Polyphenol-Rich Extract from 'Limoncella' Apple Variety Ameliorates Dinitrobenzene Sulfonic Acid-Induced Colitis and Linked Liver Damage.

Inflammatory bowel conditions can involve nearly all organ systems and induce pathological processes through increased oxidative stress, lipid peroxidation and disruption of the immune response. Patients with inflammatory bowel disease (IBD) are at high risk of having extra-intestinal manifestations, for example, in the hepatobiliary system. In 30% of patients with IBD, the blood values of liver enzymes, such as AST and ALT, are increased. Moreover, treatments for inflammatory bowel diseases may cause liver toxicity. Apple polyphenol extracts are widely acknowledged for their potential antioxidant effects, which help prevent damage from oxidative stress, reduce inflammation, provide protection to the liver, and enhance lipid metabolism. The aim of this study was to investigate whether the polyphenol apple extract from Malus domestica cv. 'Limoncella' (LAPE) may be an effective intervention for the treatment of IBD-induced hepatotoxicity. The LAPE was administrated in vivo by oral gavage (3-300 mg/kg) once a day for 3 consecutive days, starting 24 h after the induction of dinitro-benzenesulfonic acid (DNBS) colitis in mice. The results showed that LAPE significantly attenuated histological bowel injury, myeloperoxidase activity, tumor necrosis factor and interleukin (IL-1ß) expressions. Furthermore, LAPE significantly improved the serum lipid peroxidation and liver injury in DNBS-induced colitis, as well as reduced the nuclear transcription factor-kappaB activation. In conclusion, these results suggest that LAPE, through its antioxidant and anti-inflammatory properties, could prevent liver damage induced by inflammatory bowel disease.

The urotensin-II receptor: A marker for staging and steroid outcome prediction in ulcerative colitis.

BACKGROUND: Urotensin-II receptor- (UTR) related pathway exerts a key-role in promoting inflammation. The aim was to assess the relationship between UTR expression and clinical, endoscopic and biochemical severity of ulcerative colitis (UC), exploring its predictivity of intravenous (iv) steroid administration therapeutic outcome. METHODS: One-hundred patients with first diagnosis of UC and 44 healthy subjects were enrolled. UTR expression was assessed by qPCR, Western Blot (WB) and immunohistochemistry (IHC). Clinical, endoscopic and histological activity of UC were evaluated by using Truelove and Witts (T&W) severity index, Mayo Endoscopic Score (MES), and Truelove and Richards Index (TRI). The partial and full Mayo scores (PMS and FMS) were assessed to stage the disease. RESULTS: The UTR expression, resulted higher in the lesioned mucosa of UC patients in comparison to healthy subjects (p < .0001 all). Direct relationship between UTR (mRNA and protein) expression and disease severity assessment (T&W, PMS, MES and TRI) was highlighted (p < .0001 all). UTR expression resulted also higher in the 72 patients requiring iv steroids administration compared to those who underwent alternative medications, (p < .0001). The 32 steroid-non-responders showed an increased UTR expression (WB, IHC and qPCR from lesioned mucosa), compared to 40 steroid-responders (p: .0002, .0001, p < .0001 respectively). The predictive role of UTR expression (p < .05) on the negative iv steroids administration therapeutic outcome was highlighted and ROC curves identified the thresholds expressing the better predictive performance. CONCLUSIONS: UTR represents a promising inflammatory marker related to clinical, endoscopic, and histological disease activity as well as a predictive marker of steroid administration therapeutic outcome in the UC context.

TRPM8 indicates poor prognosis in colorectal cancer patients and its pharmacological targeting reduces tumour growth in mice by inhibiting Wnt/ß-catenin signalling.

BACKGROUND AND PURPOSE: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC). EXPERIMENTAL APPROACH: TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8-/- mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC. KEY RESULTS: TRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt-Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/ß-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of ß-catenin and its target oncogenes such as C-Myc and Cyclin D1. CONCLUSION AND IMPLICATIONS: Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.

Polydatin Incorporated in Polycaprolactone Nanofibers Improves Osteogenic Differentiation.

Polycaprolactone nanofibers are used as scaffolds in the field of tissue engineering for tissue regeneration or drug delivery. Polycaprolactone (PCL) is a biodegradable hydrophobic polyester used to obtain implantable nanostructures, which are clinically applicable due to their biological safety. Polydatin (PD), a glycosidic precursor of resveratrol, is known for its antioxidant, antitumor, antiosteoporotic, and bone regeneration activities. We aimed to use the osteogenic capacity of polydatin to create a biomimetic innovative and patented scaffold consisting of PCL-PD for bone tissue engineering. Both osteosarcoma cells (Saos-2) and mesenchymal stem cells (MSCs) were used to test the in vitro cytocompatibility of the PD-PCL scaffold. Reverse-phase (RP) HPLC was used to evaluate the timing release of PD from the PCL-PD nanofibers and the MTT assay, scanning electron microscopy, and alkaline phosphatase (ALP) activity were used to evaluate the proliferation, adhesion, and cellular differentiation in both osteosarcoma and human mesenchymal stem cells (MSCs) seeded on PD-PCL nanofibers. The proliferation of osteosarcoma cells (Saos-2) on the PD-PCL scaffold decreased when compared to cells grown on PLC nanofibers, whereas the proliferation of MSCs was comparable in both PCL and PD-PCL nanofibers. Noteworthy, after 14 days, the ALP activity was higher in both Saos-2 cells and MSCs cultivated on PD-PCL than on empty scaffolds. Moreover, the same cells showed a spindle-shaped morphology after 14 days when grown on PD-PCL as shown by SEM. In conclusion, we provide evidence that nanofibers appropriately coated with PD support the adhesion and promote the osteogenic differentiation of both human osteosarcoma cells and MSCs.

Casein-derived peptides from the dairy product kashk exhibit wound healing properties and antibacterial activity against Staphylococcus aureus: Structural and functional characterization.

Kashk is a fermented dairy product typical of the Middle East, traditionally produced with sour milk and/or dairy waste. The kashk water-soluble peptide fraction was characterized at the molecular level by liquid chromatography-mass spectrometry and its antibacterial and skin healing activity was evaluated. Antibacterial assays showed a significant antibacterial activity against clinical isolates of Staphylococcus aureus (S. aureus) from patients with atopic dermatitis, inhibiting bacterial growth by approximately 45% (500 µg/mL). Skin repair activity was evaluated on keratinocytes through scratch tests showing accelerated wound closure in vitro in the presence of TNF-α, by approximately 44% (500 µg/mL), compared to control cells. Furthermore, based on the MTT assay, the kashk peptide fraction did not show toxicity on keratinocytes. The results suggested that the peptide kashk extract may be useful in skin care for patients with atopic dermatitis.

H9c2 Cardiomyocytes under Hypoxic Stress: Biological Effects Mediated by Sentinel Downstream Targets.

The association between diabetes and cardiovascular diseases is well known. Related diabetes macro- and microangiopathies frequently induce hypoxia and consequently energy failure to satisfy the jeopardized myocardium basal needs. Additionally, it is widely accepted that diabetes impairs endothelial nitric oxide synthase (eNOS) activity, resulting in diminished nitric oxide (NO) bioavailability and consequent endothelial cell dysfunction. In this study, we analyzed the embryonic heart-derived H9c2 cell response to hypoxic stress after administration of a high glucose concentration to reproduce a condition often observed in diabetes. We observed that 24 h hypoxia exposure of H9c2 cells reduced cell viability compared to cells grown in normoxic conditions. Cytotoxicity and early apoptosis were increased after exposure to high glucose administration. In addition, hypoxia induced a RhoA upregulation and a Bcl-2 downregulation and lowered the ERK activation observed in normoxia at both glucose concentrations. Furthermore, a significant cell proliferation rate increases after the 1400 W iNOS inhibitor administration was observed. Again, hypoxia increased the expression level of myogenin, a marker of skeletal muscle cell differentiation. The cardiomyocyte gene expression profiles and morphology changes observed in response to pathological stimuli, as hypoxia, could lead to improper ventricular remodeling responsible for heart failure. Therefore, understanding cell signaling events that regulate cardiac response to hypoxia could be useful for the discovery of novel therapeutic approaches able to prevent heart diseases.

Metabolite Profile and In Vitro Beneficial Effects of Black Garlic (Allium sativum L.) Polar Extract.

Over the centuries, humans have traditionally used garlic (Allium sativum L.) as a food ingredient (spice) and remedy for many diseases. To confirm this, many extensive studies recognized the therapeutic effects of garlic bulbs. More recently, black garlic (BG), made by heat-ageing white garlic bulbs, has increased its popularity in cuisine and traditional medicine around the world, but there is still limited information on its composition and potential beneficial effects. In this study, the metabolite profile of methanol extract of BG (BGE) was determined by high-performance liquid chromatography coupled to tandem mass spectrometry in high-resolution mode. Results allowed to establish that BGE major components were sulfur derivatives, saccharides, peptides, organic acids, a phenylpropanoid derivative, saponins, and compounds typical of glycerophospholipid metabolism. Characterization of the BGE action in cancer cells revealed that antioxidant, metabolic, and hepatoprotective effects occur upon treatment as well as induction of maturation of acute myeloid leukemia cells. These results are interesting from the impact point of view of BG consumption as a functional food for potential prevention of metabolic and tumor diseases.

Polydatin Induces Differentiation and Radiation Sensitivity in Human Osteosarcoma Cells and Parallel Secretion through Lipid Metabolite Secretion.

Osteosarcoma is a bone cancer characterized by the production of osteoid tissue and immature bone from mesenchymal cells. Osteosarcoma mainly affects long bones (femur is most frequently site) and occur in children and young adults with greater incidence. Here, we investigated the role accomplished by polydatin, a natural antioxidative compound, in promoting osteogenic differentiation alone or after radiation therapy on osteosarcoma cells. In vitro, polydatin significantly induced cell cycle arrest in S-phase and enhanced bone alkaline phosphatase activity. Moreover, the differentiation process was paralleled by the activation of Wnt-ß-catenin pathway. In combination with radiotherapy, the pretreatment with polydatin promoted a radiosensitizing effect on osteosarcoma cancer cells as demonstrated by the upregulation of osteogenic markers and reduced clonogenic survival of tumor cells. Additionally, we analyzed, by mass spectrometry, the secretion of sphingolipid, ceramides, and their metabolites in osteosarcoma cells treated with polydatin. Overall, our results demonstrate that polydatin, through the secretion of sphingolipids and ceramide, induced osteogenic differentiation, alone and in the presence of ionizing therapy. Future investigations are needed to validate the use of polydatin in clinical practice as a potentiating agent of radiotherapy-induced anticancer effects.

Oral Microbiota and Salivary Levels of Oral Pathogens in Gastro-Intestinal Diseases: Current Knowledge and Exploratory Study.

Various bi-directional associations exist between oral health and gastro-intestinal diseases. The oral microbiome plays a role in the gastro-intestinal carcinogenesis and fusobacteria are the most investigated bacteria involved. This paper aims to review the current knowledge and report the preliminary data on salivary levels of Fusobacterium nucleatum, Porphyromonas gingivalis and Candida albicans in subjects with different gastro-intestinal conditions or pathologies, in order to determine any differences. The null hypothesis was "subjects with different gastro-intestinal diseases do not show significant differences in the composition of the oral microbiota". Twenty-one subjects undergoing esophagastroduodenoscopy or colonscopy were recruited. For each subject, a salivary sample was collected before the endoscopy procedure, immediately stored at -20 °C and subsequently used for genomic bacterial DNA extraction by real-time PCR. Low levels of F. nucleatum and P. gingivalis were peculiar in the oral microbiota in subjects affected by Helicobater pylori-negative chronic gastritis without cancerization and future studies will elucidate this association. The level of C. albicans did not statistically differ among groups. This preliminary study could be used in the future, following further investigation, as a non-invasive method for the search of gastrointestinal diseases and associated markers.

Cardioprotective Effects of Taurisolo® in Cardiomyoblast H9c2 Cells under High-Glucose and Trimethylamine N-Oxide Treatment via De Novo Sphingolipid Synthesis.

In addition to high plasma glucose, increased levels of trimethylamine N-oxide (TMAO) have been found in obese subjects, where are considered as a novel risk factor for cardiovascular diseases. The present study aimed to investigate the effect of a novel nutraceutical formulation based on grape polyphenols (registered as Taurisolo®) in counteracting TMAO- and high glucose (HG)-induced cytotoxicity in cardiomyoblast H9c2 cells. Cell damage was induced with HG (HG-H9c2) and HG+TMAO (THG-H9c2); both experimental cell models were, thus, incubated for 72 h in the presence or absence of Taurisolo®. It was observed that Taurisolo® significantly increased the cell viability and reduced lactate dehydrogenase and aspartate transaminase release in both HG- and THG-H9c2 cells. Additionally, through its antioxidant activity, Taurisolo® modulated cell proliferation via ERK activation in THG-H9c2. Furthermore, Taurisolo® was able to induce autophagic process via increasing the expression of LC3II, a protein marker involved in formation of autophagosome and ex novo synthesis of sphingomyelin, ceramides, and their metabolites both in HG- and THG-H9c2 cells. Finally, Taurisolo® reduced hypertrophy and induced differentiation of HG-H9C2 cells into cardiomyocyte-like cells. These data suggest that Taurisolo® counteracts the toxicity induced by TMAO and HG concentrations increasing autophagic process and activating de novo sphingolipid synthesis, resulting in a morphological cell remodeling. In conclusion, our results allow speculating that Taurisolo®, combined with energy restriction, may represent a useful nutraceutical approach for prevention of cardiomyopathy in obese subjects.

Urotensin II receptor expression in patients with ulcerative colitis: a pilot study.

BACKGROUND: Urotensin II (U-II) is a vasoactive peptide that interacts with a specific receptor named UTR. Recently, our group has demonstrated increased UTR expression in both human colon adenocarcinoma cell lines and adenomatous polyps, as well as in colon carcinoma samples if compared to healthy colon samples of the same patients. We also showed that an UTR agonist induced an increase in colon adenocarcinoma cell growth in vitro, whereas the UTR block with a specific antagonist caused an inhibition of their growth and an inhibition of about 50% of both motility and cell invasion. Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) associated with an increased baseline risk for colon cancer compared with the general population, and this risk is mostly attributed to chronic inflammation and immune dysregulation. This risk increases along with the duration of the disease, as demonstrated by many studies. There are no UTR expression data related to UC, and we therefore evaluated UTR expression in ill colon biopsies and in healthy colon ones of patients with UC and colon biopsies of healthy patients. METHODS: We enrolled, prior to informed consent, 11 patients (5 males and 6 females, age range 29-75 years, median age 52 years) with first UC diagnosis compared to 11 healthy controls (6 males and 5 females, age range 30-78 years, median age 55 years). We have therefore sampled inflammatory and healthy tissue in UC patients. We have also taken colic tissue samples in healthy subjects. Evaluation of receptor expression was performed by reverse transcription-polymerase chain reaction (RT-PCR), Western Blot analysis. The ANOVA Test (P<0.05) was used for statistical analysis. RESULTS: We found: 1) increased expression of UTR in 11/11 UC patients with ill mucosa biopsies compared to healthy controls in RT-PCR and in Western Blot analysis; 2) increased UTR expression in 11/11 UC patients with ill colon biopsies compared to the results obtained from healthy colon biopsies of the same patients both in RT-PCR and in Western Blot analysis; 3) increased UTR expression in 9/11 UC patients healthy colon biopsy specimens compared to healthy controls. CONCLUSIONS: UTR could be considered as an inflammatory UC disease marker because its expression is greater in the mucosa of ill colon than in the healthy colon of the same patients and compared to healthy controls.

Evaluation of the Effect Derived from Silybin with Vitamin D and Vitamin E Administration on Clinical, Metabolic, Endothelial Dysfunction, Oxidative Stress Parameters, and Serological Worsening Markers in Nonalcoholic Fatty Liver Disease Patients.

Nowadays, the nonalcoholic fatty liver disease represents the main chronic liver disease in the Western countries, and the correct medical therapy remains a big question for the scientific community. The aim of our study was to evaluate the effect derived from the administration for six months of silybin with vitamin D and vitamin E (RealSIL 100D®) on metabolic markers, oxidative stress, endothelial dysfunction, and worsening of disease markers in nonalcoholic fatty liver disease patients. We enrolled 90 consecutive patients with histological diagnosis of nonalcoholic fatty liver disease and 60 patients with diagnosis of reflux disease (not in therapy) as healthy controls. The nonalcoholic fatty liver disease patients were randomized into two groups: treated (60 patients) and not treated (30 patients). We performed a nutritional assessment and evaluated clinical parameters, routine home tests, the homeostatic model assessment of insulin resistance, NAFLD fibrosis score and fibrosis-4, transient elastography and controlled attenuation parameter, thiobarbituric acid reactive substances, tumor necrosis factor α, transforming growth factor ß, interleukin-18 and interleukin-22, matrix metalloproteinase 2, epidermal growth factor receptor, insulin growth factor-II, cluster of differentiation-44, high mobility group box-1, and Endocan. Compared to the healthy controls, the nonalcoholic fatty liver disease patients had statistically significant differences for almost all parameters evaluated at baseline (p < 0.05). Six months after the baseline, the proportion of nonalcoholic fatty liver disease patients treated that underwent a statistically significant improvement in metabolic markers, oxidative stress, endothelial dysfunction, and worsening of disease was greater than not treated nonalcoholic fatty liver disease patients (p < 0.05). Even more relevant results were obtained for the same parameters by analyzing patients with a concomitant diagnosis of metabolic syndrome (p < 0.001). The benefit that derives from the use of RealSIL 100D could derive from the action on more systems able to advance the pathology above all in that subset of patients suffering from concomitant metabolic syndrome.

Silybin-Induced Apoptosis Occurs in Parallel to the Increase of Ceramides Synthesis and miRNAs Secretion in Human Hepatocarcinoma Cells.

Silybin is a flavonolignan extracted from Silybum marianum (milk thistle) with hepatoprotective, antioxidant, and anti-inflammatory activity. Several studies have shown that silybin is highly effective to prevent and treat different types of cancer and that its antitumor mechanisms involve the arrest of the cell cycle and/or apoptosis. An MTT assay was performed to study cell viability, lipid peroxidation, extracellular NO production, and scavenger enzyme activity were studied by Thiobarbituric Acid-Reactive Species (TBARS) assay, NO assay, and MnSOD assay, respectively. Cell cycle and apoptosis analysis were performed by FACS. miRNA profiling were evaluated by real time PCR. In this study, we demonstrated that Silybin induced growth inhibition blocking the Hepg2 cells in G1 phase of cell cycle and activating the process of programmed cell death. Moreover, the antiproliferative effects of silybin were paralleled by a strong increase of the number of ceramides involved in the modulation of miRNA secretion. In particular, after treatment with silybin, miR223-3p and miR16-5p were upregulated, while miR-92-3p was downregulated (p < 0.05). In conclusion, our results suggest that silybin-Induced apoptosis occurs in parallel to the increase of ceramides synthesis and miRNAs secretion in HepG2 cells.

Intestinal Anti-Inflammatory Effect of a Peptide Derived from Gastrointestinal Digestion of Buffalo (Bubalus bubalis) Mozzarella Cheese.

Under physiological conditions, the small intestine represents a barrier against harmful antigens and pathogens. Maintaining of the intestinal barrier depends largely on cell⁻cell interactions (adherent-junctions) and cell⁻matrix interactions (tight-junctions). Inflammatory bowel disease is characterized by chronic inflammation, which induces a destructuring of the architecture junctional epithelial proteins with consequent rupture of the intestinal barrier. Recently, a peptide identified by Bubalus bubalis milk-derived products (MBCP) has been able to reduce oxidative stress in intestinal epithelial cells and erythrocytes. Our aim was to evaluate the therapeutic potential of MBCP in inflammatory bowel disease (IBD). We studied the effect of MBCP on (i) inflamed human intestinal Caco2 cells and (ii) dinitrobenzene sulfonic acid (DNBS) mice model of colitis. We have shown that MBCP, at non-cytotoxic concentrations, both in vitro and in vivo induced the adherent epithelial junctions organization, modulated the nuclear factor (NF)-κB pathway and reduced the intestinal permeability. Furthermore, the MBCP reverted the atropine and tubocurarine injury effects on adherent-junctions. The data obtained showed that MBCP possesses anti-inflammatory effects both in vitro and in vivo. These results could have an important impact on the therapeutic potential of MBCP in helping to restore the intestinal epithelium integrity damaged by inflammation.

Ameliorative effect of Silybin on bisphenol A induced oxidative stress, cell proliferation and steroid hormones oxidation in HepG2 cell cultures.

Bisphenol A (BPA) and silybin are considered xenoestrogens and could interfere with the action of endogenous hormones. It was demonstrated a higher level of BPA in plasma of nonalcoholic steatohepatitis (NASH) patients, compared to those with steatosis (NAFL). We investigated the effect of BPA and silybin, alone or in combination, on proliferation, oxidative stress and steroid metabolism in HepG2 grown in high glucose concentration medium (H-HepG2). Cell viability was assessed by adding 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). TBARS were quantified by spectrophotometry. The effect of BPA, silybin and their combination on the expression of phosphorilized extracellular signal-regulated kinase (ERK), ERK and Caspase 3 was determined by Western blot analysis. The identifications of lipids and steroid hormones was performed by mass spectrometry. BPA elicited in H-HepG2 oxidative stress and steroid hormones oxidation leading to the formation of metabolite with estrogenic and genotoxic potentials. Silybin ameliorates the harmful BPA-induced effect decreasing glucose uptake and lipid peroxidation. Moreover silybin activates the synthesis of vitamin D3 metabolites and prevent the steroid hormones oxidation. BPA could be considered as an important risk factor in worsening and progression of NAFLD. At the same time silybin could be a valid support to counteract these effects in NASH patients.

Effect of restriction vegan diet's on muscle mass, oxidative status, and myocytes differentiation: A pilot study.

This study was conceived to evaluate the effects of three different diets on body composition, metabolic parameters, and serum oxidative status. We enrolled three groups of healthy men (omnivores, vegetarians, and vegans) with similar age, weight and BMI, and we observed a significant decrease in muscle mass index and lean body mass in vegan compared to vegetarian and omnivore groups, and higher serum homocysteine levels in vegetarians and vegans compared to omnivores. We studied whether serum from omnivore, vegetarian, and vegan subjects affected oxidative stress, growth and differentiation of both cardiomyoblast cell line H9c2 and H-H9c2 (H9c2 treated with H2 O2 to induce oxidative damage). We demonstrated that vegan sera treatment of both H9c2 and H-H9c2 cells induced an increase of TBARS values and cell death and a decrease of free NO2- compared to vegetarian and omnivorous sera. Afterwards, we investigated the protective effects of vegan, vegetarian, and omnivore sera on the morphological changes induced by H2 O2 in H9c2 cell line. We showed that the omnivorous sera had major antioxidant and differentiation properties compared to vegetarian and vegan sera. Finally, we evaluated the influence of the three different groups of sera on MAPKs pathway and our data suggested that ERK expression increased in H-H9c2 cells treated with vegetarian and vegan sera and could promote cell death. The results obtained in this study demonstrated that restrictive vegan diet could not prevent the onset of metabolic and cardiovascular diseases nor protect by oxidative damage.

Switchable Protecting Strategy for Solid Phase Synthesis of DNA and RNA Interacting Nucleopeptides.

Nucleopeptides are promising nucleic acid mimetics in which the peptide backbone bears nucleobases. They can recognize DNA and RNA targets modulating their biological functions. To date, the lack of an effective strategy for the synthesis of nucleopeptides prevents their evaluation for biological and biomedical applications. Herein, we describe an unprecedented approach that enables the synthesis of cationic both homo and heterosequence nucleopeptides wholly on solid support with high yield and purity. Spectroscopic studies indicate advantageous properties of the nucleopeptides in terms of binding, thermodynamic stability and sequence specific recognition. Biostability assay and laser scanning confocal microscopy analyses reveal that the nucleopeptides feature acceptable serum stability and ability to cross the cell membrane.

Polydatin administration improves serum biochemical parameters and oxidative stress markers during chronic alcoholism: a pilot study.

AIM: Polydatin, a hydroxystilbene derived from the rhizome of Polygonum cuspidatum, elicits hepatoprotective and neuroprotective effects through its anti-oxidant properties. The present study aimed to determine the effects of oral administration of polydatin in alcoholic patients in order to improve liver biochemical parameters, serum oxidative stress and mental state. We enrolled 20 chronic alcoholic patients hospitalized for rehabilitative therapy. The patients were divided into two groups receiving the following treatment regimes for two weeks: administration of an anti-oxidant nutritional supplement containing glutathione and vitamin C (group 1), or glutathione, vitamin C and polydatin (group 2). RESULTS: The results of the present study show that elevated plasma aspartate aminotransferase and alanine aminotransferase levels in patients after two weeks of alcohol withdrawal were significantly reduced by polydatin (group 2), when compared to group 1. Polydatin also significantly reduced lipid peroxidation levels. Finally, our preliminary data resulting from the analysis of the Mini-Mental Status suggest that polydatin improves cognitive performance. CONCLUSION: Daily dietary administration of polydatin should be considered for prevention and treatment of liver disease and cognitive impairment in alcoholic patients.

Pegylated liposomal doxorubicin in the management of ovarian cancer: a systematic review and metaanalysis of randomized trials.

Ovarian cancer is the leading cause of death among gynecological tumors. Carboplatin/paclitaxel represents the cornerstone of front-line treatment. Instead, there is no consensus for management of recurrent/progressive disease, in which pegylated liposomal doxorubicin (PLD) ± carboplatin is widely used. We performed a systematic review and metaanalysis to evaluate impact of PLD-based compared with no-PLD-based regimens in the ovarian cancer treatment. Data were extracted from randomized trials comparing PLD-based treatment to any other regimens in the January 2000-January 2013 time-frame. Study end-points were overall survival (OS), progression free survival (PFS), response rate (RR), CA125 response, and toxicity. Hazard ratios (HRs) of OS and PFS, with 95% CI, odds ratios (ORs) of RR and risk ratios of CA125 response and grade 3-4 toxicity, were extracted. Data were pooled using fixed and random effect models for selected endpoints. Fourteen randomized trials for a total of 5760 patients were selected and included for the final analysis, which showed no OS differences for PLD-based compared with other regimens (pooled HR: 0.94; 95% CI: 0.88-1.02; P = 0.132) and a significant PFS benefit of PLD-based schedule (HR: 0.91; 95% CI: 0.86-0.96; P = 0.001), particularly in second-line (HR: 0.85; 95% CI: 0.75-0.91) and in platinum-sensitive (HR: 0.83; 95% CI: 0.74-0.94) subgroups. This work confirmed the peculiar tolerability profile of this drug, moreover no difference was observed for common hematological toxicities and for RR, CA125 response. PLD-containing regimens do not improve OS when compared with any other schedule in all phases of disease. A marginal PFS advantage is observed only in platinum-sensitive setting and second-line treatment.