Incretin Hormone ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Glucagon Like Peptide 1 ◽  
A Site

The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, since these drugs not only improve glycemia with minimal risk of hypoglycemia, but also have other extraglycemic beneficial effects. These agents, which are effective in improving glucose control, could also have positive effects on the incidence of cardiovascular events. The aim of this review is to summarize the present literature about the role of dipeptidyl peptidase 4 (DPP4) in cardiovascular districts, not only strictly correlated to its effect on glucagon-like peptide-1 (GLP-1) circulating levels, but also to what is known about possible cardiovascular actions. Actually, DPP4 is known to be present in many cells and tissues and its effects go beyond purely metabolic aspects. Almost always the inhibition of DPP4 activity is associated with improved cardiovascular profile, but it has shown to possess antithrombotic properties and these different effects could be connected with a site and/or species specificity of DPP4. Certainly, DPP4 seems to exert many functions, both directly and indirectly, on cardiovascular districts, opening new possibilities of prevention and treatment of complications at this level, not only in patients affected by diabetes mellitus.

scholarly journals Virtual Screening in Pharmacokinetics, Bioactivity, and Toxicity of the Amburana cearensis Secondary Metabolites

2021 ◽  
Vol 12 (6) ◽  
pp. 8471-8491
Keyword(s):  
Secondary Metabolites ◽  
Phenolic Acids ◽  
Stem Bark ◽  
New Drugs ◽  
Structure Property ◽  
In Vivo Models ◽  
Popular Medicine ◽  
Anti Inflammatory

Bioprospecting has contributed to the work of pharmaceutical chemists in the development and commercial disposal of new drugs. Currently, the pharmaceutical industry has emphasized drugs produced from bioactive compounds extracted from natural sources, based on popular medicine discussed in the literature, such as secondary metabolites isolated from the stem bark and seeds of the Amburana cearensis, rich in coumarin derivatives, flavonoids, and phenolic acids and is popularly used in the treatment of respiratory diseases and with anti-inflammatory and antioxidant bioactivity. This review is a study of the structure/activity and structure/property (SAR/SPA) relationship with the physicochemical properties calculated by the algorithms of the MarvinSketch software for the secondary metabolites of A. cearensis, as well as their correlation with in silico test values the SwissADME and admetSAR 2.0 servers and in vitro and in vivo models of the dataset from the PreADMET, GUSAR Online and PASS Online servers. The results showed that substances derived from coumarin, flavonoids, and phenolic acids have attributes of good permeability and low efflux, which favor their oral bioavailability, since phenolic heterosides, amburoside analogs, and biflavonoids are effective in local action as subcutaneous application, constituting promising antimicrobial, anti-inflammatory and antioxidant therapeutic actions in their proper administration routes.

scholarly journals Nifedipine Upregulates ATF6-α, Caspases -12, -3, and -7 Implicating Lipotoxicity-Associated Renal ER Stress

2020 ◽  
Vol 21 (9) ◽  
pp. 3147
Author(s):  
Chiung-Chi Peng ◽  
Chang-Rong Chen ◽  
Chang-Yu Chen ◽  
Yen-Chung Lin ◽  
Kuan-Chou Chen ◽  
...  
Keyword(s):  
Er Stress ◽  
Nile Red ◽  
In Vivo Models ◽  
Beneficial Effects ◽  
Homologous Protein ◽  
Renal Tubular Cells ◽  
Activating Transcription Factor ◽  
Renal Tubular

Nifedipine (NF) is reported to have many beneficial effects in antihypertensive therapy. Recently, we found that NF induced lipid accumulation in renal tubular cells. Palmitic acid-induced renal lipotoxicity was found to be partially mediated by endoplasmic reticular (ER) stress, while it can also be elicited by NF in kidney cells; we examined the induction of suspected pathways in both in vitro and in vivo models. NRK52E cells cultured in high-glucose medium were treated with NF (30 µM) for 24–48 h. ER stress-induced lipotoxicity was explored by staining with thioflavin T and Nile red, transmission electron microscopy, terminal uridine nick-end labeling, and Western blotting. ER stress was also investigated in rats with induced chronic kidney disease (CKD) fed NF for four weeks. NF induced the production of unfolded protein aggregates, resulting in ER stress, as evidenced by the upregulation of glucose-regulated protein, 78 kDa (GRP78), activating transcription factor 6α (ATF6α), C/EBP-homologous protein (CHOP), and caspases-12, -3, and -7. In vitro early apoptosis was more predominant than late apoptosis. Most importantly, ATF6α was confirmed to play a unique role in NF-induced ER stress in both models. CKD patients with hypertension should not undergo NF therapy. In cases where it is required, alleviation of ER stress should be considered to avoid further damaging the kidneys.

scholarly journals Chagas Disease Drug Discovery

2014 ◽  
Vol 20 (1) ◽  
pp. 22-35 ◽  
Author(s):  
Eric Chatelain
Keyword(s):  
Chagas Disease ◽  
New Technologies ◽  
Low Cost ◽  
Screening Strategy ◽  
New Drugs ◽  
In Vivo Models ◽  
The Right ◽  
The Impact

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed.

scholarly journals Ginger, a Possible Candidate for the Treatment of Dementias?

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5700
Author(s):  
Giovanni Schepici ◽  
Valentina Contestabile ◽  
Andrea Valeri ◽  
Emanuela Mazzon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Human Life ◽  
Zingiber Officinale ◽  
Ancient Medicine ◽  
In Vivo Models ◽  
Beneficial Effects

As the human life expectancy increases, age-linked diseases have become more and more frequent. The worldwide increment of dementia cases demands medical solutions, but the current available drugs do not meet all the expectations. Recently the attention of the scientific community was attracted by natural compounds, used in ancient medicine, known for their beneficial effects and high tolerability. This review is focused on Ginger (Zingiber officinale) and explore its properties against Alzheimer’s Disease and Vascular Dementia, two of the most common and devastating forms of dementia. This work resumes the beneficial effects of Ginger compounds, tested in computational in vitro and in vivo models of Alzheimer’s Disease and Vascular Dementia, along with some human tests. All these evidences suggest a potential role of the compounds of ginger not only in the treatment of the disease, but also in its prevention.

scholarly journals Repurposing Carvedilol as a Novel Inhibitor of the Trypanosoma cruzi Autophagy Flux That Affects Parasite Replication and Survival

2021 ◽  
Vol 11 ◽  
Author(s):  
Cynthia Vanesa Rivero ◽  
Santiago José Martínez ◽  
Paul Novick ◽  
Juan Agustín Cueto ◽  
Betiana Nebaí Salassa ◽  
...  
Keyword(s):  
Chagas Disease ◽  
Parasite Burden ◽  
Drug Repurposing ◽  
Parasite Load ◽  
New Drugs ◽  
Host Cells ◽  
Whole Body ◽  
Parasite Replication

T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.

scholarly journals Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1471 ◽  
Author(s):  
Magdalena Kusaczuk
Keyword(s):  
Bile Acid ◽  
Primary Biliary Cholangitis ◽  
In Vivo Models ◽  
Chemical Chaperone ◽  
Cytoprotective Activity ◽  
Cellular Effects ◽  
Positive Effects ◽  
Therapeutic Benefits

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.

scholarly journals Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Esmaeil Dehghan ◽  
Mohammad Goodarzi ◽  
Bahar Saremi ◽  
Rueyling Lin ◽  
Hamid Mirzaei
Keyword(s):  
Protein Kinase ◽  
Mitochondrial Function ◽  
Dependent Protein Kinase ◽  
In Vivo Models ◽  
C Elegans ◽  
Beneficial Effects ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein

Abstract Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan in C. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.

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