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Dynamic carbon 13 breath tests for the study of liver function and gastric emptying

Gastroenterology Report 2015年第1期3卷 12-21页

作者： Leonilde Bonfrate Ignazio Grattagliano Giuseppe Palasciano Piero Portincasa Department of Biomedical Sciences and Human Oncology Clinica Medica‘A.Murri’University of Bari Medical SchoolBariItaly Italian College of General Practitioners Florence and BariItaly

In gastroenterological practice,breath tests(BTs)are diagnostic tools used for indirect,non-invasive assessment of several pathophysiological metabolic processes,by monitoring the appearance in breath of a metabolite of a specific substrate.Labelled substrates originally employed radioactive carbon 14(^(14)C)and,more recently,the stable carbon 13 isotope(^(13)C)has been introduced to label specific substrates.The ingested^(13)C-substrate is metabolized,and exhaled^(13)CO_(2)is measured by mass spectrometry or infrared spectroscopy.Some^(13)C-BTs evaluate specific(microsomal,cytosolic,and mitochondrial)hepatic metabolic pathways and can be employed in liver diseases(i.***.simple liver steatosis,non-alcoholic steato-hepatitis,liver fibrosis,cirrhosis,hepatocellular carcinoma,drug and alcohol effects).Another field of clinical application for^(13)C-BTs is the assessment of gastric emptying kinetics in response to liquids(^(13)C-acetate)or solids(^(13)C-octanoic acid in egg yolk or in a pre-packed muffin or the^(13)C-Spirulina platensis given with a meal or a biscuit).Studies have shown that^(13)C-BTs,used for gastric emptying studies,yield results that are comparable to scintigraphy and can be useful in detecting either delayed-(gastroparesis)or accelerated gastric emptying or changes of gastric kinetics due to pharmacological effects.Thus,^(13)C-BTs represent an indirect,cost-effective and easy method of evaluating dynamic liver function and gastric kinetics in health and disease,and several other potential applications are being studied.

关键词： breath tests stable isotope hepatic metabolism gastric motility scintigraphy

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肠易激综合征与饮食干预

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Gastroenterology Report 2017年第1期5卷 11-19,I0001页

作者： Piero Portincasa Leonilde Bonfrate Ornella de Bari Anthony Lembo Sarah Ballou clinica medica a.murri Department of Biomedical Sciences and Human OncologyUniversity of Bari Aldo Moro Medical SchoolBariItaly Department of Medicine and Gastroenterology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA

肠易激综合征(IBS)系胃肠道慢性功能性疾病,是最常见的胃肠疾病之一。由于IBS患病率高、治疗效果欠佳、经济负担显著,其对一般人群的影响甚大。IBS的病理生理十分复杂,其治疗主要是对症治疗。对于IBS最常采用的治疗方式包括教育和安抚... 详细信息

肠易激综合征(IBS)系胃肠道慢性功能性疾病,是最常见的胃肠疾病之一。由于IBS患病率高、治疗效果欠佳、经济负担显著,其对一般人群的影响甚大。IBS的病理生理十分复杂,其治疗主要是对症治疗。对于IBS最常采用的治疗方式包括教育和安抚、生活方式的调整(尤其是营养干预)、外周药物(一般是针对肠道动力)、中枢药物(针对内脏高敏性和疼痛)及心理干预(旨在减少应激和症状引起的焦虑)。有效的饮食调节可能包括以下措施:低FODMAPs(发酵的低聚糖、单糖、二糖及多元醇)饮食,限制或禁食产气食物和/或乳糖和麸类食物,补充纤维素。一些新的治疗药物,如某些保健品,也可以作为IBS患者的一项治疗选择。本文重点探讨IBS的饮食干预,对基于营养的饮食治疗的循证医学证据进行了综述。

关键词：肠易激综合征功能性胃肠疾病 FODMAPs 耐受性肠道微生态

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Liver Research 2018年第4期2卷 186-199页

作者： Helen H.Wang Piero Portincasa Min Liu Patrick Tso David Q.-H.Wang Department of Medicine Division of Gastroenterology and Liver DiseasesMarion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNYUSA Department of Biomedical Sciences and Human Oncology Clinica Medica“A.Murri”University of Bari“Aldo Moro”Medical SchoolBariItaly Department of Pathology and Laboratory Medicine University of Cincinnati College of MedicineCincinnatiOHUSA

The terms biliary sludge and cholesterol microlithiasis(hereafter referred to as microlithiasis)were originated from different diagnostic techniques and may represent different stages of cholesterol gall-stone disease.Although the pathogenesis of biliary sludge and microlithiasis may be similar,micro-lithiasis could be preceded by biliary sludge,followed by persistent precipitation and aggregation of solid cholesterol crystals,and eventually,gallstone formation.Many clinical conditions are clearly associated with the formation of biliary sludge and microlithiasis,including total parenteral nutrition,rapid weight loss,pregnancy,organ transplantation,administration of certain medications,and a variety of acute and chronic illnesses.Numerous studies have demonstrated complete resolution of biliary sludge in approximately 40%of patients,a cyclic pattern of disappearing and reappearing in about 40%,and progression to gallstones in nearly 20%.Although only a minority of patients with ultrasonographic demonstration of biliary sludge develop gallstones,it is still a matter of controversy whether micro-lithiasis could eventually evolve to cholesterol gallstones.Biliary sludge and microlithiasis are asymp-tomatic in the vast majority of patients;however,they can cause biliary colic,acute cholecystitis,and acute pancreatitis.Biliary sludge and microlithiasis are most often diagnosed ultrasonographically and bile microscopy is considered the gold standard for their diagnosis.Specific measures to prevent the development of biliary sludge are not practical or cost-effective in the general population.Laparoscopic cholecystectomy offers the most definitive therapy on biliary sludge.Endoscopic sphincterotomy or surgical intervention is effective for microlithiasis-induced pancreatitis.Ursodeoxycholic acid can effectively prevent the recurrence of solid cholesterol crystals and significantly reduce the risk of recurrent pancreatitis.

关键词： Biliary sludge Cholesterol microlithiasis Acute cholecystitis Acute pancreatitis Biliary colic Cholesterol monohydrate crystals Lithogenic bile

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Relationships between emissions of toxic airborne molecules and type 1 diabetes incidence in children:An ecologic study

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World Journal of Diabetes 2021年第5期12卷 673-684页

作者： Agostino Di Ciaula Piero Portincasa clinica medica"a.murri" Department of Biomedical Sciences and Human OncologyUniversity of Bari Medical SchoolBari 70124Italy International Society of Doctors for Environment(ISDE) Via XXV Aprile n.34–52100 ArezzoItaly

BACKGROUND Type 1 diabetes originates from gene-environment interactions,with increasing incidence over time.AIM To identify correlates of childhood type 1 diabetes in European countries using an ecological approach.Several environmental variables potentially influencing the onset of type 1 diabetes have been previously evaluated.However,the relationships between epidemiologic data and exposure to toxic airborne molecules are scarcely studied.METHODS We employed an ecological model to explore,in a wide time period(1990-2018),associations between type 1 diabetes incidence in 19 European countries(systematic literature review)and the nationwide production of five widely diffused air pollutants:particulate matter<10μm(PM10),nitrogen oxides(NO),non-methane volatile organic compounds(VOCs),sulphur oxide(SO2),and ammonia.RESULTS Data confirm a raising incidence of type 1 diabetes in 18 out of 19 explored countries.The average difference(last vs first report,all countries)was+6.9×100000/year,with values ranging from-1.4(Germany)to+16.6(Sweden)per 100000/year.Although the overall production of pollutants decreased progressively from 1990 to 2018,type 1 diabetes incidence was positively associated with the nationwide emissions of PM10,VOCs,and NO but not with those of SO2 and ammonia.Type 1 diabetes incidence was significantly higher in countries with high emissions than in those with low emissions of PM10(27.5±2.4 vs 14.6±2.4×100000 residents,respectively),VOCs(24.5±4.4 vs 13.2±1.7×100000 residents,respectively),and NO(26.6±3 vs 13.4±2.4×100000 residents,respectively),but not of SO2 or ammonia.CONCLUSION Evidence justify further studies to explore better links between long-term air quality and type 1 diabetes onset at the individual level,which should include exposures during pregnancy.In this respect,type 1 diabetes could be,at least in part,a preventable condition.Thus,primary prevention policies acting through a marked abatement of pollutant emissions might attenuate future type 1 diabetes incidence throughout Europe.

关键词： Type 1 diabetes Epidemiology Air pollution Particulate matter Nitrogen oxide Non-methane volatile organic compounds

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Childhood obesity, cardiovascular and liver health: a growing epidemic with age

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World Journal of Pediatrics 2020年第5期16卷 438-445页

作者： Maria Felicia Faienza Mariangela Chiarito Emilio Molina-Molina Harshitha Shanmugam Frank Lammert Marcin Krawczyk Gabriele D'Amato Piero Portincasa Section of Pediatrics Department of Biomedical Sciences and Human OncologyUniversity of Bari"Aldo Moro"BariItaly clinica medica"a.murri" Department of Biomedical Sciences and Human OncologyUniversity of Bari"Aldo Moro"BariItaly Department of MedicineⅡ Saarland University Medical CenterSaarland UniversityHomburgGermany Laboratory of Metabolic Liver Diseases Center for Preclinical ResearchDepartment of GeneralTransplant and Liver SurgeryMedical University of WarsawWarsawPoland Neonatal Intensive Care Unit Di Venere HospitalBariItaly

Background The frequency of childhood obesity has increased over the last 3 decades,and the trend constitutes a worrisome epidemic worldwide.With the raising obesity risk,key aspects to consider are accurate body mass index classification,as well as metabolic and cardiovascular,and hepatic consequences.Data sources The authors performed a systematic literature search in PubMed and EMBASE,using selected key words(obesity,childhood,cardiovascular,liver health).In particular,they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health.Results We evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood,as a predisposing factor to cardiovascular and hepatic alterations.We also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences.Conclusions The epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence.Two key abnormalities in this context include cardiovascular diseases,and non-alcoholic fatty liver disease.Appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents.Nevertheless,improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity,cardiovascular diseases,and diabetes risk during adulthood.

关键词： Cardiovascular Childhood Liver health Obesity

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New insights into the role of Lith genes in the formation of cholesterol-supersaturated bile

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Liver Research 2017年第1期1卷 42-53页

作者： Helen H.Wang Tiangang Li Piero Portincasa David A.Ford Brent A.Neuschwander-Tetri Patrick Tso David Q-H.Wang Department of Internal Medicine Division of Gastroenterology and HepatologySaint Louis University School of MedicineSt.LouisMOUSA Department of Pharmacology Toxicology and TherapeuticsKansas University Medical CenterKansas CityKSUSA clinica medica“a.murri” Department of Biomedical Sciences and Human OncologyUniversity of Bari“Aldo Moro”Medical SchoolBariItaly Department of Biochemistry and Molecular Biology Saint Louis University School of MedicineSt.LouisMOUSA Department of Pathology and Laboratory Medicine University of Cincinnati College of MedicineCincinnatiOHUSA

Cholesterol gallstone formation represents a failure of biliary cholesterol homeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed.Lithogenic bile is mainly caused by persistent hepatic hypersecretion of biliary cholesterol and sustained cholesterol-supersaturated bile is an essential prerequisite for the precipitation of solid cholesterol monohydrate crystals and the formation of cholesterol gallstones.The metabolic determinants of the supply of hepatic cholesterol molecules that are recruited for biliary secretion are dependent upon the input-output balance of cholesterol and its catabolism in the liver.The sources of cholesterol for hepatic secretion into bile have been extensively investigated;however,to what extent each cholesterol source contributes to hepatic secretion is still unclear both under normal physiological conditions and in the lithogenic state.Although it has been long known that biliary lithogenicity is initiated by hepatic cholesterol hypersecretion,the genetic mechanisms that cause supersaturated bile have not been defined yet.Identification of the Lith genes that determine hepatic cholesterol hypersecretion should provide novel insights into the primary genetic and pathophysiological defects for gallstone formation.In this review article,we focus mainly on the pathogenesis of the formation of supersaturated bile and gallstones from the viewpoint of genetics and pathophysiology.A better understanding of the molecular genetics and pathophysiology of the formation of cholesterol-supersaturated bile will undoubtedly facilitate the development of novel,effective,and noninvasive therapies for patients with gallstones,which would reduce the morbidity,mortality,and costs of health care associated with gallstones,a very prevalent liver disease worldwide.

关键词： Bile flow Bile acid Biliary secretion Lith gene Micelle Vesicle

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FNDC4 and FNDC5 reduce SARS-CoV-2 entry points and spike glycoprotein S1-induced pyroptosis, apoptosis, and necroptosis in human adipocytes

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Cellular & Molecular Immunology 2021年第10期18卷 2457-2459页

作者： Gema Frühbeck Victoria Catalán Víctor Valentí Rafael Moncada Javier Gómez-Ambrosi Sara Becerril Camilo Silva Piero Portincasa Javier Escalada Amaia Rodríguez Metabolic Research Laboratory Clínica Universidad de NavarraPamplonaSpain CIBER Fisiopatología de la Obesidad y Nutrición(CIBEROBN) Instituto de Salud Carlos IIIMadridSpain Obesity and Adipobiology Group Instituto de Investigación Sanitaria de Navarra(IdiSNA)PamplonaSpain Department of Endocrinology and Nutrition Clínica Universidad de NavarraPamplonaSpain Department of Surgery Clínica Universidad de NavarraPamplonaSpain Department of Anesthesia Clínica Universidad de NavarraPamplonaSpain Department of Biomedical Sciences and Human Oncology Clinica Medica“A.Murri”University of Bari Medical SchoolPoliclinico HospitalBariItaly.

A sedentary lifestyle and obesity are important risk factors for severe COVID-19 complications and death[1,2].Excessive adipose tissue(AT)might contribute to more extensive viral spread with increased shedding,immune activation,and cytokine amplification[3].Several factors secreted by contracting muscle,termed myokines,mediate the beneficial effects of exercise in a wide range of diseases,including obesity[4].Thus,we conducted a study to explore the potential role of myokines of the fibronectin type III domain-containing family,FNDC4 and FNDC5,in mechanisms underlying the increased susceptibility to COVID-19 complications in obesity.

关键词： FNDC5 obesity FND

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Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

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World Journal of Gastroenterology 2009年第39期15卷 4865-4876页

作者： Ignazio Grattagliano Leonilde Bonfrate Catia V Diogo Helen H Wang David QH Wang Piero Portincasa Clinica Medica "A.Murri" Dipartimento di Medicina Interna e Medicina PubblicaUniversity of Bari Medical School Department of Zoology Center for Neurosciences and Cell BiologyUniversity of Coimbra Department of Medicine Liver Center and Gastroenterology DivisionBeth Israel Deaconess Medical CenterHarvard Medical School and Harvard Digestive Diseases Center

Drug-induced liver injury is a significant and still unresolved clinical problem.Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development.Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites.Aging,preexisting liver disease,enzyme induction or inhibition,genetic variances,local O2 supply and,above all,the intrinsic molecular properties of the drug may affect this process.Necrotic death follows antioxidant consumption and oxidation of intracellular proteins,which determine increased permeability of mitochondrial membranes,loss of potential,decreased ATP synthesis,inhibition of Ca2+-dependent ATPase,reduced capability to sequester Ca2+ within mitochondria,and membrane bleb formation.Conversely,activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis.Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage.Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis,in which different HLA genotypes might play a major role.This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage.Future perspectives including new frontiers for research are discussed.

关键词：生化机制肝损伤药物性免疫系统激活肝细胞损伤毒性机制肝脏疾病抗氧化剂

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Idiopathic hypereosinophilic syndrome presenting with severe vasculitis successfully treated with imatinib

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World Journal of clinical Cases 2016年第10期4卷 328-332页

作者： Paolo Fraticelli Alain Kafyeke Massimo Mattioli Giuseppe Pio Martino Marta.murri Armando Gabrielli clinica medica Department of Internal MedicineUniversità Politecnica delle Marche

Idiopathic hypereosinophilic syndrome(HES) is a rare disorder characterized by peripheral eosinophilia exceeding 1500/mm3, a chronic course, absence of secondary causes, and signs and symptoms of eosinophil-mediated tissue injury. One of the best-characterized forms of HES is the one associated with FIP1L1-PDGFRA gene rearrangement, which was recently demonstrated as responsive to treatment with the small molecule kinase inhibitor drug, imatinib mesylate. Here, we describe the case of a 51-year-old male, whose symptoms satisfied the clinical criteria for HES with cutaneous and cardiac involvement and who also presented with vasculitic brain lesions and retroperitoneal bleeding. Molecular testing, including fluorescence in situ hybridization, of bone marrow and peripheral blood showed no evidence of PDGFR rearrangements. The patient was initially treated with high-dose steroid therapy and then with hydroxyurea, but proved unresponsive to both. Upon subsequent initiation of imatinib mesilate, the patient showed a dramatic improvement in eosinophil count and progressed rapidly through clinical recovery. Long-term follow-up confirmed the efficacy of treatment with low-dose imatinib and with no need of supplemental steroid treatment, notwithstanding the absence of PDGFR rearrangement.

关键词： Idiopathic hypereosinophilic syndrome Eosinophilia Cerebral vasculitis PDGFR molecular rearrangement Imatinib mesilate

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Pathogenic role of oxidative and nitrosative stress in primary biliary cirrhosis

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World Journal of Gastroenterology 2014年第19期20卷 5746-5759页

作者： Ignazio Grattagliano Giuseppe Calamita Tiziana Cocco David Q-H Wang Piero Portincasa Italian College of General Practitioners 50100 FlorenceBari 70124Italy Department of Bioscience Biotechnologyand Biopharmaceutics"Aldo Moro" University Medical SchoolBari 70124Italy Department of Basic medical Science Neurosciencesand Sense Organs"Aldo Moro" University Medical SchoolBari 70124Italy Department of Internal Medicine Division of Gastroenterology and HepatologySaint Louis University School of MedicineSt.LouisMO 63104United States Clinica Medica "A.Murri" Department of Biomedical Sciences and Human Oncology"Aldo Moro" University Medical SchoolBari 70124Italy

Primary biliary cirrhosis is a multifactor autoimmune disease characterized by hepatic and systemic manifestations,with immune system dysregulation and abnormalities in the hepatic metabolism of bile salts,lipids,and nutrients,as well as destruction of membrane lipids and mitochondrial dysfunction.Both oxidative and nitrosative stress are associated with ongoing manifestations of the disease.In particular,abnormalities in nitric oxide metabolism and thiol oxidation already occur at early stages,thus leading to the hypothesis that these biochemical events play a pathogenic role in primary biliary cirrhosis.Moreover,the association of these metabolic abnormalities with the progression of the disease may indicate some biochemical parameters as early diagnostic markers of disease evolution,and may open up the potential for pharmacological intervention to inhibit intra-and extra-cellular stress events for resuming hepatocellular functions.The following paragraphs summarize the current knowledge by outlining molecular mechanisms of the disease related to these stress events.

关键词： Aquaporins Bile salts Chronic cholestasis Glutathi

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