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1.
Front Immunol ; 14: 1128543, 2023.
Article in English | MEDLINE | ID: mdl-37275851

ABSTRACT

Current evidence suggests that IL-23, IL-6, and TNF-α play pivotal roles in the pathogenesis of psoriasis. Although it has been established that Sirtuin 3 (SIRT3) mediates the inflammatory process, the underlying mechanisms remain largely unclear. Herein, we substantiated that the inhibition or deletion of SIRT3 increased the acetylation level of spliced form of X-box binding protein 1 (XPB1s), enhancing its transcriptional activity and IL-23a production. Pharmacologically inhibition of XBP1s with MKC8866 downregulated the expression of inflammatory cytokines in SIRT3-inhibited or Sirt3-KO BMDMs stimulated by IMQ. Inhibition or knockdown of SIRT3 could exacerbate psoriasis-like skin inflammation in an imiquimod-induced psoriasis-like mouse model. Besides, a decrease in SIRT3 expression was observed in the macrophages of psoriasis patients, which increased the expression and acetylation level of XBP1s. Overall, we provide compelling evidence of the crucial role of SIRT3 in the IL-23 axis in psoriatic inflammation and novel molecular insights into the anti-inflammatory effects of SIRT3.


Subject(s)
Dermatitis , Psoriasis , Sirtuin 3 , Animals , Mice , Imiquimod/adverse effects , Inflammation , Interleukin-23/metabolism , Macrophages/metabolism , Psoriasis/chemically induced , Psoriasis/drug therapy , Psoriasis/metabolism , Sirtuin 3/metabolism , Toll-Like Receptor 7/metabolism , X-Box Binding Protein 1/genetics
2.
J Invest Dermatol ; 143(6): 954-964, 2023 06.
Article in English | MEDLINE | ID: mdl-36623704

ABSTRACT

Although the anti-inflammatory effect of serum- and glucocorticoid-regulated protein kinase 1 (SGK1) has been established in other diseases, the possible regulatory role of SGK1 in psoriasis and the underlying molecular mechanisms remain largely unknown. In this study, we found that SGK1 expression was decreased in macrophages from patients with psoriasis. Moreover, a specific pharmacological SGK1 inhibitor, EMD638683, significantly enhanced imiquimod-mediated toll-like receptor 7/8 activity and proinflammatory cytokine production in RAW264.7 cells, and this result was confirmed by Sgk1 small interfering RNA. Further mechanistic data showed that SGK1 inhibition increased the phosphorylation of Bruton's agammaglobulinemia tyrosine kinase; moreover, Bruton's agammaglobulinemia tyrosine kinase inhibition abrogated the proinflammatory effects of the SGK1 inhibitor on toll-like receptor 7/8 activation, thereby validating that SGK1 inhibition enhances the toll-like receptor 7/8 pathway by increasing Bruton's agammaglobulinemia tyrosine kinase phosphorylation. In addition, our in vivo results showed that SGK1 inhibition significantly increased the secretion of proinflammatory cytokines, including IL-1ß, IL-6, and TNF-α, and the infiltration of T helper 17 cells in an imiquimod-induced psoriasis mouse model. Altogether, these results show that SGK1 plays a critical role in the pathogenesis of psoriasis by modulating inflammatory responses in skin lesions, indicating that SGK1‒Bruton's agammaglobulinemia tyrosine kinase signaling could be a novel therapeutic target for the control of psoriasis.


Subject(s)
Dermatitis , Psoriasis , Mice , Animals , NF-kappa B/metabolism , Cytokines/metabolism , Imiquimod/therapeutic use , Toll-Like Receptor 7 , Protein Kinases , Glucocorticoids/therapeutic use , Psoriasis/chemically induced , Psoriasis/drug therapy , Psoriasis/pathology
3.
Comb Chem High Throughput Screen ; 26(7): 1400-1413, 2023.
Article in English | MEDLINE | ID: mdl-35993468

ABSTRACT

BACKGROUND: Psoriasis is an immune-mediated skin disorder caused by the proliferation of keratinocytes. Although psoriasis is generally diagnosed based on clinical manifestations, sensitive biomarkers are needed to help diagnose psoriasis early with atypical presentations. MicroRNAs play a functional role in the development of psoriasis, and they are stable and suitable as biomarkers in psoriasis. MATERIAL AND METHODS: The GSE50790 and GSE53552 datasets from the Gene Expression Omnibus (GEO) database were used to identify Differentially Expressed Genes (DEGs) between the control group and the lesional group. DEGs were processed for enrichment analysis to explore the functions, and a Protein-Protein Interaction (PPI) network was constructed to obtain gene clusters. The signalling pathway associated with gene cluster 1 was processed to further identify related genes. Hub genes were obtained through the intersection of cluster 1 and the related genes. Hub genes were used to predict the miRNAs through a gene-miRNA interaction network. The relative expression of miRNAs was measured by qRT-PCR to identify the suitability of miRNAs as biomarkers. RESULTS: Bioinformatics analysis revealed that the chemokine signalling pathway is involved in the development of psoriasis. Five related miRNAs were mined from the datasets, and qRT-PCR showed that hsa-miR-612 (p=0.0015), hsa-miR-3194-5p (p=0.0078) and hsa-miR-4316 (p<0.0001) may be potential biomarkers in psoriasis.


Subject(s)
MicroRNAs , Psoriasis , Humans , Gene Expression Profiling , MicroRNAs/genetics , MicroRNAs/metabolism , Biomarkers , Gene Regulatory Networks , Psoriasis/diagnosis , Psoriasis/genetics , Computational Biology
4.
Clin Hemorheol Microcirc ; 81(4): 305-314, 2022.
Article in English | MEDLINE | ID: mdl-35466929

ABSTRACT

BACKGROUND: Psoriasis is associated with an increased risk for cardiovascular disease (CVD). Methotrexate (MTX) is often used as a first-line system therapy and there is a need to determine its effect on whole blood viscosity (WBV) and plasma viscosity (PV) in psoriasis.METHODSA prospective, single-center, interventional study with a total of 111 psoriatic patients who received MTX therapy from October 22, 2018, to December 28, 2019, and 111 age- and sex-matched healthy controls. Changes in WBV, PV, blood counts, liver and renal function were evaluated.RESULTSPsoriatic patients had significantly higher levels of WBV and relative viscosity (RV) at low shear rate (LSR), erythrocyte aggregation index (EAI), and PV than sex and age-matched healthy controls. PV was positively correlated with erythrocyte sedimentation rate (ESR), ESR was positively correlated with high sensitive C-reactive protein (hCRP). But only hCRP was positively associated with psoriasis area severity index (PASI) score. MTX significantly decreased the levels of PV, ESR, hCRP, and blood pressure (BP) in male patients, and the level of WBV in female patients. CONCLUSION: Sex-specific downregulation of MTX on WBV, PV, hCRP, and BP, indicating that the effect of MTX on the risk of cardiovascular disease was related with sex.


Subject(s)
Cardiovascular Diseases , Psoriasis , Blood Viscosity/physiology , Down-Regulation , Female , Humans , Male , Methotrexate/therapeutic use , Prospective Studies , Psoriasis/drug therapy , Viscosity
6.
Colloids Surf B Biointerfaces ; 199: 111532, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33385822

ABSTRACT

Aggressive inflammation is an important pathological process of secondary injury in acute spinal cord injury (SCI). However, traditional treatments of secondary injury in acute SCI have achieved little success. Novel biomaterials combined with small molecule drugs are considered as a potential treatment for SCI. Baricitinib, a highly selective JAK1/JAK2 inhibitor, can effectively inhibit the JAK2/STAT3 pathway involved in the modulation of inflammation. However, to evaluate Baricitinib's therapeutic effect on SCI remains to be confirmed. In this study, we designed an injectable PLGA-PEG-PLGA thermos-sensitive hydrogel with baricitinib (Bari-P hydrogel) and measured its efficacy, physical and biological properties in vitro. In the SCI rat, Bari-P hydrogel was injected into the injured spinal cord. Neuronal regeneration was evaluated at 3 days and 4 weeks after surgery by determining the inflammatory cytokine levels, behavioral tests, and histological analysis. The hydrogel can gel in the body, disintegrate almost within 72 h and achieve drug release. Baricitinib can effectively inhibit the JAK2/STAT3 pathway of microglia in vitro; while in vivo experiments show that Bari-P hydrogel treatment can inhibit the phosphorylation of JAK2, STAT3 and suppress the production of inflammatory cytokines, and reduces neuronal apoptosis. Histopathological analysis and behavioral tests showed that Bari-P hydrogel reduced neuronal apoptosis in the early stage of injury and later promoted functional recovery. In summary, Bari-P hydrogel reduced neuronal apoptosis and promoted functional recovery in spinal cord injured rats by inhibiting the JAK2-STAT3 pathway and controlling the expression of inflammatory cytokines in the early stages of injury.


Subject(s)
Hydrogels , Spinal Cord Injuries , Animals , Azetidines , Delayed-Action Preparations/therapeutic use , Hydrogels/therapeutic use , Inflammation/drug therapy , Janus Kinase 2 , Purines , Pyrazoles , Rats , Rats, Sprague-Dawley , STAT3 Transcription Factor , Spinal Cord , Spinal Cord Injuries/drug therapy , Sulfonamides
7.
Front Pharmacol ; 12: 795386, 2021.
Article in English | MEDLINE | ID: mdl-35002727

ABSTRACT

Abnormally high expression of aryl hydrocarbon receptor (AhR) has been implicated in dedifferentiation of radioiodine-refractory papillary thyroid cancer (RR-PTC). This study aimed to evaluate the differentiation effect of AhR antagonist in PTC, and to explore the potential mechanism of it. Results showed that AhR antagonists promoted differentiation of PTC, as shown as increase in 125I uptake and Na/I symporter (NIS) expression level. CircRNA microarray in K1 cells treated with StemRegenin 1(SR1) revealed that hsa_circ_0006741 (circSH2B3) was down-regulated in SR1 treated K1 cells. Downregulation of circSH2B3 increased 125I uptake and NIS expression levels. CircSH2B3 acted as an endogenous sponge of hsa-miR-4640-5p and modulated IGF2BP2 expression. IGF2BP2 overexpression induced dedifferentiation of PTC, while silencing IGF2BP2 accelerated differentiation of PTC cells. Rescue studies showed that the dedifferentiation activity of AhR was modulated by the circSH2B3/miR-4640-5p/IGF2BP2 axis. Our findings confirmed for the first time that AhR antagonists promote differentiation of PTC via inhibiting the circSH2B3/miR-4640-5p/IGF2BP2 axis, offering a novel therapeutic approach and a potential marker for differentiation of PTC.

8.
Biomed Res Int ; 2020: 9568976, 2020.
Article in English | MEDLINE | ID: mdl-33274232

ABSTRACT

There is growing evidence that microRNA-148b (miR-148b) can inhibit the growth of malignant cells while sirtuin 7 (SIRT7) may perform its carcinogenic effect by deacetylating H3K18. This study investigated the mechanism of miR-148b/SIRT7 on how it affects the malignant biological behavior of melanoma. It was established that the expression of miR-148b was downregulated in melanoma while that of SIRT7 was upregulated but negatively regulated by miR-148b through binding to the 3'UTR of SIRT7. Ectopic expression of miR-148b reduced the proliferation, migration, and invasion of melanoma cells, but SIRT7 reversed these functions of miR-148b. Moreover, tumor growth and metastasis experiments showed that miR-148b could significantly suppress proliferation and metastasis of melanoma in vivo. Overall, miR-148b inhibits the malignant biological behavior of melanoma by reducing the expression level of SIRT7. The development of miR-148b as a novel potential therapeutic approach for melanoma may be possible in the future.


Subject(s)
Gene Expression Regulation, Neoplastic , Melanoma/genetics , MicroRNAs/metabolism , Sirtuins/genetics , Skin Neoplasms/genetics , 3' Untranslated Regions/genetics , Animals , Base Sequence , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Down-Regulation/genetics , Humans , Melanoma/pathology , Mice, Nude , MicroRNAs/genetics , Neoplasm Invasiveness , Neoplasm Metastasis , Sirtuins/metabolism , Skin Neoplasms/pathology , Up-Regulation/genetics
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