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Article ; Online: Smad7 as a positive regulator of intestinal inflammatory diseases

Giovanni Monteleone / Federica Laudisi / Carmine Stolfi

Current Research in Immunology, Vol 4, Iss , Pp 100055- (2023)

2023

Abstract: In physiological conditions, the human gut contains more immune cells than the rest of the body, but no overt tissue damage occurs, because several regulatory mechanisms control the activity of such cells thus preventing excessive and detrimental ... ...

Abstract	In physiological conditions, the human gut contains more immune cells than the rest of the body, but no overt tissue damage occurs, because several regulatory mechanisms control the activity of such cells thus preventing excessive and detrimental responses. One such mechanism relies on the action of transforming growth factor (TGF)-β1, a cytokine that targets both epithelial cells and many immune cell types. Loss of TGF-β1 function leads to intestinal pathology in both mice and humans. For instance, disruption of TGF-β1 signaling characterizes the destructive immune-inflammatory response in patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel disease (IBD) entities. In these pathologies, the defective TGF-β1-mediated anti-inflammatory response is associated with elevated intestinal levels of Smad7, an antagonist of TGF-β1 signaling. Consistently, knockdown of Smad7 restores TGF-β1 function thereby attenuating intestinal inflammation in patients with IBD as well as in mice with IBD-like colitis. Up-regulation of Smad7 and reduced TGF-β1 signaling occurs also in necrotizing enterocolitis, environmental enteropathy, refractory celiac disease, and cytomegalovirus-induced colitis. In this article, we review the available data supporting the pathogenic role of Smad7 in the gastrointestinal tract and discuss whether and how targeting Smad7 can help attenuate detrimental immuno-inflammatory responses in the gut.
Keywords	Crohn’s disease ; Ulcerative colitis ; Inflammatory bowel diseases ; TGF-beta ; Specialties of internal medicine ; RC581-951
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Precision Medicine in Inflammatory Bowel Diseases

Irene Marafini / Giovanni Monteleone

Frontiers in Pharmacology, Vol

2021 Volume 12

Abstract: During the last decades, a better understanding of the mechanisms sustaining the pathogenic process in inflammatory bowel diseases (IBD) has contributed to expand the therapeutic armamentarium for patients with these disorders. Alongside with traditional ...

Abstract	During the last decades, a better understanding of the mechanisms sustaining the pathogenic process in inflammatory bowel diseases (IBD) has contributed to expand the therapeutic armamentarium for patients with these disorders. Alongside with traditional therapies, monoclonal antibodies against tumor necrosis factor-α, the interleukin (IL)-12/IL-23 p40 subunit and the α4β7 integrin, and tofacitinib, a small molecule inhibiting intracellular pathways downstream to cytokine receptors, have entered into the clinic. However, these drugs are not effective in all patients and some responders can lose response over time. Such a therapeutic failure is, at least in part, dependent on the fact that, in IBD, the tissue damage is driven by simultaneous activation of multiple and distinct immune-inflammatory signals and the detrimental mucosal immune response changes over time even in the same patient. Therefore, personalized approaches aimed at identifying which patient should be treated with a specific drug at a precise time point are worth pursuing. A such approach has the advantage to improve efficacy of the drug and limit adverse reactions, thereby improving quality of the life of the patients and reducing costs. In this review, we summarize all the available evidence about the possible role of precision medicine in IBD.
Keywords	crohn’s disease ; ulcerative colitis ; IBD ; personalized medicine ; anti-TNF ; Therapeutics. Pharmacology ; RM1-950
Subject code	610 ; 616
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Helicobacter pylori and Gastric Cancer

Silvia Salvatori / Irene Marafini / Federica Laudisi / Giovanni Monteleone / Carmine Stolfi

International Journal of Molecular Sciences, Vol 24, Iss 2895, p

Pathogenetic Mechanisms

2023 Volume 2895

Abstract: Gastric cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Helicobacter pylori ( H. pylori ) is one of the main risk factors for this type of neoplasia. Carcinogenetic mechanisms associated with H. ... ...

Abstract	Gastric cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Helicobacter pylori ( H. pylori ) is one of the main risk factors for this type of neoplasia. Carcinogenetic mechanisms associated with H. pylori are based, on the one hand, on the onset of chronic inflammation and, on the other hand, on bacterial-specific virulence factors that can damage the DNA of gastric epithelial cells and promote genomic instability. Here, we review and discuss the major pathogenetic mechanisms by which H. pylori infection contributes to the onset and development of gastric cancer.
Keywords	inflammation ; cytokines ; ROS ; virulence factors ; CagA ; genomic instability ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer

Edoardo Troncone / Irene Marafini / Carmine Stolfi / Giovanni Monteleone

International Journal of Molecular Sciences, Vol 22, Iss 3922, p

2021 Volume 3922

Abstract: In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor- ... ...

Abstract	In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune–inflammatory responses. In patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.
Keywords	Crohn’s disease ; ulcerative colitis ; inflammatory bowel diseases ; TGF-beta ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Anthelmintic Drugs as Emerging Immune Modulators in Cancer

Carmine Stolfi / Teresa Pacifico / Anderson Luiz-Ferreira / Giovanni Monteleone / Federica Laudisi

International Journal of Molecular Sciences, Vol 24, Iss 6446, p

2023 Volume 6446

Abstract: Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional ... ...

Abstract	Despite recent advances in treatment approaches, cancer is still one of the leading causes of death worldwide. Restoration of tumor immune surveillance represents a valid strategy to overcome the acquired resistance and cytotoxicity of conventional therapies in oncology and immunotherapeutic drugs, such as immune checkpoint inhibitors and immunogenic cell death inducers, and has substantially progressed the treatment of several malignancies and improved the clinical management of advanced disease. Unfortunately, because of tumor-intrinsic and/or -extrinsic mechanisms for escaping immune surveillance, only a fraction of patients clinically respond to and benefit from cancer immunotherapy. Accumulating evidence derived from studies of drug repositioning, that is, the strategy to identify new uses for approved or investigational drugs that are outside the scope of the original medical indication, has suggested that some anthelmintic drugs, in addition to their antineoplastic effects, exert important immunomodulatory actions on specific subsets of immune cell and related pathways. In this review, we report and discuss current knowledge on the impact of anthelmintic drugs on host immunity and their potential implication in cancer immunotherapy.
Keywords	drug repositioning ; cancer immunotherapy ; immune checkpoint inhibitors ; immunogenic cell death ; PD-1 ; PD-L1 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Long COVID in Inflammatory Bowel Diseases

Silvia Salvatori / Francesco Baldassarre / Michelangela Mossa / Giovanni Monteleone

Journal of Clinical Medicine, Vol 10, Iss 5575, p

2021 Volume 5575

Abstract: Background and aims. SARS-CoV-2-infected patients can experience long-lasting symptoms even after the resolution of the acute infection. This condition, defined as Long COVID, is now recognized as a public health priority and its negative impact on the ... ...

Abstract	Background and aims. SARS-CoV-2-infected patients can experience long-lasting symptoms even after the resolution of the acute infection. This condition, defined as Long COVID, is now recognized as a public health priority and its negative impact on the quality of life of the patients could be more relevant in individuals with debilitating pathologies. We here evaluated the frequency of Long COVID in patients with inflammatory bowel diseases (IBD). Methods. IBD patients afferent for scheduled visits to our tertiary referral center at the Tor Vergata University Hospital, Rome, were recruited from 7 September to 22 October 2021. During the visits, patients were investigated about previous COVID-19 infection and the possible development of Long COVID. Results. Fifty-three out of 528 IBD patients (10%) have had a SARS-CoV-2 infection. Of these, 21 patients (40%) developed Long COVID, and asthenia was the more frequent symptom as it occurred in nearly two-thirds of patients. Patients with Long COVID were more frequently females, while other clinical and demographic characteristics did not differ between patients with Long COVID and those without Long COVID. In particular, the IBD relapses occurred with the same frequency in the two groups. Conclusions. Long COVID appears to be common in IBD patients even though it does not influence the IBD course.
Keywords	Crohn’s disease ; ulcerative colitis ; SARS-CoV-2 ; biologics ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: TRAIL-Sensitizing Effects of Flavonoids in Cancer

Anderson Luiz-Ferreira / Teresa Pacifico / Álefe Cardoso Cruz / Federica Laudisi / Giovanni Monteleone / Carmine Stolfi

International Journal of Molecular Sciences, Vol 24, Iss 23, p

2023 Volume 16596

Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of ... ...

Abstract	Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.
Keywords	natural products ; medicinal plants ; polyphenols ; apoptosis ; tumor necrosis factor related apoptosis-inducing ligand ; DR4 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Association Between Celiac Disease and Cancer

Irene Marafini / Giovanni Monteleone / Carmine Stolfi

International Journal of Molecular Sciences, Vol 21, Iss 4155, p

2020 Volume 4155

Abstract: Celiac disease (CD) is a chronic enteropathy that develops in genetically susceptible individuals after the ingestion of gluten. There has been a substantial increase in CD prevalence in the last 50 years, and it is now estimated that this disease ... ...

Abstract	Celiac disease (CD) is a chronic enteropathy that develops in genetically susceptible individuals after the ingestion of gluten. There has been a substantial increase in CD prevalence in the last 50 years, and it is now estimated that this disease affects approximately 1% of the population in the Western world. In the large majority of cases, CD is a benign disease, characterized by the complete resolution of symptoms and a normal life expectancy after the onset of a gluten-free diet (GFD). However, failure to adhere to a strict GFD bears the risk of adverse events and increases mortality. A considerable number of studies have considered the possible association between CD and neoplasms. In particular, an increased risk of malignancies, such as cancers of the gastrointestinal tract and intestinal lymphomas, has been reported. In this review, we summarize and discuss the current evidence on the possible association between CD and cancer.
Keywords	small bowel adenocarcinoma ; T-cell lymphoma ; colorectal cancer ; gluten ; refractory celiac disease ; HLA-DQ2 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Difficult Biliary Stones

Edoardo Troncone / Michelangela Mossa / Pasquale De Vico / Giovanni Monteleone / Giovanna Del Vecchio Blanco

Medicina, Vol 58, Iss 120, p

A Comprehensive Review of New and Old Lithotripsy Techniques

2022 Volume 120

Abstract: Biliary stones represent the most common indication for therapeutic endoscopic retrograde cholangiopancreatography. Many cases are successfully managed with biliary sphincterotomy and stone extraction with balloon or basket catheters. However, more ... ...

Abstract	Biliary stones represent the most common indication for therapeutic endoscopic retrograde cholangiopancreatography. Many cases are successfully managed with biliary sphincterotomy and stone extraction with balloon or basket catheters. However, more complex conditions secondary to the specific features of stones, the biliary tract, or patient’s needs could make the stone extraction with the standard techniques difficult. Traditionally, mechanical lithotripsy with baskets has been reported as a safe and effective technique to achieve stone clearance. More recently, the increasing use of endoscopic papillary large balloon dilation and the diffusion of single-operator cholangioscopy with laser or electrohydraulic lithotripsy have brought new, safe, and effective therapeutic possibilities to the management of such challenging cases. We here summarize the available evidence about the endoscopic management of difficult common bile duct stones and discuss current indications of different lithotripsy techniques.
Keywords	endoscopic retrograde cholangiopancreatography ; ERCP ; cholangioscopy ; electro-hydraulic lithotripsy ; laser lithotripsy ; spyglass ; Medicine (General) ; R5-920
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reversibility of Frail Phenotype in Patients with Inflammatory Bowel Diseases

Silvia Salvatori / Irene Marafini / Martina Franchin / Diletta Lavigna / Mattia Brigida / Chiara Venuto / Livia Biancone / Emma Calabrese / Diana Giannarelli / Giovanni Monteleone

Journal of Clinical Medicine, Vol 12, Iss 2658, p

2023 Volume 2658

Abstract: It was recently reported that frailty status can negatively influence the clinical course of patients with inflammatory bowel diseases (IBDs). Our recent study demonstrated that 20% of patients with an IBD are frail, and disease activity increases the ... ...

Abstract	It was recently reported that frailty status can negatively influence the clinical course of patients with inflammatory bowel diseases (IBDs). Our recent study demonstrated that 20% of patients with an IBD are frail, and disease activity increases the risk of frailty. In the present study, we prospectively monitored this subgroup of frail patients, assessed whether the frailty status was reversible, and analyzed factors associated with frailty reversibility. Of the sixty-four frail patients with IBD enrolled, five (8%) were lost during the follow-up period and one (2%) underwent a colectomy. Eleven out of the fifty-eight (19%) patients maintained a frail phenotype during a median follow-up of 8 months (range 6–19 months), and thirty-five (60%) and twelve (21%) became pre-frail or fit, respectively. A comparison of the 58 patients at baseline and at the end of the study showed that frail phenotype reversibility occurred more frequently in patients who achieved clinical remission. A multivariate analysis showed that the improvement of the frail phenotype was inversely correlated with the persistence of clinically active disease (OR:0.1; 95% CI: 0.02–0.8) and a history of extra-intestinal manifestations (OR:0.1; 95% CI: 0.01–0.6) and positively correlated with the use of biologics (OR: 21.7; 95% CI: 3.4–263). Data indicate that the frail phenotype is a reversible condition in most IBD patients, and such a change relies on the improvement in disease activity.
Keywords	Crohn’s disease ; ulcerative colitis ; IBD ; frailty ; reversibility of frailty ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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