scholarly journals Coordinated activation of both TGFβ and BMP canonical pathways regulates autophagy and tissue regeneration in acetaminophen induced liver injury

2021 ◽  
Author(s):  
Athanasios Stavropoulos ◽  
Georgios Divolis ◽  
Maria Manioudaki ◽  
Ariana Gavriil ◽  
Ismini Kloukina ◽  
...  
Keyword(s):  
Liver Injury ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Liver Histopathology ◽  
Hepatic Diseases ◽  
Pathway Activation ◽  
Canonical Pathways ◽  
Context Specific ◽  
Tissue Recovery ◽  
Tgfβ Superfamily

Transforming Growth Factor-βs (TGFβs)/Activins and Bone Morphogenetic Proteins (BMPs) have been implicated in numerous aspects of hepatic pathophysiology. However, the way by which hepatocytes integrate and decode the interplay between the TGFβ/Activin and BMP branches in health and disease is still not fully understood. To address this, TGFβ/BMP Smad-responsive double transgenic reporter mice were generated and utilized to map patterns of TGFβ- and/or BMP-pathway activation during acetaminophen-induced liver injury. TGFββ signaling was blocked either pharmacologically or by Smad7 over-expression and the transcriptomes of canonical TGFβ- and/or BMP4-treated hepatospheres and Smad7-treated livers were analyzed to highlight TGFβ-superfamily-regulated pathways and processes. Acetaminophen administration led to dynamically evolving, stage- and context-specific, patterns of hepatic TGFββ/Activin and BMP-reporter expression. TGFβ-superfamily signaling was activated in an autophagy prone zone at the borders between healthy and injured tissue. Inhibition of TGFβ-superfamily signaling attenuated autophagy, exacerbated liver histopathology, and finally led to accelerated tissue-recovery. Hallmarks of this process were the paraptosis-like cell death and the attenuation of immune and reparatory cell responses. Transcriptomic analysis highlighted autophagy as a prominent TGFβ1- and BMP4-regulated process and recognized Trp53inp2 as the top TGFβ-superfamily-regulated autophagy-related gene. Collectively, these findings implicate the coordinated activation of both canonical TGFβ-superfamily signalling branches in balancing autophagic response and tissue-reparatory and -regenerative processes upon acetaminophen-induced hepatotoxicity, highlighting opportunities and putative risks associated with their targeting for treatment of hepatic diseases.

scholarly journals The TGFβ superfamily in cardiac dysfunction

2018 ◽  
Vol 50 (4) ◽  
pp. 323-335 ◽  
Author(s):  
Jian Wu ◽  
Olan Jackson-Weaver ◽  
Jian Xu
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Immune Cells ◽  
Heart Development ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Injury Repair ◽  
Differentiation Factors ◽  
Coronary Endothelial Cells ◽  
Cellular Components ◽  
Tgfβ Superfamily

Abstract TGFβ superfamily includes the transforming growth factor βs (TGFβs), bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and Activin/Inhibin families of ligands. Among the 33 members of TGFβ superfamily ligands, many act on multiple types of cells within the heart, including cardiomyocytes, cardiac fibroblasts/myofibroblasts, coronary endothelial cells, smooth muscle cells, and immune cells (e.g. monocytes/macrophages and neutrophils). In this review, we highlight recent discoveries on TGFβs, BMPs, and GDFs in different cardiac residential cellular components, in association with functional impacts in heart development, injury repair, and dysfunction. Specifically, we will review the roles of TGFβs, BMPs, and GDFs in cardiac hypertrophy, fibrosis, contractility, metabolism, angiogenesis, and regeneration.

scholarly journals TGF-β superfamily expression and actions in the endometrium and placenta

Reproduction ◽  
2006 ◽  
Vol 132 (2) ◽  
pp. 217-232 ◽  
Author(s):  
Rebecca L Jones ◽  
Chelsea Stoikos ◽  
Jock K Findlay ◽  
Lois A Salamonsen
Keyword(s):  
Embryo Development ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Maternal Serum ◽  
Preimplantation Embryos ◽  
Tissue Remodelling ◽  
Hormone Production ◽  
Tgfβ Superfamily

Transforming growth factor β (TGFβ) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFβ superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFβs and activin β subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFβs, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFβ superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFβ and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFβ superfamily members participate in modulating the extent of decidual invasion. Activins and TGFβs have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down’s syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

scholarly journals Target identification of hepatic fibrosis using Pien Tze Huang based on mRNA and lncRNA

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jinhang Zhu ◽  
Di Zhang ◽  
Ting Wang ◽  
Zhiliang Chen ◽  
Luan Chen ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Fibrosis ◽  
Drug Targets ◽  
Enrichment Analysis ◽  
Inflammatory Cells ◽  
Differentially Expressed ◽  
Control Group ◽  
Traditional Chinese Herbal Medicine ◽  
Hepatic Diseases ◽  
Pien Tze Huang

AbstractHepatic fibrosis is a spontaneous wound-healing response triggered by chronic liver injury. Pien Tze Huang (PZH), a traditional Chinese herbal medicine, has been widely used to treat various hepatic diseases in Asia. We used a CCl4-induced mouse model to establish a PZH group of hepatic fibrosis mice treated with PZH and a control group of hepatic fibrosis mice without any treatment. We performed RNA-seq and mass spectrometry sequencing to investigate the mechanism of the PZH response in hepatic fibrosis and identified multiple differentially expressed transcripts (DETs) and proteins (DEPs) that may be drug targets of PZH. Liver functional indices, including serum albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly decreased in the PZH treatment group (P < 0.05) in the eighth week. Hematoxylin–eosin (HE), Masson and Sirius red staining demonstrated that PZH significantly inhibited infiltration of inflammatory cells and collagen deposition. A total of 928 transcripts and 138 proteins were differentially expressed in PZH-treated mice compared to the control group. Gene Ontology (GO) enrichment analysis suggested that PZH may alleviate liver injury and fibrosis by enhancing the immune process. Taken together, our results revealed that multiple DETs and DEPs may serve as drug targets of PZH in hepatic fibrosis patient in future clinical practice.

scholarly journals Granulosal and thecal expression of bone morphogenetic protein- and activin-binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro

Reproduction ◽  
2011 ◽  
Vol 142 (4) ◽  
pp. 581-591 ◽  
Author(s):  
Claire Glister ◽  
Leanne Satchell ◽  
Phil G Knight
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Mrna Level ◽  
Transcript Abundance ◽  
Transforming Growth Factor Β ◽  
Follicle Development ◽  
Mrna Levels ◽  
Theca Interna

Evidence supports local roles for transforming growth factor β superfamily members including activins and bone morphogenetic proteins (BMP) in follicle development. Access of these ligands to signalling receptors is likely modulated by extracellular binding proteins (BP). In this study, we comparedex vivoexpression of four BPs (chordin, gremlin, noggin and follistatin) in granulosal (GC) and theca interna (TC) compartments of developing bovine antral follicles (1–18 mm). Effects of FSH and IGF on BMP and BP expression by cultured GC, and effects of LH and BMPs on BP expression by cultured TC were also examined. Follicular expression of all four BP transcripts was higher in GC than TC compartments (P<0.001) a finding confirmed by immunohistochemistry. Follicle category affected (P<0.01) gremlin and follistatin mRNA abundance, with a significant cell-type×follicle category interaction for chordin, follistatin and noggin. Noggin transcript abundance was lower (P<0.05) in GC of large ‘E-active’ than ‘E-inactive’ follicles while follistatin mRNA level was higher (P<0.01). FSH enhanced CYP19, FSHR, INHBA and follistatin by GC without affecting BMP or BMP–BP expression. IGF increased CYP19 and follistatin, reduced BMP4, noggin and gremlin but did not affect chordin orFSHRmRNA levels. LH increased TC androgen secretion but had no effect on BMP or BP expression. BMPs uniformly suppressed TC androgen production whilst increasing chordin, noggin and gremlin mRNA levels up to 20-fold (P<0.01). These findings support the hypothesis that extracellular BP, mostly from GC, contribute to the regulation of intrafollicular BMP/activin signalling. Enhancement of thecal BP expression by BMP implies an autoregulatory feedback role to prevent excessive signalling.

scholarly journals Calcium/Cobalt Alginate Beads as Functional Scaffolds for Cartilage Tissue Engineering

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Stefano Focaroli ◽  
Gabriella Teti ◽  
Viviana Salvatore ◽  
Isabella Orienti ◽  
Mirella Falconi
Keyword(s):  
Tissue Engineering ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Cartilage Tissue Engineering ◽  
Biomechanical Properties ◽  
Alginate Beads ◽  
Cartilage Tissue ◽  
Self Healing ◽  
Tissue Replacement

Articular cartilage is a highly organized tissue with complex biomechanical properties. However, injuries to the cartilage usually lead to numerous health concerns and often culminate in disabling symptoms, due to the poor intrinsic capacity of this tissue for self-healing. Although various approaches are proposed for the regeneration of cartilage, its repair still represents an enormous challenge for orthopedic surgeons. The field of tissue engineering currently offers some of the most promising strategies for cartilage restoration, in which assorted biomaterials and cell-based therapies are combined to develop new therapeutic regimens for tissue replacement. The current study describes thein vitrobehavior of human adipose-derived mesenchymal stem cells (hADSCs) encapsulated within calcium/cobalt (Ca/Co) alginate beads. These novel chondrogenesis-promoting scaffolds take advantage of the synergy between the alginate matrix and Co+2ions, without employing costly growth factors (e.g., transforming growth factor betas (TGF-βs) or bone morphogenetic proteins (BMPs)) to direct hADSC differentiation into cartilage-producing chondrocytes.

scholarly journals Curcumin Decreased Oxidative Stress, Inhibited NF-κB Activation, and Improved Liver Pathology in Ethanol-Induced Liver Injury in Rats

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Suchittra Samuhasaneeto ◽  
Duangporn Thong-Ngam ◽  
Onanong Kulaputana ◽  
Doungsamon Suyasunanont ◽  
Naruemon Klaikeaw
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Early Stage ◽  
Control Group ◽  
Liver Pathology ◽  
Sprague Dawley ◽  
Hepatocyte Apoptosis ◽  
Sod Activity ◽  
Ethanol Group ◽  
Liver Histopathology

To study the mechanism of curcumin-attenuated inflammation and liver pathology in early stage of alcoholic liver disease, female Sprague-Dawley rats were divided into four groups and treated with ethanol or curcumin via an intragastric tube for 4 weeks. A control group treated with distilled water, and an ethanol group was treated with ethanol (7.5 g/kg bw). Treatment groups were fed with ethanol supplemented with curcumin (400 or 1 200 mg/kg bw). The liver histopathology in ethanol group revealed mild-to-moderate steatosis and mild necroinflammation. Hepatic MDA, hepatocyte apoptosis, and NF-κB activation increased significantly in ethanol-treated group when compared with control. Curcumin treatments resulted in improving of liver pathology, decreasing the elevation of hepatic MDA, and inhibition of NF-κB activation. The 400 mg/kg bw of curcumin treatment revealed only a trend of decreased hepatocyte apoptosis. However, the results of SOD activity, PPARγprotein expression showed no difference among the groups. In conclusion, curcumin improved liver histopathology in early stage of ethanol-induced liver injury by reduction of oxidative stress and inhibition of NF-κB activation.

Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling

Gut ◽  
2021 ◽  
pp. gutjnl-2021-325065
Author(s):  
Chen-Ting Hung ◽  
Tung-Hung Su ◽  
Yen-Ting Chen ◽  
Yueh-Feng Wu ◽  
You-Tzung Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Transforming Growth Factor Β1 ◽  
Duct Ligation ◽  
Extracellular Matrix Production ◽  
Matrix Production

Background and objectivesLiver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF.DesignHistological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg, Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses.ResultsTXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice.ConclusionsER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.

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