PI3K AND SLE

Objective: Iguratimod ( IGU ) is a novel small disease-modifying compound widely used in Asia for the treatment of rheumatic diseases. IGU is a methane sulfonanilide. We applied network pharmacology to investigate the pharmacological mechanisms of IGU act on SLE. Methods: We used PharmMapper, UniProt, and OMIM databases to screen the potential targets of IGU , and the SLE-related disease targets were predicted. Hub target genes among the intersections of the potential targets ( IGU ) and related genes (SLE) were validated using the PPI network generated by the String database...

Systemic lupus erythematosus (SLE) is a typical autoimmune disease characterized by multiorgan involvement and marked variability in clinical presentation. SLE pathogenesis includes regulatory T cell dysfunction and antinuclear antibody production. Mammalian target of rapamycin (mTOR), a serine/threonine kinase in the phosphoinositide 3-kinase (PI3K)-related kinase family, is a therapeutic target for autoimmune diseases such as SLE. Rapamycin, an inhibitor of the mTOR signaling pathway, is a macrolide antibiotic with potent immunosuppressive, antiproliferative and antifibrotic effects...

Aberrant overactivation of the immune system can give rise to chronic and persistent self-attack, culminating in autoimmune disease. This is currently managed therapeutically using potent immunosuppressive and anti-inflammatory drugs. Class I phosphoinositide-3-kinases (PI3Ks) have been identified as ideal therapeutic targets for autoimmune diseases given their wide-ranging roles in immunological processes. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval with many others in development, including several intended to suppress the immune response in autoimmune and inflammatory diseases...

Systemic lupus erythematosus (SLE) is more common in women than men, but the disease is more severe when it affects men. Lupus CD4+ T cells demonstrate dysregulated DNA methylation patterns. The purpose of this study was to investigate genome-wide CD4+ T cell differential DNA methylation between men (n = 12) and women (n = 10) with SLE. DNA methylation was evaluated using the Infinium MethylationEPIC array, and differences between male versus female SLE patients were calculated with probe-wise linear regressions with adjustment for age and disease activity...

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α , β , γ , δ ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis...

Interleukin- (IL-) 33 contributes to various inflammatory processes. IL-33/ST2 activation participates in systemic lupus erythematous via binding to the receptor of Suppression of Tumorigenicity 2 protein (ST2). However, whether IL-33/ST2 interferes with the nosogenesis of cutaneous lupus erythematosus (CLE) has not been reported so far. Herein, we proposed to disclose the impacts on IL-33/ST2 activation and Ro60 on CLE and their potential implications in the photosensitization of CLE cells. IL-33, ST2, and Ro60 in CLE patients' skin lesions were detected...

BACKGROUND: Triple-negative breast cancer (TNBC) constitutes 10-20% of breast cancers and is challenging to treat due to a lack of effective targeted therapies. Previous studies in TNBC cell lines showed in vitro growth inhibition when JQ1 or GSK2801 were administered alone, and enhanced activity when co-administered. Given their respective mechanisms of actions, we hypothesized the combinatorial effect could be due to the target genes affected. Hence the target genes were characterized for their expression in the TNBC cell lines to prove the combinatorial effect of JQ1 and GSK2801...

Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a soluble form of TREM-1 released during inflammation. Elevated sTREM-1 levels have been found in neuropsychiatric systemic lupus erythematosus (NPSLE) patients; yet, the exact mechanisms remain unclear. This study investigated the role of sTREM-1 in brain damage and its underlying mechanism. The sTREM-1 recombinant protein (2.5 μg/3 μL) was injected into the lateral ventricle of C57BL/6 female mice. After intracerebroventricular (ICV) injection, the damage in hippocampal neurons increased, and the loss of neuronal synapses and activation of microglia increased compared to the control mice (treated with saline)...

Background: In this study, network pharmacological methods were used to analyze the targets of Rhizoma Dioscoreae Nipponicae (RDN) and investigate the potential underlying mechanism of RDN in the treatment of asthma. Methods: Asthma-related targets were obtained from the GeneCards and DisGeNET databases. The bioactive components of RDN were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database, and the targets of these compounds were predicted using the BATMAN-TCM database...

Objective To analyze the differentially expressed genes (DEGs) in patients with poor response to ursodeoxycholic acid (UDCA) therapy and to provide theoretical basis for the treatment of primary biliary cholangitis (PBC). Methods The GEO database was searched to obtain UDCA response related gene chip dataset. The DEGs were screened and the protein-protein interaction (PPI) network was constructed. The enrichment analysis of the biological function and signaling pathway of DEGs were carried out with the use of DAVID database...

BACKGROUND: During the pathogenesisof complex diseases, a sudden health deterioration will occur as results of the cumulative effect of various internal or external factors. The prediction of an early warning signal (pre-disease state) before such deterioration is very important in clinical practice, especially for a single sample. The single-sample landscape entropy (SLE) was proposed to tackle this issue. However, the PPI used in SLE was lack of definite biological meanings. Besides, the calculation of multiple correlations based on limited reference samples in SLE is time-consuming and suspect...

OBJECTIVE: Lupus nephritis (LN) is a major end-organ complication of systemic lupus erythematosus (SLE), and the molecular mechanism of LN is not completely clear. Accumulating pieces of evidence indicate the potential vital role of tRNA-derived small RNAs (tsRNAs) in human diseases. Current study aimed to investigate the potential roles of tsRNAs in LN. METHODS: We herein employed high-throughput sequencing to screen the expression profiles of tsRNAs in renal tissues of the LN and control groups...

ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP) is a traditional Chinese medicine (TCM) formula. According to both TCM theory and more than a decade of clinical practice, JP has been testified to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription in China. AIM OF THE STUDY: To determine the effect of JP on the treatment of SLE by glucocorticoid (GC) and to further examine the molecular mechanisms. MATERIALS AND METHODS: We conducted in vivo experiments to estimate the effect of JP on hepatic gluconeogenesis in MRL/lpr mice treated with GC...

[This corrects the article DOI: 10.3389/fped.2021.702546.].

Neuropsychiatric manifestations of systemic lupus erythematosus (SLE), specifically cognitive dysfunction and mood disorders, are widely prevalent in SLE patients, and yet poorly understood. TNF-like weak inducer of apoptosis (TWEAK) has previously been implicated in the pathogenesis of neuropsychiatric lupus (NPSLE), and we have recently shown its effects on the transcriptome of the cortex of the lupus-prone mice model MRL/lpr. As the hippocampus is thought to be an important focus of NPSLE processes, we explored the TWEAK-induced transcriptional changes that occur in the hippocampus, and isolated several genes ( Dnajc28 , Syne2 , transthyretin ) and pathways (PI3K-AKT, as well as chemokine-signaling and neurotransmission pathways) that are most differentially affected by TWEAK activation...

Introduction: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is a rare primary immune regulatory disorder caused by heterozygous gain of function mutation in the PIK3R1 gene encoding PI3Kδ regulatory p85α subunit and resulting in PI3Kδ hyperactivation. Clinical features range from recurrent infections to manifestations of immune dysregulation like autoimmunity, inflammation, systemic lymphoproliferation, and increased risk of cancer. We describe a new dominant PIK3R1 mutation causing APDS2 presenting with lymphoma and systemic refractory autoimmunity...

We identified abnormally methylated, differentially expressed genes (DEGs) and pathogenic mechanisms in different immune cells of RA and SLE by comprehensive bioinformatics analysis. Six microarray data sets of each immune cell (CD19+ B cells, CD4+ T cells and CD14+ monocytes) were integrated to screen DEGs and differentially methylated genes by using R package "limma." Gene ontology annotations and KEGG analysis of aberrant methylome of DEGs were done using DAVID online database. Protein-protein interaction (PPI) network was generated to detect the hub genes and their methylation levels were compared using DiseaseMeth 2...

Plasmacytoid dendritic cells (pDCs) play a key role in the initiation and amplification of systemic lupus erythematosus (SLE)-associated vascular injury. In this study, we found that dsDNA induced dose- and time-dependent increase in IFN-α and Toll-like receptor 7 (TLR7), TLR9 and IRF7 expression in pDCs. Co-cultured circulating endothelial cells (ECs) with activated pDCs significantly decreased proliferation, tube formation and migration in ECs. The elevated level of cellular IFN-α increased cell adhesion, promoted cell apoptosis, induced cell senescence and arrested cells at G0/G1 phase of endothelial progenitor cells (EPCs)...

Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/ lpr (that manifest lupus-like phenotype) and MRL/ lpr -Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus...

BACKGROUND: Tripterygium hypoglaucum Hutch (THH) both has prominent efficacy and unwarranted toxicity in the treatment of autoimmune diseases. Nevertheless, its pharmacological and toxicological profiles still remain to be elucidated. In the current study, the network pharmacology approach was applied to identify synergistic interaction and mechanism of efficacy and toxicity for THH from a holistic perspective. METHODS: The compounds from THH were collected using literature retrieval and relevant databases...