Sitagliptin and tofacitinib ameliorate adjuvant induced arthritis via modulating the cross talk between JAK/STAT and TLR-4/NF-κB signaling pathways

Autor: Sherihan Salaheldin Abdelhamid Ibrahim, Eman Selima, Mona Salama, Rowaida R Shehata
Rok vydání: 2020
Předmět:
Blood Glucose
Male
STAT3 Transcription Factor
0301 basic medicine
Anti-Inflammatory Agents
Arthritis
Pharmacology
030226 pharmacology & pharmacy
General Biochemistry
Genetics and Molecular Biology
stat
Rats
Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Piperidines
medicine
Animals
Hypoglycemic Agents
Pyrroles
General Pharmacology
Toxicology and Pharmaceutics
Protein Kinase Inhibitors
Janus Kinases
Tofacitinib
Interleukin-6
business.industry
Sitagliptin Phosphate
NF-kappa B
JAK-STAT signaling pathway
Drug Synergism
Receptor Cross-Talk
General Medicine
medicine.disease
Arthritis
Experimental
Lipids
Rats
Toll-Like Receptor 4
STAT Transcription Factors
Pyrimidines
030104 developmental biology
Rheumatoid arthritis
Sitagliptin
Drug Therapy
Combination
Signal transduction
business
Janus kinase
Signal Transduction
medicine.drug
Zdroj: Life Sciences. 260:118261
ISSN: 0024-3205
DOI: 10.1016/j.lfs.2020.118261
Popis: Aims Rheumatoid arthritis is an autoimmune systemic disorder causing pain, swelling, stiffness, and disability in various joints. This work was designed to evaluate the effect of sitagliptin and tofacitinib on Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) and toll like receptor (TLR-4)/nuclear factor kappa B (NF-κB) signaling pathways in adjuvant induced arthritis in rats. Materials and methods Severity of arthritis was evaluated and serum was analyzed for inflammatory mediators. The mRNA and protein expression level of the most important members of the two signaling pathways were determined. Lipid profile, transaminases and renal function parameters were assessed. Key findings Sitagliptin and tofacitinib significantly decreased the level of inflammatory parameters, the mRNA and protein expression level of the members of JAK/STAT and TLR-4/NF-κB pathways with more prominent effect of sitagliptin on TLR-4/NF-κB pathway and more expected obvious effect of tofacitinib on JAK/STAT pathway. The combination offered additional anti-inflammatory effect by inhibiting the cross talk between these pathways as inhibition of NF-κB activation decreased the serum level of IL-6 preventing the activation of STAT-3 in tibiotarsal tissues. Significance The combination of tofacitinib and sitagliptin normalized serum lipids and blood glucose level which could offer protection against cardiovascular diseases and caused partial reversal of serum transaminases and creatinine levels which can protect against tofacitinb's related hepato and nephrotoxicity. We could conclude that the combination of Sitagliptin with tofacitinib can offer synergistic anti-inflammatory effect and more protective action against side effects of tofacitinib.
Databáze: OpenAIRE
Externí odkaz: