Publications by authors named "Antonio Gnoni"

67 Publications

Inflammatory Status and Glycemic Control Level of Patients with Type 2 Diabetes and Periodontitis: A Randomized Clinical Trial.

Int J Environ Res Public Health 2021 03 15;18(6). Epub 2021 Mar 15.

Department of Oral Science, Nano and Biotechnology and CeSi-Met University of Chieti-Pescara, 66100 Chieti, Italy.

Background: Based on the holistic approach to prevention diabetic disease, the role of periodontal inflammation in type 2 diabetes mellitus (T2DM) is under intensive scrutiny. Data from clinical trials have shown benefit from a periodontal therapy in providing patients with type 2 diabetes improvement despite relatively disappointing long-terms response rates. The aim of this study was to investigate the short-term glycemic control level and systemic inflammatory status after periodontal therapy.

Methods: This was a randomized trial with a 6-months follow-up. Participants aged 56.4 ± 7.9 years with diagnosed type 2 diabetes and periodontitis were enrolled. Among the 187 type 2 diabetic patients, 93 were randomly assigned to receive non-surgical periodontal treatment immediately and 94 to receive the delayed treatment. Within and between groups comparison was done during the study period, and the differences between groups were assessed.

Results: The difference between HbA1c values at baseline ( = 7.7) and 6 months after non-surgical periodontal treatment ( = 7.2) was statistically significant, = 3174.5, = 0.012, = 0.187. However, although technically a positive correlation, the relationship between the glycated hemoglobin value and periodontal variables was weak. The differences between both the groups over 6 months were not statistically considerable, failing to reach statistical significance. At 6 months the difference between groups about the C-reactive protein (CRP) levels was statistically significant, =1839.5, = 0, = 0.472, with a lower concentration for the intervention group. Furthermore, the intervention group showed a statistically significant difference between baseline and 6 months evaluation ( = 2606.5, = 0, = 0.308).

Conclusions: The periodontal intervention potentially may allow individuals with type 2 diabetes to improve glycemic control and CRP concentrations, and diabetes alters the periodontal status.
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http://dx.doi.org/10.3390/ijerph18063018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998112PMC
March 2021

Circulating Inhibitory Factor 1 levels in adult patients with Prader-Willi syndrome.

Horm Mol Biol Clin Investig 2021 Mar 5. Epub 2021 Mar 5.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.

Objectives: Prader-Willi syndrome (PWS) is a rare genetic syndrome characterized by hyperphagia and early development of morbid obesity. Cardiovascular disease (CVD) and metabolic syndrome (MetS) are major comorbidities in these patients leading to premature death. Inhibitory factor 1 (IF) works as a regulatory protein, inhibiting the ATP hydrolase activity of mitochondrial ATP synthase and likely playing a role in lipid metabolism. We aimed to assay IF in adult patients with PWS evaluating any relationship with clinical, genetic and biochemical parameters.

Methods: We recruited 35 adult patients with genetically confirmed PWS.

Results: IF serum concentration displayed a normal distribution with an average value of 70.7 ± 22.6 pg/mL, a median value of 66.1 pg/mL. It was above the reference range only in one patient. All parameters were compared from both sides of IF median without displaying any significant differences. Patients with normal or low HDL-cholesterol did not present any difference as regards IF levels, which were not different between patients with and without MetS. Non-esterified fatty acids (NEFA) serum levels (r=0.623; p<0.001) showed a statistically significant correlation with IF. Cholesterol and its fractions did not present any correlation with IF

Conclusions: In this study we do not confirm that HDL-cholesterol and IF are correlated, but we show that in adult PWS patients, NEFA are correlated with serum IF This protein could play a role to some extent in determining the complex metabolic alterations in PWS patients.
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http://dx.doi.org/10.1515/hmbci-2020-0097DOI Listing
March 2021

Efficacy of Sea Salt-Based Mouthwash and Xylitol in Improving Oral Hygiene among Adolescent Population: A Pilot Study.

Int J Environ Res Public Health 2020 12 23;18(1). Epub 2020 Dec 23.

Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.

The scientific community has definitely demonstrated the importance of the use of mouthwash in daily oral hygiene. In our pilot study, we tested the effectiveness of a novel mouth rinse containing sea salt, xylitol, and lysozyme. growth, and plaque index in adolescent patients aged 14-17 years, were observed. The bacterial load was investigated by in vitro microbiological analysis; the plaque index was assessed through the O'Leary's Plaque Control Record (PCR). The study has shown that the use of a sea salt-based mouthwash in daily oral hygiene reduces the bacterial levels of ( < 0.01) linked to the combined action of xylitol and lysozyme, together with the action of sea salt. Our preliminary data confirm and improve the main results reported in the scientific literature on the importance of the use of xylitol, lysozyme, and sea salt in oral health.
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http://dx.doi.org/10.3390/ijerph18010044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793524PMC
December 2020

Dietary cholesterol supplementation and inhibitory factor 1 serum levels in two dizygotic Smith-Lemli-Opitz syndrome twins: a case report.

Ital J Pediatr 2020 Oct 28;46(1):161. Epub 2020 Oct 28.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.

Background: Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic neurodevelopmental disorder caused by the defect in the 7-dehydrocholesterol reductase. This defect leads to the deficiency of cholesterol biosynthesis with accumulation of 7-dehydrocholesterol. Inhibitory factor 1 (IF) is a well-known mitochondrial protein. Recently, it has been discovered in the human serum where it is reported to be involved in the HDL-cholesterol intake. Here we report the IF presence in the serum of two paediatric SLOS dizygotic twins treated with dietary cholesterol supplementation.

Case Presentation: The patients showed a typical phenotype. They started dietary supplementation with cholesterol when 2 months old. The cholesterol intake was periodically titrated on the basis of weight increase and the twin 1 required a larger supplementation than the twin 2 during the follow-up. When 6.4-year-old, they underwent IF assay that was 7-fold increased in twin 2 compared to twin 1 (93.0 pg/ml vs 13.0 pg/ml, respectively).

Conclusions: We report, for the first time, the presence of circulating IF in the serum of SLOS patients, showing different levels among them. Our findings confirm that IF could be a novel research target in cholesterol-related disorders and also in SLOS, and could contribute to the general debate on IF as a new modulator of cholesterol levels.
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http://dx.doi.org/10.1186/s13052-020-00924-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594264PMC
October 2020

Gingival Crevicular Blood as a Potential Screening Tool: A Cross Sectional Comparative Study.

Int J Environ Res Public Health 2020 10 9;17(20). Epub 2020 Oct 9.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, "Aldo Moro" University of Bari, 70124 Bari, Italy.

Background: Diabetes is known to be one of the major global epidemic diseases, significantly associated with mortality and morbidity worldwide, conferring a substantial burden to the health care system. The epidemiological transition of this chronic disease tends to worsen unless preventive health strategies are implemented. Appropriate screening devices and standardized methods are crucial to prevent this potentially inauspicious life condition. Currently, the glucometer is the conventional device employed for blood glucose level determination that outputs the blood glucose reading. Glucometer performed in the dental office may be an important device in screening diabetes, so it can be addressed during a periodontal examination. Because gingival blood is a useful source to detect the glucose level, the focus is placed on the opportunity that might provide valuable diagnostic information. This study aimed to compare gingival crevicular blood with finger-stick blood glucose measurements using a self-monitoring glucometer, to evaluate whether gingival crevicular blood could be an alternative to allow accurate chairside glucose testing.

Methods: A cross-sectional comparative study was performed among a 31-67-year-old population. Seventy participants with diagnosed type 2 diabetes and seventy healthy subjects, all with positive bleeding on probing, were enrolled. The gingival crevicular blood was collected using a glucometer to estimate the blood glucose level and compared with finger-stick blood glucose level.

Results: The mean capillary blood glucose and gingival crevicular blood levels from all samples were, respectively, 160.42 ± 31.31 mg/dL and 161.64 ± 31.56 mg/dL for diabetic participants and 93.51 ± 10.35 mg/dL and 94.47 ± 9.91 mg/dL for healthy patients. In both groups, the difference between gingival crevicular blood and capillary blood glucose levels was non-significant ( < 0.05). The highly significant correlation between capillary blood glucose and gingival crevicular blood ( = 0.9834 for diabetic patients and = 0.8153 for healthy participants) in both the groups was found.

Conclusions: Gingival crevicular blood test was demonstrated as a feasible and useful primary screening tool test for detecting diabetes and for glucose estimation in non-diabetic patients. Use of gingival crevicular blood for screening is an attractive way of identifying a reasonable option of finger-stick blood glucose measurement under the appropriate circumstances. Rapid assessment may precede diagnostic evaluation in diabetic as well as healthy patients with acute severe bleeding. In addition, gingival crevicular blood levels may be needed to monitor the diabetic output.
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http://dx.doi.org/10.3390/ijerph17207356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601154PMC
October 2020

The Effect of Gaseous Ozone Therapy in Conjunction with Periodontal Treatment on Glycated Hemoglobin Level in Subjects with Type 2 Diabetes Mellitus: An Unmasked Randomized Controlled Trial.

Int J Environ Res Public Health 2020 07 29;17(15). Epub 2020 Jul 29.

Department of Metabolic and Genetic Diseases, Giovanni XXIII Children's Hospital, 70126 Bari, Italy.

Background: It is established that inflammation is involved in the pathogenesis of Type 2 Diabetes Mellitus (T2DM) by promoting insulin resistance and impaired beta cell function in the pancreas. Among the hypothesized independent risk factors implicated in the pathogenetic basis of disease, periodontal infection has been proposed to promote an amplification of the magnitude of the advanced glycation end product (AGE)-mediated upregulation of cytokine synthesis and secretion. These findings suggest an interrelationship between periodontal disease and type 2 diabetes, describing poor metabolic control in subjects with periodontitis as compared to nondiabetic subjects and more severe periodontitis in subjects with T2DM as compared to a healthy population, with a significant positive correlation between periodontal inflammatory parameters and glycated hemoglobin level. Results from clinical trials show that periodontal treatment is able to improve glycemic control in subjects with diabetes. Many therapeutic strategies have been developed to improve periodontal conditions in conjunction with conventional treatment, among which ozone (O) is of specific concern. The principal aim of this trial was to compare the clinical effectiveness of an intensive periodontal intervention consisting of conventional periodontal treatment in conjunction with ozone gas therapy in reducing glycated hemoglobin level in type 2 diabetic patients and standard periodontal treatment.

Methods: This study was a 12-month unmasked randomized trial and included 100 patients aged 40-74 years older, with type 2 diabetes mellitus diagnosed. All the patients received conventional periodontal treatment, or periodontal treatment in conjunction with ozone gas therapy in a randomly assigned order (1:1). The primary outcome was a clinical measure of glycated hemoglobin level at 3, 6, 9 and 12 months from randomization. Secondary outcomes were changes in periodontal inflammatory parameters.

Results: At 12 months, the periodontal treatment in conjunction with ozone gas therapy did not show significant differences than standard therapy in decreasing glycated hemoglobin (HbA1C) level and the lack of significant differences in balance is evident.

Conclusions: Although the change was not significant, periodontal treatment in conjunction with the gaseous ozone therapy tended to reduce the levels of glycated hemoglobin. The study shows a benefit with ozone therapy as compared to traditional periodontal treatment.
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http://dx.doi.org/10.3390/ijerph17155467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432743PMC
July 2020

Does Periodontal Inflammation Affect Type 1 Diabetes in Childhood and Adolescence? A Meta-Analysis.

Front Endocrinol (Lausanne) 2020 5;11:278. Epub 2020 May 5.

Complex Operative Unit of Odontostomatology, Hospital S.S. Annunziata, Chieti, Italy.

The emergence of link between periodontal disease and diabetes has created conditions for analyzing new interdisciplinary approach making toward tackling oral health and systemic issues. As periodontal disease is a readily modifiable risk factor this association has potential clinical implications. The aim of this paper was systematically review the extant literature related to analytics data in order to identify the association between type 1 diabetes (T1DM) in childhood and adolescence with periodontal inflammation. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a database search between 2004 and 2019. A manual search of the literature was conducted as an additional phase of the search process, with the aim of identifying studies that were missed in the primary search. One hundred and thirty-nine records were screened and 10 fulfilled the inclusion criteria. Most studies were of moderate methodological quality. Outcomes included assessments of diabetes and periodontal status. In diabetic populations, compared to healthy subjects, interindividual differences in periodontal status are reflected in higher severity of periodontal inflammation. The most reported barriers to evidence uptake were the intrinsic limits of cross-sectional report data and relevant research, and lack of timely research output. Based on the evidence presented within the literature, the aforementioned biomarkers correlate with poor periodontal status in type 1 diabetic patients. Whilst the corpus of the evidence suggests that there may be an association between periodontal status and type 1 diabetes, study designs and methodological limitations hinder interpretation of the current research.
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http://dx.doi.org/10.3389/fendo.2020.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214631PMC
May 2020

Does Diabetes Induce the Vascular Endothelial Growth Factor (VEGF) Expression in Periodontal Tissues? A Systematic Review.

Int J Environ Res Public Health 2020 04 16;17(8). Epub 2020 Apr 16.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, "Aldo Moro" University of Bari, 70124 Bari, Italy.

Aim: Diabetes and periodontal disease are both chronic pathological conditions linked by several underlying biological mechanisms, in which the inflammatory response plays a critical role, and their association has been largely recognized. Recently, attention has been given to diabetes as an important mediator of vascular endothelial growth factor (VEGF) overexpression in periodontal tissues, by virtue of its ability to affect microvasculature. This review aims to summarize the findings from studies that explored VEGF expression in diabetic patients with periodontitis, compared to periodontally healthy subjects.

Materials And Methods: A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was carried out to identify all studies reporting findings about VEGF expression in periodontal tissues of diabetic patients up to May 2018. The inclusion criteria were studies on VEGF expression in periodontally diseased tissues of diabetic patients compared with nondiabetic subjects, with any method of analysis, and published in the English language.

Results: Eight articles met the inclusion criteria. Immunohistochemistry was used in six of the studies, reverse transcriptase polymerase chain reaction (real-time RT-PCR) aiming to quantify mRNA VEGF expression was used in one study, and ELISA analysis was used for one study. Compared with nondiabetic patients, a higher VEGF expression in gingival tissue and gingival crevicular fluid (GCF) samples in diabetic patients with periodontitis was reported.

Conclusions: Overall, novel evidence for the VEGF expression within the periodontal tissue of diabetic patients paves the way for further studies on the role of this protein in neovascularization physiology and pathophysiology in microvasculature of the periodontium.
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http://dx.doi.org/10.3390/ijerph17082765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215273PMC
April 2020

Immune system and bone microenvironment: rationale for targeted cancer therapies.

Oncotarget 2020 Jan 28;11(4):480-487. Epub 2020 Jan 28.

Medical Oncology Unit, "S. Cuore di Gesù" Hospital, Gallipoli, Italy.

Osteoimmunology was coined about twenty years ago to identify a strict cross talk between bone niche and immune system both in physiological and pathological activities, including cancer. Several molecules are involved in the complex interaction between bone niche, immune and cancer cells. The Receptor Activator of NF-kB (RANK)/RANK Ligand (RANKL/Osteoprotegerin (OPG) pathway plays a crucial role in bone cells/cancer interactions with subsequently immune system control failure, bone destruction, inhibition of effect and metastasis outcome. The bidirectional cross talk between bone and immune system could became a potential target for anticancer drugs. Several studies evidenced a direct anticancer role with improved survival of bone-targeted therapies such as bisphosphonates and RANKL antagonist Denosumab. Conversely, initial data evidenced a possible anti-bone resorption effect of systemic anticancer drugs through and immunomodulation activity, i.e. new generation antiandrogens (Abiraterone) in prostate cancer. All data could open a future rationale of combined bone, immunologic and targeted therapies in cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.27439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996902PMC
January 2020

Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise?

Molecules 2020 Jan 1;25(1). Epub 2020 Jan 1.

Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.

l-Carnitine is an amino acid derivative widely known for its involvement in the transport of long-chain fatty acids into the mitochondrial matrix, where fatty acid oxidation occurs. Moreover, l-Carnitine protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Circulating carnitine is mainly supplied by animal-based food products and to a lesser extent by endogenous biosynthesis in the liver and kidney. Human muscle contains high amounts of carnitine but it depends on the uptake of this compound from the bloodstream, due to muscle inability to synthesize carnitine. Mitochondrial fatty acid oxidation represents an important energy source for muscle metabolism particularly during physical exercise. However, especially during high-intensity exercise, this process seems to be limited by the mitochondrial availability of free l-carnitine. Hence, fatty acid oxidation rapidly declines, increasing exercise intensity from moderate to high. Considering the important role of fatty acids in muscle bioenergetics, and the limiting effect of free carnitine in fatty acid oxidation during endurance exercise, l-carnitine supplementation has been hypothesized to improve exercise performance. So far, the question of the role of l-carnitine supplementation on muscle performance has not definitively been clarified. Differences in exercise intensity, training or conditioning of the subjects, amount of l-carnitine administered, route and timing of administration relative to the exercise led to different experimental results. In this review, we will describe the role of l-carnitine in muscle energetics and the main causes that led to conflicting data on the use of l-carnitine as a supplement.
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http://dx.doi.org/10.3390/molecules25010182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982879PMC
January 2020

Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies.

Medicina (Kaunas) 2019 Nov 21;55(12). Epub 2019 Nov 21.

Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.

The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC.
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http://dx.doi.org/10.3390/medicina55120754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956203PMC
November 2019

A New Look at the Structures of Old Sepsis Actors by Exploratory Data Analysis Tools.

Antibiotics (Basel) 2019 Nov 14;8(4). Epub 2019 Nov 14.

SMBNOS-Università degli Studi di Bari, 70124 Bari, Italy.

Sepsis is a life-threatening condition that accounts for numerous deaths worldwide, usually complications of common community infections (i.e., pneumonia, etc), or infections acquired during the hospital stay. Sepsis and septic shock, its most severe evolution, involve the whole organism, recruiting and producing a lot of molecules, mostly proteins. Proteins are dynamic entities, and a large number of techniques and studies have been devoted to elucidating the relationship between the conformations adopted by proteins and what is their function. Although molecular dynamics has a key role in understanding these relationships, the number of protein structures available in the databases is so high that it is currently possible to build data sets obtained from experimentally determined structures. Techniques for dimensionality reduction and clustering can be applied in exploratory data analysis in order to obtain information on the function of these molecules, and this may be very useful in immunology to better understand the structure-activity relationship of the numerous proteins involved in host defense, moreover in septic patients. The large number of degrees of freedom that characterize the biomolecules requires special techniques which are able to analyze this kind of data sets (with a small number of entries respect to the number of degrees of freedom). In this work we analyzed the ability of two different types of algorithms to provide information on the structures present in three data sets built using the experimental structures of allosteric proteins involved in sepsis. The results obtained by means of a principal component analysis algorithm and those obtained by a random projection algorithm are largely comparable, proving the effectiveness of random projection methods in structural bioinformatics. The usefulness of random projection in exploratory data analysis is discussed, including validation of the obtained clusters. We have chosen these proteins because of their involvement in sepsis and septic shock, aimed to highlight the potentiality of bioinformatics to point out new diagnostic and prognostic tools for the patients.
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http://dx.doi.org/10.3390/antibiotics8040225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963771PMC
November 2019

Impact of Periodontal Inflammation on Nutrition and Inflammation Markers in Hemodialysis Patients.

Antibiotics (Basel) 2019 Nov 1;8(4). Epub 2019 Nov 1.

Department of Dental and Maxillofacial Sciences, "Sapienza" University of Rome, 00100 Rome, Italy.

: Malnutrition-inflammation complex syndrome (MICS) is a common and usually concurrent condition occurring in patients undergoing hemodialysis (HD), with a pathogenesis linked to biological and in situ environmental traditional risk factors. Periodontitis, one of the major types of infection-driven inflammation, often co-occurs in the in the hemodialysis population and correlates with markers of malnutrition and inflammation, such as albumin, creatinine, and C-reactive protein. : The present study aimed to determine whether the periodontal inflammatory status parameters correlate with the albumin, creatinine, and C-reactive protein serum concentrations in HD patients, and investigate whether periodontal treatment improves these markers of nutritional and systemic inflammation. : The serum creatinine, albumin, and C-reactive Protein (CRP) levels were measured at baseline and after non-surgical periodontal treatment, at 3 months and 6 months. : At 3 months, a significant correlation between plaque index and C-reactive protein (p = 0.012), bleeding on probing and C-reactive protein (p < 0.0019), and clinical attachment level and C-reactive protein (p = 0.022) was found. No significant correlation was found between clinical periodontal parameters and nutrition markers at each time. Conclusions: Our results confirmed the association between C-reactive protein serum concentration and periodontal inflammatory status, but further research is necessary to identify the contributing role of periodontitis on the onset and progression of MICS.
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http://dx.doi.org/10.3390/antibiotics8040209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963174PMC
November 2019

Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib.

Medicina (Kaunas) 2019 Oct 21;55(10). Epub 2019 Oct 21.

Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.

Sorafenib is an oral kinase inhibitor that enhances survival in patients affected by advanced hepatocellular carcinoma (HCC). According to the results of two registrative trials, this drug represents a gold quality standard in the first line treatment of advanced HCC. Recently, lenvatinib showed similar results in terms of survival in a non-inferiority randomized trial study considering the same subset of patients. Unlike other targeted therapies, predictive and prognostic markers in HCC patients treated with sorafenib are lacking. Their identification could help clinicians in the daily management of these patients, mostly in light of the new therapeutic options available in the first.
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http://dx.doi.org/10.3390/medicina55100707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843290PMC
October 2019

Emerging role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma.

Medicina (Kaunas) 2019 Oct 17;55(10). Epub 2019 Oct 17.

Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.

Hepatocellular carcinoma is the most common primary liver cancer and the fourth leading cause of cancer death worldwide. A total of 70-80% of patients are diagnosed at an advanced stage with a dismal prognosis. Sorafenib had been the standardcare for almost a decade until 2018 when the Food and Drug Administration approved an alternative first-line agent namely lenvatinib. Cabozantinib, regorafenib, and ramucirumab also displayed promising results in second line settings. FOLFOX4, however, results inan alternative first-line treatment for the Chineseclinical oncology guidelines. Moreover,nivolumab and pembrolizumab,two therapeutics against the Programmed death (PD)-ligand 1 (PD-L1)/PD1 axis have been recently approvedfor subsequent-line therapy. However, similar to other solid tumors, the response rate of single agent targeting PD-L1/PD1 axis is low. Therefore, a lot of combinatory approaches are under investigation, including the combination of different immune checkpoint inhibitors (ICIs), the addition of ICIs after resection or during loco-regional therapy, ICIs in addition to kinase inhibitors, anti-angiogenic therapeutics, and others. This review focuses on the use of ICIs for the hepatocellular carcinoma with a careful assessmentof new ICIs-based combinatory approaches.
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http://dx.doi.org/10.3390/medicina55100698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843273PMC
October 2019

Quercetin inhibition of SREBPs and ChREBP expression results in reduced cholesterol and fatty acid synthesis in C6 glioma cells.

Int J Biochem Cell Biol 2019 12 19;117:105618. Epub 2019 Sep 19.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", 70124, Bari, Italy.

Quercetin (Que), a widely distributed flavonoid in the human diet, exerts neuroprotective action because of its property to antagonize oxidative stress. Here, we investigated the effects of Que on lipid synthesis in C6 glioma cells. A rapid Que-induced inhibition of cholesterol and, to a lesser extent, of fatty acid synthesis from [1-C]acetate was observed. The maximum decrease was detected at the level of palmitate, the end product of de novo fatty acid synthesis. The effect of Que on the enzyme activities of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS), the two enzymes of this pathway, was investigated directly in situ in permeabilized C6 cells. An inhibitory effect on ACC1 was observed after 4 h of 25 μM Que treatment, while FAS activity was not affected. A reduction of polar lipid biosynthesis was also detected. A remarkable decrease of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) activity, regulatory enzyme of cholesterol synthesis, was evidenced. Expression studies demonstrated that Que acts at transcriptional level, by reducing the mRNA abundance and protein amount of ACC1 and HMGCR. Deepening the molecular mechanism, we found that Que decreased the expression of SREBP-1 and SREBP-2, transcriptional factors representing the main regulators of de novo fatty acid and cholesterol synthesis, respectively. Que also reduced the nuclear content of ChREBP, a glucose-induced transcription factor involved in the regulation of lipogenic genes. Our results represent the first evidence that a direct and rapid downregulatory effect of Que on cholesterol and de novo fatty acid synthesis is elicited in C6 cells.
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http://dx.doi.org/10.1016/j.biocel.2019.105618DOI Listing
December 2019

Periodontal Microbiological Status Influences the Occurrence of Cyclosporine-A and Tacrolimus-Induced Gingival Overgrowth.

Antibiotics (Basel) 2019 Aug 21;8(3). Epub 2019 Aug 21.

Department of Dental and Maxillofacial Sciences, "Sapienza" University of Rome, 00100 Rome, Italy.

Immune suppressed renal transplant patients are more prone to developing oral tissue alterations due to medications associated with a pleiotropic set of side effects involving the oral cavity. Drug-induced gingival overgrowth (DIGO) is the most commonly encountered side effect resulting from administration of calcineurin inhibitors such as cyclosporine-A (CsA), the standard first-line treatment for graft rejection prevention in transplant patients. Pathogenesis of gingival overgrowth (GO) is determined by the interrelation between medications and a pre-existing inflammatory periodontal condition, the main modifiable risk factor. Severity of gingival hyperplasia clinical manifestation is also related to calcium channel blocker association, frequently provided in addition to pharmacological therapy of transplant recipients. Specifically, nifedipine-induced enlargements have a higher prevalence rate compared to amlodipine-induced enlargements; 47.8% and 3.3% respectively. Available epidemiological data show a gender difference in prevalence, whereby males are generally more frequently affected than females. The impact of GO on the well-being of an individual is significant, often leading to complications related to masticatory function and phonation, a side effect that may necessitate switching to the tacrolimus drug that, under a similar regimen, is associated with a low incidence of gingival lesion. Early detection and management of GO is imperative to allow patients to continue life-prolonging therapy with minimal morbidity. The purpose of this study was threefold: firstly, to determine the prevalence and incidence of GO under the administration of CsA and Tacrolimus; secondly, to assess the correlation between periodontal status before and after periodontal therapy and medications on progression or recurrence of DIGO; and finally, to analyse the effect of immunosuppressant in association to the channel blocker agents on the onset and progression of gingival enlargement. We compared seventy-two renal transplant patients, including 33 patients who were receiving CsA, of which 25% were also receiving nifedipine and 9.72% also receiving amlodipine, and 39 patients who were receiving tacrolimus, of which 37.5% were also receiving nifedipine and 5.55% also receiving amlodipine, aged between 35 and 60 years. Medical and pharmacological data were recorded for all patients. Clinical periodontal examination, in order to establish the inflammatory status and degree of gingival enlargement, was performed at baseline (T0), 3 months (T1), 6 months (T2), and 9 months (T3). All patients were subjected to periodontal treatment. Statistically significant correlation between the reduction of the mean value of periodontal indices and degree of gingival hyperplasia at the three times was revealed. The prevalence of GO in patients taking cyclosporine was higher (33.3%) in comparison with those taking tacrolimus (14.7%). In accordance with previous studies, this trial highlighted the clinical significance of the pathological substrate on stimulating drug-induced gingival lesion, confirming the key role of periodontal inflammation in pathogenesis of gingival enlargement, but did not confirm the additional effect of calcium-channel blocker drugs in inducing gingival enlargement.
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http://dx.doi.org/10.3390/antibiotics8030124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784123PMC
August 2019

Metronomic chemotherapy with cyclophosphamide plus low dose of corticosteroids in advanced castration-resistant prostate cancer across the era of taxanes and new hormonal drugs.

Med Oncol 2019 Aug 9;36(9):80. Epub 2019 Aug 9.

Medical Oncology Division and Breast Unit, Sen. Antonio Perrino Hospital, S.S. 7, 72100, Brindisi, Italy.

The aim of our study is to investigate the efficacy of metronomic cyclophosphamide plus low dose of corticosteroids in advanced or metastatic castration-resistant prostate cancer (CRPC) before, between, and after standard chemotherapy, such as docetaxel and cabazitaxel, and new hormonal treatments, such as abiraterone and enzalutamide. A retrospective analysis was performed on 37 patients. Cyclophosphamide was given orally 50 mg per day together with low dose of corticosteroids, namely dexametasone orally 1 mg per day or prednisone 10 mg per day. Seventeen patients (51%) showed a PSA decline≥ 50%. Median progression-free survival (PFS) and overall survival (OS) were 11 and 28 months, respectively. Median PFS and OS in the subgroup of patients with a PSA decline ≥ 50% were 14 and 35 months, respectively. Treatment was very well tolerated. We suggest that oral metronomic cyclophosphamide plus low dose of oral dexamethasone or prednisone may be a good and safe therapeutic option not only in those CRPC patients unfit for standard treatments but also in those heavily pre-treated patients.
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http://dx.doi.org/10.1007/s12032-019-1304-yDOI Listing
August 2019

3,5-diiodo-L-thyronine increases de novo lipogenesis in liver from hypothyroid rats by SREBP-1 and ChREBP-mediated transcriptional mechanisms.

IUBMB Life 2019 07 1;71(7):863-872. Epub 2019 Feb 1.

Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy.

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5-Diiodo-L-thyronine (T2), a product of the 3,5,3'-triiodo-L-thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short-term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl-CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP-1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP-1), and precursor (pSREBP-1) forms of the SREBP-1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP-1- and ChREBP-dependent mechanisms. © 2019 IUBMB Life, 2019.
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http://dx.doi.org/10.1002/iub.2014DOI Listing
July 2019

Hydroxytyrosol Ameliorates Endothelial Function under Inflammatory Conditions by Preventing Mitochondrial Dysfunction.

Oxid Med Cell Longev 2018 18;2018:9086947. Epub 2018 Apr 18.

National Research Council-Institute of Clinical Physiology, Lecce, Italy.

Mitochondria are fundamental organelles producing energy and reactive oxygen species (ROS); their impaired functions play a key role in endothelial dysfunction. Hydroxytyrosol (HT), a well-known olive oil antioxidant, exerts health benefits against vascular diseases by improving endothelial function. However, the HT role in mitochondrial oxidative stress in endothelial dysfunction is not clear yet. To investigate the HT effects on mitochondrial ROS production in the inflamed endothelium, we used an model of endothelial dysfunction represented by cultured endothelial cells, challenged with phorbol myristate acetate (PMA), an inflammatory, prooxidant, and proangiogenic agent. We found that the pretreatment of endothelial cells with HT (1-30 mol/L) suppressed inflammatory angiogenesis, a crucial aspect of endothelial dysfunction. The HT inhibitory effect is related to reduced mitochondrial superoxide production and lipid peroxidation and to increased superoxide dismutase activity. HT, in a concentration-dependent manner, improved endothelial mitochondrial function by reverting the PMA-induced reduction of mitochondrial membrane potential, ATP synthesis, and ATP5 expression. In PMA-challenged endothelial cells, HT also promoted mitochondrial biogenesis through increased mitochondrial DNA content and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1, and mitochondrial transcription factor A. These results highlight that HT blunts endothelial dysfunction and pathological angiogenesis by ameliorating mitochondrial function, thus suggesting HT as a potential mitochondria-targeting antioxidant in the inflamed endothelium.
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http://dx.doi.org/10.1155/2018/9086947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932486PMC
October 2018

Oleic Acid and Hydroxytyrosol Inhibit Cholesterol and Fatty Acid Synthesis in C6 Glioma Cells.

Oxid Med Cell Longev 2017 24;2017:9076052. Epub 2017 Dec 24.

Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.

Recently, the discovery of natural compounds capable of modulating nervous system function has revealed new perspectives for a healthier brain. Here, we investigated the effects of oleic acid (OA) and hydroxytyrosol (HTyr), two important extra virgin olive oil compounds, on lipid synthesis in C6 glioma cells. OA and HTyr inhibited both de novo fatty acid and cholesterol syntheses without affecting cell viability. The inhibitory effect of the individual compounds was more pronounced if OA and HTyr were administered in combination. A reduction of polar lipid biosynthesis was also detected, while triglyceride synthesis was marginally affected. To clarify the lipid-lowering mechanism of these compounds, their effects on the activity of key enzymes of fatty acid biosynthesis (acetyl-CoA carboxylase-ACC and fatty acid synthase-FAS) and cholesterologenesis (3-hydroxy-3-methylglutaryl-CoA reductase-HMGCR) were investigated in situ by using digitonin-permeabilized C6 cells. ACC and HMGCR activities were especially reduced after 4 h of 25 M OA and HTyr treatment. No change in FAS activity was observed. Inhibition of ACC and HMGCR activities is corroborated by the decrease of their mRNA abundance and protein level. Our results indicate a direct and rapid downregulatory effect of the two olive oil compounds on lipid synthesis in C6 cells.
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http://dx.doi.org/10.1155/2017/9076052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757140PMC
August 2018

Systematic review of plasma-membrane ecto-ATP synthase: A new player in health and disease.

Exp Mol Pathol 2018 02 2;104(1):59-70. Epub 2018 Jan 2.

Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

This review summarizes recent studies on plasma-membrane ecto-ATP synthase from structural and functional standpoints to possible pathophysiological roles. This review discusses significant new contributions and perspectives in the area of ecto-ATP synthase since the topic was last reviewed in 2015. Following an extensive summary of the cell types in which the ecto-ATP synthase is present, its structural and functional mechanism are discussed and physiological and pathological roles of the ecto-ATP synthase are reviewed and evaluated. Attempts to define the possible role of ecto-ATP synthase as possible target for anti-cancer and anti-obesity interventions are discussed.
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http://dx.doi.org/10.1016/j.yexmp.2017.12.006DOI Listing
February 2018

Immunotherapeutic approaches for hepatocellular carcinoma.

Oncotarget 2017 05;8(20):33897-33910

Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy.

Hepatocellular carcinoma (HCC) is a cancer with a high mortality rate due to the fact that the diagnosis usually occurs at anadvanced stage. Even in case of curative surgical treatment, recurrence is common. Sorafenib and regorafenib are the only therapeutic agents that have been demonstrated to be effective in advanced HCC, thus novel curative approaches are urgently needed. Recent studies focus on the role of immune system in HCC. In fact, the unique immune response in the liver favors tolerance, which can represent a real challenge for conventional immunotherapy in these patients. Spontaneous immune responses against tumor antigens have been detected, and new immune therapies are under investigation: dendritic cell vaccination, immune-modulator strategy, and immune checkpoint inhibition. In recent years different clinical trials examining the use of immunotherapy to treat HCC have been conducted with initial promising results. This review article will summarize the literature data concerning the potential immunotherapeutic approaches in HCC patients.
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http://dx.doi.org/10.18632/oncotarget.15406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464921PMC
May 2017

Action of Thyroid Hormones, T3 and T2, on Hepatic Fatty Acids: Differences in Metabolic Effects and Molecular Mechanisms.

Int J Mol Sci 2017 Mar 31;18(4). Epub 2017 Mar 31.

Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.

The thyroid hormones (THs) 3,3',5,5'-tetraiodo-l-thyronine (T4) and 3,5,3'-triiodo-l-thyronine (T3) influence many metabolic pathways. The major physiological function of THs is to sustain basal energy expenditure, by acting primarily on carbohydrate and lipid catabolism. Beyond the mobilization and degradation of lipids, at the hepatic level THs stimulate the de novo fatty acid synthesis (de novo lipogenesis, DNL), through both the modulation of gene expression and the rapid activation of cell signalling pathways. 3,5-Diiodo-l-thyronine (T2), previously considered only a T3 catabolite, has been shown to mimic some of T3 effects on lipid catabolism. However, T2 action is more rapid than that of T3, and seems to be independent of protein synthesis. An inhibitory effect on DNL has been documented for T2. Here, we give an overview of the mechanisms of THs action on liver fatty acid metabolism, focusing on the different effects exerted by T2 and T3 on the regulation of the DNL. The inhibitory action on DNL exerted by T2 makes this compound a potential and attractive drug for the treatment of some metabolic diseases and cancer.
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http://dx.doi.org/10.3390/ijms18040744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412329PMC
March 2017

Acute administration of 3,5-diiodo-L-thyronine to hypothyroid rats stimulates bioenergetic parameters in liver mitochondria.

J Bioenerg Biomembr 2016 10 17;48(5):521-529. Epub 2016 Nov 17.

Center of Integrated Research, Campus Bio-Medico, University of Rome, Rome, 00100, Italy.

The role of 3,5-diiodo-L-thyronine (T), initially considered only a 3,3',5-triiodo-L-thyronine (T) catabolite, in the bioenergetic metabolism is of growing interest. In this study we investigated the acute effects (within 1 h) of T administration to hypothyroid rats on liver mitochondria fatty acid uptake and β-oxidation rate, mitochondrial efficiency (by measuring proton leak) and mitochondrial oxidative damage (by determining HO release). Fatty acid uptake into mitochondria was measured assaying carnitine palmitoyl transferase (CPT) I and II activities, and fatty acid β-oxidation using palmitoyl-CoA as a respiratory substrate. Mitochondrial fatty acid pattern was defined by gas-liquid chromatography. In hypothyroid + T vs hypothyroid rats we observed a raise in the serum level of nonesterified fatty acids (NEFA), in the mitochondrial CPT system activity and in the fatty acid β-oxidation rate. A parallel increase in the respiratory chain activity, mainly from succinate, occurs. When fatty acids are chelated by bovine serum albumin, a T-induced increase in both state 3 and state 4 respiration is observed, while, when fatty acids are present, mitochondrial uncoupling occurs together with increased proton leak, responsible for mitochondrial thermogenesis. T administration decreases mitochondrial oxidative stress as determined by lower HO production. We conclude that in rat liver mitochondria T acutely enhances the rate of fatty acid β-oxidation, and the activity of the downstream respiratory chain. The T-induced increase in proton leak may contribute to mitochondrial thermogenesis and to the reduction of oxidative stress. Our results strengthen the previously reported ability of T to reduce adiposity, dyslipidemia and to prevent liver steatosis.
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http://dx.doi.org/10.1007/s10863-016-9686-4DOI Listing
October 2016

Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue.

Oncotarget 2016 Sep;7(36):58649-58658

Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.

Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early loco-regional spread and distant metastases at diagnosis, leading to dismal prognosis with a 5-year overall survival rate moderately over than 5%. This malignancy is largely resistant to chemotherapy and radiation, but the reasons of the refractoriness to the therapies is still unknown. Evidence is accumulating to indicate that the PDAC microenvironment and vascularity strongly contribute to the clinical features of this disease. In particular, PDAC is characterized by excessive dense extracellular matrix deposition associated to vasculature collapse and hypoxia with low drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer. Strategies aimed to modulate tumor stroma favoring vasculature perfusion and chemotherapeutics delivery are under investigation.
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http://dx.doi.org/10.18632/oncotarget.10765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295459PMC
September 2016

Dietary long-chain unsaturated fatty acids acutely and differently reduce the activities of lipogenic enzymes and of citrate carrier in rat liver.

J Physiol Biochem 2016 Sep 16;72(3):485-94. Epub 2016 Jun 16.

Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy.

The activities of lipogenic enzymes appear to fluctuate with changes in the level and type of dietary fats. Polyunsaturated fatty acids (PUFAs) are known to induce on hepatic de novo lipogenesis (DNL) the highest inhibitory effect, which occurs through a long-term adaptation. Data on the acute effects of dietary fatty acids on DNL are lacking. In this study with rats, the acute 1-day effect of high-fat (15 % w/w) diets (HFDs) enriched in saturated fatty acids (SFAs) or unsaturated fatty acids (UFAs), i.e., monounsaturated (MUFA) and PUFA, of the ω-6 and ω-3 series on DNL and plasma lipid level was investigated; a comparison with a longer time feeding (21 days) was routinely carried out. After 1-day HFD administration UFA, when compared to SFA, reduced plasma triacylglycerol (TAG) level and the activities of the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), a decreased activity of the citrate carrier (CIC), a mitochondrial protein linked to lipogenesis, was also detected. In this respect, ω-3 PUFA was the most effective. On the other hand, PUFA maintained the effects at longer times, and the acute inhibition induced by MUFA feeding on DNL enzyme and CIC activities was almost nullified at 21 days. Mitochondrial fatty acid composition was slightly but significantly changed both at short- and long-term treatment, whereas the early changes in mitochondrial phospholipid composition vanished in long-term experiments. Our results suggest that in the early phase of administration, UFA coordinately reduced both the activities of de novo lipogenic enzymes and of CIC. ω-3 PUFA showed the greatest effect.
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http://dx.doi.org/10.1007/s13105-016-0495-3DOI Listing
September 2016

Function and expression study uncovered hepatocyte plasma membrane ecto-ATP synthase as a novel player in liver regeneration.

Biochem J 2016 08 10;473(16):2519-30. Epub 2016 Jun 10.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70100, Italy Center of Integrated Research, Campus Bio-Medico, University of Rome, Rome 00100, Italy

ATP synthase, canonically mitochondrially located, is reported to be ectopically expressed on the plasma membrane outer face of several cell types. We analysed, for the first time, the expression and catalytic activities of the ecto- and mitochondrial ATP synthase during liver regeneration. Liver regeneration was induced in rats by two-thirds partial hepatectomy. The protein level and the ATP synthase and/or hydrolase activities of the hepatocyte ecto- and mitochondrial ATP synthase were analysed on freshly isolated hepatocytes and mitochondria from control, sham-operated and partial hepatectomized rats. During the priming phase of liver regeneration, 3 h after partial hepatectomy, liver mitochondria showed a marked lowering of the ATP synthase protein level that was reflected in the impairment of both ATP synthesis and hydrolysis. The ecto-ATP synthase level, in 3 h partial hepatectomized hepatocytes, was decreased similarly to the level of the mitochondrial ATP synthase, associated with a lowering of the ecto-ATP hydrolase activity coupled to proton influx. Noteworthily, the ecto-ATP synthase activity coupled to proton efflux was completely inhibited in 3 h partial hepatectomized hepatocytes, even in the presence of a marked intracellular acidification that would sustain it as in control and sham-operated hepatocytes. At the end of the liver regeneration, 7 days after partial hepatectomy, the level and the catalytic activities of the ecto- and mitochondrial ATP synthase reached the control and sham-operated values. The specific modulation of hepatocyte ecto-ATP synthase catalytic activities during liver regeneration priming phase may modulate the extracellular ADP/ATP levels and/or proton influx/efflux trafficking, making hepatocyte ecto-ATP synthase a candidate for a novel player in the liver regeneration process.
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http://dx.doi.org/10.1042/BCJ20160065DOI Listing
August 2016

Extra virgin olive oil rich in polyphenols modulates VEGF-induced angiogenic responses by preventing NADPH oxidase activity and expression.

J Nutr Biochem 2016 Feb 17;28:19-29. Epub 2015 Oct 17.

National Research Council - Institute of Clinical Physiology, Lecce, Italy. Electronic address:

Previous studies have shown the antiinflammatory, antioxidant and antiangiogenic properties by pure olive oil polyphenols; however, the effects of olive oil phenolic fraction on the inflammatory angiogenesis are unknown. In this study, we investigated the effects of the phenolic fraction (olive oil polyphenolic extract, OOPE) from extra virgin olive oil and related circulating metabolites on the VEGF-induced angiogenic responses and NADPH oxidase activity and expression in human cultured endothelial cells. We found that OOPE (1-10 μg/ml), at concentrations achievable nutritionally, significantly reduced, in a concentration-dependent manner, the VEGF-induced cell migration, invasiveness and tube-like structure formation through the inhibition of MMP-2 and MMP-9. OOPE significantly (P<0.05) reduced VEGF-induced intracellular reactive oxygen species by modulating NADPH oxidase activity, p47phox membrane translocation and the expression of Nox2 and Nox4. Moreover, the treatment of endothelial cells with serum obtained 4 h after acute intake of extra virgin olive oil, with high polyphenol content, decreased VEGF-induced NADPH oxidase activity and Nox4 expression, as well as, MMP-9 expression, as compared with fasting control serum. Overall, native polyphenols and serum metabolites of extra virgin olive oil rich in polyphenols are able to lower the VEGF-induced angiogenic responses by preventing endothelial NADPH oxidase activity and decreasing the expression of selective NADPH oxidase subunits. Our results provide an alternative mechanism by which the consumption of olive oil rich in polyphenols may account for a reduction of oxidative stress inflammatory-related sequelae associated with chronic degenerative diseases.
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http://dx.doi.org/10.1016/j.jnutbio.2015.09.026DOI Listing
February 2016