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OBJECTIVE AND DESIGN: To investigate the role of heme oxygenase-1 (HO-1), carbon monoxide (CO), and biliverdin (BVD) in the zymosan-induced TMJ arthritis in rats. MATERIALS AND METHODS: Mechanical threshold was assessed before and 4 h after TMJ arthritis induction in rats. Cell influx, myeloperoxidase activity, and histological changes were measured in the TMJ lavages and tissues. Trigeminal ganglion and periarticular tissues were used for HO-1, TNF-α, and IL-1ß mRNA time course expression and immunohistochemical analyses. Hemin (0.1, 0.3, or 1 mg kg-1), DMDC (0.025, 0.25, or 2.5 µmol kg-1), biliverdin (1, 3, or 10 mg kg-1), or ZnPP-IX (1, 3 or 9 mg kg-1) were injected (s.c.) 60 min before zymosan. ODQ (12.5 µmol kg-1; s.c.) or glibenclamide (10 mg kg-1; i.p.) was administered 1 h and 30 min prior to DMDC (2.5 µmol kg-1; s.c), respectively. RESULTS: Hemin (1 mg kg-1), DMDC (2.5 µmol kg-1), and BVD (10 mg kg-1) reduced hypernociception and leukocyte migration, which ZnPP (3 mg kg-1) enhanced. The effects of DMDC were counteracted by ODQ and glibenclamide. The HO-1, TNF-α, and IL-1ß mRNA expression and immunolabelling increased. CONCLUSIONS: HO-1/BVD/CO pathway activation provides anti-nociceptive and anti-inflammatory effects on the zymosan-induced TMJ hypernociception in rats.
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Biliverdina/fisiología , Monóxido de Carbono/fisiología , GMP Cíclico , Hemo-Oxigenasa 1/fisiología , Canales KATP , Nocicepción/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Artritis/inducido químicamente , Biliverdina/genética , Citocinas/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Masculino , Umbral del Dolor , Peroxidasa/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Wistar , Trastornos de la Articulación Temporomandibular/inducido químicamente , Trastornos de la Articulación Temporomandibular/patología , Ganglio del Trigémino/efectos de los fármacos , ZimosanRESUMEN
Lectins are proteins that bind to specific mono- or oligosaccharides. This study aimed to evaluate the antinociceptive and anti-inflammatory effects of the lectin from the red marine alga Solieria filiformis. The animals (n = 6) were pretreated with S. filiformis lectin 30 min before they were given the nociceptive or inflammatory stimulus. The antinociceptive activity was evaluated in Swiss mice using the abdominal writhing, formalin, and hot plate tests. The anti-inflammatory properties were evaluated in Wistar rats using carrageenan-induced peritonitis and paw edema induced by different phlogistic agents. The S. filiformis lectin toxicity was assayed through its application in mice (7 days). S. filiformis lectin significantly reduced the number of abdominal writhings and reduced the paw licking time in the second phase of the formalin test (p < 0.05), but it did not prolong the reaction time in the hot plate test (p > 0.05). Furthermore, S. filiformis lectin reduced neutrophil migration in a peritonitis model and reduced paw edema induced by carrageenan, dextran, and serotonin (p < 0.05). Additionally, the administration of S. filiformis lectin resulted in no signs of systemic damage. Thus, S. filiformis lectin appears to have important antinociceptive and anti-inflammatory activities and could represent a potential therapeutic agent for future studies.
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Analgésicos/aislamiento & purificación , Antiinflamatorios no Esteroideos/aislamiento & purificación , Lectinas/aislamiento & purificación , Rhodophyta/química , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Femenino , Lectinas/farmacología , Masculino , Ratones , Proteínas de Plantas/aislamiento & purificación , Proteínas de Plantas/farmacología , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Wide biotechnological investigations of only a limited number of seaweed lectins have been performed. We previously demonstrated the anti-nociceptive and anti-inflammatory effects of a lectin isolated from the green seaweed Caulerpa cupressoides var. lycopodium (CcL). Herein, we further studied the mechanisms of action of CcL. METHODS: Classical acute inflammation models induced by different flogistic agents were used to evaluate the anti-inflammatory action of CcL. CcL was injected locally into the rat paw to verify a possible pro-inflammatory outcome. RESULTS: CcL (0.1, 1 or 10 mg/kg; i.v.) reduced the carrageenan-induced rat paw edema and neutrophilic infiltration, which was not altered by either mucin (inhibitor of CcL carbohydrate-binding site) or ZnPP-IX (specific HO-1 inhibitor). Immunohistochemical analyses showed that CcL (1 mg/kg) reduced the expression of the cytokines IL-1ß, TNF-α, IL-6 and COX-2. CcL (0.1, 1 or 10 mg/kg) inhibited dextran, and CcL (1 mg/kg) inhibited histamine-induced rat paw edema. Both effects were reversed by mucin inhibition. CcL (1 mg/kg) was ineffective for the treatment of serotonin- and bradykinin-induced rat paw edema. When injected via the i.pl. route, CcL (10 mg/kg) elicited rat paw edema involving a wide range of mediators. CONCLUSIONS: The anti-inflammatory action of CcL involves the inhibition of IL-1ß, TNF-α, IL-6 and COX-2 expression and histamine H1 receptors. When locally administered, CcL exerts pro-inflammatory actions.
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Antiinflamatorios/farmacología , Caulerpa/química , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Lectinas/farmacología , Animales , Carragenina , Citocinas/biosíntesis , Edema/inducido químicamente , Edema/patología , Pie/patología , Histamina , Inflamación/inducido químicamente , Masculino , Mucinas/antagonistas & inhibidores , Infiltración Neutrófila/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Marine algae are abundant sources of sulfated polysaccharides with various biological activities. Consequently, their biomolecules are of great of commercial interest. In this study, we investigated the potential antinociceptive activity of a sulfated polysaccharide obtained from the green seaweed Caulerpa racemosa (CrII) and the involvement of the hemoxigenase-1 (HO-1) pathway in its anti-inflammatory effect. METHODS: We used a systemic evaluation to verify possible toxic effects of Crll after consecutive treatments. Swiss mice and Wistar rats were used for all experiments. RESULTS: In Swiss mice, CrII (0.01, 0.1 and 1.0 mg/kg) significantly reduced the number of abdominal contortions and the duration of paw licking in the second phase after treatment with acetic acid and formalin, respectively. However, CrII was unable to prolong the reaction time of thermally stimulated animals. The anti-inflammatory effect of CrII (0.01, 0.1 and 1.0 mg/kg) was evidenced by a decreased number of leukocytes in the peritoneal cavities of the rats. CrII (0.01, 0.1 and 1.0 mg/kg) also reduced the amount of paw edema induced by carrageenan (Cg) and dextran. The anti-inflammatory effect of CrII was confirmed by reduced levels of myeloperoxidase in the paw tissue of the Cg groups. After inhibition with ZnPP IX, a specific HO-1 phenotype inhibitor, the anti-inflammatory effect of CrII was no longer observed in Cg-induced paw edema tests. Consecutive Crll (1.0 mg/kg) for 14 days did not change any biochemical or histopathological parameters, or cause mortality of mice. CONCLUSIONS: CrII did not produce any signs of toxicity and effectively decreased nociception and inflammation. Also, the anti-inflammatory effect of Crll is at least in part dependent on the integrity of the HO-1 pathway.
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Analgésicos , Antiinflamatorios , Caulerpa , Hemo Oxigenasa (Desciclizante)/metabolismo , Polisacáridos , Algas Marinas , Ácido Acético , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Carragenina , Dextranos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Femenino , Formaldehído , Calor , Masculino , Ratones , Dolor/tratamiento farmacológico , Dolor/etiología , Peritonitis/inducido químicamente , Peritonitis/tratamiento farmacológico , Peroxidasa/metabolismo , Fitoterapia , Polisacáridos/química , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Ratas Wistar , Sulfatos/químicaRESUMEN
OBJECTIVE: To describe parametric changes observed using scanning electron microscopy (SEM) in very early stages in posttraumatic osteoarthritis (OA) models in mice. METHODS: Mice (5/group) had their knees subjected to anterior cruciate ligament transection (ACLT), ACLT plus meniscectomy (MNCT) or sham surgery, sacrificed after 3, 7 or 14 days, had the articular cartilage evaluated under optical microscopy using Osteoarthritis Research Society International (OARSI) parameters as well as cartilage thickness, roughness, and a damage index using SEM. RESULTS: Alterations of the cartilage under optical microscopy were not significantly relevant among groups. SEM analysis revealed reduction of femoral and tibial cartilage thickness in ACLT and MNCT groups at 7 and 14 days, with increased cartilage roughness in MNCT group as early as 3 days postsurgery, being sustained up to 14 days. Articular damage index was significantly higher at 14 days post surgery in ACLT and MNCT vs control groups. CONCLUSION: This is the first demonstration of very early quantitative changes in the cartilage of mice subjected to posttraumatic experimental OA using SEM, revealing increased roughness and thickness as early as 3 days post surgery. These changes may be used as early surrogates for later joint damage in experimental OA.
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Cartílago Articular , Osteoartritis , Ratones , Humanos , Animales , Microscopía Electrónica de Rastreo , Modelos Animales de Enfermedad , Osteoartritis/diagnóstico por imagen , Cartílago Articular/diagnóstico por imagen , Ligamento Cruzado Anterior/cirugíaRESUMEN
Objective: Moringa oleifera possesses multiple biological effects and the 4-[(4'-O-acetyl-α-L- rhamnosyloxy) benzyl] isothiocyanate accounts for them. Based on the original isothiocyanate molecule we obtained a semisynthetic derivative, named 4-[(2',3',4'-O-triacetyl-α-L-rhamnosyloxy) N-benzyl] hydrazine carbothioamide (MC-H) which was safe and effective in a temporomandibular joint (TMJ) inflammatory hypernociception in rats. Therefore, considering that there is still a gap in the knowledge concerning the mechanisms of action through which the MC-H effects are mediated, this study aimed to investigate the involvement of the adhesion molecules (ICAM-1, CD55), the pathways heme oxygenase-1 (HO-1) and NO/cGMP/PKG/K+ ATP, and the central opioid receptors in the efficacy of the MC-H in a pre-clinical study of TMJ pain. Methods: Molecular docking studies were performed to test the binding performance of MC-H against the ten targets of interest (ICAM-1, CD55, HO-1, iNOS, soluble cGMP, cGMP-dependent protein kinase (PKG), K+ ATP channel, mu (µ), kappa (κ), and delta (δ) opioid receptors). In in vivo studies, male Wistar rats were treated with MC-H 1 µg/kg before TMJ formalin injection and nociception was evaluated. Periarticular tissues were removed to assess ICAM-1 and CD55 protein levels by Western blotting. To investigate the role of HO-1 and NO/cGMP/PKG/K+ ATP pathways, the inhibitors ZnPP-IX, aminoguanidine, ODQ, KT5823, or glibenclamide were used. To study the involvement of opioid receptors, rats were pre-treated (15 min) with an intrathecal injection of non-selective inhibitor naloxone or with CTOP, naltrindole, or norbinaltorphimine. Results: All interactions presented acceptable binding energy values (below -6.0 kcal/mol) which suggest MC-H might strongly bind to its molecular targets. MC-H reduced the protein levels of ICAM-1 and CD55 in periarticular tissues. ZnPP-IX, naloxone, CTOP, and naltrindole reversed the antinociceptive effect of MC-H. Conclusion: MC-H demonstrated antinociceptive and anti-inflammatory effects peripherally by the activation of the HO-1 pathway, as well as through inhibition of the protein levels of adhesion molecules, and centrally by µ and δ opioid receptors.
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AIMS: To establish a new model of zymosan-induced temporomandibular joint (TMJ) arthritis in the rat and to investigate the role of nitric oxide. METHODS: Inflammation was induced by an intra-articular injection of zymosan into the left TMJ. Mechanical hypernociception, cell influx, vascular permeability, myeloperoxidase activity, nitrite levels, and histological changes were measured in TMJ lavages or tissues at selected time points. These parameters were also evaluated after treatment with the nitric oxide synthase (NOS) inhibitors L-NAME or 1400 W. RESULTS: Zymosan-induced TMJ arthritis caused a time-dependent leucocyte migration, plasma extravasation, mechanical hypernociception, and neutrophil accumulation between 4 and 24 h. TMJ immunohistochemical analyses showed increased inducible NOS expression. Treatment with L-NAME or 1400 W inhibited these parameters. CONCLUSION: Zymosan-induced TMJ arthritis is a reproducible model that may be used to assess both the mechanisms underlying TMJ inflammation and the potential tools for therapies. Nitric oxide may participate in the inflammatory temporomandibular dysfunction mechanisms.
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Artritis Experimental/inmunología , Artritis Experimental/metabolismo , Modelos Animales de Enfermedad , Neutrófilos/inmunología , Óxido Nítrico/metabolismo , Trastornos de la Articulación Temporomandibular/inmunología , Trastornos de la Articulación Temporomandibular/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Masculino , Infiltración Neutrófila , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Líquido Sinovial/química , Líquido Sinovial/citología , Articulación Temporomandibular/patología , ZimosanRESUMEN
OBJECTIVES: The aim of this study was to investigate the involvement of the hemoxigenase-1 (HO-1) pathway in the anti-inflammatory action of a sulfated polysaccharide from the red seaweed Gracilaria birdiae (SP-Gb). METHODS: SP-Gb (5, 10 and 20 mg/kg) was administered to Wistar rats in a peritonitis model using carrageenan or a paw edema model using carrageenan or dextran. To analyze the involvement of HO-1 in the anti-inflammatory activity of SP-Gb, the animals were pretreated subcutaneously with a specific HO-1 inhibitor (ZnPP IX). To evaluate the systemic effects, SP-Gb (10 mg/kg) was administered to mice intraperitoneally before waiting for 48 h or for 14 days. RESULTS: SP-Gb (10 mg/kg) caused an anti-inflammatory effect that was evidenced by a decrease in leukocytes in the peritoneal cavity. SP-Gb also reduced the paw edema induced by carrageenan and inhibited the paw edema induced by dextran in the first half-hour. After being inhibited by ZnPP IX, the anti-inflammatory effect of SP-Gb on carrageenan-induced rat paw edema was not observed. SP-Gb did not cause mortality or significant changes in the biochemical, hematological and histopathological parameters. CONCLUSION: SP-Gb may be used as a tool for further investigations into the inflammatory processes associated with the hemoxigenase-1 pathway.
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Antiinflamatorios/farmacología , Edema/inmunología , Gracilaria/química , Hemo-Oxigenasa 1/inmunología , Peritonitis/inmunología , Polisacáridos/farmacología , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/uso terapéutico , Carragenina , Dextranos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Hemo-Oxigenasa 1/antagonistas & inhibidores , Recuento de Leucocitos , Masculino , Ratones , Peritonitis/inducido químicamente , Peritonitis/tratamiento farmacológico , Peroxidasa/metabolismo , Polisacáridos/aislamiento & purificación , Polisacáridos/uso terapéutico , Protoporfirinas/farmacología , Ratas , Ratas WistarRESUMEN
OBJECTIVE: Chresta martii is broadly used by folk medicine due to its anti-inflammatory effects, but there is a lack of preclinical data on its pharmacological mechanisms. This study investigated the efficacy of Chresta martii ethanolic extract (CEE) in the zymosan-induced temporomandibular joint arthritis (TMJ) and evaluated the possible role of TNF-α, nitric oxide (NO), and heme oxygenase-1 (HO-1). METHODS: Male Wistar rats (160-220 g) were pre-treated with CEE (100, 200 or 400 mg/kg; v.o) 1 h before zymosan injection (2 mg; i.art). Mechanical hypernociception (g) was assessed 4 h later. The trigeminal ganglion was collected for TNF-α quantification (ELISA), total cell count and myeloperoxidase activity (MPO) were assayed in the synovial lavage 6 h after arthritis induction. Additionally, animals were pre-treated with L-NAME (30 mg/kg; i.p.) or ZnPP-IX (3 mg/kg, s.c.) to assess the involvement of NO and HO-1, respectively. RESULTS: CEE 400 mg/kg (v.o) increased (p < 0.05) hypernociception threshold, reduced the cell counts and MPO activity in the synovial lavage, as well as decreased TNF-α levels in the trigeminal ganglion. ZnPP-IX abolished the analgesic effect of CEE, but not L-NAME. CONCLUSION: The anti-inflammatory and antinociceptive effects of CEE depended on the HO-1 pathway integrity and TNF-α suppression.
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Temporomandibular disorder is a clinical painful condition in the temporomandibular joint (TMJ) region. The purified sulfated polysaccharide from the green marine algae Caulerpa racemosa (Cr) has provided anti-inflammatory and antinociceptive activity. This study evaluated these effects on a TMJ hypernociception model. Wistar rats (180 - 250 g) were pre-treated (i.v.) with Cr at 0.01, 0.1, or 1 mg/kg or vehicle 30 min before formalin (1.5%/50 µL, i.art.), capsaicin (1.5%/20 µL, i.art.), or serotonin (225 µg/50 µL, i.art.) in the TMJ, and nociceptive behaviors were measured for 45 or 30 min upon inflammatory stimuli. Inflammatory parameters vascular permeability assay, TNF-α, and IL-1ß by ELISA, protein expression of adhesion molecules ICAM-1 and CD55 by Western blot were assessed. The involvement of heme oxygenase-1 (HO-1) and nitric oxide (NO) pathways were assessed by pharmacological inhibition. Cr (1 mg/kg) reduced nociceptive behavior, plasmatic extravasation, TNF-α, and IL-1ß levels, as well as ICAM-1 and CD55 expression in periarticular tissues. Cr antinociceptive effect was not prevented by aminoguanidine, but ZnPP-IX did reduce its antinociceptive effect. Therefore, Cr antinociceptive and anti-inflammatory effects in this experimental model of hypernociception depended on the HO-1 pathway integrity, as well as reducing peripheral inflammatory events, e.g., TNF-α and IL-1ß cytokines levels, ICAM-1 and CD55 expression.
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Analgésicos/química , Analgésicos/farmacología , Organismos Acuáticos/química , Chlorophyta/química , Polisacáridos/química , Polisacáridos/farmacología , Sulfatos/química , Animales , Artralgia/tratamiento farmacológico , Artralgia/etiología , Artralgia/metabolismo , Biomarcadores , Capsaicina/efectos adversos , Citocinas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratas , Articulación Temporomandibular/efectos de los fármacos , Articulación Temporomandibular/fisiopatologíaRESUMEN
Lonchocarpus campestris (tribe Dalbergieae) possess a mannose biding lectin (LCaL) purified by ion exchange chromatography on DEAE-Sephacel, HiTrap DEAE FF and TSKgel engaged in AKTA-HPLC system. LCaL agglutinates trypsinized rabbit erythrocytes and its activity was maintained after incubation in a wide range of temperature (4-100⯰C) and pH (4-9). The lectin had its apparent molecular weight evaluated by size-exclusion chromatography and SDS-PAGE and presented a profile of 10â¯kDa and 25â¯kDa in denaturing and native conditions, respectively. LCaL injected by intravenous route in mice showed antinociceptive activity in the behavioral tests of Formalin and Writhing. In the formalin test LCaL inhibited the licking time by 37% in the neurogenic phase and by 73% in the inflammatory phase. In the acetic acid-induced writhing test LCaL showed inhibitory effect at 0.1â¯mg/kg (72%), 1â¯mg/kg (74%) and 10â¯mg/kg (70%). The lectin also inhibited the increase in vascular permeability at 10â¯mg/kg and leukocyte migration at 0.1, 1 and 10â¯mg/kg concentrations. Additionally, LCaL inhibited paw edema (mainly from 1 to 3â¯h by 46%) and hyperalgesia (1â¯h: 82%; 3â¯h: 63%) induced by carrageenan. In conclusion, LCaL presents an antinociceptive action mainly via inhibition of inflammation.
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Antiinflamatorios/química , Antiinflamatorios/farmacología , Fabaceae/química , Lectinas/aislamiento & purificación , Nocicepción/efectos de los fármacos , Semillas/química , Animales , Hemaglutinación , Lectinas/química , Masculino , Ratones , Peso MolecularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (Mp) belongs to Leguminosae family, it is native of tropical regions and used to treat several maladies such as urinary, neurological, and menstruation disorders, constipation, edema, fever, tuberculosis, ulcers, diabetes, arthritis, dysentery, and cardiovascular diseases. Mp seeds are rich in bioactive compounds, for instance, lectins, a heterogeneous group of proteins and glycoproteins with a potential role as therapeutic tools for several conditions, including gastric disorders. This study investigated the acute toxicity, gastroprotective, and antioxidant activities of a lectin from Mucuna pruriens seeds (MpLec) on ethanol-induced gastropathy model in mice. MATERIAL AND METHODS: Mice received MpLec (5 or 10 mg/kg; i.v.) and were observed for acute toxicity signs; in another experimental series, mice were pre-treated with MpLec (0.001; 0.01 or 0.1 mg/kg, i.v.), ranitidine (80 mg/kg, p.o.), or saline (0.3 mL/30g, i.v.) before ethanol 99.9% (0.2 mL/animal, p.o.), and euthanized 30 min after ethanol challenge. Macroscopic and microscopic gastric aspects, biochemical parameters (tissue hemoglobin levels, iron-induced lipid peroxidation, GSH content, SOD activity, and gastric mucosal PGE2) were measured. Additionally, pharmacological tools (yohimbine, indomethacin, naloxone, L-NAME) were opportunely used to clarify MpLec gastroprotective mechanisms of action. RESULTS: No toxicity signs nor death were observed at acute toxicity tests. MpLec reduced ethanol-induced gastric damage, edema, and hemorrhagic patches formation, as well as decreased lipid peroxidation, SOD activity, and increased GSH content. Yohimbine and indomethacin prevented MpLec effects, suggesting the involvement of alpha-2 adrenoceptors and prostaglandins in the MpLec-mediated effects. CONCLUSION: MpLec does not present toxicity signs and shows gastroprotective and antioxidant activities via alpha-2 adrenoceptors and prostaglandins in the ethanol-induced gastropathy model.
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Antioxidantes/farmacología , Mucosa Gástrica/efectos de los fármacos , Lectinas/farmacología , Mucuna/química , Prostaglandinas/metabolismo , Receptores Adrenérgicos/metabolismo , Úlcera Gástrica/terapia , Animales , Etanol/efectos adversos , Peroxidación de Lípido , Ratones , Fitoterapia , Extractos Vegetales/uso terapéutico , Semillas/química , Úlcera Gástrica/inducido químicamente , Pruebas de Toxicidad AgudaRESUMEN
OBJECTIVES: The purpose of this study was to determine the effects of strontium ranelate on ligature-induced periodontitis in rats and assess the putative involvement of heme oxygenase-1 (HO-1) pathway in these effects. MATERIAL AND METHODS: Male Wistar rats underwent nylon ligature placement around maxillary molars and were treated (v.o.) with strontium ranelate (20 or 100 mg/kg) for 7 days. After that, rats were euthanized and histomorphometric/histopathological analyses and RT-PCR for HO-1 expression were performed. RESULTS: Strontium ranelate (20 or 100 mg/kg) prevented bone resorption by 28% and 38%, respectively. Strontium ranelate treatment (100 mg/kg) up-regulated (P < 0.05) heme oxygenase-1 mRNA levels in the gingival tissues in comparison to control groups. CONCLUSIONS: Strontium ranelate prevented periodontal bone loss in experimental periodontitis in rats while heme oxygenase-1 mRNA levels increased after treatment.
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Chemo-resistance has been reported as a relevant barrier for the efficiency of gastric cancer treatment. Therefore, the development of effective and safe drugs for cancer chemotherapy is still a challenge. The purpose of this study was to evaluate the anticancer potential of (E)-2-(((2-(benzo[d]thiazo-2-yl)hydrazono)methyl)-4-nitrophenol) (AFN01) against gastric cancer cell lines. Our results showed promising anticancer activity against gastric cancer cells ACP-02 (IC50â¯=â¯1.0⯵M) and mild activity against other cell lines including non-malignant gastric cell MNP-01 (IC50â¯=â¯3.4⯵M). This compound significantly induced S phase cell cycle arrest, prevented cell migration and triggered apoptosis in a concentration-dependent manner. Moreover, AFN01 was significantly more genotoxic against tumoral cell ACP-02, when compared to non-malignant cells, such as MNP-01 and healthy peripheral mononuclear blood cells. AFN01 also synergistically interacts with doxorubicin suppressing cell proliferation and c-MYC gene expression in gastric cancer cell line model, with remarkable c-MYC overexpression. Although further pre-clinical and clinical studies are required to explore its safety and efficiency, AFN01 may represent a promising lead anticancer agent for the treatment of gastric cancer.
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Apoptosis/efectos de los fármacos , Benzotiazoles/farmacología , ADN/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Benzotiazoles/química , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , ADN/química , Regulación hacia Abajo/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas c-myc/genética , Estereoisomerismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Temporomandibular disorders are the second most common cause of orofacial pain mediated by inflammatory compounds, which in many cases leads to chronic orofacial pain. This study assessed the antinociceptive and anti-inflammatory effects of a lectin from the green seaweed Caulerpa cupressoides (CcL) on hypernociception inflammatory in TMJ of rats and investigated the involvement of different mechanisms. Rats received i.v. CcL 30â¯min prior to injection of flogistic agentes or 0.9% saline into the left TMJ. Pretreatment with CcL (0. 1; 1 or 10â¯mg/kg) promoted a reduction (pâ¯<â¯0.05) of inflammatory hypernociception induced by 1.5% Formalin along with inhibition of inflammatory plasma extravasation, cytokines levels, ciclooxigenase-2, and intercellular adhesion molecule (ICAM-1). CcL was able to inhibit the nociceptive response induced by 1.5% Capsaicin, suggesting that CcL has an antinociceptive effect, acting directly on the primary nociceptive neurons. CcL also inhibited the nociceptive response induced by Carrageenan (100⯵g/TMJ) or Serotonin (5-HT) (225⯵g/TMJ). In conclusion, the results demonstrate that administration of CcL has a potential antinociceptive and anti-inflammatory effect, with a mechanism that is partially dependent on TNF-α, IL-1ß, COX-2 and ICAM-1 inhibition and independently from the cannabinoide and opioid system and NO/cGMP/PKG/K+ATP channel pathway.
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Analgésicos/farmacología , Caulerpa/química , Lectinas de Plantas/farmacología , Articulación Temporomandibular/efectos de los fármacos , Animales , Moléculas de Adhesión Celular/metabolismo , Ciclooxigenasa 2/metabolismo , Inflamación/fisiopatología , Interleucina-1beta/biosíntesis , Masculino , Actividad Motora/efectos de los fármacos , Nocicepción/efectos de los fármacos , Ratas , Ratas Wistar , Articulación Temporomandibular/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Abelmoschus esculentus is largely cultivated in Northeastern Brazil for medicinal purposes, e.g. inflammatory conditions. This study aimed to evaluate the efficacy of Abelmoschus esculentus lectin (AEL) in reducing formalin-induced temporomandibular joint inflammatory hypernociception in rats. The behavioral experiments were performed in male Wistar rats (180-240â¯g). Rats were pre-treated (i.v.) with AEL (0.001, 0.01 or 0.1â¯mg/kg) 30â¯min before formalin injection (i.art.). To analyze the possible effect of opioid pathways on AEL efficacy, animals were pre-treated with naloxone or CTOP (µ opioid receptor antagonist), naltrindole (δ opioid receptor antagonist) or nor-binaltorphimine (κ opioid receptor antagonist) (i.t.) 15â¯min before AEL administration followed by intra-TMJ injection of 1.5% formalin. Animals were monitored for a 45-min observation period. TMJ tissue, trigeminal ganglion, and subnucleus caudalis were collected for TNF-α dosage (ELISA). In addition, the vascular permeability was evaluated by Evans Blue extravasation. AEL significantly reduced formalin-induced TMJ inflammatory hypernociception and decreased Evans blue extravasation. It decreased TNF-α levels in the TMJ tissue, trigeminal ganglion, and subnucleus caudalis. AEL antinociceptive effects were not observed in the presence of naltrindole or nor-binaltorphimine, suggesting that AEL efficacy depends on TNF-α inhibition and the activation of δ and κ opioid receptors. AEL has provided prominent analgesic and anti-inflammatory effects in this pre-clinical model of TMJ, supporting its possible use as a pharmacological tool for the management of painful conditions.
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Abelmoschus/química , Analgésicos/farmacología , Lectinas/farmacología , Dolor/tratamiento farmacológico , Receptores Opioides/metabolismo , Articulación Temporomandibular/efectos de los fármacos , Analgésicos Opioides/farmacología , Animales , Antiinflamatorios/farmacología , Formaldehído/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Hipernutrición/tratamiento farmacológico , Hipernutrición/metabolismo , Dolor/inducido químicamente , Dolor/metabolismo , Ratas , Ratas Wistar , Articulación Temporomandibular/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Tocoyena sellowiana (Cham. & Schltdl.) K.Schum is one of the most important families of Brazilian medicinal plants. This study aimed to evaluate the effect of Tocoyena sellowiana (Cham. & Schltdl.) K.Schum ethanolic extract in a pre-clinical trial of periodontitis and to investigate possible mechanisms underlying such effects. Periodontitis was induced in Wistar rats by placing a nylon thread ligature around second upper left molars for 11 days. Rats received (per os) Tocoyena sellowiana (0.1, 1 or 10?mg?kg) or vehicle 1?h before ligature and daily until day 11. Macroscopic, histopathological, and COX-2 immunohistochemical analyses were performed to evaluate the periodontium. The gingival tissue was used to quantify the myeloperoxidase (MPO) activity and interleukin (IL)-1? levels by ELISA. Blood samples were collected to evaluate bone-specific alkaline phosphatase (BALP), the dosage of creatinine, aspartate and alanine transaminases. The liver, kidneys, spleen, and body mass variations were also evaluated. Tocoyena sellowiana decreased bone loss, reduced MPO, IL-1? levels as well as COX-2 immunostaining, and increased BALP activity. Moreover, Tocoyena sellowiana did not alter organs nor body weight. Tocoyena sellowiana reduced bone loss in rats and its efficacy was at least partially dependent upon both IL-1? and cyclooxygenase-2 inhibition.
Asunto(s)
Pérdida de Hueso Alveolar/complicaciones , Pérdida de Hueso Alveolar/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Interleucina-1beta/metabolismo , Periodontitis/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Rubiaceae/química , Fosfatasa Alcalina/sangre , Pérdida de Hueso Alveolar/sangre , Pérdida de Hueso Alveolar/patología , Animales , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Encía/patología , Tamaño de los Órganos/efectos de los fármacos , Periodontitis/sangre , Periodontitis/complicaciones , Periodontitis/patología , Peroxidasa/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Ratas WistarRESUMEN
Inflammation is a key component of many clinical conditions that affect the temporomandibular joint (TMJ) and Moringa oleifera Lam. has been used to treat inflammatory diseases. Here, we evaluated the toxicological effects on mice of a naturally-occurring isothiocyanate from M. oleifera and its seven analogue molecules. Further, the anti-nociceptive and anti-inflammatory effects on a rat model of TMJ inflammatory hypernociception were assessed. The systemic toxicological profile was determined in mice over a 14-day period: MC-1 1⯵g/kg; MC-D1 1⯵g/kg, MC-D3 100⯵g/kg, MC-D6 1⯵g/kg, MC-D7 1⯵g/kg, MC-D8 1⯵g/kg, MC-D9 10⯵g/kg, and MC-H 1⯵g/kg. The safest molecules were assayed for anti-nociceptive efficacy in the formalin (1.5%, 50⯵L) and serotonin (255â¯mg) induced TMJ inflammatory hypernociception tests. The anti-inflammatory effect was evaluated through the vascular permeability assay using Evans blue. Further, the rota-rod test evaluated any motor impairment. Among the tested molecules, MC-D7, MC-D9, and MC-H were not toxic at the survival rate test, biochemical, and hystological analysis. They reduced the formalin-induced TMJ inflammatory hypernociception, but only MC-H decreased the serotonin-induced TMJ inflammation, suggesting an adrenergic receptor-dependent effect. They diminished the plasmatic extravasation, showing anti-inflammatory activity. At the rota-rod test, no difference was observed in comparison with control groups, reinforcing the hypothesis of anti-nociceptive effetc without motor impairment in animals. The analogues MC-D7, MC-D9, and MC-H were safe at the tested doses and efficient in reducing the formalin-induced TMJ hypernociception in rats. Our next steps include determining their mechanisms of anti-nociceptive action.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Isotiocianatos/química , Moringa oleifera/efectos adversos , Moringa oleifera/química , Dolor/tratamiento farmacológico , Analgésicos/efectos adversos , Analgésicos/química , Animales , Antiinflamatorios/efectos adversos , Antiinflamatorios/química , Modelos Animales de Enfermedad , Femenino , Inflamación/metabolismo , Masculino , Ratones , Dolor/metabolismo , Extractos Vegetales/efectos adversos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Articulación Temporomandibular/efectos de los fármacosRESUMEN
Lectins are proteins able to interact specifically and reversibly with carbohydrates. They are present in all living beings, particularly in legume seeds, which have many biological functions. The aim of this study was to isolate, characterize and verify antioxidant, anti-hemolytic, antitumor and gastroprotective activities in a lectin present in seeds of Phaseolus lunatus L. var. cascavel (PLUN). The isolation of lectin was performed by size exclusion chromatography on Sephadex G-100, which was isolated from a protein capable of agglutinating only human erythrocytes type A, being this the only inhibited haemagglutination n-acetyl-d-galactosamine. Its weight was estimated by PAGE is 128kDa. The lectin is thermostable up to 80°C and is active between pH 2-11. As 8M urea was able to denature the lectin. PLUN is a glycoprotein consisting of 2% carbohydrate and has antioxidant action with ascorbic acid equivalent antioxidant capacity (µMAA/g) of 418.20, 326 and 82.9 for total antioxidant activity, ABTS radical capture and capture of DPPH radical, respectively. The lectin has antitumor activity against melanoma derived cells at doses of 100 and 50mg/ml, reducing up to 83% tumor cells, and gastroprotective action, reducing up to 63% damaged area of ââthe stomach induced by ethanol.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antioxidantes/farmacología , Fármacos Gastrointestinales/farmacología , Phaseolus/química , Lectinas de Plantas/farmacología , Úlcera Gástrica/tratamiento farmacológico , Acetilgalactosamina/química , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Benzotiazoles/antagonistas & inhibidores , Benzotiazoles/química , Compuestos de Bifenilo/antagonistas & inhibidores , Compuestos de Bifenilo/química , Línea Celular Tumoral , Eritrocitos/efectos de los fármacos , Etanol , Fármacos Gastrointestinales/química , Fármacos Gastrointestinales/aislamiento & purificación , Pruebas de Hemaglutinación , Humanos , Masculino , Ratones , Peso Molecular , Picratos/antagonistas & inhibidores , Picratos/química , Lectinas de Plantas/química , Lectinas de Plantas/aislamiento & purificación , Desnaturalización Proteica , Semillas/química , Extracción en Fase Sólida/métodos , Estómago/efectos de los fármacos , Estómago/patología , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patología , Ácidos Sulfónicos/antagonistas & inhibidores , Ácidos Sulfónicos/química , Urea/químicaRESUMEN
Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In this study, the protective effect of ω-3 PUFA administration on the 6-hydroxydopamine (6-OHDA) model of PD in rats was investigated. ω-3 PUFA (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4th day, hemiparkinsonism was induced through intrastriatal injection of 6-OHDA. On the 25th day, the animals were submitted to behavioural analysis. On the 28th day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω-3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acid levels on the striatum from hemiparkinsonian rats, followed by reduction in the number of apomorphine-induced rotations and promotion of a partial locomotor recovery. In addition, ω-3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, this study suggests that supplementation with ω-3 PUFAs prevents behavioural and neurochemical disturbances induced by 6-OHDA, presenting a potential neuroprotective action.