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1.
J Nutr ; 151(12): 3678-3688, 2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34590119

RESUMO

BACKGROUND: Obesity increases the colorectal cancer risk, in part by elevating colonic proinflammatory cytokines. Curcumin (CUR) and supplemental vitamin B-6 each suppress colonic inflammation. OBJECTIVES: We examined whether the combination of CUR and vitamin B-6 amplifies each supplement's effects and thereby suppress obesity-promoted tumorigenesis. METHODS: Male Friend Virus B (FVB) mice (4-week-old; n = 110) received 6 weekly injections of azoxymethane beginning 1 week after arrival. Thereafter, they were randomized to receive a low-fat diet (10% energy from fat), a high-fat diet (HFD; 60% energy from fat), a HFD containing 0.2% CUR, a HFD containing supplemental vitamin B-6 (24 mg pyridoxine HCl/kg), or a HFD containing both CUR and supplemental vitamin B-6 (C + B) for 15 weeks. Colonic inflammation, assessed by fecal calprotectin, and tumor metrics were the primary endpoints. The anti-inflammatory efficacy of the combination was also determined in human colonic organoids. RESULTS: HFD-induced obesity produced a 2.6-fold increase in plasma IL-6 (P < 0.02), a 1.9-fold increase in fecal calprotectin (P < 0.05), and a 2.2-fold increase in tumor multiplicity (P < 0.05). Compared to the HFD group, the C + B combination, but not the individual agents, decreased fecal calprotectin (66%; P < 0.01) and reduced tumor multiplicity and the total tumor burden by 60%-80% (P < 0.03) in an additive fashion. The combination of C + B also significantly downregulated colonic phosphatidylinositol-4,5-bisphosphate 3-kinase, Wnt, and NF-κB signaling by 31%-47% (P < 0.05), effects largely absent with the single agents. Observations that may explain how the 2 agents work additively include a 2.8-fold increased colonic concentration of 3-hydroxyanthranillic acid (P < 0.05) and a 1.3-fold higher colonic concentration of the active coenzymatic form of vitamin B-6 (P < 0.05). In human colonic organoids, micromolar concentrations of CUR, vitamin B-6, and their combination suppressed secreted proinflammatory cytokines by 41%-93% (P < 0.03), demonstrating relevance to humans. CONCLUSIONS: In this mouse model, C + B is superior to either agent alone in preventing obesity-promoted colorectal carcinogenesis. Augmented suppression of procancerous signaling pathways may be the means by which this augmentation occurs.


Assuntos
Neoplasias Colorretais , Curcumina , Animais , Masculino , Camundongos , Carcinogênese , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Curcumina/farmacologia , Dieta Hiperlipídica , Suplementos Nutricionais , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Piridoxina , Vitamina B 6/farmacologia , Vitaminas
2.
Carcinogenesis ; 41(7): 909-917, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32115637

RESUMO

Imbalance of the gut microbial community promotes inflammation and colorectal cancer (CRC). Previously, we demonstrated that freeze-dried Parabacteroides distasonis (Pd) suppressed obesity-driven colorectal tumorigenesis in mice. Here, we investigated if Pd could suppress the development of colon tumors in mice independent of obesity. Six-week-old male A/J mice were assigned to receive: (i) chow diet (CTR); (ii) chow with 0.04% wt/wt freeze-dried Pd (Pd-Early) or (iii) chow diet before switching to 0.04% Pd diet (Pd-Late). Mice remained on diet for 25 weeks with the switch for Pd-Late mice occurring after 19 weeks. All mice received 6 weekly injections of the colon carcinogen azoxymethane (AOM; 10 mg/kg I.P.) starting after 1 week on diet. Colon tumors were observed in 77, 55 and 40% in CTR, Pd-Early and Pd-Late mice, respectively (X2 = 0.047). Colonic expression of toll-like receptor 4, IL-4 and TNF-α was 40% (P < 0.01), 58% (P = 0.05) and 55% (P < 0.001) lower, respectively, in Pd-Early compared with CTR mice. Pd-Late mice displayed a 217% (P = 0.05) and 185% (P < 0.001) increase in colonic IL-10 and TGF-ß expression, respectively, compared with CTR mice and similar increases in protein abundances were detected (47-145%; P < 0.05). Pd-Early and Pd-Late mice both demonstrated increased colonic expression of the tight junction proteins Zonula occludens-1 (P < 0.001) and occludin (P < 0.001) at the transcript (2-3-fold; P < 0.01) and protein level (30-50%; P < 0.05) relative to CTR. Our results support a protective role for Pd in colonic tumorigenesis and maintenance of intestinal epithelial barrier in AOM-treated mice.


Assuntos
Azoximetano/farmacologia , Bacteroidetes/genética , Carcinogênese/genética , Neoplasias do Colo/microbiologia , Animais , Bacteroidetes/metabolismo , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Inflamação/genética , Inflamação/microbiologia , Inflamação/patologia , Interleucina-4/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/patologia , Transdução de Sinais/genética , Receptor 4 Toll-Like/genética , Fator de Crescimento Transformador beta/genética
3.
Int J Cancer ; 143(7): 1797-1805, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29696632

RESUMO

Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1ß concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week-old male A/J mice were fed a low-fat (LF) diet, high-fat (HF) diet or HF+ whole freeze-dried Pd (HF + Pd, 0.04% wt/wt) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane. PdMb robustly suppressed the production of pro-inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF + Pd mice (0 of 20) (p = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action.


Assuntos
Azoximetano/toxicidade , Bacteroidetes/fisiologia , Neoplasias do Colo/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Apoptose , Carcinógenos/toxicidade , Proliferação de Células , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos A , Células Tumorais Cultivadas
5.
Physiol Genomics ; 48(8): 545-53, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27317588

RESUMO

Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat (HF) consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and metabolome, and each has the potential to induce protumorigenic changes in the epithelial transcriptome. The physiological consequences and the degree to which these different biologic systems interact remain poorly defined. To understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of HF-fed and genetically obese (DbDb) mice with a genetic predisposition to intestinal tumorigenesis (Apc(1638N)); 266 and 584 genes were differentially expressed in the colonic mucosa of HF and DbDb mice, respectively. These genes mapped to pathways involved in immune function, and cellular proliferation and cancer. Furthermore, Akt was central within the networks of interacting genes identified in both gene sets. Regression analyses of coexpressed genes with the abundance of bacterial taxa identified three taxa, previously correlated with tumor burden, to be significantly correlated with a gene module enriched for Akt-related genes. Similarly, regression of coexpressed genes with metabolites found that adenosine, which was negatively associated with inflammatory markers and tumor burden, was also correlated with a gene module enriched with Akt regulators. Our findings provide evidence that HF consumption and excess adiposity result in changes in the colonic transcriptome that, although distinct, both appear to converge on Akt signaling. Such changes could be mediated by alterations in the colonic microbiome and metabolome.


Assuntos
Colo/metabolismo , Colo/patologia , Microbioma Gastrointestinal/fisiologia , Neoplasias Intestinais/metabolismo , Metaboloma/fisiologia , Obesidade/patologia , Transcriptoma/fisiologia , Adiposidade/fisiologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Colo/microbiologia , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Neoplasias Intestinais/microbiologia , Neoplasias Intestinais/patologia , Camundongos , Obesidade/metabolismo , Obesidade/microbiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Carga Tumoral/fisiologia
6.
Gut Microbes ; 15(2): 2288187, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38031252

RESUMO

Aging is a strong risk factor for colorectal cancer (CRC). It is well established that gut microbial dysbiosis can play a role in the etiology of CRC. Although the composition of the gut microbial community changes with age and is reported to become more pro-inflammatory, it is unclear whether such changes are also pro-tumorigenic for the colon. To address this gap, we conducted fecal microbiota transplants (FMT) from young (DY, ~6 wk) and old (DO, ~72 wk) donor mice into young (8 wk) recipient mice that were pre-treated with antibiotics. After initiating tumorigenesis with azoxymethane, recipients were maintained for 19 wk during which time they received monthly FMT boosters. Compared to recipients of young donors (RY), recipients of old donors (RO) had an approximately 3-fold higher prevalence of histologically confirmed colon tumors (15.8 vs 50%, Chi2 P = .03), approximately 2-fold higher proliferating colonocytes as well as significantly elevated colonic IL-6, IL-1ß and Tnf-α. Transcriptomics analysis of the colonic mucosa revealed a striking upregulation of mitochondria-related genes in the RO mice, a finding corroborated by increased mitochondrial abundance. Amongst the differences in fecal microbiome observed between DY and DO mice, the genera Ruminoclostridium, Lachnoclostridium and Marvinbryantia were more abundant in DY mice while the genera Bacteroides and Akkermansia were more abundant in DO mice. Amongst recipients, Ruminoclostridium and Lachnoclostridium were higher in RY mice while Bacteroides was higher in RO mice. Differences in fecal microbiota were observed between young and old mice, some of which persisted upon transplant into recipient mice. Recipients of old donors displayed significantly higher colonic proliferation, inflammation and tumor abundance compared to recipients of young donors. These findings support an etiological role for altered gut microbial communities in the increased risk for CRC with increasing age and establishes that such risk can be transmitted between individuals.


Assuntos
Neoplasias do Colo , Microbioma Gastrointestinal , Microbiota , Camundongos , Animais , Azoximetano/toxicidade , Transplante de Microbiota Fecal , Inflamação , Carcinogênese , Proliferação de Células
7.
J Nutr ; 142(8): 1554-60, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22739363

RESUMO

The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene differs in frequency in various ethnic groups that have differing prevalence of age-related cognitive impairments. We used a series of neuro-psychological tests to examine the association of the MTHFR C677T polymorphism with cognition and depression and also to assess whether genotype modifies the association of folate and homocysteine with these outcomes. This study analyzed pooled cross-sectional data from 2 ethnically diverse cohorts of community-living adults: the Boston Puerto Rican Health Study (n = 939) and the Nutrition, Aging, and Memory in Elders study (n = 1017). Individuals in both cohorts underwent anthropometric and laboratory measurements and dietary and health assessments using validated questionnaires between the years 2003 and 2007. Cognitive outcomes included measures of global cognition [Mini-Mental Status Exam (MMSE)], depression (Center for Epidemiological Studies Depression Scale), and 3 factor scores for the domains of attention, executive function, and memory that were derived from a detailed set of neuropsychological tests. Low plasma vitamin B-12 concentrations were associated with poorer MMSE scores and higher depression scores, and low vitamin B-6 concentrations were associated with lower MMSE and worse attention and executive function in the multivariate analysis. In contrast, MTHFR genotype, folate, and homocysteine were not associated with cognition or depression in either ethnicity-pooled or stratified analysis. The current study did not find evidence of an association between the MTHFR C677T TT genotype and impaired cognition or depression in a population with adequate folate status and a high prevalence of cognitive impairment and depression.


Assuntos
Ácido Fólico/sangue , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo Genético , Vitamina B 12/sangue , Vitamina B 6/sangue , Adulto , Idoso , Transtornos Cognitivos/sangue , Transtornos Cognitivos/genética , Estudos de Coortes , Estudos Transversais , Depressão/sangue , Depressão/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade
8.
FASEB J ; 25(9): 3136-45, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21646397

RESUMO

The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically related B vitamins induces in vivo activation of intestinal Wnt signaling and whether this occurs in parallel with increased tumorigenesis. A hybrid mouse was created by crossing a Wnt-reporter animal (BAT-LacZ) with a model of colorectal cancer (Apc1638N). A mild depletion of folate and vitamins B2, B6, and B12 was induced over 16 wk, and the control animals in each instance were pair fed a diet containing the basal requirement of these nutrients. The multiplicity of macroscopic tumors and aberrant crypt foci both increased by ~50% in the hybrid mice fed the depletion diet (P<0.05). A 4-fold elevation in Wnt signaling was produced by the depletion diet (P<0.05) and was accompanied by significant changes in the expression of a number of Wnt-related genes in a pattern consistent with its activation. Proliferation and apoptosis of the colonic mucosa both changed in a protransformational direction (P<0.05). In summary, mild depletion of multiple B vitamins produces in vivo activation of colonic Wnt signaling, implicating it as a key pathway by which B-vitamin inadequacies enhance intestinal tumorigenesis.


Assuntos
Neoplasias Colorretais/etiologia , Óperon Lac/fisiologia , Transdução de Sinais/fisiologia , Deficiência de Vitaminas do Complexo B/complicações , Proteínas Wnt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular , Proliferação de Células , Colo/citologia , Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Dieta , Células Epiteliais , Regulação da Expressão Gênica/fisiologia , Genes Reporter , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Óperon Lac/genética , Camundongos , Deficiência de Vitaminas do Complexo B/sangue , Deficiência de Vitaminas do Complexo B/metabolismo
9.
Gut ; 60(12): 1695-702, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21659408

RESUMO

OBJECTIVE: Variations in the intake of folate are capable of modulating colorectal tumorigenesis; however, the outcome appears to be dependent on timing. This study sought to determine the effect of altering folate (and related B vitamin) availability during in-utero development and the suckling period on intestinal tumorigenesis. DESIGN: Female wildtype mice were fed diets either mildly deficient, replete or supplemented with vitamins B(2), B(6), B(12) and folate for 4 weeks before mating to Apc(1638N) males. Females remained on their diet throughout pregnancy and until weaning. After weaning, all Apc(1638N) offspring were maintained on replete diets for 29 weeks. RESULTS: At 8 months of age tumour incidence was markedly lower among offspring of supplemented mothers (21%) compared with those of replete (59%) and deficient (55%) mothers (p=0.03). Furthermore, tumours in pups born to deficient dams were most likely to be invasive (p=0.03). The expression of Apc, Sfrp1, Wif1 and Wnt5a--all of which are negative regulatory elements of the Wnt signalling cascade--in the normal small intestinal mucosa of pups decreased with decreasing maternal B vitamin intake, and for Sfrp1 this was inversely related to promoter methylation. ß-Catenin protein was elevated in offspring of deficient dams. CONCLUSIONS: These changes indicate a de-repression of the Wnt pathway in pups of deficient dams and form a plausible mechanism by which maternal B vitamin intake modulates tumorigenesis in offspring. These data indicate that maternal B vitamin supplementation suppresses, while deficiency promotes, intestinal tumorigenesis in Apc(1638N) offspring.


Assuntos
Neoplasias Colorretais/prevenção & controle , Suplementos Nutricionais , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Complexo Vitamínico B/farmacologia , Deficiência de Vitamina D/complicações , Animais , Animais Recém-Nascidos , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Modelos Animais de Doenças , Feminino , Ácido Fólico/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Gravidez , Riboflavina/farmacologia , Vitamina B 12/farmacologia , Vitamina B 6/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
10.
Psychosom Med ; 73(5): 385-92, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21597034

RESUMO

OBJECTIVE: To examine the associations between variants of genes involved in the uptake, retention, and metabolism of folate and depressive symptoms and to analyze whether such associations are direct or through mediation by folate or homocysteine. METHODS: We performed a cross-sectional analysis of data from 976 Puerto Rican adults, aged 45 to 75 years, residing in the greater Boston area, Massachusetts. Twelve single nucleotide polymorphisms (SNPs) in genes involved in folate uptake, retention, and metabolism were investigated. These include FOLH1 (folate hydrolase), FPGS (folate polyglutamate synthase), GGH (γ-glutamyl hydrolase), MTHFR (methylenetetrahydrofolate reductase), MTR (methionine synthase), PCFT (proton-coupled folate transporter), and RFC1 (reduced folate carrier 1). The Center for Epidemiologic Studies Depression Scale (CES-D) was used to measure depressive symptoms. RESULTS: The FOLH1 rs61886492 C>T (or 1561C>T) polymorphism was significantly associated with lower CES-D score (p = .0025) after adjusting for age, sex, population admixture, smoking, and educational attainment. Individuals with the TT and TC genotypes were 49% less likely (odds ratio = 0.51, 95% confidence interval = 0.29-0.89) to report mild depressive symptoms (CES-D score ≥16 and ≤26) and 64% less likely (odds ratio = 0.36, 95% confidence interval = 0.18-0.69) to report moderate to severe depressive symptoms (CES-D score >26), compared with those with the CC genotype. No significant mediation effects by plasma folate or homocysteine on the associations between this single nucleotide polymorphism and CES-D score were observed. CONCLUSIONS: The FOLH1 1561C>T polymorphism may be associated with the risk of depressive symptoms.


Assuntos
Depressão/genética , Ácido Fólico/genética , Glutamato Carboxipeptidase II/genética , Polimorfismo de Nucleotídeo Único/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Adulto , Idoso , Boston/epidemiologia , Estudos Transversais , Depressão/sangue , Depressão/epidemiologia , Feminino , Receptor 1 de Folato/genética , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/sangue , Deficiência de Ácido Fólico/epidemiologia , Frequência do Gene , Genótipo , Homocisteína/sangue , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Transportador de Folato Acoplado a Próton/genética , Escalas de Graduação Psiquiátrica , Ácidos Pteroilpoliglutâmicos/genética , Porto Rico/etnologia , Fosfato de Piridoxal/sangue , Proteína Carregadora de Folato Reduzido/genética , Vitamina B 12/sangue , gama-Glutamil Hidrolase/genética
11.
J Nutr ; 141(4): 654-9, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21270364

RESUMO

Although methylenetetrahydrofolate reductase (MTHFR) genetic variants are associated with plasma homocysteine (Hcy) and cardiovascular disease (CVD), little is known whether dietary fatty acid intake modulates these associations. The goal was to examine the interaction of MTHFR variants with dietary fatty acids influencing plasma Hcy in 995 Boston Puerto Rican adults. We found that plasma Hcy concentration was negatively correlated with (n-3) PUFA intake (r = -0.117; P = 0.022), and the ratio of (n-3):(n-6) PUFA in the diet (r = -0.122; P = 0.009). Further, 2 functional MTHFR variants, 1298A>C and 677C>T, which are not in linkage disequilibrium in this population, were significantly associated with hypertension (OR = 1.72, P = 0.024, and OR = 1.60, P = 0.002, respectively). In addition, the 1298A>C variant was significantly associated with CVD (OR = 3.32; P = 0.030). Importantly, this variant exhibited significant interactions with intakes of total and (n-6) PUFA and the (n-3):(n-6) PUFA ratio of the diet. The plasma Hcy concentration of carriers of risk allele 1298C was greater than that of noncarriers only when participants had consumed a high-PUFA diet (>7.8% energy) but was not greater when they had low intake of PUFA (≤7.8% energy). In addition, participants with combined genotypes of both SNP (677 TT with 1298 AC or CC) who consumed high levels of (n-3) PUFA (>0.66% energy) had lower plasma Hcy compared with those who had the same genotype and consumed low levels of (n-3) PUFA (≤0.66% energy). Our study suggests that dietary PUFA intake modulates the effect of 2 MTHFR variants on plasma Hcy in Boston Puerto Rican adults.


Assuntos
Doenças Cardiovasculares/genética , Gorduras na Dieta/administração & dosagem , Ácidos Graxos Insaturados/administração & dosagem , Homocisteína/sangue , Hipertensão/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Feminino , Genótipo , Humanos , Hipertensão/sangue , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Mutagenesis ; 26(1): 193-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21164202

RESUMO

DNA damage is a fundamental cause of developmental and degenerative diseases. The in vitro cytokinesis-block micronucleus cytome (CBMN-Cyt) assay is an established comprehensive method for assessing cytostasis and chromosome stability in cells. Originally developed to study the acute effects of single environmental genotoxicants, creative applications and adaptations to the basic protocol have allowed its use in evaluating the impacts of dietary micronutrients and micronutrient combinations (nutriomes) on DNA damage. In this review, we examine some of these studies and the important findings they have generated with respect to nutrient/nutrient, nutrient/genotype and nutrient/genotoxicant interactions, as well as assessment of the carcinogenic (or protective) potential of whole dietary patterns. In addition, we outline current knowledge gaps and technical limitations and propose future adaptations to enhance the applicability of the CBMN-Cyt method for in vivo predictions.


Assuntos
Dano ao DNA/efeitos dos fármacos , Alimentos , Micronúcleos com Defeito Cromossômico , Micronutrientes/administração & dosagem , Necessidades Nutricionais , Animais , Células Cultivadas , Dieta , Raios gama , Humanos , Testes para Micronúcleos , Ratos
13.
Public Health Nutr ; 14(10): 1805-12, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21338559

RESUMO

OBJECTIVE: To investigate genetic and lifestyle factors and their interactions on plasma homocysteine (Hcy) concentrations in the Boston Puerto Rican population. DESIGN: Cross-sectional study. Plasma concentrations of Hcy, folate, vitamin B12 and pyridoxal phosphate were measured, and genetic polymorphisms were determined. Data on lifestyle factors were collected in interviews. SETTING: A population survey of health and nutritional measures. SUBJECTS: A total of 994 Puerto Rican men and women residing in the Boston metropolitan area. RESULTS: Smoking status was positively associated with plasma Hcy. Genetic polymorphisms MTHFR 677C→T, FOLH1 1561C→T, FOLH1 rs647370 and PCFT 928A→G interacted significantly with smoking for Hcy. MTHFR 1298A→C (P = 0·040) and PCFT 928A→G (P = 0·002) displayed significant interactions with alcohol intake in determining plasma Hcy. Subjects with PCFT 928GG genotype had significantly higher plasma Hcy concentrations compared with carriers of the A allele (AA+AG; P = 0·030) among non-drinking subjects. When consuming alcohol, GG subjects had lower plasma Hcy levels compared with AA+AG subjects. Physical activity interacted significantly with MTR 2756A→G in determining plasma Hcy (P for interaction = 0·002). Smoking interacted with physical activity for plasma Hcy (P for interaction = 0·023). CONCLUSIONS: Smoking and drinking were associated plasma Hcy concentrations. Genetic variants involved in folate metabolism further modify the effects of lifestyle on plasma Hcy.


Assuntos
Ácido Fólico/sangue , Interação Gene-Ambiente , Homocisteína/sangue , Estilo de Vida/etnologia , Polimorfismo de Nucleotídeo Único , Idoso , Consumo de Bebidas Alcoólicas/etnologia , Alelos , Boston , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Glutamato Carboxipeptidase II/genética , Glutamato Carboxipeptidase II/metabolismo , Humanos , Modelos Lineares , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Atividade Motora , Transportador de Folato Acoplado a Próton/genética , Transportador de Folato Acoplado a Próton/metabolismo , Porto Rico/etnologia , Fatores Sexuais , Fumar/etnologia , Vitamina B 12/sangue
14.
Front Public Health ; 9: 789402, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34976934

RESUMO

Repeated testing of a population is critical for limiting the spread of the SARS-CoV-2 virus and for the safe reopening of educational institutions such as kindergarten-grade 12 (K-12) schools and colleges. Many screening efforts utilize the CDC RT-PCR based assay which targets two regions of the novel Coronavirus nucleocapsid gene. The standard approach of testing each person individually, however, poses a financial burden to these institutions and is therefore a barrier to using testing for re-opening. Pooling samples from multiple individuals into a single test is an attractive alternate approach that promises significant cost savings-however the specificity and sensitivity of such approaches needs to be assessed prior to deployment. To this end, we conducted a pilot study to evaluate the feasibility of analyzing samples in pools of eight by the established RT-PCR assay. Participants (1,576) were recruited from amongst the Tufts University community undergoing regular screening. Each volunteer provided two swabs, one analyzed separately and the other in a pool of eight. Because the positivity rate was very low, we spiked approximately half of the pools with laboratory-generated swabs produced from known positive cases outside the Tufts testing program. The results of pooled tests had 100% correspondence with those of their respective individual tests. We conclude that pooling eight samples does not negatively impact the specificity or sensitivity of the RT-PCR assay and suggest that this approach can be utilized by institutions seeking to reduce surveillance costs.


Assuntos
COVID-19 , RNA Viral , Humanos , Projetos Piloto , SARS-CoV-2 , Instituições Acadêmicas , Manejo de Espécimes
15.
Mol Nutr Food Res ; 63(8): e1801097, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30680927

RESUMO

SCOPE: High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways. METHODS AND RESULTS: A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways. CONCLUSION: These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.


Assuntos
Anticarcinógenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/prevenção & controle , Obesidade/complicações , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/etiologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Curcumina/administração & dosagem , Curcumina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos , Obesidade/etiologia , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/metabolismo , Salicilatos/administração & dosagem , Salicilatos/farmacologia , Transdução de Sinais/efeitos dos fármacos
16.
Int J Cancer ; 123(3): 519-25, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18498130

RESUMO

Folate is required for biological methylation and nucleotide synthesis, aberrations of which are thought to be the mechanisms that enhance colorectal carcinogenesis produced by folate inadequacy. These functions of folate also depend on the availability of other B-vitamins that participate in "one-carbon metabolism," including B2, B6 and B12. Our study therefore investigated whether combined dietary restriction of these vitamins amplifies aberrations in the epigenetic and genetic integrity of the p53 gene that is induced by folate depletion alone. Ninety-six mice were group pair-fed diets with different combinations of B-vitamin depletion over 10 weeks. DNA and RNA were extracted from epithelial cells isolated from the colon. Within the hypermutable region of p53 (exons 5-8), DNA strand breaks were induced within exons 6 and 8 by folate combined with B2, B6 and B12 restriction (p < 0.05); such effects were not significantly induced by mild folate depletion alone. Similarly, a minor degree of hypomethylation of exon 6 produced by isolated folate depletion was significantly amplified (p < or = 0.05) by simultaneous depletion of all 4 B-vitamins. Furthermore, the expression of p53 and MDM2 were significantly decreased (p < or = 0.05) by the combined depletion state but not by folate depletion alone. These data indicate that inadequacies of other 1-carbon vitamins may amplify aberrations of the p53 gene induced by folate depletion alone, implying that concurrent inadequacies in several of these vitamins may have added tumorigenic potential beyond that observed with isolated folate depletion.


Assuntos
Deficiência de Ácido Fólico/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Complexo Vitamínico B/metabolismo , Deficiência de Vitaminas do Complexo B/metabolismo , Animais , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
17.
J Nutr Biochem ; 19(5): 328-35, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17681772

RESUMO

Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell lines derived from the normal human colon, HCEC, NCM356 and NCM460, were grown for 32-34 days in media containing 25, 50, 75 or 150 nM folic acid, and the expression of genes involved in cell-cycle checkpoints, intracellular signaling, folate uptake and cell adhesion and migration was determined. Expression of Folate Receptor 1 was increased with decreasing media folate in all cell lines, as was p53, p21, p16 and beta-catenin. With decreasing folate, the expression of both E-cadherin and SMAD-4 was decreased in NCM356. APC was elevated in NCM356 but unchanged in the other lines. No changes in global methylation were detected. A significant increase in p53 exon 7-8 strand breaks was observed with decreasing folate in NCM460 cells. The changes observed are consistent with DNA damage-induced activation of cell-cycle checkpoints and cellular adaptation to folate depletion. Folate-depletion-induced changes in the Wnt/APC pathway as well as in genes involved in cell adhesion, migration and invasion may underlie observed relationships between folate status and cancer risk.


Assuntos
Colo/citologia , Células Epiteliais/metabolismo , Deficiência de Ácido Fólico/genética , Deficiência de Ácido Fólico/metabolismo , Ácido Fólico/metabolismo , Regulação da Expressão Gênica , Genes cdc , Transdução de Sinais , Adulto , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quebras de DNA/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Ácido Fólico/análise , Deficiência de Ácido Fólico/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes p53/genética , Humanos , Transdução de Sinais/efeitos dos fármacos , Complexo Vitamínico B/farmacologia
18.
J Interferon Cytokine Res ; 38(10): 445-451, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30328795

RESUMO

Obesity is a prominent risk factor for colorectal cancer (CRC). One mechanism by which obesity promotes the development of CRC is by generating a chronic, low-grade state of colonic inflammation. Interleukin-1ß (IL-1ß), a proinflammatory cytokine often elevated in obesity, is known to activate several procarcinogenic signaling pathways that are implicated in colonic carcinogenesis. We therefore sought to define the role of IL-1ß in mediating some of the early biochemical and molecular events leading up to obesity-promoted CRC. Twenty-five wild-type (WT) C57BL/6J mice and 24 lacking a functional IL-1 receptor (IL1R-/-) were each randomized to either low-fat or high-fat diets, resulting in lean and obese mice. Compared to WT lean controls, WT obese mice displayed 30%-80% greater concentrations of IL-1ß and tumor necrosis factor-α (TNF-α) in the colonic mucosa (IL-1ß: P = 0.04; TNF-α: P < 0.05), activation of the Wnt signaling cascade [evidenced by a 2-fold increase in colonic crypt cells displaying intranuclear ß-catenin (P < 0.03)], and a significant expansion of the proliferation zone of the colonic crypt (P < 0.04). These obesity-induced alterations in colonic cytokines, Wnt signaling, and proliferation were absent in the obese IL1R-/- mice. In the absence of IL-1 signaling, obesity-induced elevations of colonic IL-1ß, TNF-α, Wnt activation, and enhanced epithelial proliferation no longer occur. These observations underscore the important mechanistic roles that IL-1 signaling appears to play in mediating the procancerous effects of obesity in the colon, thereby identifying a potential target for future strategies aimed at chemoprevention.


Assuntos
Colo/imunologia , Células Epiteliais/imunologia , Inflamação/imunologia , Interleucina-1/imunologia , Obesidade/imunologia , Transdução de Sinais/imunologia , Animais , Proliferação de Células , Colo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Interleucina-1/deficiência , Receptores de Interleucina-1/imunologia , Via de Sinalização Wnt/imunologia
19.
Cancer Epidemiol Biomarkers Prev ; 27(12): 1416-1423, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30291114

RESUMO

BACKGROUND: Obesity, a risk factor for colorectal cancer, raises systemic levels of proinflammatory mediators. Whether increased levels also reside in the colons of obese individuals and are accompanied by procancerous alterations in the mucosal transcriptome is unknown. METHODS: Concentrations of TNFα, IL1ß, and IL6 in blood and colonic mucosa of 16 lean and 26 obese individuals were examined. Differences in the mucosal transcriptome between the two groups were defined. RESULTS: Plasma IL6 and TNFα were 1.4- to 3-fold elevated in obese subjects [body mass index (BMI) ≥ 34 kg/m2] compared with the lean controls (P < 0.01). Among individuals with BMI ≥ 34 kg/m2 colonic concentrations of IL6 and TNFα were 2- to 3-fold greater than in lean subjects (P < 0.03). In a general linear model, adjusted for NSAID use, colonic IL6 (partial r = 0.41; P < 0.01) and TNFα (partial r = 0.41; P = 0.01) increased incrementally over the entire range of BMIs (18.1-45.7). Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with a reduction in colonic IL6 (ß = -0.65, P < 0.02). RNA sequencing (NSAID users excluded) identified 182 genes expressed differentially between lean and obese subjects. The two gene networks most strongly linked to changes in expression included several differentially expressed genes known to regulate the procarcinogenic signaling pathways, NFκB and ERK 1/2, in a pattern consistent with upregulation of each in the obese subjects. CONCLUSIONS: Incremental increases in two major proinflammatory colonic cytokines are associated with increasing BMI, and in the obese state are accompanied by procancerous changes in the transcriptome. IMPACT: These observations delineate means by which an inflammatory milieu may contribute to obesity-promoted colon cancer.


Assuntos
Adiposidade/genética , Colo/metabolismo , Interleucina-6/metabolismo , Obesidade/complicações , Fator de Necrose Tumoral alfa/metabolismo , Idoso , Colo/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transcriptoma
20.
J Nutr ; 137(12): 2701-8, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18029487

RESUMO

Preclinical and clinical studies suggest that diminished folate status increases the risk of colorectal carcinogenesis. However, many biochemical functions of folate are dependent on the adequate availability of other 1-carbon nutrients, including riboflavin, vitamin B-6, and vitamin B-12. Aberrations in the Wnt pathway are thought to play an important role in human colorectal cancers. This study therefore investigated if mild depletion of folate combined with depletion of riboflavin, vitamin B-6, and vitamin B-12 could induce alterations in the Wnt pathway in the colonic mucosa. Ninety-six mice were pair-fed diets with different combinations of B vitamin depletion for 10 wk. Genomic DNA methylation and uracil misincorporation were measured by LC/MS and GC/MS. Gene-specific methylation, strand breaks, and expressions were measured by real-time PCR and immunoblotting. Proliferation and apoptosis were determined by immunohistochemistry. DNA strand breaks within the Apc mutation cluster region were induced by folate depletion combined with inadequacies of riboflavin, vitamin B-6, and vitamin B-12 (P < 0.05), but such effects were not induced by folate depletion alone. Similarly, minor changes in the expression of Apc, beta-catenin, and cyclin D1 produced by mild folate depletion were significantly magnified by multiple vitamin depletion. Apoptosis, which can be suppressed by increased Wnt-signaling, was attenuated by the combined deficiency state (P < 0.05) but not by singlet or doublet deficiencies. These findings indicate that a mild depletion of folate that is of insufficient magnitude by itself to induce alterations in components of the Wnt pathway may produce such effects when present in conjunction with mild inadequacies of other 1-carbon nutrients.


Assuntos
Colo/metabolismo , Dieta , Deficiência de Ácido Fólico , Ácido Fólico/farmacologia , Complexo Vitamínico B/sangue , Proteínas Wnt/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células , Colo/citologia , Colo/efeitos dos fármacos , Ciclina D , Ciclinas/genética , Ciclinas/metabolismo , Dano ao DNA , Ácido Fólico/sangue , Regulação da Expressão Gênica , Genes APC , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Regulação para Cima , Complexo Vitamínico B/metabolismo
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