sirolimus and Dermatitis

The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders.

Topics: Biological Products; Dermatitis; Humans; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Psoriasis; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

FK506-binding protein 12 (FKBP12) is an endogenous protein with peptidyl-prolyl isomerase (PPIase) activity. Natural compounds FK506, rapamycin and ascomycin, are FKBP12 ligands used for treating organ transplant rejection and other diseases. Small ligands that also interact with FKBP12 are designed and synthetized based on the natural ligands. This suggests that targeting FKBP12 has potential in the treatment of multiple diseases.. This article describes the features of FKBP12 and the therapeutic actions of agents targeting FKBP12 reported in the published articles and patents.. The multiple functions of FKBP12 cause side effects during therapy with FKBP12 ligands. The interaction between FKBP12 and other receptors should be explored to guide their use as drugs in the clinical setting. In addition, the neuroprotective mechanism of small-molecule FKBP12 ligands needs further study in order to develop them as novel drugs for treating neurological disorders.

Topics: Animals; Antineoplastic Agents; Dermatitis; Humans; Immunosuppressive Agents; Ligands; Neuroprotective Agents; Patents as Topic; Sirolimus; Small Molecule Libraries; Tacrolimus; Tacrolimus Binding Protein 1A; Vision Disorders

Recently, the mTOR signaling has emerged as an important player in the pathogenesis of psoriasis. We previously found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced psoriatic skin inflammation was related to the inhibition of autophagy in keratinocytes. However, the effects and detailed molecular mechanisms of the mTOR inhibitor rapamycin and TCDD on psoriasis in vivo remain to be elucidated. In this study, we aimed to evaluate the effects of rapamycin and TCDD on skin lesions in imiquimod (IMQ)-induced psoriasis using a mouse model. TCDD aggravated skin inflammation in an IMQ-induced psoriatic mouse model. Furthermore, TCDD increased the expression of aryl hydrocarbon receptor (AHR), CYP1A1, proinflammatory cytokines, oxidative stress markers (NADPH oxidase (Nox) 2, Nox4), and phosphorylated P65NF-ĸB, whereas the expression of autophagy-related factors and the antioxidant marker nuclear factor-erythroid 2-related factor 2 (NRF2) decreased. Rapamycin reduced the aggravated skin inflammation induced by TCDD and restored TCDD-induced autophagy suppression and the increase of AHR expression, oxidative stress, and inflammatory response in the skin lesions of a psoriatic mouse model. In conclusion, we demonstrated that rapamycin alleviates TCDD-induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis through AHR and autophagy modulation.

Topics: Animals; Autophagy; Cell Differentiation; Cells, Cultured; Cytochrome P-450 CYP1A1; Dermatitis; Gene Expression Regulation; Humans; Imiquimod; Inflammation; Keratinocytes; Mice; NADPH Oxidase 4; NF-E2-Related Factor 2; Polychlorinated Dibenzodioxins; Psoriasis; Receptors, Aryl Hydrocarbon; Sirolimus

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Delayed Diagnosis; Dermatitis; Diagnostic Errors; Drug Substitution; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Prednisone; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tacrolimus; Vinblastine

A characteristic cutaneous eruption related to the use of cytostatic chemotherapeutic drugs has been described in the literature. This condition appears to be characterized by an erythematous eruption, primarily affecting the intertriginous areas bilaterally, together with eccrine squamous syringometaplasia as the main histologic feature.. We sought to establish the epidemiologic, clinical, and histologic characteristics of this poorly defined chemotherapy drug-related eruption.. Retrospective data were collected from 21 consecutive patients with this clinical and histopathologic pattern who attended an oncology center between January 1999 and September 2009. Two skin biopsy specimens were obtained from all patients, with the first being taken within 24 hours of onset, and the second 72 to 96 hours after onset.. The patients analyzed were predominantly female (72%), with a mean age of 52 years (range 10-69 years). The lesions presented clinically as bilateral erythematous plaques affecting both axillae (95%), groin (88%), and side aspects of the neck (48%). The main histologic feature in all cases was eccrine squamous syringometaplasia, characterized by the transformation of the eccrine cuboidal epithelium into two or more layers of squamous cells with intercellular bridges. The onset of the eruption appeared within 30 days (range 2-30 days) after the initiation of the cytostatic agent infusion. The lesions resolved with desquamation and postinflammatory hyperpigmentation. The same cutaneous pattern recurred in up to 50% of patients in whom the oncologist reintroduced the cytostatic treatment.. Small sample size was a limitation.. We suggest the term "chemotherapy-related bilateral dermatitis associated with eccrine squamous syringometaplasia" to describe this distinctive entity, which is primarily associated with pegylated liposomal doxorubicin infusions and chemotherapeutic regimens used in autologous bone-marrow transplantation.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Axilla; Child; Cytostatic Agents; Dermatitis; Doxorubicin; Drug Eruptions; Eccrine Glands; Female; Groin; Humans; Liposomes; Male; Middle Aged; Neck; Retrospective Studies; Sirolimus; Young Adult