Sex reporting of cells used in cancer research: A systematic review.

Sex and gender disparities in biomedical research have been emphasized to improve scientific knowledge applied for the health of both men and women. Despite sex differences in cancer incidence, prognosis, and responses to therapeutic agents, mechanistic explanations at molecular levels are far from enough. Recent studies suggested that cell sex is an important biological variable due to differences in sex chromosome gene expression and differences in events associated with developmental biology. The objective of this study was to analyze the reporting of sex of cells used in cancer research using articles published in Cancer Cell, Molecular Cancer, Journal of Hematology & Oncology, Journal for ImmunoTherapy of Cancer, and Cancer Research in 2020, and to examine whether there exists any sex bias. We found that the percentage of cells with sex notation in the article was 36.5%. Primary cells exhibited higher sex notation compared to cell lines. A higher percentage of female cells were used in cell cultures with sex notation. Also, sex-common cells omitted sex description more often compared to sex-specific cells. None of the cells isolated from embryo and esophagus reported the cell sex in the article. Our results indicate cell sex report in cancer research is limited to a small proportion of cells used in the study. These results call for acknowledging the sex of cells to increase the applicability of biomedical research discoveries.

Sex differences in colonic gene expression and fecal microbiota composition in a mouse model of obesity-associated colorectal cancer.

This study investigated the sex-specific correlation between obesity and colorectal cancer emphasizing a more pronounced association in males. Estrogen, chromosomal genes, and gut bacteria were assessed in C57BL6/J male, female and ovariectomized (OVX) female mice, subjected to either a low-fat diet (LFD) or high-fat diet (HFD) for 14 weeks. Induction of colon tumor involved azoxymethane (10 mg/kg) administration, followed by three cycles of dextran sulfate sodium. Male mice on HFD exhibited higher final body weight and increased colon tumors compared to females. Colonic mucin 2 expression was significantly higher in females. HFD-modulated differentially expressed genes numbered 290 for males, 64 for females, and 137 for OVX females. Only one up-regulated gene (Gfra3) overlapped between females and OVX females, while two down-regulated genes (Thrsp and Gbp11) overlapped between males and OVX females. Genes up-regulated by HFD in males were linked to cytokine-cytokine interaction, HIF-1 signaling pathway, central carbon metabolism in cancer. Sex-specific changes in gut microbial composition in response to HFD were observed. These findings suggest a male-specific vulnerability to HFD-induced colon tumor formation, implicating key genes and colonic bacteria in colon tumorigenesis.

The Effect of Omega-3 Enriched Oral Nutrition Supplement on Nutritional Indices and Quality of Life in Gastrointestinal Cancer Patients: A Randomized Clinical Trial.

OBJECTIVE: Gastrointestinal (GI) cancer patients often experience severe malnutrition during cancer therapies due to gastrointestinal dysfunctions including poor digestion and absorption as well as tumor-associated anorexia. In this study, we performed a randomized clinical trial to determine the efficacy of oral nutrition supplement (ONS) enriched with omega-3 fatty acids on nutritional status, quality of life (QOL), and pro-inflammatory indices. METHODS: Patients diagnosed with GI cancers were recruited and screened for eligibility. A total of 58 patients were randomly allocated to either the control group (n=27) or the experimental group (n=31). The intervention group received 200 ml ONS twice a day while the control group received routine care. Anthropometrics, Patient-Generated Subjective Global Assessment (PG-SGA) score, QOL score and nutrient intake data were collected at baseline, week 4 and week 8. Blood was drawn for biochemical assessments. Nine patients from each group dropped out of the study Forty patients (18 control patients and 22 intervention patients) completed the study. RESULTS: This study showed that ONS intervention improved PG-SGA scores in the intervention group (p<0.01). Scores of physical functioning score and role functioning were declined only in the control group and the difference between week 8 and baseline for role functioning was significant (p<0.001). Fatigue score was steadily decreased in the experiment group, and the differences between week 8 and baseline was significant between two groups (p<0.02). However, no statistically significant improvement in biochemical markers of nutritional status and pro-inflammatory cytokine concentrations were found. These results suggests that ONS intervention for 8 weeks improves PG-SGA scores and QOL scores in patients undergoing cancer therapy.

Effect of coadministration of enriched Korean Red Ginseng (Panax ginseng) and American ginseng (Panax quinquefolius L) on cardiometabolic outcomes in type-2 diabetes: A randomized controlled trial.

BACKGROUND: Diabetes mellitus and hypertension often occur together, amplifying cardiovascular disease (CVD) risk and emphasizing the need for a multitargeted treatment approach. American ginseng (AG) and Korean Red Ginseng (KRG) species could improve glycemic control via complementary mechanisms. Additionally, a KRG-inherent component, ginsenoside Rg3, may moderate blood pressure (BP). Our objective was to investigate the therapeutic potential of coadministration of Rg3-enriched Korean Red Ginseng (Rg3-KRG) and AG, added to standard of care therapy, in the management of hypertension and cardiometabolic risk factors in type-2 diabetes. METHODS: Within a randomized controlled, parallel design of 80 participants with type-2 diabetes (HbA1c: 6.5-8%) and hypertension (systolic BP: 140-160 mmHg or treated), supplementation with either 2.25 g/day of combined Rg3-KRG + AG or wheat-bran control was assessed over a 12-wk intervention period. The primary endpoint was ambulatory 24-h systolic BP. Additional endpoints included further hemodynamic assessment, glycemic control, plasma lipids and safety monitoring. RESULTS: Combined ginseng intervention generated a mean ± SE decrease in primary endpoint of 24-h systolic BP (-3.98 ± 2.0 mmHg, p = 0.04). Additionally, there was a greater reduction in HbA1c (-0.35 ± 0.1% [-3.8 ± 1.1 mmol/mol], p = 0.02), and change in blood lipids: total cholesterol (-0.50 ± 0.2 mmol/l, p = 0.01), non-HDL-C (-0.54 ± 0.2 mmol/l, p = 0.01), triglycerides (-0.40 ± 0.2 mmol/l, p = 0.02) and LDL-C (-0.35 ± 0.2 mmol/l, p = 0.06) at 12 wks, relative to control. No adverse safety outcomes were observed. CONCLUSION: Coadministration of Rg3-KRG + AG is an effective addon for improving BP along with attaining favorable cardiometabolic outcomes in individuals with type 2 diabetes. Ginseng derivatives may offer clinical utility when included in the polypharmacy and lifestyle treatment of diabetes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01578837.

Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer.

Cancer is the second leading cause of death worldwide, with 9.6 million people estimated to have died of cancer in 2018. Excess body fat deposition is a risk factor for many types of cancer. Men and women exhibit differences in body fat distribution and energy homeostasis regulation. This systematic review aimed to understand why sex disparities in obesity are associated with sex differences in the incidence of gastrointestinal cancers. Cancers of the esophagus, liver, and colon are representative gastrointestinal cancers, and obesity is a convincing risk factor for their development. Numerous epidemiological studies have found sex differences in the incidence of esophageal, liver, and colorectal cancers. We suggest that these sexual disparities are partly explained by the availability of estrogens and other genetic factors regulating inflammation, cell growth, and apoptosis. Sex differences in gut microbiota composition may contribute to differences in the incidence and phenotype of colorectal cancer. To establish successful practices in personalized nutrition and medicine, one should be aware of the sex differences in the pathophysiology and associated mechanisms of cancer development.

Erratum: Efficacy of Cereal-based Oral Nutrition Supplement on Nutritional Status, Inflammatory Cytokine Secretion and Quality of Life in Cancer Patients Under Cancer Therapy.

[This corrects the article on p. 55 in vol. 25, PMID: 32266180.].

Efficacy of Cereal-based Oral Nutrition Supplement on Nutritional Status, Inflammatory Cytokine Secretion and Quality of Life in Cancer Patients Under Cancer Therapy.

A rapid increase in cancer incidence accompanied by aging population requires evidence-based supportive cancer care practices. Cancer therapies often accompany adverse events which induce malnutrition and declined quality of life. We conducted an 8-week non-randomized clinical trial to evaluate efficacy of cereal-based oral nutritional supplement (ONS) intervention on nutritional status, quality of life and inflammatory responses in cancer patients undergoing cancer therapy with 5% < weight loss. The study included 34 pateints (24 in control group, 10 in intervention group) with 15 drop-outs. ONS used in this intervention contained 0.5% arabinoxylan-rich fermented rice bran powder and 5.5% black rice powder as active ingredients in a regular cereal-based formula. Results showed that ONS intervention for 8 weeks did not show significant improvement in blood biomarkers of nutritional status or patient-generated subjective global assessment scores. However, 8-week of intervention showed reduced interleukin (IL)-6 and IL-1ß secretion in lipopolysaccharide-stimulated peripheral blood mononuclear cells while IL-12p70 level was increased. For health-related quality of life (HRQoL) indices, emotional functioning and fatigue symptoms were improved after 4 weeks only in the intervention group although no difference was found at week 8. These results suggest that ONS intervention may improve chronic inflammatory status and HRQoL indices (at week 4) in cancer patients receiving treatments.

Z-ajoene from Crushed Garlic Alleviates Cancer-Induced Skeletal Muscle Atrophy.

Skeletal muscle atrophy is one of the major symptoms of cancer cachexia. Garlic (Allium sativum), one of the world's most commonly used and versatile herbs, has been employed for the prevention and treatment of diverse diseases for centuries. In the present study, we found that ajoene, a sulfur compound found in crushed garlic, exhibits protective effects against muscle atrophy. Using CT26 tumor-bearing BALB/c mice, we demonstrate in vivo that ajoene extract alleviated muscle degradation by decreasing not only myokines secretion but also janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) and SMADs/forkhead box (FoxO) signaling pathways, thereby suppressing muscle-specific E3 ligases. In mouse skeletal myoblasts, Z-ajoene enhanced myogenesis as evidenced by increased expression of myogenic markers via p38 mitogen-activated protein kinase (MAPK) activation. In mature myotubes, Z-ajoene protected against muscle protein degradation induced by conditioned media from CT26 colon carcinoma cells, by suppressing expression of muscle specific E3 ligases and nuclear transcription factor kappa B (NF-κB) phosphorylation which contribute to muscle atrophy. Moreover, Z-ajoene treatment improved myofiber formation via stimulation of muscle protein synthesis. These findings suggest that ajoene extract and Z-ajoene can attenuate skeletal muscle atrophy induced by cancer cachexia through suppressing inflammatory responses and the muscle wasting as well as by promoting muscle protein synthesis.

Dietary fat intake and age modulate the composition of the gut microbiota and colonic inflammation in C57BL/6J mice.

BACKGROUND: More than half of the adult population worldwide is overweight or obese, while excess adiposity has been linked to chronic low-grade inflammation, contributing to the development of chronic diseases. Recent studies have showed that diet-induced alterations to the gut microbiota composition play a pivotal role in the development of obesity. However, the cause-effect relationship between obesity and gut microbiota composition is not yet fully understood. In this study, we investigated the short-term responses of gut microbiota composition to diets with different fat contents and their associations with inflammatory biomarkers. RESULTS: Sixty male C57BL/6 J mice were fed a normal diet (ND; 15% fat) or a high-fat diet (HFD; 45% fat) for 10 or 20 weeks. The relative proportion of the phylum Actinobacteria was elevated by the HFD and was positively associated with body weight and proinflammatory cytokines including TNF-α, IL-1ß, and IL-6. The proportion of the phylum Firmicutes increased with aging and was also positively correlated with proinflammatory cytokines. The proportions of Actinobacteria and Firmicutes were inversely associated with tight junction proteins claudin-1 and E-cadherin, respectively. The proportions of the class Clostridia and the family Ruminococcaceae within the phylum Firmicutes were affected by both diet and age. In addition, the proportions of the phylum Bacteroidetes, the family Bacteroidaceae, and the genus Bacteroides decreased with aging and were inversely correlated with colonic proinflammatory cytokines representing a positive association with tight junction proteins. CONCLUSIONS: Host age and dietary fat intake are important elements that induce proportional changes in gut microbiota, and these changes are also associated with systemic inflammation. This study provides evidence that diet affects the gut microbiota composition within a short period of time.

Dietary Inflammatory Index and Risk of Breast Cancer Based on Hormone Receptor Status: A Case-Control Study in Korea.

Breast cancer is the most common cancer in women globally, and the risk of developing breast cancer is associated with inflammation. The present study aimed to examine the association between the Dietary Inflammatory Index (DII®) and breast cancer in Korean women and investigate whether the tumor's hormone receptor status affects this association. In this case-control study, we enrolled 364 breast cancer patients and 364 age-matched controls. DII scores were calculated from dietary intake evaluated by a 106-item food frequency questionnaire. The DII score was significantly higher in cases than in controls. After adjusting for potential confounders, the odds ratio (OR) of breast cancer was higher in the highest DII tertile (OR = 3.68, 95% confidence interval (CI): 2.34-5.80, p for trend < 0.0001) than in the lowest tertile. We found that higher DII scores were related to an increased risk of breast cancer for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors regardless of menopausal status (OR = 2.59, 95% CI: 1.37-4.88 in the highest DII category, p for trend = 0.01 for premenopausal women; OR = 11.00, 95% CI: 2.93-41.30 in the highest DII category, p for trend = 0.0004 for postmenopausal women), but not for ER-/PR- status. Our results suggested that the DII scores are positively associated with breast cancer risk in Korean women and that this relationship is more robust in ER+/PR+ tumors.

Genome-wide association study of seed protein, oil and amino acid contents in soybean from maturity groups I to IV.

KEY MESSAGE: Genomic regions associated with seed protein, oil and amino acid contents were identified by genome-wide association analyses. Geographic distributions of haplotypes indicate scope of improvement of these traits. Soybean [Glycine max (L.) Merr.] protein and oil are used worldwide in feed, food and industrial materials. Increasing seed protein and oil contents is important; however, protein content is generally negatively correlated with oil content. We conducted a genome-wide association study using phenotypic data collected from five environments for 621 accessions in maturity groups I-IV and 34,014 markers to identify quantitative trait loci (QTL) for seed content of protein, oil and several essential amino acids. Three and five genomic regions were associated with seed protein and oil contents, respectively. One, three, one and four genomic regions were associated with cysteine, methionine, lysine and threonine content (g kg-1 crude protein), respectively. As previously shown, QTL on chromosomes 15 and 20 were associated with seed protein and oil contents, with both exhibiting opposite effects on the two traits, and the chromosome 20 QTL having the most significant effect. A multi-trait mixed model identified trait-specific QTL. A QTL on chromosome 5 increased oil with no effect on protein content, and a QTL on chromosome 10 increased protein content with little effect on oil content. The chromosome 10 QTL co-localized with maturity gene E2/GmGIa. Identification of trait-specific QTL indicates feasibility to reduce the negative correlation between protein and oil contents. Haplotype blocks were defined at the QTL identified on chromosomes 5, 10, 15 and 20. Frequencies of positive effect haplotypes varied across maturity groups and geographic regions, providing guidance on which alleles have potential to contribute to soybean improvement for specific regions.

Risk Factors for Vitamin D, Zinc, and Selenium Deficiencies in Korean Patients with Inflammatory Bowel Disease.

BACKGROUND/AIMS: Studies on the micronutrient status of Asian patients with inflammatory bowel disease (IBD) are scarce. We evaluated the prevalence of micronutrient deficiency and verified the risk factors for micronutrient deficiency in Korean patients with IBD. METHODS: We measured the serum levels of 25-hydroxyvitamin D3 [25-(OH)D], zinc, and selenium to analyze the clinical risk factors for micronutrient levels below the reference values. In addition, we compared the 25-(OH)D levels of patients with IBD to those of age- and sex-matched healthy controls. RESULTS: Among the 83 patients, 74 (89.2%) had suboptimal serum 25-(OH)D levels. The mean plasma 25-(OH)D level in patients with IBD was significantly reduced compared to that of the healthy controls (12.3±6.2 ng/mL vs 20.0±6.7 ng/mL; p<0.001). The proportions of patients with lower serum zinc and selenium levels were 39.0% and 30.9%, respectively. Female sex (p=0.012) and Crohn's disease (p=0.012) were associated with vitamin D deficiency. Patients younger than 40 years were at increased risk for zinc deficiency (p=0.045). Female sex (p=0.015) and low serum albumin level (<3.3 g/dL) (p=0.047) were risk factors for selenium deficiency. CONCLUSIONS: Many Korean patients with IBD have vitamin D, zinc, and selenium deficiencies, suggesting the necessity for monitoring levels of these micronutrients.

Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet.

Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks. Serum concentrations of insulin, insulin-like growth factor-1 (IGF-1), leptin, and adiponectin were measured as obesity-related phenotypic markers. Genome-wide gene expression profiles of colon tissue were determined, followed by statistical analyses to detect differentially expressed and serum phenotype-associated genes. HFD-fed mice showed higher serum concentrations of leptin (P < 0.001) and insulin (P < 0.01) than those in the ND group, whereas serum IGF-1 and adiponectin concentrations did not differ between the two dietary groups. Among differentially expressed genes affected by HFD, 135, 128, 110, and 341 genes were associated with serum levels of leptin, insulin, IGF-1, and adiponectin, respectively. We identified 17 leptin-associated genes and 4 insulin-associated genes that inversely responded to HFD and ND. Among these, leptin-associated Peli3 (Pellino E3 ubiquitin protein ligase family member 3), Creb1 (cAMP responsive element binding protein 1), and Enpp2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, autotaxin) and insulin-associated Centg1 (AGAP2, ArfGAP with GTPase domain) are reported to play a role either in obesity or colonic diseases. mRNA expression of these genes was validated by RT-qPCR. Our data suggest Peli3, Creb1, Enpp2, and Centg1 as potential early biomarker candidates for obesity-induced pathophysiological changes in the colon. Future studies verifying the function of these candidates are needed for the prevention, early detection, and treatment of colon diseases.

Time-course microarray analysis for identifying candidate genes involved in obesity-associated pathological changes in the mouse colon.

BACKGROUND: Obesity is known to increase the risk of colorectal cancer. However, mechanisms underlying the pathogenesis of obesity-induced colorectal cancer are not completely understood. The purposes of this study were to identify differentially expressed genes in the colon of mice with diet-induced obesity and to select candidate genes as early markers of obesity-associated abnormal cell growth in the colon. METHODS: C57BL/6N mice were fed normal diet (11% fat energy) or high-fat diet (40% fat energy) and were euthanized at different time points. Genome-wide expression profiles of the colon were determined at 2, 4, 8, and 12 weeks. Cluster analysis was performed using expression data of genes showing log2 fold change of ≥1 or ≤-1 (twofold change), based on time-dependent expression patterns, followed by virtual network analysis. RESULTS: High-fat diet-fed mice showed significant increase in body weight and total visceral fat weight over 12 weeks. Time-course microarray analysis showed that 50, 47, 36, and 411 genes were differentially expressed at 2, 4, 8, and 12 weeks, respectively. Ten cluster profiles representing distinguishable patterns of genes differentially expressed over time were determined. Cluster 4, which consisted of genes showing the most significant alterations in expression in response to high-fat diet over 12 weeks, included Apoa4 (apolipoprotein A-IV), Ppap2b (phosphatidic acid phosphatase type 2B), Cel (carboxyl ester lipase), and Clps (colipase, pancreatic), which interacted strongly with surrounding genes associated with colorectal cancer or obesity. CONCLUSIONS: Our data indicate that Apoa4, Ppap2b, Cel, and Clps are candidate early marker genes associated with obesity-related pathological changes in the colon. Genome-wide analyses performed in the present study provide new insights on selecting novel genes that may be associated with the development of diseases of the colon.

The Efficacy of Oral Nutritional Intervention in Malnourished Cancer Patients: a Systemic Review.

Cancer is currently a leading cause of deaths worldwide and the number of new cases is growing rapidly in both, developed and developing countries. Nutritional management during and after cancer treatment affects treatment efficacy and patient quality of life (QOL). This review systemically examined the effect of oral nutritional interventions on nutritional and clinical outcomes in cancer patients. We especially focused on outcomes such as nutritional status indices, immune-associated biochemical markers, and QOL assessments to provide insights on the applicability of different outcomes. A total of 28 papers were selected for systematic review. The nutritional composition of oral nutritional supplements (ONS), outcome measures, and efficacy of the oral nutritional interventions were summarized and discussed. Most ONS contain 1 or more functional components in addition to basic nutrients. Each study used various outcome measures and significant efficacy was observed for a limited number of measures. Nutritional status indices, QOL measures, and the duration of hospital stay improved in about 40% of the studies. One or more markers of immune function and inflammatory responses were improved by ONS in 65% of the selected studies. These results suggest that appropriate use of ONS may be an ideal way to improve treatment efficacy; however, additional intervention trials are required to confirm these findings.

Association of nutritional status-related indices and chemotherapy-induced adverse events in gastric cancer patients.

BACKGROUND: Malnutrition in gastrectomized patients receiving chemotherapy is associated with the susceptibility to chemotherapy-related adverse events. This study evaluated pre-operative nutritional status-related indices associated with adverse events in post-operation gastric cancer patients receiving chemotherapy. METHODS: Medical records of 234 gastrectomized patients under adjuvant tegafur/gimeracil/oteracil chemotherapy with extended lymph node dissection were analyzed. Nutritional status assessment included Patient-Generated Subjective Global Assessment (PG-SGA), body weight, body mass index, serum albumin concentration, and Nutrition Risk Index (NRI). Chemotherapy-originated adverse events were determined using Common Terminology Criteria for Adverse Events. RESULTS: PG-SGA indicated 59% of the patients were malnourished, and 27.8% of the patients revealed serious malnutrition with PG-SGA score of ≥9. Fifteen % of patients lost ≥10% of the initial body weight, 14.5% of the patients had hypoalbuminemia (<3.5 g/dL), and 66.2% had NRI score less than 97.5 indicating moderate to severe malnutrition. Hematological adverse events were present in 94% (≥grade 1) and 16.2% (≥grade 3). Non-hematological adverse events occurred in 95.7% (≥grade1) and 16.7% (≥grade 3) of the patients. PG-SGA and NRI score was not associated with treatment-induced adverse events. Multivariate analyses indicated that female, low body mass index, and hypoalbuminemia were independent risk factors for grade 3/4 hematological adverse events. Age was an independent risk factor for grade 3/4 non-hematological adverse events. Neutropenia was the most frequently occurring adverse event, and associated risk factors were female, total gastrectomy, and hypoalbuminemia. CONCLUSIONS: Hypoalbuminemia, not PG-SGA or NRI may predict chemotherapy-induced adverse events in gastrectomized cancer patients.

Erratum: High-fat Diet Accelerates Intestinal Tumorigenesis Through Disruption Intestinal Cell Membrane Integrity.

[This corrects the article on p. 95 in vol. 21, PMID: 27390738.].

High-fat Diet Accelerates Intestinal Tumorigenesis Through Disrupting Intestinal Cell Membrane Integrity.

BACKGROUND: Excess energy supply induces chronic low-grade inflammation in association with oxidative stress in various tissues including intestinal epithelium. The objective of this study was to investigate the effect of high-fat diet (HFD) on intestinal cell membrane integrity and intestinal tumorigenesis in Apc(Min/+) mice. METHODS: Mice were fed with either normal diet (ND) or HFD for 12 weeks. The number of intestinal tumors were counted and biomarkers of endotoxemia, oxidative stress, and inflammation were determined. Changes in intestinal integrity was measured by fluorescein isothiocyanate (FITC)-dextran penetration and membrane gap junction protein expression. RESULTS: HFD group had significantly higher number of tumors compared to ND group (P < 0.05). Blood total antioxidant capacity was lower in HFD group, while colonic 8-hydroxy-2'-deoxyguanosine level, a marker of oxidative damage, was higher in HFD group compared to that of ND group (P < 0.05). The penetration of FITC-dextran was substantially increased in HFD group (P < 0.05) while the expressions of membrane gap junction proteins including zonula occludens-1, claudin-1, and occludin were lower in HFD group (P < 0.05) compared to those in ND group. Serum concentration of lipopolysaccharide (LPS) receptor (CD14) and colonic toll-like receptor 4 (a LPS receptor) mRNA expression were significantly higher in HFD group than in ND group (P < 0.05), suggesting that significant endotoxemia may occur in HFD group due to the increased membrane permeability. Serum interleukin-6 concentration and myeloperoxidase activity were also higher in HFD group compared to those of ND group (P < 0.05). CONCLUSIONS: HFD increases oxidative stress disrupting intestinal gap junction proteins, thereby accelerating membrane permeability endotoxemia, inflammation, and intestinal tumorigenesis.

The Soy Peptide Phe-Leu-Val Reduces TNFα-Induced Inflammatory Response and Insulin Resistance in Adipocytes.

Obesity-induced adipose inflammation plays a crucial role in the development of obesity-induced metabolic disorders such as insulin resistance and type 2 diabetes. In the presence of obesity, hypertrophic adipocytes release inflammatory mediators, including tumor necrosis factor-alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1), which enhance the recruitment and activation of macrophages, and in turn augment adipose inflammation. We demonstrate that the soy peptide Phe-Leu-Val (FLV) reduces inflammatory responses and insulin resistance in mature adipocytes. Specifically, the soy peptide FLV inhibits the release of inflammatory cytokines (TNFα, MCP-1, and IL-6) from both TNFα-stimulated adipocytes and cocultured adipocytes/macrophages. This inhibition is mediated by the inactivation of the inflammatory signaling molecules c-Jun N-terminal kinase (JNK) and IκB kinase (IKK), and the downregulation of IκBα in the adipocytes. In addition, soy peptide FLV enhances insulin responsiveness and increases glucose uptake in adipocytes. More importantly, we, for the first time, found that adipocytes express peptide transporter 2 (PepT2) protein, and the beneficial action of the soy peptide FLV was disrupted by the peptide transporter inhibitor GlySar. These findings suggest that soy peptide FLV is transported into adipocytes by PepT2 and then downregulates TNFα-induced inflammatory signaling, thereby increasing insulin responsiveness in the cells. The soy peptide FLV, therefore, has the potential to prevent obesity-induced adipose inflammation and insulin resistance.

Estrogen deprivation and excess energy supply accelerate 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in C3H/HeN mice.

BACKGROUND/OBJECTIVES: Obesity is a risk factor of breast cancer in postmenopausal women. Estrogen deprivation has been suggested to cause alteration of lipid metabolism thereby creating a cellular microenvironment favoring tumor growth. The aim of this study is to investigate the effects of estrogen depletion in combination with excess energy supply on breast tumor development. MATERIALS/METHODS: Ovariectomized (OVX) or sham-operated C3H/HeN mice at 4 wks were provided with either a normal diet or a high-fat diet (HD) for 16 weeks. Breast tumors were induced by administration of 7,12-dimethylbenz(a)anthracene once a week for six consecutive weeks. RESULTS: Study results showed higher serum concentrations of free fatty acids and insulin in the OVX+HD group compared to other groups. The average tumor volume was significantly larger in OVX+HD animals than in other groups. Expressions of mammary tumor insulin receptor and mammalian target of rapamycin proteins as well as the ratio of pAKT/AKT were significantly increased, while pAMPK/AMPK was decreased in OVX+HD animals compared to the sham-operated groups. Higher relative expression of liver fatty acid synthase mRNA was observed in OVX+HD mice compared with other groups. CONCLUSIONS: These results suggest that excess energy supply affects the accelerated mammary tumor growth in estrogen deprived mice.