Deoxyeritadenine methyl ester

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin β3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.

Psoriasis is the most prevalent inflammatory skin disorders, affecting 1-3% of the worldwide population. We previously reported that topical application of methyl 4-(adenin-9-yl)-2-hydroxybutanoate (DZ2002), a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor, was a viable treatment in murine psoriatic skin inflammation. In current study, we further explored the mechanisms of DZ2002 on keratinocyte dysfunction and skin infiltration, the key pathogenic events in psoriasis. We conducted genome-wide DNA methylation analysis in skin tissue from imiquimod (IMQ)-induced psoriatic and normal mice, demonstrated that topical administration of DZ2002 directly rectified aberrant DNA methylation pattern in epidermis and dermis of psoriatic skin lesion. Especially, DZ2002 differentially regulated DNA methylation of GATA3 and LCN2 promoters, which maintained keratinocytes differentiation and reduced inflammatory infiltration in psoriatic skin respectively. In vitro studies in TNF-α/IFN-γ-elicited HaCaT manifested that DZ2002 treatment rectified compromised keratinocyte differentiation via GATA3 enhancement and abated chemokine expression by reducing LCN2 production under inflammatory stimulation. Chemotaxis assays conducted on dHL-60 cells confirmed that suppression of LCN2 expression by DZ2002 was accompanied by CXCR1 and CXCR2 downregulation, and contributed to the inhibition of CXCL8-driven neutrophils migration. In conclusion, therapeutic benefits of DZ2002 are achieved through differentially regulating DNA methylation of GATA3 and LCN2 promoters in psoriatic skin lesion, which efficiently interrupt the pathogenic interplay between keratinocytes and infiltrating immune cells, thus maintains epidermal keratinocytes differentiation and prevents dermal immune infiltration in psoriatic skin.