Tea flavonols in cardiovascular disease and cancer epidemiology

Tea is an important dietary source of flavonols in countries such as the Netherlands, the United Kingdom and Japan. Flavonols may have beneficial health effects because of their antioxidant properties and their inhibitory role in various stages of tumor development in animal studies. The association between flavonol intake and cancer risk was investigated in three prospective studies (Zutphen Elderly Study in the Netherlands, a Finnish cohort, and the Netherlands Cohort Study). Only one study (Finnish cohort) showed an inverse association with cancer mortality. The intake of flavonols with subsequent cardiovascular disease was studied in six prospective epidemiological studies. In some populations (Seven Countries Study, Zutphen Elderly Study, a Finnish cohort) a clear protective effect was observed. In a large US cohort, a protective effect was only found in a subgroup with previous history of coronary heart disease, whereas in Welsh men, flavonol intake, mainly from tea, was associated with an increased risk of coronary heart disease. These conflicting results may be due to confounding by coronary risk factors associated with tea consumption. The question of whether flavonols protect against cardiovascular disease remains still open; a protective effect of flavonols against cancer is less likely.     

The combination of coffee compounds attenuates early fibrosis-associated hepatocarcinogenesis in mice: involvement of miRNA profile modulation

Aberrant microRNA expression implicates on hepatocellular carcinoma (HCC) development. Conversely, coffee consumption reduces by ~40% the risk for fibrosis/cirrhosis and HCC, while decaffeinated coffee does not. It is currently unknown whether these protective effects are related to caffeine (CAF), or to its combination with other common and/or highly bioavailable coffee compounds, such as trigonelline (TRI) and chlorogenic acid (CGA). We evaluated whether CAF individually or combined with TRI and/or CGA alleviates fibrosis-associated hepatocarcinogenesis, examining the involvement of miRNA profile modulation. Then, male C3H/HeJ mice were submitted to a diethylnitrosamine/carbon tetrachloride-induced model. Animals received CAF (50 mg/kg), CAF+TRI (50 and 25 mg/kg), CAF+CGA (50 and 25 mg/kg) or CAF+TRI+CGA (50, 25 and 25 mg/kg), intragastrically, 5×/week, for 10 weeks. Only CAF+TRI+CGA combination reduced the incidence, number and proliferation (Ki-67) of hepatocellular preneoplastic foci while enhanced apoptosis (cleaved caspase-3) in adjacent parenchyma. CAF+TRI+CGA treatment also decreased hepatic oxidative stress and enhanced the antioxidant Nrf2 axis. CAF+TRI+CGA had the most pronounced effects on decreasing hepatic pro-inflammatory IL-17 and NFκB, contributing to reduce CD68-positive macrophage number, stellate cell activation, and collagen deposition. In agreement, CAF+TRI+CGA upregulated tumor suppressors miR-144-3p, miR-376a-3p and antifibrotic miR-15b-5p, frequently deregulated in human HCC. CAF+TRI+CGA reduced the hepatic protein levels of pro-proliferative EGFR (miR-144-3p target), antiapoptotic Bcl-2 family members (miR-15b-5p targets), and the number of PCNA (miR-376a-3p target) positive hepatocytes in preneoplastic foci. Our results suggest that the combination of most common and highly bioavailable coffee compounds, rather than CAF individually, attenuates fibrosis-associated hepatocarcinogenesis by modulating miRNA expression profile.     

Modification of the Lipid Phase of Biological and Model Membranes by Bilberry Leaf Extract

The leaves of blueberry are a rich source of polyphenols, chlorogenic acid (CGA) being the dominant constituent. It exerts beneficial health effects on living organisms. However, the mechanism of its interaction with biological systems at the molecular and cell level is not yet fully known. For this reason, biophysical studies were undertaken to investigate the effect of the polyphenolic compounds contained in the extract on the physical properties of cells, biological and model lipid membranes; and to assess the extract’s antioxidant activity in relation to the erythrocyte membrane and membrane lipids extracted from erythrocyte membranes. The hemolytic studies have shown that extract exert no destructive effect on the erythrocyte membrane, but make it more resistant to changes in tonicity of the medium. The studies of shapes of erythrocytes and of changes induced by the extract in different areas of the membrane showed that the compounds bind mainly to the outer lipid monolayer of the membrane. The biological activity of the polyphenolic compounds present in the blueberry leaf extract consists primarily in protecting the membranes against the harmful effects of free radicals, probably owing to a barrier that they form on the surface of the membrane. In addition, the close link demonstrated between the antioxidant activity of the extract and the activity of CGA means that the extract may, at appropriately selected high concentrations, be used as a widely available, cheap CGA substitute, in those pharmacological preparations where CGA has long been used, without the risk of side effects.     

Chlorogenic acid ameliorates intestinal mitochondrial injury by increasing antioxidant effects and activity of respiratory complexes

Dietary polyphenols are thought to be beneficial for human health by acting as antioxidants. Chlorogenic acid (CGA) is abundant in plant-based foods as an ester of caffeic acid and quinic acid. In this study, we investigated the effects of CGA on mitochondrial protection. Our results demonstrated that pretreatment with CGA ameliorated the intestinal mitochondrial injury induced by H₂O₂; membrane potential was increased, mitochondrial swelling, levels of reactive oxygen species, contents of 8-hydroxy-2-deoxyguanosine, and cytochrome c released were decreased. The beneficial effects of CGA were accompanied by an increase in antioxidant and respiratory-chain complex I, IV, and V activities. In trinitrobenzene-sulfonic acid-induced colitic rats indicated that CGA supplementation improved mitochondria ultrastructure and decreased mitochondrial injury. Our results suggest a promising role for CGA as a mitochondria-targeted antioxidant in combating intestinal oxidative injury. Daily intake of diets containing CGA, such as coffee and honeysuckle, may be useful for prevention of intestinal diseases.     

Comprehensive geriatric assessment for older women with early breast cancer - a systematic review of literature

ABSTRACT: BACKGROUND: The Comprehensive Geriatric Assessment (CGA) is an analytical tool increasingly implemented in clinical practice. Breast cancer is primarily a disease of older people; however, most evidence-based research is aimed at younger patients. METHODS: A systematic review of literature was carried out to assess the use of CGA in older breast cancer patients for clinical decision making. The PubMed, Embase and Cochrane databases were searched. RESULTS: A total of nine useful full text article results were found. Only five of these were exclusively concerned with early breast cancer; thus, studies involving a variety of cancer types, stages and treatments were accepted, as long as they included early breast cancer. The results comprised a series of low sources of evidence. However, all results shared a common theme: the CGA has a use in determining patient suitability for different types of cancer treatment and subsequently maximizing the patient's quality of life. CONCLUSIONS: There is not yet sufficient high level evidence to instate CGA guidelines as a mandatory practice in the management of breast cancer, due to the heterogeneity of available studies. More studies need to be conducted to cement current work on the benefits of the CGA. An area of particular interest is with regard to treatment options, especially surgery and chemotherapy, and identifying patients who may be suitable for these treatments.     

Coffee pulp koji of Aspergillus sojae as stable immobilized catalyst of chlorogenate hydrolase

Chlorogenate hydrolase (EC 3.1.1.42, CHase) was highly induced in mycelia of Aspergillus sojae AKU 3312 grown in Czapek medium containing either instant coffee powder or coffee pulp as inducer. No CHase formation was observed in the mycelia when cultivated without the inducer. CHase was purified readily from CHase-induced mycelia to high homogeneity, and the purified CHase revealed the molecular weight of 180,000 consisting of two identical subunits of 88 kDa. Equimolar quinate (QA) and caffeate (CA) were confirmed on hydrolysis of chlorogenate (CGA). The purified CHase was only useful for a laboratory scale hydrolysis of CGA. For practical QA and CA production using scaled up hydrolysis of vegetable extracts of natural CGA resources, the enzyme activity of purified CHase decreased and denatured irreversibly. Preparation of coffee pulp koji and its application to QA and CA production were proposed instead of purified CHase. When coffee pulp koji was heated at 60°C for 30 min, CHase survived without any appreciable loss of enzyme activity while vegetative mycelial growth and spore germination were terminated. The heated coffee pulp koji thus prepared was effective itself as stable immobilized catalyst of CHase for QA and CA production from vegetable CGA resources such as coffee powders, coffee pulp, and others.     

Prospects for cancer prevention.

As in many other countries, the New Zealand Cancer Society produces guidelines for cancer prevention. These recommend avoiding asbestos, smoking, sunlight, alcohol, fatty food and obesity. Women are advised to have a regular cervical smear test. Additional 'probably helpful' suggestions include eating plenty of fresh fruit and vegetables and dietary fibre. However, considerable data from animal studies and more slowly accumulating data from human intervention studies suggest additional and more specific advice may be appropriate. Fruit and vegetable servings should total a minimum of five each day. Some specific fruits and vegetables (e.g., tomato, broccoli, onions) may have particular benefits against individual cancer types. Positive human evidence on potential benefits of increasing dietary fibre comes from studies where wheat bran was added to the diet. This is not a dietary fibre per se, but merely a good fibre source. Indeed, our own studies suggest that it could be various phytochemicals in the bran, rather than dietary fibre, which is beneficial. An increase either in whole wheat or wheat bran, rather than fibre, would be a sounder recommendation. Although there is some evidence that multivitamin supplementation can protect against cancer, this may be only in the special situation where the population is already significantly vitamin-deficient. For example, a combination of beta-carotene, vitamin E and selenium significantly reduced cancer mortality in a Chinese population, whereas lung cancer risks (in already high risk groups) were increased in Finnish and American trials with high dose beta-carotene. Various other chemopreventive drugs are being actively developed and at various stages in clinical trials. The enhanced cancer incidence in the beta-carotene trial illustrates the potential benefit of utilising surrogate endpoints of malignant disease rather than incident cancer as a trial endpoint.     

Correlation between chromogranin A, neuron-specific enolase and synaptophysin expression, and some clinico-pathological features of colorectal cancer

Several studies employing various techniques have demonstrated the occurrence of neuroendocrine cells in colorectal cancers. Chromogranin A (CGA), neuron-specific enolase (NSE) and synaptophysin (SYN) are general markers of neuroendocrine cells. The aims of the present study were to evaluate the possible correlations between CGA and/or NSE and/or SYN expression in colorectal cancer and some of its clinico-pathological features. The study was conducted on 48 patients with colorectal cancer treated with surgery only at the Department of Surgical Gastroenterology, Medical Academy and District Oncology Center, Bia?ystok. There were no statistically significant relationships between colorectal cancer CGA and/or NSE and/or SYN expression and tumor site, histopathological type, grading, lymph node metastases, age and sex of patients. However, high ratio of lymph node metastases in colorectal cancers with neuroendocrine cells suggests their more agressive clinical course.     

A multiscale probabilisitic framework to model early steps in tumor metastasis

Tumor metastasis is the leading cause of nearly all cancer related deaths. While several experimental and computational studies have addressed individual stages of the complex metastasis process, a comprehensive systems-biology model that links various stages of metastasis has not been put forth as of yet. In this paper we discuss the formulation and application of such a model that utilizes basic principles of cell biology, physics and mechanics to study the migratory patterns of tumor cells as they move from the parent tumor site to the connective tissue via the basement membrane. The model is first of its kind in capturing the essential early features of metastasis in a single simulation and shows good agreement with recent experimental studies.     

A Multisclae Probabilisitc Framework to Model Early Steps in Tumor Metastasis

Tumor metastasis is the leading cause of nearly all cancer related deaths. While several experimental and computational studies have addressed individual stages of the complex metastasis process, a comprehensive systems-biology model that links various stages of metastasis has not been put forth as of yet. In this paper we discuss the formulation and application of such a model that utilizes basic principles of cell biology, physics and mechanics to study the migratory patterns of tumor cells as they move from the parent tumor site to the connective tissue via the basement membrane. The model is first of its kind in capturing the essential early features of metastasis in a single simulation and shows good agreement with recent experimental studies.     

Coffee Consumption Decreases Risks for Hepatic Fibrosis and Cirrhosis: A Meta-Analysis

Background and Aim

Previous studies have demonstrated that coffee consumption may be inversely correlated with hepatic fibrosis and cirrhosis. However, the reported results have been inconsistent. To summarize previous evidences quantitatively, a meta-analysis was performed.

Methods

The Medline, Web of Science, and Embase databases (from inception to June 2015) were searched to identify relevant trials that evaluated the effects of coffee consumption on hepatic fibrosis or cirrhosis. Odds ratios (ORs) of advanced hepatic fibrosis or cirrhosis for low or moderate, high, and any coffee consumption versus no consumption were pooled. Two cups per day was used as the cut-off level between low or moderate and high consumption.

Results

Sixteen studies were included, involving 3034 coffee consumers and 132076 people who do not consume coffee. The pooled results of the meta-analysis indicated that coffee consumers were less likely to develop cirrhosis compared with those who do not consume coffee, with a summary OR of 0.61 (95%CI: 0.45–0.84). For low or moderate coffee consumption versus no consumption, the pooled OR of hepatic cirrhosis was 0.66 (95%CI: 0.47–0.92). High coffee consumption could also significantly reduce the risk for hepatic cirrhosis when compared with no coffee consumption (OR = 0.53, 95%CI: 0.42–0.68). The effect of coffee consumption on hepatic fibrosis was summarized as well. The pooled OR of advanced hepatic fibrosis for coffee consumption versus no consumption was 0.73 (95%CI: 0.58–0.92). The protective effect of coffee on hepatic fibrosis and cirrhosis was also identified in subgroup meta-analyses of patients with alcoholic liver disease and chronic hepatitis C virus (HCV) infection.

Conclusion

Coffee consumption can significantly reduce the risk for hepatic fibrosis and cirrhosis.     

Gas Chromatography Time-Of-Flight Mass Spectrometry (GC-TOF-MS)-Based Metabolomics for Comparison of Caffeinated and Decaffeinated Coffee and Its Implications for Alzheimer’s Disease

Findings from epidemiology, preclinical and clinical studies indicate that consumption of coffee could have beneficial effects against dementia and Alzheimer’s disease (AD). The benefits appear to come from caffeinated coffee, but not decaffeinated coffee or pure caffeine itself. Therefore, the objective of this study was to use metabolomics approach to delineate the discriminant metabolites between caffeinated and decaffeinated coffee, which could have contributed to the observed therapeutic benefits. Gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to characterize the metabolic differences between caffeinated and decaffeinated coffee. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed distinct separation between the two types of coffee (cumulative Q² = 0.998). A total of 69 discriminant metabolites were identified based on the OPLS-DA model, with 37 and 32 metabolites detected to be higher in caffeinated and decaffeinated coffee, respectively. These metabolites include several benzoate and cinnamate-derived phenolic compounds, organic acids, sugar, fatty acids, and amino acids. Our study successfully established GC-TOF-MS based metabolomics approach as a highly robust tool in discriminant analysis between caffeinated and decaffeinated coffee samples. Discriminant metabolites identified in this study are biologically relevant and provide valuable insights into therapeutic research of coffee against AD. Our data also hint at possible involvement of gut microbial metabolism to enhance therapeutic potential of coffee components, which represents an interesting area for future research.     

Calorimetric,volumetric and structural studies of the interaction between chlorogenic acid and dipalmitoylphosphatidylcholine bilayers

Chlorogenic acid (CGA) is the main component of coffee and an antioxidant. CGA has been reported to bear various good health effects. At the same time, it has been found that the addition of CGA induces an undesirable deformation of red blood cells. This fact suggests that CGA may bind to the proteins or/and membrane lipids of red blood cells. This study aimed to examine how CGA binds the bilayers of phosphatidylcholine (PC), one of red blood cells' primary lipids. To this end, we investigated the effect of CGA on the phase behavior and the structure of dipalmitoyl-PC (DPPC) bilayers in the form of multi-lamellar vesicles. Calorimetry and dilatometry measurements showed that the DPPC chain melting transition cooperativity decreases as increasing CGA concentrations. In addition, X-ray diffraction results showed that the lamellar repeat periodicity becomes disordered, and the periodicity disappears completely at high CGA concentrations. Together with these findings, it can be inferred that the CGA molecules do not penetrate inside the DPPC bilayers but bind to their surface in a negatively charged form.     

Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes

Chlorogenic acid (CGA) has been shown to delay intestinal glucose absorption and inhibit gluconeogenesis. Our aim was to investigate the role of CGA in the regulation of glucose transport in skeletal muscle isolated from db/db mice and L6 skeletal muscle cells. Oral glucose tolerance test was performed on db/db mice treated with CGA and soleus muscle was isolated for 2-deoxyglucose transport study. 2DG transport was also examined in L6 myotubes with or without inhibitors such as wortmannin or compound c. AMPK was knocked down with AMPKα1/2 siRNA to study its effect on CGA-stimulated glucose transport. GLUT 4 translocation, phosphorylation of AMPK and Akt, AMPK activity, and association of IRS-1 and PI3K were investigated in the presence of CGA. In db/db mice, a significant decrease in fasting blood sugar was observed 10 minutes after the intraperitoneal administration of 250 mg/kg CGA and the effect persisted for another 30 minutes after the glucose challenge. Besides, CGA stimulated and enhanced both basal and insulin-mediated 2DG transports in soleus muscle. In L6 myotubes, CGA caused a dose- and time-dependent increase in glucose transport. Compound c and AMPKα1/2 siRNA abrogated the CGA-stimulated glucose transport. Consistent with these results, CGA was found to phosphorylate AMPK and ACC, consistent with the result of increased AMPK activities. CGA did not appear to enhance association of IRS-1 with p85. However, we observed activation of Akt by CGA. These parallel activations in turn increased translocation of GLUT 4 to plasma membrane. At 2 mmol/l, CGA did not cause any significant changes in viability or proliferation of L6 myotubes. Our data demonstrated for the first time that CGA stimulates glucose transport in skeletal muscle via the activation of AMPK. It appears that CGA may contribute to the beneficial effects of coffee on Type 2 diabetes mellitus.     

Experimental studies on Echinococcus multilocularis in Japan, focusing on biohazardous stages of the parasite

Alveolar echinococcosis (AE), caused by the active growth of larval Echinococcus multilocularis mostly in the liver, is usually fatal zoonotic disease if not adequately treated. Humans become infected via oral ingestion of the parasite eggs, which are thus biohazardous to humans and should be handled under restricted conditions. In this review, we present findings in experimental studies mainly performed at a safety facility in Japan, examining the biohazadous stages of the parasite (Hokkaido isolate) including its egg and adult worm stages. This article deals mainly with the parasite development in various experimental and wild animals, environmental factors affecting viability of the parasite eggs, and molecular biological studies on adult worms. The findings shown herein have provided a basis to better understand basic biology and natural transmission of E. multilocularis in Hokkaido, a highly endemic area of AE in northern Japan, and also to establish effective preventive measures against the disease.     

Inhibiting TGF-β signaling in hepatocellular carcinoma

One of the main complications in patients with liver fibrosis is the development of hepatocellular carcinoma (HCC). An understanding of the molecular mechanisms leading to HCC is important in order to be able to design new pharmacological agents serving either to prevent or mitigate the outcome of this malignancy. The transforming growth factor-beta (TGF-β) cytokine and its isoforms initiate a signaling cascade which is closely linked to liver fibrosis, cirrhosis and subsequent progression to HCC. Because of its role in these stages of disease progression, TGF-β appears to play a unique role in the molecular pathogenesis of HCC. Thus, it is a promising target for pharmacological treatment strategies. Recent studies have shown that inhibition of TGF-β signaling results in multiple synergistic down-stream effects which will likely improve the clinical outcome in HCC. We also review a number of TGF-β inhibitors, most of which are still in a preclinical stage of development, but may soon be available for trial in HCC patients. Hence, it is anticipated that there will soon be new agents available for clinical investigations to evaluate the role of the TGF-β-associated signaling in this deadly cancer.     

Screening of onion seed sets for resistance against new Iranian isolates of Fusarium oxysporum f. sp. cepa

Root and basal rot disease (RBR) of onion, Fusarium oxysporum f. sp. cepa (FOC), is one of the most important diseases, which cause tremendous losses in onion-growing areas worldwide. In this survey, various onion genotypes, including eight main and dominant Iranian seed sets and two exotic ones, were tested against FOC incidence in greenhouse and field conditions of various growing stages. The incidence of the RBR was determined at three stages, such as early, flowering and seed-setting stages, on the basis of disease severity. The genotypes reacted differentially to FOC within and between various stages with a very high significant level. The genotypes were classified in five scoring scales, accordingly. Highly infected ones tended to be associated with the highest mean scores of 75–100% severity and the least infected genotypes had the lowest scores of 0–10%. Moreover, the examined genotypes were ranked from 1 to 10 according to their markedly differing reactions to FOC at various stages. Variance and cluster analysis also showed similar results among the genotypes with various levels of infections. There was a direct, positive and enhancing correlation for every genotype to infection as the growing stages were reaching to the maturing stage.     

Coffee, caffeine, and coronary heart disease

PURPOSE OF REVIEW: This review summarizes and highlights recent advances in current knowledge of the relationship between coffee and caffeine consumption and risk of coronary heart disease. Potential mechanisms and genetic modifiers of this relationship are also discussed. RECENT FINDINGS: Studies examining the association between coffee consumption and coronary heart disease have been inconclusive. Coffee is a complex mixture of compounds that may have either beneficial or harmful effects on the cardiovascular system. Randomized controlled trials have confirmed the cholesterol-raising effect of diterpenes present in boiled coffee, which may contribute to the risk of coronary heart disease associated with unfiltered coffee consumption. A recent study examining the relationship between coffee and risk of myocardial infarction incorporated a genetic polymorphism associated with a slower rate of caffeine metabolism and provides strong evidence that caffeine also affects risk of coronary heart disease. Several studies have reported a protective effect of moderate coffee consumption, which suggests that coffee contains other compounds that may be beneficial. SUMMARY: Diterpenes present in unfiltered coffee and caffeine each appear to increase risk of coronary heart disease. A lower risk of coronary heart disease among moderate coffee drinkers might be due to antioxidants found in coffee.     

Chlorogenic acid inhibits hepatocellular carcinoma in vitro and in vivo

Curative treatment of patients with hepatocellular carcinoma (HCC) is poor. There is an urgent need to develop more effective strategies for the chemoprevention of HCC. Chlorogenic acid (CGA), a type of polyphenol present in the diet, especially from coffee, has many biological activities. Patients with viral hepatitis who drank coffee everyday experienced a reduction in the incidence of HCC. In the present study, we evaluated the effects of CGA on HCC. CGA inhibited the proliferation of HepG2 cells in vitro and the progression of HepG2 xenograft in vivo. CGA induced the inactivation of ERK1/2 and suppressed the expression of MMP-2 and MMP-9 in HepG2 xenograft tissue. These data demonstrate that CGA can prevent the progression of HCC through multiple pathways. CGA appears to be an effective chemopreventive agent for hepatocellular carcinoma.     

Chromogranin A (CGA) in the gastro-entero-pancreatic (GEP) endocrine system

Summary Chromogranin A (CGA), a protein at first detected in the adrenal medulla, has recently been found also in other organs, e.g. the endocrine pancreas. However, immunohistochemical findings concerning the cellular source of pancreatic CGA were controversial. Therefore, the endocrine pancreas of 10 mammalian species (man, tupaia, mole, cat, dog, pig, guinea pig, rabbit, rat) was investigated immunohistochemically for CGA-like immunoreactivities on serial semithin plastic sections using a high-titer polyclonal antiserum against bovine CGA. The results show that basically all pancreatic endocrine cell types are CGA-immunoreactive; however, every species has its own pattern of CGA-immunoreactive cell types. Other findings of the present studies indicate that the physiological function of CGA in pancreatic endocrine cells is related to the storage mechanisms of peptide hormones. Finally, a methodological approach is given to obtain not only qualitative but also semiquantitative data during immunohistochemical investigations.