International Journal of Molecular Sciences

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30 pages, 7346 KiB

Open AccessArticle

Mitochondrial Dysfunction and Induction of Apoptosis in Hepatocellular Carcinoma and Cholangiocarcinoma Cell Lines by Thymoquinone

by Reem J. Abdualmjid and Consolato M. Sergi

Int. J. Mol. Sci. 2022, 23(23), 14669; https://doi.org/10.3390/ijms232314669 - 24 Nov 2022

Cited by 3 | Viewed by 1833

Abstract

Thymoquinone (TQ), a plant-based bioactive constituent derived from the volatile oil of Nigella sativa, has been shown to possess some anti-neoplastic activities. The present study aimed to investigate the mitochondria and apoptosis observed when TQ is applied against hepatocellular carcinoma (HepG2) and [...] Read more.

Thymoquinone (TQ), a plant-based bioactive constituent derived from the volatile oil of Nigella sativa, has been shown to possess some anti-neoplastic activities. The present study aimed to investigate the mitochondria and apoptosis observed when TQ is applied against hepatocellular carcinoma (HepG2) and cholangiocarcinoma (HuCCT1) cells, two of the most common primary tumors of the liver. All cell lines were treated with increasing concentrations of TQ for varying durations. The anti-proliferative effect of TQ was measured using the methoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and resulted in dose- and time-dependent growth inhibition in both cell lines. Cell cycle, apoptosis, and assessment of mitochondria viability by morphology assessment and evaluation of the mitochondrial membrane potential were investigated. The present study confirms that TQ caused cell cycle arrest at different phases and induced apoptosis in both cell lines. A systematic review of rodent animal models was also carried out. Overall, our data seem to represent the most robust results, suggesting that TQ possesses promising therapeutic potential as an anti-tumor agent for the treatment of hepatocellular carcinoma and cholangiocarcinoma. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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14 pages, 1911 KiB

Open AccessArticle

Predicting the Recurrence of Gastric Cancer Using the Textural Features of Perigastric Adipose Tissue on [¹⁸F]FDG PET/CT

by Hyein Ahn, Geum Jong Song, Si-Hyong Jang, Myoung Won Son, Hyun Ju Lee, Moon-Soo Lee, Ji-Hye Lee, Mee-Hye Oh, Geum Cheol Jeong, Jong Hyuk Yun, Sang Mi Lee and Jeong Won Lee

Int. J. Mol. Sci. 2022, 23(19), 11985; https://doi.org/10.3390/ijms231911985 - 09 Oct 2022

Cited by 4 | Viewed by 1474

Abstract

This study aimed to assess the relationship between the histopathological and textural features of perigastric adipose tissue (AT) on 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) and to evaluate the prognostic significance of perigastric AT textural features in predicting [...] Read more.

This study aimed to assess the relationship between the histopathological and textural features of perigastric adipose tissue (AT) on 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) and to evaluate the prognostic significance of perigastric AT textural features in predicting recurrence-free survival (RFS) in patients with gastric cancer. Sixty-nine patients with gastric cancer who underwent staging [¹⁸F]FDG PET/CT and subsequent curative surgery were retrospectively reviewed. Textural features of perigastric AT were extracted from PET images. On histopathological analysis, CD4, CD8, and CD163 cell infiltration and matrix metalloproteinase-11 and interleukin-6 (IL-6) expression in perigastric AT were graded. The degree of CD163 cell infiltration in perigastric AT was significantly correlated with the mean standardized uptake value (SUV), SUV histogram entropy, grey-level co-occurrence matrix (GLCM) energy, and GLCM entropy of perigastric AT. The degree of IL-6 expression in the perigastric AT was significantly correlated with the mean and median SUVs of perigastric AT. In multivariate survival analysis, GLCM entropy, GLCM dissimilarity, and GLCM homogeneity of perigastric AT were significant predictors of RFS. The textural features of perigastric AT on [¹⁸F]FDG PET/CT significantly correlated with inflammatory response in perigastric AT and were significant prognostic factors for predicting RFS in patients with gastric cancer. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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13 pages, 1484 KiB

Open AccessArticle

Association of Hypomagnesemia and Liver Injury, Role of Gut-Barrier Dysfunction and Inflammation: Efficacy of Abstinence, and 2-Week Medical Management in Alcohol Use Disorder Patients

by Evan J. Winrich, Khushboo S. Gala, Abhas Rajhans, Christian D. Rios-Perez, Amor J. Royer, Zarlakhta Zamani, Ranganathan Parthasarathy, Luis S. Marsano-Obando, Ashutosh J. Barve, Melanie L. Schwandt and Vatsalya Vatsalya

Int. J. Mol. Sci. 2022, 23(19), 11332; https://doi.org/10.3390/ijms231911332 - 26 Sep 2022

Cited by 3 | Viewed by 1646

Abstract

(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking [...] Read more.

(1) We investigated the involvement of serum magnesium level in early alcoholic liver disease (ALD), gut barrier dysfunction, and inflammation in alcohol use disorder (AUD) patients; and lastly, the efficacy of 2-week abstinence and medical management to alleviate hypomagnesemia. (2) Forty-eight heavy drinking AUD patients (34 males (M)/14 females (F)) participated in this study. Patients were grouped by serum alanine aminotransferase (ALT) level (a marker of liver injury) as group 1 (Group 1 (Gr.1); ALT ≤ 40 U/L, 7M/8F, without any indication of early-stage ALD) and group 2 (Group 2 (Gr.2); ALT > 40 U/L, 27M/6F or early-stage ALD). These patients were sub-divided within each group into patients with normal magnesium (0.85 and more mmol/L) and deficient magnesium (less than 0.85 mmol/L) levels. All participants were assessed at baseline (BL) and received standard medical management for 2 weeks with reassessment at the treatment end (2w). (3) Female participants of this study showed a significantly lower baseline level of magnesium than their male counterparts. Gr.2 patients showed a greater propensity in the necrotic type of liver cell death, who reported higher chronic and recent heavy drinking. Magnesium level improved to the normal range in Gr.2 post-treatment, especially in the hypomagnesemia sub-group (0.77 ± 0.06 mmol/L (BL) vs. 0.85 ± 0.05 mmol/L (2w), p = 0.02). In Gr.2, both apoptotic (K18M30) and necrotic (K18M65) responses were significantly and independently associated with inflammasome activity comprising of LBP (Lipopolysaccharide binding-protein) and TNFα (Tumor necrosis factor -α), along with serum magnesium. (4) In AUD patients with liver injury, 2-week medical management seems to improve magnesium to a normal level. This group exhibited inflammatory activity (LBP and TNFα) contributing to clinically significant hypomagnesemia. In this group, the level of magnesium, along with the unique inflammatory activity, seems to significantly predict apoptotic and necrotic types of hepatocyte death. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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11 pages, 820 KiB

Open AccessArticle

Macrophage Activation Markers Predict Liver-Related Complications in Primary Biliary Cholangitis

by Yukihisa Fujinaga, Tadashi Namisaki, Yuki Tsuji, Junya Suzuki, Koji Murata, Soichi Takeda, Hiroaki Takaya, Takashi Inoue, Ryuichi Noguchi, Yuki Fujimoto, Masahide Enomoto, Norihisa Nishimura, Koh Kitagawa, Kosuke Kaji, Hideto Kawaratani, Takemi Akahane, Akira Mitoro and Hitoshi Yoshiji

Int. J. Mol. Sci. 2022, 23(17), 9814; https://doi.org/10.3390/ijms23179814 - 29 Aug 2022

Cited by 3 | Viewed by 1626

Abstract

Primary biliary cholangitis (PBC) has a wide variation in clinical presentation and course. There is no significant correlation between these symptoms and the disease stage, although patients with more advanced stages generally have more symptoms. It is important to develop biomarkers in order [...] Read more.

Primary biliary cholangitis (PBC) has a wide variation in clinical presentation and course. There is no significant correlation between these symptoms and the disease stage, although patients with more advanced stages generally have more symptoms. It is important to develop biomarkers in order to identify patients with an increased risk of complications and end-stage liver disease. This study investigated surrogate markers for risk estimation of PBC-related complications, including a study population of 77 patients with PBC who underwent liver biopsy and were measured for serum levels of macrophage activation markers, soluble CD163 (sCD163), soluble mannose receptor (sMR), and zonulin. Patients with PBC were divided into symptomatic (Group S, n = 20) and asymptomatic (Group A, n = 57) groups. The correlations of histological stages based on both Scheuer and Nakanuma classifications with the three serum markers were investigated. The Nakanuma classification involves grading for liver fibrosis and bile duct loss. The three biomarkers were assessed for their diagnostic ability to identify patients with PBC having high risk of developing complications. The predictive factors of these complications were examined as well. Group S had significantly higher serum sMR (p = 0.011) and sCD163 (p = 0.048) levels versus Group A. A composite index of sMR and sCD163 measurements had significantly better prediction performance than sCD163 alone (p = 0.012), although not when compared to sMR alone (p = 0.129). Serum sMR was an independent factor for developing complications on both univariate (Odds ratio (OR) = 30.20, 95% confidence interval (95% CI): 3.410–267.0, p = 0.00220), and multivariate (OR = 33.70, 95% CI: 3.6600–311.0, p = 0.0019) analyses. Patients with PBC having sMR of ≥56.6 had a higher incidence of clinical complications versus those with a sMR of <56.6. Serum sMR predicts the development of complications in patients with PBC. sMR plus sCD163 showed better predictive power than either marker alone, although the addition of sCD163 did not improve the predictive power of sMR. Future prospective studies are required in order to validate the findings of the present study. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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20 pages, 10299 KiB

Open AccessArticle

Chemokine CXCL10 Modulates the Tumor Microenvironment of Fibrosis-Associated Hepatocellular Carcinoma

by Elisa F. Brandt, Maike Baues, Theresa H. Wirtz, Jan-Niklas May, Petra Fischer, Anika Beckers, Björn-Carsten Schüre, Hacer Sahin, Christian Trautwein, Twan Lammers and Marie-Luise Berres

Int. J. Mol. Sci. 2022, 23(15), 8112; https://doi.org/10.3390/ijms23158112 - 23 Jul 2022

Cited by 5 | Viewed by 2691

Abstract

Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping [...] Read more.

Hepatocellular carcinoma (HCC) constitutes a devastating health burden. Recently, tumor microenvironment-directed interventions have profoundly changed the landscape of HCC therapy. In the present study, the function of the chemokine CXCL10 during fibrosis-associated hepatocarcinogenesis was analyzed with specific focus on its impact in shaping the tumor microenvironment. C57BL/6J wild type (WT) and Cxcl10 knockout mice (Cxcl10^−/−) were treated with diethylnitrosamine (DEN) and tetrachloromethane (CCl₄) to induce fibrosis-associated HCCs. Cxcl10 deficiency attenuated hepatocarcinogenesis by decreasing tumor cell proliferation as well as tumor vascularization and modulated tumor-associated extracellular matrix composition. Furthermore, the genetic inactivation of Cxcl10 mediated an alteration of the tumor-associated immune response and modified chemokine/chemokine receptor networks. The DEN/CCl₄-treated Cxcl10^−/− mice presented with a pro-inflammatory tumor microenvironment and an accumulation of anti-tumoral immune cells in the tissue. The most striking alteration in the Cxcl10^−/− tumor immune microenvironment was a vast accumulation of anti-tumoral T cells in the invasive tumor margin. In summary, our results demonstrate that CXCL10 exerts a non-redundant impact on several hallmarks of the tumor microenvironment and especially modulates the infiltration of anti-tumorigenic immune cells in HCC. In the era of microenvironment-targeted HCC therapies, interfering with CXCL10 defines a novel asset for further improvement of therapeutic strategies. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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18 pages, 6349 KiB

Open AccessArticle

Deficiency in Inactive Rhomboid Protein2 (iRhom2) Alleviates Alcoholic Liver Fibrosis by Suppressing Inflammation and Oxidative Stress

by Yangwenshu Liu, Qin Kuang, Xianling Dai, Minxia Zhan, Li Zhou, Liancai Zhu and Bochu Wang

Int. J. Mol. Sci. 2022, 23(14), 7701; https://doi.org/10.3390/ijms23147701 - 12 Jul 2022

Cited by 3 | Viewed by 1827

Abstract

Chronic alcohol exposure can lead to liver pathology relating to inflammation and oxidative stress, which are two of the major factors in the incidence of liver fibrosis and even liver cancer. The underlying molecular mechanisms regarding hepatic lesions associated with alcohol are not [...] Read more.

Chronic alcohol exposure can lead to liver pathology relating to inflammation and oxidative stress, which are two of the major factors in the incidence of liver fibrosis and even liver cancer. The underlying molecular mechanisms regarding hepatic lesions associated with alcohol are not fully understood. Considering that the recently identified iRhom2 is a key pathogenic mediator of inflammation, we performed in vitro and in vivo experiments to explore its regulatory role in alcohol-induced liver fibrosis. We found that iRhom2 knockout significantly inhibited alcohol-induced inflammatory responses in vitro, including elevated expressions of inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) and genes associated with inflammatory signaling pathways, such as TACE (tumor necrosis factor-alpha converting enzyme), TNFR1 (tumor necrosis factor receptor 1), and TNFR2, as well as the activation of NF-κB. The in vivo results confirmed that long-term alcohol exposure leads to hepatocyte damage and fibrous accumulation. In this pathological process, the expression of iRhom2 is promoted to activate the TACE/NF-κB signaling pathway, leading to inflammatory responses. Furthermore, the deletion of iRhom2 blocks the TACE/NF-κB signaling pathway and reduces liver damage and fibrosis caused by alcohol. Additionally, the activation of the JNK/Nrf2/HO-1 signaling pathway caused by alcohol exposure was also noted in vitro and in vivo. In the same way, knockout or deleting iRhom2 blocked the JNK/Nrf2/HO-1 signaling pathway to regulate the oxidative stress. Therefore, we contend that iRhom2 is a key regulator that promotes inflammatory responses and regulates oxidative stress in alcoholic liver fibrosis lesions. We posit that iRhom2 is potentially a new therapeutic target for alcoholic liver fibrosis. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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20 pages, 5887 KiB

Open AccessArticle

Theragnostic Efficacy of K18 Response in Alcohol Use Disorder with Clinically Significant Fibrosis Using Gut-Liver Axis

by Manasa Sagaram, Ranganathan Parthasarathy, Sally L. Condon, Charles F. Closson, Maiying Kong, Melanie L. Schwandt, Loretta L. Jophlin, Wenke Feng, Ashutosh J. Barve and Vatsalya Vatsalya

Int. J. Mol. Sci. 2022, 23(10), 5852; https://doi.org/10.3390/ijms23105852 - 23 May 2022

Cited by 4 | Viewed by 1835

Abstract

(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard [...] Read more.

(1) Background: Fibrosis in early-stage alcohol-associated liver disease (ALD) is commonly under-diagnosed in routine clinical practice. This study characterized the liver-injury and cell death response in alcohol use disorder (AUD) patients with ALD who also exhibited fibrosis and assessed the efficacy of standard of care (SOC) treatment in the improvement in liver injury. (2) Methods: Forty-eight heavy-drinking AUD patients aged 21–65 yrs. without clinical manifestations of liver injury were grouped by Fibrosis-4 (FIB-4) score, as negative (Gr.1 < 1.45, n = 21) or positive (Gr.2 ≥ 1.45, n = 27). Patients received 2-weeks (2 w) inpatient SOC. Data on demographics, drinking patterns, liver-injury, immune markers, and liver cell death (K18s) markers were analyzed at baseline (BL) and after 2 w SOC. (3) Results: Lifetime drinking (LTDH, yrs.) and acute heavy drinking (Heavy Drinking Days Past 90 Days [HDD90]) markers were significantly higher in Gr.2 vs. Gr.1. BL ALT, AST, AST:ALT and K18M65 were considerably higher in Gr.2. Dysregulated gut dysfunction and elevated immune activity were evident in Gr.2 characterized by TNF-α, IL-8 and LPS levels. After SOC, Gr.2 showed improvement in AST, ALT, AST/ALT ratio; and in the K18M65, K18M30 and K18M65/M30 ratio vs. Gr.1. The true positivity of BL IL-8 response to predict the improvement in K18M65 to normal levels among Gr.2 patients against those who did not have improvement after 2 w SOC was very high (AUROC = 0.830, p = 0.042). (4) Conclusions: Gut dysfunction, elevated cytokine response and necrotic liver cell death were elevated in AUD patients with early-stage ALD. K18 showed promise as a predictive theragnostic factor to differentiate among the AUD patients with early-stage ALD and baseline fibrosis who had improvement in liver injury against those who did not, by the levels of baseline IL-8. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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13 pages, 2767 KiB

Open AccessArticle

Pressure Loading Induces DNA Damage in Human Hepatocyte Line L02 Cells via the ERK1/2–Dicer Signaling Pathway

by Yanping Tang, Yanan Fan, Qing Luo and Guanbin Song

Int. J. Mol. Sci. 2022, 23(10), 5342; https://doi.org/10.3390/ijms23105342 - 10 May 2022

Cited by 2 | Viewed by 1744

Abstract

Alteration of liver tissue mechanical microenvironment is proven to be a key factor for causing hepatocyte injury and even triggering the occurrence of hepatocellular carcinoma; however, the underlying mechanisms involved are not fully understood. In this study, using a customized, pressure-loading device, we [...] Read more.

Alteration of liver tissue mechanical microenvironment is proven to be a key factor for causing hepatocyte injury and even triggering the occurrence of hepatocellular carcinoma; however, the underlying mechanisms involved are not fully understood. In this study, using a customized, pressure-loading device, we assess the effect of pressure loading on DNA damage in human hepatocytes. We show that pressure loading leads to DNA damage and S-phase arresting in the cell cycle, and activates the DNA damage response in hepatocytes. Meanwhile, pressure loading upregulates Dicer expression, and its silencing exacerbates pressure-induced DNA damage. Moreover, pressure loading also activates ERK1/2 signaling molecules. Blockage of ERK1/2 signaling inhibits pressure-upregulated Dicer expression and exacerbates DNA damage by suppressing DNA damage response in hepatocytes. Our findings demonstrate that compressive stress loading induces hepatocyte DNA damage through the ERK1/2–Dicer signaling pathway, which provides evidence for a better understanding of the link between the altered mechanical environment and liver diseases. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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16 pages, 1927 KiB

Open AccessArticle

The Involvement of the Endogenous Opioid System in the Gastrointestinal Aging in Mice and Humans

by Agata Szymaszkiewicz, Marcin Talar, Jakub Włodarczyk, Mikołaj Świerczyński, Adrian Bartoszek, Julia Krajewska, Anna Mokrowiecka, Ewa Małecka-Wojciesko, Jakub Fichna and Marta Zielińska

Int. J. Mol. Sci. 2022, 23(7), 3565; https://doi.org/10.3390/ijms23073565 - 24 Mar 2022

Cited by 2 | Viewed by 1976

Abstract

Nearly 20% of elderly patients suffer from constipation, but the age-related changes in the gastrointestinal (GI) tract remain insufficiently elucidated. In this study, the alterations within the endogenous opioid system (EOS) as a potential cause of constipation in the elderly were evaluated. The [...] Read more.

Nearly 20% of elderly patients suffer from constipation, but the age-related changes in the gastrointestinal (GI) tract remain insufficiently elucidated. In this study, the alterations within the endogenous opioid system (EOS) as a potential cause of constipation in the elderly were evaluated. The GI functions were assessed in vitro and in vivo and compared between 6-, 12- and 18-month old mice. Moreover, the effect of opioid receptor (MOP, DOP, KOP) agonists on the mouse GI tract functions and the EOS components expression in mouse tissues and colonic biopsies from patients with functional constipation were determined. In the oldest mice, the GI peristalsis was significantly impaired as compared to the younger groups. The tissue response to MOP and DOP, but not KOP, agonists weakened with age in vitro; for DOP, it was confirmed in vivo. In the mouse upper GI tract, Oprm1, Oprd1, Oprk1 expression decreased with age; in the colon, Oprm1 expression increased. There were no differences in the expression of these genes in the colonic biopsies from patients >50 years old as compared to the younger group. In conclusion, the age-related impairment of the GI peristalsis may result from reduced MOP and DOP response to the activation with opioid agonists or the alterations in the EOS expression. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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Review

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20 pages, 925 KiB

Open AccessReview

MAFLD and Celiac Disease in Children

by Serena Scapaticci, Annamaria Venanzi, Francesco Chiarelli and Cosimo Giannini

Int. J. Mol. Sci. 2023, 24(2), 1764; https://doi.org/10.3390/ijms24021764 - 16 Jan 2023

Cited by 2 | Viewed by 2770

Abstract

Celiac disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten whose clinical presentation ranges from the asymptomatic form to clinical patterns characterized by multiple systemic involvement. Although CD is a disease more frequently diagnosed in patients with symptoms of [...] Read more.

Celiac disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten whose clinical presentation ranges from the asymptomatic form to clinical patterns characterized by multiple systemic involvement. Although CD is a disease more frequently diagnosed in patients with symptoms of malabsorption such as diarrhea, steatorrhea, weight loss, or failure to thrive, the raised rate of overweight and obesity among general pediatric and adult populations has increased the possibility to diagnose celiac disease in obese patients as well. Consequently, it is not difficult to also find obesity-related disorders in patients with CD, including “metabolic associated fatty liver disease” (MAFLD). The exact mechanisms linking these two conditions are not yet known. The going assumption is that a gluten-free diet (GFD) plays a pivotal role in determining an altered metabolic profile because of the elevated content of sugars, proteins, saturated fats, and complex carbohydrates, and the higher glycemic index of gluten-free products than gluten-contained foods, predisposing individuals to the development of insulin resistance. However, recent evidence supports the hypothesis that alterations in one of the components of the so-called “gut–liver axis” might contribute to the increased afflux of toxic substances to the liver triggering the liver fat accumulation and to the subsequent hepatocellular damage. The aim of this paper was to describe the actual knowledge about the factors implicated in the pathogenesis of hepatic steatosis in pediatric patients with CD. The presented review allows us to conclude that the serological evaluations for CD with anti-transglutaminase antibodies, should be a part of the general workup in the asymptomatic patients with “non-alcoholic fatty liver disease” (NAFLD) when metabolic risk factors are not evident, and in the patients with steatohepatitis when other causes of liver disease are excluded. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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12 pages, 288 KiB

Open AccessReview

Mechanosensing in the Physiology and Pathology of the Gastrointestinal Tract

by Job Baffin Kola, Tibor Docsa and Karen Uray

Int. J. Mol. Sci. 2023, 24(1), 177; https://doi.org/10.3390/ijms24010177 - 22 Dec 2022

Cited by 7 | Viewed by 1664

Abstract

Normal gastrointestinal function relies on sensing and transducing mechanical signals into changes in intracellular signaling pathways. Both specialized mechanosensing cells, such as certain enterochromaffin cells and enteric neurons, and non-specialized cells, such as smooth muscle cells, interstitial cells of Cajal, and resident macrophages, [...] Read more.

Normal gastrointestinal function relies on sensing and transducing mechanical signals into changes in intracellular signaling pathways. Both specialized mechanosensing cells, such as certain enterochromaffin cells and enteric neurons, and non-specialized cells, such as smooth muscle cells, interstitial cells of Cajal, and resident macrophages, participate in physiological and pathological responses to mechanical signals in the gastrointestinal tract. We review the role of mechanosensors in the different cell types of the gastrointestinal tract. Then, we provide several examples of the role of mechanotransduction in normal physiology. These examples highlight the fact that, although these responses to mechanical signals have been known for decades, the mechanosensors involved in these responses to mechanical signals are largely unknown. Finally, we discuss several diseases involving the overstimulation or dysregulation of mechanotransductive pathways. Understanding these pathways and identifying the mechanosensors involved in these diseases may facilitate the identification of new drug targets to effectively treat these diseases. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

12 pages, 299 KiB

Open AccessReview

Roles of Keratins in Intestine

by Jeongwon Mun, Whan Hur and Nam-On Ku

Int. J. Mol. Sci. 2022, 23(14), 8051; https://doi.org/10.3390/ijms23148051 - 21 Jul 2022

Cited by 4 | Viewed by 2088

Abstract

Keratins make up a major portion of epithelial intermediate filament proteins. The widely diverse keratins are found in both the small and large intestines. The human intestine mainly expresses keratins 8, 18, 19, and 20. Many of the common roles of keratins are [...] Read more.

Keratins make up a major portion of epithelial intermediate filament proteins. The widely diverse keratins are found in both the small and large intestines. The human intestine mainly expresses keratins 8, 18, 19, and 20. Many of the common roles of keratins are for the integrity and stability of the epithelial cells. The keratins also protect the cells and tissue from stress and are biomarkers for some diseases in the organs. Although an increasing number of studies have been performed regarding keratins, the roles of keratin in the intestine have not yet been fully understood. This review focuses on discussing the roles of keratins in the intestine. Diverse studies utilizing mouse models and samples from patients with intestinal diseases in the search for the association of keratin in intestinal diseases have been summarized. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

16 pages, 682 KiB

Open AccessReview

Biliary Atresia Animal Models: Is the Needle in a Haystack?

by Nutan Pal, Parijat S. Joy and Consolato M. Sergi

Int. J. Mol. Sci. 2022, 23(14), 7838; https://doi.org/10.3390/ijms23147838 - 16 Jul 2022

Cited by 7 | Viewed by 1929

Abstract

Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case [...] Read more.

Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000–20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a “needle in a haystack”. This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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31 pages, 2325 KiB

Open AccessReview

Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic

by Laura Marinela Ailioaie, Constantin Ailioaie, Gerhard Litscher and Dragos Andrei Chiran

Int. J. Mol. Sci. 2022, 23(14), 7719; https://doi.org/10.3390/ijms23147719 - 13 Jul 2022

Cited by 8 | Viewed by 2815

Abstract

Celiac disease (CD) comprises over 1% of the world’s population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection [...] Read more.

Celiac disease (CD) comprises over 1% of the world’s population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection and possible severe forms of COVID-19. A better understanding of the interaction and effects of SARS-CoV-2 infection in CD is very important, as is the role of environmental and genetic factors, but especially the molecular mechanisms involved in modulating intestinal permeability with impact on autoimmunity. CD inspired the testing of a zonulin antagonist for the fulminant form of multisystem inflammatory syndrome in children (MIS-C) and paved the way for the discovery of new molecules to regulate the small intestine barrier function and immune responses. Original published works on COVID-19 and CD, new data and points of view have been analyzed because this dangerous virus SARS-CoV-2 is still here and yet influencing our lives. Medical science continues to focus on all uncertainties triggered by SARS-CoV-2 infection and its consequences, including in CD. Although the COVID-19 pandemic seems to be gradually extinguishing, there is a wealth of information and knowledge gained over the last two years and important life lessons to analyze, as well as relevant conclusions to be drawn to deal with future pandemics. Zonulin is being studied extensively in immunoengineering as an adjuvant to improving the absorption of new drugs and oral vaccines. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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22 pages, 443 KiB

Open AccessReview

The Role of Inflammatory Mediators in the Development of Gastrointestinal Motility Disorders

by Tibor Docsa, Adám Sipos, Charles S. Cox and Karen Uray

Int. J. Mol. Sci. 2022, 23(13), 6917; https://doi.org/10.3390/ijms23136917 - 22 Jun 2022

Cited by 10 | Viewed by 2217

Abstract

Feeding intolerance and the development of ileus is a common complication affecting critically ill, surgical, and trauma patients, resulting in prolonged intensive care unit and hospital stays, increased infectious complications, a higher rate of hospital readmission, and higher medical care costs. Medical treatment [...] Read more.

Feeding intolerance and the development of ileus is a common complication affecting critically ill, surgical, and trauma patients, resulting in prolonged intensive care unit and hospital stays, increased infectious complications, a higher rate of hospital readmission, and higher medical care costs. Medical treatment for ileus is ineffective and many of the available prokinetic drugs have serious side effects that limit their use. Despite the large number of patients affected and the consequences of ileus, little progress has been made in identifying new drug targets for the treatment of ileus. Inflammatory mediators play a critical role in the development of ileus, but surprisingly little is known about the direct effects of inflammatory mediators on cells of the gastrointestinal tract, and many of the studies are conflicting. Understanding the effects of inflammatory cytokines/chemokines on the development of ileus will facilitate the early identification of patients who will develop ileus and the identification of new drug targets to treat ileus. Thus, herein, we review the published literature concerning the effects of inflammatory mediators on gastrointestinal motility. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

17 pages, 863 KiB

Open AccessReview

Pathophysiology of Diverticular Disease: From Diverticula Formation to Symptom Generation

by Maria Raffaella Barbaro, Cesare Cremon, Daniele Fuschi, Giovanni Marasco, Marta Palombo, Vincenzo Stanghellini and Giovanni Barbara

Int. J. Mol. Sci. 2022, 23(12), 6698; https://doi.org/10.3390/ijms23126698 - 15 Jun 2022

Cited by 14 | Viewed by 9377

Abstract

Diverticular disease is a common clinical problem, particularly in industrialized countries. In most cases, colonic diverticula remain asymptomatic throughout life and sometimes are found incidentally during colonic imaging in colorectal cancer screening programs in otherwise healthy subjects. Nonetheless, roughly 25% of patients bearing [...] Read more.

Diverticular disease is a common clinical problem, particularly in industrialized countries. In most cases, colonic diverticula remain asymptomatic throughout life and sometimes are found incidentally during colonic imaging in colorectal cancer screening programs in otherwise healthy subjects. Nonetheless, roughly 25% of patients bearing colonic diverticula develop clinical manifestations. Abdominal symptoms associated with diverticula in the absence of inflammation or complications are termed symptomatic uncomplicated diverticular disease (SUDD). The pathophysiology of diverticular disease as well as the mechanisms involved in the shift from an asymptomatic condition to a symptomatic one is still poorly understood. It is accepted that both genetic factors and environment, as well as intestinal microenvironment alterations, have a role in diverticula development and in the different phenotypic expressions of diverticular disease. In the present review, we will summarize the up-to-date knowledge on the pathophysiology of diverticula and their different clinical setting, including diverticulosis and SUDD. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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32 pages, 2070 KiB

Open AccessReview

Liver Steatosis: A Marker of Metabolic Risk in Children

by Costanza Renata Neri, Serena Scapaticci, Francesco Chiarelli and Cosimo Giannini

Int. J. Mol. Sci. 2022, 23(9), 4822; https://doi.org/10.3390/ijms23094822 - 27 Apr 2022

Cited by 7 | Viewed by 2870

Abstract

Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation [...] Read more.

Obesity is one of the greatest health challenges affecting children of all ages and ethnicities. Almost 19% of children and adolescents worldwide are overweight or obese, with an upward trend in the last decades. These reports imply an increased risk of fat accumulation in hepatic cells leading to a series of histological hepatic damages gathered under the acronym NAFLD (Non-Alcoholic Fatty Liver Disease). Due to the complex dynamics underlying this condition, it has been recently renamed as ‘Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD)’, supporting the hypothesis that hepatic steatosis is a key component of the large group of clinical and laboratory abnormalities of Metabolic Syndrome (MetS). This review aims to share the latest scientific knowledge on MAFLD in children in an attempt to offer novel insights into the complex dynamics underlying this condition, focusing on the novel molecular aspects. Although there is still no treatment with a proven efficacy for this condition, starting from the molecular basis of the disease, MAFLD’s therapeutic landscape is rapidly expanding, and different medications seem to act as modifiers of liver steatosis, inflammation, and fibrosis. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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21 pages, 1272 KiB

Open AccessReview

Role of Microbiota-Derived Metabolites in Alcoholic and Non-Alcoholic Fatty Liver Diseases

by Ji-Won Park, Sung-Eun Kim, Na Young Lee, Jung-Hee Kim, Jang-Han Jung, Myoung-Kuk Jang, Sang-Hoon Park, Myung-Seok Lee, Dong-Joon Kim, Hyoung-Su Kim and Ki Tae Suk

Int. J. Mol. Sci. 2022, 23(1), 426; https://doi.org/10.3390/ijms23010426 - 31 Dec 2021

Cited by 36 | Viewed by 4762

Abstract

Chronic liver disease encompasses diseases that have various causes, such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Gut microbiota dysregulation plays a key role in the pathogenesis of ALD and NAFLD through the gut–liver axis. The gut microbiota consists [...] Read more.

Chronic liver disease encompasses diseases that have various causes, such as alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Gut microbiota dysregulation plays a key role in the pathogenesis of ALD and NAFLD through the gut–liver axis. The gut microbiota consists of various microorganisms that play a role in maintaining the homeostasis of the host and release a wide number of metabolites, including short-chain fatty acids (SCFAs), peptides, and hormones, continually shaping the host’s immunity and metabolism. The integrity of the intestinal mucosal and vascular barriers is crucial to protect liver cells from exposure to harmful metabolites and pathogen-associated molecular pattern molecules. Dysbiosis and increased intestinal permeability may allow the liver to be exposed to abundant harmful metabolites that promote liver inflammation and fibrosis. In this review, we introduce the metabolites and components derived from the gut microbiota and discuss their pathologic effect in the liver alongside recent advances in molecular-based therapeutics and novel mechanistic findings associated with the gut–liver axis in ALD and NAFLD. Full article

(This article belongs to the Special Issue Gut and the Liver in Health and Disease)

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