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Intestinal epithelial barrier and neuromuscular compartment in health and disease

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World Journal of Gastroenterology 2020年第14期26卷 1564-1579页

作者： Vanessa D’Antongiovanni Carolina Pellegrini Matteo Fornai Rocchina Colucci corrado blandizzi Luca Antonioli Nunzia Bernardini Department of Clinical and Experimental Medicine University of PisaPisa 56126Italy Department of Pharmacy University of PisaPisa 56126Italy Department of Pharmaceutical and Pharmacological Sciences University of PadovaPadova 35131Italy

A number of digestive and extra-digestive disorders,including inflammatory bowel diseases,irritable bowel syndrome,intestinal infections,metabolic syndrome and neuropsychiatric disorders,share a set of clinical features at gastrointestinal level,such as infrequent bowel movements,abdominal distension,constipation and secretory *** lines of evidence indicate that morphological and molecular changes in intestinal epithelial barrier and enteric neuromuscular compartment contribute to alterations of both bowel motor and secretory functions in digestive and extra-digestive *** present review has been conceived to provide a comprehensive and critical overview of the available knowledge on the morphological and molecular changes occurring in intestinal epithelial barrier and enteric neuromuscular compartment in both digestive and extra-digestive *** addition,our intent was to highlight whether these morphological and molecular alterations could represent a common path(or share some common features)driving the pathophysiology of bowel motor dysfunctions and related symptoms associated with digestive and extra-digestive *** assessment might help to identify novel targets of potential usefulness to develop original pharmacological approaches for the therapeutic management of such disturbances.

关键词： Digestive disease Enteric nervous system Intestinal epithelial barrier Intestinal motility Metabolic disorders Neuropsychiatric disorders

Overlap of functional heartburn and gastroesophageal reflux disease with irritable bowel syndrome

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World Journal of Gastroenterology 2013年第35期19卷 5787-5797页

作者： Nicola de Bortoli Irene Martinucci Massimo Bellini Edoardo Savarino Vincenzo Savarino corrado blandizzi Santino Marchi Division of Gastroenterology University of Pisa Division of Gastroenterology University of Padua Division of Gastroenterology University of Genoa Division of Pharmacology and Chemotherapy University of Pisa

Several studies indicate a significant degree of overlap between irritable bowel syndrome(IBS)and gastroesophageal reflux disease(GERD).Likewise,both functional heartburn(FH)and IBS are functional digestive disorders that may occur in the same ***,data establishing a solid link between FH and IBS are lacking,mainly because the clinical definition of FH has undergone substantial changes over the *** available literature on the overlap between GERD or FH and IBS highlights considerable heterogeneity in terms of the criteria and diagnostic procedures used to assess heartburn and *** particular,several epidemiological studies included patients with concomitant IBS and GERD without any attempt to distinguish FH(as defined by the RomeⅢcriteria)from GERD via pathophysiological *** of these critical issues,there is preliminary evidence supporting a significantdegree of FH-IBS *** underscores the need for studies based on updated diagnostic criteria and accurate pathophysiological classifications,particularly to distinguish FH from *** distinction would represent an essential starting point to achieving a better understanding of pathophysiology in the subclasses of patients with GERD and FH and properly assessing the different degrees of overlap between IBS and the subcategories of *** present review article intends to appraise and critically discuss current evidence supporting a possible concomitance of GERD or FH with IBS in the same patients and to highlight the pathophysiological relationships between these disorders.

关键词： Functional gastrointestinal disorders Gastroesophageal reflux disease/Gastro-oesophageal reflux disease Irritable bowel syndrome Acidity(esophageal) Hypersensitivity

Constipation,deficit in colon contractions and alpha-synuclein inclusions within the colon precede motor abnormalities and neurodegeneration in the central nervous system in a mouse model of alphasynucleinopathy

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Translational Neurodegeneration 2019年第1期8卷 48-62页

作者： Lucia Rota Carolina Pellegrini Laura Benvenuti Luca Antonioli Matteo Fornai corrado blandizzi Antonino Cattaneo Emanuela Colla Bio@SNS Laboratory Scuola Normale SuperiorePiazza dei Cavalieri 756126 PisaItaly Department of Pharmacy University of PisaVia Roma 5556126 PisaItaly Department of Clinical and Experimental Medicine University of PisaVia Roma 5556126 PisaItaly Neurotrophins and Neurodegenerative Diseases Laboratory Rita Levi-Montalcini European Brain Research InstituteViale Regina Elena 295Rome 00161Italy.

Background:Gastrointestinal dysfunction can affect Parkinson’s disease(PD)patients long before the onset of motor ***,little is known about the relationship between gastrointestinal abnormalities and the development of *** to other animal models,the human A53T alpha-synuclein(αS)transgenic mice,Line G2–3,developsαS-driven neurological and motor impairments after 9 months of age,displaying a long presymptomatic phase free of central nervous system(CNS)***:To determine whether this line can be suitable to study constipation as it occurs in prodromal PD,gastrointestinal functionality was assessed in young mice through a multidisciplinary approach,based on behavioral and biochemical analysis combined with electrophysiological recordings of mouse intestinal ***:We found that the A53TαS mice display remarkable signs of gastrointestinal dysfunction that precede motor abnormalities andαS pathology in the CNS by at least 6 ***αS mice show a drastic delay in food transit along the gastrointestinal tract,of almost 2 h in 3 months old mice that increased to more than 3 h at 6 *** impairment was associated with abnormal formation of stools that resulted in less abundant but longer pellets excreted,suggesting a deficit in the intestinal *** agreement with this,electrically evoked contractions of the colon,but not of the ileum,showed a reduced motor response in both longitudinal and circular muscle layers inαS mice already at 3 months of age,that was mainly due to an impaired cholinergic transmission of the underlying enteric nervous ***,the presence of insoluble and aggregatedαS was found in enteric neurons in both myenteric and submucosal plexi only in the colon of 3 months oldαS mice,but not in the small intestine,and exacerbated with age,mimicking the increase in transit delay and the contraction deficit showed by behavioral and electrical recordings ***:Gastrointest

关键词： Alpha-synuclein Constipation Gastrointestinal dysfunction Bowel dysmotility Non-motor symptoms Parkinson’s disease Enteric nervous system Alpha-synucleinopathy

Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage

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World Journal of Gastroenterology 2005年第26期11卷 4052-4060页

作者： corrado blandizzi Matteo Fornai Rocchina Colucci Gianfranco Natale Valter Lubrano Cristina Vassalle Luca Antonioli Gloria Lazzeri Mario Del Tacca Division of Pharmacology and Chemotherapy Department of Oncology Transplants and Advanced Technologies in Medicine University of PisaPisaItaly Department of Human Morphology and Applied Biology University of Pisa Pisa Italy Institute of Clinical Physiology National Research Council Pisa Italy Division of Pharmacology and Chemotherapy Department of Oncology Transplants and Advanced Technologies in Medicine University of Pisa Pisa Italy

AIM:This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal anti-inflammatory drugs (NSAIDs) in rats. METHODS: Male Sprague-Dawley rats were orally treated with indomethacin (100 μmol/kg), diclofenac (60 μmol/kg), piroxicam (150 μmol/kg) or ketoprofen (150 μmol/kg). Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 umol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 μmol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate. RESULTS: All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 μmol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 μmol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 μmol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro. CONCLUSION: These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced gastr

关键词： Lansoprazole Gastric injury Non-steroidal anti-inflammatory drugs

Understanding and treating refractory constipation

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2014年第2期5卷 77-85页

作者： Gabrio Bassotti corrado blandizzi Gastroenterology and Hepatology Section Department of MedicineUniversity of Perugia06156 PerugiaItaly Division of Pharmacology and Chemotherapy Department of Clinical and Experimental MedicineUniversity of Pisa56126 PisaItaly

Chronic constipation is a frequently encountered disorder in clinical practice. Most constipated patients benefit from standard medical approaches. However, current therapies may fail in a proportion of patients. These patients deserve better evaluation and thorough investigations before their labeling as refractory to treatment. Indeed, several cases of apparent refractoriness are actually due to misconceptions about constipation, poor basal evaluation (inability to recognize secondary causes of constipation, use of constipating drugs) or inadequate therapeutic regimens. After a careful reevaluation that takes into account the above factors, a certain percentage of patients can be defined as being actually resistant to first-line medical treatments. These subjects should firstly undergo specific diagnostic examination to ascertain the subtype of constipation. The subsequent therapeutic approach should be then tailored according to their underlying dysfunction. Slow transit patients could benefit from a more robust medical treatment, based on stimulant laxatives (or their combination with osmotic laxatives, particularly over the short-term), enterokinetics (such as prucalopride) or secretagogues (such as lubiprostone or linaclotide). Patients complaining of obstructed defecation are less likely to show a response to medical treatment and might benefit from biofeedback, when available. When all medical treatments prove to be unsatisfactory, other approaches may be attempted in selected patients (sacral neuromodulation, local injection of botulinum toxin, anterograde continence enemas), although with largely unpredictable outcomes. A further although irreversible step is surgery (subtotal colectomy with ileorectal anastomosis or stapled transanal rectal resection), which may confer some benefit to a few patients with refractoriness to medical treatments.

关键词： Chronic constipation Laxatives Medical treatment Refractory constipation Surgical treatment

TWENTY-EIGHT YEARS WITH “HYPERBOLIC CONSERVATION LAWS WITH RELAXATION”

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Acta Mathematica Scientia 2015年第4期35卷 807-831页

作者： corrado MASCIA Dipartimento di Matematica "G. Castelnuovo" Sapienza Università di Roma P.le Aldo Moro

This paper is a review on the results inspired by the publication “Hyperbolic conservation laws with relaxation” by Tai-Ping Liu [1], with emphasis on the topic of nonlinear waves （specifically, rarefaction and shock waves）. The aim is twofold： firstly, to report in details the impact of the article on the subsequent research in the area; secondly, to detect research trends which merit attention in the （near） future.

关键词： conservation laws relaxation nonlinear waves stability

Algorithms to Compute the Largest Invariant Set Contained in an Algebraic Set for Continuous-Time and Discrete-Time Nonlinear Systems

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IEEE/CAA Journal of Automatica Sinica 2020年第1期7卷 57-69页

作者： Laura Menini corrado Possieri Antonio Tornambè Dipartimento di Ingegneria Industriale Universitàdi Roma Tor VergataRoma 00133Italy Istituto di Analisi dei Sistemi ed Informatica“A.Ruberti ”Consiglio Nazionale delle Ricerche(IASI-CNR)Roma 00185Italy Dipartimento di Ingegneria Civile e Ingegneria Informatica Universitàdi Roma Tor VergataRoma 00133Italy

In this paper, some computational tools are proposed to determine the largest invariant set, with respect to either a continuous-time or a discrete-time system, that is contained in an algebraic set. In particular, it is shown that if the vector field governing the dynamics of the system is polynomial and the considered analytic set is a variety, then algorithms from algebraic geometry can be used to solve the considered problem. Examples of applications of the method(spanning from the characterization of the stability to the computation of the zero dynamics) are given all throughout the paper.

关键词： Asymptotic stability discrete-time systems invariance nonlinear systems

On “Over-Sized” High-Gain Practical Observers for Nonlinear Systems

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IEEE/CAA Journal of Automatica Sinica 2018年第3期5卷 691-698页

作者： Daniele Carnevale corrado Possieri Antonio Tornambè Dipartimento di Ingegneria Civile e Ingegneria Informatica Universita di Roma Tor Vergata

In this paper,it is shown that the performances of a class of high-gain practical observers can be improved by estimating the time derivatives of the output up to an order that is greater than the dimension of the system, which is assumed to be in observability form and, possibly, time-varying. Such an improvement is achieved without increasing the gain of the observers, thus allowing their use in a wide variety of control and identification applications.

关键词： Filtering properties nonlinear systems observability observer design

Chronic proctalgia and chronic pelvic pain syndromes:New etiologic insights and treatment options

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World Journal of Gastroenterology 2011年第40期17卷 4447-4455页

作者： Giuseppe Chiarioni corrado Asteria William E Whitehead Division of Gastroenterology of the University of Verona Azienda Ospedaliera Universitaria Integrata di Verona Valeggio sul Mincio Hospital 37067 Valeggio sul Mincio Verona Italy Department of Surgery and Orthopedics General Surgery Unit Azienda Ospedaliera Carlo Poma di Mantova Asola General Hospital 46041 Asola Mantova Italy Division of Gastroenterology and Hepatology Division of Urogynecology and Center for Functional Gastrointestinal and Motility Disorders University of North Carolina at Chapel Hill Chapel Hill NC 27599-7080 United States

This systematic review addresses the pathophysiology, diagnostic evaluation, and treatment of several chronic pain syndromes affecting the pelvic organs:chronic proctalgia, coccygodynia, pudendal neuralgia, and chronic pelvic pain. Chronic or recurrent pain in the anal canal, rectum, or other pelvic organs occurs in 7% to 24% of the population and is associated with impaired quality of life and high health care costs. However, these pain syndromes are poorly understood, with little research evidence available to guide their diagnosis and treatment. This situation appears to be changing:A recently published large randomized,controlled trial by our group comparing biofeedback, electrogalvanic stimulation, and massage for the treatment of chronic proctalgia has shown success rates of 85% for biofeedback when patients are selected based on physical examination evidence of tenderness in response to traction on the levator ani muscle-a physical sign suggestive of striated muscle tension. Excessive tension (spasm) in the striated muscles of the pelvic floor appears to be common to most of the pelvic pain syndromes. This suggests the possibility that similar approaches to diagnostic assessment and treatment may improve outcomes in other pelvic pain disorders.

关键词： Biofeedback Chronic pelvic pain Chronicproctalgia Coccygodynia Levator ani syndrome Pudendal neuralgia