Aceclofenac and methotrexate combination therapy could influence Th1/Th17 axis to modulate rheumatoid-arthritis-induced inflammation

Negi, Sushmita; Tandel, Nikunj; Sharma, Prakriti; Kumar, Rajinder; Tyagi, Rajeev K.

doi:10.1016/j.drudis.2023.103671

Cited by 10 publications

(3 citation statements)

References 81 publications

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“…We propose to dissect the mechanism by which the combination drug regimen could influence the Th1/Th17 axis to inhibit inflammation-dependent conversion of Th1 to Th17 phenotype. 80 …”

Section: Discussionmentioning

confidence: 99%

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis

Negi,

Tandel,

Garg

et al. 2024

IJN

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Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.

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“…We propose to dissect the mechanism by which the combination drug regimen could influence the Th1/Th17 axis to inhibit inflammation-dependent conversion of Th1 to Th17 phenotype. 80 …”

Section: Discussionmentioning

confidence: 99%

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis

Negi,

Tandel,

Garg

et al. 2024

IJN

Self Cite

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“…Immune cell-mediated inflammatory signals activate RA-FLS aggressiveness and subsequent bone destructive process [ 1 ]. Biological disease-modifying anti-rheumatic drugs have been developed to reduce inflammatory components [ 54 , 55 ]. Although vigorous studies have been performed for many years, non-responsive endpoints, limited clinical use, or ethical limitation require a new paradigm for the treatment of RA.…”

Section: Discussionmentioning

confidence: 99%

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine

Lee

Hong

2023

IJMS

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Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.

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“…Согласно недавним исследованиям, комбинированный режим приема метотрексата и ацеклофенака влияет на иммунологические механизмы воспаления таким образом, что вызванное РА воспаление уменьшается при комбинированном медикаментозном лечении. Было показано, что комбинированное лечение метотрексатом и ацеклофенаком регулирует сигнальный путь, контролируемый NF-κB и FOXO1, и может повлиять на ось Th1/Th17, смещая баланс в сторону иммунорегуляторного (Th1) фенотипа для установления иммунного гомеостаза [13].…”

Section: лечение болевого синдрома и место нестероидных противовоспал...unclassified

Treatment of Rheumatoid Arthritis in the Context of Modern International Recommendations

Волкова

2024

Рецепт

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Ревматоидный артрит (РА) является наиболее распространенным и тяжелым хроническим аутоиммунным заболеванием и характеризуется негативным влиянием на продолжительность и качество жизни, трудовую деятельность пациентов, значительными материальными затратами системы здравоохранения. Раннее выявление и лечение РА имеет большое значение для уменьшения негативных последствий заболевания. С этой целью разработаны новые классификационные критерии, которые позволяют диагностировать РА на ранней стадии, сформулирована четкая терапевтическая стратегия «Лечение до достижения цели». В настоящей статье приведены международные рекомендации по лечению РА, которые включают информацию о трех типах лекарственных средств, используемых при лечении заболевания: синтетических, таргетных синтетических и биологических болезнь-модифицирующих противоревматических препаратах. В статье также обсуждены вопросы, связанные с лечением болевого синдрома при РА. Rheumatoid arthritis (RA) is the most common and severe chronic autoimmune disease and is characterized by a negative impact on the duration and quality of life, work activity of patients, significant material costs of the healthcare system. Early detection and treatment of RA is very important to reduce the negative consequences of the disease. Thus, new classification criteria have been developed that allow the diagnosis of RA at an early stage, and a clear therapeutic strategy "treat to target" has been formulated. This article presents international recommendations for the treatment of RA, which include information on three types of medicines used in the treatment of the disease: synthetic, targeted synthetic and biological disease-modifying anti-rheumatic drugs. The article also discusses issues related to the treatment of pain syndrome in RA.

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Aceclofenac and methotrexate combination therapy could influence Th1/Th17 axis to modulate rheumatoid-arthritis-induced inflammation

Cited by 10 publications

References 81 publications

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine

Treatment of Rheumatoid Arthritis in the Context of Modern International Recommendations

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