Glutamine‐Based Metabolism Normalization and Oxidative Stress Alleviation by Self‐Assembled Bilirubin/V9302 Nanoparticles for Psoriasis Treatment

Abstract

Psoriasis is an immune-mediated chronic inflammatory skin disorder characterized by epidermal hyperplasia and infiltration of inflammatory cells. Even though the pathogenesis remains unclear, T helper 17 (Th17) cells-mediated inflammation and keratinocyte-involved proliferation are considered to play key roles during the occurrence and the development of psoriasis. Therefore, suppressing the infiltration/function of Th17 and the abnormal hyperplasia of keratinocytes can be a rational strategy for ameliorating and treating psoriasis. In this study, a self-assembly nanoparticle (BVn) is developed with bilirubin (an endogenous antioxidant) and V9302 (a blocker of ASCT2, an amino acid transporter mediating glutamine influx for providing energy and activating mammalian target of rapamycin [mTOR] pathway) to intervene the local metabolism and alleviate oxidative stress for psoriasis treatment. BVn effectively suppresses inflammatory keratinocyte proliferation and scavenges excess reactive oxygen species (ROS). In the in vivo psoriasis mouse model, BVn shows increased permeation and delayed retention in the psoriatic lesion and reverses the psoriasis-related symptoms, evidenced by the normalized keratinocyte condition and decreased Th17 infiltration/activation. Mechanism study indicates that BVn not only cut off the energy supply but also suppressed cell proliferation or lymph cell expansion by deactivating mTOR pathway, besides alleviated oxidative stress. BVn-based glutamine metabolism modulation strategy offers a promising strategy for psoriasis therapy.

Bilirubin ameliorates osteoarthritis via activating Nrf2/HO‐1 pathway and suppressing NF‐κB signalling

“…Bilirubin (BR), a yellow bile pigment and the final metabolite of the heme catabolic pathway, was once considered a potentially harmful substance that indicates jaundice. However, it is actually a potent endogenous antioxidant that can scavenge various ROS, protecting cells and the body from oxidative stress‐mediated damage 19,49–54 . BR binds to multiple cellular targets and transduces cellular signalling during metabolic homeostasis, and numerous studies have reported its antioxidant and anti‐inflammatory effects on inflammatory diseases 50,51 .…”

Bilirubin Nanoparticles Alleviate Sepsis-Induced Acute Lung Injury by Protecting Pulmonary Endothelia Glycocalyx and Reducing Inflammation

“…BRNP were prepared using a modified nanoprecipitation method. 11 In brief, 2 mg of BR was dissolved in 1 mL of dimethyl sulfoxide (DMSO) to obtain a BR solution of 2 mg/mL. A BR solution was added to 1 mL of double-distilled water in 10 batches (10 μL each) to obtain the preliminary nanoparticles (BRn).…”

“…BRNP were prepared using a modified nanoprecipitation method . In brief, 2 mg of BR was dissolved in 1 mL of dimethyl sulfoxide (DMSO) to obtain a BR solution of 2 mg/mL.…”

“…BR could act as a scavenger of ROS and has been shown to inhibit the proinflammatory signaling pathway. These characteristics have spurred investigations into its potential as a therapeutic agent; our group has studied its therapeutic effect in treating numerous inflammation-associated diseases, including osteoarthritis, psoriasis, , ischemic kidney injury, and so on. , It should be pointed out that the potential of BR to restore glycocalyx integrity has not been reported. The insolubility inherent to BR has constrained its therapeutic viability and application potential.…”

Development of a Deep Eutectic Solvent-Assisted Kaempferol Hydrogel: A Promising Therapeutic Approach for Psoriasis-like Skin Inflammation

“…Psoriasis has also been linked to dysregulation of the antioxidant system and increased ROS production. At present, psoriasis may not be completely cured, but the disease process can be alleviated through available treatment methods, including topical therapies, 15,16 phototherapy, 17 systemic medications, and biologics, which can help alleviate symptoms and improve the quality of life for individuals with the condition. 18 For example, several traditional immunosuppressive drugs, such as TNF-α, IL-17, and IL-23 inhibitors, have demonstrated high efficacy in treating psoriasis vulgaris.…”