Autophagy is involved in the activation of hepatic stellate cells (HSCs), which is the key process of liver fibrosis. We reasoned that chloroquine, based on its ability to inhibit autophagy, might exert beneficial effects in liver fibrosis. Liver fibrosis in rats was induced by carbon tetrachloride (CCl 4 ). Rats were divided into three groups, a normal control group (N group), model group (M group), and chloroquine group (CQ group). Liver fibrosis in the rats was evaluated by hematoxyline-eosin (H&E) and Masson staining. The activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) were determined using an automated biochemistry analyzer. Total hepatic hydroxyproline levels were determined with a kit. The expressions of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were detected by immunofluorescence staining, and the expressions of LC3-II and p62 were determined by Western blotting. Compared with N group, M group showed impaired liver function, liver fibrosis, increased hydroxyproline content, up-regulated expressions of α-SMA and TGF-β1, which have been reported to be pro-fibrogenic genes in vivo, and increased autophagy flux as indicated by the accumulation of LC3-II and degradation of p62. These changes were attenuated by chloroquine treatment. Chloroquine exerts beneficial effects in CCl 4 -induced liver fibrosis. The mechanism of action includes inhibition of autophagy pathways and inhibition of activation of HSCs.Key words chloroquine; liver fibrosis; autophagy; hepatic stellate cell Hepatic fibrosis, characterized by excessive scar formation due to overproduction and deposition of the extracellular matrix, is the common response to chronic liver injury, ultimately leading to cirrhosis. This process usually occurs over a long period of time and can lead to organ dysfunction and death. 1)Activation of hepatic stellate cells (HSCs) is considered to play a major role in the occurrence and development of hepatic fibrosis.2) Insights into mechanisms regulating HSC activation are considered as key targets for the treatment of hepatic fibrosis.Autophagy, a highly evolutionarily energy-dependent process implicated as a cell death mechanism, degrades and recycles subcellular organelles.3) During autophagy, the cytoplasmic form LC3-I is processed and recruited to phagophores, where LC3-II is generated by site-specific proteolysis and lipidatio at the C-terminus. Thus this characteristic conversion from endogenous LC3-I to LC3-II can be used to monitor autophagic activity. Recent studies suggest that autophagic flux is increased during HSC activation, and in vitro study have showed that treatment with an autophagy inhibitor partly inhibited HSC activation.4,5) Hence, treatment with an autophagy inhibitor could be a potential new therapeutic strategy for hepatic fibrosis.Chloroquine (CQ), an autophagy inhibitor, is a commonly used therapeutic agent in skin disorders. Growing evidence also suggest that CQ could be useful in fibroblastic d...
Increasing evidence has demonstrated that the heat shock protein 70 (HSP70) gene may be closely associated with tissue fibrosis; however, the association between HSP70 and liver fibrosis remains to be fully elucidated. The present study hypothesized that geranylgeranylacetone (GGA) exerts beneficial effects on liver fibrosis though upregulation of the expression of HSP70. Liver fibrosis was induced in rats using carbon tetrachloride (CCl4). The rats were subsequently divided into three groups: Control group, CCl4 model group and CCl4 model + GGA group. Liver fibrosis in the rats was evaluated using hematoxylin and eosin staining, Masson's trichrome staining and Sirius red staining. The levels of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin were determined using an automated biochemistry analyzer. The levels of total hepatic hydroxyproline were also determined. The expression levels of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) were determined using immunofluorescence staining and western blotting, and the protein expression levels of HSP70 were determined using western blotting. The CCl4-induced rats exhibited liver fibrosis, increased hydroxyproline content, impaired liver function, upregulated expression levels of the α-SMA and TGF-β1 pro-fibrogenic proteins, and increased expression of HSP70, compared with the control group. These changes were attenuated by treatment with GGA. These results demonstrated that GGA exerted beneficial effects in CCl4-induced liver fibrosis via upregulating the expression of HSP70.
Diabetic nephropathy (DKD) is the most common chronic microvascular complication of diabetes. About 20%-40% of diabetics develop DKD, which eventually leads to chronic kidney failure. Although progress has been made in diagnosis and treatment tools, diabetic nephropathy is still a major clinical problem. In recent years, circular RNA (CircRNA) has become a research hotspot. CircRNA is a non-coding RNA formed by covalently closing the 5 'and 3' ends of the precursor RNA. CircRNA has powerful biological functions. CircRNA can regulate the expression of target genes through competitive binding with microRNA, thus playing the biological role of endogenous RNA (CeRNA). Many studies have shown that circRNAs plays an important role in malignant tumors, autoimmune system diseases, coronary heart disease and other diseases. More and more studies have shown that it can also be used as a biomarker of diabetes and diabetic nephropathy. This review summarizes the origin, classification, biogenesis and regulatory mechanisms of circRNAs. In addition, the pathogenesis and clinical significance of circRNAs as competing endogenous RNAs involved in diabetic nephropathy were also introduced. This will help us fully understand the pathological mechanism of diabetic nephropathy and develop new therapeutic targets or treatment options to improve the prognosis of patients with diabetic nephropathy.
As a deacetylase relying on NAD, sirtuin 1 (SIRT1) has been proven to inhibit osteoclastogenesis directly by repressing reactive oxygen species (ROS) production and TRPV1 channel stimulation modulated by TNF-α. MicroRNAs do not have coding functions, but they influence the expression of particular genes after transcription.Nevertheless, the current understanding of the impact of SIRT1 on osteoclastogenesis is insufficient. Our research explored whether and how miRNAs contributed to osteoclast differentiation modulated by SIRT1 in vitro. In osteoclastogenesis induced by RANKL in bone marrow-derived macrophages (BMMs), repression of SIRT1 expression and enhancement of miR-506 expression were discovered. Transfection with an miR-506 inhibitor repressed miR-506 concentration in BMMs treated with RANKL. Additional research revealed that BMMs with repressed miR-506 treated with RANKL displayed phenotypes with suppressed osteoclastogenesis, as demonstrated by TRAP staining, reduced function, decreased expression of osteoclast markers and correlated genes, and reduced multinuclear cell quantity. Bioinformatics prediction outcomes and the dual-luciferase reporter test suggested that miR-506 targeted the SIRT1 3′-UTR for silencing. Decreased miR-506 in BMMs induced by RANKL caused SIRT1 upregulation. Additionally, treatment with EX-527 (SIRT1 repressor) or SIRT1 silencing attenuated repression caused by miR-506 depletion in BMMs treated with RANKL. Furthermore, TNF-α was repressed via miR-506 inhibition but was enhanced following EX-527 incubation as well as SIRT1 depletion.TRPV1 channel stimulation and ROS generation, which was related to osteoclastogenesis, were reduced via miR-506 depletion. miR-506 modulated osteoclastogenesis by targeting SIRT1 expression in part through modulation of the TRPV1 channel, ROS production, and TNF-α. KEYWORDSbone marrow-derived macrophages, miR-506, osteoclastogenesis, reactive oxygen species, sirtuin 1, TNF-α, transient receptor potential vanilloid 1 Shu Yan and Lujie Miao contributed equally to this work and should be considered as equal first coauthors.
Dynamic RNPs (ribonucleoprotein particles) are formed when RNAbinding proteins assemble with RNA. RNP compositions vary depending on the maturation or the functional state of the RNA as well as the cell environment. [1][2][3] All aspects of RNA life, including splicing, transcription, intracellular trafficking, modification, translation, as well as decay, are regulated by RBPs. In turn, RNA can modulate the location or activity of RBPs through a process called "riboregulation." 4 The PRK (protein kinase R) induces autophosphorylation and dimerization of proteins through their binding to double-stranded RNA, which activates the enzyme and is a prime example of riboregulation (Figure 1). 5 RBP dysfunction and dysregulation are correlated to several muscular atrophies and neurological disorder diseases in humans, like amyotrophic lateral sclerosis, 6 cancer, 7 and genetic abnormalities. 8 RBPs are conserved evolutionarily and have a wide distribution in tissues, in line with their common roles concerning housekeeping. In spite of these attributes, alterations or mutations in RBPs responsible for housekeeping can often lead to specific tissue defects.How does this occur? First, RBPs possibly act on their RNA targets or regulatory partners that express tissue specificity. Secondly, RBPs may attach to RNA targets with various specificities and affinities, regulated by modifications in RNA post-translation, their interactions, and local structure or sequence, causing regulatory complex formation to specific cell types. 9-12 Third, attachment of RNA by itself may not always lead to regulatory effects. Even though RBPs are capable of binding hundreds of RNA targets, only some of them are regulated in particular cellular conditions. In RNA regulons, a set of RNAs are coordinated and regulated by a given RBP under the influence of stimuli. 13,14 Finally, the RBPs cause the formation of extensive network structures with their RNA targets and other
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.