scholarly journals RSPO4-CRISPR alleviates liver injury and restores gut microbiota in a rat model of liver fibrosis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Linghua Yu ◽  
Linlin Wang ◽  
Xiaojun Wu ◽  
Huixing Yi
Keyword(s):  
Liver Fibrosis ◽  
Wnt Signaling ◽  
Curative Effect ◽  
Tissue Samples ◽  
Fibrotic Liver ◽  
Rrna Sequencing ◽  
Liver Fibrogenesis ◽  
Underlying Mechanisms ◽  
16 S Rrna

AbstractWnt signaling dysfunction and gut dysbiosis may lead to liver fibrosis, yet the underlying mechanisms are not well elucidated. This study demonstrated the role of RSPO4, a Wnt signaling agonist, in liver fibrogenesis and its impact on the gut microbiome. RSPO4 gene in CCl4-induced fibrotic-liver rats was knockout by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system, with healthy rats served as the control. Tissue samples and hepatic stellate cells (HSCs) isolated from rats were examined for curative effect of RSPO4-CRISPR treatment. Fecal sample were collected and analyzed with 16 S rRNA sequencing. We found RSPO4-CRISPR relieved liver fibrosis in rats and reversed HSC activation. Further, results showed RSPO4-CRISPR tended to restore the microflora composition. Significance species between groups were identified. Bacteroides and Escherichia-Shigella were the key microbes in the model and negative group, whereas Lactobacillus, Romboutsia, and Lachnospiraceae NK4A136 group were abundant in the control. Notably, Bacteroidales S24-7 group and Ruminococcaceae UCG-005 were the significantly enriched in CRISPR group. We show that the microbiome of rats treated with RSPO4-CRISPR presents a trend towards the restoration of the original condition. Our findings pave a new way to evaluate the curative effect of liver fibrosis treatment.

scholarly journals Co-option of the Limb Patterning Program in Cephalopod Lens Development

2021 ◽  
Author(s):  
Stephanie Neal ◽  
Kyle J. McCulloch ◽  
Francesca Napoli ◽  
Christina M. Daly ◽  
James H. Coleman ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Functional Significance ◽  
Limb Development ◽  
Lens Development ◽  
Limb Patterning ◽  
Regulatory Relationship ◽  
Radial Patterning ◽  
Underlying Mechanisms

AbstractAcross the Metazoa, similar genetic programs are found in the development of analogous, independently evolved, morphological features. The functional significance of this reuse and the underlying mechanisms of co-option remain unclear. Here we identify the co-option of the canonical bilaterian limb pattering program redeployed during cephalopod lens development, a functionally unrelated structure. We show radial expression of transcription factorsSP6-9/sp1, Dlx/dll, Pbx/exd, Meis/hth, and aPrdlhomolog in the squidDoryteuthis pealeii, similar to expression required inDrosophilalimb development. We assess the role of Wnt signaling in the cephalopod lens, a positive regulator in the developing limb, and find the regulatory relationship reversed, with ectopic Wnt signaling leading to lens loss. This regulatory divergence suggests that duplication of SP6-9 in cephalopods may mediate this co-option. These results suggest that the limb network does not exclusively pattern appendage outgrowth but is performing a more universal developmental function: radial patterning.

scholarly journals Long Noncoding RNA HOXB-AS1 Is Upregulated in Endometrial Carcinoma and Sponged miR-149-3p to Upregulate Wnt10b

2020 ◽  
Vol 19 ◽  
pp. 153303382096746
Author(s):  
Da Liu ◽  
Min Qiu ◽  
Lili Jiang ◽  
Kuiran Liu
Keyword(s):  
Endometrial Carcinoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Competing Endogenous Rna ◽  
Tissue Samples ◽  
Invasion And Migration ◽  
Underlying Mechanisms ◽  
And Migration ◽  
Oncogenic Function

The functions of Long noncoding RNA (lncRNA) HOXB-AS1 have been investigated in glioblastoma and multiple myeloma. However, the role of lncRNA HOXB-AS1 in endometrial carcinoma (EC) remains largely unknown. This study investigated the underlying mechanisms of the lncRNA HOXB-AS1 on the progression of EC. In this study, We found that HOXB-AS1 expression was significantly upregulated in EC tissue samples and was associated with shorter survival time. Furthermore, upregulation of HOXB-AS1 promoted proliferation, invasion, and migration of EC cell. HOXB-AS1 and Wnt10b directly bound to miR-149-3p. HOXB-AS1 increased the expression of Wnt10b by binding to miR-149-3p. We further verified the upregulation of β-catenin, cyclin D1, and c-myc induced by HOXB-AS1. In conclusion, our results indicated that HOXB-AS1 exerted oncogenic function as competing endogenous RNA (ceRNA) of miR-149-3p to release Wnt10b and activated Wnt/β-catenin pathway.

scholarly journals Co-option of the limb patterning program in cephalopod eye development

BMC Biology ◽  
2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Stephanie Neal ◽  
Kyle J. McCulloch ◽  
Francesca R. Napoli ◽  
Christina M. Daly ◽  
James H. Coleman ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Limb Development ◽  
Lens Development ◽  
Limb Patterning ◽  
Regulatory Relationship ◽  
Radial Patterning ◽  
Refractive Lens ◽  
Underlying Mechanisms ◽  
Novel Structures

Abstract Background Across the Metazoa, similar genetic programs are found in the development of analogous, independently evolved, morphological features. The functional significance of this reuse and the underlying mechanisms of co-option remain unclear. Cephalopods have evolved a highly acute visual system with a cup-shaped retina and a novel refractive lens in the anterior, important for a number of sophisticated behaviors including predation, mating, and camouflage. Almost nothing is known about the molecular-genetics of lens development in the cephalopod. Results Here we identify the co-option of the canonical bilaterian limb patterning program during cephalopod lens development, a functionally unrelated structure. We show radial expression of transcription factors SP6-9/sp1, Dlx/dll, Pbx/exd, Meis/hth, and a Prdl homolog in the squid Doryteuthis pealeii, similar to expression required in Drosophila limb development. We assess the role of Wnt signaling in the cephalopod lens, a positive regulator in the developing Drosophila limb, and find the regulatory relationship reversed, with ectopic Wnt signaling leading to lens loss. Conclusion This regulatory divergence suggests that duplication of SP6-9 in cephalopods may mediate the co-option of the limb patterning program. Thus, our study suggests that this program could perform a more universal developmental function in radial patterning and highlights how canonical genetic programs are repurposed in novel structures.

scholarly journals Inhibition of SIRT2 suppresses hepatic fibrosis

2016 ◽  
Vol 310 (11) ◽  
pp. G1155-G1168 ◽  
Author(s):  
Maribel Arteaga ◽  
Na Shang ◽  
Xianzhong Ding ◽  
Sherri Yong ◽  
Scott J. Cotler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cells ◽  
Histone Deacetylases ◽  
Critical Role ◽  
Stellate Cells ◽  
Novel Strategy ◽  
Underlying Mechanisms

Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.

scholarly journals Hepatic BRD4 Is Upregulated in Liver Fibrosis of Various Etiologies and Positively Correlated to Fibrotic Severity

2021 ◽  
Vol 8 ◽  
Author(s):  
Cichun Wu ◽  
Da Cheng ◽  
Yanghui Peng ◽  
Ying Li ◽  
Chunyan Fu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cellular Localization ◽  
Quantitative Polymerase Chain Reaction ◽  
Critical Role ◽  
Serum Levels ◽  
Healthy Controls ◽  
Fibrotic Liver ◽  
Chemokine Ligand ◽  
Liver Tissues

Bromodomain-containing protein 4 (BRD4) has been implicated to play a regulatory role in fibrogenic gene expression in animal models of liver fibrosis. The potential role of BRD4 in liver fibrosis in humans remains unclear. We sought to investigate the expression and cellular localization of BRD4 in fibrotic liver tissues. Human liver tissues were collected from healthy individuals and patients with liver fibrosis of various etiologies. RNA-seq showed that hepatic BRD4 mRNA was elevated in patients with liver fibrosis compared with that in healthy controls. Subsequent multiple manipulations such as western blotting, real-time quantitative polymerase chain reaction, and dual immunofluorescence analysis confirmed the abnormal elevation of the BRD4 expression in liver fibrosis of various etiologies compared to healthy controls. BRD4 expression was positively correlated with the severity of liver fibrosis, and also correlated with the serum levels of aspartate aminotransferase and total bilirubin. Moreover, the expression of C-X-C motif chemokine ligand 6 (CXCL6), a factor interplayed with BRD4, was increased in hepatic tissues of the patients with liver fibrosis. Its expression level was positively correlated with BRD4 level. BRD4 is up-regulated in liver fibrosis, regardless of etiology, and its increased expression is positively correlated with higher degrees of liver fibrosis. Our data indicate that BRD4 play a critical role in the progress of liver fibrosis, and it holds promise as a potential target for intervention of liver fibrosis.

scholarly journals Modelling Porcine NAFLD by Deletion of Leptin and defining the role of AMPK in hepatic fibrosis

2021 ◽  
Author(s):  
Tan Tan ◽  
Zhiyuan Song ◽  
Runming Wang ◽  
Shuheng Jiang ◽  
Zuoxiang Liang ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver ◽  
Hepatic Fibrosis ◽  
Alcoholic Fatty Liver ◽  
Ampk Signaling ◽  
Stat3 Phosphorylation ◽  
Advanced Liver Fibrosis ◽  
Liver Fibrogenesis

Liver fibrosis occurs during chronic liver disease. Advanced liver fibrosis results in cirrhosis, liver failure and often requires liver transplantation. However, due to the lack of human models, mechanisms underlining the pathogenesis of liver fibrosis remain unclear. Recent studies implicated a central role of deranged lipid metabolism in its pathogenesis. In this study, we generated LEPTIN deficient LEPTIN --//--) pigs using zinc finger nuclease technology to investigate the mechanisms of liver fibrosis associated with obesity . The LEPTIN pigs showed increased body fat and significant insulin resistance by 12 months of age . To resemble non alcoholic fatty liver disease (NAFLD) patients , LEPTIN pig developed the phenotypic features of fatty liver, non alcoholic steatohepatitis ( and hepatic fibrosis with age. Mean while, LEPTIN absence reduced phosphorylation of JAK2 STAT3 and AMPK. The alteration of JAK2 STAT3 enhanced fatty acid β oxidation, whereas inactivation of AMPK le d to mitochondrial autophagy, and both contributed to increased oxidative 2stress in hepatocytes . Although Leptin deletion in the rat liver altered JAK2 STAT3 phosphorylation, it activated the AMPK pathway and prevented liver fibrogenesis i n contrast with the LEPTIN pig. To our knowledge, the LEPTIN pig provides the first model recapitulating the full pathogenesis of NAFLD and its progression toward liver fibrosis . The activity of AMPK signaling pathway suggests a potential target for development of new strategies for the diagnosis and treatment of NAFLD.

scholarly journals Role of the spleen on liver fibrogenesis in experimental liver fibrosis.

Kanzo ◽  
1988 ◽  
Vol 29 (5) ◽  
pp. 703-704 ◽  
Author(s):  
Hiroshi MIYAZAKI ◽  
Hitoshi SATA ◽  
Tomonobu KAWABE ◽  
Sanae OKUYAMA ◽  
Hiroki TAKAHASHI ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Fibrogenesis ◽  
Experimental Liver

scholarly journals Modulation of Liver Inflammation and Fibrosis by Interleukin-37

2021 ◽  
Vol 12 ◽  
Author(s):  
Steffeni Mountford ◽  
Maria Effenberger ◽  
Heidi Noll-Puchta ◽  
Lucas Griessmair ◽  
Andrea Ringleb ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Disease Severity ◽  
Stellate Cells ◽  
Liver Inflammation ◽  
Clinical Cohort ◽  
Duct Ligation ◽  
Early Markers ◽  
Liver Fibrogenesis ◽  
Novel Target

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-β. TGF-β promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-β signaling cascade to modulate liver fibrogenesis.Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity.Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-β-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1β stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis.Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis.

scholarly journals Oncofetal protein CRIPTO regulates wound healing and fibrogenesis in regenerating liver and is associated with the initial stages of cardiac fibrosis

2021 ◽  
Author(s):  
Sofia Karkampouna ◽  
Danny van der Helm ◽  
Bart van Hoek ◽  
Hein W Verspaget ◽  
Marie Jose TH Goumans ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Mouse Models ◽  
Cardiac Fibrosis ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Liver Fibrogenesis ◽  
One Year ◽  
End Stage

Background: Oncofetal protein, Cripto, is silenced during postnatal life and often re-expressed in different neoplastic processes. In the present study we investigated the potential role of Cripto in hepatic and cardiac fibrosis. In this study, the aim was to explore whether Cripto is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of Cripto expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Methods: Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and one year after LT. The expression of Cripto and fibrotic markers (aSMA, collagen I) were determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure and of mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4) were evaluated for Cripto expression and fibrotic markers. Cripto was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for Cripto and fibrotic markers, in three models of heart injury; following myocardial infarction, pressure overload and ex vivo induced fibrosis. Results: Patients with end-stage liver cirrhosis showed elevated Cripto levels in plasma, which had decreased one year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of Cripto in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. Cripto expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, Cripto-positve cells were observed in damaged liver areas around the central vein, which preceded the expression of aSMA-positive stellate cells, i.e. mediators of fibrosis. Whereas in the chronic mouse models the fibrosis and Cripto expression was still present after 11 weeks, in the acute model the liver regenerated and the fibrosis and Cripto expression resolved. In vivo overexpression of Cripto in this model, led to an increase in fibrotic markers while blockage of Cripto secreted function inhibited the extend of fibrotic areas and marker expression (αSMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. Cripto expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction Cripto is upregulated initially in cardiac interstitial cells, followed by expression in αSMA-positive myofibroblasts throughout the infarct area. After the scar formation, Cripto expression decreased concomitantly with the aSMA expression. Temporal expression of Cripto in αSMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis. Furthermore, Cripto expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Conclusion: Our results are indicative for a functional role of Cripto in induction of fibrogenesis and potential applications in antifibrotic treatments and stimulation of tissue regeneration.

14-kDa Phosphohistidine Phosphatase is a Potential Therapeutic Target for Liver Fibrosis

2021 ◽  
Author(s):  
Anjian Xu ◽  
Jichao Zhou ◽  
Yanmeng Li ◽  
Luyao Qiao ◽  
Caicai Jin ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Therapeutic Target ◽  
Early Stage ◽  
Potential Therapeutic Target ◽  
Inflammatory Infiltration ◽  
Fibrotic Liver ◽  
Liver Fibrogenesis ◽  
And Migration ◽  
Lamellipodia Formation

Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14-kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl4-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.

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