Interaction of a small molecule Natura-α and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis

Chiao, Jen Wei; Melikian, Maxime; Han, Liying; Xue, Chengsen; Tsao, A; Wang, Luxi; Mencher, Simon K.; Fallon, John T.; Solangi, Karim; Bertho, Gildas; Wang, Long G.

doi:10.1016/j.bcp.2015.11.018

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…Mice were treated for 29 weeks, and two doses (25 and 75 mg/kg) were given orally. Similar improvements were observed [20]. The findings from this study are especially encouraging because current treatments mainly focus on slowing down the deterioration of kidney injuries, and the reversal of glomerular lesions has not been achieved in LN patients.…”

Section: Introductionsupporting

confidence: 76%

“…Consistent with this, IL-6 and IFN-γ levels were significantly upregulated [19]. Treatment with the STAT3 Y705 inhibitor Natura-α in 19-week-old NZB/W F1 mice effectively reduced proteinuria, significantly improved survival, and reversed glomerular lesions [20]. Mice were treated for 29 weeks, and two doses (25 and 75 mg/kg) were given orally.…”

Section: Introductionsupporting

confidence: 55%

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Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Shao,

Shao

2024

IJMS

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Systemic lupus erythematosus (SLE) is a prototype inflammatory autoimmune disease, characterized by breakdown of immunotolerance to self-antigens. Renal involvement, known as lupus nephritis (LN), is one of the leading causes of morbidity and a significant contributor to mortality in SLE. Despite current pathophysiological advances, further studies are needed to fully understand complex mechanisms underlying the development and progression of LN. Transcription factors (TFs) are proteins that regulate the expression of genes and play a crucial role in the development and progression of LN. The mechanisms of TF promoting or inhibiting gene expression are complex, and studies have just begun to reveal the pathological roles of TFs in LN. Understanding TFs in the pathogenesis of LN can provide valuable insights into this disease’s mechanisms and potentially lead to the development of targeted therapies for its management. This review will focus on recent findings on TFs in the pathogenesis of LN and newly developed TF-targeted therapy in renal inflammation.

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Section: Introductionsupporting

confidence: 76%

Section: Introductionsupporting

confidence: 55%

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Shao,

Shao

2024

IJMS

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“…To investigate the possibility that CQMU151 and CQMU152 directly inhibit STAT3 and to study possible off-target effects, molecular docking studies of COMU151 and CQMU152 against the STAT3 SH2 domain were investigated, which would block Y705 phosphorylation and further prevent dimerization and transcriptional activity of STAT3 29 , 30 . The results showed that the ligand-binding pocket of STAT3 is totally different from that of RORγt.…”

Section: Resultsmentioning

confidence: 99%

Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation

et al. 2020

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Th17 cells, a lymphocyte subpopulation that is characterized by the expression of the transcription factor "retinoic acid receptor-related orphan receptor gamma-t" (RORγt), plays an important role in the pathogenesis of autoimmune disease. The current study was set up to discover novel and non-steroidal small-molecule inverse agonists of RORγt and to determine their effects on autoimmune disease. Structure-based virtual screening (SBVS) was used to find compounds targeting RORγt. Flow cytometry was used to detect the Th17 cell differentiation. Inverse agonists were intraperitoneally administered to mice undergoing experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE) or type 1 diabetes. The effects of the inverse agonists were evaluated by clinical or histopathological scoring. Among 1.3 million compounds screened, CQMU151 and CQMU152 were found to inhibit Th17 cell differentiation without affecting the differentiation of Th1 and Treg lineages (both P = 0.001). These compounds also reduced the severity of EAU (P = 0.01 and 0.013) and functional studies showed that they reduced the number of Th17 cell and the expression of IL-17(Th17), but not IFN-γ(Th1) and TGF-β(Treg) in mouse retinas. Further studies showed that these compounds may reduce the expression of p-STAT3 by reducing the positive feedback loop of IL-17/IL-6/STAT3. These compounds also reduced the impaired blood-retinal barrier function by upregulating the expression of tight junction proteins. These compounds were also found to reduce the severity of EAE and type 1 diabetes. Our results showed that RORγt inverse agonists may inhibit the development of autoimmune diseases and may provide new clues for the treatment of Th17-mediated immune diseases.

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“…Moreover, the SH2 domain possesses a dual function as a receptor recruitment module rather than a dimerization domain, which represents the preferable binding site of DNA with STATs. Consequently, the SH2 domain has become the favored target in the rational design and inhibition of STAT3 phosphorylation and/or dimerization, arising as one of the promising targets for developing anti-cancer motifs (Figure 9) [59][60][61][62].…”

Section: In Silico Molecular Docking Of Epi-obtusane and Stat 3 Receptormentioning

confidence: 99%

Pro-Apoptotic Activity of Epi-Obtusane against Cervical Cancer: Nano Formulation, In Silico Molecular Docking, and Pharmacological Network Analysis

Abdelhafez,

Abdel-Rahman,

Alaaeldin

et al. 2023

Pharmaceuticals

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Cancer is a major disease that threatens human health all over the world. Intervention and prevention in premalignant processes are successful ways to prevent cancer from striking. On the other hand, the marine ecosystem is a treasure storehouse of promising bioactive metabolites. The use of such marine products can be optimized by selecting a suitable nanocarrier. Therefore, epi-obtusane, previously isolated from Aplysia oculifera, was investigated for its potential anticancer effects toward cervical cancer through a series of in vitro assays in HeLa cells using the MTT assay method. Additionally, the sesquiterpene was encapsulated within a liposomal formulation (size = 130.8 ± 50.3, PDI = 0.462, zeta potential −12.3 ± 2.3), and the antiproliferative potential of epi-obtusane was investigated against the human cervical cancer cell line HeLa before and after encapsulation with liposomes. Epi-obtusane exhibited a potent effect against the HeLa cell line, while the formulated molecule with liposomes increased the in vitro antiproliferative activity. Additionally, cell cycle arrest analysis, as well as the apoptosis assay, performed via FITC-Annexin-V/propidium iodide double staining (flow cytofluorimetry), were carried out. The pharmacological network enabled us to deliver further insights into the mechanism of epi-obtusane, suggesting that STAT3 might be targeted by the compound. Moreover, molecular docking showed a comparable binding score of the isolated compound towards the STAT3 SH2 domain. The targets possess an anticancer effect through the endometrial cancer pathway, regulation of DNA templated transcription, and nitric oxide synthase, as mentioned by the KEGG and ShinyGo 7.1 databases.

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Interaction of a small molecule Natura-α and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis

Cited by 6 publications

References 37 publications

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Transcription Factors in the Pathogenesis of Lupus Nephritis and Their Targeted Therapy

Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation

Pro-Apoptotic Activity of Epi-Obtusane against Cervical Cancer: Nano Formulation, In Silico Molecular Docking, and Pharmacological Network Analysis

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