Mitochondrial and redox dysfunction in post-menopause as risk factor of neurodegenerative disease: a pilot study testing the role of a validated Japanese functional food.

During the menopause women may experience increased oxidative stress and decreased antioxidant capacity and, together with the decline of neurosteroids, this represents a risk factor for Alzheimer's disease. The aim of the present study was to test a functional food (FPP-ORI, Osato Research Institute, Gifu, Japan) on redox and mitochondrial efficiency in post-menopausal women. The study population consisting of 69 untreated post-menopausal women were given supplements as follows: Group A was given a multivitamin (MV) 1c 2 times a day, and group B was given FPP 4.5 g 2 times a day. Group C consisted of 23 fertile premenopausal women as the control group. The tests carried out on entry, and at 3 and 6 months were erythrocyte redox parameters, plasma oxidated proteins, brain-derived neurotrophic factor (BDNF) and peripheral blood mononuclear cell (PBMC) mitochondria cytochrome c oxidase Vmax activity. Menopausal women showed an increased malondialdehyde (MDA) (p<0.05 vs control) which was normalized by both treatments (p<0.05), but MV failed to do so in the BMI ≥26 subgroup (p<0.05). All other redox enzymes and BDNF were significantly lower in menopausal women and they responded only to FPP (p<0.05). Carbonyl protein level was higher in "BMI ≥ 26" subgroup (p<0.05) and reduced only by FPP (p<0.05). The PBMC cyclooxygenase to citrate synthase activity was reduced (<40%) in the menopausal group (p<0.01) and only FPP caused a significant restoration (p<0.05). Although preliminary, these data confirm the redox and mitochondrial dysfunction occurring in post-menopause and responsive to FPP but very poorly to high dosage antioxidants. This may lead to potential preventive opportunities in menopause-associated neurodegenerative disease.

Iron supplementation in young iron-deficient females causes gastrointestinal redox imbalance: protective effect of a fermented nutraceutical.

The aim of this study was to assess whether the concomitant supplementation of certified fermented papaya preparation (FPP, ORI, Gifu, Japan) together with iron supplementation could beneficially affect lipid peroxidation either systemically and at a intraluminal gut level in women with low iron stores. Treatment compliance and iron absorption was assessed as well. Fifty-two non-pregnant, fertile, non-smokers, healthy women with iron deficiency were recruited. The women were given iron supplements (100 mg Fe/d as ferrous sulfate) to be taken daily for 12 weeks (group A). Group B patients were also supplemented with 6g/day of a FPP. A detailed life style questionnaire was administered to all subjects. Iron, ferritin, transferrin receptors (Tf R) and malondialdehyde (MDA) in plasma were measured. The RBCs lysate was used for the estimation of superoxide dismutase (SOD) and glutathione peroxidase (GPx). The total and free iron concentration as well as analysis of oxidative stress in the feces was measured. FPP-supplemented subjects showed a significantly lower degree of gastrointestinal discomfort (p less than 0.05) and abolished the iron supplementation-induced increase of MDA (p less than 0.001) and the depletion of SOD and GPx (p less than 0.01). Moreover, the nutraceutical co-administration brought about a significant reduction of gut oxidative damage and lower fecal content of either total and free iron (p less than 0.05 vs group A). Overall, group B showed a better TfR/ferritin ratio response (p less than 0.05 vs group A). While iron supplementation maintains its clinical relevance considering the prevalence of iron deficiency among females, a careful clinical evaluation and a protective nutraceutical co-administration, as our data suggest with FPP, should be considered.

Irritable bowel syndrome: new findings in pathophysiological and therapeutic field.

Irritable bowel syndrome (IBS) is a high prevalence disease, whose symptoms are reported by a large number of young adults with significant effects on quality of life and social costs. Traditionally, IBS has been treated with dietary and lifestyle modification, fiber supplementation, psychological and pharmacological therapy. Since its complex and multifactorial etiopathogenesis is only partially known, therapeutic choices may be difficult and not always effective. New research efforts focused on the role of relationship between central nervous system and gut disorders (brain-gut axis), altered composition of gut microbiota (e.g. an eight times increased risk for IBS after Salmonella infection), immune activation with an increased number of T lymphocytes and mast cells associated with mucosa as well as an increased level of pro-inflammatory cytokines (IL-10 and IL-12, suggesting Th1 polarization), visceral hypersensitivity causing perception of pain even for minimal abdominal distension. Based on these findings, new possibilities of treatment are emerging with encouraging outcomes. Attention is directed to drugs that showed good tolerability profile and poor systemic absorption, which may make them suitable for repeated or long term treatments, as frequently required in patients with IBS. They have been successfully used drugs such as tachykinin receptors antagonists, tryptophan hydroxylase inhibitors, bile acid sequestrants, µ agonist and δ antagonist opioid receptors. Recent studies are discussed in this review, focusing both on new therapeutic approaches and innovative adaptation of previously available treatments.

Liver fibrosis: evaluation with diffusion-weighted magnetic resonance imaging in patients with chronic liver disease.

AIM: Liver fibrosis is often a possible evolution of chronic liver disease (CLD), with a risk of progression to cirrhosis. This study was designed to determine if the measure of apparent diffusion coefficient (ADC) is clinically accurate in the staging of fibrosis. METHODS: The study was conducted in the period 2008-2012. We recruited 84 patients with CLD. The control group included 67 patients whose laboratory, ultrasound and magnetic resonance imaging exams demonstrated liver's normal conditions. For ethical reasons, these patients did not undergo liver biopsy. Patients were examined using diffusion-weighted magnetic resonance imaging with a 1.5 Tesla magnet and with single shot echo-planar technique. Patients did undergo liver biopsy and the samples were evaluated with the Metavir score (F0-F4), Ishak score (0-6) and Brunt score (0-6). Patients were divided into three groups according to the different degree of fibrosis and the ADC was compared with U-test of Mann-Whitney. Moreover, it was used the analysis Receiver Operating Characteristic (ROC). RESULTS: A significant difference between group 1 (F0-F1) and group 3 (F3-F4) was found, with P=0.0024 and between group 2 (F2) and group 3, with P=0.027, but there was no significant difference of the ADC values in group 1 and group 2. CONCLUSION: The study showed a correlation between reduction of ADC and increasing of liver fibrosis degree. The ADC seems to be useful in staging liver fibrosis in patients with CLD, in particular to distinguish the later stages of fibrosis from early and intermediate stages.

Beneficial effect of a sturgeon-based bioactive compound on gene expression of tumor necrosis factor-alpha, matrix metalloproteinases and type-10 collagen in human chondrocytes.

In the present study, we examined the effect of a marine bioactive compound containing high-purity caviar-derived DNA, collagen elastin and protein extracts from sturgeon (LD-1227, Caviarlieri, Laboratoires Dom, Switzerland) on IL-1beta-induced activation and production of TNFalpha and MMP-13 in human osteo-arthritis (OA) chondrocytes and intracellular signaling factors. Human chondrocytes were derived from OA cartilage and stimulated with IL-1beta. Gene expression of TNFalpha, MMP-13, MMP-1 and Col10A1 was measured by quantitative RT-PCR. TNFalpha protein in culture medium was determined using cytokine-specific ELISA. Western immunoblotting was used to analyze the MMP-13 production in the culture medium and the activation of NF-kB. DNA binding activity of NF-kB p65 was determined using a highly sensitive and specific ELISA. MMP-13 activity in the culture medium was assayed by gelatine zymography. LD-1227 significantly decreased IL-1beta-stimulated gene expression and production of TNFalpha, MMP-1, MMP-13 and Col10A1 in human chondrocytes. The inhibitory effect of LD-1227 on the IL-1beta-induced expression of these genes was mediated at least in part via suppression of NF-kB p65. These data show that LD-1227 can inhibit IL-1beta-induced proliferation and inflammatory reactions via inhibited activation of the transcription factor NF-kB pathway in human chondrocytes derived from OA patients. These novel pharmacological actions of LD-1227 on IL-1beta-stimulated human OA chondrocytes provide suggestions that this marine biology compound may inhibit cartilage degradation by suppressing IL-1beta-mediated activation and the catabolic response in human chondrocytes.

[Autoimmune pancreatitis today: clinical features and diagnostic strategies]. / La pancreatite autoimmune oggi: caratteristiche cliniche e strategie diagnostiche.

Autoimmune pancreatitis (AIP) is a particular form of chronic pancreatitis recognized as clinical entity only in recent decades. Peculiar clinical, serological, histological and radiological features make it different from other types of pancreatitis. The diagnosis of AIP represents a challenge for the clinicians. Particularly in its focal form, it shows several features in common with pancreatic adenocarcinoma. Both of these conditions, in fact, are often associated with obstructive jaundice, cause increase of the volume of the pancreas and can share the radiologic appearance of a focal mass. The autoimmune pancreatitis instead of pancreatic cancer regresses promptly after treatment with oral corticosteroids. Because of the different management of the two diseases a correct differential diagnosis is imperative. From 5% to 21% of AIP cases are diagnosed in patients after pancreatic resection performed for suspected malignancy. Still not identified a specific serological marker of AIP which can allow a definitive diagnosis of the disease. Both the diagnosis of pancreatic cancer as AIP is paid on the basis of different clinical tests: the diagnosis of pancreatic cancer requires imaging studies, laboratory tests and biopsy of the pancreas, while the diagnosis of AIP requires confirmation of the diagnostic histological, serological and radiological criteria, the involvement of other organs and a positive response to treatment with corticosteroids. Recently, three different diagnostic strategies for AIP have been proposed.

[Pancreatic hyperenzymemia: new advances in the field of clinical-diagnostic approach, with particular attention about Gullo's syndrome]. / Iperenzimemia pancreatica: recenti acquisizioni in tema di approccio clinico-diagnostico, con particolare attenzione alla sindrome di Gullo.

An increase in serum levels of pancreatic enzymes is a well-known manifestation of pancreatic disease, especially of inflammatory or neoplastic nature, even if several extrapancreatic diseases can equally cause that increase. In addition to this pathological type of hyperenzymemia, different "non-pathological" forms have also been identified, including macroamylasemia, salivary, and mixed salivary and pancreatic hyperamylasemia, in all of which only amylase elevations are seen. Nevertheless, in 1996 a new syndrome characterized by an abnormal, chronic, benign increase in levels of serum amylase, pancreatic isoamylase, lipase and trypsin, asymptomatic and usually discovered incidentally, was described for the first time by Lucio Gullo et al. Hyperamylasemia/hyperlipasemia's observation is nowadays on the increase because general practitioners tend to include more frequently amylase and lipase in routine blood tests and, moreover, because the constant evaluation of this biochemical alteration in the Emergency Unit: for this reason, this syndrome was clearly identified only recently. Therefore, it's characterized by serum elevation of all pancreatic enzymes in the absence of underlying diseases; it occurs in either sporadic or familial form and it persists over time with considerable fluctuation in serum enzyme concentrations, including frequent normalizations. Proper diagnosis of this form of hyperenzymemia is important because it reassures the subjects having this anomaly that the syndrome is benign, and because it can prevent multiple and expensive diagnostic tests or useless hospitalizations or therapies.

Advantage of carbonate-versus citrate-based alkalinization on bone metabolism in moderately exercising aged male rats fed an acidogenic diet.

This study aims to determine the effects of different alkaline supplementations on high protein diet-induced abnormalities affecting bone metabolism in rats which were also undergoing physical exercise of moderate intensity. Sixty elderly Sprague-Dawley rats were randomly divided into four groups of 10 rats each and treated for 16 weeks as follows: baseline control group fed normal food (C); acidic high-protein diet supplemented group (chronic acidosis, CA group), bicarbonate-based alkaline formula (Basenpulver, Named, Italy) supplemented chronic acidosis (BB-CA) and citrate-based alkaline supplement (CB-CA). Throughout the supplementation period, rats were put on a treadmill training mimicking a moderate level of exercise. In the CA group, 24-hour urinary calcium (Ca) and phosphorus (P) excretion were increased over 30 percent (p<0.05 vs normal diet controls). However serum Ca was not significantly changed. Femural and tibial BMD and BMC was significantly decreased in the CA group (p<0.05) but both alkaline supplementations prevented such phenomenon (p<0.05 vs CA), without significant difference between the two formulations although the BB-CA group showed significantly more preserved trabecular bone volume (p<0.05 vs CB-CA group). An increased level of over 50 percent of urinary Dpd observed in the CA group (p<0.001) was reverted to normal by both supplementations (p<0.001 vs CA group). The same applied to urinary net acid excretion (p<001) with BB-supplementation performing better than CB-supplementation (p<0.05). Moreover, while the latter did not modify Nterminal telopeptide value, BB-supplementation significantly normalized this parameter (p<0.05 vs CA group) which exercise and acidic protein diet had modified (p<0.01 vs control diet). Overall, the present study shows that a bicarbonate-based alkaline formula, when administered to a dose amenable to clinical use, may significantly protect bone structure in exercising aged animals to a greater extent than a quali/quantitavely similar citrate-based formula.

Beneficial nutraceutical modulation of cerebral erythropoietin expression and oxidative stress: an experimental study.

The main object of this study is to examine the effect of Klamin®, a nutraceutical containing phenylethylamine, phycocyanins, mycosporine-like aminoacids and aphanizomenon flos aquae-phytochrome on the learning and memory ability, the oxidative status and cerebral erythropoietin and its receptor EPO/EPOR system in prematurely senescent (PS) mice. A total of 28 PS mice, selected according to a prior T-maze test, and 26 non-prematurely senescent mice (NPS) mice were chosen. PS animals were divided into 3 groups and followed for 4 weeks: A) normal chow diet; B) added with Klamin® at 20 mg/kg/day (low dose); C) added with Klamin® at 100mg/kg/day (high dose). A further group of NPS mice given either normal food (group D) or high dose Klamin® (group E) was also considered. The behavioral procedures of spatial learning ability (Morris test) showed that PS mice had significantly longer learning time as compared to their NPS counterpart (p<0.01), but this effect was prevented especially in mice supplemented with high-dose Klamin® (p<0.05) which improved performances in NPS mice (p<0.05). High-dose Klamin® supplementation restored the depleted total thiol concentration in the brain observed in PS mice while normalizing their increased malonildialdehyde level (p<0.05). Moreover, the high-dosage only caused a significant upregulation of EPO/EPOR system both in PS and in NPS animals (p<0.05). Taken together, these data suggest that this specific alga Klamath extract has considerable antioxidant and adaptogenic properties, also through a stimulatory effect of cerebral EPO/EPO system.

Redox balance signalling in occupational stress: modification by nutraceutical intervention.

There is increasing evidence that psychosocial stress can be viewed as a system-wide derangement of cellular homeostasis, with heightened oxidative stress and triggered proinflammatory mechanisms. The aim of this study is twofold: a) to replicate findings that psychological stress increases oxidative damage and b) to determine whether a fermented papaya preparation known to exert significant protective antioxidant properties could buffer such increases in nuclear DNA damage while also inducing epigenetic protective mechanisms. Twenty-eight sedentary men and women (age range: 28-52), who reported living a stressful lifestyle but with an overall positive attitude, were recruited for this study. Chronic diseases as well as severe burnout and use of drugs for anxiety constituted exclusion criteria. Subjects were supplemented for 1 month with 9 g/day (4.5 g twice a day) of a certified fermented papaya preparation. All subjects were given a stress and sleep quality questionnaire together with a diet and life style assessment. Blood was collected at 2 and 4 week, erythrocyte and leukocyte were separated to assess redox balance and heme oxygenase-1 (HO-1) gene expression while bilirubin oxidized metabolites (BOMs) were tested in the urine. Stressed individuals showed a significant abnormality of redox status with increased MDA of erythrocyte and increased level of 8-0HdG in leukocyte and BOMs excretion (p<0.05). Nutraceutical supplementation brought about a normalization of such values already at the 2 week observation (p<0.05) together with a significant upregulation of HO-1 (p<0.01). Taken together, the results of this study confirm that stressful occupational life per se, without any overt psychiatric illness, may be associated to increased oxidative stress. Supplementation with functional food affecting redox regulation may be part of the therapeutic armamentarium to be considered in this clinical setting.

Comparative study of cinnamon oil and clove oil on some oral microbiota.

A comparative study was carried out between cinnamon oil and clove oil on the oral micro-biota causing dental caries. Cinnamon oil was found to be more effective than clove oil exhibiting broad spectrum of antibacterial activity inhibiting all the ten test bacterial species involved in dental caries. Cinnamon oil produced maximum inhibition zone of diameter (IZD) of 24.0 mm against Streptococcus mutans (major causative bacteria of dental plaque) as compared to clove oil (IZD = 13.0mm). This is contrary to the popular belief that clove oil is effective in tooth decay and dental plaque. This study shows the potential of cinnamon oil over clove oil in the treatment of dental caries. (www.actabiomedica.it).

The gut microbiota and its correlations with the central nervous system disorders.

A mutual impact of gastrointestinal tract (GIT) and central nervous system (CNS) functions has been recognized since the mid-twentieth century. It is accepted that the so-called gut-brain axis provides a two-way homeostatic communication, through immunological, hormonal and neuronal signals. A dysfunction of this axis has been associated with the pathogenesis of some diseases both within and outside the GIT, that have shown an increase in incidence over the last decades. Studies comparing germ-free animals and animals exposed to pathogenic bacterial infections, probiotics or antibiotics suggest the participation of the microbiota in this communication and a role in host defense, regulation of immunity and autoimmune disease appearance. The GIT could represent a vulnerable area through which pathogens influence all aspects of physiology and even induce CNS neuro-inflammation. All those concepts may suggest the modulation of the gut microbiota as an achievable strategy for innovative therapies in complex disorders. Moving from this background, the present review discusses the relationship between intestinal microbiota and CNS and the effects in health and disease. We particularly look at how the commensal gut microbiota influences systemic immune response in some neurological disorders, highlighting its impact on pain and cognition in multiple sclerosis, Guillain-Barrè Syndrome, neurodevelopmental and behavioral disorders and Alzheimer's disease. In this review we discuss recent studies showing that the potential microbiota-gut-brain dialogue is implicated in neurodegenerative diseases. Gaining a better understanding of the relationship between microbiota and CNS could provide an insight on the pathogenesis and therapeutic strategies of these disorders.

Helicobacter pylori-positive duodenal ulcer: three-day antibiotic eradication regimen.

BACKGROUND: The most widely used treatments for ulcer healing and Helicobacter pylori eradication consist of a 1-2 week regimen of a proton pump inhibitor plus two or three antimicrobials. AIMS: To evaluate the efficacy, safety, cost, and tolerance of a three-day regimen with three antibiotics vs. a 10-day treatment with a proton pump inhibitor or vs. a ranitidine bismuth citrate triple therapy. METHODS: Two hundred and twenty-one patients with endoscopically-proven H. pylori-positive duodenal ulcers were recruited to the study. Recruited patients were assigned to one of the following four regimens: (I) omeprazole 40 mg o.m. plus amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 10 days (OAC: 55 patients); (ii) omeprazole 40 mg o.m. on days 1-5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. on days 3-5 (OACM: 56 patients); (iii) ranitidine bismuth citrate 400 mg b.d. plus amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 10 days (RAC: 54 patients); (iv) ranitidine bismuth citrate 400 mg b.d. on days 1-5, plus amoxycillin 1 g b.d., clarithromycin 500 mg b.d. and metronidazole 500 mg b.d. on days 3-5 (RACM: 56 patients). Fisher's exact test was used to compare data regarding healing and eradication in the four groups. RESULTS: The intention-to-treat eradication and ulcer healing rates for the RACM regimen were 95% and 98%, respectively. Statistically significant differences were observed, relating to the eradication and healing of ulcers, between RACM and either the RAC or OAC regimens. CONCLUSION: The three-day antibiotic therapy with amoxycillin, clarithromycin and metronidazole in addition to ranitidine bismuth citrate is a very effective anti-H. pylori regimen.

Ranitidine bismuth citrate versus omeprazole triple therapy for the eradication of Helicobacter pylori and healing of duodenal ulcer.

AIM: To compare the efficacy and safety of triple therapy with omeprazole plus amoxycillin and clarithromycin vs. ranitidine bismuth citrate plus amoxycillin and clarithromycin in the treatment of Helicobacter pylori-associated duodenal ulcers. METHODS: Eighty-one patients with duodenal ulcers were randomized to the following treatments: 39 cases with amoxycillin 1 g b.d. and clarithromycin 500 mg b.d. for 1 week plus omeprazole 20 mg b.d. for 2 weeks (omeprazole + amoxycillin + clarithromycin (OAC)), and 42 cases to the same regimen of amoxycillin and clarithromycin for 7 days plus ranitidine bismuth citrate 400 mg b.d. for 2 weeks (ranitidine bismuth citrate + amoxycillin + clarithromycin (RbAC)). Upper gastrointestinal endoscopy was performed together with a rapid urease test and histological examination of antral and corpus biopsy samples prior to treatment and 4 weeks after the end of therapy. RESULTS: Thirty-four patients in the OAC group and 38 in the RbAC group completed the treatment and 4-week follow-up. H. pylori was eradicated in 30 of 34 patients (88%) in the OAC group and in 32 of 38 patients (84%) in the RbAC group according to a per-protocol analysis (P = N.S.). Thirty-three (97%) patients treated with OAC and 36 (95%) treated with RbAC presented healed duodenal ulcers at 4 weeks (P = N.S.). On an intention-to-treat basis there was no difference in H. pylori eradication between the OAC (77%) and RbAC groups (76%); duodenal ulcer healing was achieved in 85 and 86% of patients in the OAC and RbAC groups, respectively (P = N.S.). CONCLUSION: The OAC and RbAC triple therapy regimens proved equally effective in both H. pylori eradication and in duodenal ulcer healing.

[Levosulpiride versus domperidone in the treatment of functional dyspepsia]. / Levosulpiride vs domperidone nel trattamento della dispepsia funzionale.

Levosulpiride, a dopaminergic antagonist was compared in a double-blind randomized study with domperidone for treatment of functional dyspepsia in 50 patients divided into two groups of 25 subjects each. Group I received 25 mg levosulpiride 3 times daily, group II received 10 mg domperidone 3 times daily, all for 30 days. Periodic clinical examination at days 0, 7, 15, 30 showed symptomatic changes. Gallbladder and gastric emptying was studied by ultrasonography at the start and end of treatment. Both drugs had a positive influence on dyspeptic symptoms and on gastric and gallbladder emptying, but the latter parameters were improved significantly more effectively by levosulpiride. As to tolerability, there have been 3 drop-outs and a further 6 patients complained of sides effects that did not require suspension of treatment.

Effect of Celergen, a marine derivative, on in vitro hepatocarcinogenesis.

The aim of this study was to test for a potential anticarcinogenic effect of Celergen, a marine derivative devoid of traceable amounts of inorganic arsenic, on cell proliferation, cell cycle progression and apoptosis in the HepG2 human liver cancer cell line. Celergen significantly inhibited the proliferation of cancer cells in a dose-dependent manner while limiting the cell cycle progression at the G1 phase and significantly inducing apoptosis. Further examination showed that Celergen enhanced expression of the p21(CIPl1WAF1), GADD153 genes and downregulated the c-myc gene. These results suggest that Celergen exerts promising chemopreventive properties to be further investigated.