Ginkgo biloba
is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of
Ginkgo biloba
on ...cardiovascular diseases remain poorly elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of
Ginkgo biloba
-mediated neuroprotection, we aimed to investigate whether
Ginkgo biloba
extract (GBE) promotes cardioprotection
via
activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M
2
) and downregulation of β
1
-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection
in vivo
, we performed
in vitro
studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs
via
activation of M
2
/NO pathway uncovering a new mechanism involved in the cardioprotective action of
Ginkgo biloba
.
Neuropathic pain (NP) is a difficult condition to treat because of the modest efficacy of available drugs. New treatments are required. In the study we aimed to investigate the effects of the ...essential oil from Lippia grata alone or complexed in β-cyclodextrin (LG or LG-βCD) on persistent inflammatory and neuropathic pain in a mouse model. We also investigated Ca2+ currents in rat dorsal root ganglion (DRG) neurons. Male Swiss mice were treated with LG or LG/β-CD (24 mg/kg, i.g.) and their effect was evaluated using an acute inflammatory pleurisy model and nociception triggered by intraplantar injection of an agonist of the TRPs channels. We also tested their effect in chronic pain models: injection of Freund's Complete Adjuvant and partial sciatic nerve ligation (PSNL). In the pleurisy model, LG reduced the number of leukocytes and the levels of TNF-α and IL-1β. It also inhibited cinnamaldehyde and menthol-induced nociceptive behavior. The pain threshold in mechanical and thermal hyperalgesia was increased and paw edema was decreased in models of inflammatory and neuropathic pain. PSNL increased inflammatory protein contents and LG and LG-βCD restored the protein contents of TNF-α, NF-κB, and PKA, but not IL-1β and IL-10. LG inhibited voltage gated Ca2+ channels from DRG neurons. Our results suggested that LG or LG-βCD produce anti-hyperalgesic effect in chronic pain models through reductions in TNF-α levels and PKA, and inhibited voltage-gated calcium channels and may be innovative therapeutic agents for the management of NP.
Background. Cardiomyopathies remain among the leading causes of death worldwide, despite all efforts and important advances in the development of cardiovascular therapeutics, demonstrating the need ...for new solutions. Herein, we describe the effects of the redox-active therapeutic Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP5+), on rat heart as an entry to new strategies to circumvent cardiomyopathies. Methods. Wistar rats weighing 250-300 g were used in both in vitro and in vivo experiments, to analyze intracellular Ca2+ dynamics, L-type Ca2+ currents, Ca2+ spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP5+-treated cells, hearts, or animals. Cells and hearts were treated with 20 μM MnTE-2-PyP5+ and animals with 1 mg/kg, i.p. daily. Additionally, we performed electrocardiographic and echocardiographic analysis. Results. Using isolated rat cardiomyocytes, we observed that MnTE-2-PyP5+ reduced intracellular Ca2+ transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP5+ did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP5+ reduced Ca2+ spark frequency and increased sarcoplasmic reticulum (SR) Ca2+ load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP5+ preserves cardiac function, increases SR Ca2+ load, and reduces arrhythmia index, indicating an antiarrhythmic effect. In vivo experiments showed that MnTE-2-PyP5+ treatment increased Ca2+ transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP5+ was effective both to prevent and to treat cardiac arrhythmias. Conclusion. MnTE-2-PyP5+ prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP5+ preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.
Oncological pain is one of the most prevalent and difficult-to-treat symptoms in patients with cancer. p-Cymene (PC) is a monoterpene found in more than 100 different plant species, endowed with ...various pharmacological properties—particularly antinociceptive.
PC has antinociceptive effect in a model of oncologic pain due to the activation of the descending inhibitory pathway of pain.
A pre-clinical, longitudinal, blind and randomized study.
Male Swiss mice were induced with S180 cells in the right hind paw, then treated daily with PC (12.5, 25 and 50 mg/kg, s.c.) and screened for mechanical hyperalgesia, spontaneous nociception, nociception induced by non-noxious palpation, tumor growth, changes in the neuromuscular function and existence of bone degradation in the tumor area. The effect of PC on Ca2+ currents (electrophysiological records), histological and neurochemical changes (immunofluorescence for Fos) were also evaluated.
PC reduced (p < 0.05) the mechanical hyperalgesia, the spontaneous (p < 0.001) and non-noxious palpation (p < 0.001) nociceptions, not changing the tumor development, neuromuscular function or histopathological aspects of the paw affected. PC reduced Fos expression in the spinal cord (p < 0.001) and increased this expression in the PAG (p < 0.05) and in the NRM (p < 0.01). PC decreased the density of calcium channel currents (p < 0.05).
These results suggest the antinociceptive effect of PC on oncologic pain, probably acting in both ascending and descending pain pathways, and modulating the calcium channel currents in order to exert its effects.
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The aim of this work was to evaluate the pharmacological effect of seven structurally related terpenes on the contractility of cardiac muscle. The effect of terpenes was studied on isolated ...electrically driven guinea pig left atrium. From concentration-response curves for inotropic effect were determined the EC
50
and relative potency of such terpenes. Our results revealed that all terpenes, except phytol, showed ability to reduce the contractile response of guinea pig left atrium. Further, relative potency was directly related to the number of isoprene units and to the lipophilicity of the compounds. For example, sesquiterpenes farnesol and nerolidol showed higher relative potency when compared with the monoterpenes citronellol, geraniol and nerol. We can conclude that most of the evaluated terpenes showed a promising negative inotropism on the atrial muscle. Future studies are necessary to investigate their action mechanism.
Abstract
Objectives
Considering that γ-terpinene (γ-TPN) is a monoterpene found in Cannabis oil, with high lipophilicity and limited pharmacokinetics, our objective was to evaluate whether its ...complexation in β-cyclodextrin (γ-TPN/β-CD) could improve its physicochemical properties and action on cancer pain, as well as verify the mechanisms of action involved.
Methods
The γ-TPN/β-CD was prepared and submitted to physicochemical characterization. Animals with sarcoma 180 were treated (vehicle, γ-TPN 50 mg/kg, γ-TPN/β-CD 5 mg/kg or morphine) and assessed for hyperalgesia, TNF-α and IL-1β levels, iNOS and c-Fos activity. The effects of γ-TPN on calcium channels were studied by patch-clamp and molecular docking.
Results
β-CD improved the physicochemical properties and prolonged the anti-hyperalgesic effect of γ-TPN. This compound also reduced the levels of IL-1β, TNF-α and iNOS in the tumour, and c-Fos protein in the spinal cord. In addition, it reduced Ca2+ current, presenting favourable chemical interactions with different voltage-dependent calcium channels.
Conclusion
These results indicate that the complexation of γ-TPN into β-CD increases its stability and time effect, reducing spinal neuroactivity and inflammation by blocking calcium channels.
is the most popular phytotherapic agent used worldwide for treatment of several human disorders. However, the mechanisms involved in the protective actions of
on cardiovascular diseases remain poorly ...elucidated. Taking into account recent studies showing beneficial actions of cholinergic signaling in the heart and the cholinergic hypothesis of
-mediated neuroprotection, we aimed to investigate whether
extract (GBE) promotes cardioprotection
activation of cholinergic signaling in a model of isoproterenol-induced cardiac hypertrophy. Here, we show that GBE treatment (100 mg/kg/day for 8 days, v.o.) reestablished the autonomic imbalance and baroreflex dysfunction caused by chronic β-adrenergic receptor stimulation (β-AR, 4.5 mg/kg/day for 8 days, i.p.). Moreover, GBE prevented the upregulation of muscarinic receptors (M
) and downregulation of β
-AR in isoproterenol treated-hearts. Additionally, we demonstrated that GBE prevents the impaired endothelial nitric oxide synthase activity in the heart. GBE also prevented the pathological cardiac remodeling, electrocardiographic changes and impaired left ventricular contractility that are typical of cardiac hypertrophy. To further investigate the mechanisms involved in GBE cardioprotection
, we performed
studies. By using neonatal cardiomyocyte culture we demonstrated that the antihypertrophic action of GBE was fully abolished by muscarinic receptor antagonist or NOS inhibition. Altogether, our data support the notion that antihypertrophic effect of GBE occurs
activation of M
/NO pathway uncovering a new mechanism involved in the cardioprotective action of
.
Rats and mice are the most common species used in experimental cardiac electrophysiology studies. Electrocardiogram (ECG) recording shows paramount importance for monitoring arrhythmias and cardiac ...function in several disease models, including QT syndrome. However, the lack of standardized reference values and QT correction formula for different animal species and lineages represent a challenge for ECG interpretation. The aim of this study is to provide an improved method for ECG recording, establishing reference range values and determine the QT formulas with higher correlation to heart rate (HR). A total of 10 Wistar rats, 10 Swiss mice, 10 C57BL/6 mice and 10 FVB/NJ mice were used in the study. Animals were submitted to anesthesia with isoflurane and ECG recording was performed using a six-channel non-invasive electrocardiograph. QT was corrected using the following formulas: Bazzett, Fridericia, Mitchell, Hodges, Van der Water and Framingham. Normal range values for ECG parameters were established in all animals studied. Pearsons’ correlation defined Hodges formula as the most suitable for QT correction. This study demonstrated an improved method of ECG recording with reference values for Swiss, FVB/NJ, C57BL/6 mice, and Wistar rats. Hodges’ formula was the most effective formula for QT correction in rodents, whereas Bazett’s and Friderica formulas were ineffective for such animals. The present work contributes to arrhythmias investigation in experimental cardiology and may reduce misinterpretations in rodents’ ECG.
RESUMO: Ratos e camundongos são as espécies mais comumente utilizadas em estudos experimentais de eletrofisiologia cardíaca. O registro do eletrocardiograma (ECG) é de suma importância para o monitoramento de arritmias e função cardíaca em vários modelos de patologias. No entanto, a falta de valores de referência padronizados e a fórmula de correção do QT para diferentes espécies e linhagens animais representam um desafio para a interpretação do ECG. O objetivo deste estudo é fornecer um método melhorado para o registro de ECG, estabelecendo valores de referência e determinar as fórmulas QT com maior correlação com a freqüência cardíaca (FC). Um total de 10 ratos Wistar, 10 camundongos Swiss, 10 camundongos C57BL/6 e 10 camundongos FVB/NJ foram utilizados no estudo. Os animais foram submetidos à anestesia com isoflurano e o registro de ECG foi realizado com eletrocardiógrafo não invasivo de seis canais. O QT foi corrigido usando as seguintes fórmulas: Bazzett, Fridericia, Mitchell, Hodges, Van der Water e Framingham. Os valores da normalidade para os parâmetros do ECG foram estabelecidos em todos os animais estudados. A correlação de Pearson definiu a fórmula de Hodges como a mais adequada para a correção do QT. Este estudo demonstra um método melhorado de registro de ECG com valores de referência para camundongos Swiss, FVB/NJ, C57BL/6 e Wistar. A fórmula de Hodges foi a mais eficaz para correção de QT em roedores, enquanto as fórmulas de Bazett e Friderica apresentaram valores mais baixos de correlação. O presente trabalho contribui para a investigação de arritmias em cardiologia experimental e pode reduzir interpretações erradas no ECG de roedores.
Poor oral health has been reported as a risk factor in the etiology of head and neck cancer. Data on oral health were ascertained as part of two multicenter case-control studies comprising 924 cases ...and 928 controls in central Europe and 2,286 cases and 1,824 controls in Latin America. Incident cases of squamous cell carcinoma of the head and neck (oral cavity, pharynx, larynx) and esophagus, as well as age (in quinquennia)- and sex frequency-matched controls, were enrolled from 1998 to 2003. Poor condition of the mouth (central Europe: odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.74, 4.81; Latin America: OR = 1.89, 95% CI: 1.47, 2.42), lack of toothbrush use (Latin America: OR = 2.36, 95% CI: 1.28, 4.36), and daily mouthwash use (Latin America: OR = 3.40, 95% CI: 1.96, 5.89) emerged as risk factors for head and neck cancer, independent of tobacco use and alcohol consumption. Missing between six and 15 teeth was an independent risk factor for esophageal cancer (central Europe: OR = 2.84, 95% CI: 1.26, 6.41; Latin America: OR = 2.18, 95% CI: 1.04, 4.59). These results indicate that periodontal disease (as indicated by poor condition of the mouth and missing teeth) and daily mouthwash use may be independent causes of cancers of the head, neck, and esophagus.
The challenge of antibiotic resistance and the emergence of new infections have generated considerable interest in the exploration of natural products from plant origins as combination therapy. In ...this context, crude ethanolic extract (CEE), ethyl acetate fraction (EAF), and methanolic fraction (MF) from Anacardium microcarpum were tested alone or in combination with antibiotics (amikacin, gentamicin, ciprofloxacin, and imipenem) against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus.
Antibiotic resistance-modifying activity was performed using the microdilution method by determining the minimal inhibitory concentration (MIC). In addition, phytochemical prospecting analyses of tested samples were carried out.
Our results indicated that all the extracts showed low antibacterial activity against multidrug-resistant strains (MIC =512 μg/mL). However, addition of CEE, EAF, and MF to the growth medium at the subinhibitory concentration (MIC/8=64 μg/mL) significantly modulated amikacin- and gentamicin-resistant E. coli 06. CEE and EAF also demonstrated a significant (P<0.001) synergism with imipenem against S. aureus. In contrast, MF antagonized the antibacterial effect of ciprofloxacin and gentamicin against P. aeruginosa 03 and S. aureus 10, respectively. Qualitative phytochemical analysis of the extracts revealed the presence of secondary metabolites including phenols, flavonoids, xanthones, chalcones, and tannin pyrogallates.
Taken together, our results suggest that A. microcarpum is a natural resource with resistance-modifying antibacterial activity that needs to be further investigated to overcome the present resistant-infection problem.
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