RESUMO
Several international guidelines recommend a peri-operative immunonutrition (IN) support for patients care in elective colorectal surgery, to reduce postoperative complications, particularly infections. In Crohn's patients, is also used to mitigate the severity of the disease. We performed a pilot study on 16 Crohn's patients undergoing intestinal surgery for active disease, not responsive to pharmacological treatment; half of them received an oral nutritional supplement enriched with immunonutrients (IN patients) for 7 days prior to surgery, in addition to normal food intake. Markers of oxidative stress (Advanced Glycated End-products (AGEs) and Advanced Oxidation Protein Products (AOPPs) were measured both in plasma and tissue samples wherein the Receptor for Advanced Glycation End products (RAGE) and Tight Junction Protein 1 (TJP1) gene expression were also determined. Plasma AGEs were significantly and positively correlated with tissue levels of AGEs (p = 0.0354) and AOPPs (p = 0.0043) while they were negatively correlated with TJP1 expression (p = 0.0159). The expression of RAGE was also negatively correlated with that of TJP1 gene (p = 0.0146). IN patients exhibited significantly lower AGEs plasma levels (p = 0.0321) and a higher mucosal TJP1 expression (p = 0.0182). No patient had postoperative complications and the length of hospital stay was similar in the two groups, but IN patients, showed a significantly shorter time to resume fluid and solid diet. These preliminary data suggest that IN might support patient's recovery by improving intestinal mucosa barrier function through the regulation of AGEs/RAGE signaling.
Assuntos
Doença de Crohn , Dieta de Imunonutrição , Estresse Oxidativo , Humanos , Produtos da Oxidação Avançada de Proteínas , Doença de Crohn/metabolismo , Doença de Crohn/cirurgia , Produtos Finais de Glicação Avançada/metabolismo , Projetos Piloto , Complicações Pós-Operatórias , Receptor para Produtos Finais de Glicação Avançada/metabolismoRESUMO
Recent studies reported the association between increased risk of nonmelanoma skin cancers (NMSCs) and the use of hydrochlorothiazide (HCTZ), one of the most commonly prescribed diuretic, antihypertensive drug, over the world. Although HCTZ is known to be photosensitizing, the mechanisms involved in its potential prophotocarcinogenic effects remain unclear. Under acute exposure, therapeutically relevant concentrations of HCTZ (70, 140, and 370 ng/mL) amplified UVA-induced double-strand breaks, oxidative DNA, and protein damage in HaCaT human keratinocytes, and this effect was associated to a defective activity of the DNA repair enzyme, OGG1. Oxidative damage to DNA, but not that to proteins, was reversible within few hours. After chronic, combined exposure to HCTZ (70 ng/mL) and UVA (10 J/cm2), for 9 weeks, keratinocytes acquired a dysplastic-like phenotype characterized by a multilayered morphology and alterations in cell size, shape, and contacts. At the ultrastructural level, several atypical and enlarged nuclei and evident nucleoli were also observed. These transformed keratinocytes were apoptosis resistant, exhibited enhanced clonogenicity capacity, increased DNA damage and inflammation, defective DNA repair ability, and increased expression of the oncogene ΔNp63α and intranuclear ß-catenin accumulation (a hallmark of Wnt pathway activation), compared to those treated with UVA alone. None of these molecular, morphological, or functional effects were observed in cells treated with HCTZ alone. All these features resemble in part those of preneoplastic lesions and NMSCs and provide evidence of a biological plausibility for the association among exposure to UVA, use of HCTZ, and increased risk of NMSCs. These results are of translational relevance since we used environmentally relevant UVA doses and tested HCTZ at concentrations that reflect the plasma levels of doses used in clinical practice. This study also highlights that drug safety data should be followed by experimental evaluations to clarify the mechanistic aspects of adverse events.
Assuntos
Dano ao DNA , Hidroclorotiazida/farmacologia , Queratinócitos/metabolismo , Estresse Oxidativo , Neoplasias Cutâneas/prevenção & controle , Raios Ultravioleta/efeitos adversos , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Humanos , Queratinócitos/patologia , Melanoma , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Crohn' disease (CD) patients are at high risk of postoperative recurrence and new tools for the assessment of disease activity are needed to prevent long-term complications. In these patients, the over-production of ROS generated by inflamed bowel tissue and inflammatory cells activates a pathogenic cascade that further exacerbates inflammation and leads to increased oxidative damage to DNA, proteins, and lipids. We measured the products of protein/lipid oxidation and the total antioxidant capacity (ferric reducing ability of plasma, FRAP) in the serum of CD patients with severe disease activity requiring surgery with the aim to characterize their redox status and identify associations between oxidative stress-related markers and their clinical characteristics. At the systemic level, CD was associated with increased levels of protein and lipid oxidation products when compared to healthy volunteers, even though the FRAP values were similar. Advanced oxidation protein product (AOPP) levels showed the highest difference between patients and the controls (11.25, 5.02-15.15, vs. 1.36, 0.75-2.70, median, interquartile range; p < 0.0001) and the analysis of receiver operating characteristic (ROC) curves, indicated for AOPP, the best area under the curve (AUC) value for CD prediction. Advanced glycated end-products (AGEs) were also significantly higher in CD patients (p < 0.01), which is of interest since AOPP and AGEs are both able to activate the membrane receptor for advanced glycation end products (RAGE) involved in inflammatory diseases. Thiobarbituric acid reactive substance (TBARS) levels were significantly higher in CD patients with ileal localization and aggressive disease behavior, in smokers, and in patients suffering from allergies. In conclusion, our data indicate that circulating oxidative stress biomarkers may be attractive candidates as disease predictors as well as for clinical or therapeutic monitoring of CD. Our results also suggest that AOPP/AGEs and RAGE signaling may represent a pathogenic factor and a potential therapeutic target in CD.
RESUMO
The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that ß3-adrenergic receptor (ß3-AR) is involved in tumor progression, playing an important role in metastasis. Among ß-adrenergic receptors, ß3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. ß3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, ß3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that ß3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The ß3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific ß3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of ß3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Células-Tronco Embrionárias/metabolismo , Melanoma/metabolismo , Mitocôndrias/metabolismo , Propanolaminas/farmacologia , Animais , Linhagem Celular , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/patologia , Humanos , Melanoma/patologia , Camundongos , Mitocôndrias/efeitos dos fármacos , Receptores Adrenérgicos beta 3/metabolismoRESUMO
BACKGROUND: Human studies have demonstrated that olive oil phenolic compounds reduce inflammatory markers associated with chronic diseases. OBJECTIVES: To explore the anti-inflammatory effects of extra-virgin olive oil polyphenols in an experimental model of inflammatory bowel disease (IBD). METHODS: HLA-B27 transgenic rats were fed an AIN-76 diet containing 10% corn oil (CO) or extra-virgin olive oil with high (EVOO) or low phenolic content (ROO) for 3 months. Wild-type rats (WT) were fed the CO diet. RESULTS: CO-fed HLA-B27 animals developed intestinal inflammation characterized by diarrhea, increased myeloperoxidase activity, and mucosal injury. None of these parameters were influenced by EVOO. Gene expression profiling indicated that proinflammatory pathways were upregulated in the colon mucosa of CO-fed HLA-B27 rats compared to WT, and this was further confirmed by RT-PCR for the iNOS, TNFα, and IL1ß genes. EVOO significantly reduced TNFα gene expression in the colon mucosa and decreased total cholesterol blood levels compared to CO HLA-B27 rats (89.43 ± 3.66 vs. 111.5 ± 8.10 mg/dL, p < 0.05). This latter effect with EVOO was associated with reduced HMGCR and increased PPAR-α hepatic gene expression, compared to ROO. CONCLUSION: These data indicate that olive oil polyphenols do not control colon inflammation in HLA-B27 transgenic rats but exert a positive effect on blood lipids by reducing total cholesterol levels. This preliminary result suggests the need to explore the efficacy of EVOO rich in polyphenols as a complementary strategy for managing hypercholesterolemia and to potentially limit statin-associated myotoxicity.
Assuntos
Anticolesterolemiantes/farmacologia , Colite/patologia , Hipercolesterolemia/prevenção & controle , Fígado/efeitos dos fármacos , Azeite de Oliva/farmacologia , Polifenóis/farmacologia , Animais , Colite/complicações , Colite/genética , Colo/efeitos dos fármacos , Colo/patologia , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Antígeno HLA-B27/genética , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Inflamação/genética , Inflamação/patologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Fígado/metabolismo , Masculino , PPAR alfa/genética , PPAR alfa/metabolismo , Ratos , Ratos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Electronic cigarettes (e-cigs) are devices designed to deliver nicotine in a vaping solution rather than smoke and without tobacco combustion. Perceived as a safer alternative to conventional cigarettes, e-cigs are aggressively marketed as lifestyle-choice consumables, thanks to few restrictions and a lack of regulatory guidelines. E-cigs have also gained popularity among never-smokers and teenagers, becoming an emergent public health issue. Despite the burgeoning worldwide consumption of e-cigs, their safety remains largely unproven and it is unknown whether these devices cause in vivo toxicological effects that could contribute to cancer. Here we demonstrate the co-mutagenic and cancer-initiating effects of e-cig vapour in a rat lung model. We found that e-cigs have a powerful booster effect on phase-I carcinogen-bioactivating enzymes, including activators of polycyclic aromatic hydrocarbons (PAHs), and increase oxygen free radical production and DNA oxidation to 8-hydroxy-2'-deoxyguanosine. Furthermore, we found that e-cigs damage DNA not only at chromosomal level in peripheral blood, such as strand breaks in leucocytes and micronuclei formation in reticulocytes, but also at gene level such as point mutations in urine. Our results demonstrate that exposure to e-cigs could endanger human health, particularly among younger more vulnerable consumers.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Antioxidantes/metabolismo , Dano ao DNA , Cromatografia Gasosa-Espectrometria de Massas , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Neoplasias/patologia , Oxirredução , Ratos , Espécies Reativas de Oxigênio/metabolismo , Medição de Risco , Fatores de Risco , Compostos Orgânicos Voláteis/efeitos adversos , Compostos Orgânicos Voláteis/análiseRESUMO
Apc-mutated Pirc rats, spontaneously developing intestinal tumours, are resistant to 1,2-dimethylhydrazine- (DMH-) induced colon apoptosis. To understand this phenomenon, we analyzed the expression of genotoxic stress-related genes Mgmt, Gsta1, and Gstp1 in the colon of wt and Pirc rats in basal conditions and 24 h after DMH; plasmatic oxidant/antioxidant status was also evaluated. After DMH, Mgmt expression was increased in both genotypes but significantly only in wt rats; Gsta1 expression was significantly increased in both genotypes. Gstp1 expression did not vary after DMH but was lower in Pirc rats. Moreover, for each genotype, we studied by microarray technique whole gene expression profile after DMH. By unsupervised cluster analysis, 28 genes were differentially modulated between the two genotypes. Among them were interferon-induced genes Irf7, Oas1a, Oasl2, and Isg15 and the transcription factor Taf6l, overexpressed in DMH-treated wt rats and unchanged in Pirc rats. RT-PCR confirmed their overexpression in DMH-treated wt rats and showed a slighter variation in DMH-treated Pirc rats. Taken together, despite a blunted induction of Irf7, Oas1a, and Mgmt, defective apoptosis in Pirc rats 24 h after DMH is not mirrored by major differences in gene expression compared with wt rats.
Assuntos
Apoptose/genética , Carcinogênese/genética , Colo/metabolismo , Mucosa Intestinal/metabolismo , Mutação/genética , Transcriptoma/genética , Animais , Metilases de Modificação do DNA/genética , Genes APC/fisiologia , Variação Genética/genética , Genótipo , Glutationa Transferase/genética , Isoenzimas/genética , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
BACKGROUND: Recently, we showed that Sulindac (SU; 320 ppm) reduces precancerous lesions in the colon of Pirc rats, mutated in the Apc gene. Surprisingly, previous data in Apc-mutated mice showed that SU, with reported efficacy in Familial Adenomatous Polyposis (FAP), increases colon carcinogenesis. Therefore, we assessed the effect of SU 320 ppm in a long-term carcinogenesis experiment in Pirc rats. Moreover, since side effects of SU hamper its chronic use and a combination of drugs could be more effective and less toxic than single agents, we also studied whether two natural compounds, 3,3'-diindolylmethane (DIM; 250 ppm) and curcumin (CUR; 2000 ppm), with or without lower doses of SU could affect carcinogenesis METHODS: Pirc rats were fed an AIN76 diet containing SU, DIM and CUR and sacrificed at 8 months of age to measure intestinal tumours. Apoptosis and proliferation in the normal colon mucosa, as well as gene expression profile were studied RESULTS: Colon tumours were significantly reduced by SU 320 ppm (62 % reduction over Controls), by DIM and CUR without or with SU 80 and 160 ppm (50, 53 and 58 % reduction, respectively) but not by SU 80 ppm alone. Total tumours (colon and small intestine) were reduced by SU (80 and 320 ppm) and by DIM and CUR. Apoptosis in the normal mucosa was significantly increased by SU 320 ppm, and slightly increased by DIM and CUR with or without SU. A slight reduction in Survivin-Birc5 expression was observed with all the treatments compared to Controls. Proliferative activity was not varied CONCLUSIONS: The results on SU reinforce the validity of Pirc rats to identify chemopreventive products. Moreover, the efficacy of the DIM and CUR combination to lower colon tumours, suggests an alternative strategy to be exploited in patients at risk.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Curcumina/administração & dosagem , Genes APC , Indóis/administração & dosagem , Sulindaco/administração & dosagem , Animais , Apoptose , Quimioprevenção/métodos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Dieta , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Mucosa Intestinal/patologia , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Increased reactive oxygen species (ROS) levels produced by hyperglycemia and angiotensin-II (AT-II) are considered among the pathogenic factors in the malignant transformation of diabetic renal cells. We aimed to investigate the potential role of AT-II in the increased cancer risk seen in diabetes; measuring oxidative damage to renal DNA and protective antioxidant defenses, including adiponectin (Adp) and plasma antioxidant capacity by the Ferric Reducing Ability of Plasma (FRAP) method. In the kidney of streptozotocin (STZ)-induced (55 mg/kg) diabetic rats either treated or not treated for 3 weeks with losartan, an AT-II type 1 receptor antagonist (20 mg/kg/day); we measured 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) levels, as an index of oxidative DNA damage, circulating Adp and FRAP. Diabetic rats showed significantly higher 8-oxodGuo levels in renal DNA (8.48 ± 0.98 × 10(-6) dG, mean ± SEM n = 11) than normoglycemic ones (1.18 ± 0.04 × 10(-6) dG, mean ± SEM, n=7) and lower plasma Adp and FRAP levels in comparison to normoglycemics. The treatment of diabetic rats with losartan significantly (P < 0.01) reduced 8-oxodGuo levels (5.4 ± 0.58 × 10(-6) dG, mean ± SEM n=9) in renal DNA and conserved FRAP values. Moreover, an inverse correlation was found between 8-oxodGuo in kidney DNA and circulating Adp levels in normoglycemic and diabetic rats. Losartan treatment preserves FRAP levels, reduces DNA oxidative injury and thus the carcinogenesis risk. Furthermore, our results indicate that Adp plasma levels are a further marker of oxidative injury to the kidney and confirm that it is an important part of the plasma antioxidant defense.
Assuntos
Antioxidantes/química , Dano ao DNA , Diabetes Mellitus Experimental/sangue , Rim/efeitos dos fármacos , Losartan/química , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina , Adiponectina/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , DNA/química , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Diabetes Mellitus Experimental/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Hiperglicemia/tratamento farmacológico , Rim/metabolismo , Lipídeos/química , Malondialdeído/química , Oxigênio/química , Distribuição Aleatória , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
PIRC rats (F344/NTac-Apc (am1137) ) mutated in the Apc gene spontaneously develop colon tumors thus mimicking familial adenomatous polyposis (FAP) and sporadic colorectal cancer (CRC) more closely than Apc-based rodent models developing tumors mostly in the small intestine. To understand whether microscopic dysplastic lesions precede the development of macroscopic tumors, PIRC rat colon was examined for the presence of mucin depleted foci (MDF), microadenomas of the rodent and human colon. Few MDF (about 4/animal) were already present in 1-month-old rats and their number rapidly increases to about 250 in 8-month-old rats. These lesions showed Wnt signaling activation (nuclear ß-catenin accumulation) and were dramatically decreased by sulindac (320 ppm), a drug with chemopreventive activity (MDF/rat at 4 months: 156 ± 8 and 38 ± 6 in controls and sulindac-treated rats, respectively, means ± SE, p < 0.001). Since altered proliferation and apoptosis could underlie the early phases of carcinogenesis, we studied these processes in the apparently normal colon mucosa (NM) of 1-month-old PIRC and wt rats. Colon proliferation (PCNA expression) was significantly higher in PIRC rats. Notably, PIRC rat NM showed resistance to apoptosis since it sustained proliferation and had lower apoptosis after a cytotoxic insult with 1,2 dimethylhydrazine. Gene expression of Myc, p21, Birc5, Ogg1, Apex1 and Sod2 were significantly up-regulated in the NM of PIRC rat. The overall results put forward PIRC rat as useful model of colon carcinogenesis, either to study the process itself or to test in vivo chemopreventive agents in both short- and long-term studies.
Assuntos
Apoptose , Neoplasias do Colo/etiologia , Pólipos do Colo/patologia , Genes APC , Mucinas/fisiologia , Mutação , Animais , Proliferação de Células , Colo/patologia , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Feminino , Genes myc , Masculino , Proteínas Associadas aos Microtúbulos/fisiologia , Ratos , Ratos Endogâmicos F344 , Sulindaco/farmacologia , SurvivinaRESUMO
Type 2 diabetes mellitus (T2DM) and insulin resistance (IR) increase colon cancer risk. Antidiabetic drugs stabilizing incretin hormones, such as inhibitors of dipeptidyl peptidase-4 activity (DPP4i), may affect colon carcinogenesis; however, the data remain controversial. Therefore, the authors studied whether long-term administration of the DPP4i Sitagliptin (SITA) affects 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Male F344 rats fed a high-fat (HF) diet promoting colon carcinogenesis and IR, were induced with DMH (100 mg/kg × 2 times). One week later, the animals were allocated to two groups: one continuing with HF diet (controls; n = 8) and one receiving SITA (n = 8) mixed in the diet (260 ppm). Body weight, food consumption and glycemia were not affected by SITA. Fifteen weeks after DMH, the number of the precancerous lesions mucin-depleted foci (MDF) was significantly lower in rats treated with SITA [MDF/colon: 9.5 ± 0.9 and 6.4 ± 0.9 in controls (n = 8) and SITA groups (n = 8), respectively; means ± SE, p < 0.05]. Reactive oxygen species in the blood were also significantly lower in the SITA group [6.75 ± 0.69 and 5.63 ± 0.75 (H2 O2 in mM) in controls (n = 5) and SITA (n = 6), respectively; means ± SE, p < 0.05]. Rats treated with SITA had a lower DPP4 activity in the intestine but not in the plasma. Intestine growth morphometric parameters and colon proliferation, as proliferating cell nuclear antigen expression, were not affected by SITA. In conclusion, the results suggest a protective effect of DPP4i against colon carcinogenesis that could be exploited in chemoprevention trials.
Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias do Colo/prevenção & controle , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pirazinas/farmacologia , Triazóis/farmacologia , 1,2-Dimetilidrazina , Animais , Peso Corporal/efeitos dos fármacos , Carcinogênese/metabolismo , Neoplasias do Colo/sangue , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Masculino , Mucinas/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Espécies Reativas de Oxigênio/sangue , Fosfato de SitagliptinaRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and painful adverse reaction of cancer treatment in patients that is little understood or treated. Cytotoxic drugs that cause CIPN exert their effects by increasing oxidative stress, which activates the ion channel TRPA1 expressed by nociceptors. In this study, we evaluated whether TRPA1 acted as a critical mediator of CIPN by bortezomib or oxaliplatin in a mouse model system. Bortezomib evoked a prolonged mechanical, cold, and selective chemical hypersensitivity (the latter against the TRPA1 agonist allyl isothiocyanate). This CIPN hypersensitivity phenotype that was stably established by bortezomib could be transiently reverted by systemic or local treatment with the TRPA1 antagonist HC-030031. A similar effect was produced by the oxidative stress scavenger α-lipoic acid. Notably, the CIPN phenotype was abolished completely in mice that were genetically deficient in TRPA1, highlighting its essential role. Administration of bortezomib or oxaliplatin, which also elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyl-lysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or α-lipoic acid could completely prevent hypersensitivity if administered before the cytotoxic drug. Our findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. Furthermore, they suggest prevention strategies for CIPN in patients through the use of early, short-term treatments with TRPA1 antagonists.
Assuntos
Antineoplásicos/toxicidade , Doenças do Sistema Nervoso Periférico/prevenção & controle , Canais de Potencial de Receptor Transitório/antagonistas & inibidores , Acetanilidas/farmacologia , Animais , Ácidos Borônicos/toxicidade , Bortezomib , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organoplatínicos/toxicidade , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Purinas/farmacologia , Pirazinas/toxicidade , Canal de Cátion TRPA1 , Ácido Tióctico/farmacologia , Canais de Potencial de Receptor Transitório/análise , Canais de Potencial de Receptor Transitório/fisiologiaRESUMO
BACKGROUND AND PURPOSE Preclinical pharmacology of 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO. EXPERIMENTAL APPROACH We investigated the effects of injecting T1AM (i.c.v.) on (i) feeding behaviour, hyperglycaemia and plasma levels of thyroid hormones and (ii) T1AM systemic bioavailability, in overnight fasted mice, under control conditions and after pretreatment with the MAO inhibitor clorgyline. T1AM (1.3, 6.6, 13, 20 and 26 µg·kg(-1) ) or vehicle were injected i.c.v. in fasted male mice not pretreated or pretreated i.p. with clorgyline (2.5 mg·kg(-1) ). Glycaemia was measured by a glucorefractometer, plasma triiodothyronine (fT3) by a chemiluminescent immunometric assay, c-fos activation immunohistochemically and plasma T1AM by HPLC coupled to tandem-MS. KEY RESULTS T1AM, 1.3 µg·kg(-1) , produced a hypophagic effect (-24% vs. control) and reduced c-fos activation. This dose showed systemic bioavailability (0.12% of injected dose), raised plasma glucose levels and reduced peripheral insulin sensitivity (-33% vs. control) and plasma fT3 levels. These effects were not linearly related to the dose injected. Clorgyline pretreatment strongly increased the systemic bioavailability of T1AM and prevented the hyperglycaemia and reduction in fT3 induced by T1AM. CONCLUSIONS AND IMPLICATIONS T1AM induces central and peripheral effects including hyperglycaemia and a reduction in plasma fT3 levels in fasted mice. These effects critically depend on the concentration of T1AM or its metabolites in target organs.
Assuntos
Hiperglicemia/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tironinas/farmacologia , Animais , Glicemia/análise , Clorgilina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Exenatida , Jejum/fisiologia , Hiperglicemia/induzido quimicamente , Hipoglicemiantes/farmacologia , Hipotálamo/metabolismo , Resistência à Insulina , Masculino , Camundongos , Inibidores da Monoaminoxidase/farmacologia , Pâncreas/metabolismo , Peptídeos/farmacologia , Glândula Tireoide/metabolismo , Hormônios Tireóideos/sangue , Tironinas/sangue , Tironinas/farmacocinética , Peçonhas/farmacologiaRESUMO
The aim of the present study was to verify whether extra-virgin olive oil, a dietary component naturally containing phenolic antioxidants, has the potential to protect the brain from the deleterious effects of ageing. To accomplish this goal, we used male rats fed a high-energy diet containing either maize oil, or extra-virgin olive oil with high or low phenol content (720 or 10 mg total phenols/kg oil, corresponding to a daily dose of 4 or 0.05 mg total phenols/kg body weight, respectively) from age 12 months to senescence. The measured endpoints were biochemical parameters related to oxidative stress and functional tests to evaluate motor, cognitive and emotional behaviour. Olive oil phenols did not exert major protective actions on motor and cognitive function, as we observed only a tendency to improved motor coordination on the rotarod in the old animals treated with the oil rich in phenols (40 % average increase in the time to first fall; P = 0.18). However, an interesting finding of the present study was a reduced step-through latency in the light-dark box test, found in the older animals upon treatment with the oil rich in antioxidant phenols, possibly indicating an anxiety-lowering effect. This effect was associated with decreased glutathione reductase activity and expression in the brain, a phenomenon previously associated with decreased anxiety in rodents. These results indicate a previously undetected effect of a diet containing an olive oil rich in phenols. Further studies are warranted to verify whether specific food antioxidants might also have an effect on emotional behaviour.
Assuntos
Envelhecimento/fisiologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiologia , Gorduras Insaturadas na Dieta/administração & dosagem , Óleos de Plantas/administração & dosagem , Envelhecimento/efeitos dos fármacos , Animais , Antioxidantes/administração & dosagem , Antioxidantes/análise , Ansiedade/prevenção & controle , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cognição/efeitos dos fármacos , Glutationa Redutase/genética , Glutationa Redutase/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Azeite de Oliva , Estresse Oxidativo/efeitos dos fármacos , Fenóis/administração & dosagem , Óleos de Plantas/química , RNA Mensageiro/análise , Ratos , Ratos Wistar , Aumento de PesoRESUMO
Inflammatory bowel diseases (IBD) are immunomediated ailments affecting millions of individuals. Although diet is regarded as an important factor influencing IBD, there are no accepted dietary recommendations presently available. We administered 7.6 % lyophilised apples obtained from two cultivars (Golden Delicious and Marie Ménard, low and high in polyphenols, respectively) to HLA-B27 transgenic rats which develop spontaneous IBD. After 3 months feeding, rats fed Marie Ménard apples had reduced myeloperoxidase activity (3.6 (sem 0.3) v. 2.2 (sem 0.2) U/g tissue; P < 0.05) and reduced cyclo-oxygenase-2 (P < 0.05) and inducible NO synthase gene expression (P < 0.01) in the colon mucosa and significantly less diarrhoea (P < 0.05), compared with control rats. Cell proliferation in the colon mucosa was reduced significantly by feeding Golden Delicious apples, with a borderline effect of Marie Ménard apples. Gene expression profiling of the colon mucosa, analysed using the Whole Rat Genome 4 x 44 K Agilent Arrays, revealed a down-regulation of the pathways of PG synthesis, mitogen-activated protein kinase (MAPK) signalling and TNFalpha-NF-kappaB in Marie Ménard-fed rats. In the stools of the animals of this group we also measured a significant reduction of bacteria of the Bacteriodes fragilis group. In conclusion, the administration of Marie Ménard apples, rich in polyphenols and used at present only in the manufacturing of cider, ameliorates colon inflammation in transgenic rats developing spontaneous intestinal inflammation, suggesting the possible use of these and other apple varieties to control inflammation in IBD patients.
Assuntos
Colite/dietoterapia , Flavonoides/análise , Antígeno HLA-B27/genética , Malus/química , Fenóis/análise , Animais , Bactérias/isolamento & purificação , Colite/genética , Colite/microbiologia , Colite/patologia , Ciclo-Oxigenase 2/metabolismo , Dieta , Fezes/microbiologia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Mucosa Intestinal/enzimologia , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Peroxidase/metabolismo , Polifenóis , Ratos , Ratos Transgênicos , Especificidade da EspécieRESUMO
The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effects attributed to fruit and vegetable intake. Although their properties have been relatively well studied, the activity of their metabolites, produced after ingestion, has been poorly investigated. Thus, the aim of this work was to study the potential anti-inflammatory effect of 18 polyphenol metabolites, derived from colon microbiota. They were screened by measuring prostaglandin E(2) (PGE(2)) production by CCD-18 colon fibroblast cells stimulated with IL-1beta. Metabolites that inhibited more than 50% PGE(2) production were hydrocaffeic (HCAF), dihydroxyphenyl acetic (dOHPA), and hydroferulic acid (HFER), that subsequently were tested with the writhing and paw pressure test in rodents where all three compounds showed an anti-inflammatory effect. The effect of HCAF administered orally (50 mg/kg) was also tested in the dextran sodium sulfate (DSS)-induced colitis model. Weight loss and fecal water content were more pronounced in DSS rats than in DSS-HCAF treated rats. HCAF treatment diminished the expression of the cytokines IL-1beta, IL-8, and TNF-alpha, reduced malonyldialdehyde (MDA) levels and oxidative DNA damage (measured as 8-oxo-2'-deoxyguanosine levels) in distal colon mucosa. These results indicate that HCAF, dOHPA, and HFER have anti-inflammatory activity in vitro and in vivo.
Assuntos
Anti-Inflamatórios/farmacologia , Bactérias/metabolismo , Colite/tratamento farmacológico , Colo/microbiologia , Flavonoides/farmacologia , Fenóis/farmacologia , Animais , Dinoprostona/biossíntese , Fezes/química , Flavonoides/análise , Masculino , Camundongos , Fenóis/análise , Polifenóis , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Espécies Reativas de OxigênioRESUMO
In addition to the well-known link between smoking and lung cancer, large epidemiological studies have shown a relationship between smoking and cancers of the nose, oral cavity, oropharynx, larynx, esophagus, pancreas, bladder, kidney, stomach, liver, colon and cervix, as well as myeloid leukemia. Epidemiological evidence has reported a direct link between exposure of non-smokers to environmental tobacco smoke and disease, most notably, lung cancer. Much evidence demonstrates that carcinogenic-DNA adducts are useful markers of tobacco smoke exposure, providing an integrated measurement of carcinogen intake, metabolic activation, and delivery to the DNA in target tissues. Monitoring accessible surrogate tissues, such as white blood cells or bronchoalveolar lavage (BAL) cells, also provides a means of investigating passive and active tobacco exposure in healthy individuals and cancer patients. Levels of DNA adducts measured in many tissues of smokers are significantly higher than in non-smokers. While some studies have demonstrated an association between carcinogenic DNA adducts and cancer in current smokers, no association has been observed in ex or never smokers. The role of genetic susceptibility in the development of smoking related-cancer is essential. In order to establish whether smoking-related DNA adducts are biomarkers of tobacco smoke exposure and/or its carcinogenic activity we summarized all data that associated tobacco smoke exposure and smoking-related DNA adducts both in controls and/or in cancer cases and studies where the effect of genetic polymorphisms involved in the activation and deactivation of carcinogens were also evaluated. In the future we hope we will be able to screen for lung cancer susceptibility by using specific biomarkers and that subjects of compared groups can be stratified for multiple potential modulators of biomarkers, taking into account various confounding factors.
Assuntos
Biomarcadores Tumorais/metabolismo , Adutos de DNA/metabolismo , Fumar/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Exposição Ambiental , Humanos , Neoplasias/etiologia , Fumar/efeitos adversosRESUMO
Healthy volunteers (n=50) were enrolled for studying the variation of gene expression induced by smoking in peripheral lymphocytes. RNAs from smokers (>3 cigarettes/day, n=20) and passive smokers (exposed to tobacco smoke >3 h/day, n=10) were hybridized versus a reference pool obtained by mixing equal amounts of RNA from 20 nonsmokers, and gene expression was analyzed using DNA microarrays containing 13,971 oligos. Principal component analysis showed that 99.7% of gene expression variability was related to plasma cotinine, age, and DNA oxidation damage. SAM and GenMAPP/MAPPFinder analyses showed that smokers, compared to nonsmokers, had 129 down-regulated and 87 up-regulated genes, whereas passive smokers, compared to nonsmokers, had 44 down-regulated and 159 up-regulated genes, mainly involved in pathways associated with the activation of defensive responses. Hierarchical cluster analysis identified two distinct clusters of smokers, characterized by different oxidative DNA damage: smokers with high DNA oxidation damage, compared to smokers with low DNA oxidation damage, had a large number (150) of down-regulated genes, mainly associated with xenobiotic metabolism, DNA damage and repair, inflammatory responses, lymphocyte activation, and cytokine activity, suggesting a reduced cellular response to toxic agents in this subset of smokers that could lead to an increased DNA oxidation damage.
Assuntos
Dano ao DNA/fisiologia , Perfilação da Expressão Gênica , Fumar/metabolismo , Poluição por Fumaça de Tabaco , Adolescente , Adulto , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredução , Análise de Componente Principal , Fumar/genética , Poluição por Fumaça de Tabaco/efeitos adversos , Regulação para CimaRESUMO
p-Coumaric acid (3-(4-hydroxyphenyl)-2-propenoic acid; 4CA), is a ubiquitous plant metabolite with antioxidant and anti-inflammatory properties. The antiplatelet activity of this compound was analysed both ex vivo and in vitro. 4-CA, administered to rabbits for 2 weeks at the dose of 5 mg/kg, mixed with food, inhibited ADP-induced platelet aggregation without affecting blood coagulation. This effect was associated with a marked increase in plasma antioxidant activity, measured as ferric reducing ability of plasma, and with the reduction of thromboxane B2 production. The antiplatelet effect was confirmed by in vitro experiments on human blood: 4CA (500 microM and 1 mM) reduced ADP-induced platelet aggregation (55 x 2 (se 4 x 01) % and 35 x 6 (se 2 x 35) % relative to basal level, respectively). 4CA was able to modify platelet function, measured with PFA-100, a shear-inducing device that simulates primary haemostasis. 4CA interfered also with arachidonic acid cascade, reducing thromboxane B2 production and lipopolysaccharide-induced prostaglandin E2 generation (ic50 371 and 126 microM, respectively). The data show that 4CA is an antioxidant compound with good antiplatelet activity at doses that can be obtained with dietary intervention, suggesting possible applications for primary prevention of vascular disease.