In the search for novel natural compounds effective against visceral nociception, the triterpenoid mixture alpha- and beta-amyrin, isolated from Protium heptaphyllum resin, was assessed in two ...established mouse models of visceral nociception. Mice were pretreated orally with alpha- and beta-amyrin (3, 10, 30, and 100 mg/kg) or vehicle, and the pain-related behavioral responses to intraperitoneal cyclophosphamide or to intracolonic mustard oil were analyzed. The triterpenoid mixture showed a dose-related significant antinociception against the cyclophosphamide-induced bladder pain, and at 100 mg/kg, the nociceptive behavioral expression was almost completely suppressed. Intracolonic mustard oil-induced nociceptive behaviors were maximally inhibited by 10 mg/kg alpha- and beta-amyrin mixture in a naloxone-reversible manner. While pretreatment with ruthenium red (3 mg/kg, s. c.), a non-specific transient receptor potential cation channel V1 (TRPV1) antagonist, also caused significant inhibition, the alpha (2)-adrenoceptor antagonist, yohimbine (2 mg/kg, s. c.), showed no significant effect. The triterpene mixture (10 mg/kg, p. o.) neither altered significantly the pentobarbital sleeping time, nor impaired the ambulation or motor coordination in open-field and rotarod tests, respectively, indicating the absence of sedative or motor abnormalities that could account for its antinociception. These results indicate that the antinociceptive potential of alpha- and beta-amyrin possibly involves the opioid and vanilloid (TRPV1) receptor mechanisms and further suggests that it could be useful to treat visceral pain of intestinal and pelvic origins.
Purpose
Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of ...attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis.
Methods
iNOS-knockout (iNOS
−/−
) and C57BL/6 (WT, wild type) animals (
n
= 5–6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility.
Results
Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS
−/−
mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS
−/−
mice when compared with wild-type animals that were given irinotecan.
Conclusions
This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.
Hydrogen sulphide (H2S) has shown to relax gastrointestinal muscle. Here in, we evaluated the effects of H2S donors on gastric emptying and in pyloric sphincter muscle relaxation, and whether these ...effects involved KATP channels or TRPV1 receptors. Mice were treated with l-cysteine (alone or with propargylglycine-an inhibitor of H2S synthesis), NaHS, Lawesson’s reagent (H2S donors) or saline. After 30min, mice were gavaged with a liquid meal containing a nonabsorbable marker and then killed at 10, 20 or 30min intervals to assess marker recovery from the stomach and intestine. This experiment was repeated in mice pre-treated with KATP channel (glibenclamide) or TRPV1 receptor (capsazepine) antagonists. In addition, pyloric sphincter muscles were mounted in an organ bath, incubated with saline, glibenclamide or capsazepine, and NaHS dose–responses were determined. H2S donors and l-cysteine enhanced gastric emptying in a dose-dependent manner; propargylglycine reversed the effect of l-cysteine. Both glibenclamide and capsazepine abolished l-cysteine and H2S donors’ augmentation of gastric emptying. Dose-dependent inductions of pyloric sphincter relaxation by NaHS were abolished by glibenclamide or capsazepine. These data suggest that H2S donors-induced acceleration of gastric emptying and relaxation of pyloric sphincter muscle by KATP channel and TRPV1 receptor activations.
Background
Bisphosphonates (BF) rise proinflammatory markers and irreversibly bind to bone. Chronically, BF can lead to an inflammatory status and can increase the local oxidative stress in ...periodontium. Therefore, the objective of this study was to evaluate whether the chronic infusion of Zoledronic Acid (ZA) increases inflammatory markers in periodontium of rats.
Methods and results
Chronically, infusion therapy was performed with ZA (0.04, 0.2 or 1 mg/kg or saline) by four doses in over a 70‐day period to analyze periodontium of the first right inferior molar using histologic, histochemical (toluidine blue), and immunohistochemical (CD68, tumor necrosis factor‐α (TNF‐α), interleukin‐1beta (IL‐1β), inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF‐kB)) tests. The experiment was replicated (ZA 0.2 mg/kg versus saline) for myeloperoxidase (MPO) assay and dose TNF‐α, IL‐1β, malondialdehyde (MDA) and glutathione (GSH) in gingiva of the same tooth. Despite there is no alteration in mast cells (P = .608) and CD68 mononuclear‐positive cells (P = .351), in the periodontium of the ZA‐treated group, was observed an increase in the presence of inflammatory cells (P = .001) and cytoplasmic immunostaining for TNF‐α (P = .003), IL‐1b (P = .004), iNOS (P = .008), and NF‐kB (P = .025). Levels of MPO (P < .001), TNF‐α (P = .002), IL‐1β (P < .001), and GSH (P = .005) were augmented in gingiva of ZA‐treated group but MDA (P = .993) levels and NF‐kB nuclear staining (P = .923) were not altered.
Conclusions
Chronic treatment with ZA increase proinflammatory cytokines and the number of inflammatory cells in periodontium of rats and GSH are expressed probably in a compensatory manner.
Oral mucositis is an important dose-limiting and costly side effect of cancer chemotherapy. Soluble proteins obtained of the latex of
Calotropis procera
have been extensively characterized as ...anti-inflammatory in different experimentally induced inflammatory conditions, including arthritis and sepsis. In this study, the phytomodulatory laticifer proteins (LP) were challenged to regress the inflammatory events associated with 5-fluorouracil-induced oral mucositis. We also evaluated the expression of pro-inflammatory cytokines and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Oral mucositis was induced in hamsters by two injections of 5-fluorouracil (5-FU; 60 and 40 mg/kg, i.p., on experimental days 1 and 2, respectively). LP (5 mg/kg, i.p.) was injected 24 h before and 24 h after mechanical trauma of the cheek pouches. A normal control group received only saline. On day 10, the animals were sacrificed, and the cheek pouches were excised for macroscopic and histopathological analysis, myeloperoxidase activity measurement, and immunohistochemical assessment of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), iNOS, and COX-2. LP significantly inhibited macroscopic histopathological scores and myeloperoxidase activity compared with the 5-FU control group. 5-Fluorouracil also induced marked immunostaining of TNF-α, IL-1β, iNOS, and COX-2 on inflamed conjunctive and epithelial tissue compared with the normal control group. Such damage was significantly inhibited (
p
< 0.05) by LP treatment compared with the 5-FU group. These findings demonstrate an anti-inflammatory effect of LP on 5-FU-induced oral mucositis. The protective mechanism appears to involve inhibition of the expression of iNOS, COX-2, TNF-α, and IL-1β.
Background: The passing decision-making performance in volleyball is important because it determines the quality of a team's attack. However, no study has analysed the effect of imagery training on ...passing decision-making performance in young volleyball athletes. Purpose: The objective was to analyse the effect of eight weeks of imagery training on passing decision-making performance. Method: Participants were 33 young male athletes (under 17 years U-17). Participants were randomly assigned to two groups: experimental (EG, n = 17) and control group (CG, n = 16). The CG watched videos of advertisements, while EG participated in the imagery training. A cognitive-general imagery programme was adopted, that asks the athletes to imagine themselves executing passes during a competitive event (e.g. reception of the service with variations of speed and displacement, pass to middle attacker, pass to other attackers, and pass with projection of the body on the ground). The passing decision-making was evaluated in a simulation of a volleyball official game. The analysis of actions was based on the Game Performance Assessment instrument. A heart rate monitor was adopted as an indicator of the autonomic nervous system response during the sessions for the EG and CG. Results: The results revealed a group versus intervention interaction (p < .01) for the passing decision-making, with improvement only in the EG (p = .01). A statistically significant difference in heart rate was identified between the groups (p = .01), with a higher value in the EG. Conclusions: It was concluded that imagery training enhanced passing decision-making performance.
Essential oils from fresh leaves of Eucalyptus urophylla (EOEU) and E. brassiana (EOEB), obtained by hydrodistillation, were orally administered to Swiss male mice 60 min before experimental ...procedures. EOEU and EOEB at either 200 or 400 mg/kg were evaluated for sedative/hypnotic activity through pentobarbital sleeping time, locomotor activity by open-field procedure, and anticonvulsant activity through seizures induced by pentylenetetrazole. EOEU and EOEB were effective in increasing the sleeping time, as well as diminishing ambulation in the open-field test. In addition, EOEU (but not EOEB) significantly increased the number of mice protected against PTZ-induced death. Our results are in accord with the ethnopharmacological use of Eucalyptus species, and, after complementary toxicological studies, could support further investigations to assess their use as sedative agents.
Colorectal cancer (CRC) is a disease with high incidence and mortality. Colonoscopy is a gold standard among tests used for CRC traceability. However, serious complications, such as colon ...perforation, may occur. Non-invasive diagnostic procedures are an unmet need. We aimed to identify a plasma microRNA (miRNA) signature for CRC detection. Plasma samples were obtained from subjects (
= 109) at different stages of colorectal carcinogenesis. The patients were stratified into a non-cancer (27 healthy volunteers, 17 patients with hyperplastic polyps, 24 with adenomas), and a cancer group (20 CRC and 21 metastatic CRC). miRNAs (381) were screened by TaqMan Low-Density Array. A classifier based on four differentially expressed miRNAs (miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p) was able to discriminate cancer versus non-cancer cases. The overexpression of these miRNAs was confirmed by RT-qPCR, and a cross-study validation step was implemented using eight data series retrieved from Gene Expression Omnibus (GEO). In addition, another external data validation using CRC surgical specimens from The Cancer Genome Atlas (TCGA) was carried out. The predictive model's performance in the validation set was 76.5% accuracy, 59.4% sensitivity, and 86.8% specificity (area under the curve, AUC = 0.716). The employment of our model in the independent publicly available datasets confirmed a good discrimination performance in five of eight datasets (median AUC = 0.823). Applying this algorithm to the TCGA cohort, we found 99.5% accuracy, 99.7% sensitivity, and 90.9% specificity (AUC = 0.998) when the model was applied to solid colorectal tissues. Overall, we suggest a novel signature of four circulating miRNAs, i.e., miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p, as a predictive tool for the detection of CRC.
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