scholarly journals MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor

2017 ◽  
Vol 115 (1) ◽  
pp. 180-185 ◽  
Author(s):  
Xing He ◽  
Yue Sun ◽  
Nanhang Lei ◽  
Xiaobin Fan ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Vitamin D ◽  
Hepatic Fibrosis ◽  
Vitamin D Receptor ◽  
Early Stage ◽  
Aberrant Expression ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Ifn Γ ◽  
Fibrotic Diseases ◽  
Sustained Inhibition

Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host miR-351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 in liver tissues using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that miR-351 is negatively regulated by IFN-γ in HSCs during infection. At the early stage of infection, the elevated levels of IFN-γ inhibited the expression of miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre–miR-351. Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases.

scholarly journals Adeno-Associated Virus Serotype 2 Vector–Mediated Reintroduction of microRNA-19b Attenuates Hepatic Fibrosis

2018 ◽  
Vol 29 (6) ◽  
pp. 674-686 ◽  
Author(s):  
Elizabeth Brandon-Warner ◽  
Jennifer H. Benbow ◽  
Jacob H. Swet ◽  
Nicole A. Feilen ◽  
Catherine R. Culberson ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Adeno Associated Virus ◽  
Virus Serotype

METTL3 facilitates hepatic fibrosis progression via m6A-YTHDF2 dependent silencing of GPR161

2021 ◽  
Author(s):  
Xueyin Pan ◽  
Yihui Bi ◽  
Miao Chen ◽  
Zhenzhen Qian ◽  
Ling Wang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Hepatic Fibrosis ◽  
Hedgehog Pathway ◽  
Nuclear Accumulation ◽  
Fibrotic Liver ◽  
Adeno Associated Virus ◽  
Pathway Activation ◽  
Genes Expression ◽  
Virus Serotype

Hepatic fibrosis (HF) is a very common condition seen in millions of patients with various liver diseases. N6-methyladenosine (m6A) plays critical roles in various biological and pathological processes. However, the role of m6A and its main methyltransferase METTL3 in HF remains obscure. Here, we reported that METTL3 expression was elevated in HSCs from CCl4 induced fibrotic liver. METTL3 knockdown in HSCs mediated by recombinant adeno-associated-virus serotype 9 packed short hairpin RNA against METTL3 alleviated liver injury and fibrosis compared to empty carrier group. Mechanistically, the decreased liver fibrosis in CCl4-treated HSC-specific METTL3 knockdown mice was due to the increased GPR161 that is a suppressor of Hedgehog pathway, a well-known pathway to activate in liver injury and regeneration. As expect, GPR161 transferred into HSCs alleviated liver fibrosis and HSC activation. Forced GPR161 expression inhibited Gli3 activated form nuclear accumulation and subsequently suppressed fibrosis-associate gene expression. Conclusion, HSC-specific deletion of METTL3 inhibits liver fibrosis via elevated GPR161 expression, which subsequently suppressed Hedgehog pathway activation and fibrosis-associated genes expression, providing novel therapeutic targets for HF therapy.

scholarly journals The Role of the Vitamin D Receptor in the Pathogenesis, Prognosis, and Treatment of Cutaneous Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Alyssa L. Becker ◽  
Evan L. Carpenter ◽  
Andrzej T. Slominski ◽  
Arup K. Indra
Keyword(s):  
Vitamin D ◽  
Prognostic Marker ◽  
Vitamin D Receptor ◽  
Vitamin D3 ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Treatment Resistance ◽  
Surgical Excision ◽  
1,25 Dihydroxy Vitamin D3

Melanoma is the malignant transformation of melanocytes and represents the most lethal form of skin cancer. While early-stage melanoma localized to the skin can be cured with surgical excision, metastatic melanoma often requires a multi-pronged approach and even then can exhibit treatment resistance. Understanding the molecular mechanisms involved in the pathogenesis of melanoma could lead to novel diagnostic, prognostic, and therapeutic strategies to ultimately decrease morbidity and mortality. One emerging candidate that may have value as both a prognostic marker and in a therapeutic context is the vitamin D receptor (VDR). VDR is a nuclear steroid hormone receptor activated by 1,25 dihydroxy-vitamin D3 [calcitriol, 1,25(OH)2D3]. While 1,25 dihydroxy-vitamin D3 is typically thought of in relation to calcium metabolism, it also plays an important role in cell proliferation, differentiation, programmed-cell death as well as photoprotection. This review discusses the role of VDR in the crosstalk between keratinocytes and melanocytes during melanomagenesis and summarizes the clinical data regarding VDR polymorphisms, VDR as a prognostic marker, and potential uses of vitamin D and its analogs as an adjuvant treatment for melanoma.

scholarly journals Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription

2002 ◽  
Vol 22 (8) ◽  
pp. 2777-2787 ◽  
Author(s):  
Marcos Vidal ◽  
Chilakamarti V. Ramana ◽  
Adriana S. Dusso
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Cross Talk ◽  
Protein Interactions ◽  
Nuclear Accumulation ◽  
Protein Protein Interactions ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Key Enzyme ◽  
Ifn Γ

ABSTRACT The cytokine gamma interferon (IFN-γ) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-γ induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-γ-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-γ and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-γ action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-γ/Stat1-induced transcription. This novel 1,25D-IFN-γ cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.

Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

1990 ◽  
Vol 48 (3) ◽  
pp. 548-549
Author(s):  
T. A. Stewart ◽  
D. Liggitt ◽  
S. Pitts ◽  
L. Martin ◽  
M. Siegel ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Disease Process ◽  
Class Ii ◽  
Class I ◽  
Type I ◽  
Aberrant Expression ◽  
Mhc Molecules ◽  
Endogenous Insulin ◽  
Class Ii Mhc ◽  
Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

Association of vitamin D receptor genotypes with early onset rheumatoid arthritis

2001 ◽  
Vol 28 (1) ◽  
pp. 89-93 ◽  
Author(s):  
J. R. Garcia-Lozano ◽  
M. F. Gonzalez-Escribano ◽  
A. Valenzuela ◽  
A. Garcia ◽  
A. Nunez-Roldan
Keyword(s):  
Rheumatoid Arthritis ◽  
Vitamin D ◽  
Vitamin D Receptor ◽  
Early Onset

803: Interactions Between Ultraviolet Radiation and Polymorphisms in the Vitamin D Receptor Gene Mediate Prostate Cancer Susceptibility

2006 ◽  
Vol 175 (4S) ◽  
pp. 260-260
Author(s):  
Nicholas J. Rukin ◽  
Samuel J. Moon ◽  
Dhaval Bodiwala ◽  
Christopher J. Luscombe ◽  
Mark F. Saxby ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Vitamin D ◽  
Ultraviolet Radiation ◽  
Vitamin D Receptor ◽  
Cancer Susceptibility ◽  
Receptor Gene ◽  
Vitamin D Receptor Gene ◽  
Prostate Cancer Susceptibility
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