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1.
Artículo en Inglés | MEDLINE | ID: mdl-38492161

RESUMEN

While oncotherapy has made rapid progress in recent years, side effects of anti-cancer drugs and treatments have also come to the fore. These side effects include cardiotoxicity, which can cause irreversible cardiac damages with long-term morbidity and mortality. Despite the continuous in-depth research on anti-cancer drugs, an improved knowledge of the underlying mechanisms of cardiotoxicity are necessary for early detection and management of cardiac risk. Although most reviews focus on the cardiotoxic effect of a specific individual chemotherapeutic agent, the aim of our review is to provide comprehensive insight into various agents that induced cardiotoxicity and their underlying mechanisms. Characterization of these mechanisms are underpinned by research on animal models and clinical studies. In order to gain insight into these complex mechanisms, we emphasize the role of inflammatory processes and oxidative stress on chemotherapy-induced cardiac changes. A better understanding and identification of the interplay between chemotherapy and inflammatory/oxidative processes hold some promise to prevent or at least mitigate cardiotoxicity-associated morbidity and mortality among cancer survivors.

2.
Antioxidants (Basel) ; 12(8)2023 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-37627526

RESUMEN

Inflammatory bowel diseases (IBDs) are autoimmune disorders of the gut. It is increasingly clear that voluntary exercise (VE) may exert protection against IBDs, but the exact background mechanism needs to be elucidated. In the present study, we aimed to investigate the possible role of NETosis and the antioxidant peroxiredoxin (Prdx) enzyme family in VE-induced protection. Wistar Han rats were randomly divided into two groups: sedentary (SED) and VE. After the 6-week voluntary wheel running, animals were treated with 2,4,6-trinitrobenzene sulphonic acid (TNBS) as a model of colitis. Here, we found that VE significantly decreased inflammation and ulceration of the colon in the VE TNBS group compared with SED TNBS. We also found that VE significantly decreased the expression of protein arginine deiminase 4 (PAD4) and myeloperoxidase (MPO), and markedly reduced citrullinated histone H3 (citH3) compared with SED TNBS. Furthermore, VE caused a significant increase in the levels of Prdx6 in the control and TNBS groups. Taken together, we found that a prior 6-week VE effectively reduces inflammation in TNBS-induced colitis, and we suggest that the protective effect of VE may be mediated via the inhibition of NETosis and upregulation of Prdx6 antioxidant.

3.
Antioxidants (Basel) ; 12(7)2023 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-37507988

RESUMEN

Although the morphological features and functions of adipose tissue are well-described in obesity-prone animal models, less information is available on animals such as the stroke-prone spontaneously hypertensive (SHRSP) strain with cardiovascular abnormalities, which is not characterized by excessive adiposity. Our aim was to focus on lifestyle-induced (type of diet and physical exercise) effects on adipokine profile and lipid peroxidation in SHRSP rats. In our study, male Wistar-kyoto (control) and SHRSP rats were used. SHRSP rats were fed either standard chow or a high-fat diet with 40% fat content (HFD). One group of the animals was placed into cages fitted with a running-wheel; thus, the dietary and training period started at the same time and lasted for 12 weeks. At the end of the experimental period, adiponectin, leptin, omentin, and chemerin concentrations were determined from adipose tissue and serum. Besides adipokines, malondialdehyde (MDA) levels were also measured. Twelve weeks of HFD significantly decreased adiponectin and omentin concentrations of both adipose tissue and serum, which were ameliorated by physical exercise. Serum leptin, chemerin, and MDA values were elevated in HFD groups; however, physical exercise was able to mitigate these adverse changes. Our results underpin the crosstalk between lifestyle changes and dysfunctional adipose tissue in SHRSP rats.

4.
Br J Clin Pharmacol ; 89(11): 3364-3374, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37272312

RESUMEN

AIMS: Pleural mesothelioma (PM) is a highly aggressive thoracic tumour with poor prognosis. Although reduced tissue drug accumulation is one of the key features of platinum (Pt) resistance, little is known about Pt distribution in human PM. METHODS: We assessed Pt levels of blood samples and surgically resected specimens from 25 PM patients who had received neoadjuvant Pt-based chemotherapy (CHT). Pt levels and tissue distributions were measured by laser ablation-inductively coupled plasma-mass spectrometry and correlated with clinicopathological features. RESULTS: In surgically resected PM specimens, mean Pt levels of nontumourous (fibrotic) areas were significantly higher (vs tumourous regions, P = 0.0031). No major heterogeneity of Pt distribution was seen within the tumourous areas. Pt levels correlated neither with the microvessel area nor with apoptosis rate in the tumourous or nontumourous regions. A significant positive correlation was found between serum and both full tissue section and tumourous area mean Pt levels (r = 0.532, P = 0.006, 95% confidence interval [95% CI] 0.161-0.771 and r = 0.415, P = 0.039, 95% CI 0.011-0.702, respectively). Furthermore, a significant negative correlation was detected between serum Pt concentrations and elapsed time from the last cycle of CHT (r = -0.474, P = 0.017, 95% CI -0.738--0.084). Serum Pt levels correlated negatively with overall survival (OS) (P = 0.029). CONCLUSIONS: There are major differences in drug distribution between tumourous and nontumourous areas of PM specimens. Serum Pt levels significantly correlate with full section and tumourous area average Pt levels, elapsed time from the last CHT cycle, and OS. Further studies investigating clinicopathological factors that modulate tissue Pt concentration and distribution are warranted.


Asunto(s)
Terapia por Láser , Mesotelioma , Humanos , Mesotelioma/cirugía , Mesotelioma/tratamiento farmacológico , Platino (Metal)/uso terapéutico , Platino (Metal)/análisis , Espectrometría de Masas/métodos
5.
Antioxidants (Basel) ; 12(5)2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37237891

RESUMEN

Inflammatory bowel diseases (IBD) are chronic, inflammatory disorders of the gastrointestinal (GI) system, which have become a global disease over the past few decades. It has become increasingly clear that oxidative stress plays a role in the pathogenesis of IBD. Even though several effective therapies exist against IBD, these might have serious side effects. It has been proposed that hydrogen sulfide (H2S), as a novel gasotransmitter, has several physiological and pathological effects on the body. Our present study aimed to investigate the effects of H2S administration on antioxidant molecules in experimental rat colitis. As a model of IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used intracolonically (i.c.) to induce colitis in male Wistar-Hannover rats. Animals were orally treated (2 times/day) with H2S donor Lawesson's reagent (LR). Our results showed that H2S administration significantly decreased the severity of inflammation in the colons. Furthermore, LR significantly suppressed the level of oxidative stress marker 3-nitrotyrosine (3-NT) and caused a significant elevation in the levels of antioxidant GSH, Prdx1, Prdx6, and the activity of SOD compared to TNBS. In conclusion, our results suggest that these antioxidants may offer potential therapeutic targets and H2S treatment through the activation of antioxidant defense mechanisms and may provide a promising strategy against IBD.

6.
Orv Hetil ; 164(2): 51-56, 2023 Jan 15.
Artículo en Húngaro | MEDLINE | ID: mdl-36641759

RESUMEN

INTRODUCTION: SARS-CoV-2 has defined our everyday lives over the past three years and by constituting a serious risk factor for patients with pre-existing respiratory illnesses, it placed an unexpected burden on the health care systems worldwide. OBJECTIVE: The aim of this study was to explore the association between COVID-19 and pre-existing respiratory comorbidities such as chronic obstructive pulmonary disease (COPD) and asthma. METHOD: In our current study, we retrospectively processed the data of nearly 29 000 Hungarian patients. RESULTS: We found that COPD was directly associated with the severity of COVID-19 and slightly increased the risk of intensive care unit admission and the need for mechanical ventilation during the SARS-CoV-2 infection. On the other hand, the presence of asthma influenced neither the severity of COVID-19 nor the need for intensive care unit admission or mechanical ventilation significantly. DISCUSSION: International studies suggest that COPD does not significantly increase the risk of SARS-CoV-2 infection. However, the likelihood of hospitalization due to COVID-19 is much higher in COPD patients and the presence of COPD is associated with a more severe disease course. Given the structural alterations and abnormal regeneration processes of the airways that occur during lung injury in COPD patients, these individuals require increased attention and personalized rehabilitation protocols after the onset of the viral infection. CONCLUSION: Altogether, the assessment of clinical manifestations associated with different COPD phenotypes (as well as other chronic lung diseases) and SARS-CoV-2 infection is essential for the implementation of personalized therapeutic approach in the future. Orv Hetil. 2023; 164(2): 51-56.


Asunto(s)
Asma , COVID-19 , Enfermedad Pulmonar Obstructiva Crónica , Enfermedades Respiratorias , Humanos , COVID-19/epidemiología , COVID-19/complicaciones , SARS-CoV-2 , Estudios Retrospectivos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Asma/epidemiología
7.
Life (Basel) ; 12(8)2022 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-36013384

RESUMEN

Type 2 diabetes mellitus (T2DM) is one of the world's leading causes of death and life-threatening conditions. Therefore, we review the complex vicious circle of causes responsible for T2DM and risk factors such as the western diet, obesity, genetic predisposition, environmental factors, and SARS-CoV-2 infection. The prevalence and economic burden of T2DM on societal and healthcare systems are dissected. Recent progress on the diagnosis and clinical management of T2DM, including both non-pharmacological and latest pharmacological treatment regimens, are summarized. The treatment of T2DM is becoming more complex as new medications are approved. This review is focused on the non-insulin treatments of T2DM to reach optimal therapy beyond glycemic management. We review experimental and clinical findings of SARS-CoV-2 risks that are attributable to T2DM patients. Finally, we shed light on the recent single-cell-based technologies and multi-omics approaches that have reached breakthroughs in the understanding of the pathomechanism of T2DM.

8.
Magy Onkol ; 66(1): 43-49, 2022 Mar 28.
Artículo en Húngaro | MEDLINE | ID: mdl-35343974

RESUMEN

The COVID-19 pandemic has posed significant challenges to healthcare systems worldwide. Patients with cancer, and particularly those with lung malignancies, represent a highrisk group for COVID-19 since they are more susceptible to infection and have a higher risk of severe outcomes. However, the restructuration of the healthcare environment, the development of guidelines for treatment and surveillance, and the improvement of vaccination coverage allowed adequate patient shielding and continuity of oncological care of cancer patients. By shedding light on the characteristics of COVID-19 patients with thoracic malignancies, recent studies also contributed to the development of personalized therapeutic strategies. Accordingly, several determinants were identified to predict disease outcomes. These include the ECOG performance status, the levels of C-reactive protein, neutrophils and procalcitonin, the disease stage, and the presence of pneumonia. COVID-19 vaccines are safe in patients with lung cancer. In order to obtain adequate immunization, the booster dose is recommended in these patients.


Asunto(s)
Neoplasias de la Mama , COVID-19 , Neoplasias Pulmonares , COVID-19/prevención & control , Vacunas contra la COVID-19 , Femenino , Humanos , Programas de Inmunización , Neoplasias Pulmonares/terapia , Pandemias/prevención & control
9.
Int J Mol Sci ; 22(23)2021 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-34884536

RESUMEN

Inflammatory bowel diseases (IBD) are chronic, immune-mediated disorders, which affect the gastrointestinal tract with intermittent ulceration. It is increasingly clear that neutrophil extracellular traps (NETs) seem to have a role in IBD; however, the associated pathogenesis is still not known. Furthermore, several conventional therapies are available against IBD, although these might have side effects. Our current study aimed to investigate the effects of hydrogen sulfide (H2S) treatment on NETs formation and on the expression of inflammatory mediators in experimental rat colitis. To model IBD, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was administered intracolonically (i.c.) to Wistar-Harlan male rats. Animals were treated (2 times/day) with H2S donor Lawesson's reagent per os. Our results showed that H2S treatment significantly decreased the extent of colonic lesions. Furthermore, the expression of members of NETs formation: peptidyl arginine deiminase 4 (PAD4), citrullinated histone H3 (citH3), myeloperoxidase (MPO) and inflammatory regulators, such as nuclear transcription factor-kappa B (NF-κB) and high-mobility group box 1 (HMGB1) were reduced in H2S treated group compared to TNBS. Additionally, H2S donor administration elevated the expression of ubiquitin C-terminal hydroxylase L1 (UCHL-1), a potential anti-inflammatory mediator. Taken together, our results showed that H2S may exert anti-inflammatory effect through the inhibition of NETs formation, which suggests a new therapeutic approach against IBD.


Asunto(s)
Antiinflamatorios/farmacología , Colitis/tratamiento farmacológico , Trampas Extracelulares/efectos de los fármacos , Sulfuro de Hidrógeno/farmacología , FN-kappa B/metabolismo , Ácido Trinitrobencenosulfónico/toxicidad , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Gasotransmisores/farmacología , Mediadores de Inflamación/metabolismo , Masculino , FN-kappa B/genética , Ratas , Ratas Wistar , Transducción de Señal
10.
Sci Rep ; 11(1): 5798, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33707612

RESUMEN

Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.


Asunto(s)
Apelina/efectos adversos , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/secundario , Linfangiogénesis , Melanoma Experimental/patología , Neovascularización Patológica/patología , Animales , Estudios de Casos y Controles , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/sangre , Masculino , Melanoma Experimental/sangre , Ratones , Persona de Mediana Edad , Invasividad Neoplásica , Neovascularización Patológica/sangre , Factor A de Crecimiento Endotelial Vascular/sangre
11.
Antioxidants (Basel) ; 9(11)2020 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-33158023

RESUMEN

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Since the treatment of IBD is still an unresolved issue, we designed our study to investigate the effect of a novel therapeutic target, sigma-1 receptor (σ1R), considering its ability to activate antioxidant molecules. As a model, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to induce colitis in Wistar-Harlan male rats. To test the beneficial effects of σ1R, animals were treated intracolonically (i.c.): (1) separately with an agonist (fluvoxamine (FLV)), (2) with an antagonist of the receptor (BD1063), or (3) as a co-treatment. Our results showed that FLV significantly decreased the severity of inflammation and increased the body weight of the animals. On the contrary, simultaneous treatment of FLV with BD1063 diminished the beneficial effects of FLV. Furthermore, FLV significantly enhanced the levels of glutathione (GSH) and peroxiredoxin 1 (PRDX1) and caused a significant reduction in 3-nitrotyrosine (3-NT) levels, the effects of which were abolished by co-treatment with BD1063. Taken together, our results suggest that the activation of σ1R in TNBS-induced colitis through FLV may be a promising therapeutic strategy, and its protective effect seems to involve the antioxidant pathway system.

12.
Int J Mol Sci ; 21(11)2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32516975

RESUMEN

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar-Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [3H](+)-pentazocine binding sites, and FLV treatment increased the reduced σ1R maximum binding capacity in TNBS-induced colitis. Furthermore, FLV significantly attenuated the colonic damage, the effect of which was abolished by the administration of BD1063. Additionally, FLV potentially increased the expression of ubiquitin C-terminal hydrolase ligase-1 (UCHL-1) and the levels of endothelial nitric oxide synthase (eNOS), and decreased the levels of interleukin-6 (IL-6) and inducible NOS (iNOS) expression. In summary, our study offers evidence for the anti-inflammatory potential of FLV and σ1R in experimental colitis, and our results present a promising approach to the development of new σ1R-targeted treatment options against IBD.


Asunto(s)
Colitis/etiología , Colitis/metabolismo , Interleucina-6/metabolismo , Receptores sigma/metabolismo , Transducción de Señal , Ácido Trinitrobencenosulfónico/efectos adversos , Ubiquitina Tiolesterasa/metabolismo , Animales , Colitis/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Fluvoxamina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/metabolismo , Mediadores de Inflamación/metabolismo , Ligandos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peroxidasa/metabolismo , Unión Proteica , Ratas , Receptores sigma/agonistas , Receptores sigma/genética , Índice de Severidad de la Enfermedad , Receptor Sigma-1
13.
Am J Physiol Heart Circ Physiol ; 316(2): H400-H407, 2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30575421

RESUMEN

The progression of coronary artery diseases in premenopausal women is lower than in age-matched men; however, its probability increases rapidly after menopause. The aim of our study was to investigate the postconditioning-like effects of voluntary physical exercise on postmenopausal cardiovascular outcomes after myocardial infarction. We used fertile Wistar females [control (CTRL)] and pharmacologically induced estrogen-deficient (POVX; 750 µg/kg triptorelin im, every 4th week) rats. CTRL and POVX animals were randomly assigned to receive an injection of 0.1 mg isoproterenol (ISO)/kg. At the 20th hour after ISO injection, serum markers of myocardial injury, such as lactate dehydrogenase (LDH) and myoglobin, were measured. After a 3-wk resting period, ISO-treated and untreated animals were further divided into subgroups on the basis of 6 wk of physical exercise. At the end of the experiment, cardiac activity and content of the antioxidative heme oxygenase (HO) enzyme, levels of GSH and GSH + GSSG, activity of myeloperoxidase, as well as the concentration of TNF-α were determined. At the end of the experimental period, we observed a significant decrease in the activity and content of HO enzymes in POVX and POVX/ISO rats, whereas physical exercise significantly improved HO and GSH values in both CTRL and POVX rats. Furthermore, our training protocol significantly reduced the pathological levels of myeloperoxidase and TNF-α. Our findings clearly demonstrate that modulation of the HO system by voluntary physical exercise is a key process to decrease inflammatory parameters and ameliorate the antioxidative status in estrogen-deficient conditions postmyocardial injury. NEW & NOTEWORTHY We used a noninvasive rat model of estrogen deficiency and myocardial infarction. The long-term effects of isoproterenol treatment revealed reduced heme oxygenase enzyme activity and expression and decreased glutathione levels. Isoproterenol treatment enhanced the myeloperoxidase enzyme activity. Voluntary physical exercise ameliorated the antioxidative status by increasing of the heme oxygenase enzyme system. Voluntary physical exercise is a potential therapeutic tool to improve cardiac antioxidant status in menopausal women postmyocardial injury.


Asunto(s)
Enfermedad de la Arteria Coronaria/terapia , Menopausia/fisiología , Estrés Oxidativo , Condicionamiento Físico Animal/métodos , Animales , Enfermedad de la Arteria Coronaria/metabolismo , Enfermedad de la Arteria Coronaria/prevención & control , Estrógenos/deficiencia , Femenino , Glutatión/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo
14.
J Sports Sci Med ; 17(4): 580-588, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30479526

RESUMEN

Cardiovascular morbidity and mortality of premenopausal women are significantly lower compared to men of similar age. However, this protective effect evidently decreases after the onset of menopause. We hypothesized that physical exercise could be a potential therapeutic strategy to improve inflammatory processes and cardiovascular antioxidant homeostasis, which can be affected by the loss of estrogen and the adverse environmental factors, such as overnutrition. Ovariectomized (OVX, n= 40) and sham-operated (SO, n= 40) female Wistar rats were randomized to exercising (R) and non-exercising (NR) groups. Feeding parameters were chosen to make a standard chow (CTRL) or a high triglyceride diet (HT) for 12 weeks. Aortic and cardiac heme oxygenase (HO) activity and HO-1 concentrations significantly decreased in all of the NR OVX and SO HT groups. However, the 12-week physical exercise was found to improve HO-1 values. Plasma IL-6 concentrations were higher in the NR OVX animals and rats fed HT diet compared to SO CTRL rats. TNF-α concentrations were significantly higher in the NR OVX groups. 12 weeks of exercise significantly reduced the concentrations of both TNF-α and IL-6 compared to the NR counterparts. The activity of myeloperoxidase enzyme (MPO) was significantly increased as a result of OVX and HT diet, however voluntary wheel-running exercise restored the elevated values. Our results show that estrogen deficiency and HT diet caused a significant decrease in the activity and concentration of HO enzyme, as well as the concentrations of TNF-α, IL-6, and the activity of MPO. However, 12 weeks of voluntary wheel-running exercise is a potential non-pharmacological therapy to ameliorate these disturbances, which determine the life expectancy of postmenopausal women.


Asunto(s)
Dieta Alta en Grasa , Hemo Oxigenasa (Desciclizante)/fisiología , Condicionamiento Físico Animal/fisiología , Triglicéridos/administración & dosificación , Animales , Aorta/enzimología , Peso Corporal , Enfermedades Cardiovasculares , Estrógenos/sangre , Estrógenos/deficiencia , Femenino , Inflamación/sangre , Interleucina-6/sangre , Miocardio/enzimología , Ovariectomía , Peroxidasa/metabolismo , Distribución Aleatoria , Ratas Wistar , Factores de Riesgo , Factor de Necrosis Tumoral alfa/sangre
15.
Int J Mol Sci ; 19(10)2018 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-30340421

RESUMEN

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks' Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (L-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.


Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Sustancias Protectoras/farmacología , Fosfato de Sitagliptina/farmacología , Animales , Biomarcadores , Calcio/metabolismo , Modelos Animales de Enfermedad , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Miocardio/metabolismo , Miocardio/patología , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Canales Catiónicos TRPV/metabolismo
16.
Sci Rep ; 8(1): 7647, 2018 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-29769710

RESUMEN

The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.


Asunto(s)
Cardiomegalia/patología , Fibrosis/patología , Insuficiencia Cardíaca/patología , Infarto del Miocardio/patología , Miocitos Cardíacos/patología , Proteínas Represoras/metabolismo , Animales , Cardiomegalia/etiología , Células Cultivadas , Fibrosis/etiología , Insuficiencia Cardíaca/etiología , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/etiología , Miocitos Cardíacos/metabolismo , Proteínas Represoras/genética
17.
Oxid Med Cell Longev ; 2018: 6709742, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29636852

RESUMEN

Myocardial extracellular matrix (ECM) is essential for proper cardiac function and structural integrity; thus, the disruption of ECM homeostasis is associated with several pathological processes. Female Wistar rats underwent surgical ovariectomy (OVX) or sham operation (SO) and were then divided into eight subgroups based on the type of diet (standard chow or high-triglyceride diet/HT) and exercise (with or without running). After 12 weeks, cardiac MMP-2 activity, tissue inhibitor of metalloproteinase-2, content of collagen type I, the level of nitrotyrosine (3-NT) and glutathione (GSH), and the ratio of infarct size were determined. Our results show that OVX and HT diet caused an excessive accumulation of collagen; however, this increase was not observed in the trained animals. Twelve weeks of exercise promoted elevation in the levels of 3-NT and GSH and similarly an increase in MMP-2 activity of both SO and OVX animals. The high infarct-size ratio caused by OVX and HT diet was mitigated by physical exercise. Our findings demonstrate that ovarian estrogen loss and HT diet caused collagen accumulation and increased ratio of the infarct size. However, exercise-induced cardiac remodeling serves as a compensatory mechanism by enhancing MMP-2 activity and reducing fibrosis, thus minimizing the ischemia/reperfusion injury.


Asunto(s)
Ovariectomía , Condicionamiento Físico Animal , Remodelación Ventricular , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Colágeno Tipo I/metabolismo , Estrógenos/deficiencia , Femenino , Glutatión/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Infarto del Miocardio/patología , Miocardio/enzimología , Ratas Wistar , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
18.
Inflammopharmacology ; 26(2): 479-489, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28770475

RESUMEN

Hydrogen sulfide (H2S) is an endogenous mediator that contributes to many important physiological processes including vasodilation and vascular smooth muscle relaxation; in turn, preventing tissue damage and reducing inflammation. Heme oxygenase (HO) enzymes, of which HO-1 is inducible by harmful stimuli, were found to regulate intestinal inflammation in experimental animal models of colitis. We aimed to investigate the protective effects of H2S against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats, and whether HO enzyme system is involved in the H2S-induced colonic cytoprotection. Male Wistar rats were treated with TNBS to induce colitis, and H2S donor (Lawesson's reagent) was prepared two times/day at different concentrations, and delivered per os (from day 1 to day 3). Our results suggest that daily treatment (2 times/day) with H2S donor, could significantly decrease the extent of colonic inflammation compared to vehicle treatment, and the most effective daily dose of H2S donor against inflammation was 18.75 µM/kg/day. Per os administration of H2S donor increased the colonic HO enzyme activity; on the contrary, the protective effect of H2S was abolished by the co-treatment with HO inhibitor. Our findings suggest that H2S confers colonoprotection, probably by modulation of anti-inflammatory parameters and HO enzyme activity.


Asunto(s)
Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Hemo Oxigenasa (Desciclizante)/metabolismo , Sulfuro de Hidrógeno/farmacología , Ácido Trinitrobencenosulfónico/farmacología , Regulación hacia Arriba/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Modelos Animales , Ratas , Ratas Wistar
19.
Sci Rep ; 7(1): 6832, 2017 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-28754996

RESUMEN

Chemical imaging is a powerful tool for understanding the chemical composition and nature of heterogeneous samples. Recent developments in elemental, vibrational, and mass-spectrometric chemical imaging with high spatial resolution (50-200 nm) and reasonable timescale (a few hours) are capable of providing complementary chemical information about various samples. However, a single technique is insufficient to provide a comprehensive understanding of chemically complex materials. For bulk samples, the combination of different analytical methods and the application of statistical methods for extracting correlated information across different techniques is a well-established and powerful concept. However, combined multivariate analytics of chemical images obtained via different imaging techniques is still in its infancy, hampered by a lack of analytical methodologies for data fusion and analysis. This study demonstrates the application of multivariate statistics to chemical images taken from the same sample via various methods to assist in chemical structure determination.

20.
Theranostics ; 7(2): 400-412, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28042343

RESUMEN

Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies.


Asunto(s)
Inhibidores de la Angiogénesis/farmacocinética , Resistencia a Medicamentos , Inhibidores Enzimáticos/farmacocinética , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Ratones , Neoplasias/patología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción
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