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USA Sweden study found strong inverse associations between quercetin and the risk of noncardia gastric adenocarcinoma cancer
- Thread starter ginfreely
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Abstract
Background: To study the impact of the dietary antioxidant quercetin on risk of gastric adenocarcinoma.Patients and methods: Using data from a large Swedish population-based case–control study of gastric cancer (505 cases and 1116 controls), we studied the association between quercetin and risk of anatomic (cardia/noncardia) and histological (intestinal and diffuse) subtypes of gastric cancer.
Results: We found strong inverse associations between quercetin and the risk of noncardia gastric adenocarcinoma, with an adjusted odds ratio (OR) of 0.57 (95% confidence interval 0.40–0.83) for the highest quintile (≥11.9 mg) of daily quercetin intake relative to the lowest quintile of intake (<4 mg quercetin/day), supported by a significant decreasing linear trend (Pvalue < 0.001). Similar findings were observed for the intestinal and diffuse subtype. For cardia cancer, we found a less evident and nonsignificant inverse relationship. The protection of quercetin appeared to be stronger among female smokers, with the OR leveled of at values <0.2 in quintiles 3–5 (>6 mg quercetin/day).
Conclusions: High dietary quercetin intake is inversely related to the risk of noncardia gastric adenocarcinoma, and the protection appears to be particularly strong for women exposed to oxidative stress, such as tobacco smoking.
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introduction
Stomach cancer is the fourth most common cancer and the second most common cause of cancer death worldwide [1]. The huge geographic and gender discrepancies (gastric cancer being eight times more common among Asian men than among North American women) indicate the importance of lifestyle and environmental factors, as well as the potential for prevention through change in exposures. Prevention opportunities are particularly important, given the dismal overall prognosis and the nature of the disease making early diagnosis rare [2, 3]. Since Helicobacter pylori infection was proposed as a necessary cause of noncardia gastric cancer [4–6] through inflammation and oxidative stress [7–9], the role of bioactive redox substances has emerged as highly relevant. While contrasting results from intervention trials have cast doubt on the positive influence of antioxidants on human health [10] and gastric cancer prevention [11, 12], only a few antioxidants (mainly β-carotene, vitamins A, C and E), out of the hundreds present in plant foods, have actually been investigated thoroughly. In a recent study, we measured a marker of antioxidant function, the total radical-trapping antioxidant potential (TRAP) of plant foods, and we showed that a diet with high total antioxidant capacity (TAC) was associated with >30% reduction in gastric cancer risk [13]. The risk reduction was even stronger among individuals whose gastric mucosa was likely to be under oxidative stress, i.e. long-term smokers and those infected with H. pylori [13]. Still, only some of the reduced cancer risk could be attributed to vitamins C and E and β-carotene, while a significant part remained unexplained [14]. Since flavonoids are major determinants of the in vitro TAC of plant products [15, 16], some of the preventive effect of plant foods on gastric tumors could be attributable to quercetin, a main dietary source of flavonoids [17], despite contradictory evidence from other cancer studies [18–21]. Quercetin not only possess strong antioxidant properties through free radical scavenging [15] but also reduces inflammation and inhibits cell proliferation and angiogenesis [22].Thus, we investigated the association between quercetin dietary intake and gastric cancer risk using data from a large population-based case–control study conducted in Sweden, with detailed information both on known important covariates and on gastric cancer subtypes.
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patients and methods
This study was conducted in two Swedish regions (five counties with a total population of 1.3 million) with differing gastric cancer incidence. The study base consisted of all individuals aged 40–79 years, born in Sweden and living in the study counties from February 1989 through January 1995. The methods have been described in detail previously [14]. Briefly, we identified all patients with newly diagnosed gastric adenocarcinoma through a comprehensive case ascertainment scheme involving contact persons at all hospitals in the study area, hospital pathology departments and regional cancer registries. Our completeness slightly exceeded that of the Swedish Cancer Register [23]. Of 908 patients who met the eligibility criteria, 567 agreed to participate in an interview. Reasons for nonparticipation were early death/very advanced disease (270), mental or physical illness other than gastric cancer (40), and patient refusal (28), while 3 could not be located.All tumors were uniformly classified according to tumor subsite (cardia versus noncardia) where cardia cancers were defined as centered within 1 cm proximal and 2 cm distal of the origin of the longitudinal gastric folds [24]. Tumors were also classified according to their predominant histological pattern and divided into intestinal (n = 337), diffuse (n = 184) or as being of mixed type (n = 37) when different patterns were exhibited equally. In nine patients, the histological type could not be determined with certainty [14, 25]. Two controls per case were randomly selected from age- and gender-strata in the continuously updated computerized population register and frequency matched to cases. Of 1534 control subjects invited to participate, 1165 were interviewed. Reasons for nonparticipation were refusal (245) and mental or physical illness (other than gastric cancer, 90), while 34 could not be located for interview.
collection of exposure data
Professional interviewers from the Statistics Sweden conducted face-to-face interviews to assess dietary habits 20 years before interview using a food-frequency questionnaire validated for consistency and reliability [26], including 45 foods and beverages [27]. Due to the severity of the disease, it was not always possible to blind case–control status, but the interviewers were unaware of the study hypotheses and trained to treat all subjects uniformly. We did not use substitute responders.The nine predetermined response categories of consumption ranged from ‘never’ to ‘twice daily or more’, for each dietary item. With the exception for bread and beverages, we did not ask about portion size but instead computed average daily intake of calories and nutrients by multiplying frequency data with standard portion sizes and then linking each item to a food composition database developed at the Swedish National Food Administration [27].
The average content of quercetin in different types of fruits, vegetables, wine, tea, coffee and fruit juices as determined by Hertog et al. [28, 29] is displayed in Figure 1. During the exposure period of interest (around 1970), green tea was basically nonexistent on the Swedish market, thus all tea was assumed to be black. Similarly, since practically all wine consumed in Sweden at the time was sold through government monopoly retail, where sales constituted 2/3 red wine and 1/3 white [30], 2/3 of the quercetin content of red wine was multiplied with the frequency of wine intake to get wine attributable quercetin intake. Other potential sources of quercetin, such as berries and olives, were judged to be of minor or no importance.
results
Table 1 shows demographics, clinical and behavioral characteristics of cases and controls according to tumor subsite. Owning to the frequency matching, age and sex distributions were similar among cases and controls, but patients with tumors in the gastric cardia were more likely to be younger and of male and had, on average, a lower socioeconomic status than those with noncardia gastric cancer. The percentage of ever smokers was lower among control subjects, as well as the percentage of ever infected with H. pylori. Controls had a lower salt intake than cases. The crude intake of major sources of quercetin intake also differed between cases and controls, cases reporting on average a lower intake of wine (grams per month) and fruit–vegetables (times per month).
In Table 4, a finer stratifications on both gender and smoking indicated that in women the inverse association was almost entirely confined to ever smokers (P value for interaction = 0.01) Among the latter, the adjusted OR in the second quintile of quercetin intake, relative to the first, was 0.24 (95% CI 0.08–0.74) and remained between 0.11 and 0.19 in quintiles 3–5. No association between quercetin intake and noncardia gastric cancer risk was observed among female never smokers. A similar effect modification of quercetin could not be statistically confirmed among men (Pvalue for interaction = 0.26).
discussion
Quercetin intake was strongly negatively associated with the risk of gastric cancer, particularly for noncardia gastric cancers and already at moderate levels of intake; a 50% reduction in risk was observed at the third lowest quintile of intake (6–8 mg quercetin/day), while no substantial further decline was associated with additional intake of quercetin. We also found a statistically significant interaction between quercetin intake and smoking in the fully adjusted analysis of noncardia cancer risk. We, further, found a statistically significant interaction between quercetin intake and smoking in the fully adjusted analysis of noncardia cancer risk, but differences between smokers and nonsmokers were mainly confined in the second and third quintiles of quercetin intake; in addition, when considering only women, the protective effect of quercetin on noncardia cancer risk was confined only on smokers. The last results should, of course, carefully be interpreted, in light also of the reduced sample size based on which the models were fitted.
Although risk estimates were not modified after adjustment for the other antioxidants, we cannot be certain that quercetin is the critical agent among many other antioxidants and wholesome substances in quercetin-rich plant foods, the true protective substance may just covary with quercetin. In fact, we cannot even confidently rule out that residual confounding, or confounding from unmeasured factors related to a healthy lifestyle (including high consumption of quercetin-rich food), might have inflated—although perhaps not entirely explained—the observed inverse association.
However, the current results are in line with our previous findings of TRAP, ascorbic acid, β-carotene and α-tocopherol [13], indicating a stronger preventive effect of antioxidants (measured as TAC) on gastric cancer among long-term smokers and those infected with H. pylori [13]. We hypothesize that a certain minimum level of antioxidant compounds are needed to maintain our defense against oxidative stress and cancer development. The existence of a possible threshold for the presumed protective effect of dietary antioxidants could suggest the existence of regulatory hierarchies that modulate the interaction between antioxidants and oxidative stress to achieve a physiological redox balance. Consequently, those under higher oxidative pressure may require a somewhat higher intake of antioxidants to keep the redox balance and avoid oxidative stress [39]. Given the large gender discrepancy in gastric cancer incidence, we found the strong inverse association between quercetin intake and noncardia cancer among female smokers, as opposed to male smokers, very interesting. Previous studies have seen lower basic levels of antioxidants in plasma and tissues among females compared with males [40]. Recent reviews also indicate a possible difference between men and women in terms of redox enzymes (myeloperoxidase, xanthine oxidase and superoxide dismutase) as well as in the molecular targets of free radicals (NF-κB) and MAP-kinases [41]. However, the literature on this issue is incomplete and fragmentary and fails to identify a common mechanism for interactions between gender and redox status. If our results are a random finding, influenced by an endogenous redox pattern of females, or, linked to a potential effect of estrogens remains to be shown and further studies are indeed needed.
However, the current results are in line with our previous findings of TRAP, ascorbic acid, β-carotene and α-tocopherol [13], indicating a stronger preventive effect of antioxidants (measured as TAC) on gastric cancer among long-term smokers and those infected with H. pylori [13]. We hypothesize that a certain minimum level of antioxidant compounds are needed to maintain our defense against oxidative stress and cancer development. The existence of a possible threshold for the presumed protective effect of dietary antioxidants could suggest the existence of regulatory hierarchies that modulate the interaction between antioxidants and oxidative stress to achieve a physiological redox balance. Consequently, those under higher oxidative pressure may require a somewhat higher intake of antioxidants to keep the redox balance and avoid oxidative stress [39]. Given the large gender discrepancy in gastric cancer incidence, we found the strong inverse association between quercetin intake and noncardia cancer among female smokers, as opposed to male smokers, very interesting. Previous studies have seen lower basic levels of antioxidants in plasma and tissues among females compared with males [40]. Recent reviews also indicate a possible difference between men and women in terms of redox enzymes (myeloperoxidase, xanthine oxidase and superoxide dismutase) as well as in the molecular targets of free radicals (NF-κB) and MAP-kinases [41]. However, the literature on this issue is incomplete and fragmentary and fails to identify a common mechanism for interactions between gender and redox status. If our results are a random finding, influenced by an endogenous redox pattern of females, or, linked to a potential effect of estrogens remains to be shown and further studies are indeed needed.
Apart from its role as an antioxidant, quercetin may also block the activation of procarcinogens by modulating the expression of cytochrome P450 enzymes [42]. Additionally, other researchers have associated quercetin with enhanced DNA repair [43] and increased expression of phase II conjugating enzymes that facilitate our elimination of carcinogenic products (e.g. polycyclic aromatic compounds from smoking and adducts from phase I metabolism), by making them more soluble and disposable by secretion [44].
Among the limitations of the present study is the investigation of a single flavonoids among at least 30 known classes. However, quercetin is widely present in many food items of plan origin, it has been more frequently studied and has a strong antioxidant capacity [45].
Among the limitations of the present study is the investigation of a single flavonoids among at least 30 known classes. However, quercetin is widely present in many food items of plan origin, it has been more frequently studied and has a strong antioxidant capacity [45].
In conclusion, although the enthusiasm for cancer prevention with dietary antioxidants was severely hampered by negative results in randomized controlled trials of galenic antioxidant supplements [42], one should not dismiss the potential for cancer prevention by dietary means. This study suggests that dietary interventions among individuals under oxidative stress and very low intake of plant foods, particularly women, might decrease their gastric cancer risk.
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