Dataset Information

A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte.

ABSTRACT: The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human β defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.

SUBMITTER: Kim AR

PROVIDER: S-EPMC8396041 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte.

Kim A-Ram AR Lee Seungbeom S Shin Jung U JU Seok Seung Hui SH Suh Young-Ger YG Kim Dong Hyun DH

International journal of molecular sciences 20210816 16

The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypo ...[more]

PMID: 34445513

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Project description:BackgroundThe effects of some drugs, aging, cancers, and other diseases can cause muscle wasting. Currently, there are no effective drugs for treating muscle wasting. In this study, the effects of ginsenoside Rd (GRd) on muscle wasting were studied.MethodsTumour necrosis factor-alpha (TNF-α)/interferon-gamma (IFN-γ)-induced myotube atrophy in mouse C2C12 and human skeletal myoblasts (HSkM) was evaluated based on cell thickness. Atrophy-related signalling, reactive oxygen species (ROS) level, mitochondrial membrane potential, and mitochondrial number were assessed. GRd (10 mg/kg body weight) was orally administered to aged mice (23-24 months old) and tumour-bearing (Lewis lung carcinoma [LLC1] or CT26) mice for 5 weeks and 16 days, respectively. Body weight, grip strength, inverted hanging time, and muscle weight were assessed. Histological analysis was also performed to assess the effects of GRd. The evolutionary chemical binding similarity (ECBS) approach, molecular docking, Biacore assay, and signal transducer and activator of transcription (STAT) 3 reporter assay were used to identify targets of GRd.ResultsGRd significantly induced hypertrophy in the C2C12 and HSkM myotubes (average diameter 50.8 ± 2.6% and 49.9% ± 3.7% higher at 100 nM, vs. control, P ≤ 0.001). GRd treatment ameliorated aging- and cancer-induced (LLC1 or CT26) muscle atrophy in mice, which was evidenced by significant increases in grip strength, hanging time, muscle mass, and muscle tissue cross-sectional area (1.3-fold to 4.6-fold, vs. vehicle, P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). STAT3 was found to be a possible target of GRd by the ECBS approach and molecular docking assay. Validation of direct interaction between GRd and STAT3 was confirmed through Biacore analysis. GRd also inhibited STAT3 phosphorylation and STAT3 reporter activity, which led to the inhibition of STAT3 nuclear translocation and the suppression of downstream targets of STAT3, such as atrogin-1, muscle-specific RING finger protein (MuRF-1), and myostatin (MSTN) (29.0 ± 11.2% to 84.3 ± 30.5%, vs. vehicle, P ≤ 0.05; P ≤ 0.01; P ≤ 0.001). Additionally, GRd scavenged ROS (91.7 ± 1.4% reduction at 1 nM, vs. vehicle, P ≤ 0.001), inhibited TNF-α-induced dysregulation of ROS level, and improved mitochondrial integrity (P ≤ 0.05; P ≤ 0.01; P ≤ 0.001).ConclusionsGRd ameliorates aging- and cancer-induced muscle wasting. Our findings suggest that GRd may be a novel therapeutic agent or adjuvant for reversing muscle wasting.

Project description:Background/Objectives: This study aims to investigate whether Signal Transducer and Activator of Transcription 4 (STAT4) influences the anti-tumor immune response and is possibly involved in the initiation or relapse of pituitary adenomas (PAs) by examining STAT4 polymorphisms and serum levels. This research seeks to uncover potential connections that could inform future therapeutic strategies and improve our understanding of PA pathogenesis. Materials and Methods: This study was conducted at the Laboratory of Ophthalmology, Lithuanian University of Health Sciences. DNA was extracted from peripheral venous blood samples, and the genotyping of four STAT4 SNPs (rs7574865, rs10181656, rs7601754, and rs10168266) was performed using real-time PCR with TaqMan® Genotyping assays. The serum STAT4 levels were measured via ELISA, and the optical density was read at 450 nm. Genotype frequencies, allele distributions, and serum STAT4 levels were statistically analyzed to assess associations with pituitary adenoma occurrence. Results: A binary logistic regression revealed that the STAT4 rs7574865 GT + GG genotypes vs. TT were associated with 1.7-fold increased odds of PA occurrence under the dominant genetic model (p = 0.012). The stratification by gender showed no significant associations in females; however, in males, the STAT4 rs10168266 CC + CT genotypes compared to TT were linked to 2.5-fold increased odds of PA under the dominant genetic model (p = 0.005). STAT4 rs10181656, rs7574865, rs7601754, and rs10168266 were analyzed to evaluate the associations with the pituitary adenoma size. We found that the STAT4 rs7574865 GG genotype was statistically significantly less frequent in the macro PA group compared to in the reference group (p = 0.012). For PA relapse, the rs7574865 G allele was less frequent in the PA group without relapse (p = 0.012), and the GT + GG genotypes were associated with a 1.8-fold increase in the PA group without relapse occurrence (p = 0.008). The serum STAT4 levels were higher in the PA patients compared to those of the reference group (p < 0.001). Elevated STAT4 serum levels were observed in PA patients with the STAT4 rs10181656 CC or CG genotypes (CC: p = 0.004; CG: p = 0.023), and with the rs7574865 GG or GT genotypes (GG: p = 0.003; GT: p = 0.021). The PA patients with the STAT4 rs7601754 AA genotype exhibited higher serum levels compared to those of the reference group (p < 0.001). Similarly, higher serum levels were found in the PA patients with the STAT4 rs10168266 CC or CT genotypes (CC: p = 0.004; CT: p = 0.027). A haplotype frequency analysis revealed no statistically significant results. Conclusions: The STAT4 genotypes were significantly associated with the PA occurrence, size, and relapse. Elevated serum STAT4 levels were observed in the PA patients, highlighting its potential role in PA pathogenesis.

Dataset Information

A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte.

Publications

A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte.

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