scholarly journals The Specific NLRP3 Antagonist IFM-514 Decreases Fibrosis and Inflammation in Experimental Murine Non-Alcoholic Steatohepatitis

2021 ◽  
Vol 8 ◽  
Author(s):  
Sandra Torres ◽  
Maximilian J Brol ◽  
Fernando Magdaleno ◽  
Robert Schierwagen ◽  
Frank E. Uschner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Portal Pressure ◽  
Liver Steatosis ◽  
Inflammatory Cells ◽  
Therapeutic Effects ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Markers Of Inflammation

Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH.Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached.Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.

scholarly journals LncRNA NEAT1/microRNA-129-5p/SOCS2 axis regulates liver fibrosis in alcoholic steatohepatitis

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Junfeng Ye ◽  
Yuanqiang Lin ◽  
Ying Yu ◽  
Di Sun
Keyword(s):  
Liver Fibrosis ◽  
Liver Function ◽  
Inflammatory Factors ◽  
Cytokine Signaling ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Inflammation Reaction

Abstract Background Long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported to play an essential role in non-alcoholic fatty liver disease. However, the role of NEAT1 in regulation of alcoholic steatohepatitis (ASH) remains largely unknown. This study aims to explore the role of NEAT1 in ASH by mediating microRNA-129-5p (miR-129-5p) targeting suppressor of cytokine signaling 2 (SOCS2). Methods NEAT1, miR-129-5p and SOCS2 expression in serum of ASH patients were assessed. In the in vitro cellular experiment, we transfected siRNAs, oligonucleotides or plasmids into ethanol-induced AML-12 mouse hepatocytes to alter NEAT1 and miR-129-5p expression, and inflammatory factors and lipid content were determined. In the in vivo animal experiment, we injected lentiviruses carrying siRNAs, oligonucleotides or plasmids onto ASH mice (ASH induced by feeding mice a Lieber-DeCarli ethanol diet) to alter NEAT1 and miR-129-5p expression through the tail vein. Serum liver function, blood lipids and inflammatory factors were detected; liver histopathology, liver cell apoptosis, and fibrosis were observed. The relationship between NEAT1 and miR-129-5p, or between miR-129-5p and SOCS2 was verified. Results MiR-129-5p was reduced while NEAT1 and SOCS2 were elevated in ASH. Inhibited NEAT1 or elevated miR-129-5p suppressed the elevated lipid metabolism and restrained inflammation reaction in ethanol-stimulated AML-12 cells. The promoted miR-129-5p and inhibited NEAT1 could improve the liver function and repress blood lipid, inflammation reaction, hepatocyte apoptosis and liver fibrosis in ethanol-induced ASH mice. Furthermore, NEAT1 could negatively regulate miR-129-5p to target SOCS2. Conclusion We have found that the inhibited NEAT1 could suppress liver fibrosis in ASH mice by promoting miR-129-5p and restraining SOCS2, thereby decelerating the development of ASH.

scholarly journals Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

2018 ◽  
Author(s):  
Faycal Guedj ◽  
Jeroen LA Pennings ◽  
Ashley E Siegel ◽  
Fatimah Alsebaa ◽  
Lauren J Massingham ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Down Syndrome ◽  
Mouse Model ◽  
Trisomy 21 ◽  
Therapeutic Effects ◽  
Prenatal Treatment ◽  
Wild Type Littermate

ABSTRACTHuman fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. Prenatal diagnosis provides a potential opportunity to begin treatment in utero. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with DS and mouse models we can discover novel targets for therapy. Here, we tested the safety and efficacy of apigenin (4’, 5, 7-trihydroxyflavone), identified using this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. The experiments compared treated to untreated results in T21 and euploid cells, as well as in Ts1Cje mice and their wild-type littermate controls. T21 cells cultured with apigenin (2µM) had significantly reduced oxidative stress and improved antioxidant defense response in vitro. Apigenin (333-400 mg/kg/day), mixed with chow, was initiated prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, with males showing significantly more improvement than females. Global gene expression analyses demonstrated that apigenin targets similar signaling pathways through common upstream regulators both in vitro and in vivo. These studies provide proof-of-principle that apigenin has therapeutic effects in preclinical models of Down syndrome.ONE SENTENCE SUMMARYAs a candidate prenatal treatment for Down syndrome, apigenin improved oxidative stress/antioxidant capacity imbalance and reduced pathways associated with inflammation in human cells while improving aspects of behavior in the Ts1Cje mouse model.

scholarly journals DIPG-14. TARGETING POLO-LIKE KINASE 1 IN COMBINATION WITH KEY ONCOGENIC DRIVERS IN DIPG: FROM SINGLE AGENT TO COMBINATION STRATEGIES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii289-iii289
Author(s):  
Laura Franshaw ◽  
Elisha Hayden ◽  
Swapna Joshi ◽  
Jie Liu ◽  
Anahid Ehteda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Growth ◽  
Single Agent ◽  
Treatment Strategies ◽  
Therapeutic Effects ◽  
Loss Of Function ◽  
Microtubule Organization

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) are devastating paediatric brainstem tumours. Loss of function mutations in DIPG decrease genetic stability and impair DNA damage response pathways promoting tumourigenesis. Polo-like Kinase 1 (PLK1) is a pivotal controller of cell growth, regulating key intermediaries of DNA replication, homologous repair, the cell cycle and cell division. We have found DIPG cultures consistently overexpress PLK1 with inhibition resulting in decreased tumour cell growth, heightened cell cycle arrest and apoptosis. Single agent treatment using PLK1 inhibitors unprecedentedly doubled the median survival of animals harbouring DIPG tumours. Through gene expression analysis, we’ve showed PLK1 inhibition affected multiple pathways which control the cell cycle, cell death regulation, microtubule organization and regulation of cell migration. We found these pathways of differentially expressed genes were significantly enriched for known targets of both E2F1 and E2F4. Analysis of gene expression and proteomic studies also revealed PLK1 inhibition decreased the activation and expression of key tumour promoting mediators within multiple phases of the cell cycle, decreased expression of tumour promoters including MYC and the PI3K/mTOR pathway and reactivated tumour suppressors p53 and PTEN. Assessing these changes in the treated transcriptome and proteome, we aim to develop multiple potentially translatable combination treatment strategies for DIPG. We have performed mechanistic studies and identified synergism with PLK1 inhibitors and the epigenetic regulator panobinostat, bet/bromodomain inhibitor JQ1, dual PI3K/mTOR inhibitor bimiralisib and PI3K inhibitor BKM120. Finally, we found PLK1 inhibitors act as potent radiosensitizers, enhancing the therapeutic effects of radiotherapy in vitro and in vivo.

scholarly journals Physalin A Inhibits MAPK and NF-κB Signal Transduction Through Integrin αVβ3 and Exerts Chondroprotective Effect

2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Lu ◽  
Xiaojun Yu ◽  
Shuang Liang ◽  
Peng Cheng ◽  
Zhenggang Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Integrin Αvβ3 ◽  
The Elderly ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
Anti Inflammatory ◽  
Chondroprotective Effect

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1β-induced chondrocyte inflammation response. Moreover, PA reduced IL-1β-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1β-induced chondrocytes could be reversed when integrin αVβ3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVβ3. Thus, PA or integrin αVβ3 might be a promising agent or molecular target for the treatment of OA.

scholarly journals Ibrutinib as a Potential Therapeutic for Cocaine Use Disorder

2021 ◽  
Author(s):  
Spencer B. Huggett ◽  
Jeffrey S. Hatfield ◽  
Joshua D. Walters ◽  
John E. McGeary ◽  
Justine W. Welsh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Expression Patterns ◽  
Public Health Problem ◽  
Therapeutic Effects ◽  
Cocaine Exposure ◽  
Self Administration ◽  
Cocaine Use

ABSTRACTCocaine use presents a worldwide public health problem with high socioeconomic cost. Current treatments for cocaine use disorder (CUD) are suboptimal and rely primarily on behavioral interventions. To explore pharmaceutical treatments for CUD, we analyzed genome-wide gene expression data from publically availble human brain tissues (midbrain, hippocampus and prefrontal cortex neurons) from 71 individuals (mean age = 39.9, 100% male, 36 with CUD and 35 matched controls). We leveraged the L1000 database to investigate molecular associations between neuronal mRNA profiles from 825 repurposable compounds (e.g., FDA approved) with human CUD gene expression in the brain. We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). We tested the effectiveness of these compounds using independent transcriptome-wide in vitro (neuronal cocaine exposure; n=18) and in vivo (mouse cocaine self-administration; prefrontal cortex, hippocampus and midbrain; n = 12-15) datasets. Among these medications, Ibrutinib demonstrated negative associations with both neuronal cocaine exposure and mouse cocaine self-administration. To obtain experimental confirmation of therapeutic effects of Ibrutinib on CUD, we used the Drosophila melanogaster model, which enables highthroughput quantification of behavioral responses in defined genetic backgrounds and controlled environmental conditions. Ibrutinib altered cocaine-induced changes in startle response and reduced the occurrence of cocaine-induced seizures (n = 61-142 per group; sex: 51%female). Our results identify Ibrutinib, an FDA approved medication, as a potential therapeutic for cocaine neurotoxicity.

scholarly journals Chemokines, Chemokine Receptors, and Renal Disease: From Basic Science To Pathophysiologic and Therapeutic Studies

2000 ◽  
Vol 11 (1) ◽  
pp. 152-176
Author(s):  
STEPHAN SEGERER ◽  
PETER J. NELSON ◽  
DETLEF SCHLÖNDORFF
Keyword(s):  
Chemokine Receptors ◽  
Kidney Diseases ◽  
Inflammatory Cells ◽  
Renal Tissue ◽  
Renal Diseases ◽  
Special Focus ◽  
Therapeutic Effects ◽  
Inflammatory Processes

Abstract. Leukocyte trafficking from peripheral blood into affected tissues is an essential component of the inflammatory reaction to virtually all forms of injury and is an important factor in the development of many kidney diseases. Advances in the past few years have highlighted the central role of a family of chemotactic cytokines called chemokines in this process. Chemokines help to control the selective migration and activation of inflammatory cells into injured renal tissue. Chemokines and their receptors are expressed by intrinsic renal cells as well as by infiltrating cells during renal inflammation. This study summarizes the in vitro and in vivo data on chemokines and chemokine receptors in renal diseases with a special focus on potential therapeutic effects on inflammatory processes.

Fatty Acids and Effects on In Vitro and In Vivo Models of Liver Steatosis

2019 ◽  
Vol 26 (19) ◽  
pp. 3439-3456 ◽  
Author(s):  
Laura Vergani
Keyword(s):  
Fatty Acids ◽  
Animal Models ◽  
Fatty Liver ◽  
Liver Steatosis ◽  
In Vivo Models ◽  
Alcoholic Fatty Liver ◽  
Cellular Models ◽  
Advantages And Disadvantages

Background: Fatty liver, or steatosis, is a condition of excess accumulation of lipids, mainly under form of triglycerides (TG), in the liver, and it is the hallmark of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disorder world-wide and it has frequently been associated with obesity, hyperlipidemia and insulin resistance. Free fatty acids (FA) are the major mediators of hepatic steatosis; patients with NAFLD have elevated levels of circulating FA that correlate with disease severity. Methods: Steatosis is a reversible condition that can be resolved with changed behaviors, or that can progress towards more severe liver damages such as steatohepatitis (NASH), fibrosis and cirrhosis. In NAFLD, FA of exogenous or endogenous origin accumulate in the hepatocytes and trigger liver damages. Excess TG are stored in cytosolic lipid droplets (LDs) that are dynamic organelles acting as hubs for lipid metabolism. Results: In the first part of this review, we briefly reassumed the main classes of FA and their chemical classification as a function of the presence and number of double bonds, their metabolic pathways and effects on human health. Then, we summarized the main genetic and diet-induced animal models of NAFLD, as well as the cellular models of NAFLD. Conclusions: In recent years, both the diet-induced animal models of NAFLD as well as the cellular models of NAFLD have found ever more application to investigate the mechanisms involved in NAFLD, and we referred to their advantages and disadvantages.

scholarly journals The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 933
Author(s):  
Carmine Izzo ◽  
Monica Annunziata ◽  
Giuseppe Melara ◽  
Roberta Sciorio ◽  
Marcello Dallio ◽  
...  
Keyword(s):  
Liver Disease ◽  
Therapeutic Effects ◽  
Alcoholic Fatty Liver ◽  
Liver Disorders ◽  
Liver Protection ◽  
New Treatment ◽  
Alcoholic Fatty Liver Disease

Many studies have shown that resveratrol has a lot of therapeutic effects on liver disorders. Its administration can significantly increase the survival rate after liver transplantation, reduce fat deposition and ischemia-induced necrosis and apoptosis in Wistar rats. Resveratrol can provide Liver protection against chemical, cholestatic, and alcohol-mediated damage. It can improve glucose metabolism and lipid profile, reduce liver fibrosis, and steatosis. Additionally, it is capable of altering the fatty acid composition of the liver cells. Resveratrol may be a potential treatment option for the management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant, and calorie-restricting effects. There are also studies that have evaluated the effect of resveratrol on lipid and liver enzyme profiles among patients with metabolic syndrome (MetS) and related disorders. Based on the extent of liver disease worldwide and the need to find new treatment possibilities, this review critically examines current in vitro and in vivo preclinical studies and human clinical studies related to liver protection.

scholarly journals In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Régis Linhares Oliveira ◽  
Pedro Cesar Chagastelles ◽  
Patrícia Sesterheim ◽  
Patricia Pranke
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Inflammatory Cells ◽  
Therapeutic Effects ◽  
Allogeneic Mscs ◽  
Inflammatory Conditions ◽  
Immunogenic Response

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into cells from the mesenchymal lineage. The hypoimmunogenic characteristic of MSCs has encouraged studies using allogeneic MSCs for the treatment of autoimmune diseases and inflammatory conditions. Promising preclinical results and the safety of allogeneic MSC transplantation have created the possibility of “off-the-shelf” clinical application of allogeneic cells. This study has aimed to evaluate the survival of untreated and IFN-γ- and TNF-α-treated (preactivated) allogeneic MSCs transplanted under the kidney capsule of immunocompetent mice together with the role of preactivated MSCs after cotransplantation with allogeneic islets. The preactivation of MSCs upregulated the gene expression of anti-inflammatory molecules and also enhanced their immunomodulatory capacity in vitro. In vivo, allogeneic MSCs provoked an immunogenic response, with the infiltration of inflammatory cells at the transplant site and full graft rejection in both the untreated and preactivated groups. Allogeneic islets cotransplanted with preactivated MSCs prolonged graft survival for about 6 days, compared with islet alone. The present results corroborate the hypothesis that allogeneic MSCs are not immune-privileged and that after playing their therapeutic role they are rejected. Strategies that reduce allogeneic MSC immunogenicity can potentially prolong their in vivo persistence and improve the therapeutic effects.

scholarly journals Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Tian Shen ◽  
Tao Lei ◽  
Lin Chen ◽  
Bing-Bing Zhu ◽  
Bi-Lin Xu ◽  
...  
Keyword(s):  
Cell Death ◽  
Lipid Accumulation ◽  
Luciferase Reporter ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Alcoholic Fatty Liver ◽  
Caspase 1

Non-alcoholic fatty liver disease (NAFLD)is accompanied by typical inflammatory damage and cell death. As a pro-inflammatory form of cell death, pyroptosis participates in important pathological processes involved in NAFLD. Regulatory roles of both CCCTC-binding factor (CTCF) and dipeptidyl peptidase-4 (DPP4) have been reported in NAFLD, but it is still unclear whether the mechanism of action of gardenoside, a potential therapeutic for NAFLD, can be driven via these proteins. In this study, the direct interaction between CTCF and DPP4 was first confirmed by a dual-luciferase reporter assay system. Then, a cell model of NAFLD was established by induction with palmitic acid (PA) and lipopolysaccharide (LPS). A mouse NAFLD model was established, and the effect of gardenoside on both the cell and mouse models of NAFLD was also investigated. Increased lipid accumulation, NLRP3 inflammasome activation, and hepatocyte pyroptosis were recorded in NAFLD in vitro and in vivo. Gardenoside treatment effectively reduced the lipid accumulation, increased cell viability, reduced reactive oxygen species (ROS) generation, and attenuated pyroptosis and apoptosis in NAFLD in the in vitro and in vivo models. Alterations in these biological processes were evidenced by the decreased expression levels of several pro-pyroptotic markers including the NLR family, pyrin domain-containing 3 (NLRP3), apoptosis-related speckle-like protein (ASC), caspase-1 p20, Gasdermin D N-terminal domain (GSDMD-N), and IL-1β, along with simultaneously decreased CTCF and DPP4 levels. Importantly, CTCF silencing or DPP4 silencing exhibited effects similar to gardenoside treatment, while CTCF overexpression counteracted this trend, which indicated that CTCF might be a target responsible for gardenoside-induced alleviation of NAFLD, such therapeutic effects might be achieved through controlling the expression of the direct target of CTCF (DPP4) and several downstream molecules. In general, the current study provides a promising strategy for NAFLD treatment.

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