RESUMEN
BACKGROUND: Several studies have aimed to identify molecules that inhibit the toxic actions of snake venom phospholipases A2 (PLA2s). Studies carried out with PLA2 inhibitors (PLIs) have been shown to be efficient in this assignment. OBJECTIVE: This work aimed to analyze the interaction of peptides derived from Bothrops atrox PLIγ (atPLIγ) with a PLA2 and to evaluate the ability of these peptides to reduce phospholipase and myotoxic activities. METHODS: Peptides were subjected to molecular docking with a homologous Lys49 PLA2 from B. atrox venom modeled by homology. Phospholipase activity neutralization assay was performed with BthTX-II and different ratios of the peptides. A catalytically active and an inactive PLA2 were purified from the B. atrox venom and used together in the in vitro myotoxic activity neutralization experiments with the peptides. RESULTS: The peptides interacted with amino acids near the PLA2 hydrophobic channel and the loop that would be bound to calcium in Asp49 PLA2. They were able to reduce phospholipase activity and peptides DFCHNV and ATHEE reached the highest reduction levels, being these two peptides the best that also interacted in the in silico experiments. The peptides reduced the myotubes cell damage with a highlight for the DFCHNV peptide, which reduced by about 65%. It has been suggested that myotoxic activity reduction is related to the sites occupied in the PLA2 structure, which could corroborate the results observed in molecular docking. CONCLUSION: This study should contribute to the investigation of the potential of PLIs to inhibit the toxic effects of PLA2s.
Asunto(s)
Fosfolipasas A2 Grupo IV/antagonistas & inhibidores , Mioblastos/efectos de los fármacos , Péptidos/farmacología , Inhibidores de Fosfolipasa A2/farmacología , Animales , Bothrops , Células Cultivadas , Evaluación Preclínica de Medicamentos , Fosfolipasas A2 Grupo IV/aislamiento & purificación , Fosfolipasas A2 Grupo IV/metabolismo , Ratones , Modelos Moleculares , Péptidos/síntesis química , Péptidos/química , Inhibidores de Fosfolipasa A2/síntesis química , Inhibidores de Fosfolipasa A2/químicaRESUMEN
The Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the predisposition for multiple tumors caused by germline mutations in the tumor suppressor gene VHL. This disease is associated with a high morbidity and mortality and presents a variable expression, with different phenotypes from family to family, affecting different organs during the lifetime. The main manifestations of VHL are hemangioblastomas of the central nervous system and retina, renal carcinomas and cysts, bilateral pheochromocytomas, cystic and solid tumors of the pancreas, cystadenomas of the epididymis, and endolymphatic sac tumors. The discovery of any of the syndrome components should raise suspicion of this disease and other stigmas must then be investigated. Due to the complexities associated with management of the various VHL manifestation, the diagnosis and the follow-up of this syndrome is a challenge in the clinical practice and a multidisciplinary approach is needed. The particular relevance to endocrinologists is the detection of pheochromocytomas in 35% and islet cell tumors in 17% of VHL patients, which can be associated with hypertension, hypoglycemia, cardiac arrhythmias, and carcinoid syndrome. The purpose of this review is to define the Von Hippel-Lindau syndrome addressing its clinical aspects and classification, the importance of genetic counseling and to propose a protocol for clinical follow-up.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Mutación de Línea Germinal , Hemangioblastoma/genética , Feocromocitoma/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/genética , Neoplasias de las Glándulas Suprarrenales/patología , Hemangioblastoma/patología , Humanos , Feocromocitoma/patología , Enfermedad de von Hippel-Lindau/patologíaRESUMEN
OBJECTIVE AND BACKGROUND: To evaluate the association between periodontal disease, tooth loss and coronary heart disease (CHD). There is still controversy about the relationship between periodontal disease and tooth loss with vessel obstruction assessed using coronary angiography. MATERIAL AND METHODS: This cross-sectional study included 195 patients that underwent coronary angiography and presented with at least six teeth. Patients were classified into three categories of coronary obstruction severity: absence; one or more vessels with ≤ 50% obstruction; and one or more vessels with ≥ 50% obstruction. The extent of coronary obstruction was dichotomized into 0 and ≥ 1 affected vessels. A periodontist blinded to patient CHD status conducted a full mouth examination to determine mean clinical attachment loss, mean periodontal probing depth and tooth loss. Multiple logistic regression models were applied adjusting for age, gender, hypertension, smoking, body mass index, low-density lipoprotein cholesterol and C-reactive protein. RESULTS: Most patients were males (62.1%) older than 60 years (50.8%), and 61% of them had CHD. Mean periodontal probing depth, clinical attachment loss and tooth loss were 2.64 ± 0.72 mm, 4.40 ± 1.31 mm and 12.50 ± 6.98 teeth respectively. In the multivariable models, tooth loss was significantly associated with a higher chance of having at least one obstructed vessel (odds ratio = 1.04; 95% confidence interval 1.01-1.09) and with vessel obstruction ≥ 50% (odds ratio = 1.06; 95% confidence interval 1.01-1.11). No significant associations were found between periodontal variables and vessel obstruction. CONCLUSION: Tooth loss was found to be a risk indicator for CHD.
Asunto(s)
Enfermedades Periodontales , Angiografía Coronaria , Enfermedad Coronaria , Estudios Transversales , Humanos , Masculino , Pérdida de la Inserción Periodontal , Factores de Riesgo , Fumar , Pérdida de DienteRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Lecythis pisonis Camb., also known in Brazil as sapucaia, is used in folk medicine against pruritus, muscle pain and gastric ulcer. AIM OF THE STUDY: To investigate the antinociceptive effect of ethanol extract from Lecythis pisonis leaves (LPEE), fractions (hexane-LPHF, ether-LPEF and ethyl acetate-LPEAF) and mixture of triterpenes [ursolic and oleanolic acids (MT)] in mice. MATERIALS AND METHODS: LPEE and LPEF were evaluated on the acetic acid induced writhings and formalin, capsaicin and glutamate tests. In addition, MT was investigated on the writhings induced by acetic acid, capsaicin and glutamate tests. In the study of some possible mechanisms involved on the antinociceptive effect of LPEF, it was investigated the participation of opioid system, K+ATP channels and L-arginine-nitric oxide pathway. RESULTS: LPEE (12.5 and 25 mg/kg, p.o.), LPEF and MT (6.25, 12.5 and 25 mg/kg, p.o.) reduced the writhings in comparison to saline. LPEE (100 mg/kg, p.o.) and LPEF (50 mg/kg, p.o.) were effective in inhibiting both phases of formalin test. In capsaicin test, LPEE (100 and 200 mg/kg, p.o.), LPEF (12.5-50 mg/kg, p.o) and MT (6.25-25 mg/kg, p.o.) showed a significant antinociceptive effect compared to the control. LPEE (25 and 50 mg/kg, p.o.), LPEF (50 and 100 mg/kg, p.o.) and MT (12.5 and 25 mg/kg, p.o.) reduced the glutamate-evoked nociceptive response. Treatment with naloxone, L-arginine and glibenclamide reversed the effect of LPEF in glutamate test. CONCLUSIONS: These results indicate the antinociceptive effect of Lecythis pisonis leaves and suggest that this effect may be related to opioid pathway, K+ATP channels, and L-arginine-nitric oxide modulation. Furthermore, these data support the ethnomedical use of this plant.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos/uso terapéutico , Lecythidaceae , Fitoterapia , Extractos Vegetales/uso terapéutico , Ácido Acético , Dolor Agudo/inducido químicamente , Analgésicos/farmacología , Animales , Arginina/farmacología , Conducta Animal/efectos de los fármacos , Capsaicina , Modelos Animales de Enfermedad , Formaldehído , Ácido Glutámico , Gliburida/farmacología , Masculino , Ratones , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Extractos Vegetales/farmacología , Hojas de la PlantaRESUMEN
To gain insight into stress-responsive gene regulation in soybean plants, we identified consensus sequences that could categorize the transcription factors MYBJ7, BZIP50, C2H2, and NAC2 as members of the gene families myb, bzip, c2h2, and nac, respectively. We also investigated the evolutionary relationship of these transcription factors and analyzed their expression levels under drought stress. The NCBI software was used to find the predicted amino acid sequences of the transcription factors, and the Clustal X software was used to align soybean and other plant species sequences. Phylogenetic trees were built using the Mega 4.1 software by neighbor joining and the degree of confidence test by Bootstrap. Expression level studies were carried out using hydroponic culture; the experiments were designed in completely randomized blocks with three repetitions. The blocks consisted of two genotypes, MG/BR46 Conquista (drought-tolerant) and BR16 (drought-sensitive) and the treatments consisted of increasingly long dehydration periods (0, 25, 50, 75, and 100 min). The transcription factors presented domains and/or conserved regions that characterized them as belonging to the bzip, c2h2, myb, and nac families. Based on the phylogenetic trees, it was found that the myb, bzip and nac genes are closely related to myb78, bzip48 and nac2 of soybean and that c2h2 is closely related to c2h2 of Brassica napus. Expression of all genes was in general increased under drought stress in both genotypes. Major differences between genotypes were due to the lowering of the expression of the mybj7 and c2h2 genes in the drought-tolerant variety at some times. Over-expression or silencing of some of these genes has the potential to increase stress tolerance.
Asunto(s)
Sequías , Regulación de la Expresión Génica de las Plantas , Glycine max/genética , Glycine max/fisiología , Raíces de Plantas/genética , Estrés Fisiológico/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Perfilación de la Expresión Génica , Genes de Plantas , Datos de Secuencia Molecular , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raíces de Plantas/fisiología , Alineación de Secuencia , Factores de Transcripción/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The stem barks of Zanthoxylum rhoifolium Lam. (Rutaceae), locally known as "mamica de cadela", are popularly used in dyspepsies, stomachic, tonic, antitumoral, antipyretic and are used in treating flatulence and colic. The objective of this study was to evaluate the gastroprotective effect of the ethanolic extract of Zanthoxylum rhoifolium (EEZR) stem barks in acute gastric lesion models, investigating their possible mechanisms. MATERIALS AND METHODS: Mice were used for the evaluation of the acute toxicity, and mice and rats to study the gastroprotective activity. The gastroprotective action of EEZR was analyzed in the absolute ethanol, HCl/ethanol and indomethacin-induced gastric lesion models in mice, hypothermic-restraint stress, and ischemia/reperfusion in rats. In the investigation of the gastroprotective mechanisms of EEZR, the participation of the NO-synthase pathway, ATP-sensitive potassium channels (K(ATP)), the levels of the non-protein sulfhydril groups (NP-SH) and the catalase activity using the ethanol-induced gastric mucosa lesion model and the quantification of the gastric mucus and the antisecretory activity through pylorus ligature model in rats were analyzed. RESULTS: The animals did not present any signs of acute toxicity for the EEZR (up to the 4 g/kg dose, po), and it was not possible to calculate the DL(50). EEZR (125-500 mg/kg) exhibited a significant gastroprotective effect in absolute ethanol, HCl/ethanol, hypothermic-restraint stress, and ischemia/reperfusion-induced gastric lesion models. EEZR (250 and 500 mg/kg) exhibited still a gastroprotective activity in the indomethacin-induced ulcer model. Gastroprotection of EEZR was significantly decreased in pre-treated mice with l-NAME or glibenclamide, the respective nitric oxide synthase and K(ATP) channels inhibitors. Our studies revealed that EEZR (500 mg/kg) prevented the decrease of the non-protein sulfhydril groups (NP-SH) and increased the catalase levels in ethanol-treated animals. Furthermore, the extract (500 mg/kg) significantly increased the mucus production, however, the gastric secretion parameters (volume, [H(+)], pH) did not show any alteration. CONCLUSIONS: Our results indicate that the ethanolic extract of Zanthoxylum rhoifolium exhibits a significant gastroprotection, because it inhibits the formation of gastric lesions using different models. The release of the nitric oxide, the opening of the K(ATP) channels, the participation of the non-protein sulfhydril groups (NP-SH), catalase and the increase of mucous secretion seem to be involved in the gastroprotection activity of the EEZR. Nevertheless, this activity does not seem to be related to antisecretory mechanisms.
Asunto(s)
Antiulcerosos/farmacología , Mucosa Gástrica/efectos de los fármacos , Extractos Vegetales/farmacología , Daño por Reperfusión/prevención & control , Úlcera Gástrica/prevención & control , Zanthoxylum , Animales , Antiulcerosos/química , Antiulcerosos/aislamiento & purificación , Antiulcerosos/toxicidad , Catalasa/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Etanol , Femenino , Jugo Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Ácido Clorhídrico , Concentración de Iones de Hidrógeno , Indometacina , Canales KATP/antagonistas & inhibidores , Canales KATP/metabolismo , Masculino , Ratones , Moco/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Corteza de la Planta , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Wistar , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Úlcera Gástrica/etiología , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Estrés Fisiológico , Zanthoxylum/químicaRESUMEN
Previous studies on Combretum leprosum, a tree growing in the Northeastern states of Brazil, have shown antinociceptive effects of the ethanol extract of its leaves and bark, but studies examining its constituents are rare. The objective of this study was to evaluate the antinociceptive effect of the hydroalcoholic fraction (HF) of one of its constituents, the flavonoid (-) epicatechin (EPI), administered orally to mice (20-30 g) in models of chemical nociception, and the possible mechanisms involved. Different doses of HF (62.5 to 500 mg/kg) and EPI (12.5 to 50 mg/kg) were evaluated in models of abdominal writhing, glutamate, capsaicin, and formalin in animals pretreated with different antagonists: naloxone, ondansetron, yohimbine, ketanserin, pindolol, atropine, and caffeine in the abdominal writhing test. To determine the role of nitric oxide, the animals were pretreated with L-arginine (600 mg/kg, ip) in the glutamate test. The HF was effective (P < 0.05) in all protocols at different doses and EPI was effective in the abdominal writhing, capsaicin and glutamate tests (P < 0.05) at doses of 25 and 50 mg/kg. However, in the formalin test it was only effective in the second phase at a dose of 25 mg/kg. The antinociceptive effect of HF was inhibited when HF was associated with yohimbine (0.15 mg/kg), ketanserine (0.03 mg/kg), and L-arginine (600 mg/kg), but not with the other antagonists. HF and EPI were effective in models of chemical nociception, with the suggested participation of the adrenergic, serotonergic and nitrergic systems in the antinociceptive effect of HF.
Asunto(s)
Analgésicos/farmacología , Catequina/farmacología , Combretum/química , Flavonoides/farmacología , Dolor/tratamiento farmacológico , Extractos Vegetales/farmacología , Enfermedad Aguda , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Dimensión del DolorRESUMEN
Previous studies on Combretum leprosum, a tree growing in the Northeastern states of Brazil, have shown antinociceptive effects of the ethanol extract of its leaves and bark, but studies examining its constituents are rare. The objective of this study was to evaluate the antinociceptive effect of the hydroalcoholic fraction (HF) of one of its constituents, the flavonoid (-) epicatechin (EPI), administered orally to mice (20-30 g) in models of chemical nociception, and the possible mechanisms involved. Different doses of HF (62.5 to 500 mg/kg) and EPI (12.5 to 50 mg/kg) were evaluated in models of abdominal writhing, glutamate, capsaicin, and formalin in animals pretreated with different antagonists: naloxone, ondansetron, yohimbine, ketanserin, pindolol, atropine, and caffeine in the abdominal writhing test. To determine the role of nitric oxide, the animals were pretreated with L-arginine (600 mg/kg, ip) in the glutamate test. The HF was effective (P < 0.05) in all protocols at different doses and EPI was effective in the abdominal writhing, capsaicin and glutamate tests (P < 0.05) at doses of 25 and 50 mg/kg. However, in the formalin test it was only effective in the second phase at a dose of 25 mg/kg. The antinociceptive effect of HF was inhibited when HF was associated with yohimbine (0.15 mg/kg), ketanserine (0.03 mg/kg), and L-arginine (600 mg/kg), but not with the other antagonists. HF and EPI were effective in models of chemical nociception, with the suggested participation of the adrenergic, serotonergic and nitrergic systems in the antinociceptive effect of HF.
Asunto(s)
Animales , Masculino , Ratones , Analgésicos/farmacología , Catequina/farmacología , Combretum/química , Flavonoides/farmacología , Dolor/tratamiento farmacológico , Extractos Vegetales/farmacología , Enfermedad Aguda , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Dimensión del DolorRESUMEN
AIM OF THE STUDY: Zanthoxylum rhoifolium Lam. (Rutaceae) is locally known as "mamica de cadela", and its bark is popularly used for toothache and earache. The objective of this study was to investigate the antinociceptive effect of the ethanolic extract from this species' stem bark (EtOH), its fractions of partition (hexane-HEX, ethyl acetate-AcOEt, aqueous-AQ) and lupeol (a triterpene obtained from HEX) in models of acute pain. MATERIALS AND METHODS: Male and female Swiss mice (25-35 g, n=6-12 animals/group) were used to assess acute toxicity and nociception (Animal Ethics Committee/UFPI, No. 09/2008). Acute toxicity was studied up to 2 g/kg p.o. of EtOH. In the formalin test (2%, 20 microL/paw), the licking time of the stimulated paw was quantified during the first 5 min (first phase) and at 15-30 min (second phase), 1h after oral treatment with EtOH, HEX, AcOEt or saline, and 30 min after use of morphine-MOR (5 mg/kg i.p.). The same response evoked by capsaicin (2 microg/20 microL/paw) was quantified during 5 min, after administration of EtOH, HEX, AcOEt, AQ, saline and MOR. The licking time of the paw that was stimulated with glutamate (10 micromol/20 microL) was measured (15 min) after treatment with EtOH, HEX, AcOEt, AQ, lupeol, saline or MK801 (0.03 mg/kg, i.p.). Mice were submitted to the rota-rod task and open-field test in order to assess any non-specific muscle-relaxant or sedative effects of EtOH (250 mg/kg p.o.) and HEX (500 mg/kg p.o.). RESULTS: The animals did not exhibit any acute toxicity to EtOH (up to 2 g/kg p.o.), so it was not possible to calculate the LD50. EtOH, HEX and AcOEt (62.5-250 mg/kg) produced a significant antinociceptive effect in the formalin and capsaicin tests. However, AQ was ineffective. EtOH, HEX, AcOEt and lupeol reduced the glutamate-evoked nociceptive response, but AQ had no effect. EtOH and HEX did not alter the locomotion of animals in the open-field or rota-rod tests, which suggest a lack of a central depressant effect. CONCLUSION: The results confirm the popular use of Zanthoxylum rhoifolium as an analgesic, and contribute to the pharmacological knowledge of this species because it was shown that EtOH and its less polar partition fractions (HEX, AcOEt) have an antinociceptive effect in models of chemical nociception, and that lupeol appears to be one of the constituents responsible for this effect.
Asunto(s)
Analgésicos/uso terapéutico , Dolor/tratamiento farmacológico , Triterpenos Pentacíclicos/uso terapéutico , Fitoterapia , Extractos Vegetales/uso terapéutico , Zanthoxylum/química , Analgésicos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Capsaicina , Modelos Animales de Enfermedad , Maleato de Dizocilpina , Etanol/farmacología , Femenino , Formaldehído , Ácido Glutámico/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Morfina/farmacología , Dolor/inducido químicamente , Triterpenos Pentacíclicos/farmacología , Corteza de la Planta , Extractos Vegetales/química , Extractos Vegetales/farmacología , Tallos de la PlantaRESUMEN
This study assesses the antinociceptive effect induced by different dosages of topiramate (TP), an anticonvulsant drug that is orally administered in models of neuropathic pain and acute pain in rats and mice, respectively. Orally administered TP (80 mg/Kg) in mice causes antinociception in the first and second phases of a formalin test, while in doses of 20 and 40 mg/Kg it was only effective in the second phase. TP (80 mg/Kg, p.o) also exhibited antinociceptive action in the hot plate test, however, it did not have an effect in the capsaicin test in mice, nor in the model of neuropathic pain in diabetic rats. The antinociceptive effect caused by TP (80 mg/Kg, p.o) in the formalin test was reversed by prior treatment with naloxone (opioid antagonist), but not with glibenclamide (antagonist of the potassium channel), ondansetron (antagonist of the serotonin 5HT3 receptor) or cyproheptadine (antagonist of the serotonin 5HT2A receptor).The data show that TP has an important antinociceptive effect in the models of nociception induced by chemical (formalin) or thermal (hot plate) stimuli, and that the opioid system plays a part in the antinociceptive effect, as shown by formalin.