JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 6
·e70372
·
IF 4.2
Wang Huikang,Cao Shiya,Pan Di,Faisal Ayub Kiani,Li Hao,Nan Sha,Lin Xuan,Mahmoud M. Abouelfetouh,Zulfiqar Ahmed,Ding Mingxing,Ding Yi
Neuropathic pain (NP), resulting from nerve damage, is difficult to manage and often requires long-term treatment. However, prolonged use of pain medications can lead to addiction and reduced effectiveness over time. Understanding drug tolerance is essential for developing improved pain management strategies. Dexmedetomidine (DEX) is effective in targeting the α2 -adrenergic receptor, providing relief from pain, especially NP. However, its extended use leads to tolerance and hinders its clinical utility. Herein, we investigated tolerance mechanisms and potential applications of this drug in managing NP. Adult C57BL/6 mice (male) were distributed into DEX Dosage Groups ( n = 48), DEX Tolerance Model Groups ( n = 32), SGK1 Inhibitor GSK650394 Groups ( n = 48), and NF - κB Inhibitor PDTC Groups ( n = 32) to explore dexmedetomidine's effects on NP and tolerance mechanisms. NP was established via selective ligation of the sciatic nerve branch (SNI), followed by administration of DEX. The results revealed a dose-dependent analgesic effect of DEX, with significant increases in pain thresholds observed compared to the sham group ( p < 0.05). Optimal efficacy was found at a dose of 30 μg/kg, indicating its potential as an effective treatment for NP ( p < 0.05). However, continuous administration of DEX over 13 days induced analgesic tolerance, evidenced by an initial increase in pain thresholds followed by a gradual decrease ( p < 0.05). Despite an initial efficacy in elevating pain thresholds, the analgesic effect of DEX diminished over time, returning to pre-dose levels after 5 days ( p < 0.05). Transcriptome sequencing of spinal cord samples from mice receiving multiple DEX injections revealed differential gene expression patterns, notably upregulation of SGK1 , NR2A , and NR2B subunits ( p < 0.05). Inhibiting SGK1 mitigated DEX-induced tolerance, suggesting its involvement in tolerance development ( p < 0.05). Moreover, NF - κB inhibition reversed DEX-induced tolerance and implicated the SGK1 - NF - κB pathway in the mediation of analgesic tolerance. To sum up, these findings revealed the molecular mechanism underlying DEX-induced analgesic tolerance in the NP model and offer potential avenues for future therapeutic interventions.
研究领域:
药理学
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疼痛管理
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Hailin Liu,Lian Zhou,Xifeng Wang,Qingcui Zheng,Fenfang Zhan,Lanqian Zhou,Yao Dong,Yanhong Xiong,Pengcheng Yi,Guohai Xu,Fuzhou Hua
The side effects of high-dose dexamethasone in anti-infection include increased ROS production and immune cell apoptosis. Dexamethasone effectively activates serum/glucocorticoid-regulated kinase 1 (SGK1), which upregulates various ion channels by activating store-operated calcium entry (SOCE), leading to Ca 2+ oscillations. PIEZO1 plays a crucial role in macrophages' immune activity and function, but whether dexamethasone can regulate PIEZO1 by enhancing SOCE via SGK1 activation remains unclear. The effects of dexamethasone were assessed in a mouse model of sepsis, and primary BMDMs and the RAW264.7 were treated with overexpression plasmids, siRNAs, or specific activators or inhibitors to examine the relationships between SGK1, SOCE, and PIEZO1. The functional and phenotypic changes of mouse and macrophage models were detected. The results indicate that high-dose dexamethasone upregulated SGK1 by activating the macrophage glucocorticoid receptor, which enhanced SOCE and subsequently activated PIEZO1. Activation of PIEZO1 resulted in Ca 2+ influx and cytoskeletal remodelling. The increase in intracellular Ca 2+ mediated by PIEZO1 further increased the activation of SGK1 and ORAI1/STIM1, leading to intracellular Ca 2+ peaks. In the context of inflammation, activation of PIEZO1 suppressed the activation of TLR4/NFκB p65 in macrophages. In RAW264.7 cells, PIEZO1 continuous activation inhibited the change in mitochondrial membrane potential, accelerated ROS accumulation, and induced autophagic damage and cell apoptosis in the late stage. CaMK2α was identified as a downstream mediator of TLR4 and PIEZO1, facilitating high-dose dexamethasone-induced macrophage immunosuppression and apoptosis. PIEZO1 is a new glucocorticoid target to regulate macrophage function and activity. This study provides a theoretical basis for the rational use of dexamethasone.
研究领域:
免疫学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Journal of Stomatology Oral and Maxillofacial Surgery
·
2022
·
IF 2.48
Yi Sun,Jianlu Shi,Xiaoan Luo,Xuehong Xu
Objective Human periodontal ligament stem cells (hPDLSCs) refer to one kind of somatic stem cells that are capable of differentiating into multiple cell kinds and undergoing robust clonal self-renewal. This work was unearthed to elucidate the possible molecular mechanism of miR-142–3p in mediating osteogenic differentiation of hPDLSCs by targeting SGK1 . Methods The hPDLSCs were isolated, cultured, and identified. hPDLSCs were identified by immunofluorescence staining and multiple differentiation ability detection. Cell proliferation ability was assessed by CCK-8 assay. hPDLSCs were induced using osteogenic differentiation medium. ALP activity was detected by alkaline phosphatase (ALP) staining and ALP activity assay, and mineralized nodule formation was determined by alizarin red staining. The expression levels of osteogenic differentiation marker proteins ALP, RUNX2, and OCN were measured by RT-qPCR. miR-142–3p candidate targets were obtained through bioinformatics analysis. The relationship between miR-142–3p and SKG1 was verified. Results miR-142–3p in hPDLSCs after osteogenic induction was down-regulated. Elevated miR-142–3p restricted hPDLSCs proliferation, and diminished ALP activity and mineralized nodule formation, as well as the expression of ALP, RUNX2, and OCN, while miR-142–3p inhibition led to inverse results. miR-142-3p inhibited SKG1 expression. SKG1 overexpression promoted hPDLSC proliferation and osteogenic differentiation, and reversed the inhibitory function of miR-142–3p on hPDLSCs. Conclusion This study highlights that miR-142–3p represses osteogenic differentiation of hPDLSCs by reducing SGK1 expression.
研究领域:
干细胞生物学
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分子生物学
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口腔生物学
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PubMed
高影响因子
Chinese Medicine
·
2023
·Vol. 18
·期 1
·1-16
·
IF 4.9
Wang Xiaohu,Shen Chaozhuang,Wang Xingwen,Tang Jin,Wu Zijing,Huang Yunzhe,Shao Wenxin,Geng Kuo,Xie Haitang,Pu Zhichen
Background According to the Chinese Pharmacopoeia, the fruit of Schisandra chinensis (Turcz.) Baill. (SC) is an important traditional Chinese medicine that can be used to treat diarrhea. Despite the increasing research on the anti-inflammatory and anti-oxidant aspects of SC, the studies on the anti-ulcerative colitis of Schisandrin (SCH), the main constituent of SC, are relatively few.Methods The mice used in the study were randomly distributed into 6 groups: control, model, 5-ASA, and SCH (20, 40, 80 mg/kg/d). The mice in the model group were administered 3% (w/v) dextran sulfate sodium (DSS) through drinking water for 7 days, and the various parameters of disease activity index (DAI) such as body weight loss, stool consistency, and gross blood were measured. ELISA was used to detect inflammatory factors, and bioinformatics combined with transcriptome analysis was done to screen and verify relevant targets. 16S rDNA high-throughput sequencing was used to analyze the composition of the gut microbiota(GM), while mass spectrometry was done to analyze the changes in the content of bile acids (BAs) in the intestine.Results Mice treated with SCH experienced significant weight gain, effectively alleviating the severity of colitis, and decreasing the levels of inflammatory factors such as TNF-α, IL-1β, IL-18, IL-6, and other related proteins (NLRP3, Caspase-1, SGK1) in UC mice. Furthermore, the analysis of GM and BAs in mice revealed that SCH increased the relative abundance of Lactobacilli spp, reduced the relative abundance of Bacteroides, and promoted the conversion of primary BAs to secondary BAs. These effects contributed to a significant improvement in the DSS-induced GM imbalance and the maintenance of intestinal homeostasis.Conclusion It seems that there is a close relationship between the SCH mechanism and the regulation of SGK1/NLRP3 pathway and the restoration of GM balance. Therefore, it can be concluded that SCH could be a potential drug for the treatment of UC.
研究领域:
药理学
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免疫学
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胃肠病学
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微生物学
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DOI
PubMed
高影响因子
Journal of Translational Internal Medicine
·
2023
·Vol. 11
·期 3
·294-308
·
IF 4.9
Naiquan Liu,Dongyang Li,Dajun Liu,Ying Liu,Jing Lei
Background
Fos-related antigen 2 ( FOSL2 ) plays a facilitative role in fibrotic disease; however, its role in renal fibrosis remains unclear. This study aimed to clarify the role and underlying mechanisms of FOSL2 in renal fibrosis.
Methods
Upregulated genes in unilateral ureteral obstruction (UUO)-injured kidneys were screened in Gene Expression Omnibus (GEO) databases, and overlapping genes were identified using Venn diagram software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for these genes. The UUO-induced mouse model and transforming growth factor-β1 (TGF-β1)-induced cell model were used for the in vivo and in vitro studies.
Results
A total of 43 commonly upregulated genes were identified. GO and KEGG pathway analyses indicated that FOSL2 may be involved in fibrosis. Furthermore, FOSL2 was confirmed to be upregulated in UUO-injured kidneys and TGF-β1–induced cells. Knockdown of FOSL2 ameliorated interstitial fibrosis, extracellular matrix deposition, and epithelial-mesenchymal transition via the downregulation of fibronectin, α-smooth muscle actin (α-SMA), collagen type I ( Col1a1 and Col1a2 ), and Col5a1 and upregulation of E-cadherin . Bioinformatics analysis revealed that serum/glucocorticoid regulated kinase 1 ( SGK1 ) may be regulated by FOSL2 and involved in renal fibrosis. Further experiments confirmed that TGF-β1 enhanced SGK1 expression and transcription, which were reversed by FOSL2 silencing. Moreover, FOSL2 was bound to the SGK1 promoter, and SGK1 overexpression reversed the effects of FOSL2 silencing in TGF-β1–induced cells.
Conclusion
FOSL2 plays an essential role in promoting renal fibrosis in an SGK1 -dependent manner, and targeting the FOSL2 / SGK1 signaling axis may offer a potential strategy for the treatment of renal fibrosis.
研究领域:
肾病学
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分子生物学
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细胞生物学
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病理学
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DOI
PubMed
高影响因子
FEBS Open Bio
·
2021
·Vol. 11
·期 5
·1395-1405
·
IF 2.693
Dan Wang,Zikun Zhang,Zekun Si,Yanlin Yang,Shuangshuang Li,Yaoming Xue
An imbalance between T helper 17 (Th17) and T regulatory (Treg) cell subsets contributes to the pathogenesis of diabetic kidney disease (DKD). However, the underlying regulatory mechanisms that cause this imbalance are unknown. Serum/glucocorticoid-regulated kinase 1 (SGK1) has been suggested to affect Th17 polarization in a salt-dependent manner, and sodium/glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to regulate sodium-mediated transportation in the renal tubules. This study aimed to evaluate the potential benefits of dapagliflozin (Dap) on DKD, as well as its influence on shifting renal T-cell polarization and related cytokine secretion. We treated male db/db mice with Dap or voglibose (Vog) and measured blood and kidney levels of Th17 and Treg cells using flow cytometry. We found that Th17 cells were significantly increased, while Treg cells were significantly decreased in diabetic mice. Moreover, Dap suppressed the polarization of Th17/Treg cells by inhibiting SGK1 in diabetic kidneys, and this was accompanied by attenuation of albuminuria and tubulointerstitial fibrosis independent of glycemic control. Taken together, these results demonstrate that the imbalance of Th17/Treg cells plays an important role in the progression of DKD. Moreover, Dap protects against DKD by inhibiting SGK1 and reversing the T-cell imbalance.
研究领域:
药理学
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免疫学
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糖尿病学
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肾病学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2024
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IF 8.2
Jianzhi Wu,Liping Gong,Yijie Li,Tiegang Liu,Rong Sun,Kexin Jia,Runping Liu,Fei Dong,Xiaohong Gu,Xiaojiaoyang Li
Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic matrix deposition and irreversible aberrant tissue remodeling. Their mechanisms of action are associated with the activation of macrophages and a disturbed immune environment. We aim to determine how these activated macrophages influenced the pathogenesis of pulmonary fibrosis. We found the fibrotic areas of IPF patients contained more serum and glucocorticoid-induced kinase 1 (SGK1)-positive and M2-type macrophages. Similarly, bleomycin (BLM)+LPS significantly triggered high expression of SGK1 in the IPF mice, accompanied by destroyed lung structure and function, increased fibrosis markers and disturbed immune microenvironment. Mechanistically, SGK1 markedly promoted the reprogramming of M2-type macrophages in fibrotic lungs by triggering glycogen synthase kinase 3beta (GSK3β)-tat-interacting protein 60 (TIP60)- histone-3 lysine-27 acetylation (H3K27ac) signalings, which further released chemokine (C-C motif) ligand 9 (CCL9) to attract Th17 cells and delivered TGF-β to fibroblasts for synergistically destroying immune microenvironment, which was largely reversed by macrophage depletion in mice. We took macrophages as the entry point to deeply analyze IPF pathogenesis and further provided insights for the development of novel drugs represented by SGK1.
研究领域:
肺科学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
STEROIDS
·
2019
·
IF 2.136
Shu-Qi Dong,Shuang-Shuang Wang,Ji-Xiao Zhu,Rong-Hao Mu,Cheng-Fu Li,Di Geng,Qing Liu,Li-Tao Yi
Our previous study has demonstrated that oleanolic acid produced an antidepressant-like effect in mice exposed to chronic stress. Considering that serine/threonine-protein kinase 1 (SGK1) is involved in stress response, the present study aimed to evaluate the involvement of SGK1 in the antidepressant-like effects of oleanolic acid in depression-like mice induced by long term corticosterone (CORT) injection. Behaviors, SGK1, brain-derived neurotrophic factor (BDNF) and its downstream targets were assessed after administration with oleanolic for three weeks. The results indicated that oleanolic acid increased the sucrose preference and decreased the immobility time. In addition, oleanolic acid decreased SGK1 and activated BDNF-AKT/mTOR signaling in the hippocampus of CORT-induced animals. However, we found that GSK650394, an inhibitor of SGK1 did not exert any effects on the behaviors, GR levels and BDNF signaling. The number of spines in hippocampal neurons was not changed by GSK650394 as well. Taken together, this study demonstrated that oleanolic acid produced the antidepressant-like effects, which might be related to the down-regulation of SGK1. However, inhibition of SGK1 directly lacks the effects in the treatment of depression.
研究领域:
药理学
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神经科学
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精神病学
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DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2023
·Vol. 26
·期 2
·1-10
·
IF 2.7
Yao-Meng Huang,Tong-Xin Li,Shu-Yu Li,Xiao-Ran Zhu,Ying Li,Dang-Yang Liu,Wei-Min Li,Lin-Quan Yang,Kun-Shen Liu,Chao Liu
Natriuretic peptides, which are produced by the heart, bind to natriuretic peptide receptor A (NPR1 encoded by natriuretic peptide receptor 1 gene) and cause vasodilation and natriuresis. Thus, they serve an important role in regulating blood pressure. In the present study, microinjection of CRISPR associated protein 9/single guide RNA into fertilized C57BL/6N mouse eggs was performed to generate filial generation zero (F0) Npr1 knockout homozygous mice (Npr1‑/‑). F0 mice mated with wild‑type (WT) mice to obtain F1 Npr1 knockout heterozygous mice with stable heredity (Npr1+/‑). F1 self‑hybridization was used to expand the population of heterozygous mice (Npr1+/‑). The present study performed echocardiography to investigate the impact of NPR1 gene knockdown on cardiac function. Compared with those in the WT group (C57BL/6N male mice), the left ventricular ejection fraction, myocardial contractility and renal sodium and potassium excretion and creatinine‑clearance rates were decreased, indicating that Npr1 knockdown induced cardiac and renal dysfunction. In addition, expression of serum glucocorticoid‑regulated kinase 1 (SGK1) increased significantly compared with that in WT mice. However, glucocorticoids (dexamethasone) upregulated NPR1 and inhibited SGK1 and alleviated cardiac and renal dysfunction caused by Npr1 gene heterozygosity. SGK1 inhibitor GSK650394 ameliorate cardiorenal syndrome by suppressing SGK1. Briefly, glucocorticoids inhibited SGK1 by upregulating NPR1, thereby ameliorating cardiorenal impairment caused by Npr1 gene heterozygosity. The present findings provided novel insight into the understanding of cardiorenal syndrome and suggested that glucocorticoids targeting the NPR1/SGK1 pathway may be a potential therapeutic target to treat cardiorenal syndrome.
研究领域:
心脏病学
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肾病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
International Heart Journal
·
2026
·Vol. 67
·期 4
·396-405
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IF 1.4
Xingchun Mo,Ping Lu,Xiaojing Yang
Endothelial cell pyroptosis is a key factor promoting plaque instability in atherosclerosis (AS). Serum/Glucocorticoid Regulated Kinase 1 (SGK1) is upregulated in AS, but its upstream regulatory mechanisms and role in pyroptosis remain unclear. This study aims to elucidate the mechanism of action of the GATA Binding Protein 3 (GATA3)/SGK1 axis in ox-LDL-induced endothelial cell pyroptosis.
""AS and pyroptosis"" related genes were screened using bioinformatics analysis. Transcription factor binding sites in the SGK1 promoter region were predicted using JASPAR. After establishing a pyroptosis model in ox-LDL-induced mouse aortic endothelial cells (MAECs), the effects of the GATA3/SGK1 regulatory axis on pyroptosis were detected using qRT-PCR, LDH release assays, and ELISA; the regulatory relationship was validated using the GATA3 inhibitor Pyrrothiogatain and SGK1 overexpression; and the mechanism of action of SGK1 was elucidated using a Caspase1 inhibitor (VX-765).
Bioinformatics analysis identified 65 pyroptosis-related genes that were upregulated in AS, and this study focused on SGK1. The SGK1 promoter region contains 4 GATA3 binding sites. Ox-LDL significantly upregulated GATA3, SGK1, cleaved-Caspase-1, GSDMD-N and NLRP3 expression, while pyrrothiogatain reduced SGK1 expression and alleviated cellular damage and excessive inflammation. SGK1 overexpression reversed the protective effect of Pyrrothiogatain. Mechanistic studies showed that SGK1 overexpression exacerbated ox-LDL-induced pyroptosis, while VX-765 significantly reversed this effect.
This study elucidates that GATA3 activated SGK1 transcription by directly binding to its promoter region, thereby promoting Caspase1/GSDMD-dependent endothelial cell pyroptosis.
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DOI
PubMed
高影响因子
JOURNAL OF INVESTIGATIVE DERMATOLOGY
·
2023
·
IF 6.5
Qinqin Meng,Mei Bai,Meiliang Guo,Zhengxiao Li,Wanwen Liu,Xiaojing Fan,Rui Sun,Xinrong Yang,Dingfen Yuan,Yuling Shi,Hui Deng
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-1β, 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.
研究领域:
免疫学
·
皮肤病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
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