Leandro Barbosa

• PhD
• Professor (Associate) at Federal University of São João del-Rei

Neuroinflammation, often driven by the overproduction of reactive oxygen species (ROS), plays a crucial role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. The susceptibility of the brain to oxidative stress is attributed to its high metabolic activity and limited antioxidant defense. This study aime...

Cardiotonic steroids modulate various aspects of the inflammatory response. The synthetic cardiotonic steroid γ-benzylidene digoxin 15 (BD-15), a digoxin derivative, has emerged as a promising candidate with potential immunomodulatory effects. However, its biological activity remains largely unexplored. This study investigated the anti-mycobacteria...

Cancer is a leading cause of death worldwide and its treatment is hampered by the lack of specificity and side effects of current drugs. Cardiotonic steroids (CTS) interact with Na⁺/K⁺-ATPase (NKA) and induce antineoplastic effects, but their narrow therapeutic window is key limiting factor. The synthesis of digitoxigenin derivatives with glycosidi...

Cardiotonic steroids are known to bind to Na+/K+-ATPase and regulate several biological processes, including the immune response. The synthetic cardiotonic steroid γ-Benzylidene Digoxin 8 (BD-8) is emerging as a promising immunomodulatory molecule, although it has remained largely unexplored. Therefore, we tested the immunomodulatory potential of B...

The antitumor effect of cardiotonic steroids (CTS) has stimulated the search for new methods to evaluate both kinetic and thermodynamic aspects of their binding to Na+/K+-ATPase (NKA, EC 3.6.3.9). We propose a real-time assay based on a chromogenic substrate for phosphatase activity (pNPPase activity), using only two concentrations with an inhibito...

Introduction: Na, K-ATPase is a transmembrane enzyme crucial for cellular homeostasis, particularly in the kidney, where it exists as an oligomer (αβγ). The γ subunit, which is the FXYD2 domain, is absent in the majority of Na,K-ATPase preparations, but it is present in kidney medulla. Our group described that it behaves as a Na,K-ATPase activator....

Epilepsy is a neurological disorder characterized by epileptic seizures resulting from neuronal hyperexcitability, which may be related to failures in Na,K-ATPase activity and oxidative stress participation. We conducted this study to investigate the impact of antioxidant therapy on oxidative stress, Na,K-ATPase activity, seizure factors, and morta...

A lipopolysaccharide (LPS)-induced neuroinflammation rat model was used to study the effects of ouabain (OUA) at low concentrations, which can interact with the Na,K-ATPase, causing the modulation of intracellular signalling pathways in the Central Nervous System. Our study aimed to analyse the effects of OUA on glutamate transport in the hippocamp...

Through its classic ATP‐dependent ion‐pumping function, basolateral Na/K‐ATPase (NKA) generates the Na⁺ gradient that drives apical Na⁺ reabsorption in the renal proximal tubule (RPT), primarily through the Na⁺/H⁺ exchanger (NHE3). Accordingly, activation of NKA‐mediated ion transport decreases natriuresis through activation of basolateral (NKA) an...

A lipopolysaccharide (LPS)-induced neuroinflammation rat model was used to study the effects of ouabain (OUA) at low concentrations, which can interact with the Na, K-ATPase, causing the modulation of intracellular signalling pathways in the central nervous system. Our study aimed to analyse the effects of OUA on glutamate transport in the hippocam...

The Na⁺/K⁺-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na⁺/K⁺-ATPase. Here, we conducted a systematic review of the in vitro effects of cardiotonic steroids on Ca²⁺ in the brain of rats and mice. M...

The poor outcome of treatments for fungal infections is a consequence of the increasing incidence of resistance to antifungal agents, mainly due to the overexpression of efflux pumps. To surpass this mechanism of resistance, a substance able to inhibit these pumps could be administered in association with antifungals. Saccharomyces cerevisiae posse...

Brain ischemia is one of the diseases with the highest mortality rate today. Among the victims who do not die, most will have some functional disability as a sequel. Currently, tissue plasminogen activator (rt-PA) is the only pharmacological treatment for ischemia and there are no treatments with neuroprotective effects for this disease. Recently,...

Iron is a key element in cell function; however, its excess in iron overload conditions can be harmful through the generation of reactive oxygen species (ROS) and cell oxidative stress. Activity of Na,K-ATPase has been shown to be implicated in cellular iron uptake and iron modulates the Na,K-ATPase function from different tissues. In this study, w...

Na,K-ATPase (NKA) and cardiotonic steroids (CTS) have shown potent cytotoxic and anticancer effects. Here, we have synthesized a series of CTS digoxin derivatives (γ-benzylidene) with substitutions in the lactone ring and evaluated the cytotoxicity caused by digoxin derivatives in tumor and non-tumor cells lines, as well as their effects on NKA. Th...

We have previously shown that 21-benzylidene digoxin (21-BD) increases the total cholesterol and phospholipid content on the membrane of HeLa cells. Lipid modulation caused by cardiotonic steroids (CTS) is still unexplored. Therefore, the aim of the present study was to evaluate the cholesterol and phospholipid modulation of the cell membrane cause...

Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na+/K+‐ATPase to induce anti‐neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi‐synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective a...

Changes in metabolism are mechanisms that are largely implicated in the development, progression, and metastasis of head and neck squamous cell carcinoma (HNSCC) and also in resistance to different anticancer therapies. Identification of biomarkers for differentiation between cancerous and normal epithelium, treatment design and prognosis remain a...

Cardiac glycosides (CGs) are useful drugs to treat cardiac illnesses and have potent cytotoxic and anticancer effects in cultured cells and animal models. Their receptor is the Na⁺,K⁺ ATPase, but other plasma membrane proteins might bind CGs as well. Herein, we evaluated the short- and long-lasting cytotoxic effects of the natural cardenolide gluco...

Our study aimed to investigate the effects of the new cardiotonic steroid BD-15 (γ-benzylidene derivatives) in the behavioral parameters, oxidative stress and the Na, K-ATPase activity in the hippocampus, prefrontal cortex and heart from rats to verify the safety and possible utilization in brain disorders. For this study, groups of male Wistar rat...

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous and complex disease, both from a clinical and molecular point of view. The prolonged use of alcohol and tobacco, along with the release of tumor secretions can modulate blood cells, such as erythrocytes. Here, this study was conducted with 24 patients diagnosed with HNSCC and an equal...

Insect cuticle lipids are involved in various types of chemical communication between species, and reduce the penetration of insecticides, chemicals, and toxins, as well as provide protection against the attack of microorganisms, parasitic insects, and predators. Ecological studies related to the insect Rhynchophorus palmarum are well‐known; howeve...

Hydroxyurea (HU) is used as a therapy in sickle cell anemia (SCA). Many studies have established that HU improves patient quality of life by reducing symptoms. However, the effect of HU on erythrocytes is not well-described. We evaluated several parameters related to oxidative stress and total lipid content of erythrocytes in patients with SCA. The...

Cardiotonic steroids (CTS) are agents traditionally known for their capacity to bind to the Na,K-ATPase (NKA), affecting the ion transport and the contraction of the heart. Natural CTS have been shown to also have effects on cell signaling pathways. With the goal of developing a new CTS derivative , we synthesized a new digoxin derivative, 21-benzy...

Iron is an essential element for human life. However, it is a pro-oxidant agent capable of reacting with hydrogen peroxide. An iron overload can cause cellular changes, such as damage to the plasma membrane leading to cell death. Effects of iron overload in cellular biochemical processes include modulating membrane enzymes, such as the Na, K-ATPase...

Bufadienolide compounds have been used for growth inhibition and apoptosis induction in tumor cells. Those families of cardiotonic steroids can bind the Na,K-ATPase, causing its inhibition. The use of bufadienolides is widely described in the literature as an anticancer function. The aim of this study was to evaluate the effects of bufadienolides a...

FXYD2, a subunit of Na,K-ATPase may be involved in forming the receptor site for cardiac glycoside binding and it is abnormal expressed in some cancer cells line, as exemple A549 but not WI 26 VA-4. Cardenolides are well known to inhibit the Na,K-ATPase, and have been described as a target for study anticancer drugs. In this respect the aim of this...

Recently, cardiotonic steroids (CTS) have been shown to lead to the activation of Na,K-ATPase at low concentrations in brain, promoting neuroprotection against ischemia. We report here the results of the use of digoxin and its semisynthetic derivatives BD-14, BD-15, and BD-16 against partial chemical ischemic induction followed by reperfusion in mu...

In this study, renal tissue, subdivided into the cortex and medulla of Wistar rats subjected to a cafeteria diet (CAF) for 24 days or to normal diet, was used to analyze whether the renal enzyme Na,K‐ATPase activity was modified by CAF diet, as well as to analyze the α1 subunit of renal Na,K‐ATPase expression levels. The lipid profile of the renal...

Despite the growing interest in the antitumor effect of cardiotonic steroids, combination treatments with well‐established chemotherapy drugs like paclitaxel have been rarely investigated. Moreover, paclitaxel has been suggested as a Na⁺/K⁺‐ATPase inhibitor. Here we investigated the effect of paclitaxel and digoxin alone or in combination on the vi...

This work aimed to evaluate the inhibition of Candida rugosa lipase by five guanylhydrazone derivatives through biological, biophysical and theoretical studies simulating physiologic conditions. The compound LQM11 (IC50 = 14.70 μM) presented the highest inhibition against the enzyme. Therefore, for a better understanding of the interaction process,...

Our study aimed to analyze the effect of ouabain (OUA) administration on lipopolysaccharide (LPS)-induced changes in hippocampus of rats. Oxidative parameters were analyzed in Wistar rats after intraperitoneal injection of OUA (1.8 µg/kg), LPS (200 µg/kg), or OUA plus LPS or saline. To reach our goal, activities of superoxide dismutase (SOD), catal...

Eight molecules, 4 peptides (SPs) and 4 lipopeptides (LPs) derived by rational design from surfactin, a well-known secreted biosurfactant from Bacillus subtilis, were produced employing Fmoc-based solid-phase synthesis. These new peptides were tested to evaluate their potential biosurfactant and biological activities, aiming at possible application...

Cardiac glycosides (CGs) are natural compounds used to treat congestive heart failure. They have garnered attention as a potential cancer treatment option, especially because they bind to Na+/K+-ATPase as a target and activate intracellular signaling pathways leading to a variety of cellular responses. In this study we evaluated AMANTADIG, a semisy...

It is widely known that high fat diet (HFD) can contribute to the advent of health problems. Recent studies have indicated that obesity imposes a hemodynamic overload to the kidneys. In order to further investigate such injuries, two groups of six Swiss mice each were fed with a controlled AIN93G diet or a high fat (AIN93G modified) diet for eight...

Iron is a chemical element that is active in the fundamental physiological processes for human life, but its burden can be toxic to the body, mainly because of the stimulation of membrane lipid peroxidation. For this reason, the action of iron on many ATPases has been studied, especially on P-ATPases, such as the Na⁺,K⁺-ATPase and the Ca²⁺-ATPase....

113 Background: OSCC is a public health problem worldwide, mainly due to its advanced stage diagnosis. The late diagnosis is a nonsense problem in view of this neoplasia often begins as PML. Clinical, molecular and immunological factors have been associated with the cancerization process. Objective: evaluate clinical differences and immunohistochem...

https://meetinglibrary.asco.org/record/156427/abstract

Cardiac glycosides (CGs) are natural compounds widely used to treat several cardiac conditions and more recently have been recognized as potential antitumor agents. They are known as Na,K-ATPases ligands, which is a promising drug target in cancer. In this study, the short and long-lasting cytotoxic effects of the natural cardenolide digitoxigenin...

Cardiac steroids, with an attached unsaturated butyrolactone or an α-pyrone on C17, which are also referred to as cardiac glycosides or digitalis-like compounds, have been extensively used for the treatment of heart failure. Their structure is composed of a conserved four-ring steroidal nucleus with the possible presence of a sugar moiety attached...

The Wistar Audiogenic Rat (WAR) is a well-characterized seizure-prone, inbred rodent strain that, when acutely stimulated with high-intensity sounds, develops brainstem-dependent tonic-clonic seizures that can evolve to limbic-like, myoclonic (forebrain) seizures when the acoustic stimuli are presented chronically (audiogenic kindling). In order to...

Cisplatin and other platinum-containing drugs have played a crucial role in anticancer treatments for over 30 years. However, treatment with cisplatin may cause serious side effects, such as myelosuppression, nausea, ototoxicity, nephrotoxicity and cell resistance processes. In addition, cardiotonic steroids, particularly digoxin, have recently bee...

Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the l...

Lipases have key roles in insect lipid acquisition, storage, and mobilization and are also fundamental to many physiological processes in insects. Lipids are an important component of insect diets, where they are hydrolyzed in the midgut lumen, absorbed, and used for the synthesis of complex lipids. The South American palm weevil Rhynchophorus palm...

Our study aimed to analyze the effect of ouabain administration on lipopolysaccharide (LPS)-induced changes in oxidative parameters, membrane lipid composition, and the activities of some important enzymes of the nervous system. The content of phospholipids, cholesterol and gangliosides were analyzed in Wistar rats after intraperitoneal injection o...

Drug delivery systems could be applied to locally treat cervical cancer, thus preventing the drawbacks of conventional therapy. In this study, anti-proliferative and anti-angiogenic effects of digoxin incorporated into poly(ε-caprolactone) implants were evaluated, aiming at the local treatment of cervical cancer. Implants were characterized, and th...

Cardiotonic steroids (CTS) are compounds which bind to the Na,K-ATPase, leading to its inhibition and in some cases initiating signaling cascades. Long utilized as a treatment for congestive heart disease, CTS have more recently been observed to inhibit proliferation and cause apoptosis in several cancer cell lines. A synthetic derivative of the CT...

The hormone ouabain has been shown to enhance the cystic phenotype of autosomal dominant polycystic kidney disease (ADPKD). Among other characteristics, the ADPKD phenotype includes cell de-differentiation and epithelial to mesenchymal transition (EMT). Here, we determined whether physiological concentrations of ouabain induces EMT in human renal e...

Cardenolides are cardiac glycosides, mostly obtained from natural sources. They are well known for their inhibitory action on the Na,K-ATPase, an effect that regulates cardiovascular alterations such as congestive heart failure and atrial arrhythmias. In recent years, they have also sparked new interest in their anticancer potential. In the present...

Culex quinquefasciatus is the main vector of lymphatic filariasis and combating this insect is of great importance to public health. There are reports of insects that are resistant to the products currently used to control this vector, and therefore, the search for new products has increased. In the present study, we have evaluated the effects of f...

The aim of this study was to evaluate the profile of BRCA1 mutations among cancer-affected Brazilian women from the Midwest region of Minas Gerais state with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC) syndrome. In this Brazilian region, the first Center for Hereditary Cancer Control began operation in 2011, and 90...

Iron is a chemical element essential to humans; however, its overhead can be toxic to the body, because it can mediate events of lipid peroxidation, stimulate the formation of collagen and produce reactive oxygen species (ROS). The objective of this work was evaluate the modulation of iron on erythrocyte Na,K‐ATPase activity. Red blood cells (RBC)...

The application of medicinal plants as a mechanism of cure, prevention and treatment of diseases has increased significantly in recent years. Several substances can also cause adverse effects and toxicity, lead to analytical interferences in laboratory tests. This study aimed to evaluate the in vitro analytical interference caused by the applicatio...

Recently, cardiotonic steroids (CTS), used in heart failure treatment, have shown interesting antitumor effect acting by several intracellular signaling pathways triggered by Na, K-ATPase. Several signaling pathways activated by CTS are involved in tumor progression, metastasis, and proliferation, leading an interesting perspective to study the rel...

The effects of ouabain (OUA) and lipopolysaccharide (LPS) in vivo on hippocampal membranes (RHM) of Wistar male rats aged 3 months were analyzed. After intraperitoneal (i.p.) injection of OUA only, LPS only, OUA plus LPS, or saline, the content of proteins, phospholipids, cholesterol and gangliosides from RHM was analyzed. The total protein and cho...

The rates of breast cancer mortality remain high in Brazil. Docetaxel is a semi-synthetic taxane used to treat various tumors, particularly tumors of the breast, lung and prostate. In this study ADR that occurred in 45 docetaxel users with breast cancer were surveyed. They were identified by type, causality (Naranjo algorithm and World Health Organ...

Iron is an essential chemical element for human life. However, in some pathological conditions , such as hereditary hemochromatosis type 1 (HH1), iron overload induces the production of reactive oxygen species that may lead to lipid peroxidation and a change in the plasma-membrane lipid profile. In this study, we investigated whether iron overload...

Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) wit...

The Actinomyces sp has been linked to osteoradionecrosis of the jaw. The identification of these bacteria on histopathological findings confers a determining factor of poor prognosis and is related to difficulties of local control of bone necrosis and risk of recurrent infections. The treatment is complicated due to insidious growth pattern of Acti...

Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their recepto...

Aim: The present study evaluated the expression of α1 and β1 Na,K-ATPase, as well as the effects of digoxin (DGX) on oral squamous cell carcinomas (OSCCs). Patients and Methods: Immunohistochemical expression of α1 and β1 Na,K-ATPase were evaluated in 60 patients who underwent treatment at the São João de Deus Hospital. SCC-25 viability was assesse...

Impact of ERK1/2 pathway inhibition on the ouabain-induced effects in β1 Na,K-ATPase levels. Monolayers of Caco-2 cells were grown, pretreated with an inhibitor of the ERK1/2 pathway (PD98059) for 1 h (when indicated) and incubated with ouabain for 6 h. After treatment, total cell lysates were harvested and the expression of β1 Na,K-ATPase was visu...

Effect of low dose of ouabain and ionic imbalance on cell distribution of E-cadherin.Monolayers of Caco-2 cells were grown on glass coverslips. Cells were treated with a low concentration of ouabain (100 nM) for 6 h or with a molar excess of NaCl (250 mM) for 2.5 h. After, cells were processed for immunofluorescence analysis of E-cadherin distribut...

The sarcomatoid carcinoma or spindle cell carcinoma is a rare malignancy that can develop in various subsites of the head and neck. It is composed of a squamous cell carcinoma and spindle cell carcinoma with sarcomatous appearance. The diagnosis is confirmed by the finding of a malignant neoplasm of spindle cells, associated with a specific immunoh...

An investigation into the effects of irradiation and of the storage time on aging and quality are a relevant issue to ensure the safety and the efficiency of irradiation in the prevention of transfusion-associated graft-versus-host disease (TA-GVHD). In this work, the biochemical properties and alterations presented by erythrocyte membranes, up to...

Studies have reported that Na,K-ATPase interacts with E-cadherin to stabilize (AJs) and regulate the expression of claudins, the main proteins present in the tight junction (TJ) in epithelial cells containing caveolae. However, the role of this ATPase in the regulation of the AJ and TJ proteins in colorectal cancer cells as well as the molecular ev...

Previous studies have reported that the Na,K‐ATPase interacts with E‐cadherin to stabilize adherens junctions (AJ) and maintain the cell‐cell adhesion. In the other hands, several papers have demonstrated that the activation of signaling pathway through the cardiotonic steroids is dependent of caveolin‐1 and caveolae. Here, we have used ouabain and...

Glicosideos cardiacos como a digoxina e digitoxina em doses terapeuticas possuem um efeito inibitorio da Na + /K + -ATPase. Novos compostos sintetizados a partir da digoxina ainda nao possuem nenhuma caracterizacao biologica de efeitos na Na + /K + -ATPase e nem seu potencial efeito antiproliferativo em celulas tumorais. O objetivo do estudo foi ve...

There is a lack of biological studies using selenium and tellurium compounds, specially concern with cancer therapy. The aim of this study is to evaluate the cytotoxicity action of nine β-chalcogen-substituted Michael-aldol-type adducts on HeLa and RKO cancer cell lines. The cytotoxic effect was assessed by MTT assay and was performed in HeLa and R...

A digoxina consiste em um glicosideo digitalico utilizado no tratamento da insuficiencia cardiaca congestiva e arritmia, entretanto sua atividade citotoxica contra celulas tumorais tem sido amplamente estudada. O objetivo desse trabalho foi avaliar o efeito citotoxico da digoxina em linhagem celular derivada de carcinoma espinocelular bucal humano...

O processo neuroinflamatorio e caracterizado por resposta da microglia sobre acoes no Sistema Nervoso Central (SNC) que possuem carater semelhante de inflamacao. Como modelo estudado de inducao desse processo usa-se lipopolissacarideos (LPS) que podem ativar diretamente a microglia e esta ativada libera uma gama de neurotoxinas que induz a inflamac...

Context: Methotrexate (MTX) is used in the treatment of malignancies; however, its clinical application is limited by its toxic dose-related side effects. An alternative to overcome the toxicity of the MTX in healthy tissues is the design of an implantable device capable of controlling the delivery of this drug for an extended period within the tu...

Poly(ε-caprolactone) implants containing etoposide, an important chemotherapeutic agent and topoisomerase II inhibitor, were fabricated by a melt method and characterized in terms of content uniformity, morphology, drug physical state, and sterility. In vitro and in vivo drug release from the implants was also evaluated. The cytotoxic activity of i...

RESUMO A transfusão de sangue é vital para a gestão de pacientes que necessitam de transplante hepático, pois muitos deles são hemotransfundidos durante o curso da doença, ou para alcançar o sucesso do procedimento cirúrgico. A amostra de sangue do paciente que necessita de politransfusões deve ser fenotipada para antígenos altamente imunogênicos,...

The FXYD2 is a single span membrane protein that are describe to regulate the Na,K‐ATPase. In this study we demonstrated that the dopamine can inhibit Na,K‐ATPase from kidney medulla in about 33%, and that the addition of an excess of FXYD2 reverse this. PKC and PKA inhibitors also protect the Na,K‐ATPase from dopamine inhibition and we did not obs...

The importance of Na,K‐ATPase for the formation of junctional complexes is well established. The aim of this work is to characterize the biological effect of a digoxin derivative, 21‐benzylidene digoxin (21‐BD) on tight junctions. MDCK cells are treated with 5, 10 and 50 μM 21‐BD and the immunofluorescence of tight junctions (TJs) proteins α1 Na,K‐...

Recently, new data began to consider cardiac glycoside as a potential antitumor drug. We synthesized 21‐benzylidene digoxin (21‐BD) through an aldol condensation of digoxin lactone ring. Molecular docking was performed to assess the main interactions between cardiac glycosides and Na,K‐ATPase, demonstrating a more stable binding energy for 21‐BD, c...

The use of γ‐radiation in blood products causes T lymphocytes inactivation, which mediated Graft‐versus‐host disease, preventing their development. Thus, it is interesting to understand the structural changes induced by irradiation and storage period, to provide the high quality of blood components. The CPDA‐1 bags of red blood cells (RBC) were sep...

The aim of the present work was to evaluate the redox and oligomeric effects associated with the human hemoglobin of stored red blood cells that had been previously submitted to gamma radiation. Whole blood was collected from healthy donors and irradiated with 25 Gy of γ-radiation within 24 h of collection. At days 3, 5, 7, 9, 11, 14, and 28 postir...

A series of new chalcones substituted with azide/triazole groups were designed and synthesized, and their cytotoxic activity was evaluated in vitro against the HeLa cell line. O-Alkylation, Claisen-Schmidt condensation and Cu(I)-catalyzed cycloaddition of azides with terminal alkynes were applied in key steps. Fifteen compounds were tested against...