21 results on '"Dothel G"'
Search Results
2. Escherichia coli Nissle 1917 restores epithelial permeability alterations induced by irritable bowel syndrome mediators
- Author
-
Barbaro, M. R., primary, Fuschi, D., additional, Cremon, C., additional, Carapelle, M., additional, Dino, P., additional, Marcellini, M. M., additional, Dothel, G., additional, De Ponti, F., additional, Stanghellini, V., additional, and Barbara, G., additional
- Published
- 2018
- Full Text
- View/download PDF
3. OC.05.4: MUCOSAL MEDIATORS FROM PATIENTS WITH IRRITABLE BOWEL SYNDROME STIMULATE ENTERIC CHOLINERGIC MOTOR NEURONS IN VITRO VIA PURINERGIC, PROSTAGLANDIN, AND TRPV1 PATHWAYS
- Author
-
Cremon, C., primary, Balestra, B., additional, Dothel, G., additional, Carini, G., additional, Zecchi, L., additional, Bellacosa, L., additional, Vasina, V., additional, De Giorgio, R., additional, Stanghellini, V., additional, De Ponti, F., additional, Tonini, M., additional, Corinaldesi, R., additional, and Barbara, G., additional
- Published
- 2011
- Full Text
- View/download PDF
4. OC.05.1: COLONIC MUCOSAL NEUROPLASTICITY AND ITS INVOLVEMENT IN SYMPTOM GENERATION IN PATIENTS WITH IRRITABLE BOWEL SYNDROME
- Author
-
Cremon, C., primary, Vasina, V., additional, Dothel, G., additional, Gargano, L., additional, Zecchi, L., additional, Carini, G., additional, Bellacosa, L., additional, De Giorgio, R., additional, Stanghellini, V., additional, De Ponti, F., additional, Corinaldesi, R., additional, and Barbara, G., additional
- Published
- 2011
- Full Text
- View/download PDF
5. CS.1.1 ALTERED SEROTONIN SIGNALING AND EXTRINSIC SENSORY NEURON ACTIVATION IN IRRITABLE BOWEL SYNDROME
- Author
-
Cremon, C., primary, Carini, G., additional, Dothel, G., additional, Vasina, V., additional, De Giorgio, R., additional, Stanghellini, V., additional, De Ponti, F., additional, Tonini, M., additional, Corinaldesi, R., additional, and Barbara, G., additional
- Published
- 2010
- Full Text
- View/download PDF
6. OC.10.1 NEUROPLASTIC CHANGES IN THE COLONIC MUCOSA OF PATIENTS WITH IRRITABLE BOWEL SYNDROME
- Author
-
Barbara, G., primary, Cremon, C., additional, Gargano, L., additional, Vasina, V., additional, Dothel, G., additional, Carini, G., additional, De Giorgio, R., additional, Stanghellini, V., additional, Cogliandro, R., additional, Tonini, M., additional, De Ponti, F., additional, and Corinaldesi, R., additional
- Published
- 2010
- Full Text
- View/download PDF
7. Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology
- Author
-
Dothel G, Emanuel Raschi, Rimondini R, and De Ponti F
8. Ex vivo effect of vascular wall stromal cells secretome on enteric ganglia
- Author
-
Giovanni Dothel, Chiara Bernardini, Fabrizio De Ponti, Roberta Salaroli, Monica Forni, Augusta Zannoni, Maria Rosaria Spirito, Maria Laura Bacci, Dothel G., Bernardini C., Zannoni A., Spirito M.R., Salaroli R., Bacci M.L., Forni M., and De Ponti F.
- Subjects
Pathology ,medicine.medical_specialty ,Stromal cell ,Mesenchymal stromal cells ,Inflammatory bowel disease ,Guinea pig ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Glial fibrillary acidic protein ,biology ,Mesenchymal stromal cell ,Mesenchymal stem cell ,Gastroenterology ,General Medicine ,Basic Study ,Ganglion ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,030211 gastroenterology & hepatology ,Enteric nervous system ,Ganglia ,Translational models ,Ex vivo - Abstract
Background Mesenchymal stromal cell (MSC)-based therapy is currently under study to treat inflammatory bowel diseases. MSC bioactive products could represent a valid alternative to overcome issues associated with systemic whole-cell therapies. However, MSC anti-inflammatory mechanisms differ between rodents and humans, impairing the reliability of preclinical models. Aim To evaluate the effect of conditioned medium (CM) derived from porcine vascular wall MSCs (pVW-MSCs) on survival and differentiation of porcine and guinea pig enteric ganglia exposed to lipopolysaccharide (LPS). Methods Primary cultures of enteric ganglia were obtained by mechanic and enzymatic digestion of ileum resections from guinea pigs (Cavia porcellus) (GPEG) and pigs (Suus scrofa) (PEG). pVW-MSCs were derived by enzymatic digestion from vascular wall resections of porcine aorta and tested by immunoflowcytometry for MSC immune profile. Enteric ganglia were treated with increasing concentrations of LPS, CM derived by pVW-MSCs or a combination of CM and LPS 1 µg/mL. Cell count and morphometric analysis of HuD positive neurons and glial fibrillary acidic protein positive glial cells were performed by immunofluorecent staining of cultured ganglia. Results PEG showed a higher number of neurons compared to GPEG. Overall, CM exerted a protective role on LPS-treated enteric ganglia. CM in combination with LPS increased the number of glial cells per ganglion in both cultures evoking glial cells differentiation in porcine cultures. Conclusion These findings suggest an immunomodulating activity of pVW-MSCs mediators on the enteric nervous system in inflammatory conditions.
- Published
- 2019
9. Constitutive and LPS-stimulated secretome of porcine Vascular Wall-Mesenchymal Stem Cells exerts effects on in vitro endothelial angiogenesis
- Author
-
Martina Bertocchi, Roberta Salaroli, Irvin Tubon, Maria Laura Bacci, Giovanni Dothel, Mercedes Fernandez, Chiara Bernardini, Monica Forni, Augusta Zannoni, Laura Calzà, Bernardini C., Bertocchi M., Zannoni A., Salaroli R., Tubon I., Dothel G., Fernandez M., Bacci M.L., Calza L., and Forni M.
- Subjects
Vascular Wall-MSC ,Lipopolysaccharides ,Chemokine ,040301 veterinary sciences ,Angiogenesis ,Swine ,Neovascularization, Physiologic ,Stimulation ,Lipopolysaccharide ,Regenerative medicine ,0403 veterinary science ,Transcriptome ,03 medical and health sciences ,Vascular Wall-MSCs ,Animals ,Cells, Cultured ,030304 developmental biology ,Secretome ,Pig animal model ,0303 health sciences ,lcsh:Veterinary medicine ,General Veterinary ,biology ,Chemistry ,Animal ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,04 agricultural and veterinary sciences ,General Medicine ,In vitro ,Cell biology ,Angiogenesi ,Mesenchymal Stem Cell ,Gene Expression Regulation ,biology.protein ,lcsh:SF600-1100 ,Endothelium, Vascular ,Stem cell ,Research Article - Abstract
Background MSCs secretome is under investigation as an alternative to whole-cell-based therapies, since it is enriched of bioactive molecules: growth factors, cytokines and chemokines. Taking into account the translational value of the pig model, the leading aim of the present paper was to characterize the secretome of porcine Vascular Wall–Mesenchymal Stem Cells (pVW-MSCs) and its change in presence of LPS stimulation. Moreover, considering the importance of angiogenesis in regenerative mechanisms, we analysed the effect of pVW-MSCs secretome on in vitro angiogenesis. Results Our results demonstrated that conditioned medium from unstimulated pVW-MSCs contained high levels of IL-8, GM-CSF, IFN-γ and other immunomodulatory proteins: IL-6 IL-18 IL-4 IL-2 IL-10. LPS modulates pVW-MSCs gene expression and secretome composition, in particular a significant increase of IL-6 and IL-8 was observed; conversely, the amount of GM-CSF, IFN-γ, IL-2, IL-4, IL-10 and IL-18 showed a significant transient decrease with the LPS stimulation. Conditioned medium from unstimulated pVW-MSCs induced in vitro endothelial angiogenesis, which is more evident when the conditioned medium was from LPS stimulated pVW-MSCs. Conclusions The lines of evidence here presented shed a light on possible future application of secretome derived by pVW-MSCs on research studies in translational regenerative medicine.
- Published
- 2019
10. µ-opioid receptor, β-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients
- Author
-
Lin Chang, Cesare Cremon, Vincenzo Stanghellini, Wendy Shih, Fabrizio De Ponti, Catia Sternini, Emeran A. Mayer, Giovanni Dothel, Maria Raffaella Barbaro, Giovanni Barbara, Dothel G., Chang L., Shih W., Barbaro R., Cremon C., Stanghellini V., De Ponti F, Mayer E.A., Barbara G., and Sternini C.
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Constipation ,Physiology ,medicine.medical_treatment ,Receptors, Opioid, mu ,neuro-immune cross talk ,Article ,Receptor, Cannabinoid, CB2 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,Cannabinoid receptor type 2 ,medicine ,Humans ,Intestinal Mucosa ,Receptor ,Irritable bowel syndrome ,irritable bowel syndrome ,Sex Characteristics ,Endocrine and Autonomic Systems ,business.industry ,beta-Endorphin ,Gastroenterology ,Visceral pain ,cannabinoid ,medicine.disease ,immune system ,030104 developmental biology ,Endocrinology ,Opioid ,opioid ,lipids (amino acids, peptides, and proteins) ,030211 gastroenterology & hepatology ,Female ,Cannabinoid ,medicine.symptom ,business ,medicine.drug - Abstract
Background and aims The gut immune, cannabinoid, and opioid systems constitute an integrated network contributing to visceral sensation and pain modulation. We aimed to assess the expression of the µ-opioid receptor (MOR), its ligand β-endorphin (β-END), and cannabinoid receptor-2 (CB2 ) in patients with irritable bowel syndrome (IBS) and asymptomatic controls (AC) and their correlation with sex and symptom perception. Methods Mucosal biopsies were obtained from the left colon of 31 IBS patients (45% women) with predominant constipation (IBS-C, 9) or diarrhea (IBS-D, 10) or with mixed bowel habits (IBS-M, 12) and 32 AC (44% women) and processed for qRT-PCR, Western blotting, and immunohistochemistry. Key results µ-opioid receptor and CB2 mRNA and protein expression and β-END protein levels were increased in patients with IBS compared to AC (all Ps=0.021). A significant sex by IBS interaction was found in relation to CB2 mRNA expression (P = .003) with women showing a markedly higher expression to men (P = .035). In contrast, in AC, men had higher expression than women (P = .033). β-END, MOR, and CB2 immunoreactivities (IR) were localized to CD4+T cells including EMR-1+ eosinophils and CD31+ T cells but not to mast cells. Conclusions The increased expression of MOR, β-END, and CB2 in the mucosa of IBS patients, where they are localized to immune cells, suggests that opioid and cannabinoid systems play an immune-related compensatory role in visceral pain in IBS patients. Further work is necessary to support this hypothesis.
- Published
- 2019
11. Escherichia coli Nissle 1917 restores epithelial permeability alterations induced by irritable bowel syndrome mediators
- Author
-
Giovanni Barbara, Cesare Cremon, F. De Ponti, Daniele Fuschi, Maria Raffaella Barbaro, M. M. Marcellini, P. Dino, Giovanni Dothel, M. Carapelle, Vincenzo Stanghellini, Barbaro, M.R., Fuschi, D., Cremon, C., Carapelle, M., Dino, P., Marcellini, M.M., Dothel, G., De Ponti, F., Stanghellini, V., and Barbara, G.
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Abdominal pain ,Physiology ,Gastroenterology ,Endocrine and Autonomic System ,law.invention ,03 medical and health sciences ,Probiotic ,0302 clinical medicine ,law ,Internal medicine ,medicine ,Irritable bowel syndrome ,irritable bowel syndrome ,Intestinal permeability ,Endocrine and Autonomic Systems ,business.industry ,Abdominal distension ,medicine.disease ,In vitro ,Escherichia coli Nissle 1917 ,030104 developmental biology ,Paracellular transport ,030211 gastroenterology & hepatology ,Tumor necrosis factor alpha ,medicine.symptom ,permeability ,business ,probiotic - Abstract
Background Intestinal permeability is altered in a subgroup of irritable bowel syndrome (IBS) patients and may contribute to symptom development. The aim of this study was to evaluate the in vitro effect of the probiotic Escherichia coli Nissle 1917 (EcN) on Caco-2 permeability alterations induced by mediators released by IBS mucosal biopsies compared to asymptomatic controls (AC). Methods Caco-2 cells were used as an in vitro model of intestinal permeability. Seven AC and 28 well-phenotyped IBS (9 IBS-D, 8 IBS-C, and 11 IBS-M) patients were enrolled. Mucosal mediators spontaneously released (SUP) by IBS and AC biopsies were collected. Two concentrations of EcN (108 and 106 ) were applied to Caco-2 with or without SUP or SLIGRL (a protease-activated receptor-2 activating peptide), tumor necrosis factor-α, and interferon-γ. Paracellular permeability was assessed by evaluating the flow of sulfonic-acid conjugated to fluorescein through Caco-2 monolayer. Key results EcN 108 significantly reinforced Caco-2 monolayer compared to cells incubated with medium alone. IBS SUP induced a significant increase in paracellular permeability compared to AC SUP, independently of IBS bowel habit. EcN 108 induced a significant recovery of permeability rate compared to IBS SUP. Permeability increase induced by IBS SUP significantly correlated with severity and frequency of abdominal pain and abdominal distension. The co-incubation of EcN and IBS SUP abolished the above significant correlations. Conclusions and inferences EcN reinforces the integrity of Caco-2 monolayer and reverts the increase of permeability induced by mediators released by IBS biopsies. Future studies should investigate EcN therapeutic potentials in IBS.
- Published
- 2018
12. New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics.
- Author
-
Dothel G, Barbaro MR, Di Vito A, Ravegnini G, Gorini F, Monesmith S, Coschina E, Benuzzi E, Fuschi D, Palombo M, Bonomini F, Morroni F, Hrelia P, Barbara G, and Angelini S
- Subjects
- Humans, Epigenesis, Genetic, Permeability, Irritable Bowel Syndrome genetics, Gastrointestinal Microbiome physiology, Microbiota
- Abstract
Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
13. µ-opioid receptor, β-endorphin, and cannabinoid receptor-2 are increased in the colonic mucosa of irritable bowel syndrome patients.
- Author
-
Dothel G, Chang L, Shih W, Barbaro MR, Cremon C, Stanghellini V, De Ponti F, Mayer EA, Barbara G, and Sternini C
- Subjects
- Female, Humans, Male, Receptor, Cannabinoid, CB2 analysis, Receptors, Opioid, mu analysis, Sex Characteristics, beta-Endorphin analysis, Intestinal Mucosa metabolism, Irritable Bowel Syndrome metabolism, Receptor, Cannabinoid, CB2 biosynthesis, Receptors, Opioid, mu biosynthesis, beta-Endorphin biosynthesis
- Abstract
Background and Aims: The gut immune, cannabinoid, and opioid systems constitute an integrated network contributing to visceral sensation and pain modulation. We aimed to assess the expression of the µ-opioid receptor (MOR), its ligand β-endorphin (β-END), and cannabinoid receptor-2 (CB
2 ) in patients with irritable bowel syndrome (IBS) and asymptomatic controls (AC) and their correlation with sex and symptom perception., Methods: Mucosal biopsies were obtained from the left colon of 31 IBS patients (45% women) with predominant constipation (IBS-C, 9) or diarrhea (IBS-D, 10) or with mixed bowel habits (IBS-M, 12) and 32 AC (44% women) and processed for qRT-PCR, Western blotting, and immunohistochemistry., Key Results: µ-opioid receptor and CB2 mRNA and protein expression and β-END protein levels were increased in patients with IBS compared to AC (all Ps=0.021). A significant sex by IBS interaction was found in relation to CB2 mRNA expression (P = .003) with women showing a markedly higher expression to men (P = .035). In contrast, in AC, men had higher expression than women (P = .033). β-END, MOR, and CB2 immunoreactivities (IR) were localized to CD4+T cells including EMR-1+ eosinophils and CD31+ T cells but not to mast cells., Conclusions: The increased expression of MOR, β-END, and CB2 in the mucosa of IBS patients, where they are localized to immune cells, suggests that opioid and cannabinoid systems play an immune-related compensatory role in visceral pain in IBS patients. Further work is necessary to support this hypothesis., (© 2019 John Wiley & Sons Ltd.)- Published
- 2019
- Full Text
- View/download PDF
14. Ex vivo effect of vascular wall stromal cells secretome on enteric ganglia.
- Author
-
Dothel G, Bernardini C, Zannoni A, Spirito MR, Salaroli R, Bacci ML, Forni M, and Ponti F
- Subjects
- Animals, Blood Vessels cytology, Cell Differentiation drug effects, Cell Differentiation immunology, Cell Survival drug effects, Cell Survival immunology, Cells, Cultured, Culture Media, Conditioned pharmacology, Enteric Nervous System cytology, Enteric Nervous System immunology, Extracellular Vesicles metabolism, Guinea Pigs, Humans, Ileum blood supply, Ileum immunology, Ileum innervation, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases therapy, Intestinal Mucosa blood supply, Intestinal Mucosa immunology, Intestinal Mucosa innervation, Lipopolysaccharides toxicity, Male, Mesenchymal Stem Cell Transplantation, Neuroglia immunology, Neurons drug effects, Neurons immunology, Primary Cell Culture, Sus scrofa, Enteric Nervous System drug effects, Extracellular Vesicles immunology, Mesenchymal Stem Cells metabolism, Neuroglia drug effects
- Abstract
Background: Mesenchymal stromal cell (MSC)-based therapy is currently under study to treat inflammatory bowel diseases. MSC bioactive products could represent a valid alternative to overcome issues associated with systemic whole-cell therapies. However, MSC anti-inflammatory mechanisms differ between rodents and humans, impairing the reliability of preclinical models., Aim: To evaluate the effect of conditioned medium (CM) derived from porcine vascular wall MSCs (pVW-MSCs) on survival and differentiation of porcine and guinea pig enteric ganglia exposed to lipopolysaccharide (LPS)., Methods: Primary cultures of enteric ganglia were obtained by mechanic and enzymatic digestion of ileum resections from guinea pigs ( Cavia porcellus ) (GPEG) and pigs ( Suus scrofa ) (PEG). pVW-MSCs were derived by enzymatic digestion from vascular wall resections of porcine aorta and tested by immunoflowcytometry for MSC immune profile. Enteric ganglia were treated with increasing concentrations of LPS, CM derived by pVW-MSCs or a combination of CM and LPS 1 µg/mL. Cell count and morphometric analysis of HuD positive neurons and glial fibrillary acidic protein positive glial cells were performed by immunofluorecent staining of cultured ganglia., Results: PEG showed a higher number of neurons compared to GPEG. Overall, CM exerted a protective role on LPS-treated enteric ganglia. CM in combination with LPS increased the number of glial cells per ganglion in both cultures evoking glial cells differentiation in porcine cultures., Conclusion: These findings suggest an immunomodulating activity of pVW-MSCs mediators on the enteric nervous system in inflammatory conditions., Competing Interests: Conflict-of-interest statement: None of the authors have any potential conflicts of interest associated with this research.
- Published
- 2019
- Full Text
- View/download PDF
15. Constitutive and LPS-stimulated secretome of porcine Vascular Wall-Mesenchymal Stem Cells exerts effects on in vitro endothelial angiogenesis.
- Author
-
Bernardini C, Bertocchi M, Zannoni A, Salaroli R, Tubon I, Dothel G, Fernandez M, Bacci ML, Calzà L, and Forni M
- Subjects
- Animals, Cells, Cultured, Endothelium, Vascular metabolism, Gene Expression Regulation drug effects, Mesenchymal Stem Cells metabolism, Swine, Transcriptome, Endothelium, Vascular drug effects, Lipopolysaccharides pharmacology, Mesenchymal Stem Cells drug effects, Neovascularization, Physiologic drug effects
- Abstract
Background: MSCs secretome is under investigation as an alternative to whole-cell-based therapies, since it is enriched of bioactive molecules: growth factors, cytokines and chemokines. Taking into account the translational value of the pig model, the leading aim of the present paper was to characterize the secretome of porcine Vascular Wall-Mesenchymal Stem Cells (pVW-MSCs) and its change in presence of LPS stimulation. Moreover, considering the importance of angiogenesis in regenerative mechanisms, we analysed the effect of pVW-MSCs secretome on in vitro angiogenesis., Results: Our results demonstrated that conditioned medium from unstimulated pVW-MSCs contained high levels of IL-8, GM-CSF, IFN-γ and other immunomodulatory proteins: IL-6 IL-18 IL-4 IL-2 IL-10. LPS modulates pVW-MSCs gene expression and secretome composition, in particular a significant increase of IL-6 and IL-8 was observed; conversely, the amount of GM-CSF, IFN-γ, IL-2, IL-4, IL-10 and IL-18 showed a significant transient decrease with the LPS stimulation. Conditioned medium from unstimulated pVW-MSCs induced in vitro endothelial angiogenesis, which is more evident when the conditioned medium was from LPS stimulated pVW-MSCs., Conclusions: The lines of evidence here presented shed a light on possible future application of secretome derived by pVW-MSCs on research studies in translational regenerative medicine.
- Published
- 2019
- Full Text
- View/download PDF
16. Altered globotriaosylceramide accumulation and mucosal neuronal fiber density in the colon of the Fabry disease mouse model.
- Author
-
Masotti M, Delprete C, Dothel G, Donadio V, Rimondini R, Politei JM, Liguori R, and Caprini M
- Subjects
- Animals, Cytokines blood, Female, Male, Mice, Mice, Knockout, Myenteric Plexus metabolism, Myenteric Plexus pathology, Trihexosylceramides genetics, Ubiquitin Thiolesterase genetics, alpha-Galactosidase genetics, Colon metabolism, Colon pathology, Fabry Disease metabolism, Fabry Disease pathology, Nerve Fibers pathology, Trihexosylceramides metabolism
- Abstract
Background: Fabry disease (FD) is a hereditary X-linked metabolic storage disorder characterized by deficient or absent lysosomal α-galactosidase A (α-Gal A) activity. This deficiency causes progressive accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in nearly all organ systems. Gastrointestinal (GI) symptoms can be very debilitating and are among the most frequent and earliest of the disease. As the pathophysiology of these symptoms is poorly understood, we carried out a morphological and molecular characterization of the GI tract in α-Gal A knockout mice colon in order to reveal the underlying mechanisms., Methods: Here, we performed the first morphological and biomolecular characterization of the colon wall structure in the GI tract of the α-Gal A knock-out mouse (α-Gal A -/0), a murine model of FD., Key Results: Our data show a greater thickness of the gastrointestinal wall in α-Gal A (-/0) mice due to enlarged myenteric plexus' ganglia. This change is paralleled by a marked Gb3 accumulation in the gastrointestinal wall and a decreased and scattered pattern of mucosal nerve fibers., Conclusions and Inferences: The observed alterations are likely to be a leading cause of gut motor dysfunctions experienced by FD patients and imply that the α-Gal A (-/0) male mouse represents a reliable model for translational studies on enteropathic pain and GI symptoms in FD., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
17. Advancements in drug development for diarrhea-predominant irritable bowel syndrome.
- Author
-
Dothel G, Barbaro MR, Raschi E, Barbara G, and De Ponti F
- Subjects
- Animals, Benzimidazoles adverse effects, Benzimidazoles pharmacology, Benzimidazoles therapeutic use, Diarrhea etiology, Drug Design, Drug and Narcotic Control, Gastrointestinal Agents adverse effects, Gastrointestinal Agents pharmacology, Humans, Imidazoles adverse effects, Imidazoles pharmacology, Imidazoles therapeutic use, Internationality, Irritable Bowel Syndrome physiopathology, Phenylalanine adverse effects, Phenylalanine analogs & derivatives, Phenylalanine pharmacology, Phenylalanine therapeutic use, Diarrhea drug therapy, Gastrointestinal Agents therapeutic use, Irritable Bowel Syndrome drug therapy
- Abstract
Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches., Areas Covered: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA., Expert Opinion: The new 5-HT
3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.- Published
- 2018
- Full Text
- View/download PDF
18. Mesenchymal stromal cell-based therapy: Regulatory and translational aspects in gastroenterology.
- Author
-
Dothel G, Raschi E, Rimondini R, and De Ponti F
- Subjects
- Animals, Biomarkers metabolism, Gastroenterology legislation & jurisprudence, Gastrointestinal Diseases diagnosis, Gastrointestinal Diseases metabolism, Gastrointestinal Diseases physiopathology, Humans, Mesenchymal Stem Cells metabolism, Patient Safety, Phenotype, Regeneration, Regenerative Medicine legislation & jurisprudence, Risk Factors, Translational Research, Biomedical legislation & jurisprudence, Treatment Outcome, Gastroenterology methods, Gastrointestinal Diseases surgery, Government Regulation, Health Policy, Mesenchymal Stem Cell Transplantation adverse effects, Mesenchymal Stem Cell Transplantation legislation & jurisprudence, Mesenchymal Stem Cells physiology, Regenerative Medicine methods, Translational Research, Biomedical methods
- Abstract
The past decade has witnessed an outstanding scientific production focused towards the possible clinical applications of mesenchymal stromal cells (MSCs) in autoimmune and chronic inflammatory diseases. This raised the need of novel standards to adequately address quality, efficacy and safety issues of this advanced therapy. The development of a streamlined regulation is currently hampered by the complexity of analyzing dynamic biological entities rather than chemicals. Although numerous pieces of evidence show efficacy in reducing intestinal inflammation, some inconsistencies between the mechanisms of action of rodent vs human MSCs suggest caution before assigning translational value to preclinical studies. Preliminary evidence from clinical trials showed efficacy of MSCs in the treatment of fistulizing Crohn's disease (CD), and preparations of heterologous MSCs for CD treatment are currently tested in ongoing clinical trials. However, safety issues, especially in long-term treatment, still require solid clinical data. In this regard, standardized guidelines for appropriate dosing and methods of infusion could enhance the likelihood to predict more accurately the number of responders and the duration of remission periods. In addition, elucidating MSC mechanisms of action could lead to novel and more reliable formulations such as those derived from the MSCs themselves ( e.g ., supernatants)., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
19. Nerve fiber outgrowth is increased in the intestinal mucosa of patients with irritable bowel syndrome.
- Author
-
Dothel G, Barbaro MR, Boudin H, Vasina V, Cremon C, Gargano L, Bellacosa L, De Giorgio R, Le Berre-Scoul C, Aubert P, Neunlist M, De Ponti F, Stanghellini V, and Barbara G
- Subjects
- Adult, Aged, Animals, Biomarkers metabolism, Biopsy, Case-Control Studies, Cell Line, Tumor, Colon metabolism, Enteric Nervous System metabolism, Female, GAP-43 Protein metabolism, Humans, Intestinal Mucosa metabolism, Irritable Bowel Syndrome metabolism, Male, Middle Aged, Nerve Growth Factor metabolism, Neuritis metabolism, Phosphopyruvate Hydratase metabolism, Rats, Receptor, trkA metabolism, Young Adult, Colon innervation, Enteric Nervous System pathology, Intestinal Mucosa innervation, Irritable Bowel Syndrome pathology, Neuritis pathology, Neurogenesis
- Abstract
Background & Aims: Mediators released by the intestinal mucosa of patients with irritable bowel syndrome (IBS) affect the function of enteric and extrinsic sensory nerves, which can contribute to the development of symptoms. Little is known about the effects of mucosal mediators on intestinal neuroplasticity. We investigated how these mediators affect the phenotypes of colonic mucosa nerve fibers, neuron differentiation, and fiber outgrowth., Methods: We analyzed mucosal biopsy samples collected from 101 patients with IBS and 23 asymptomatic healthy individuals (controls). We measured levels of neuronal-specific enolase, growth-associated protein 43, nerve growth factor (NGF), and tyrosine kinase receptor A (NTRK1) by immunohistochemistry and enzyme-linked immunosorbent assay. Primary rat enteric neurons and human SH-SY5Y cells were incubated with supernatants from the mucosal biopsies and analyzed by morphometric and polymerase chain reaction analyses., Results: Compared with mucosal tissues of controls, mucosa from patients with IBS had a significant increase in the area of lamina propria occupied by neuronal-specific enolase-positive (57.7% increase) and growth-associated protein 43-positive fibers (56.1% increase) and staining density of NGF (89.3% increase) (P < .05 for all). Levels of NGF protein were also increased in tissues from patients with IBS vs controls (18% increase; P = .16) along with levels of NTRK1 (64% increase; P < .05). Mucosal supernatants from tissues of patients with IBS induced higher levels of neuritogenesis in primary culture of enteric neurons, compared with controls, and more NGF-dependent neuronal sprouting in SH-SY5Y cells., Conclusions: Nerve fiber density and sprouting, as well as expression of NGF and NTRK1, are significantly increased in mucosal tissues of patients with IBS. Mucosal mediators participate to these neuroplastic changes., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
20. Animal models of chemically induced intestinal inflammation: predictivity and ethical issues.
- Author
-
Dothel G, Vasina V, Barbara G, and De Ponti F
- Subjects
- Animals, Biomedical Research ethics, Drug Evaluation, Preclinical ethics, Humans, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases physiopathology, Research Design, Disease Models, Animal, Inflammatory Bowel Diseases chemically induced
- Abstract
The debate about the ethical and scientific issues regarding the use of animals in research is mainly focused on these questions: a) whether preclinical studies in animals are still ethically acceptable; b) whether it is possible to establish more soundly their predictivity; c) what measures should be taken to reduce the clinical attrition often due to biased preclinical assessment of potential efficacy of new drugs. This review aims at a critical revision of animal models of chemically induced intestinal inflammation in drug development. These models, notwithstanding differences among species, still represent a major source of information about biological systems and can have undisputable translational value, provided that appropriate measures are taken to ensure that experiments are both scientifically and ethically justified. These measures include: a) more stringent application to preclinical experiments of standards used in clinical studies (such as sample size, randomization, inclusion/exclusion criteria, blinding); b) selection of the animal model after careful pathophysiological scrutiny bearing in mind inherent limitations of each model (e.g. acute self-limiting vs chronic disease, animal species, role of the intestinal immune system and microbiome); and c) experimental design duly considering the specific pharmacological profile of each agent to be screened (such as bioavailability, route of administration, full consideration of the pharmacological spectrum). In this perspective, the new European legislation is an opportunity to fully apply these standards so that in vivo animal models can provide an invaluable mean to study complex physiological and biochemical interactions, which cannot be completely simulated in silico and/or in vitro., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
21. Mechanisms underlying visceral hypersensitivity in irritable bowel syndrome.
- Author
-
Barbara G, Cremon C, De Giorgio R, Dothel G, Zecchi L, Bellacosa L, Carini G, Stanghellini V, and Corinaldesi R
- Subjects
- Humans, Hypersensitivity immunology, Irritable Bowel Syndrome immunology
- Abstract
Visceral hypersensitivity is currently considered a key pathophysiological mechanism involved in pain perception in large subgroups of patients with functional gastrointestinal disorders, including irritable bowel syndrome (IBS). In IBS, visceral hypersensitivity has been described in 20%-90% of patients. The contribution of the central nervous system and psychological factors to visceral hypersensitivity in patients with IBS may be significant, although still debated. Peripheral factors have gained increasing attention following the recognition that infectious enteritis may trigger the development of persistent IBS symptoms, and the identification of mucosal immune, neural, endocrine, microbiological, and intestinal permeability abnormalities. Growing evidence suggests that these factors play an important role in pain transmission from the periphery to the brain via sensory nerve pathways in large subsets of patients with IBS. In this review, we will report on recent data on mechanisms involved in visceral hypersensitivity in IBS, with particular attention paid to peripheral mechanisms.
- Published
- 2011
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.