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Pathogenesis of alcoholic liver disease:Role of oxidative metabolism

World Journal of Gastroenterology 2014年第47期20卷 17756-17772页

作者： Elisabetta Ceni Tommaso Mello andrea galli Gastroenterology Unit Department of Experimental and Clinical Biochemical SciencesUniversity of Florence50139 FlorenceItaly Center of Excellence for Research Transfer and High EducationDENOtheUniversity of Florence50139 FlorenceItaly Fior Gen Foundation 50123 FlorenceItaly

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with ce

关键词： Alcohol metabolism Acetaldehyde Reactive oxygen species Alcoholic liver disease Protein adducts Hepatic stellate cells Liver fibrosis CYP2E1

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Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis

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World Journal of Gastroenterology 2014年第33期20卷 11630-11640页

作者： Mirko Tarocchi Simone Polvani Giada Marroncini andrea galli Department of Experimental and Clinical Biomedical Sciences University of Florence 50139 Florence Italy FiorGen Foundation 50139 Florence Italy

Hepatitis B virus(HBV) infection is a global public health problem with approximately 2 billion people that have been exposed to the virus. HBV is a member of a family of small, enveloped DNA viruses called hepadnaviruses, and has a preferential tropism for hepatocytes of mammals and birds. Epidemiological studies have proved a strong correlation between chronic hepatitis B virus infection and the development of hepatocellular carcinoma(HCC). HCC is the fifth most common malignancy with about 700000 new cases each year, and more than 50% of them arise in HBV carriers. A large number of studies describe the way in which HBV can contribute to HCC development. Multiple mechanisms have been proposed, including the accumulation of genetic damage due to immune-mediated hepatic inflammation and the induction of oxidative stress. There is evidence of the direct effects of the viral proteins HBx and HBs on the cell biology. Integration of HBV-DNAinto the human genome is considered an early event in the carcinogenic process and can induce, through insertional mutagenesis, the alteration of gene expression and chromosomal instability. HBV has also epigenetic effects through the modification of the genomic methylation status. Furthermore, the virus plays an important role in the regulation of microRNA expression. This review will summarize the many mechanisms involved in HBV-related liver carcinogenesis.

关键词： Hepatocellular carcinoma Hepatocarcino-genesis Hepatitis B Virus Chronic hepatitis B infection Cell biology

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Nuclear receptors and pathogenesis of pancreatic cancer

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World Journal of Gastroenterology 2014年第34期20卷 12062-12081页

作者： Simone Polvani Mirko Tarocchi Sara Tempesti andrea galli Department of Experimental and Clinical Biomedical Sciences University of Florence50134 FlorenceItaly

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.

关键词： Peroxisome proliferator activated receptor Pancreatic intraepithelial neoplasia COUP-TFⅡ Nuclear receptors Orphan nuclear receptor Nuclear receptors 4A2 Nuclear receptors 2F2 Pancreatic cancer Retinoid X receptor Testicular receptor 3

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Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer

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World Journal of Gastroenterology 2016年第8期22卷 2441-2459页

作者： Simone Polvani Mirko Tarocchi Sara Tempesti Lapo Bencini andrea galli Department of Experimental and Clinical Biomedical Sciences "Mario Serio" University of Florence Chirurgia Generale Oncologica Azienda Ospedaliero Universitaria Careggi

Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

关键词： Insulin Pancreatic cancer Adipose tissue Metformin Nuclear receptor Leptin Adiponectin Inflammation Thiazolidinediones

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Telomerase reactivation is associated with hepatobiliary and pancreatic cancers

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Hepatobiliary & Pancreatic Diseases International 2020年第5期19卷 420-428页

作者： Vito Sansone Marco Le Grazie Jenny Roselli Simone Polvani andrea galli Francesco Tovoli Mirko Tarocchi Department of Medical and Surgical Sciences University of BolognaBolognaItaly Department of Experimental and Clinical Biomedical Sciences"Mario Serio" University of Florence50139 FirenzeItaly

Background:Human telomerase reverse transcriptase(hTERT)and its components play a significant role in cancer progression,but recent data demonstrated that telomeres and telomerase alterations could be found in other diseases;increasing evidence suggests a key role of this enzyme in the fields of hepatobiliary and pancreatic *** sources:We performed a PubMed search with the following keywords:telomerase,hepatocellular carcinoma,cholangiocarcinoma,pancreatic adenocarcinoma by December *** reviewed the relevant publications that analyzed the correlation between telomerase activity and hepatobiliary and pancreatic ***:Telomerase reactivation plays a significant role in the development and progression of hepatobiliary and pancreatic tumors and could be used as a diagnostic biomarker for hepatobiliary and pancreatic cancers,as a predictor for prognosis and a promising therapeutic ***:Our review summarized the evidence about the critical role of hTERT in cancerous and precancerous lesions of the alteration and its activity in hepatobiliary and pancreatic diseases.

关键词： Telomerase Telomere Cancer Hepatobiliary and pancreatic disease

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Muscle fatigue in women with primary biliary cirrhosis:Spectral analysis of surface electromyography

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World Journal of Gastroenterology 2006年第32期12卷 5186-5190页

作者： Maria Rosa Biagini Alessandro Tozzi Antonello Grippo andrea galli Stefano Milani Aldo Amantini Department of Clinical Pathophysiology Gastroenterology Unit University of FlorenceAOU CareggiFirenzeItaly Department of Neurological Science Neurophysiological Unit University of FlorenceAOU CareggiFirenzeItaly

AIM： To evaluate the myoelectric manifestations of peripheral fatigability in patients with primary biliary cirrhosis in comparison to healthy subjects. METHODS： Sixteen women with primary biliary cirrhosis without comorbidity and 13 healthy women matched for age and body mass index （BMI） completed the selfreported questionnaire fatigue impact scale. All subjects underwent surface electromyography assessment of peripheral fatigability. Anterior tibial muscle isometric voluntary contraction was executed for 20 s at 80% of maximal voluntary isometric contraction. During the exercise electromyographic signal series were recorded and root mean square （expression of central drive） as well as mean and median of electromyographic signal frequency spectrum （estimates of muscle fatigability） were com- puted. Each subject executed the trial two times. EMG parameters were normalized, then linear regression was applied and slopes were calculated. RESULTS： Seven patients were fatigued （median fatigue impact scale score： 38, range： 26-66） and 9 were not fatigued （median fatigue impact scale score： 7, range： 0-17）. The maximal voluntary isometric contraction was similar in patients （82, 54-115 N） and controls （87, 74-101 N）, and in patients with high （81, 54-115 N） and low fatigue impact scale scores （86, 65-106 N）. Root mean square as well as mean and median of frequency spectrum slopes were compared with the Mann-Whitney U test, and no significant difference was found between fatigued and non-fatigued patients and controls. CONCLUSION： No instrumental evidence of peripheral fatigability can be found in women with primary biliary cirrhosis but no comorbidity, suggesting that fatigue in such patients may be of central origin.

关键词： Primary biliary cirrhosis Cholestasis Surfaceelectromyography Peripheral fatigue Muscle fatigue Fatigability Root mean square Mean frequency Medianfrequency Fatigue impact scale

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Practical insights into chronic management of hepatic Wilson’s disease

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World Journal of Clinical Cases 2022年第14期10卷 4334-4347页

作者： Erica Nicola Lynch Claudia Campani Tommaso Innocenti Gabriele Dragoni Paolo Forte andrea galli Gastroenterology Research Unit Department of Experimental and Clinical Biomedical Sciences“Mario Serio”University of FlorenceFlorence 50134Italy Department of Experimental and Clinical Medicine University of FlorenceFlorence 50134Italy Department of Medical Biotechnologies University of SienaSiena 53100Italy Division of Gastroenterology University Hospital“Careggi”Florence 50134Italy

Wilson’s disease(WD)is a rare inherited disorder of human copper metabolism,with an estimated prevalence of 1:30000-1:50000 and a broad spectrum of hepatic and neuropsychiatric *** healthy individuals,the bile is the main route of elimination of *** WD patients,copper accumulates in the liver,it is released into the bloodstream,and is excreted in *** can also be accumulated in the brain,kidneys,heart,and osseous matter and causes damage due to direct toxicity or oxidative *** WD is commonly but not exclusively diagnosed in childhood or young ***,non-cirrhotic WD patients seem to have a normal life ***,chronic management of patients with Wilson’s disease is challenging,as available biochemical tests have many limitations and do not allow a clear identification of non-compliance,overtreatment,or treatment *** provide optimal care,clinicians should have a complete understanding of these limitations and counterbalance them with a thorough clinical *** aim of this review is to provide clinicians with practical tools and suggestions which may answer doubts that can arise during chronic management of patients with hepatic *** particular,it summarises current knowledge on Wilson’s disease clinical and biochemical monitoring and *** also analyses available evidence on pregnancy and the role of low-copper diet in *** research should focus on trying to provide new copper metabolism tests which could help to guide treatment adjustments.

关键词： Wilson’s disease Urinary copper excretion Non-ceruloplasmin-bound copper D-penicillamine Trientine Zinc salts

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Effect of a counseling-supported treatment with the Mediterranean diet and physical activity on the severity of the non-alcoholic fatty liver disease

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World Journal of Gastroenterology 2017年第17期23卷 3150-3162页

作者： Chiara Gelli Mirko Tarocchi Ludovico Abenavoli Laura Di Renzo andrea galli Antonino De Lorenzo Division of Clinical Nutrition and Nutrigenomics Department of Biomedicine and PreventionUniversity of Rome“Tor Vergata” Department of Experimental and Clinical Biomedical Sciences University of Florence Department of Health Sciences University Magna Graecia

AIM To determine the clinical effectiveness of nutritional counseling on reduction of non-alcoholic fatty liver disease(NAFLD) severity, weight loss, metabolic and anthropometric indexes and liver *** Forty-six adults with NAFLD received a 6-mo clinical and a dietary intervention(based on Mediterranean diet) carried out respectively by a gastroenterologist and a nutritionist with counseling license. The counseling process consisted of monthly meeting(about 45 min each). The effect of the treatment was evaluated monitoring liver enzymes, metabolic parameters, cardiovascular risk indexes, NAFLD severity [assessed by ultrasound(US)] and related indexes. All parameters were assessed at baseline. Biochemistry was also assessed at mid-and end-interventions and US was repeated at *** The percentage of patients with steatosis grade equal or higher than 2 was reduced from 93% to 48% and steatosis regressed in 9 patients(20%). At the end of the treatment the end-point concerning the weight(i.e., a 7% weight reduction or achievement/maintenance of normal weight) was accomplished by 25 out of 46 patients(i.e., 54.3%). As far as the liver enzymes is concerned, all three liver enzymes significantly decrease during the treatment the normalization was particularly evident for the ALT enzyme(altered values reduced from 67% down to 11%). Several parameters, i.e., BMI, waist circumference, waist-to-hip ratio, AST, ALT, GGT, HDL, serum glucose, Tot-Chol/HDL, LDL/HDL, TG/HDL, AIP, HOMA, FLI, Kotronen index, VAI, NAFLD liver fat score and LAP, showed a significant improvement(P < 0.01) between baseline and *** Outcomes of this study further strengthen the hypothesis that Med Diet and more active lifestyle can be considered a safe therapeutic approach for reducing risk and severity of NAFLD and related disease states. The proposed approach may be proposed as a valid and recommended approach for improving the clinical profile of NAFLD p

关键词： Non-alcoholic fatty liver disease Non-alcoholic steatohepatitis Mediterranean diet Metabolic syndrome Therapeutic approach Counseling Diet Life-style

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Therapeutic usability of two different fiducial gold markers for robotic stereotactic radiosurgery of liver malignancies:A pilot study

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World Journal of Hepatology 2016年第17期8卷 731-738页

作者： Maria Marsico Tommaso Gabbani Lorenzo Livi Maria Rosa Biagini andrea galli Integrate Activity Department 1 Gastroen-terology AOU Modena University Hospital Oncology Department Clinical Gastroenterology AOU CareggiFlorence University Hospital Oncology Department Radiotherapy SOD AOU Careggi Florence University Hospital

AIM: To assess how the application of different types of markers affects the tracking accuracy of Cyber Knife'***: Fifteen patients were recruited and subjected to the ultrasound-guided placement of markers. Two different type of needles 25 gauge(G) and 17 G containing two different fiducial marker, gold notched flexible anchor wire 0.28 mm × 10 mm(25 G needle) and gold cylindrical grain 1 mm × 4 mm(17 G), were used. Seven days after the procedure, a Cyber Knife planning computed tomography(CT) for the simulation of radiation treatment was performed on all patients.A binary CT score was assigned to the fiducial markers visualization. Also, the CT number was calculated for each fiducial and the values compared with a specific ***: For each patient from 1 to 5, intra-hepatic markers were placed(one in 2 patients, three in 8 patients, four in 3 patients, and five in 2 patients). A total of 48 needles were used(thirty-two 17 G and sixteen 25 G) and 48 gold markers were placed(32 Grain shaped markers and 16 Gold Anchor). The result showed that the CT visualization of the grain markers was better than the anchor markers(P = 5 × 10^(-9)). Furthermore, the grain markers were shown to present minor late complications(P = 3 × 10^(-6)), and the best CT threshold number(P = 0.0005). CONCLUSION: The study revealed that the Gold Anchor fiducial marker is correlated with a greater number of late minor complications and low visualization by the CT.

关键词： Robotic radiosurgery Fiducial markers Liver malignancies Cyber Knife Radiation therapy Stereotactic radiosurgery

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Chemotherapy for hepatocellular carcinoma:The present and the future

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World Journal of Hepatology 2017年第21期9卷 907-920页

作者： Marco Le Grazie Maria Rosa Biagini Mirko Tarocchi Simone Polvani andrea galli Gastroenterology Research Unit Department of Experimental and Clinical Biochemical Sciences"Mario Serio"University of Florence50139 FlorenceItaly

Hepatocellular carcinoma(HCC) is the most common primary tumor of the liver. Its relationship to chronic liver diseases, in particular cirrhosis, develops on a background of viral hepatitis, excessive alcohol intake or metabolic steatohepatitis, leads to a high incidence and prevalence of this neoplasia worldwide. Despite the spread of HCC, its treatment it's still a hard challenge, due to high rate of late diagnosis and to lack of therapeutic options for advanced disease. In fact radical surgery and liver transplantation, the most radical therapeutic approaches, are indicated only in case of early diagnosis. Even local therapies, such as transarterial chemoembolization, find limited indications, leading to an important problem regarding treatment of advanced disease. In this situation, until terminal HCC occurs, systemic therapy is the only possible approach, with sorafenib as the only standard treatment available. Anyway, the efficacy of this drug is limited and many efforts are necessary to understand who could benefit more with this treatment. Therefore, other molecules for a targeted therapy were evaluated, but only regorafenib showed promising results. Beside molecular target therapy, also cytotoxic drugs, in particular oxaliplatinand gemcitabine-based regimens, and immune-checkpoint inhibitors were tested with interesting results. The future of the treatment of this neoplasia is linked to our ability to understand its mechanisms of resistance and to find novel therapeutic targets, with the objective to purpose individualized approaches to patients affected by advanced HCC.

关键词： Hepatocellular carcinoma Systemic therapy Chemotherapy Molecular targeted therapy Cytotoxic therapy Immunotherapy Perspectives

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