ASSOCIAÇÃO ENTRE ALIMENTAÇÃO VEGETARIANA E A PREVENÇÃO DO CÂNCER COLORRETAL: UMA REVISÃO DE LITERATURA

O câncer colorretal representa a neoplasia maligna mais comum do trato gastrointestinal e a terceira causa de morte relacionada ao câncer no mundo. Ele pode ter origem hereditária ou esporádica, sendo esta última responsável por aproximadamente 95% dos casos. Vários fatores de risco contribuem para o desenvolvimento dessa neoplasia, porém, a alimentação parece ser o fator mais influente, pois é capaz de modular a composição da microbiota intestinal. O objetivo desse estudo foi revisar a literatura referente à alimentação e o desencadeamento do câncer colorretal, a relação de uma dieta rica em carnes no desenvolvimento dessa patologia e investigar a alimentação vegetariana atuando como possível fator de prevenção. O método constitui-se de uma revisão bibliográfica narrativa, realizada a partir de buscas de artigos originais e de revisão. O alto consumo de carne vermelha e processada pode estar relacionado com o surgimento de câncer colorretal por causar alterações na microbiota, bem como produzir compostos N-nitrosos, aminas aromáticas policíclicas e hidrocarbonetos aromáticos policíclicos, compostos considerados genotóxicos. Além disso, o ferro heme pode elevar a síntese das espécies reativas de oxigênio e estimular a formação endógena de compostos N-nitrosos. No entanto, a alimentação vegetariana pode ser capaz prevenir a disbiose e manter a microbiota intestinal saudável devido ao consumo elevado de alimentos vegetais que disponibilizam fitoquímicos, antioxidantes e anti-inflamatorios, ou seja, potenciais agentes anti-tumorigênicos. Sugere-se que através de mudanças nos hábitos alimentares e comportamentais, torna-se possível retardar ou prevenir o surgimento de câncer

Mechanisms Involved in the Nociception Triggered by the Venom of the Armed Spider <i>Phoneutria nigriventer</i>

<div><p>Background</p><p> The frequency of accidental spider bites in Brazil is growing, and poisoning due to bites from the spider genus <i>Phoneutria nigriventer</i> is the second most frequent source of such accidents. Intense local pain is the major symptom reported after bites of <i>P. nigriventer</i>, although the mechanisms involved are still poorly understood. Therefore, the aim of this study was to identify the mechanisms involved in nociception triggered by the venom of <i>Phoneutria nigriventer</i> (PNV).</p><p>Methodology/Principal Findings</p><p> Twenty microliters of PNV or PBS was injected into the mouse paw (intraplantar, i.pl.). The time spent licking the injected paw was considered indicative of the level of nociception. I.pl. injection of PNV produced spontaneous nociception, which was reduced by arachnid antivenin (ArAv), local anaesthetics, opioids, acetaminophen and dipyrone, but not indomethacin. Boiling or dialysing the venom reduced the nociception induced by the venom. PNV-induced nociception is not dependent on glutamate or histamine receptors or on mast cell degranulation, but it is mediated by the stimulation of sensory fibres that contain serotonin 4 (5-HT₄) and vanilloid receptors (TRPV1). We detected a kallikrein-like kinin-generating enzyme activity in tissue treated with PNV, which also contributes to nociception. Inhibition of enzymatic activity or administration of a receptor antagonist for kinin B₂ was able to inhibit the nociception induced by PNV. PNV nociception was also reduced by the blockade of tetrodotoxin-sensitive Na⁺ channels, acid-sensitive ion channels (ASIC) and TRPV1 receptors.</p><p>Conclusion/Significance</p><p>Results suggest that both low- and high-molecular-weight toxins of PNV produce spontaneous nociception through direct or indirect action of kinin B₂, TRPV1, 5-HT₄ or ASIC receptors and voltage-dependent sodium channels present in sensory neurons but not in mast cells. Understanding the mechanisms involved in nociception caused by PNV are of interest not only for better treating poisoning by <i>P. nigriventer</i> but also appreciating the diversity of targets triggered by PNV toxins.</p></div

PNV effect on functional TRPV1 channels.

<p>Normalised levels of fluorescence over time from HEK293 cells transfected with rat TRPV1 cDNA and stained with the fluorescent Ca²⁺ probe fluo-4/AM. Capsaicin (A) or PNV (C) were applied in 20 s pulses as indicated by the horizontal bars above the graphs. No Ca²⁺ transient signals were observed for capsaicin or PNV addition in non-transfected cells (insets in A and C). Dose-response curves for capsaicin (B) or PNV (D) on transient calcium signals. When applied to cells twice, both capsaicin (200 nM) (E) and PNV (1 µg/mL) (G) elicited Ca²⁺ transient signals with similar amplitudes. Such response was totally abolished by pre-incubation (300 s) with 10 µM SB366791 (F and H). Points denote mean±S.E.M. of representative plates (10–30 cells, 3 independent experiments).</p

Involvement of TRPV1, ASIC, cyclooxygenase or sodium channels in PNV-induced nociception.

<p>The effect of i.pl. treatment with the acid-sensitive ion channel (ASIC) blocker amiloride (100 nmol/paw, A), the cyclooxygenase inhibitor indomethacin (30 µmol/paw, B), the sodium channel blocker tetrodotoxin (TTX) (20 pmol/paw, C) or the selective TRPV1 antagonist SB366791 (1 nmol/paw, D) on PNV-induced (3 µg/paw, i.pl.) nociception in mice. E) The specific binding of [³H]-resiniferatoxin to spinal cord membranes in the presence or absence of capsaicin (10 µM) or PNV (1.5–150 µg/ml). Each column represents the mean± S.E.M of 5–6 mice (A–D) of 3 experiments carried out in duplicate (E). The asterisks denote the significance levels. *P<0.05, ***P<0.001, compared with the vehicle group (A–D: Student's t-test, E: one-way ANOVA followed by the Student-Newman-Keuls test).</p

Nociception and oedema induced by i.pl. injection of PNV in mice.

<p>(A–B) Time-course (A) and dose-response (B) curves for the ongoing nociception, measured as an increase in amount of time spent licking the injected paw, induced by PNV. (C–D) Time-course (C) and sum (Σ, D) of the pain-related behaviour scores from 0 to 240 minutes after PNV injection. (E) Time-course of the paw oedema caused by i.pl. injection of PNV in mice. Each point or bar on the curve represents the mean±S.E.M or the medians and interquartile ranges of 5–7 animals. The asterisks denote the significance levels. **P<0.01, ***P<0.001 compared with the PBS group (A, E: two-way ANOVA followed Bonferroni's test, B: one-way ANOVA followed by Dunnett's test, C, D: Mann-Whitney U test).</p

Role of tissue kallikrein and kinins in PNV-induced nociception.

<p>The effect of i.pl. treatment with the kallikrein inhibitors aprotinin (10 µg/paw, A) and SBTI (3 µg/paw, B) or the B₂ receptor antagonist HOE140 (3 nmol/paw, D) on PNV-induced (3 µg/paw, i.pl.) nociception in mice. Each column represents the mean± S.E.M of 5–6 mice (A, B and C). The asterisks denote the significance levels. *P<0.05, **P<0.01 compared with the PNV group (A, B, C: Student's t-test).</p

Effect of boiling or dialysing venom in the PNV-induced nociception.

<p>The nociceptive effect produced by i.pl. injection of boiled (A) or dialysed (B) PNV (3 µg/paw) in mice. Each column represents the mean± S.E.M of 6 mice. The asterisks denote the significance levels. **P<0.01, ***P<0.001 compared with the PBS group. ^#P<0.05, ^##P<0.01 compared with the non-boiled or non-dialysed PNV group (one-way ANOVA followed by the Student-Newman-Keuls test).</p

The tissue kallikrein-like activity of PNV <i>in vitro</i>.

<p>The time-course (A) and concentration-response (B) curves of tissue kallikrein-like activity in PNV. (C) The substrate (D-Val-Leu-Arg p-nitroaniline, 0.09–3.00 mM) concentration curve for the kallikrein-like activity of PNV (150 µg/ml). (D) Kinin detection after the incubation of PNV (150 mg/ml) with human high- (HMWK) or low- (LMWK) molecular-weight kininogen (200 nM). (E) The kallikrein-like activity of PNV in the presence or absence of the plasma kallikrein inhibitor SBTI (3 µg/ml) or the tissue kallikrein inhibitor aprotinin (10 µg/ml) or after boiling. Each point or bar represents the mean±S.E.M of 3 experiments carried out in duplicate. The asterisks denote the significance levels. *P<0.05, ***P<0.001, compared with the vehicle group. ^###P<0.001 compared with the vehicle plus PNV group (one-way ANOVA followed by the Student-Newman-Keuls test).</p

Role of glutamate, histamine, serotonin and mast cells in the nociceptive effect triggered by PNV.

<p>The effect of i.pl. treatment with the AMPA/kainate receptor antagonist DNQX (1 nmol/paw, A), the NMDA receptor antagonist MK-801 (1 nmol/paw, B), the 5-HT receptor antagonist metysergide (10 nmol/paw, C), the 5-HT₄ receptor antagonist GR113808 (15 nmol/paw, D), the 5-HT₃ receptor antagonist ondansetron (30 nmol/paw, E), the H₁ receptor antagonist promethazine (3 nmol/paw, i.pl., F) or pre-treatment with compound 48/80 (1, 3, 10 and 10 µg/paw, i.pl., G) on PNV-induced (3 µg/paw, i.pl.) nociception in mice. Each column represents the mean± S.E.M of 6–8 mice. The asterisks denote the significance levels. *P<0.05 compared with the vehicle group (Student's t-test).</p

Clinically used analgesics reduced PNV nociception.

<p>The effect of systemic pre- (A–D) or post-treatment (G–J) with dipyrone (500 mg/kg, i.p., A and G), morphine (10 mg/kg, i.p., B and H), acetaminophen (400 mg/kg, i.p., C and I) or indomethacin (30 mg/kg, i.p., D and J) on PNV-induced (3 µg/paw) nociception in mice. The effect of local co-administration (E–F) or post-treatment (K–M) with lidocaine (0.4 µmol/paw, i.pl., E and K) or arachnid antivenin (ArAv 1∶30, i.pl., F and M) on PNV-induced (3 µg/paw) nociception. Each column represents the mean or median of 6–8 animals, and the vertical lines show the S.E.M. or interquartile ranges *P<0.05, **P<0.01 ***P<0.001 compared with the vehicle group. A–E: Student's t-test and G–M: Mann-Whitney U test, F: one-way ANOVA followed by Dunnett's test.</p