Correction: Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS.
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PROVIDER: S-EPMC8674567 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Radiation therapy is the mainstay in the treatment of lung cancer, and lung fibrosis is a radiotherapy-related major side effect that can seriously reduce patient's quality of life. Nevertheless, effective strategies for protecting against radiation therapy-induced fibrosis have not been developed. Hence, we investigated the radioprotective effects and the underlying mechanism of the standardized herbal extract PM014 on radiation-induced lung fibrosis. Ablative radiation dose of 75 Gy was focally delivered to the left lung of mice. We evaluated the effects of PM014 on radiation-induced lung fibrosis in vivo and in an in vitro model. Lung volume and functional changes were evaluated using the micro-CT and flexiVent system. Fibrosis-related molecules were evaluated by immunohistochemistry, western blot, and real-time PCR. A orthotopic lung tumour mouse model was established using LLC1 cells. Irradiated mice treated with PM014 showed a significant improvement in collagen deposition, normal lung volume, and functional lung parameters, and these therapeutic effects were better than those of amifostine. PM104 attenuated radiation-induced increases in NF-κB activity and inhibited radiation-induced p65 translocation, ROS production, DNA damage, and epithelial-mesenchymal transition. PM104 effectively alleviated fibrosis in an irradiated orthotopic mouse lung tumour model while not attenuating the efficacy of the radiation therapy by reduction of the tumour. Standardized herbal extract PM014 may be a potential therapeutic agent that is able to increase the efficacy of radiotherapy by alleviating radiation-induced lung fibrosis.
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Project description:Carcinoma-associated fibroblasts (CAFs) play a key onco-supportive role during prostate cancer (PCa) development and progression. We previously reported that the reactive oxygen species (ROS)-producing enzyme NADPH oxidase 4 (Nox4) is essential for TGF?1-mediated activation of primary prostate human fibroblasts to a CAF-like phenotype. This study aimed to further investigate the functional relevance of prostatic Nox4 and determine whether pharmacological inhibition of stromal Nox4 abrogates paracrine-mediated PCa-relevant processes. RNA in situ hybridization revealed significantly elevated Nox4 mRNA levels predominantly in the peri-tumoral stroma of clinical PCa with intense stromal Nox4 staining adjacent to tumor foci expressing abundant TGF? protein levels. At pharmacologically relevant concentrations, the Nox1/Nox4 inhibitor GKT137831 attenuated ROS production, CAF-associated marker expression and migration of TGF?1-activated but not nonactivated primary human prostate fibroblasts. Similar effects were obtained upon shRNA-mediated silencing of Nox4 but not Nox1 indicating that GKT137831 primarily abrogates TGF?1-driven fibroblast activation via Nox4 inhibition. Moreover, inhibiting stromal Nox4 abrogated the enhanced proliferation and migration of PCa cell lines induced by TGF?1-activated prostate fibroblast conditioned media. These effects were not restricted to recombinant TGF?1 as conditioned media from PCa cell lines endogenously secreting high TGF?1 levels induced fibroblast activation in a stromal Nox4- and TGF? receptor-dependent manner. Importantly, GKT137831 also attenuated PCa cell-driven fibroblast activation. Collectively, these findings suggest the TGF?-Nox4 signaling axis is a key interface to dysregulated reciprocal stromal-epithelial interactions in PCa pathophysiology and provide a strong rationale for further investigating the applicability of Nox4 inhibition as a stromal-targeted approach to complement current PCa treatment modalities.
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Project description:Liver fibrosis is an abnormal proliferation of connective tissue in the liver caused by various pathogenic factors. Chronic liver injury leads to release of inflammatory cytokines and reactive oxygen species (ROS) from damaged hepatocytes, which activates hepatic stellate cells (HSCs) to secrete extracellular matrix proteins, thereby leading to fibrosis. Thus, inhibition of hepatocyte injury and HSC activation, and promotion of apoptosis of activated HSCs are important strategies for prevention of liver fibrosis. In this study, we showed that the germacrone (GER), the main component in the volatile oil of zedoary turmeric, inhibited hepatic fibrosis by regulating multiple signaling pathways. First, GER improved the cell survival rate by inhibiting the production of ROS after hepatocyte injury caused by acetaminophen (APAP). In addition, GER inhibited the activation of HSCs and expression of collagen I by blocking TGF-β/Smad pathway in LX-2 cells. However, when the concentration of GER was higher than 60 μM, it specifically induced HSCs apoptosis by promoting the expression and activation of apoptosis-related proteins, but it had no effect on hepatocytes. Importantly, GER significantly attenuated the methionine- and choline-deficient (MCD) diet-induced liver fibrosis by inhibiting liver injury and the activation of HSCs in vivo. In summary, GER can not only protect hepatocytes by reducing ROS release to avoid the liver injury-induced HSC activation, but also directly inhibit the activation and survival of HSCs by regulating TGF-β/Smad and apoptosis pathways. These results demonstrate that GER can be used as a potential therapeutic drug for the treatment of liver fibrosis.
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Project description:While a higher incidence of lung cancer in subjects with previous tuberculous infection has been reported in epidemiologic data, the mechanism by which previous tuberculosis affects lung cancer remains unclear. We investigated the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo.Heat-killed Mycobacterium tuberculosis-stimulated mesothelial cells augmented the migrationand invasive potential of lung cancer cells in a NOX4-dependent manner. Mice with Mycobacterium bovis bacillus Calmette-Guérin (BCG) pleural infection exhibited increased expression of NOX4 and enhanced malignant potential of lung cancer compared to mice with intrathoracic injection of phosphate-buffered saline. The BCG+ KLN205 (KLN205 cancer cell injection after BCG treatment) NOX4 KO mice group showed reduced tuberculous fibrosis-promoted metastatic potential of lung cancer, increased autophagy, and decreased expression of TGF-β, IL-6, and TNF-α compared to the BCG+KLN205 WT mice group. Finally, NOX4 silencing mitigated the malignant potential of A549 cells that was enhanced by tuberculous pleural effusion and restored autophagy signaling. Our results suggest that the NOX4-autophagy axis regulated by tuberculous fibrosis could result in enhanced tumorigenic potential and that NOX4-P62 might serve as a target for tuberculous fibrosis-induced lung cancer.
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Project description:Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [NOX] enzymes serve several hemostatic and host defense functions in various lung diseases, but the role of NOX4 signaling in tuberculous pleurisy is not well understood. The role of NOX4 signaling in tuberculous pleural fibrosis was studied using invitro pleural mesothelial cell (PMC) experiments and a murine model of Mycobacterium bovis bacillus Calmette⁻Guérin (BCG) pleural infection. The production of NOX4 reactive oxygen species (NOX4⁻ROS) and the epithelial mesenchymal transition (EMT) in PMCs were both induced by heat-killed mycobacterium tuberculosis (HKMT). In cultured PMCs, HKMT-induced collagen-1 synthesis and EMT were blocked by pretreatment with small interfering RNA (siRNA) NOX4. Moreover, NOX4⁻ROS production and subsequent fibrosis were reduced by treatment with losartan and the toll-like receptor 4 (TLR4) inhibitor TAK-242. The HKMT-induced EMT and intracellular ROS production were mediated by NOX4 via the activation of extracellular signal-regulated kinase (ERK) signaling. Finally, in a BCG-induced pleurisy model, recruitment of inflammatory pleural cells, release of inflammatory cytokines, and thickened mesothelial fibrosis were attenuated by SiNOX4 compared to SiCon. Our study identified that HKMT-induced pleural fibrosis is mediated by NOX4⁻ERK⁻ROS via TLR4 and Angiotensin II receptor type1 (AT1R). There results suggest that NOX4 may be a novel therapeutic target for intervention in tuberculous pleural fibrosis.
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Project description:Liver fibrosis is a major endpoint of patients with chronic liver diseases. The molecular mechanisms behind liver fibrosis remain largely unknown. Many studies have indicated the role of microRNA (miRNA) in hepatic tumorigenesis. But the role of miRNA in liver fibrosis is little known. Activated hepatic stellate cells (HSCs) can secret extracellular matrix proteins (ECM) and are the major contributors to liver fibrosis/cirrhosis. Here, a microarray assay of quiescent and transforming growth factor ?1 (TGF-?1) activated HSCs indicated that miR-98 might play a crucial role in liver fibrosis. We found that miR-98 was significantly downregulated in activated HSCs. miR-98 overexpression inhibited HSCs activation. Furthermore, we hypothesized that miR-98 regulated hepatic leukemia factor (HLF) expression by binding to the 3' UTR of its mRNA directly, as evidenced by luciferase reporter assay. HLF overexpression increased HSCs activation by inducing hypoxia inducible factor-1 alpha (HIF-1?) expression, resulting in the activation of TGF-?/Smad2/3 signaling pathway. Besides, low expression of miR-98 was also found in liver tissues from various fibrotic murine models, including carbon tetrachloride (CCl4), bile duct ligation (BDL), and high-fat diet (HFD)-induced liver fibrosis. miR-98 overexpression in vivo by ago-miR-98 injection could attenuate CCl4-, BDL-, and HFD-induced murine hepatic fibrosis. Meanwhile, miR-98 overexpression suppressed HLF expression and reduced fibrosis marker expression. Collectively, our study demonstrates that miR-98 suppress HSCs activation by targeting HLF directly and interacting with HIF-1?/TGF-?/Smad2/3 signaling pathway, which may be an effective therapeutic target for liver fibrosis.
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Project description:Renal fibrosis is the final common pathway of various renal injuries and it leads to chronic kidney disease. Autophagy is a cellular process of degradation of damaged cytoplasmic components and regulates cell death and proliferation. Cellular response during unilateral ureteral obstruction (UUO) is tubular segment specific. Thus the role of autophagy on renal tubulointerstitial fibrosis (TIF) after UUO may be different according to segment of nephron. The role of autophagy during UUO remains unclear especially in distal tubules. In this study, we investigated the role of autophagy in distal tubules on renal TIF using conditional knockout mice in which Atg7 was genetically ablated specifically in distal tubular epithelial cell (TEC). In green fluorescent protein (GFP)-LC3 transgenic mice, GFP-LC3 puncta was highly expressed in distal tubular cells of the obstructed kidneys after UUO. Genetic deletion of Atg7 specifically in distal TEC increased renal tubulointerstial fibrosis and epithelial-mesenchymal transition-like phenotype change after UUO through Smad4-dependent transforming growth factor (TGF)-β pathway. Distal tubule-specific autophagy-deficient mice increased the accumulation of damaged mitochondria and SQSTM1/p62-positive aggregates in the obstructed kidney and resulted in increased expression of NLRP3 inflammasome, interleukin (IL) 1-β and caspase-1. Distal TEC-specific Atg7 deletion enhanced apoptosis of TECs after UUO. In summary, our data showed that autophagy in distal TEC plays a protective role in development of renal tubulointerstial fibrosis through regulating the expression of TGF-β an IL1-β after UUO.
| S-EPMC6349890 | biostudies-literature
Project description:Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of autophagy in the process of LD disappearance, and to further examine the underlying mechanisms in this molecular context. We found that LD disappearance during HSC activation was associated with a coordinate increase in autophagy. Inhibition or depletion of autophagy by Atg5 siRNA impaired LD disappearance of quiescent HSCs, and also restored lipocyte phenotype of activated HSCs. In contrast, induction of autophagy by Atg5 plasmid accelerated LD loss of quiescent HSCs. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of autophagy activation. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented autophagosome generation and autophagic flux during HSC activation. Besides, we found that HSC activation triggered Rab25 overexpression, and promoted the combination of Rab25 and PI3KCIII, which direct autophagy to recognize, wrap and degrade LDs. Down-regulation of Rab25 activity, using Rab25 siRNA, blocked the target recognition of autophagy on LDs, and inhibited LD disappearance of quiescent HSCs. Moreover, the scavenging of excessive ROS could disrupt the interaction between autophagy and Rab25, and increase intracellular lipid content. Overall, these results provide novel implications to reveal the molecular mechanism of LD disappearance during HSC activation, and also identify ROS-Rab25-dependent autophagy as a potential target for the treatment of liver fibrosis.
| S-EPMC5199192 | biostudies-literature
Project description:BackgroundStudies have shown that both NOX4 and RhoA play essential roles in fibrosis and that they regulate each other. In lung fibrosis, NOX4/ROS is located upstream of the RhoA/ROCK1 signaling pathway, and the two molecules are oppositely located in renal fibrosis. Currently, no reports have indicated whether the above mechanisms or other regulatory mechanisms exist in liver fibrosis.ObjectivesTo investigate the effects of the NOX4/ROS and RhoA/ROCK1 signaling pathways on hepatic stellate cell (HSC)-T6 cells, the interaction mechanisms of the two pathways, and the impact of UA on the two pathways to elucidate the role of UA in the reduction of hepatic fibrosis and potential mechanisms of HSC-T6 cell proliferation, migration, and activation.MethodsStable cell lines were constructed using the lentiviral transduction technique. Cell proliferation, apoptosis, migration, and invasion were examined using the MTS, TdT-mediated dUTP nick-end labeling, cell scratch, and Transwell invasion assays, respectively. The DCFH-DA method was used to investigate the ROS levels in each group. RT-qPCR and western blotting techniques were utilized to assess the mRNA and protein expression in each group. CoIP and the Biacore protein interaction analysis systems were used to evaluate protein interactions.ResultsThe NOX4/ROS and RhoA/ROCK1 signaling pathways promoted the proliferation, migration, and activation of HSCs. UA inhibited cell proliferation, migration, and activation by inhibiting the activation of the two signaling pathways, but the mechanism of apoptosis was independent of these two pathways. The NOX4/ROS pathway was upstream of and positively regulated the RhoA/ROCK1 pathway in HSCs. No direct interaction between the NOX4 and RhoA proteins was detected.ConclusionThe NOX4/ROS and RhoA/ROCK1 signaling pathways are two critical signaling pathways in a series of behavioral processes in HSCs, and NOX4/ROS regulates RhoA/ROCK1 through an indirect pathway to control the activation of HSCs. Additionally, NOX4/ROS and RhoA/ROCK1 constitute a new target for UA antifibrosis treatment.
| S-EPMC6510285 | biostudies-literature
Project description:FK866 exhibits a protective effect on D-galactosamine (GaIN)/lipopolysaccharide (LPS) and concanavalin A (ConA)-induced acute liver failure (ALF), but the mechanism by which FK866 affords this benefit has not yet been elucidated. Autophagy has a protective effect on acute liver injury. However, the contribution of autophagy to FK866-conferred hepatoprotection is still unclear. This study aimed to investigate whether FK866 could attenuate GaIN/LPS and ConA-induced ALF through c-jun-N-terminal kinase (JNK)-dependent autophagy. In vivo, Mice were pretreated with FK866 at 24, 12, and 0.5?h before treatment with GaIN/LPS and ConA. 3-methyladenine (3MA) or rapamycin were used to determine the role of autophagy in FK866-conferred hepatoprotection. In primary hepatocytes, autophagy was inhibited by 3MA or autophagy-related protein 7 (Atg7) small interfering RNA (siRNA). JNK was suppressed by SP600125 or Jnk siRNA. FK866 alleviated hepatotoxicity and increased autophagy while decreased JNK activation. Suppression of autophagy abolished the FK866-conferred protection. Inhibition of JNK increased autophagy and exhibited strongly protective effect. Collectively, FK866 could ameliorate GaIN/LPS and ConA-induced ALF through induction of autophagy while suppression of JNK. These findings suggest that FK866 acts as a simple and applicable preconditioning intervention to protect against ALF; autophagy and JNK may also provide therapeutic targets for ALF treatment.
| S-EPMC5438370 | biostudies-literature