Inflammatory Bowel Diseases: An Updated Overview on the Heat Shock Protein Involvement.

Inflammatory bowel diseases (IBDs) represent chronic idiopathic disorders, including Crohn's disease (CD) and ulcerative colitis (UC), in which one of the trigger factors is represented by aberrant immune interactions between the intestinal epithelium and the intestinal microbiota. The involvement of heat shock proteins (HSPs) as etiological and pathogenetic factors is becoming of increasing interest. HSPs were found to be differentially expressed in the intestinal tissues and sera of patients with CD and UC. It has been shown that HSPs can play a dual role in the disease, depending on the stage of progression. They can support the inflammatory and fibrosis process, but they can also act as protective factors during disease progression or before the onset of one of the worst complications of IBD, colorectal cancer. Furthermore, HSPs are able to mediate the interaction between the intestinal microbiota and intestinal epithelial cells. In this work, we discuss the involvement of HSPs in IBD considering their genetic, epigenetic, immune and molecular roles, referring to the most recent works present in the literature. With our review, we want to shed light on the importance of further exploring the role of HSPs, or even better, the role of the molecular chaperone system (CS), in IBD: various molecules of the CS including HSPs may have diagnostic, prognostic and therapeutic potential, promoting the creation of new drugs that could overcome the side-effects of the therapies currently used.

Inflammatory bowel disease and infertility: analysis of literature and future perspectives.

BACKGROUND: inflammatory bowel diseases (IBD) are chronic disorders that affect the gastrointestinal tract but which also present extraintestinal manifestations. One of the problems related to IBD is the presence of both female and male infertility. AIM: determine the correlation between IBD and male and female infertility by analyzing the literature. MATERIAL AND METHODS: Studies carried out in the last twenty years have been selected through the pubmed search engine. Only studies were selected that in their conclusions showed a real correlation between IBD and infertility. RESULTS: the first cause of infertility in both sexes is related to the surgical interventions that patients have to face during the course of the disease, but there are also psychological causes or causes related to the use of drugs used for therapy. CONCLUSIONS: further studies are needed to understand what are the real mechanisms underlying infertility in subjects suffering from IBD.

Extracellular vesicles derived from gut microbiota in inflammatory bowel disease and colorectal cancer.

The human gut microbiome encompasses inter alia, the myriad bacterial species that create the optimal host-microorganism balance essential for normal metabolic and immune function. Various lines of evidence suggest that dysregulation of the microbiota-host interaction is linked to pathologies such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Extracellular vesicles (EVs), found in virtually all body fluids and produced by both eukaryotic cells and bacteria are involved in cell-cell communication and crosstalk mechanisms, such as the immune response, barrier function and intestinal flora. This review highlights advancements in knowledge of the functional role that EVs may have in IBD and CRC, and discusses the possible use of EVs derived from intestinal microbiota in therapeutic strategies for treating these conditions.

Effects of oleuropein on tumor cell growth and bone remodelling: Potential clinical implications for the prevention and treatment of malignant bone diseases.

Oleuropein (Ole) is the main bioactive phenolic compound present in olive leaves, fruits and olive oil. This molecule has been shown to exert beneficial effects on several human pathological conditions. In particular, recent preclinical and observational studies have provided evidence that Ole exhibits chemo-preventive effects on different types of human tumors. Studies undertaken to elucidate the specific mechanisms underlying these effects have shown that this molecule may thwart several key steps of malignant progression, including tumor cell proliferation, survival, angiogenesis, invasion and metastasis, by modulating the expression and activity of several growth factors, cytokines, adhesion molecules and enzymes involved in these processes. Interestingly, experimental observations have highlighted the fact that most of these signalling molecules also appear to be actively involved in the homing and growth of disseminating cancer cells in bones and, ultimately, in the development of metastatic bone diseases. These findings, and the experimental and clinical data reporting the preventive activity of Ole on various pathological conditions associated with a bone loss, are indicative of a potential therapeutic role of this molecule in the prevention and treatment of cancer-related bone diseases. This paper provides a current overview regarding the molecular mechanisms and the experimental findings underpinning a possible clinical role of Ole in the prevention and development of cancer-related bone diseases.

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals.

Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.

Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature.

BACKGROUND: Folic acid and its derivates, known as folates, are chemoprotective micronutrients of great interest because of their essential role in the maintenance of health and genomic integrity. The supplementation of folic acid during pregnancy has long been known to reduce the risk of neural tube defects (NTDs) in the foetus. Folate metabolism can be altered by many factors, including adequate intake through diet. Folate deficiency can compromise the synthesis, repair and methylation of DNA, with deleterious consequences on genomic stability and gene expression. These processes are known to be altered in chronic diseases, including cancer and cardiovascular diseases. MAIN BODY: This review focuses on the association between folate intake and the risk of childhood leukaemia. Having compiled and analysed studies from the literature, we show the documented effects of folates on the genome and their role in cancer prevention and progression with particular emphasis on DNA methylation modifications. These changes are of crucial importance during pregnancy, as maternal diet has a profound impact on the metabolic and physiological functions of the foetus and the susceptibility to disease in later life. Folate deficiency is capable of modifying the methylation status of certain genes at birth in both animals and humans, with potential pathogenic and tumorigenic effects on the progeny. Pre-existing genetic polymorphisms can modify the metabolic network of folates and influence the risk of cancer, including childhood leukaemias. The protective effects of folic acid might be dose dependent, as excessive folic acid could have the adverse effect of nourishing certain types of tumours. CONCLUSION: Overall, maternal folic acid supplementation before and during pregnancy seems to confer protection against the risk of childhood leukaemia in the offspring. The optimal folic acid requirements and supplementation doses need to be established, especially in conjunction with other vitamins in order to determine the most successful combinations of nutrients to maintain genomic health and wellbeing. Further research is therefore needed to uncover the role of maternal diet as a whole, as it represents a main factor capable of inducing permanent changes in the foetus.

Vitamin D in cancer chemoprevention.

CONTEXT: There is increasing evidence that Vitamin D (Vit D) and its metabolites, besides their well-known calcium-related functions, may also exert antiproliferative, pro-differentiating, and immune modulatory effects on tumor cells in vitro and may also delay tumor growth in vivo. OBJECTIVE: The aim of this review is to provide fresh insight into the most recent advances on the role of Vit D and its analogues as chemopreventive drugs in cancer therapy. METHODS: A systematic review of experimental and clinical studies on Vit D and cancer was undertaken by using the major electronic health database including ISI Web of Science, Medline, PubMed, Scopus and Google Scholar. RESULTS AND CONCLUSION: Experimental and clinical observations suggest that Vit D and its analogues may be effective in preventing the malignant transformation and/or the progression of various types of human tumors including breast cancer, prostate cancer, colorectal cancer, and some hematological malignances. These findings suggest the possibility of the clinical use of these molecules as novel potential chemopreventive and anticancer agents.

Fluticasone furoate maintains epithelial homeostasis via leptin/leptin receptor pathway in nasal cells.

Leptin is involved in the lung epithelial homeostasis. Its role in the nasal tract is largely unknown. Allergic rhinitis (AR) is induced by the allergen exposure leading to consequential structural abnormalities in the nasal epithelium. Topical corticosteroids are recommended as first-line therapy in AR. Parietaria pollen is one of the most important allergenic sources in the southern Europe. In vitro, in human nasal epithelial cell line RPMI 2650, we aimed to determine whether allergen stimulation acts on leptin/leptin receptor pathway and how fluticasone furoate (FF) influences this pathway. The effects of the major allergen recombinant Par j 1 (rPar j 1), of FF, of leptin, and of TGF-ß1 on cell proliferation, on leptin/leptin receptor expression and modulation (by clonogenic test, by RT-q-RT-PCR, by immunocytochemistry and by flow-cytometry), and on STAT-3 activation (assessing nuclear translocation by western blot analysis) were assessed. We found that rPar j 1 and TGF-ß1 significantly decreased cell proliferation and down-regulated the leptin/leptin receptor pathway, whereas FF and leptin reverted them, both alone and in combination. Furthermore, rPar j 1 reduced, while leptin and FF increased STAT-3 activation. In conclusion, FF and leptin itself are able to preserve nasal epithelial homeostasis restoring the leptin/leptin receptor pathway altered by rPar j 1 exposure.

Flavonols and flavan-3-ols as modulators of xanthine oxidase and manganese superoxide dismutase activity.

Experiments were performed to assess the dose-dependent effects of quercetin, kaempferol, (+) catechin, and (-) epicatechin on superoxide radical production through the modulation of manganese superoxide dismutase and xanthine oxidase activities. The experiments were carried out at flavanoid concentrations ranging from 1 µM to 100 µM. This investigation highlighted that flavonols induced opposite effects on superoxide radical production at different doses, i.e. pro-oxidant at the highest concentration (100 µM) and anti-oxidant at the lowest concentration (1 µM). Similar behaviors were observed for xanthine oxidase with flavan-3ols. The diastereoisomer (the catechin) acted as a stronger radical scavenger than the epicatechin. However, flavan-3ols were less pro-oxidant than flavonols: in fact, the addition of the superoxide dismutase enzyme was able to cancel the flavan-3ols' pro-oxidant effect. This study also shows that the absence of the 4-carbonyl group conjugated with the 2-3 double bonds in the heterocyclic ring cancelled the pro-oxidant effect of flavan-3ols. The opposite dose-dependent effects of flavonols suggest that they may be used as either a pro-oxidant or antioxidant.

Follistatin as potential therapeutic target in prostate cancer.

Follistatin is a single-chain glycosylated protein whose primary function consists in binding and neutralizing some members of the transforming growth factor-ß superfamily such as activin and bone morphogenic proteins. Emerging evidence indicates that this molecule may also play a role in the malignant progression of several human tumors including prostate cancer. In particular, recent findings suggest that, in this tumor, follistatin may also contribute to the formation of bone metastasis through multiple mechanisms, some of which are not related to its specific activin or bone morphogenic proteins' inhibitory activity. This review provides insight into the most recent advances in understanding the role of follistatin in the prostate cancer progression and discusses the clinical and therapeutic implications related to these findings.

Apigenin affects leptin/leptin receptor pathway and induces cell apoptosis in lung adenocarcinoma cell line.

BACKGROUND: Apigenin, a common edible plant flavonoid, is a well characterised antioxidant. The adipokine leptin exerts proliferative and anti-apoptotic activities in a variety of cell types. In cancer cells, apigenin may induce a pro-apoptotic pathway whereas leptin has an anti-apoptotic role. The purpose of the study is to investigate the role of apigenin and of leptin/leptin receptor pathway on proliferation and on apoptosis in lung adenocarcinoma. METHODS: Immunocytochemistry, flow cytometry and RT-q-RT PCR, were used to investigate the expression and modulation of leptin receptors on the lung adenocarcinoma cell line A549 in presence or absence of apigenin and of leptin, alone or combined. Clonogenic test to evaluate cell proliferation was assessed. Exogenous leptin binding to its receptors by flow cytometry, reactive oxygen species (ROS) by dichlorofluorescein diacetate analysis, cell death by ethidium bromide and apoptosis by annexin V analysis were assessed. Apoptosis was assessed also in presence of lung adenocarcinoma pleural fluids (PF) (n=6). RESULTS: A549 express leptin/leptin receptor pathway and its expression is upregulated by apigenin. Apigenin alone or combined with leptin significantly decreases cell proliferation and significantly increases the spontaneous release of ROS, with augmented cell death and apoptosis, this latter also in the presence of lung adenocarcinoma PF. Leptin alone significantly increases cell proliferation and significantly decreases cell death. CONCLUSIONS: These results strongly suggest the potential utility of the flavonoid apigenin in the complementary therapeutic approach of patients with lung adenocarcinoma.

Long-term effects of dietary sodium intake on cytokines and neurohormonal activation in patients with recently compensated congestive heart failure.

BACKGROUND: A growing body of evidence suggests that the fluid accumulation plays a key role in the pathophysiology of heart failure (HF) and that the inflammatory and neurohormonal activation contribute strongly to the progression of this disorder. METHODS AND RESULTS: The study evaluated the long-term effects of 2 different sodium diets on cytokines neurohormones, body hydration and clinical outcome in compensated HF outpatients (New York Heart Association Class II). A total of 173 patients (105 males, mean age 72.5+/-7) recently hospitalized for worsening advanced HF and discharged in normal hydration and in clinical compensation were randomized in 2 groups (double blind). In Group 1, 86 patients received a moderate restriction in sodium (120mmol to 2.8g/day) plus oral furosemide (125 to 250mg bid); in Group 2, 87 patients: received a low-sodium diet (80mmol to 1.8g/day) plus oral furosemide (125 to 250mg bid). Both groups were followed for 12 months and the treatment was associated with a drink intake of 1000mL daily. Neurohormonal (brain natriuretic peptide, aldosterone, plasma rennin activity) and cytokines values (tumor necrosis factor-alpha, interleukin-6) were significantly reduced with a significant increase of the anti-inflammatory cytokine interleukin-10 at 12 months in normal, P < .0001) than low-sodium group. The low-sodium diet showed a significant activation of neurohormones and cytokines and worsening the body hydration, whereas moderate sodium restriction maintained dry weigh and improved outcome in the long term. CONCLUSIONS: Our results appear to suggest a surprising efficacy of a new strategy to improve the chronic diuretic response by increasing Na intake and limiting fluid intake. This counterintuitive approach underlines the need for a better understanding of factors that regulate sodium and water handling in chronic congestive HF. A larger sample of patients and further studies are required to evaluate whether this is due to the high dose of diuretic used or the low-sodium diet.

Food safety in hospital: knowledge, attitudes and practices of nursing staff of two hospitals in Sicily, Italy.

BACKGROUND: Food hygiene in hospital poses peculiar problems, particularly given the presence of patients who could be more vulnerable than healthy subjects to microbiological and nutritional risks. Moreover, in nosocomial outbreaks of infectious intestinal disease, the mortality risk has been proved to be significantly higher than the community outbreaks and highest for foodborne outbreaks. On the other hand, the common involvement in the role of food handlers of nurses or domestic staff, not specifically trained about food hygiene and HACCP, may represent a further cause of concern. The purpose of this study was to evaluate knowledge, attitudes, and practices concerning food safety of the nursing staff of two hospitals in Palermo, Italy. Association with some demographic and work-related determinants was also investigated. METHODS: The survey was conducted, by using a semi-structured questionnaire, in March-November 2005 in an acute general hospital and a paediatric hospital, where nursing staff is routinely involved in food service functions. RESULTS: Overall, 401 nurses (279, 37.1%, of the General Hospital and 122, 53.5%, of the Paediatric Hospital, respectively) answered. Among the respondents there was a generalized lack of knowledge about etiologic agents and food vehicles associated to foodborne diseases and proper temperatures of storage of hot and cold ready to eat foods. A general positive attitude towards temperature control and using clothing and gloves, when handling food, was shared by the respondents nurses, but questions about cross-contamination, refreezing and handling unwrapped food with cuts or abrasions on hands were frequently answered incorrectly. The practice section performed better, though sharing of utensils for raw and uncooked foods and thawing of frozen foods at room temperatures proved to be widely frequent among the respondents. Age, gender, educational level and length of service were inconsistently associated with the answer pattern. More than 80% of the respondent nurses did not attend any educational course on food hygiene. Those who attended at least one training course fared significantly better about some knowledge issues, but no difference was detected in both the attitude and practice sections. CONCLUSION: Results strongly emphasize the need for a safer management of catering in the hospitals, where non professional food handlers, like nursing or domestic staff, are involved in food service functions.

Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure: a double-blind study.

OBJECTIVES: The aim of this study was to evaluate the effect of a new treatment for refractory congestive heart failure (CHF) on brain natriuretic peptide (BNP) plasma levels and hydration station. BACKGROUND: The study was aimed at evaluating the effects of the combination of high-dose furosemide and small-volume hypertonic saline solution (HSS) in refractory CHF patients. METHODS: A total of 94 patients (34 women/60 men) with refractory CHF (age 55 to 80 years) were enrolled. They had to have an ejection fraction <35%, serum creatinine <2 mg/dl, blood urea nitrogen <60 mg/dl, a reduced urinary volume, and a low natriuresis (<500 ml/24 h and <60 mEq/24 h, respectively). Patients were divided (double-blind) into two groups: group 1 (18 women/30 men) received an intravenous furosemide (500 to 1,000 mg) plus HSS twice a day in 30 min. Group 2 (16 women/30 men) received an intravenous bolus of furosemide (500 to 1,000 mg/twice a day) alone, for four to six days. At entry, body weight, blood pressure, heart rate, and laboratory parameters were checked during hospitalization; BNP levels were measured on admission, 6 and 30 days after discharge, while on admission and 6 days after, impedance plethysmography was performed. The HSS group received 120 mmol of Na intake versus 80 mmol in non-HSS group. Fluid intake of 1,000 was given to both groups. RESULTS: The groups were similar for clinical characteristics. A significant increase in daily diuresis and natriuresis was observed in HSS group, p < 0.05. The BNP values showed significant intragroup and intergroup differences, 6 and 30 days after treatment. The patients from the HSS group reached a better hydration state than the non-HSS group after six days. In addition, the HSS group showed a significant reduction in hospitalization time and readmission rate. CONCLUSIONS: Our data show that the HSS group reached dry weight more rapidly, a significantly faster reduction in BNP levels, shorter hospitalization stay, and lower incidence in readmissions in the 30-day study period.

Testosterone and aggressiveness.

Aggressiveness is an ancestral behavior common to all animal species. Its neurophysiological mechanisms are similar in all vertebrates. Males are generally more aggressive than females. In this review, aggressive behavior in rodents, monkeys, and man and the role of testosterone and brain serotonin levels have been considered. Interspecific aggressiveness in rats has been studied considering the mouse-killing behavior; the neonatal androgenization of females increases adult mouse-killing as does the administration of testosterone in adults. Intraspecific aggressiveness was studied by putting two or more male rats (or mice) in the same cage; the condition of subjection or dominance is influenced by testosterone. In monkeys, testosterone is related to aggressiveness and dominance and, during the mating season, increases in testosterone levels and aggressive attitude are observed. In men, higher testosterone levels were obtained in perpetrators of violent crimes, in men from the army with antisocial behaviors, in subjects with impulsive behaviors, alcoholics and suicidals, in athletes using steroids, and during competitions. Aggressive and dominant behavior are distinguished. Testosterone influences both of these, even if man is usually inclined to affirm his power without causing physical damage. Testosterone receptors are mainly in some hypothalamic neurons, where it is aromatized into estrogens, which determine the increase in aggressiveness. A relation between testosterone levels and diencephalic serotonin has been shown: in fact, the lack of serotonin increases aggressive behaviors both in animals and man. Testosterone also increases ADH levels in the medial amygdala, lateral hypothalamus, and preoptical medial area, involved in aggressive behaviors.

The phenolic compounds of olive oil: structure, biological activity and beneficial effects on human health.

The Mediterranean diet is rich in vegetables, cereals, fruit, fish, milk, wine and olive oil and has salutary biological functions. Epidemiological studies have shown a lower incidence of atherosclerosis, cardiovascular diseases and certain kinds of cancer in the Mediterranean area. Olive oil is the main source of fat, and the Mediterranean diet's healthy effects can in particular be attributed not only to the high relationship between unsaturated and saturated fatty acids in olive oil but also to the antioxidant property of its phenolic compounds. The main phenolic compounds, hydroxytyrosol and oleuropein, which give extra-virgin olive oil its bitter, pungent taste, have powerful antioxidant activity both in vivo and in vitro. The present review focuses on recent works analysing the relationship between the structure of olive oil polyphenolic compounds and their antioxidant activity. These compounds' possible beneficial effects are due to their antioxidant activity, which is related to the development of atherosclerosis and cancer, and to anti-inflammatory and antimicrobial activity.

Relationship between ACE-DD polymorphism and diastolic performance in healthy subjects.

BACKGROUND: The ACE-D allele has been associated with cardiovascular disease. The study evaluates the relationship between the ACE-ID genotypes and diastolic function in healthy subjects after 6 years of follow-up. METHODS: Two hundred and seventy-five healthy volunteers aged 25-55 years had normal physical examination, 12-lead ECG, acceptable echocardiographic windows and echocardiogram at entry. Venous blood was drawn for DNA analysis. RESULTS: Two hundred and forty-two subjects completed 6 years of follow-up. Three genetically distinct groups were obtained: ACE-DD group (n=71, 26F/45M, mean age 48 +/- 7 years); ACE-ID (n=115, 39F/76M, mean age 40 +/- 7 years); and ACE-II (n=56, 20F/36M, mean age 47 +/- 6 years). Significant differences in E/A ratio were found between ACE-DD and ACE-ID, and ACE II (p=0.028, <0.0001, 0.0001), respectively. After 6 years, echocardiography showed a significant reduction of E/A ratio in the ACE-DD group, p=0.0001. CONCLUSION: The data suggest that ACE-DD is associated with deteriorating myocardial diastolic properties.