Inflammasomes in Intestinal Disease: Mechanisms of Activation and Therapeutic Strategies.

NOD-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) implicated in the innate immune sensing of pathogens and damage signals. NLRs act as sensors in multi-protein complexes called inflammasomes. Inflammasome activity is necessary for the maintenance of intestinal homeostasis, although their aberrant activation contributes to the pathogenesis of several gastrointestinal diseases.

An 8-Week Very Low-Calorie Ketogenic Diet (VLCKD) Alters the Landscape of Obese-Derived Small Extracellular Vesicles (sEVs), Redefining Hepatic Cell Phenotypes.

Very low-calorie ketogenic diets (VLCKD) are an effective weight-loss strategy for obese individuals, reducing risks of liver conditions such as non-alcoholic steatohepatitis and fibrosis. Small extracellular vesicles (sEVs) are implicated in liver fibrosis by influencing hepatic cell phenotypes and contributing to liver damage. This study investigates sEVs derived from serum of 60 obese adults categorized into low fibrosis risk (LR) and intermediate/high fibrosis risk (IHR) groups based on FibroScan elastography (FIB E scores, limit value 8 kPa) and all participants underwent an 8-week VLCKD intervention.

The Neoangiogenic Transcriptomic Signature Impacts Hepatocellular Carcinoma Prognosis and Can Be Triggered by Transarterial Chemoembolization Treatment.

: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. : This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates.

Differential Impact of Tumor Endothelial Angiopoietin-2 and Podoplanin in Lymphatic Endothelial Cells on HCC Outcomes with Tyrosine Kinase Inhibitor Treatment According to Sex.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are the only potential treatment option.

Identification of a Novel miR-195-5p/PNN Axis in Colorectal Cancer.

Pinin (PNN) is a desmosome-associated protein that reinforces the organization of keratin intermediate filaments and stabilizes the anchoring of the cytoskeleton network to the lateral surface of the plasma membrane. The aberrant expression of PNN affects the strength of cell adhesion as well as modifies the intracellular signal transduction pathways leading to the onset of CRC. In our previous studies, we characterized the role of miR-195-5p in the regulation of desmosome junctions and in CRC progression.

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases.

Extracellular vesicles (EVs), acting as inherent nanocarriers adept at transporting a range of different biological molecules such as proteins, lipids, and genetic material, exhibit diverse functions within the gastroenteric tract. In states of normal health, they participate in the upkeep of systemic and organ homeostasis. Conversely, in pathological conditions, they significantly contribute to the pathogenesis of gastrointestinal diseases (GIDs).

Downregulation of γ-Catenin by miR-195-5p Inhibits Colon Cancer Progression, Regulating Desmosome Function.

Desmosomes are essential structures for ensuring tissue functions, and their deregulation is involved in the development of colorectal cancer (CRC). JUP (γ-catenin) is a desmosome adhesion component that also acts as a signaling hub, suggesting its potential involvement in CRC progression. In this context, we recently demonstrated that miR-195-5p regulated JUP and desmosome cadherins expression.

miR-195-5p as Regulator of γ-Catenin and Desmosome Junctions in Colorectal Cancer.

Desmosomes play a key role in the regulation of cell adhesion and signaling. Dysregulation of the desmosome complex is associated with the loss of epithelial cell polarity and disorganized tissue architecture typical of colorectal cancer (CRC). The aim of this study was to investigate and characterize the effect of miR-195-5p on desmosomal junction regulation in CRC.

Artificial Intelligence and Complex Network Approaches Reveal Potential Gene Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the number of cases is constantly increasing. Early and accurate HCC diagnosis is crucial to improving the effectiveness of treatment. The aim of the study is to develop a supervised learning framework based on hierarchical community detection and artificial intelligence in order to classify patients and controls using publicly available microarray data.

The oleic/palmitic acid imbalance in exosomes isolated from NAFLD patients induces necroptosis of liver cells via the elongase-6/RIP-1 pathway.

Excessive toxic lipid accumulation in hepatocytes underlies the development of non-alcoholic fatty liver disease (NAFLD), phenotypically characterized by necrosis and steato-fibrosis, whose molecular mechanism is not yet fully understood. Patients with NAFLD display an imbalanced palmitic (PA) to oleic acid (OA) ratio. Moreover, increasing experimental evidence points out a relevant involvement of the exosomal content in disease progression.

miR-369-3p Modulates Intestinal Inflammatory Response via BRCC3/NLRP3 Inflammasome Axis.

Inflammasomes are multiprotein complexes expressed by immune cells in response to distinct stimuli that trigger inflammatory responses and the release of pro-inflammatory cytokines. Evidence suggests a different role of inflammasome NLRP3 in IBD. NLRP3 inflammasome activation can be controlled by post-translational modifications such as ubiquitination through BRCC3.

Autotaxin inhibitor IOA-289 reduces gastrointestinal cancer progression in preclinical models.

Background: Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA stimulates cell proliferation and migration and promotes wound repair following tissue damage. ATX levels are directly correlated with stage and grade in several human cancers.

Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma.

The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-β) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-β-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-β. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells.

Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-β inhibition.

Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of the extracellular (ECM) matrix components. Liver fibroblasts close to the tumor, activated by transforming growth factor (TGF)-β1 and expressing high levels of α-smooth muscle actin (α-SMA), become cancer-associated fibroblasts (CAFs). CAFs are deputed to produce and secrete ECM components and crosstalk with cancer cells favoring tumor progression and resistance to therapy.

A Novel Mechanism of Immunoproteasome Regulation via miR-369-3p in Intestinal Inflammatory Response.

The immunoproteasome is a multi-catalytic protein complex expressed in hematopoietic cells. Increased expression of immuno-subunits followed by increased proteasome activities is associated with the pathogenesis of IBD. Therefore, the identification of molecules that could inhibit the activities of this complex has been widely studied.

Identification of Gene Products Upregulation Marking the Intestinal Epithelial Monolayer of Ulcerative Colitis Patients.

SLC15A4/PHT1 is an endolysosome-resident carrier of oligopeptides and histidine recently come into view as a key path marker of immune/autoimmune/inflammatory pathways in immune cells. Yet, its emerging role in inflammatory processes directly targeting the gastrointestinal epithelial layer, as in the multifactorial pathophysiology of inflammatory bowel disease (IBD), is poorly investigated. Here, the first identification of gene products in human colonic epithelium of ulcerative colitis (UC) patients is reported, showing protein primarily localized in intracellular vesicle-like compartments.

The Increase of miR-195-5p Reduces Intestinal Permeability in Ulcerative Colitis, Modulating Tight Junctions' Expression.

Defects in the intestinal epithelial barrier functions characterize inflammatory conditions such as Inflammatory Bowel Disease (IBD). Overexpression of pro-inflammatory cytokines such as TNF-α, IL-1B, IL-6 and INF-γ trigger epithelial damage. These cytokines are due to upregulation of claudin-2 (CLDN2) that form a pore channel, resulting in redistribution of TJs and an alteration of barrier permeability.

The Tumor Microenvironment Drives Intrahepatic Cholangiocarcinoma Progression.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression.

miR-195-5p Regulates Tight Junctions Expression via Claudin-2 Downregulation in Ulcerative Colitis.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation associated with an increased intestinal permeability. Several studies have shown that microRNAs (miRNAs) are involved in the IBD pathogenesis. Here, we aimed to functionally characterize the role of miRNAs in the regulation of intestinal permeability and barrier function.