Potential of ephedrine to suppress the gene expression of TNF-α, IL-1β, IL-6 and PGE2: A novel approach towards management of rheumatoid arthritis

Life Sciences ◽  
2021 ◽  
pp. 119825
Author(s):  
Haseeb Ahsan ◽  
Hafiz Muhammad Irfan ◽  
Alamgeer ◽  
Shah Jahan ◽  
Muhammad Shahzad ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Novel Approach ◽  
Tnf Α

scholarly journals Anti-Rheumatic Effect of Antisense Oligonucleotide Cytos-11 Targeting TNF-α Expression

2021 ◽  
Vol 22 (3) ◽  
pp. 1022
Author(s):  
Tatyana P. Makalish ◽  
Ilya O. Golovkin ◽  
Volodymyr V. Oberemok ◽  
Kateryna V. Laikova ◽  
Zenure Z. Temirova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Rat Model ◽  
Peripheral Blood ◽  
Antisense Oligonucleotide ◽  
Joint Inflammation ◽  
Blood Concentrations ◽  
Tnf Α ◽  
Effective Drugs ◽  
First Time

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund’s adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.

The Function and Molecular Mechanism of MicroRNA-429 in Rheumatoid Arthritis

2020 ◽  
Vol 10 (7) ◽  
pp. 945-950
Author(s):  
Pengdong Zhang ◽  
Bailong Yu ◽  
Bin Lei ◽  
Changlin Li ◽  
Xiaoqiang Yuan
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Molecular Mechanism ◽  
Synovial Tissue ◽  
Luciferase Assay ◽  
Rt Pcr ◽  
Tnf Α ◽  
Tlr4 Gene ◽  
Synovial Tissues ◽  
D Model

Objective: To explain the function and molecular mechanism of miRNA-429 in Rheumatoid Arthritis development. Methods: Collecting synovial tissue of 36 RA patients and 36 traumatic amputation patients, the miRNA-429 and TLR4 gene expressions were measured by RT-PCR. The SD rats were divided into NC, 14 d Model and 28 d Model groups. The IL-1β and TNF-α concentrations of serum were measured by Elisa assay in difference rats groups; The synovial tissue pathology was evaluated by HE staining; the miRNA-429 gene expression of rats groups were measured by RT-PCR, the TLR4 and NF-κB proteins expressions of rats groups were evaluated by IHC staining; the correlation between miRNA-429 and TLR4 were evaluated by Double luciferase assay. Results: Compared with normal synovial tissues, the miRNA-429 and TLR4 gene expression of synovial tissues were significantly difference in RA patients. In rats vivo study, we found that IL-1 and TNF-α concentrations were significantly up-regulation with time increasing (P < 0 05, respectively); inflammation degree was serious by HE staining and miRNA-429 gene expression was significantly reduced (P < 0.05, respectively); TLR4 and NF-κB proteins expressions were significantly up-regulation (P < 0.05, respectively) with time increasing; TLR4 was the target gene of miRNA-429 by Double luciferase assay. Conclusion: miRNA-429 over-expression stimulated RA development.

Berberine Inhibits the gene Expression and Production of Proinflammatory Cytokines by Mononuclear cells in Rheumatoid Arthritis and Healthy Individuals

2020 ◽  
Vol 16 ◽  
Author(s):  
Niloofar Ghorbani ◽  
Maryam Sahebari ◽  
Mahmoud Mahmoudi ◽  
Maryam Rastin ◽  
Shahrzad Zamani ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Mononuclear Cells ◽  
Inhibitory Effect ◽  
Healthy Individuals ◽  
High Concentration ◽  
Antiinflammatory Property ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Objective: Rheumatoid arthritis (RA) is the most prevalent autoimmune arthritis. Berberine is an alkaloid isolated from Berberis vulgaris and its anti-inflammatory effect has been identified. Method: Twenty newly diagnosed RA patients and 20 healthy controls participated. Peripheral mononuclear cells were prepared and stimulated with bacterial lipopolysachharide (LPS,1 µg/ml), exposed to different concentrations of berberine (10 and 50µM) and dexamethasone (10-7 M) as a reference. Toxicity of compounds was evaluated by WST-1 assay. Expression of TNF-α and IL-1β were determined by quantitative real-time PCR. Protein level of secreted TNF-α and IL1β were measured by using ELISA. Result: Berberine did not have any toxic effect on cells, whereas Lipopolysachharide (LPS) stimulation caused a noticeable rise in TNF-α and IL-1β production. Berberine markedly downregulated the expression of both TNF-α and IL1β and inhibits TNF-α and IL-1β secretion from LPS-stimulated PBMCs. Discussion: This study provided molecular basis for anti-inflammatory effect of berberine on human mononuclear cells through the suppression of TNF-a and IL-1secretion. Our findings highlighted the significant inhibitory effect of berberine on proinflammatory responses of mononuclear cells from rheumatoid arthritis individuals, which may be responsible for antiinflammatory property of Barberry. We observed that berberine at high concentration exhibited anti-inflammatory effect in PBMCs of both healthy and patient groups by suppression of TNF-a and IL-1cytokines at both mRNA and protein levels. Conclusions: Berberine may inhibit the gene expression and production of pro-inflammatory cytokines by mononuclear cells in rheumatoid arthritis and healthy individuals without affecting cells viability. Future studies with larger sample size is needed to prove the idea.

Gene expression profiling in peripheral blood cells of patients with rheumatoid arthritis in response to anti-TNF-α treatments

2011 ◽  
Vol 43 (7) ◽  
pp. 365-371 ◽  
Author(s):  
E. Meugnier ◽  
F. Coury ◽  
J. Tebib ◽  
C. Ferraro-Peyret ◽  
S. Rome ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Calcium Binding ◽  
Mononuclear Cells ◽  
Gene Expression Signature ◽  
Fold Change ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Apoptosis Protein

The efficacy of anti-TNF-α therapies highlights the role of TNF-α in the pathogenesis of rheumatoid arthritis (RA). However, the mechanism of action of these agents is poorly understood at the molecular level. The aim of this study was to characterize the effects of anti-TNF-α treatment on the global gene expression profile in peripheral blood mononuclear cells (PBMCs) of responder RA patients. Changes in gene expression were determined using oligonucleotide microarrays (25,341 genes) in PBMCs obtained before and after 12 wk of treatment with either etanercept or adalimumab from responder RA patients. Two hundred fifty-one genes displayed significant changes (false discovery rate < 0.1%) in expression level (178 upregulations with mean fold change = 1.5 and 73 downregulations with mean fold change = −1.50) after 12 wk of treatment. Importantly, the expression of several genes, including those coding for the calcium binding proteins S100A12 and A8, CD14 antigen, Selectin P, or ribosomal protein L39, reported to be upregulated in RA patients, were found to be decreased after anti-TNF-α treatment. Globally, inflammation, immune response, apoptosis, protein synthesis, and mitochondrial oxido-reduction were the most affected pathways in response to anti-TNF-α treatment. The obtained gene expression signature in PBMCs provides new information to better understand the mechanisms of action of anti-TNF-α treatment in RA patients.

scholarly journals Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn’s Disease and Rheumatoid Arthritis

2021 ◽  
Vol 22 (16) ◽  
pp. 8883
Author(s):  
Ameera M. Shaw ◽  
Ahmad Qasem ◽  
Saleh A. Naser
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Cell Proliferation ◽  
T Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Clinical Samples ◽  
Jurkat T Cells ◽  
Tnf Α ◽  
Ifn Γ

Crohn’s Disease (CD) and Rheumatoid Arthritis (RA) share some single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor types 2 and 22 (PTPN2/22). Recently, we reported that clinical samples from CD and RA patients associated with PTPN2:rs478582 or PTPN22:rs2476601 genotypes were linked to overactive immune response and exacerbation of inflammation. Here, we investigated in vitro the effects of these SNPs in Jurkat T-cells using CRISPR-Cas9. All cells were evaluated for PTPN22/22 loss of function and effects on cell response. We measured gene expression via RT-qPCR and cytokines by ELISA. We also measured cell proliferation using a BrdU labeling proliferation ELISA, and T-cell activation using CD-25 fluorescent immunostaining. In PTPN2 SNP-edited cells, PTPN2 expression decreased by 3.2-fold, and proliferation increased by 10.2-fold compared to control. Likewise, expression of PTPN22 decreased by 2.4-fold and proliferation increased by 8.4-fold in PTPN22 SNP-edited cells. IFN-γ and TNF-α secretions increased in both edited cell lines. CD25 expression (cell activation) was 80.32% in PTPN2 SNP-edited cells and 85.82% in PTPN22 SNP-edited cells compared to 70.48% in unedited Jurkat T-cells. Treatment of PTPN2 and PTPN22-edited cells with a maximum 20 μM spermidine restored PTPN2/22 expression and cell response including cell proliferation, activation, and cytokines secretion. Most importantly, the effect of spermidine on edited cells restored normal expression and secretion of IFN-γ and TNF-α. The data clearly demonstrated that edited SNPs in PTPN2 or PTPN22 were associated with reduced gene expression, which resulted in an increase in cell proliferation and activation and overactive immune response. The data validated our earlier observations in CD and RA clinical samples. Surprisingly, spermidine restored PTPN2/22 expression in edited Jurkat T-cells and the consequent beneficial effect on cell response and inflammation. The study supports the use of polyamines dietary supplements for management of CD and in RA patients.

scholarly journals AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Eslam E. Abd El-Fattah ◽  
Sameh Saber ◽  
Mahmoud E. Youssef ◽  
Hanan Eissa ◽  
Eman El-Ahwany ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Ki 67 ◽  
Tissue Invasion ◽  
Novel Approach ◽  
Promising Target ◽  
Tnf Α ◽  
Key Factor ◽  
Potential Basis ◽  
Α Level

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.

scholarly journals Hydroquinone Exposure Worsens Rheumatoid Arthritis through the Activation of the Aryl Hydrocarbon Receptor and Interleukin-17 Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 929
Author(s):  
Cintia Scucuglia Heluany ◽  
Paula Barbim Donate ◽  
Ayda Henriques Schneider ◽  
André Luis Fabris ◽  
Renan Augusto Gomes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Cigarette Smoke Exposure ◽  
Interleukin 17 ◽  
Aryl Hydrocarbon ◽  
Tnf Α

Rheumatoid arthritis (RA) development is strongly associated with cigarette smoke exposure, which activates the aryl hydrocarbon receptor (AhR) as a trigger for Th17 inflammatory pathways. We previously demonstrated that the exposure to hydroquinone (HQ), one of the major compounds of cigarette tar, aggravates the arthritis symptomatology in rats. However, the mechanisms related to the HQ-related RA still remain elusive. Cell viability, cytokine secretion, and gene expression were measured in RA human fibroblast-like synoviocytes (RAHFLS) treated with HQ and stimulated or not with TNF-α. Antigen-induced arthritis (AIA) was also elicited in wild type (WT), AhR −/− or IL-17R −/− C57BL/6 mice upon daily exposure to nebulized HQ (25ppm) between days 15 to 21. At day 21, mice were challenged with mBSA and inflammatory parameters were assessed. The in vitro HQ treatment up-regulated TNFR1, TNFR2 expression, and increased ROS production. The co-treatment of HQ and TNF-α enhanced the IL-6 and IL-8 secretion. However, the pre-incubation of RAHFLS with an AhR antagonist inhibited the HQ-mediated cell proliferation and gene expression profile. About the in vivo approach, the HQ exposure worsened the AIA symptoms (edema, pain, cytokines secretion and NETs formation) in WT mice. These AIA effects were abolished in HQ-exposed AhR −/− and IL-17R −/− animals though. Our data demonstrated the harmful HQ influence over the onset of arthritis through the activation and proliferation of synoviocytes. The HQ-related RA severity was also associated with the activation of AhR and IL-17 pathways, highlighting how cigarette smoke compounds can contribute to the RA progression.

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