Review
Oncology
Moein Piroozkhah, Ali Aghajani, Pooya Jalali, Arvin Shahmoradi, Mobin Piroozkhah, Younes Tadlili, Zahra Salehi
Summary: This systematic review focuses on the latest research on the guanylate cyclase-C (GC-C) signaling axis in colorectal cancer (CRC). The findings reveal that alterations in GC-C signaling compartments in CRC tissue have potential as diagnostic, prognostic, and therapeutic markers. Moreover, the GC-C signaling axis may be a promising target for treating CRC.
FRONTIERS IN ONCOLOGY
(2023)
Article
Oncology
David S. Weinberg, Nathan R. Foster, Gary Della'Zanna, Ryan P. McMurray, Walter K. Kraft, Angela Pallotto, David M. Kastenberg, Leo C. Katz, Christopher H. Henry, Stephanie M. Moleski, Paul J. Limburg, Scott A. Waldman
Summary: Studies suggest that oral GUCY2C agonist could be an effective chemoprevention agent for colorectal cancer, but the investigational oral uroguanylin analog dolcanatide did not activate GUCY2C in epithelial cells of the distal rectum in healthy volunteers, indicating its enhanced stability and extended persistence may not be sufficient to regulate GUCY2C across the colorectum for tumor prevention.
CANCER BIOLOGY & THERAPY
(2021)
Article
Chemistry, Medicinal
Nayara Braga Emidio, Hue N. T. Tran, Asa Andersson, Philip E. Dawson, Fernando Albericio, Irina Vetter, Markus Muttenthaler
Summary: The high susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs, such as linaclotide, for gastrointestinal disorders. Improvements in gastrointestinal stability through strategic modifications of linaclotide analogues can significantly enhance their therapeutic efficacy and create potential for the development of the next generation of orally administered peptide drugs for gastrointestinal disorders.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Endocrinology & Metabolism
Aaron Otero, Sara Becerril, Marina Martin, Javier A. Cienfuegos, Victor Valenti, Rafael Moncada, Victoria Catalan, Javier Gomez-Ambrosi, Maria A. Burrell, Amaia Rodriguez, Gema Fruhbeck
Summary: Obesity leads to fat deposition in non-adipose organs, including the pancreas, which is associated with inflammation and beta-cell dysfunction. This study aimed to investigate the mechanisms behind the improvement of pancreas fat accumulation after bariatric surgery. It was found that sleeve gastrectomy reduced pancreas steatosis and inflammation, and upregulated GUCA2A and GUCY2C in the pancreas, which might contribute to the beneficial effects of bariatric surgery. Additionally, guanylin and uroguanylin were found to alleviate lipotoxicity in beta-cells and modulate insulin synthesis and release.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Pharmacology & Pharmacy
Adi Caspi, Ariana A. Entezari, Madison Crutcher, Adam E. Snook, Scott A. Waldman
Summary: Colorectal cancer is a major cause of mortality in the USA, and while current therapies focus on generic treatment, there is a growing need for effective targets and biomarkers. Guanylyl cyclase C, which regulates intestinal homeostasis and is universally expressed in advanced metastatic colorectal tumors, has emerged as a promising target and biomarker for gastrointestinal malignancies.
PERSONALIZED MEDICINE
(2022)
Review
Endocrinology & Metabolism
Hari Prasad, John Kandam Kulathu Mathew, Sandhya S. Visweswariah
Summary: This review highlights the importance of Receptor Guanylyl Cyclase C (GC-C) in regulating intestinal fluid and ion homeostasis, and its causal link to intestinal inflammation, dysbiosis, and tumorigenesis. The GC-C signaling pathway plays a role in extra gastrointestinal functions such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has also uncovered the involvement of GC-C in the ion-microbiome-immune axis in inflammatory bowel disease and suggests potential therapeutic strategies.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Medicine, Research & Experimental
Rodger A. Liddle
Summary: Visceral pain associated with irritable bowel syndrome affects 15% of the US population. Recent studies have discovered a new pathway for gut signal communication to the nervous system through synaptic connections between guanylyl cyclase C (GUCY2C)-promoting neurons and submucosal neurons. Selective deletion of GUCY2C in mouse models indicates that defective GUCY2C neuropod-cell signaling is responsible for visceral pain. Unveiling the role of neuropod cells is a significant step in understanding and potentially treating visceral pain.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Gastroenterology & Hepatology
Brooks D. Cash, Amol Sharma, Anna Walker, Adam P. Laitman, Lin Chang
Summary: This study aimed to evaluate the effectiveness of plecanatide in patients with chronic idiopathic constipation (CIC) or irritable bowel syndrome with constipation (IBS-C) with severe constipation. The results showed that plecanatide significantly improved the symptoms of severe constipation in both CIC and IBS-C patients.
NEUROGASTROENTEROLOGY AND MOTILITY
(2023)
Review
Physiology
S. Samanta, A. G. Chaudhuri
Summary: Intestinal guanyl peptides play a crucial role in maintaining fluid-ion balance in the intestine through the GC-C/cGMP signaling pathway, influencing intestinal fluid volume, mucous hydration, and cellular functions, making them potentially useful for treating a range of intestinal disorders.
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
(2021)
Article
Gastroenterology & Hepatology
William D. Chey, Gregory S. Sayuk, Wilmin Bartolini, David S. Reasner, Susan M. Fox, Wieslaw Bochenek, Ramesh Boinpally, Elizabeth Shea, Kenneth Tripp, Niels Borgstein
Summary: The study demonstrates that the delayed-release formulation of linaclotide and MD-7246 show better improvement in abdominal pain compared to placebo. MD-7246 shows sustained but modest effects on pain relief, suggesting further investigation as a novel treatment for abdominal pain.
AMERICAN JOURNAL OF GASTROENTEROLOGY
(2021)
Article
Gastroenterology & Hepatology
Lin Chang, Brian E. Lacy, Baha Moshiree, Amy Kassebaum, Jessica L. Abel, Jennifer Hanlon, Wilmin Bartolini, Ramesh Boinpally, Wieslaw Bochenek, Susan M. Fox, Madhuja Mallick, Ken Tripp, Nicholas Omniewski, Elizabeth Shea, Niels Borgstein
Summary: Linaclotide significantly improved abdominal symptoms related to constipation-predominant irritable bowel syndrome (IBS-C) compared to placebo, including bloating, discomfort, and pain. The study found that linaclotide had a higher overall change from baseline in abdominal score (AS) and a higher responder rate for abdominal symptoms improvement, with diarrhea being the most common side effect. The use of a novel multi-item AS derived from the Diary for IBS Symptoms-Constipation may be valuable in future clinical studies for IBS-C to measure meaningful improvements beyond traditional endpoints.
AMERICAN JOURNAL OF GASTROENTEROLOGY
(2021)
Article
Gastroenterology & Hepatology
Alejandro Velez Lopez, Amanda Waddell, Simona Antonacci, Daniel Castillo, Neha Santucci, Nicholas J. Ollberding, Emily M. Eshleman, Lee A. Denson, Theresa Alenghat
Summary: This study demonstrated that microbiota-derived butyrate can dampen human colonic responses to linaclotide in patient-derived colonoids, providing support for the incorporation of microbiota and metabolomic assessment to improve precision medicine for DGBI patients.
NEUROGASTROENTEROLOGY AND MOTILITY
(2023)
Article
Multidisciplinary Sciences
Pragya Rampuria, Lidia Mosyak, Adam R. Root, Kristine Svenson, Michael J. Agostino, Edward R. LaVallie
Summary: This study identified the binding epitope of the GUCY2C receptor using a yeast surface display approach and peptide mapping strategy, and revealed its role in the anti-GUCY2CxCD3 bispecific antibody. The epitope was found to be located in the N-terminal helical region of GUCY2C, which is essential for the close spatial proximity of the antibody arms and the tumor killing activity.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Kang Wang, Wenjun Li, Hongli Cui, Song Qin
Summary: This study investigates the turnover proteins of c-di-GMP in Arthrospira and confirms the existence of a functional c-di-GMP network in this cyanobacteria genus.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Ariana A. Entezari, Adam E. Snook, Scott A. Waldman
Summary: GUCY2C has emerged as a promising target for chemoprevention and therapy for GI malignancies, with potential roles in immunotherapy and diagnostic management as well. Clinical trials are underway to explore its use as an immunotherapeutic target for preventing metastatic disease. GUCY2C is an emerging target across the disease continuum, from chemoprevention to the prevention of metastatic diseases.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Article
Cell Biology
Yu-Qiang Yu, Veronika Thonn, Jay Patankar, Oana-Maria Thoma, Maximilian Waldner, Marta Zielinska, Li-li Bao, Miguel Gonzalez-Acera, Stefan Wallmueller, Felix B. Engel, Michael Stuerzl, Markus F. Neurath, Eva Liebing, Christoph Becker
Summary: This study reveals that SMYD2 is overexpressed in colorectal cancer and plays a crucial role in tumor growth while inhibiting TNF-induced apoptosis and necroptosis.
CELL DEATH & DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Agata Szymaszkiewicz, Marcin Talar, Jakub Wlodarczyk, Mikolaj Swierczynski, Adrian Bartoszek, Julia Krajewska, Anna Mokrowiecka, Ewa Malecka-Wojciesko, Jakub Fichna, Marta Zielinska
Summary: Nearly 20% of elderly patients suffer from constipation, but the age-related changes in the gastrointestinal (GI) tract remain insufficiently elucidated. This study evaluated the alterations within the endogenous opioid system (EOS) as a potential cause of constipation in the elderly. The results showed that the age-related impairment of GI peristalsis may result from reduced MOP and DOP response to opioid agonists or alterations in EOS expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Marzena Mazur, Jakub Wlodarczyk, Mikolaj Swierczynski, Radzislaw Kordek, Marcin M. Grzybowski, Jacek Olczak, Jakub Fichna
Summary: In this study, a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor was proposed. The study demonstrated the significant anti-inflammatory effect of the AMCase inhibitor in a dextran sulfate sodium (DSS)-induced colitis model. Additionally, the inhibitor reduced TNF-alpha mRNA levels and MPO activity, and improved colon length and body weight.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Agata Twardowska, Adam Makaro, Agata Binienda, Jakub Fichna, Maciej Salaga
Summary: Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines can lead to intestinal hyperpermeability and the development of various diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract can cause chronic inflammation and progression of disorders. Dietary intervention has shown potential in improving barrier function and restricting bacterial invasion, but there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with leaky gut syndrome.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Tomasz Mackiewicz, Jakub Wlodarczyk, Marta Zielinska, Marcin Wlodarczyk, Adam Durczynski, Piotr Hogendorf, Lukasz Dziki, Jakub Fichna
Summary: This study measured the expression of GPR35 in colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC) patients using real-time polymerase chain reaction (RT-PCR). The results showed significantly higher GPR35 expression in tumor samples compared to paired healthy samples, and correlations with tumor characteristics were observed. These findings suggest the potential prognostic value of GPR35 testing in CRC and PDAC patients.
ADVANCES IN CLINICAL AND EXPERIMENTAL MEDICINE
(2023)
Review
Medicine, General & Internal
Jakub Wlodarczyk, Jacek Burzynski, Bartlomiej Czerwinski, Mateusz Prusisz, Katarzyna Socala, Ewa Poleszak, Jakub Fichna, Kasper Marynczak, Marcin Wlodarczyk, Lukasz Dziki
Summary: Crohn's disease is a subtype of chronic inflammatory bowel diseases characterized by skip lesions and transmural inflammation. It can affect the entire gastrointestinal tract and persistent pain is one of the main symptoms. This study aims to provide an abbreviated summary of the current knowledge on the origins and treatment of pelvic pain in Crohn's disease.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Pharmacology & Pharmacy
Marek Pajak, Magdalena Wozniczka, Miroslawa Swiatek, Bartlomiej Czerwinski, Jakub Wlodarczyk, Jakub Fichna
Summary: The complexation properties of two synthetic nucleosides, beta-D-ribofuranoside-4-pyrimidinone (ribo) and beta-D-deoxyribofuranoside-4-pyrimidinone (deoxy), with Ag(I) ions in aqueous solution were investigated. The stability constants of the coordination entities formed were calculated and the percentage of each entity in solution was estimated. The results suggest that these coordination entities have potential antiviral, antibacterial, and antitumor properties, as well as potential applications in nanobiotechnology.
ACTA POLONIAE PHARMACEUTICA
(2023)
Review
Pharmacology & Pharmacy
Karolina Merecz, Mikolaj Hirsa, Olga Biniszewska, Jakub Fichna, Aleksandra Tarasiuk
Summary: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that affects approximately 10% of the global population. Recent studies have shown that antagonism of the serotonin 5-HT3 receptor is an effective treatment for IBS-D. The modulation of serotonin function plays a crucial role in maintaining intestinal homeostasis.
EXPERT OPINION ON PHARMACOTHERAPY
(2023)
Article
Biochemistry & Molecular Biology
Jakub Wlodarczyk, Julia Krajewska, Lukasz Szeleszczuk, Patrycja Szalwinska, Agata Gurba, Szymon Lipiec, Przemyslaw Taciak, Remigiusz Szczepaniak, Izabela Mlynarczuk-Bialy, Jakub Fichna
Summary: Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are global health problems with increasing frequency and unclear pathogenesis. Current treatment involves drugs like corticosteroids and derivative compounds, but more specific and effective therapies are desired. In this study, novel gold complexes were tested and found to have anti-inflammatory potential both in vitro and in vivo, particularly TGS 703, which was able to alleviate inflammation in a mouse model of colitis and showed a link to antioxidant systems. These findings suggest that gold(III) complexes may have therapeutic applications in the treatment of IBD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Jacek Burzynski, Jakub Fichna, Aleksandra Tarasiuk
Summary: Acute pancreatitis (AP) and chronic pancreatitis (CP) are severe diseases that pose a great threat to human health in high-income countries. Oxidative stress plays a significant role in the development of AP and CP, and there is growing interest in the use of antioxidant therapy to manage these conditions. Vitamin A, a well-known antioxidant, has been understudied in relation to its impact on oxidative stress in AP and CP. This review aims to evaluate the molecular targets of vitamin A and its potential role in attenuating oxidative stress in AP and CP. The findings suggest that vitamin A may influence several molecular pathways involved in antioxidative defense and cytoprotection, indicating its potential to alter the disease course of AP and CP.
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
(2023)
Article
Toxicology
Szymon Lipiec, Agata Gurba, Izabela M. Agnieszczak, Andrzej Antoni Szczepankiewicz, Przemyslaw Szymanski, Przemyslaw Taciak, Remigiusz Szczepaniak, Lukasz Szeleszczuk, Hanna Nieznanska, Jakub Wlodarczyk, Jakub Fichna, Lukasz P. Bialy, Izabela Mlynarczuk-Bialy
Summary: Metal-based agents in cancer therapy, like cisplatin and its derivates, have established clinical applications but also can induce serious side effects. Thus, metallotherapeutic alternatives for platinum derivatives are developed and intensively studied. Platinum is replaced by several transition metals including gold. Especially gold (III) complexes can have the same square-planar structure and are isoelectric with platinum (II).
TOXICOLOGY IN VITRO
(2023)
Article
Immunology
Adam Makaro, Mikolaj Swierczynski, Kacper Pokora, Barbara Sarniak, Radzislaw Kordek, Jakub Fichna, Maciej Salaga
Summary: Inflammatory bowel diseases (IBD) is a chronic and relapsing inflammation in the gastrointestinal tract. The incidence and prevalence of IBD are high and increasing, and current therapeutic strategies are suboptimal. This study focused on gliflozins, a group of anti-diabetic drugs, and found that they have anti-inflammatory properties. In vitro experiments showed that two gliflozins, EMPA and DAPA, suppressed nitric oxide production in macrophages, and in vivo experiments demonstrated that EMPA alleviated colitis in mice. Our findings suggest that SGLT-2 inhibitors have anti-inflammatory effects independent of their hypoglycemic effects.
INFLAMMOPHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Marcin Sochal, Marta Ditmer, Agata Binienda, Agata Gabryelska, Piotr Bialasiewicz, Renata Talar-Wojnarowska, Jakub Fichna, Ewa Malecka-Wojciesko
Summary: Inflammatory bowel disease (IBD) patients often experience sleep and mood disorders which may be related to the disruption of the brain-gut axis. This study found that IBD patients had lower expression of BDNF mRNA but higher concentrations of proBDNF and BDNF protein compared to healthy controls. BDNF protein levels were positively correlated with sleep efficiency in the IBD group and depression severity was associated with BDNF mRNA and protein levels in the remission group.
Article
Medicine, General & Internal
Marcin Sochal, Alicja Witkowska, Agata Binienda, Agata Gabryelska, Piotr Bialasiewicz, Jakub Fichna, Renata Talar-Wojnarowska, Ewa Malecka-Wojciesko
Summary: The study investigates the impact of the serotonergic pathway on the pathogenesis and course of inflammatory bowel diseases (IBDs), and its relationship with sleep and mood disorders. The results show that patients with active IBD have higher levels of 5-HT and SERT protein expression, which are positively correlated with insomnia severity. After treatment, only 5-HT levels are decreased.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Biology
Marcin Wlodarczyk, Adam Makaro, Mateusz Prusisz, Jakub Wlodarczyk, Marta Nowocien, Kasper Marynczak, Jakub Fichna, Lukasz Dziki
Summary: Crohn's disease (CD) is a chronic, relapsing inflammatory bowel disease characterized by transmural inflammation in the gastrointestinal tract. Chronic fatigue is a common and often underestimated symptom in CD patients, with a higher prevalence compared to the general population. Its underlying causes and mechanisms are complex and not fully understood. Routine screening and a comprehensive, multidisciplinary approach, including psychological support, may play a crucial role in managing CD patients with chronic fatigue. Further research is needed to predict, prevent, identify, and treat fatigue associated with CD. This review aims to summarize the current knowledge on the etiology, diagnosis, and treatment of chronic fatigue in CD patients.
