Modulation Of Function Research Articles

Generation and characterization of a zebrafish knockout model of abcb4, a homolog of the human multidrug efflux transporter P-glycoprotein

The ATP-binding cassette subfamily B member 1 (ABCB1), encoding a multidrug transporter referred to as P-glycoprotein (Pgp), plays a critical role in the efflux of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. Therefore, developing high-throughput animal models to screen for Pgp function and bioavailability of substrates and inhibitors is paramount. Here, we generated and validated a zebrafish knockout line of abcb4, a human Pgp transporter homolog. CRISPR/Cas9 genome editing technology was deployed to generate a frameshift mutation in exon 4 of zebrafish abcb4. The zebrafish abcb4 homozygous mutant exhibited elevated accumulation of fluorescent rhodamine 123, a substrate of human Pgp, in the intestine and brain area of embryos. Moreover, abcb4 knockout embryos were sensitized toward toxic compounds such as doxorubicin and vinblastine compared to the WT zebrafish. Immunostaining for zebrafish Abcb4 colocalized in the endothelial brain cells of adult zebrafish. Transcriptome profiling using Gene Set Enrichment Analysis uncovered that the 'cell cycle process,' 'mitotic cell cycles,' and 'microtubule-based process' were significantly downregulated in the abcb4 knockout brain with age. This study establishes and validates the abcb4 knockout zebrafish as an animal model to study Pgp function in vivo. Unexpectedly it reveals a potentially novel role for zebrafish abcb4 in age-related changes in the brain. The zebrafish lines generated here will provide a platform to aid in the discovery of modulators of Pgp function as well as the characterization of human mutants thereof.

The Intergeneration Long-Lasting Consequences of Pre-Conceptional Exposure to Sofosbuvir on the Ovarian Tissues of F1 Offspring: Experimental Study on Rats.

Sofosbuvir (SOF), a nucleos(t)ide polymerase inhibitor, has been used during the past decade for mass treatment of viral hepatitis C in endemic countries like Egypt, increasing the exposure of women at childbearing age to SOF. This study investigated the long-lasting consequences of the pre-conceptional exposure of young female rats to SOF on the ovarian tissues of F1 offspring and explored the possible molecular mechanisms of these intergenerational effects at various levels. The study was conducted on young female rats that were divided into control group and SOF-exposed group at a dose of 4 mg/kg/day for three months. After that, pregnancy was induced in both groups by mating with healthy male rats. After delivery, the female neonates were followed for 4 months, and the ovarian tissues were collected to assess the studied parameters. Pre-conceptional exposure to SOF affected the ovarian functions of F1 offspring through modulation of estrogen receptors, ovarian Kiss1 and its receptor, increased lipid peroxidation marker, DNA oxidation marker, and redox-sensitive nuclear factor kappa B, and decreased nuclear erythroid-2-related factor 2, mitochondrial function, and biogenesis. SOF affected the ovarian function of the F1 offspring by inducing oxidative stress and inflammation, leading to the modulation of mitochondrial functions and biogenesis.

Modified Peptide Molecules As Potential Modulators of Shelterin Protein Functions; TRF1.

In this work, we present studies on relatively new and still not well-explored potential anticancer targets which are shelterin proteins, in particular the TRF1 protein can be blocked by in silico designed "peptidomimetic" molecules. TRF1 interacts directly with the TIN2 protein, and this protein-protein interaction is crucial for the proper functioning of telomere, which could be blocked by our novel modified peptide molecules. Our chemotherapeutic approach is based on assumption that modulation of TRF1-TIN2 interaction may be more harmful for cancer cells as cancer telomeres are more fragile than in normal cells. We have shown in vitro within SPR experiments that our modified peptide PEP1 molecule interacts with TRF1, presumably at the site originally occupied by the TIN2 protein. Disturbance of the shelterin complex by studied molecule may not in short term lead to cytotoxic effects, however blocking TRF1-TIN2 resulted in cellular senescence in cellular breast cancer lines used as a cancer model. Thus, our compounds appeared useful as starting model compounds for precise blockage of TRF proteins.

Beta cell primary cilia mediate somatostatin responsiveness via SSTR3

ABSTRACT Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically encoded beta cell-specific GCaMP6f calcium reporter shows that somatostatin signaling alters beta cell calcium flux after physiologic glucose stimulation, an effect that depends on endogenous SSTR3 expression and the presence of intact primary cilia on beta cells. Comparative in vitro studies using SSTR isoform antagonists demonstrate a role for SSTR3 in mediating somatostatin regulation of insulin secretion in mouse islets. Our findings support a model in which ciliary SSTR3 mediates a distinct pathway of delta-to-beta cell regulatory crosstalk and may serve as a target for paracrine modulation.

OS04-03: Gene transfer in differentiated HepaRG™ cells: Application to the modulation of specific hepatocyte functions

OS04-03: Gene transfer in differentiated HepaRG™ cells: Application to the modulation of specific hepatocyte functions

3D Hybrid Segmented Layer Modeling of On-Load Magnetic Fields and Torques for Coreless Axial-Flux Permanent Magnet Synchronous Motor

This paper presents a novel 3-dimensional hybrid segmented layer model (3D HSLM) for coreless axial-flux permanent magnet synchronous motors (AFPMSMs). In the proposed 3D HSLM, the magnetic field sources are divided into the PM array and current-driven electro-magnets, which are captured by the combination of the magnetic scalar potential and vector potential models. This paper proposes a geometry function and cylindrical harmonic index modulation functions in order to correctly capture the curvature effect by the PMs and coils with arbitrary shapes and also the radial edge effect from the finite lengths of the rotor and the stator. The proposed modeling method also enables accurate estimation of the motor characteristics on the on-load conditions using the magnetic vector potential model. The fidelity of the proposed 3D HSLM is validated against the equivalent FEM models for various cases with different PM and coil shapes, in terms of the airgap magnetic fields, motor torque, and flux linkage. The comparison results show that the proposed 3D HSLM yields a modeling accuracy of more than 98% while significantly reducing the calculation time by two orders of magnitude as compared to the FEM models.

Modulation of Human Dendritic Cell Functions by Phosphodiesterase-4 Inhibitors: Potential Relevance for the Treatment of Respiratory Diseases.

Inhibitors of phosphodiesterase-4 (PDE4) are small-molecule drugs that, by increasing the intracellular levels of cAMP in immune cells, elicit a broad spectrum of anti-inflammatory effects. As such, PDE4 inhibitors are actively studied as therapeutic options in a variety of human diseases characterized by an underlying inflammatory pathogenesis. Dendritic cells (DCs) are checkpoints of the inflammatory and immune responses, being responsible for both activation and dampening depending on their activation status. This review shows evidence that PDE4 inhibitors modulate inflammatory DC activation by decreasing the secretion of inflammatory and Th1/Th17-polarizing cytokines, although preserving the expression of costimulatory molecules and the CD4+ T cell-activating potential. In addition, DCs activated in the presence of PDE4 inhibitors induce a preferential Th2 skewing of effector T cells, retain the secretion of Th2-attracting chemokines and increase the production of T cell regulatory mediators, such as IDO1, TSP-1, VEGF-A and Amphiregulin. Finally, PDE4 inhibitors selectively induce the expression of the surface molecule CD141/Thrombomodulin/BDCA-3. The result of such fine-tuning is immunomodulatory DCs that are distinct from those induced by classical anti-inflammatory drugs, such as corticosteroids. The possible implications for the treatment of respiratory disorders (such as COPD, asthma and COVID-19) by PDE4 inhibitors will be discussed.

Emotional state as a modulator of autonomic and somatic nervous system activity in postural control: a review.

Advances in our understanding of postural control have highlighted the need to examine the influence of higher brain centers in the modulation of this complex function. There is strong evidence of a link between emotional state, autonomic nervous system (ANS) activity and somatic nervous system (somatic NS) activity in postural control. For example, relationships have been demonstrated between postural threat, anxiety, fear of falling, balance confidence, and physiological arousal. Behaviorally, increased arousal has been associated with changes in velocity and amplitude of postural sway during quiet standing. The potential links between ANS and somatic NS, observed in control of posture, are associated with shared neuroanatomical connections within the central nervous system (CNS). The influence of emotional state on postural control likely reflects the important influence the limbic system has on these ANS/somatic NS control networks. This narrative review will highlight several examples of behaviors which routinely require coordination between the ANS and somatic NS, highlighting the importance of the neurofunctional link between these systems. Furthermore, we will extend beyond the more historical focus on threat models and examine how disordered/altered emotional state and ANS processing may influence postural control and assessment. Finally, this paper will discuss studies that have been important in uncovering the modulatory effect of emotional state on postural control including links that may inform our understanding of disordered control, such as that observed in individuals living with Parkinson's disease and discuss methodological tools that have the potential to advance understanding of this complex relationship.

Beauvericin Immunotoxicity Prevention by Gentiana lutea L. Flower In Vitro.

Beauvericin (BEA) is an emerging mycotoxin produced by some species of Fusarium genera that widely contaminates food and feed. Gentiana lutea is a protected medicinal plant known for its antioxidant and anti-inflammatory properties, which are attributed to its rich content of bioactive compounds. In order to evaluate the beneficial effects of G. lutea flower against BEA cytotoxicity, the aim of this study is to evaluate changes in protein expression after Jurkat cell exposure through a proteomics approach. To carry out the experiment, cells were exposed to intestinally digested G. lutea flower alone or in combination with the BEA standard (100 nM) over 7 days. Differentially expressed proteins were statistically evaluated (p < 0.05), revealing a total of 172 proteins with respect to the control in cells exposed to the BEA standard, 145 proteins for G. lutea alone, and 139 proteins when exposing the cells to the combined exposure. Bioinformatic analysis revealed processes implicated in mitochondria, ATP-related activity, and RNA binding. After careful analysis of differentially expressed proteins, it was evident that G. lutea attenuated, in most cases, the negative effects of BEA. Furthermore, it decreased the presence of major oncoproteins involved in the modulation of immune function.

Expression of circadian regulatory genes is dysregulated by increased cytokine production in mice subjected to concomitant intestinal injury and parenteral nutrition.

We have developed a mouse model of Parenteral Nutrition Associated Cholestasis (PNAC) in which combining intestinal inflammation and PN infusion results in cholestasis, hepatic macrophage activation, and transcriptional suppression of bile acid and sterol signaling and transport. In the liver, the master circadian gene regulators Bmal/Arntl and Clock drive circadian modulation of hepatic functions, including bile acid synthesis. Once activated, Bmal and Clock are downregulated by several transcription factors including Reverbα (Nr1d1), Dbp (Dbp), Dec1/2 (Bhlhe40/41), Cry1/2 (Cry1/2) and Per1/2 (Per1/2). The aim of this study was to examine the effects of PN on expression of hepatic circadian rhythm (CR) regulatory genes in mice. WT, IL1KO or TNFRKO mice were exposed to dextran sulfate sodium (DSS) for 4 days followed by soy-oil lipid emulsion-based PN infusion through a central venous catheter for 14 days (DSS-PN) and the expression of key CR regulatory transcription factors evaluated. Animals were NPO on a 14 hr light-dark cycle and were administered PN continuously over 24 hrs. Mice were sacrificed, and hepatic tissue obtained at 9-10AM (Zeitgeber Z+3/Z+4 hrs). PNAC was defined by increased serum aspartate aminotransferase, alanine aminotransferase, total bile acids, and total bilirubin and the effect of i.p. injection of recombinant IL-1β (200ng/mouse) or TNFα (200ng/mouse) on CR expression was examined after 4 hrs. In the PNAC model, DSS-PN increased serum biomarkers of hepatic injury (ALT, AST, serum bile acids) which was suppressed in both DSS-PN IL1KO and DSS-PN TNFRKO mice. In WT DSS-PN, mRNA expression of Arntl and Dec1 was suppressed corresponding to increased Nr1d1, Per2, Dbp and Dec2. These effects were ameliorated in both DSS-PN IL1KO and DSS-PN TNFRKO groups. Western analysis of the circadian transcription factor network revealed in WT mice DSS-PN significantly suppressed Reverbα, Bmal, Dbp, Per2 and Mtnr1b. With the exception of Dbp, DSS-PN mediated suppression was ameliorated by both IL1KO and TNFRKO. Intraperitoneal injection of IL-1β or TNFα into WT mice increased serum AST and ALT and suppressed mRNA expression of Nr1d1, Arntl and Clock and increased Dbp and Per2. Altered expression of CR-dependent regulatory genes during PNAC accompanies cholestasis and is, in part, due to increased cytokine (IL-1β and TNFα) production. Evaluation of the effects of modulating CR in PNAC thus deserves further investigation.

Porous Metal-Organic Frameworks for Light Hydrocarbon Separation.

The separation of light hydrocarbon compounds is an important process in the chemical industry. Currently, its separation methods mainly include distillation, membrane separation, and physical adsorption. However, these traditional methods or materials have some drawbacks and disadvantages, such as expensive equipment costs and high energy consumption, poor selectivity, low separation ratios, and separation efficiencies. Therefore, it is important to develop novel separation materials for light hydrocarbon separation. As a new type of organic-inorganic hybrid crystalline material, metal-organic frameworks (MOFs) are promising materials for light hydrocarbon separation due to their designability of structure and easy modulation of function. This review provides an overview of recent advances in the design, synthesis, and application of MOFs for light hydrocarbon separation in recent years, with a focus on the separation of alkane, alkene, and alkyne. We discuss strategies for improving the adsorption selectivity and capacity of MOFs, including pore size limitation, physical adsorption, and chemisorption. In addition, we discuss the advantages/disadvantages, challenges, and prospects of MOFs in the separation of light hydrocarbon.

Physio-Biochemical Integrators and Transcriptome Analysis Reveal Nano-Elicitation Associated Response during Dendrocalamus asper (Schult. and Schult. F.) Backer ex K. Heyne Micropropagation.

Bamboos are perennial, arborescent, monocarpic and industrially important non-timber plants. They are important for various purposes, such as carbon sequestration, biodiversity support, construction, and food and fiber production. However, traditional vegetative propagation is insufficient for bamboo multiplication. Moreover, little is known about the mechanism of gold nanoparticles (AuNPs) in vitro proliferation and regulation of physiological and biochemical properties. In this study, we investigated the impacts of citrate and cetyltrimethylammonium bromide (CTAB) coated AuNPs on in vitro proliferation, photosynthetic pigment content and antioxidant potential of Dendrocalamus asper (Schult. and Schult. F.) Backer ex K. Heyne. Various morpho-physiological and biochemical parameters were differentially affected along the citrate- and CTAB-coated AuNPs concentration gradients (200-600 µM). In vitro shoot proliferation, photosynthetic pigment content and antioxidant activities were higher in D. asper grown on Murashige and Skoog medium supplemented with 2 mg·L-1 benzyladenine and 400 µM citrate-coated AuNPs than in those grown on Murashige and Skoog medium supplemented with 600 µM CTAB- coated AuNPs. Identification of genes regulating in vitro D. asper proliferation will help understand the molecular regulation of AuNPs-mediated elicitation for modulating various physiological and biochemical activities during micropropagation. Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analyses identified differentially expressed genes associated with in vitro modulation of AuNPs-regulated biological processes and molecular functions. The findings of this study provide new insight into AuNPs-mediated elicitation of in vitro mass scale bamboo propagation.

CSF-1R+ Macrophages Control the Gut Microbiome-Enhanced Liver Invariant NKT Function through IL-18.

The gut microbiome is an important modulator of the host immune system. In this study, we found that altering the gut microbiome by oral vancomycin increases liver invariant NKT (iNKT) cell function. Enhanced iNKT cytokine production and activation marker expression were observed in vancomycin-treated mice following both Ag-specific and Ag-independent invivo iNKT stimulations, with a more prominent effect in the liver than in the spleen. Fecal transplantation studies demonstrated that the iNKT functional regulation is mediated by altering the gut microbiome but uncoupled from the modulation of iNKT cell population size. Interestingly, when stimulated invitro, iNKT cells from vancomycin-treated mice did not show increased activation, suggesting an indirect regulation. iNKT cells expressed high levels of IL-18 receptor, and vancomycin increased the expression of IL-18 in the liver. Blocking IL-18 by neutralizing Ab or using genetically deficient mice attenuated the enhanced iNKT activation. Liver macrophages were identified as a major source of IL-18. General macrophage depletion by clodronate abolished this iNKT activation. Using anti-CSF-1R depletion or LyzCrexCSF-1RLsL-DTR mice identified CSF-1R+ macrophages as a critical modulator of iNKT function. Vancomycin treatment had no effect on iNKT cell function invivo in IL-18 knockout macrophage reconstituted mice. Together, our results demonstrate that the gut microbiome controls liver iNKT function via regulating CSF-1R+ macrophages to produce IL-18.

Persistent extrasynaptic hyperdopaminergia in the mouse hippocampus induces plasticity and recognition memory deficits reversed by the atypical antipsychotic sulpiride.

Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.

Malonate induces the browning of white adipose tissue in high-fat diet induced obesity model

Obesity increases the risk of various diseases, and many studies have examined prevention and treatment strategies. Browning of white adipocytes promotes triglyceride (TG) metabolism and is the new focus for treating obesity. This study investigated the role of malonate—a modulator of mitochondrial function—in adipocyte browning, and its potential as a therapeutic agent in obesity. Our findings revealed that malonate increased oxygen consumption without inhibiting ATP synthesis. Malonate induced expression of PRDM16—an important transcription factor for browning—and uncoupling protein 1 (beige adipocyte marker), suggesting that malonate induces browning in white adipocytes. In an obesity mouse model induced by a high-fat diet, malonate significantly reduced body weight and white adipose tissue weight, as well as improved insulin resistance. Importantly, malonate stimulated browning in white adipose tissue and maintained the mass of brown adipose tissue in the high-fat diet-induced obesity mouse model. We propose that manipulation of mitochondrial function by malonate is a promising therapeutic approach for obesity.

Control of tissue homeostasis by the extracellular matrix: Synthetic heparan sulfate as a promising therapeutic for periodontal health and bone regeneration.

Proteoglycans are core proteins associated with carbohydrate/sugar moieties that are highly variable in disaccharide composition, which dictates their function. These carbohydrates are named glycosaminoglycans, and they can be attached to proteoglycans or found free in tissues or on cell surfaces. Glycosaminoglycans such as hyaluronan, chondroitin sulfate, dermatan sulfate, keratan sulfate, and heparin/heparan sulfate have multiple functions including involvement in inflammation, immunity and connective tissue structure, and integrity. Heparan sulfate is a highly sulfated polysaccharide that is abundant in the periodontium including alveolar bone. Recent evidence supports the contention that heparan sulfate is an important player in modulating interactions between damage associated molecular patterns and inflammatory receptors expressed by various cell types. The structure of heparan sulfate is reported to dictate its function, thus, the utilization of a homogenous and structurally defined heparan sulfate polysaccharide for modulation of cell function offers therapeutic potential. Recently, a chemoenzymatic approach was developed to allow production of many structurally defined heparan sulfate carbohydrates. These oligosaccharides have been studied in various pathological inflammatory conditions to better understand their function and their potential application in promoting tissue homeostasis. We have observed that specific size and sulfation patterns can modulate inflammation and promote tissue maintenance including an anabolic effect in alveolar bone. Thus, new evidence provides a strong impetus to explore heparan sulfate as a potential novel therapeutic agent to treat periodontitis, support alveolar bone maintenance, and promote bone formation.

ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis

BackgroundNon-alcoholic Fatty Liver Disease (NAFLD), now better known as Metabolic (Dysfunction)-Associated Fatty Liver Disease (MAFLD) and its progression to Nonalcoholic Steatohepatitis (NASH), more recently referred to as Metabolic (Dysfunction)-Associated Steatohepatitis (MASH) are the most common causes of liver failure and chronic liver damage. The new names emphasize the metabolic involvement both in relation to liver function and pathological features with extrahepatic manifestations. This study aims to explore the role of the immunometabolic enzyme ATP citrate lyase (ACLY), with a critical function in lipogenesis, carbohydrate metabolism, gene expression and inflammation.MethodsACLY function was investigated in TNFα-triggered human hepatocytes and in PBMC-derived macrophages from MASH patients. Evaluation of expression levels was carried out by western blotting and/or RT-qPCR. In the presence or absence of ACLY inhibitors, ROS, lipid peroxidation and GSSG oxidative stress biomarkers were quantified. Chromatin immunoprecipitation (ChIP), transient transfections, immunocytochemistry, histone acetylation quantitation were used to investigate ACLY function in gene expression reprogramming. IL-6 and IL-1β were quantified by Lumit immunoassays.ResultsMechanistically, ACLY inhibition reverted lipid accumulation and oxidative damage while reduced secretion of inflammatory cytokines in TNFα-triggered human hepatocytes. These effects impacted not only on lipid metabolism but also on other crucial features of liver function such as redox status and production of inflammatory mediators. Moreover, ACLY mRNA levels together with those of malic enzyme 1 (ME1) increased in human PBMC-derived macrophages from MASH patients when compared to age-matched healthy controls. Remarkably, a combination of hydroxycitrate (HCA), the natural ACLY inhibitor, with red wine powder (RWP) significantly lowered ACLY and ME1 mRNA amount as well as IL-6 and IL-1β production in macrophages from subjects with MASH.ConclusionCollectively, our findings for the first time highlight a broad spectrum of ACLY functions in liver as well as in the pathogenesis of MASH and its diagnostic and therapeutic potential value.Graphical

Three-dimensional human bile duct formation from chemically induced human liver progenitor cells.

Background: The intrahepatic bile ducts (BDs) play an important role in the modification and transport of bile, and the integration between the BD and hepatocytes is the basis of the liver function. However, the lack of a source of cholangiocytes limits in vitro research. The aim of the present study was to establish three-dimensional BDs combined with human mature hepatocytes (hMHs) in vitro using chemically induced human liver progenitor cells (hCLiPs) derived from hMHs. Methods: In this study, we formed functional BDs from hCLiPs using hepatocyte growth factor and extracellular matrix. BDs expressed the typical biliary markers CK-7, GGT1, CFTR and EpCAM and were able to transport the bile-like substance rhodamine 123 into the lumen. The established three-dimensional BDs were cocultured with hMHs. These cells were able to bind to the BDs, and the bile acid analog CLF was transported from the culture medium through the hMHs and accumulated in the lumen of the BDs. The BDs generated from the hCLiPs showed a BD function and a physiological system (e.g., the transport of bile within the liver) when they were connected to the hMHs. Conclusion: We present a novel in vitro three-dimensional BD combined with hMHs for study, drug screening and the therapeutic modulation of the cholangiocyte function.

The Ion Channels Involved in Oxidative Stress-Related Gastrointestinal Diseases

The pathogenesis of various gastrointestinal (GI) disorders, including gastritis, ulcers, inflammatory bowel disease (IBD) and cancer, can be linked to oxidative stress. It is known that reactive species carry out a crucial role in the genesis and progression of these pathologies; however, the contribution of ionic channels in their development is still under discussion. The function of ion channels in the gastrointestinal tract influences a variety of cellular processes. Acid-base balance, mucus layer, microbiota and mucosal blood flow are only some of the essential features for maintaining the mucosal integrity of the cellular barrier in the intestine, allowing for the preservation of proper permeability and ensuring tissue homeostasis. As the functional modulation of several ion channels is altered during oxidative stress conditions associated with gastrointestinal inflammation, this review focuses on contributing new insight into the roles of and the relationship between ion channels and oxidative stress in GI diseases. The association between ion channels and oxidative stress conditions could be used in diagnostics and the development of new pharmacological treatments for major gastrointestinal diseases.

High-density lipoproteins and non-alcoholic fatty liver disease

Background and aimsNon-alcoholic fatty liver disease (NAFLD), a high incidence liver pathology, is associated with a ∼1.5-fold higher cardiovascular disease risk. This phenomenon is generally attributed to the NAFLD-associated increase in circulating levels of pro-atherogenic apolipoprotein B100-containing small dense low-density lipoprotein and plasma hypertriglyceridemia. However, also a significant reduction in cholesterol transported by anti-atherogenic high-density lipoproteins (HDL) is frequently observed in subjects suffering from NAFLD as compared to unaffected people. In this review, we summarize data regarding the relationship between NAFLD and plasma HDL-cholesterol levels, with a special focus on highlighting potential causality between the NAFLD pathology and changes in HDL metabolism. Methods and resultsPublications in PUBMED describing the relationship between HDL levels and NAFLD susceptibility and/or disease severity, either in human clinical settings or genetically-modified mouse models, were critically reviewed for subsequent inclusion in this manuscript. Furthermore, relevant literature describing effects on lipid loading in cultured hepatocytes of models with genetic alterations related to HDL metabolism have been summarized. ConclusionsAlthough in vitro observations suggest causality between HDL formation by hepatocytes and protection against NAFLD-like lipid accumulation, current literature remains inconclusive on whether relative HDL deficiency is actually driving the development of fatty liver disease in humans. In light of the current obesity pandemic and the associated marked rise in NAFLD incidence, it is of clear scientific and societal interest to gain further insight into the relationship between HDL-cholesterol levels and fatty liver development to potentially uncover the therapeutic potential of pharmacological HDL level and/or function modulation.