Phytocompounds in Precision Dermatology: COX-2 Inhibitors as a Therapeutic Target in Atopic-Prone Skin Muhammad Suleman, Abrar Mohammad Sayaf, Chiara Moltrasio, Paola Maura Tricarico, Francesco Giambuzzi, Erika Rimondi, Elisabetta Melloni, Paola Secchiero, Annalisa Marcuzzi, Angelo Valerio Marzano, Sergio Crovella Biomolecules, 2025 Atopic dermatitis (AD) is a chronic, multifactorial inflammatory skin disease characterized by persistent pruritus, immune system dysregulation, and an increased expression of cyclooxygenase-2 (COX-2), an enzyme that plays a central role in the production of prostaglandins and the promotion of inflammatory responses. In this study, we employed a comprehensive computational pipeline to identify phytocompounds capable of inhibiting COX-2 activity, offering an alternative to traditional non-steroidal anti-inflammatory drugs. The African and Traditional Chinese Medicine natural product databases were subjected to molecular screening, which identified six top compounds, namely, Tophit1 (−16.528 kcal/mol), Tophit2 (−10.879 kcal/mol), Tophit3 (−9.760 kcal/mol), Tophit4 (−9.752 kcal/mol), Tophit5 (−8.742 kcal/mol), and Tophit6 (−8.098 kcal/mol), with stronger binding affinities to COX-2 than the control drug rofecoxib (−7.305 kcal/mol). Molecular dynamics simulations over 200 ns, combined with MM/GBSA binding free energy calculations, consistently identified Tophit1 and Tophit2 as the most stable complexes, exhibiting exceptional structural integrity and a strong binding affinity to the target protein. ADMET profiling via SwissADME and pkCSM validated the drug-likeness, oral bioavailability, and safety of the lead compounds, with no Lipinski rule violations and favorable pharmacokinetic and toxicity profiles. These findings underscore the therapeutic potential of the selected phytocompounds as novel COX-2 inhibitors for the management of atopic-prone skin and warrant further experimental validation.
Pharmacological evaluation of drug therapies in Aicardi-Goutières syndrome: insights from patient-derived neural stem cells Stefania Braidotti, Rosalba Monica Ferraro, Raffaella Franca, Elena Genova, Francesco Giambuzzi, Andrea Mancini, Valentina Marinozzi, Letizia Pugnetti, Giulia Zudeh, Alessandra Tesser, Alberto Tommasini, Giuliana Decorti, Silvia Clara Giliani, Gabriele Stocco Frontiers in Pharmacology, 2025 Aicardi-Goutières syndrome (AGS) is a rare genetic disorder classified among type I interferonopathies. Current pharmacological management of AGS is symptomatic and supportive, with recent clinical applications of JAK inhibitors (JAKi) and antiretroviral therapies (RTIs). To investigate the effects of these therapies, patient-specific induced pluripotent stem cells (iPSCs) were generated by reprogramming fibroblasts from three AGS patients with distinct genetic mutations (AGS1, AGS2, AGS7) and differentiated into neural stem cells (NSCs). iPSCs and NSCs derived from commercial BJ fibroblasts of a healthy donor served as control. The cytotoxic effects of glucocorticoids, thiopurines, JAK inhibitors (ruxolitinib, baricitinib, tofacitinib, pacritinib), and RTIs (abacavir, lamivudine, zidovudine) were evaluated using the MTT assay. Results showed that glucocorticoids did not compromise NSC viability. Among thiopurines, thioguanine, but not mercaptopurine, exhibited cytotoxicity in NSCs. All tested JAK inhibitors, except pacritinib, were non-toxic to iPSCs and NSCs. Interestingly, high concentrations of certain JAK inhibitors (ruxolitinib, baricitinib, tofacitinib) led to an unexpected increase in cell viability in AGS patient-derived cells compared to control, suggesting potential alterations in cell proliferation or stress responses. RTIs demonstrated no cytotoxicity, except for zidovudine, which showed selective toxicity in AGS2-derived iPSCs compared to controls. These findings suggest that glucocorticoids, JAK inhibitors (excluding pacritinib), and RTIs are likely safe for NSCs of AGS patients, while caution is warranted with thioguanine and pacritinib. Further studies are needed to explore the mechanisms underlying increased cell viability at high JAK inhibitor concentrations and the selective sensitivity to zidovudine.
