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| 1 | Biochemical mechanisms in drug-induced liver injury:Certainties and doubts显示文摘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. | Ignazio Grattagliano Leonilde Bonfrate Catia V Diogo Helen H Wang David QH Wang Piero Portincasa | 2009 | World Journal of Gastroenterology2009，15，39： | 30 |
| 2 | Pan-enteric dysmotility,impaired quality of life and alexithymia in a large group of patients meeting ROMEⅡ criteria for irritable bowel syndrome显示文摘AIM:Psychological factors, altered motility and sensation disorders of the intestine can be variably associated with irritable bowel syndrome (IBS). Such aspects have not been investigated simultaneously. The aim of this paper was to evaluate gastrointestinal motility and symptoms, psychological spectrum and quality of life in a large group of IBS patients in southern Italy.METHODS: One hundred IBS patients (F:M=73:27, age 48±2 years, mean±SE) fulfilling ROME Ⅱ criteria matched with 100 healthy subjects (F:M=70:30, 45±2 years). Dyspepsia,bowel habit, alexithymia, psycho-affective profile and quality of life were assessed using specific questionnaires. Basally and postprandially, changes in gallbladder volumes and antral areas after liquid meal and orocaecal transit time (OCTT)were measured respectively by ultrasonography and H2-breath test. Appetite, satiety, fullness, nausea, and epigastric pain/discomfort were monitored using visual-analogue scales.RESULTS: Compared with controls, IBS patients had increased dyspepsia (score 12.6±0.7 VS 5.1±0.2, P<0.0001),weekly bowel movements (12.3±0.4 VS 5.5±0.2, P<0.00001, comparable stool shape), alexithymia (score 59.11.1 VS40.5±1.0, P=0.001), poor quality of life and psychoaffective profile. IBS patients had normal gallbladderemptying, but delayed gastric emptying (T50:35.5±1.0 VS 26.1±0.6 min, P=0.00001) and OCTT (163.0±5.4 VS96.6±1.8min, P=0.00001). Fullness, nausea, and epigastric pain/discomfort were greater in IBS than in controls.CONCLUSION: ROME Ⅱ IBS patients have a pan-enteric dysmotility with frequent dyspepsia, associated with psychological morbidity and greatly impaired quality of life.The presence of alexithymia, a stable trait, is a novel finding of potential interest to detect subgroups of IBS patients with different patterns recoveed after therapy. | Piero Portincasa Antonio Moschetta Giuseppe Baldassarre Donato F. Altomare Giuseppe Palasciano | 2003 | World Journal of Gastroenterology2003，9，10： | 23 |
| 3 | Therapy of gallstone disease:What it was,what it is,what it will be显示文摘Cholesterol gallstone disease is a common clinical condition influenced by genetic factors,increasing age,female gender,and metabolic factors.Although laparoscopic cholecystectomy is currently considered the gold standard in treating patients with symptomatic gallstones,new perspectives regarding medical therapy of cholelithiasis are currently under discussion,also taking into account the pathogenesis of gallstones,the natural history of the disease and the analysis of the overall costs of therapy.A careful selection of patients may lead to successful nonsurgical therapy in symptomatic subjects with a functioning gallbladder harboring small radiolucent stones.The classical oral litholysis by ursodeoxycholic acid has been recently paralleled by new experimental observations,suggesting that cholesterol-lowering agents which inhibit cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe),or drugs acting on specific nuclear receptors involved in cholesterol and bile acid homeostasis,might be proposed as additional approaches for treating cholesterol gallstones.In this review we discuss old,recent and future perspectives on medical treatment of cholesterol cholelithiasis. | Piero Portincasa Agostino Di Ciaula Leonilde Bonfrate David QH Wang | 2012 | World Journal of Gastrointestinal Pharmacology and Therapeutics2012，3，2： | 21 |
| 4 | Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells显示文摘AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma Fa O cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations(25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.RESULTS: Lipid-loading resulted in intracellular triglyceride(TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors(PPARs) and sterol regulatory element-binding protein-1c(SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species(ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B(NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1(CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.CONCLUSION: We demonstrated the direct antisteatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies. | Giulia Vecchione Elena Grasselli Adriana Voci Francesca Baldini Ignazio Grattagliano David QH Wang Piero Portincasa Laura Vergani | 2016 | World Journal of Gastroenterology2016，22，26： | 13 |
| 5 | Primary sclerosing cholangitis: Updates in diagnosis and therapy显示文摘Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown origin mostly found in males, and characterized by diffuse inflammation and fibrosis of both intra- and extra-hepatic bile ducts. So far, PSC is considered as an autoimmune hepatobiliary disease. In most cases the progression of PSC towards liver cirrhosis and liver failure is slow but irreversible, and liver transplantation is currently the only definitive treatment. In recent years,PSC has been an area of active research worldwide with great interest in etiology, pathogenesis, diagnosis, and therapeutic options such as hydrophilic ursodeoxycholic acid and immunosuppressive agent tacrolimus. Recent updates on clinical and therapeutic aspects of PSC are discussed in the present review. | Piero Portincasa Michele Vacca Antonio Moschetta Michele Petruzzelli Giuseppe Palasciano Karel J.van Erpecum Gerard P.van Berge-Henegouwen | 2005 | World Journal of Gastroenterology2005，11，1： | 7 |
| 6 | A silybin-phospholipids complex counteracts rat fatty liver degeneration and mitochondrial oxidative changes显示文摘AIM:To investigate the effectiveness of antioxidant compounds in modulating mitochondrial oxidative alterations and lipids accumulation in fatty hepatocytes.METHODS:Silybin-phospholipid complex containing vitamin E(Realsil) was daily administered by gavage(one pouch diluted in 3 mL of water and containing 15 mg vitamin E and 47 mg silybin complexed with phospholipids) to rats fed a choline-deprived(CD) or a high fat diet [20% fat,containing 71% total calories as fat,11% as carbohydrate,and 18% as protein,high fat diet(HFD)] for 30 d and 60 d,respectively.The control group was fed a normal semi-purified diet containing adequate levels of choline(35% total calories as fat,47% as carbohydrate,and 18% as protein).Circulating and hepatic redox active and nitrogen regulating molecules(thioredoxin,glutathione,glutathione peroxidase),NO metabolites(nitrosothiols,nitrotyrosine),lipid peroxides [malondialdehyde-thiobarbituric(MDA-TBA)],and pro-inflammatory keratins(K-18) were measured on days 0,7,14,30,and 60.Mitochondrial respiratory chain proteins and the extent of hepatic fatty infiltration were evaluated.RESULTS:Both diet regimens produced liver steatosis(50% and 25% of liver slices with CD and HFD,respectively) with no signs of necro-inflammation:fat infiltration ranged from large droplets at day 14 to disseminated and confluent vacuoles resulting in microvesicular steatosis at day 30(CD) and day 60(HFD).In plasma,thioredoxin and nitrosothiols were not significantly changed,while MDA-TBA,nitrotyrosine(from 6 ± 1 nmol/L to 14 ± 3 nmol/L day 30 CD,P < 0.001,and 12 ± 2 nmol/L day 60 HFD,P < 0.001),and K-18(from 198 ± 20 to 289 ± 21 U/L day 30 CD,P < 0.001,and 242 ± 23 U/L day 60 HFD,P < 0.001) levels increased significantly with ongoing steatosis.In the liver,glutathione was decreased(from 34.0 ± 1.3 to 25.3 ± 1.2 nmol/mg prot day 30 CD,P < 0.001,and 22.4 ± 2.4 nmol/mg prot day 60 HFD,P < 0.001),while thioredoxin and glutathione peroxidase were initially increased and then decreased.Nitrosothiols were constantly increased.MDA-TBA levels were five-fold increased from 9.1 ± 1.2 nmol/g to 75.6 ± 5.4 nmol/g on day 30,P < 0.001(CD) and doubled with HFD on day 60.Realsil administration significantly lowered the extent of fat infiltration,maintained liver glutathione levels during the first half period,and halved its decrease during the second half.Also,Realsil modulated thioredoxin changes and the production of NO derivatives and significantly lowered MDA-TBA levels both in liver(from 73.6 ± 5.4 to 57.2 ± 6.3 nmol/g day 30 CD,P < 0.01 and from 27.3 ± 2.1 nmol/g to 20.5 ± 2.2 nmol/g day 60 HFD,P < 0.01) and in plasma.Changes in mitochondrial respiratory complexes were also attenuated by Realsil in HFD rats with a major protective effect on Complex Ⅱ subunit CII-30.CONCLUSION:Realsil administration effectively contrasts hepatocyte fat deposition,NO derivatives formation,and mitochondrial alterations,allowing the liver to maintain a better glutathione and thioredoxin antioxidant activity. | Ignazio Grattagliano Catia V Diogo Maria Mastrodonato Ornella de Bari Michele Persichella David QH Wang Adriana Liquori Domenico Ferri Maria Rosaria Carratù Paulo J Oliveira Piero Portincasa | 2013 | World Journal of Gastroenterology2013，19，20： | 6 |
| 7 | Management of liver cirrhosis between primary care and specialists显示文摘This article discusses a practical, evidence-based approach to the diagnosis and management of liver cirrhosis by focusing on etiology, severity, presence of complications, and potential home-managed treatments. Relevant literature from 1985 to 2010 (PubMed) was reviewed. The search criteria were peer-reviewed full papers published in English using the following MESH headings alone or in combination: 'ascites', 'liver fibrosis', 'cirrhosis', 'chronic hepatitis', 'chronic liver disease', 'decompensated cirrhosis', 'hepatic encephalopathy', 'hypertransaminasemia', 'liver transplantation' and 'portal hypertension'. Forty-nine papers were selected based on the highest quality of evidence for each section and type (original, randomized controlled trial, guideline, and review article), with respect to specialist setting (Gastroenterology, Hepatology, and Internal Medicine) and primary care. Liver cirrhosis from any cause represents an emerging health issue due to the increasing prevalence of the disease and its complications worldwide. Primary care physicians play a key role in early identification of risk factors, in the management of patients for improving quality and length of life, and for preventing complications. Specialists, by contrast, should guide specific treatments, especially in the case of complications and for selecting patient candidates for liver transplantation. An integrated approach between specialists and primary care physicians is essential for providing better outcomes and appropriate home care for patients with liver cirrhosis. | Ignazio Grattagliano Enzo Ubaldi Leonilde Bonfrate Piero Portincasa | 2011 | World Journal of Gastroenterology2011，17，18： | 5 |
| 8 | Significant factors associated with fatal outcome in emergency open surgery for perforated peptic ulcer显示文摘AIM: To evaluate the main factors associated with mortality in patients undergoing surgery for perforated peptic ulcer referred to an academic department of general surgery in a large southern Italian city.METHODS: One hundred and forty-nine consecutive patients (M:F ratio=110:39, mean age 52 yrs, range 16-95) with peptic ulcer disease were investigated for clinical history (including age, sex, previous history of peptic ulcer, associated diseases, delayed abdominal surgery, ulcer site, operation type, shock on admission, postoperative general complications,and intra-abdominal and/or wound infections), serum analyses and radiological findings.RESULTS: The overall mortality rate was 4.0%. Among all factors, an age above 65 years, one or more associated diseases, delayed abdominal surgery, shock on admission,postoperative abdominal complications and/or wound infections, were significantly associated (χ2) with increased mortality in patients undergoing surgery (0.0001 | Mario Testini Piero Portincasa Giuseppe Piccinni Germana Lissidini Fabio Pellegrini Luigi Greco | 2003 | World Journal of Gastroenterology2003，9，10： | 5 |
| 9 | Pathogenic role of oxidative and nitrosative stress in primary biliary cirrhosis显示文摘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. | Ignazio Grattagliano Giuseppe Calamita Tiziana Cocco David Q-H Wang Piero Portincasa | 2014 | World Journal of Gastroenterology2014，20，19： | 5 |
| 10 | Concomitant, sequential, and hybrid therapy for H. pylori eradication: a pilot study.显示文摘 | Angelo Zullo Giuseppe Scaccianoce Vincenzo De Francesco Valentina Ruggiero Pasquale D’Ambrosio Luigi Castorini Leonilde Bonfrate Lucy Vannella Cesare Hassan Piero Portincasa | 2013 | Clinics and Research in Hepatology and Gastroenterology2013，，： | 4 |
| 11 | Microbiota in health and irritable bowel syndrome: current knowledge, perspectives and therapeutic options显示文摘 | Leonilde Bonfrate Jan Tack Ignazio Grattagliano Rosario Cuomo Piero Portincasa | 2013 | Scandinavian Journal of Gastroenterology2013，，9： | 3 |
| 12 | Similarities and differences between biliary sludge and microlithiasis: Their clinical and pathophysiological significances显示文摘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. | Helen H.Wang Piero Portincasa Min Liu Patrick Tso David Q.-H.Wang | 2018 | Liver Research2018，2，4： | 3 |
| 13 | Ultrasonographic study of postcibal gastro-esophageal reflux and gastric emptying in infants with recurrent respiratory disease显示文摘AIM: To check the utility of postcibal ultrasonography for the evaluation of reflux in relation to gastric emptying in infants with recurrent respiratory symptoms and to link imaging with clinical data.METHODS: Esophageal reflux (hyperechoic retrograde filling) and gastric emptying (antral areas) were quantified before and after ingestion of a standard formula in 35 untreated infants (13 with chronic cough,22 with recurrent bronchitis) and in 31 controls.RESULTS: The prevalence of abnormal (≥8 episodes)postcibal refluxes was 74% in patients and 3% in controls. Number, duration of the longest episode and extent of refluxes were significantly higher in patients compared to controls. Number of refluxes was higher in patients with symptomatic refluxes than in those without.Infants with recurrent bronchitis had more refluxes than those with chronic cough and controls. Extent and timing of gastric emptying were similar in patients and controls.CONCLUSION: Esophageal ultrasonography is a useful and physiological test in infants with recurrent respiratory diseases, which have a high prevalence of abnormal postcibal esophageal reflux and a gastric emptying similar to that of normal controls. Esophageal reflux is more severe in subjects with recurrent bronchitis than in those with chronic cough. | Agostino Di Ciaula Piero Portincasa Leonardo Di Terlizzi Domenico Paternostro Giuseppe Palasciano | 2005 | World Journal of Gastroenterology2005，11，46： | 3 |
| 14 | Role of mitochondria in nonalcoholic fatty liver disease-from origin to propagation显示文摘 | Ignazio Grattagliano Ornella de Bari Telma C. Bernardo Paulo J. Oliveira David Q.-H. Wang Piero Portincasa | 2012 | Clinical Biochemistry2012，，9： | 2 |
| 15 | Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management显示文摘 | Piero Portincasa Ignazio Grattagliano Vincenzo O. Palmieri Giuseppe Palasciano | 2004 | Clinical Biochemistry2004，，3： | 2 |
| 16 | Effect of gallbladder hypomotility on cholesterol crystallization and growth in CCK-deficient mice显示文摘 | Helen H. Wang Piero Portincasa Min Liu Patrick Tso Linda C. Samuelson David Q.-H. Wang | 2009 | BBA - Molecular and Cell Biology of Lipids2009，，2： | 2 |
| 17 | Long-term ursodeoxycholate improves circulating redox changes in primary biliary cirrhotic patients显示文摘 | Ignazio Grattagliano Vincenzo O. Palmieri Piero Portincasa Francesco Minerva Giuseppe Palasciano | 2011 | Clinical Biochemistry2011，，17： | 2 |
| 18 | Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease显示文摘 | Agostino Di Ciaula David Q.-H. Wang Leonilde Bonfrate Piero Portincasa Gloria L. Vega | 2013 | Cholesterol2013，，： | 2 |
| 19 | Gallstone disease: Symptoms and diagnosis of gallbladder stones显示文摘 | Portincasa P Moschetta A Petruzzelli M | 2006 | Best Pract Res Clin Gastroenterol2006，20，6： | 1 |
| 20 | Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms显示文摘Portal hypertension in cirrhosis is defined as an increase in the portal pressure gradient(PPG)between the portal and hepatic veins and is traditionally estimated by the hepatic venous pressure gradient(HVPG),which is the difference in pressure between the free-floating and wedged positions of a balloon catheter in the hepatic vein.By convention,��HVPG≥10mmHg indicates clinically significant portal hypertension,which is associated with adverse clinical outcomes.Nonalcoholic fatty liver disease(NAFLD)is a common disorder with a heterogeneous clinical course,which includes the development of portal hypertension.There is increasing evidence that portal hypertension in NAFLD deserves special considerations.First,elevated PPG often precedes fibrosis in NAFLD,suggesting a bidirectional relationship between these pathological processes.Second,HVPG underestimates PPG in NAFLD,suggesting that portal hypertension is more prevalent in this condition than currently believed.Third,cellular mechanoresponses generated early in the pathogenesis of NAFLD provide a mechanistic explanation for the pressurefibrosis paradigm.Finally,a better understanding of liver mechanobiology in NAFLD may aid in the development of novel pharmaceutical targets for prevention and management of this disease. | Emilie K.Mitten Piero Portincasa György Baffy | 2023 | Journal of Clinical and Translational Hepatology2023，11，5： | 1 |
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