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Biomedicines
Special Issues
Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease
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Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 7020

Special Issue Editor

Dr. Felipe Leite De Oliveira

E-Mail Website
Guest Editor
Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
Interests: gastroenterology; gastrointestinal diseases; cancer; mucosal inflammation

Special Issue Information

Dear Colleagues,

Diseases of the gastrointestinal tract encompass a wide range of disorders that affect the digestive system, and they have attracted the attention of researchers and health professionals around the world. The cellular and molecular mechanisms underlying these diseases, such as inflammatory bowel diseases, irritable bowel syndrome, gastroesophageal reflux, peptic ulcer, celiac disease, gastrointestinal motility disorders, liver diseases, and others, are diverse and involve various components of the gastrointestinal tract. Papers addressing gastrointestinal comorbidities are also welcome in this Special Issue. Cell targets are present in the epithelial barriers, mucosal tissues, accessory glands, immune system, enteric nervous system, neuromuscular junctions, and others. Molecular signaling includes mechanisms that regulate inflammation (cytokines and chemokines), fibrosis, aberrant immune responses, genetic susceptibility, abnormalities in the gut–brain axis, visceral hypersensitivity, pathogens, disruption of mucosa, cancer, smooth muscle abnormalities, and others. Understanding these cellular and molecular mechanisms is crucial for developing targeted therapies, diagnostic tools, and interventions for the diverse array of gastrointestinal diseases resulting in precision medicine and personalized treatment approaches. Studies in this area involve the oral cavity, esophagus, stomach, small and large intestines, salivary glands, liver, pancreas, and gallbladder. This Special Issue aims to improve both preventive and therapeutic protocols and methodologies for precision diagnosis. Advances in molecular and cell biology in gastrointestinal diseases continue to enhance our understanding of these mechanisms and drive innovation in medical research and healthcare. Papers on other topics linked to gastrointestinal tract diseases not included here, however, will also be considered by the editorial team.

Dr. Felipe Leite De Oliveira
Guest Editor

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Keywords

  • cellular mechanisms
  • molecular mechanisms
  • diagnosis
  • treatment
  • experimental models
  • signaling pathways
  • comorbidities

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Published Papers (4 papers)

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Research

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20 pages, 5920 KiB  
Article
UHT Cow’s Milk Supplementation Affects Cell Niches and Functions of the Gut–Brain Axis in BALB/c Mice
by Felipe S. Lemos, Caio A. Prins, Ana M. B. Martinez, Raul Carpi-Santos, Arthur S. Neumann, Nathalia Meireles-da-Costa, Roberto Luisetto, Valeria de Mello-Coelho and Felipe L. Oliveira
Biomedicines 2024, 12(11), 2448; https://doi.org/10.3390/biomedicines12112448 - 25 Oct 2024
Viewed by 1294
Abstract
Background/Objectives: Cow’s milk is a bioactive cocktail with essential nutritional factors that is widely consumed during early childhood development. However, it has been associated with allergic responses and immune cell activation. Here, we investigate whether cow’s milk consumption regulates gut–brain axis functions and [...] Read more.
Background/Objectives: Cow’s milk is a bioactive cocktail with essential nutritional factors that is widely consumed during early childhood development. However, it has been associated with allergic responses and immune cell activation. Here, we investigate whether cow’s milk consumption regulates gut–brain axis functions and affects patterns of behaviors in BALB/c mice, previously described by present low sociability, significant stereotypes, and restricted interest features. The major objectives consist of to investigate cow’s milk supplementation as possible triggers interfering with cellular niches of the gut–brain axis and behavioral patterns. Methods: Male BALB/c at 6 weeks were randomly divided into two groups, one supplemented with cow’s milk processed at ultra-high temperature (UHT) and another group receiving water (controls) three times per day (200 μL per dose) for one week. Results: Milk consumption disturbed histological compartments of the small intestine, including niches of KI67+-proliferating cells and CD138+ Ig-secreting plasma cells. In the liver, milk intake was associated with pro-inflammatory responses, oxidative stress, and atypical glycogen distribution. Milk-supplemented mice showed significant increase in granulocytes (CD11b+SSChigh cells) and CD4+ T cells in the blood. These mice also had neuroinflammatory signals, including an enhanced number of cortical Iba-1+ microglial cells in the brain and significant cerebellar expression of nitric oxide synthase 2 by Purkinje cells. These phenotypes and tissue disorders in milk-supplemented mice were associated with atypical behaviors, including low sociability, high restricted interest, and severe stereotypies. Moreover, synaptic niches were also disturbed after milk consumption, and Shank-3+ and Drebrin+ post-synaptic cells were significantly reduced in the brain of these mice. Conclusions: Together, these data suggest that milk consumption interfered with the gut–brain axis in BALB/c mice and increased atypical behaviors, at least in part, linked to synapse dysfunctions, neuroinflammation, and oxidative stress regulation. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)
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Figure 1

Figure 1
<p>Behavioral pattern of BALB/c mice supplemented with cow’s milk. (<b>A</b>–<b>D</b>) Autistic-like behaviors were analyzed in BALB/c mice and the time spent in social interaction with a familiar or unfamiliar mouse was evaluated (<b>A</b>): (<b>B</b>) stereotyped repetitive movements, (<b>C</b>) time exploring new objects, and (<b>D</b>) restricted interest were also measured in control (ctr) and milk-supplemented mice (milk). The perimeter of the circular arena was monitored for both mice (<b>E</b>). The global motility test was used to investigate total perimeter (<b>F</b>), velocity (<b>G</b>), and distance (<b>H</b>) during the travel through the arena. These important tests also revealed that milk consumption did not influence fine motor skills (<b>I</b>), motor functions (<b>J</b>), or protopathic sensibility (<b>K</b>). White bars represent control mice (supplemented with water) and black bars indicate milk-treated mice values. These data are representative of three independent experiments. (*) <span class="html-italic">p</span> &lt; 0.05; (**) <span class="html-italic">p</span> &lt; 0.01, (***) <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 2
<p>Phenotypical and quantitative analysis of blood leukocytes of mice supplemented with cow’s milk. By flow cytometry, blood leukocytes were analyzed with phenotyping as follows: (<b>A</b>) Myeloid cells were gated by the expression of CD11b. These cells were subdivided into CD11b<sup>+</sup>SSC<sup>high</sup> granulocytes (up gate) and CD11b<sup>+</sup>SSC<sup>low</sup> monocytes (down gate). They were quantified in (<b>B</b>,<b>C</b>), respectively. (<b>D</b>) B lymphoid cells expressing B220 (B220<sup>+</sup>SSC<sup>low</sup>) were selected (cubic gate) and quantified in (<b>E</b>). (<b>F</b>) T lymphoid cells expressing CD4 or CD8 were subdivided into CD4<sup>+</sup>CD8<sup>−</sup> T helper cells and CD4<sup>−</sup>CD8<sup>+</sup> T cytotoxic cells. They were quantified in (<b>G</b>,<b>H</b>), respectively. Control indicates mice receiving water (white bars) and Milk indicates mice supplemented with cow’s milk (black bars). Data are representative of three independent experiments. (*) <span class="html-italic">p</span> &lt; 0.05; (***) <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 3
<p>Morphological analysis of the small intestine in mice supplemented with cow’s milk. Representative photomicrographs of the small intestine obtained from mice receiving water ((<b>A</b>): CTR—controls) or milk ((<b>B</b>): MILK). Inserts show detailed images of the villi. (<b>C</b>) Quantitative analysis of intraepithelial lymphocytes (IELs) in the intestinal epithelial tissue of the mucosa. Immunohistochemistry staining to KI-67 localizes proliferative cells in the gut mucosa in control (<b>D</b>) and milk-treated mice (<b>E</b>). (<b>F</b>) Quantitative analysis of KI-67 expressing cells in the mucosal epithelial cells. Immunohistochemistry staining to CD138 localizes immunoglobulin secreting plasma cells in villi of control (<b>G</b>) and milk-treated mice (<b>H</b>). (<b>I</b>) Quantitative analysis of CD138-expressing cells in the connective tissue of the mucosa. Data are representative of three independent experiments. Amplification: 1000× (inserts). (**) <span class="html-italic">p</span> &lt; 0.01; (***) <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 4
<p>Morphological analysis of the liver in mice supplemented with cow’s milk. Representative photomicrographs of the liver obtained from mice receiving water ((<b>A</b>): CTR—controls) or milk ((<b>B</b>): MILK). Inserts (<b>A</b>,<b>B</b>) show detailed images of the lobular zone. Immunofluorescence analysis staining to NOS2 enzyme localizes oxidative stress niches in the liver of control (<b>C</b>) and milk-treated mice (<b>D</b>). Inserts (<b>C</b>,<b>D</b>) show detailed images of hepatic cells in the oxidative stress niches. PAS staining identifies glycogen accumulation by hepatic cells in control (<b>E</b>) and milk-treated mice (<b>F</b>). Data are representative of three independent experiments. Amplification: 100× (<b>A</b>–<b>D</b>); 400× (<b>E</b>,<b>F</b>); 1000× (inserts).</p> Full article ">Figure 5
<p>Quantitative analysis of mRNA gene expression by hepatic cells of mice supplemented with cow’s milk. Bar graphs represent the mRNA gene expression by RT-PCR on hepatic cells of mice receiving water (CTR—controls, white bars) or milk (MILK, black bars). (<b>A</b>) Interleukin 1-beta (IL-1β); (<b>B</b>) C-C motif ligand 2 (CCL2); (<b>C</b>) Chemokine (C-X-C motif) ligand 1 (CXCL1); (<b>D</b>) C-X3-C motif chemokine ligand 1 or fractalkine (CX3CL1); (<b>E</b>) Cytochrome P450 1A2 (CYP1A2); (<b>F</b>) Cytochrome P450 family 1 subfamily A member 1 (CYP1A1); (<b>G</b>) Aryl hydrocarbon receptor (AhR); (<b>H</b>) Glucocorticoid receptor agonist (GRa). Data are representative of three independent experiments. (*) <span class="html-italic">p</span> &lt; 0.05; (**) <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 6
<p>Localization of Iba-1<sup>+</sup> and NOS-2<sup>+</sup> cells to link neuroinflammation and oxidative stress with cow’s milk intake in mice. Immunohistochemistry staining to Iba-1 localizes cortical microglial cells in control (<b>A</b>) and milk-treated mice (<b>B</b>). The bar graphs indicate the percentage of cortical cells expressing Iba-1 (<b>C</b>). Cerebellar Iba-1<sup>+</sup> microglial cells were localized in controls (<b>D</b>) and milk-treated mice (<b>E</b>). The bar graphs indicate the percentage of cerebellar cells expressing Iba-1 (<b>F</b>). NOS-2<sup>+</sup> cells related to oxidative stress were localized in controls (<b>G</b>) and milk-treated mice (<b>H</b>). These NOS-2<sup>+</sup> cells showed morphology compatible with Purkinje cells ((<b>G</b>,<b>H</b>), inserts) and they were quantified in the cerebellum (<b>I</b>). White bars: control group (Ctr). Black bars: milk-treated mice. Black boxes highlight amplified images of Purkinje cells. These data are representative of three independent experiments. (*) <span class="html-italic">p</span> &lt; 0.05; (***) <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 7
<p>Immunohistochemical and immunofluorescence analyses of cerebral cortex in BALB/c mice supplemented with cow’s milk. Immunohistochemistry staining localizes Shank-3<sup>+</sup> cells in the cerebral cortex of control (<b>A</b>) and milk-treated mice (<b>B</b>). The bar graphs indicate the percentage of cortical cells expressing Shank-3. White bars represent mice supplemented with water (controls) and black bars indicate milk-treated mice values (<b>C</b>). Immunofluorescence microscopy revealed Synaptophysin<sup>+</sup> cells (red) and Drebrin<sup>+</sup> cells (green) in the cortex of control (<b>D</b>) and experimental group (<b>E</b>). In both, merge represents an overlay of images (preferentially orange in (<b>D</b>) and red in (<b>E</b>)); in blue, nucleus. These data are representative of three independent experiments. Amplification: 200× (<b>A</b>,<b>B</b>); 400× (<b>D</b>,<b>E</b>). (***) <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">
20 pages, 6161 KiB  
Article
First Application of a Mixed Porcine–Human Repopulated Bioengineered Liver in a Preclinical Model of Post-Resection Liver Failure
by Philipp Felgendreff, Seyed Mohammad Hosseiniasl, Anna Minshew, Bruce P. Amiot, Silvana Wilken, Boyukkhanim Ahmadzada, Robert C. Huebert, Nidhi Jalan Sakrikar, Noah G. Engles, Peggy Halsten, Kendra Mariakis, John Barry, Shawn Riesgraf, Chris Fecteau, Jeffrey J. Ross and Scott L. Nyberg
Biomedicines 2024, 12(6), 1272; https://doi.org/10.3390/biomedicines12061272 - 7 Jun 2024
Viewed by 1853
Abstract
In this study, a mixed porcine–human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the [...] Read more.
In this study, a mixed porcine–human bioengineered liver (MPH-BEL) was used in a preclinical setup of extracorporeal liver support devices as a treatment for a model of post-resection liver failure (PRLF). The potential for human clinical application is further illustrated by comparing the functional capacity of MPH-BEL grafts as assessed using this porcine PRLF model with fully human (FH-BEL) grafts which were perfused and assessed in vitro. BEL grafts were produced by reseeding liver scaffolds with HUVEC and primary porcine hepatocytes (MPH-BEL) or primary human hepatocytes (FH-BEL). PRLF was induced by performing an 85% liver resection in domestic white pigs and randomized into the following three groups 24 h after resection: standard medical therapy (SMT) alone, SMT + extracorporeal circuit (ECC), and SMT + MPH-BEL. The detoxification and metabolic functions of the MPH-BEL grafts were compared to FH-BEL grafts which were perfused in vitro. During the 24 h treatment interval, INR values normalized within 18 h in the MPH-BEL therapy group and urea synthesis increased as compared to the SMT and SMT + ECC control groups. The MPH-BEL treatment was associated with more rapid decline in hematocrit and platelet count compared to both control groups. Histological analysis demonstrated platelet sequestration in the MPH-BEL grafts, possibly related to immune activation. Significantly higher rates of ammonia clearance and metabolic function were observed in the FH-BEL grafts perfused in vitro than in the MPH-BEL grafts. The MPH-BEL treatment was associated with improved markers of liver function in PRLF. Further improvement in liver function in the BEL grafts was observed by seeding the biomatrix with human hepatocytes. Methods to reduce platelet sequestration within BEL grafts is an area of ongoing research. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)
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Figure 1

Figure 1
<p>Reseeding setup and timeline. (<b>A</b>) Automated perfusion system used for reendothelialization and repopulation of an acellular scaffold; 1–3 are marking the automated clamps controlling the repopulation procedure (<b>B</b>) reendothelialization and repopulation timeline.</p> Full article ">Figure 2
<p>Study timeline (<b>A</b>) and treatment groups (<b>B</b>). SMT: standard medical therapy, ECC: extracorporeal circuit without BEL graft, MPH-BEL: Bioengineered livers containing mixed populations of porcine hepatocytes and human endothelial cells.</p> Full article ">Figure 3
<p>Illustration of Extracorporeal BEL treatment in the PRLF model including the BEL graft, the control unit, roller pumps and the reservoir.</p> Full article ">Figure 4
<p>Kaplan–Meier curve comparing the survival rate of the three investigated study groups using the log-rank test. SMT: standard medical therapy, SMT + ECC (extracorporeal circuit without BEL graft), SMT + MPH-BEL (bioengineered livers containing mixed populations of porcine hepatocytes and human endothelial cells). The red line marks 48 h, the end of treatment interval. (<span class="html-italic">p</span> = 0.10).</p> Full article ">Figure 5
<p>Mean serum concentration of ammonia (<b>A</b>) and urea (<b>B</b>) are presented as a function of study period for each treatment group. SMT: standard medical therapy is indicated by open circles, SMT + ECC: extracorporeal circuit without BEL grafts is indicated by open diamonds, SMT + MPH-BEL: bioengineered livers containing mixed populations of porcine hepatocytes and human endothelial cells is indicated by closed squares. (<b>A</b>) *<sup>1</sup> Significant difference (Student’s <span class="html-italic">t</span>-test; <span class="html-italic">p</span> &lt; 0.05) in ammonia level in the comparison of time point baseline (Tbaseline) and 24 h after 85% liver resection (T24) in all study groups, ns: not significant (<b>B</b>) *<sup>1,</sup>*<sup>2</sup> Significant difference (Student’s <span class="html-italic">t</span>-test; <span class="html-italic">p</span> &lt; 0.05) of urea level in the comparison of SMT and SMT + MPH-BEL at 42 h (T42) and 48 h (T48) after 85% liver resection.</p> Full article ">Figure 6
<p>INR values during the study period. Red line indicates a cut-off of 1.5; SMT: standard medical therapy, SMT + ECC (extracorporeal circuit without BEL graft), SMT + MPH-BEL (bioengineered livers containing mixed populations of porcine hepatocytes and human endothelial cells). *<sup>1</sup> Significant difference (Student’s <span class="html-italic">t</span>-test; <span class="html-italic">p</span> &lt; 0.05) of INR level in the comparison of time point baseline (Tbaseline) and 24 h after 85% liver resection (T24) in all study groups; *<sup>2,</sup>*<sup>3</sup> Significant difference (Student’s <span class="html-italic">t</span>-test; <span class="html-italic">p</span> &lt; 0.05) of INR level in the comparison of SMT and SMT + MPH-BEL at 42 h (T42) and 48 h (T48) after 85% liver resection.</p> Full article ">Figure 7
<p>CBC results as well as Interleukin 6 values during the treatments. (<b>A</b>) Hematocrit, (<b>B</b>) Platelets, (<b>C</b>) White blood count, (<b>D</b>) Interleukin 6 values; SMT: standard medical therapy, SMT + ECC (extracorporeal circuit without BEL graft), SMT + MPH-BEL (bioengineered livers containing mixed populations of porcine hepatocytes and human endothelial cells). (<b>A</b>) * Significant difference (<span class="html-italic">p</span> &lt; 0.05) of hematocrit in the comparison of SMT and SMT + MPH-BEL at T24 and T48; (<b>B</b>) *<sup>1,</sup>*<sup>2,</sup>*<sup>3,</sup>*<sup>4</sup> Significant difference (Student’s <span class="html-italic">t</span>-test; <span class="html-italic">p</span> &lt; 0.05) of platelet count level in the comparison of SMT and SMT + MPH-BEL at 24 h after 85% liver resection (T24) vs. 30 h after 85% liver resection (T30); 24 h after 85% liver resection (T24) vs. 36 h after 85% liver resection (T36); 24 h after 85% liver resection (T24) vs. 42 h after 85% liver resection (T42) and 24 h after 85% liver resection (T24) vs. 48 h after 85% liver resection (T48). (<b>C</b>) * Significant difference (Student’s <span class="html-italic">t</span>-test; <span class="html-italic">p</span> &lt; 0.05) of white blood count in the comparison of SMT and SMT + MPH-BEL at 42 h (T42) and 48 h (T48) after 85% liver resection.</p> Full article ">Figure 8
<p>Representative histological slides of the PPLC-BEL following in vitro perfusion and following the PRLF treatment. (<b>A</b>,<b>B</b>): hematoxylin-eosin staining, successful recellularization with large numbers of hepatocytes (black arrows); post-PRLF treatment there is significant immune cell infiltration (framed arrowheads) in the periportal area (asterisk: portal vein); (<b>C</b>,<b>D</b>): Sirius red staining; preserved extracellular matrix in the periportal area (asterisk: portal vein) both after recellularization and after treatment, (<b>A</b>): fine extracellular matrix within hepatocyte aggregates; (<b>E</b>,<b>F</b>): CD 61 immunohistochemical staining; significant sequestration of platelets in the periportal area (asterisk: portal vein) after treatment; (<b>G</b>,<b>H</b>): immunofluorescence staining for CD 61, LYVE1 and DAPI; (<b>A</b>): successful endothelialization with HUVECs; (<b>B</b>): preserved endothelialization after treatment (continuous endothelium in lower right corner of image), significant immune cell infiltration and platelet sequestration in the periportal area.</p> Full article ">Figure 9
<p>In vitro function of the MPH-BEL and the FH-BEL in the three-day long-term perfusion study. The function of the grafts was compared with regards to the detoxification and synthetic function (<b>A</b>–<b>D</b>) of the grafts. *: <span class="html-italic">p</span> &lt; 0.05 using Student’s <span class="html-italic">t</span>-test; **: <span class="html-italic">p</span> &lt; 0.01 using Student’s <span class="html-italic">t</span>-test; nd: no difference.</p> Full article ">

Review

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22 pages, 3709 KiB  
Review
Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking
by Emile Levy, Catherine Fallet-Bianco, Nickolas Auclair, Natalie Patey, Valérie Marcil, Alain Théophile Sané and Schohraya Spahis
Biomedicines 2024, 12(7), 1548; https://doi.org/10.3390/biomedicines12071548 - 12 Jul 2024
Viewed by 1560
Abstract
Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways [...] Read more.
Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways involved, while simultaneously identifying novel therapeutic targets and diagnostic tools. This research not only delves into specific and rare malabsorptive conditions, such as chylomicron retention disease (CRD), but also contributes to our understanding of normal physiology through the utilization of cutting-edge cellular and animal models alongside advanced research methodologies. This review elucidates how modern techniques have facilitated the decoding of CRD gene defects, the identification of dysfunctional cellular processes, disease regulatory mechanisms, and the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites. Moreover, experimental approaches have shed light on the multifaceted functions of SAR1B GTPase, wherein loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD. In addition to dissecting the primary disease pathology, genetically modified animal models have emerged as invaluable assets in exploring various ancillary aspects, including responses to environmental challenges such as dietary alterations, gender-specific disparities in disease onset and progression, and embryonic lethality or developmental abnormalities. In summary, this comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)
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Figure 1

Figure 1
<p>Members of the RAS superfamily and their functions. The RAS superfamily is a group of small GTPase proteins that play crucial roles in various cellular processes, including cell growth, differentiation, and intracellular signaling. The present figure illustrates the key members of the RAS superfamily and examples of their functions, including cell proliferation, differentiation, motility, migration, adhesion, and survival, as well as nucleocytoplasmic transport, actin cytoskeleton organization, and intracellular vesicle trafficking and budding, transport, and fusion with target membranes. Notably, the Arf family are the founding members of Arf-like, Arf-related, and Sar proteins, which have diverse functions in membrane trafficking, cytoskeletal organization, and cell signaling pathways. They regulate processes such as vesicle budding and actin dynamics.</p> Full article ">Figure 2
<p>The GTP/GDP cycle ensures control of cellular signaling pathways. RAS is activated upon binding to GTP to promote cell proliferation. The hydrolysis of GTP to GDP and Pi turns off the active form of RAS. An equilibrium is maintained between RAS-GTP and RAS-GDP forms and GTPase activating protein and GTP exchange factor coordinate the relative proportions of each form.</p> Full article ">Figure 3
<p>The formation of COPII Transport Vesicle. The building of the COPII complex is a highly regulated process that ensures efficient and selective transport of cargo proteins from the ER to the Golgi apparatus, contributing to the maintenance of cellular homeostasis and proper protein trafficking within the secretory pathway. The assemblage of the COPII vesicle complex occurs in five steps: (1) activation of SAR1 via phosphorylation of SAR1-GDP by SEC12; (2) selection of cargo proteins via the Pro28 N-terminal ER peptide signal of NUCB1 (nucleobindin 1); (3) recruitment of the SEC23/SEC24 subunit to form the inner vesicle layer; (4) recruitment of the SEC13/SEC31 subunit to form the outer vesicle layer; and (5) stabilization of the COPII complex by SEC16 and budding of the vesicle to the Golgi. Importantly, the SEC23 protein (with 5 distinct domains) activates SAR1-GTP hydrolysis to stimulate vesicle transportation.</p> Full article ">Figure 4
<p><span class="html-italic">SAR1B</span> genetic defects and gender-related differences. After stratifying the animal groups by sex, the genetically modified animals exhibited more significant gender divergences in (<b>A</b>) body weight, (<b>B</b>) plasma insulin levels, (<b>C</b>–<b>E</b>) plasma lipid profile, as well as (<b>F</b>,<b>G</b>) intestinal and (<b>H</b>,<b>I</b>) liver <span class="html-italic">Apo B</span> and <span class="html-italic">MTTP</span> gene expressions. Results represent the means ± SEM of 10–13 mice in each group. CM = control male, CF = control females, MM = <span class="html-italic">Sar1b<sup>mut/+</sup></span> males, MF = <span class="html-italic">Sar1b<sup>mut/+</sup></span> females, DM = <span class="html-italic">Sar1b<sup>del/+</sup></span> males, and DF = <span class="html-italic">Sar1b<sup>del/+</sup></span> females. This figure is a new supplementary analysis obtained as part of previous data [<a href="#B53-biomedicines-12-01548" class="html-bibr">53</a>,<a href="#B54-biomedicines-12-01548" class="html-bibr">54</a>].</p> Full article ">Figure 5
<p>Embryonic expression of SAR1 and Apo B proteins and alkaline phosphatase gene. E18.5 embryos of a <span class="html-italic">Sar1b<sup>del/+</sup></span> pregnant mouse from intercross of two <span class="html-italic">Sar1b<sup>del/+</sup></span> mice were collected and genotyped. Afterwards, two whole embryos from each genetic background were homogenized in cold PBS buffer containing antiproteases. Then, total protein extracts were subjected to 4–20% SDS-PAGE gradient gel and electroblotted onto a same nitrocellulose membrane. The membrane was subsequently reacted with anti-SAR1 (<b>A</b>) (provided by Dr Randy Schekman, University of California, Berkeley), anti-Apo B (<b>B</b>), and anti-β-actin as loading control using the BLUeye Prestained Potein Ladder, Tris-Glycine 4-20% as a quality control for the molecular weight. In parallel, total RNA (1 μg) from three flash-frozen jejunums of different genetic backgrounds was used for cDNA synthesis in 5X All-In-One RT Master Mix. PCR was then performed with primers for mouse intestinal alkaline phosphatase (m<span class="html-italic">IAP</span>) (forward: TCCAGCTGAAGAGGAGAAC; reverse: TTAGGATCCTGGTGGCTGTC) and mouse actin gene (forward: GACAGGATGCAGAAGGAGATTACTG; reverse: CCACCGATCCACACAGTACTT) with Taq DNA polymerase. PCR products were run against 1.5% agarose gel and ethidium bromide reactive bands were visualized with ChemiDoc imaging system (<b>C</b>). Bands densitometry was calculated with Image Lab 6.0 software (Bio-Rad, Montreal, CA, USA). Mice are usually from the same litter and are segregated after genotyping. Results represent the means ± SEM of two to three specimens as for preliminary investigation. The original gels This figure is a new analysis obtained as part of previous data [<a href="#B53-biomedicines-12-01548" class="html-bibr">53</a>,<a href="#B54-biomedicines-12-01548" class="html-bibr">54</a>].</p> Full article ">Figure 6
<p>Coronal sections of embryonic mice brain showing dilated ventricles in anterior part of the hemispheres, in basal ganglia and in the third ventricle of SAR1B animal models. In coronal sections of embryonic mice (13.5 days), the presence of dilated ventricles in animal models, particularly in <span class="html-italic">del/+</span> and <span class="html-italic">del/del</span> mice (as indicated by red arrows) is observed. As ventricles are fluid-filled cavities playing important roles in cerebrospinal fluid circulation and brain development, the observation of dilated ventricles in <span class="html-italic">Sar1b<sup>del/+</sup></span> and <span class="html-italic">Sar1b<sup>del/del</sup></span> mice implies disruptions or alterations in normal brain development processes. Particularly, dilation is predominant in the anterior part of the lateral ventricles (<b>A</b>), in ganglia (<b>B</b>), and in the third ventricle (<b>C</b>), and is identical in heterozygotes and homozygotes. These abnormalities may lead to impaired neurogenesis, altered neuronal migration, or defective formation of brain structures, resulting in the observed dilation of the ventricles. Overall, the presence of dilated ventricles in embryonic mice brain sections may serve as a morphological indicator of potential brain developmental abnormalities in these animal models. This figure is a new supplementary analysis obtained as part of previous data [<a href="#B53-biomedicines-12-01548" class="html-bibr">53</a>].</p> Full article ">
13 pages, 1605 KiB  
Review
Progastrin: An Overview of Its Crucial Role in the Tumorigenesis of Gastrointestinal Cancers
by Rodanthi Fioretzaki, Panagiotis Sarantis, Nikolaos Charalampakis, Konstantinos Christofidis, Adam Mylonakis, Evangelos Koustas, Michalis V. Karamouzis, Stratigoula Sakellariou and Dimitrios Schizas
Biomedicines 2024, 12(4), 885; https://doi.org/10.3390/biomedicines12040885 - 17 Apr 2024
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Abstract
Defining predictive biomarkers for targeted therapies and optimizing anti-tumor immune response is a main challenge in ongoing investigations. Progastrin has been studied as a potential biomarker for detecting and diagnosing various malignancies, and its secretion has been associated with cell proliferation in the [...] Read more.
Defining predictive biomarkers for targeted therapies and optimizing anti-tumor immune response is a main challenge in ongoing investigations. Progastrin has been studied as a potential biomarker for detecting and diagnosing various malignancies, and its secretion has been associated with cell proliferation in the gastrointestinal tract that may promote tumorigenesis. Progastrin is a precursor molecule of gastrin, synthesized as pre-progastrin, converted to progastrin after cleavage, and transformed into amidated gastrin via biosynthetic intermediates. In cancer, progastrin does not maturate in gastrin and becomes a circulating and detectable protein (hPG80). The development of cancer is thought to be dependent on the progressive dysregulation of normal signaling pathways involved in cell proliferation, thus conferring a growth advantage to the cells. Understanding the interaction between progastrin and the immune system is essential for developing future cancer strategies. To that end, the present review will approach the interlink between gastrointestinal cancers and progastrin by exploring the underlying molecular steps involved in the initiation, evolution, and progression of gastrointestinal cancers. Finally, this review will focus on the clinical applications of progastrin and investigate its possible use as a diagnostic and prognostic tumor circulating biomarker for disease progression and treatment effectiveness, as well as its potential role as an innovative cancer target. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Gastrointestinal Tract Disease)
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<p>The figure shows a schematic representation of intestinal tumorigenesis, showing the accumulation of mutations, the activation of signaling pathways, and the role of progastrin (This figure was created based on the tools provided by <a href="http://Biorender.com" target="_blank">Biorender.com</a>).</p> Full article ">Figure 2
<p>The figure shows the clinical implications of progastrin(this figure was created based on the tools provided by <a href="http://Biorender.com" target="_blank">Biorender.com</a>).</p> Full article ">
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