Dietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine

doi:10.1016/j.canlet.2004.05.019

Cancer Letters

Volume 215, Issue 1, 8 November 2004, Pages 21-28

https://doi.org/10.1016/j.canlet.2004.05.019 Get rights and content

Abstract

Dietary isoflavone intake has been linked to cancer prevention and their anti-inflammation activity was examined. Intraperitoneal lipopolysaccharide (LPS) injection in mice led to a decrease in the liver antioxidant glutathione level but this decrease was prevented in mice fed with an isoflavone-containing diet. Similarly, isoflavone diet prevented the inflammation-associated induction of metallothionein (MT) in the intestine; and the induction of manganese superoxide dismutase (Mn-SOD) in the liver. Results from the intestinal cell studies suggest that isoflavones suppress the intestinal response to inflammation by modulating the action of pro-inflammatory cytokine, IL-6. IL-6 secretion and the STAT3 (signal transducer and activator of transcription protein 3) nuclear translocation in response to IL-6 were both decreased by genistein.

Introduction

Inflammation is an essential biological defense yet excess immune response can lead to tissue damages [1]. Consistent with this, anti-inflammatory agents have been found to have the cancer prevention activity [1]. Dietary isoflavones were implied in cancer prevention [2], [3] but their in vivo effects on immune response remain to be clarified. Intraperitoneal injected genistein was shown to protect rats from the endotoxin-induced organ failure [4]. Subcutaneously injected or oral intake of isoflavone genistein was found to decrease thymic size and humoral immunity in castrated or ovariectomized mice [5]. On the other hand, genistein by gavage was found to enhance host resistance to intravenously-injected tumor cells [6]. Since the main route of isoflavone exposure in human population is through soybean ingestion, we determined the immune-modulating effect of dietary soy isoflavones in normal mice here.

Intestine is potentially a target organ for the chemoprevention activity of isoflavones based on epidemiological studies [2]. Since anti-inflammatory agents have colon cancer prevention activity [1], [7], we are interested in the intestinal immune response in soy isoflavones-fed mice. In addition, orally-ingested isoflavones can be transported across the intestinal epithelium [8], [9], [10], [11] although their systemic availability is limited [12]. Liver, because of its proximity to the intestine in blood supply, could also benefit from the dietary component. Indeed, inflammatory responses in intestine and liver have been described before [13], [14], [15] and were shown to be modulated by dietary component [13]. In this paper, we compared the endotoxin-induced inflammation reaction in these two organs in mice that were fed diet with or without isoflavones. In addition, the potential mechanisms of immune suppression by genistein were examined using cultured cells.

Section snippets

Animal studies

Male 9 weeks-old C57/BL6 mice were used for the study. After acclimation to the isoflavones-free AIN-93M diet (C diet), they were randomly assigned to C diet or AIN-93M supplemented with 0.3% (3 g/kg) Novasoy^® (Archer Daniel Midland Co., Decatur, IL). (ISF diet). The composition of Novasoy® was determined by LC-PDA and LC-MS analysis [16], [17] (Table 1). The mice were housed individually under 12-h light/dark cycle (10 PM/10 AM). Food intake and body weight were monitored twice every week.

Effect of isoflavone diet on body weight, food intake and tissue glutathione levels

The body weight of four groups of mice, control (C) diet with saline injection, isoflavone (ISF) diet with saline injection, C diet with LPS injection, and ISF diet with LPS injection was 29.5±2.9, 29.0±3.0, 28.1±3.6, and 29.6±2.8 g, respectively (mean±SD, N=8–9 in each group). The daily food intake of these four groups of mice was 3.5±0.2, 3.4±0.4, 3.5±0.3, and 3.5±0.3 g, respectively (mean±SD, N=8–9 in each group). There were no differences among groups in body weight or food intake.

Glutathione

Discussion

We demonstrated here the ability of a diet containing soy-derived isoflavones to modulate the tissue response to endotoxin challenge. Mice given soy isoflavone diet did not exhibit LPS-induced hepatic glutathione loss (Table 2) and had less LPS-induced hepatic and intestinal gene induction (Fig. 1). Previously, a diet with a similar concentration of soy isoflavones was found ineffective in increasing cardiac graft survival although intraperitoneal genistein has the immunosuppressive property

Acknowledgements

We thank James Boyer, Wan-Jung Tsai and Di Tan for technical support. This study was supported in part by NIH grant DK33886 (to H.B.) and DK54728 (to S.-M. K.)

References (49)

H. Ohshima et al.
Chemical basis of inflammation-induced carcinogenesis
Arch. Biochem. Biophys.
(2003)
T.L. Guo et al.
Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice
J. Nutr.
(2001)
J. Sfakianos et al.
Intestinal uptake and biliary excretion of the isoflavone genistein in rats
J. Nutr.
(1997)
J.P.E. Spencer et al.
The small intestine can both absorb and glucuronidate luminal flavonoids
Fed. Eur. Biochem. Soc. Lett.
(1999)
W. Andlauer et al.
Absorption and metabolism of genistin in the isolated rat small intestine
Fed. Eur. Biochem. Soc. Lett.
(2000)
K. Murota et al.
Unique uptake and transport of isoflavone aglycones by human Caco-2 cells: comparison of isoflavonoids and flavonoids
J. Nutr.
(2002)
K.D.R. Setchell et al.
Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability
J. Nutr.
(2001)
C.W. Lush et al.
Regulation of intestinal nuclear factor-kappaB activity and E-selectin expression during sepsis: a role for peroxynitrite
Gastroenterology
(2003)
A.P. Griffith et al.
Improved methods for the extraction and analysis of isoflavones from soy-containing foods and nutritional supplements by reverse-phase high-performance liquid chromatography and liquid chromatography-mass-spectrometry
J. Chromatogr. A
(2001)
F. Tietze
Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione
Anal. Biochem.
(1969)

S.-M. Kuo

Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells

Cancer Lett.

(1996)

H. Okabe et al.

Endotoxin causes early changes in glutathione concentrations in rabbit plasma and liver

J. Surgical. Res.

(1994)

S.K. De et al.

Endotoxin induction of murine metallothionein gene expression

J. Biol. Chem.

(1990)

X.W. Chen et al.

Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway

Biochem. Biophys. Res. Commun.

(2002)

S.Z. Ding et al.

Regulation of interleukin 6 production in a human gastric epithelial cell line MKN-28

Cytokine

(2000)

T. Akiyama et al.

Genistein, a specific inhibitor of tyrosine-specific protein kinases

J. Biol. Chem.

(1987)

M. Carballo et al.

Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes

J. Biol. Chem.

(1999)

T.P. O'Connor et al.

A high isoflavone soy protein diet and intravenous genistein delay rejection of rat cardiac allografts

J. Nutr.

(2002)

A.J. Day et al.

Deglycosylation of flavonoids and isoflavonoid glycosides by human small intestine and liver β-glucosidase activity

Fed. Eur. Biochem. Soc. Lett.

(1998)

I.-W. Peng et al.

Flavonoid structure affects the inhibition of lipid peroxidation in Caco-2 intestinal cells at physiological concentrations

J. Nutr.

(2003)

Q. Guo et al.

ESR and cell culture studies on free radical-scavenging and antioxidant activities of isoflavonoids

Toxicology

(2002)

G.C. Yen et al.

Inhibitory effects of isoflavones on nitric oxide- or peroxynitrite-mediated DNA damage in RAW 264.7 cells and phiX174 DNA

Food Chem. Toxicol.

(2002)

P. Hua et al.

Estrogen response element-independent regulation of gene expression by genistein in intestinal cells

Biochim. Biophys. Acta

(2003)

A. Murakami et al.

Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferon gamma-induced IkappaB degradation in RAW264.7 macrophages

Cancer Lett.

(2003)

Cited by (98)

Polyphenols inhibiting MAPK signalling pathway mediated oxidative stress and inflammation in depression
2022, Biomedicine and Pharmacotherapy
Citation Excerpt :
Quercetin can reportedly reduce paw edema induced by carrageenan. Studies also revealed that the inflammatory response caused by LPS infusion can be altered by glycitin, daidzin, genistein, and their glucosides [174]. Polyphenols can modulate the enzyme and signaling system implicated in the process of inflammation, including tyrosine-protein kinase and threonine-serine protein kinase.
Depression is one of the most debilitating psychiatric disorders affecting people of all ages worldwide. Despite significant heterogeneity between studies, increased inflammation and oxidative stress have been found in depression. Oxidative stress and inflammation are involved in the pathogenesis of depression. In the current review, we discussed the markers of oxidative stress and inflammation in depressive disorder and the association between these markers and the antidepressant treatment. The role of natural polyphenols in regulating various cell signaling pathways related to oxidative stress and inflammation has also been reviewed. The inhibitory effect of polyphenols on several cell signaling pathways reveals the vital role of polyphenols in the prevention and treatment of depressive disorder. Understanding the mechanism of polyphenols implicated in the regulation of cell signaling pathways is essential for the identification of lead compounds and the development of novel effective compounds for the prevention and treatment of depressive disorder.
Targeting the tumor immune microenvironment with “nutraceuticals”: From bench to clinical trials
2021, Pharmacology and Therapeutics
The occurrence of immune effector cells in the tissue microenvironment during neoplastic progression is critical in determining tumor growth outcomes. On the other hand, tumors may also avoid immune system-mediated elimination by recruiting immunosuppressive leukocytes and soluble factors, which coordinate a tumor microenvironment that counteracts the efficiency of the antitumor immune response. Checkpoint inhibitor therapy results have indicated a way forward via activation of the immune system against cancer. Widespread evidence has shown that different compounds in foods, when administered as purified substances, can act as immunomodulators in humans and animals. Although there is no universally accepted definition of nutraceuticals, the term identifies a wide category of natural compounds that may impact health and disease statuses and includes purified substances from natural sources, plant extracts, dietary supplements, vitamins, phytonutrients, and various products with combinations of functional ingredients.
In this review, we summarize the current knowledge on the immunomodulatory effects of nutraceuticals with a special focus on the cancer microenvironment, highlighting the conceptual benefits or drawbacks and subtle cell-specific effects of nutraceuticals for envisioning future therapies employing nutraceuticals as chemoadjuvants.
Soy intake and colorectal cancer risk: Results from a pooled analysis of prospective cohort studies conducted in china and japan
2020, Journal of Nutrition
Soy is commonly consumed in east Asian countries and is suggested to reduce colorectal cancer (CRC) risk. However, results from epidemiologic studies are inconsistent, despite the anti-inflammatory and antiproliferative properties of soy isoflavones and soy protein.
We evaluated the association between soy isoflavones and soy protein and CRC risk using 4 prospective cohort studies from China and Japan.
Data were pooled from the Shanghai Women's Health Study (SWHS), Shanghai Men's Health Study (SMHS), Japan Public Health Center–based Prospective Study Cohort 1 (JPHC1), and Cohort 2 (JPHC2). Cox proportional hazards models estimated HRs and corresponding 95% CIs for the association of soy protein and isoflavone intake with CRC risk. The study included 205,060 individuals, among whom 2971 were diagnosed with incident CRC over an average follow-up of 12.7 y.
No statistically significant associations with CRC risk were observed for soy protein or isoflavone intake. No association was observed among ever smokers consuming higher isoflavones (HR_isoflavones: 0.83; 95% CI: 0.68, 1.00) and soy protein (HR_{soy protein}: 0.81; 95% CI: 0.39, 1.10). However, risk reductions were observed among premenopausal women with a body mass index [BMI (kg/m²)] <23.0 at baseline for higher isoflavone (HR_isoflavones: 0.58, 95% CI: 0.34, 0.98).
No evidence for an overall reduction in CRC risk by increasing soy food intake (i.e., protein or isoflavones) was observed. However, the association between soy and CRC risk may vary by BMI, smoking, and menopausal status among women. Future investigations are needed to further understand the biologic mechanisms observed.
Anti-inflammatory isoflavones and isoflavanones from the roots of Pongamia pinnata (L.) Pierre
2018, Bioorganic and Medicinal Chemistry Letters
A phytochemical study on the roots of Pongamia pinnata afforded five new isoflavone and isoflavanone derivatives (1–5), including two previously undescribed phenylisoflavones possessing an 1,2-oxetane ring, along with 21 known compounds (6–26) among which compound 18 is the first time to be isolated from nature. The structures of the isolated compounds were determined on the basis of 1D, 2D NMR, and HRESIMS. The absolute configurations of the compounds were assigned via analysis of the specific rotations and circular dichroism (CD) spectra, as well as by comparison of the calculated and experimental electronic circular dichroism (ECD) data. All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated BV-2 microglial cells. Twelve compounds exhibited different levels of inhibitory effects against NO production, and compound 1 showed the best activity with an IC₅₀ value at 9.0 μM.
Comparing Antioxidants in Liver Disease: L-Carnitine, N-Acetylcysteine, and Genistein
2018, The Liver: Oxidative Stress and Dietary Antioxidants
Liver diseases resulting from acute or chronic etiologies, manifest different pathological steps from acute injury, toxicity and necrosis to fibrosis, cirrhosis, and cancer. The balance of oxidant/antioxidant status is important in these steps. Therefore, it is considered that antioxidants may have protective and therapeutic effects in liver diseases. For this purpose, experimental and clinical studies in hepatopathological models have been performed with many agents having antioxidant features including l-carnitine, N-acetylcysteine, and genistein.
Quercetin suppresses NLRP3 inflammasome activation in epithelial cells triggered by Escherichia coli O157:H7
2017, Free Radical Biology and Medicine
Citation Excerpt :
Quercetin is a flavonoid widely found in a variety of plants and fruits, which exhibits anti-hyperuricemia and anti-hyperlipidemia in human [25,26]. It also shows ROS scavenging and anti-inflammation activity in liver [27] and kidney [28], but its anti-inflammasome function upon pathogenic infection has not been reported. Thus, our hypothesis is that quercetin inhibits E. coli O157:H7-induced inflammasome activation through blocking ROS production and mediating autophagy activation.
Inflammatory responses elicited by LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is induced by a wide variety of stress signals including infectious agents and cellular disorders. E. coli O157:H7 causes serious gastrointestinal diseases that results in severe inflammation and oxidative stress, causing host cell damage. In this study, we found that E. coli O157:H7 infection induced NLRP3 assembly, caspase-1 activation and interleukin (IL)-1β and IL-18 release in Caco-2 cells. Infection also resulted in mitochondrial dysfunction with disrupted mitochondrial potential and mitochondrial complex-I activity, as well as the cytosolic release of cytochrome c and altered mitochondrial respiratory chain. The damage of mitochondria led to increased production of reactive oxygen species (ROS) and cytosolic release of mitochondrial DNA. Moreover, ROS was required for E. coli O157:H7 induced NLRP3 assembly as inhibiting mitochondrial ROS release by ROS scavengers Mito-TEMPO and N-acetylcysteine abrogated NLRP3 inflammasome activation in Caco-2 cells in response to E. coli O157:H7. Quercetin, one of the most important flavonoids in plant origin foods, had a protective role in inhibiting NLRP3 activation upon E. coli O157:H7 infection by protecting mitochondrial integrity and inhibiting mitochondrial ROS release. In addition, E. coli O157:H7 infection inhibited the host autophagy while quercetin treatment augmented autophagy activation, which further blocked ROS generation and IL-1β and IL-18 release. In summary, E. coli O157:H7 infection induced mitochondrial ROS release and NLRP3 assembly in host cells, while quercetin exerted a preventive role in host cells upon E. coli O157:H7 infection partially due to prevention of ROS production and activation of autophagy.

View all citing articles on Scopus

View full text

Dietary isoflavones suppress endotoxin-induced inflammatory reaction in liver and intestine

Abstract

Introduction

Section snippets

Animal studies

Effect of isoflavone diet on body weight, food intake and tissue glutathione levels

Discussion

Acknowledgements

Arch. Biochem. Biophys.

J. Nutr.

J. Nutr.

Fed. Eur. Biochem. Soc. Lett.

Fed. Eur. Biochem. Soc. Lett.

J. Nutr.

J. Nutr.

Gastroenterology

J. Chromatogr. A

Anal. Biochem.

Cancer Lett.

J. Surgical. Res.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Cytokine

J. Biol. Chem.

J. Biol. Chem.

J. Nutr.

Fed. Eur. Biochem. Soc. Lett.

J. Nutr.

Toxicology

Food Chem. Toxicol.

Biochim. Biophys. Acta

Cancer Lett.