Exosomes are nanosized extracellular vesicles that mediate intercellular communication by transferring bioactive molecules. Mesenchymal stem cells (MSCs) from different tissue sources secrete exosomes with potentially distinct therapeutic properties. In this study, we compared the anti-inflammatory efficacy of exosomes derived from human adipose-derived MSCs (hADMSCs-EXOs) and human umbilical cord-derived MSCs (hUCMSCs-EXOs), together with desoximetasone (DSM), in an imiquimod-induced psoriasis mouse model. Psoriasiform lesions were induced, and treatment outcomes were assessed through clinical, histological, and immunological assessments. Both hADMSCs-EXOs and hUCMSCs-EXOs significantly attenuated psoriasiform lesions, as clinically evidenced by reduced cumulative Psoriasis Severity Index (PSI) scores by day 6 of treatment. Notably, hUCMSCs-EXOs and DSM significantly reduced epidermal and dermal thickness to no significant difference compared to the control group. Immune cell infiltration, including CD3[+], CD4[+], CD8[+] T cells, CD68[+] macrophages, CD117[+] mast cells, and neutrophils, was also markedly reduced in the hUCMSCs-EXOs and DSM groups. Importantly, unlike DSM, hUCMSCs-EXOs did not induce skin thinning or systemic adverse effects. Growth factor (GF) profiling revealed that hADMSCs-EXOs were enriched in FGFs, PDGFs, and VEGF, whereas hUCMSCs-EXOs contained higher levels of HGF, a key modulator of immunoregulation and tissue repair. Collectively, these findings suggest that MSC-derived exosomes exert therapeutic effects through both anti-inflammatory and regenerative mechanisms, with hUCMSCs-EXOs demonstrating superior anti-inflammatory efficacy over hADMSCs-EXOs and a lower likelihood of inducing local or systemic adverse effects compared with DSM. Given the influence of MSC tissue origin on exosome content and function, our results support the potential of hUCMSCs-EXOs as a promising steroid-sparing therapeutic approach for psoriasis.

Sakuranetin, a methoxylated flavanone with known anti-inflammatory and antioxidant properties, has yet to be explored for its therapeutic potential in psoriasis treatment. This study evaluates its efficacy in an imiquimod-induced psoriasis-like murine model, focusing on both immune modulation and skin barrier restoration. Topical administration of sakuranetin significantly attenuated psoriatic inflammation, with high-dose treatment achieving comparable efficacy to desoximetasone. RNA sequencing and qPCR validation revealed that sakuranetin modulates keratinization, cornified envelope formation, and kallikrein-related peptidase activity, suggesting its role in epidermal homeostasis. Notably, sakuranetin selectively downregulated IL-17A while maintaining IL-17F expression, supporting a targeted immunomodulatory effect. Additionally, sakuranetin upregulated KRT1, KRT16, KLK7, Sprr2f, and Wfdc18 while downregulating Sprr2k and Sprr3, indicating a refined regulation of skin barrier proteins. The observed upregulation of Tslp suggests a potential role in epidermal repair mechanisms. These findings highlight sakuranetin as a novel, plant-derived therapeutic candidate with dual anti-inflammatory and skin barrier-enhancing properties, providing a potential corticosteroid-sparing approach for long-term psoriasis management.

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to identify, by network analysis, the miRNAs involved in CVD as potential biomarkers, either by interacting with small molecules such as toxins and pollutants or by searching for new drugs. Our study shows an updated landscape of the signaling pathways involving miRNAs in CVD pathology. This latest research includes data found through experimental tests and uses predictions to propose both miRNAs and genes as potential biomarkers to develop diagnostic and therapeutic methods for the early detection of CVD in the clinical setting. In addition, our pharmacological network analysis has, for the first time, shown how to use these potential biomarkers to find small molecules that may regulate them. Between the small molecules in this research, toxins, pollutants, and drugs showed outstanding interactions with these miRNAs. One of them, hesperidin, a widely prescribed drug for treating CVD and modulating the gene expression associated with CVD, was used as a reference for searching for new molecules that may interact with miRNAs involved in CVD. Among the drugs that exhibit the same miRNA expression profile as hesperidin, potential candidates include desoximetasone, curcumin, flurandrenolide, trifluridine, fludrocortisone, diflorasone, gemcitabine, floxuridine, and reversine. Further investigation of these drugs is essential to improve the treatment of cardiovascular disease. Additionally, supporting the clinical use of miRNAs as biomarkers for diagnosing and predicting CVD is crucial.

Familial Reactive Perforating Collagenosis (FRPC) is a very rare form of benign dermatosis frequently presented during early childhood and not associated with systemic diseases. Less than 50 FRPC patients have been reported in the literature. Due to the limited number of cases, the pathophysiology of this unique entity remains elusive; moreover, no standard treatment has been agreed upon. Here, we report a case of FRPC in a 20-year-old male who was presented with generalized multiple discrete papules covered with central keratotic plugs in all regions of his body, particularly in the facial area, neck, abdominal, and extensor region of the extremities for more than 7 years. Similar symptoms were acknowledged in the patient's family members. Histopathological analyses identified the crateriform shape invagination in the epidermis filled with inflammatory lymphocytes and basophilic debris and perforated by basophilic collagen bundles from the underlying dermis. Based on the clinical and histopathological findings, the patient was diagnosed with FRPC. He was treated with topical desoximetasone 0.25% cream applied 2-3 times daily. A follow-up evaluation after 4 weeks revealed a near-complete resolution of skin papules. To our knowledge, this is the first report of FRPC case from Indonesia. Unlike the majority of FRPC patients who had their disease onsets during infancy or early childhood, FRPC skin manifestations in our patient started during the adolescence period. The resolution of skin manifestations after daily application of topical desoximetasone suggests that topical corticosteroids are a potential treatment option for FRPC patients.

The administration of therapeutic drugs through dermal routes, such as creams and ointments, has emerged as an increasingly popular alternative to traditional delivery methods, such as tablets and injections. In the context of drug development, it is crucial to identify the optimal doses and delivery routes that ensure successful outcomes. Physiologically based pharmacokinetic (PBPK) models have been proposed to simulate drug delivery and optimize drug formulations, but the calibration of these models is challenging due to the multitude of variables involved and limited experimental data. One significant research gap that this article addresses is the need for more efficient and accurate methods for calibrating PBPK models for dermal drug delivery. This manuscript presents a novel approach and an integrated dermal drug delivery model to address this gap that leverages virtual in vitro release (IVRT) and permeation (IVPT) testing data to optimize mechanistic models. The proposed approach was demonstrated through a study involving Desoximetasone cream and ointment formulations, where the release kinetics and permeation profiles of Desoximetasone were determined experimentally, and a computational model was created to simulate the results. The experimental studies showed that, even though the cumulative permeation of Desoximetasone at the end of the permeation study was comparable, there was a significant difference seen in the lag time in the permeation of Desoximetasone between the cream and ointment. Additionally, there was a significant difference seen in the amount of Desoximetasone permeated through human cadaver skin at early time points when the cream and ointment were compared. The computational model was optimized and validated, suggesting that this approach has the potential to bridge the existing research gap by improving the accuracy and efficiency of drug development processes. The model results show a good fit between the experimental data and model predictions. During the model optimization process, it became evident that there was variability in both the permeability and the partition coefficient within the stratum corneum. This variability had a significant and noteworthy influence on the overall performance of the model, especially when it came to its capacity to differentiate between cream and ointment formulations. Leveraging virtual models significantly aids the comprehension of drug release and permeation, mitigating the demanding data requirements. The use of virtual IVRT and IVPT data can accelerate the calibration of PBPK models, streamline the selection of the appropriate doses, and optimize drug delivery. Moreover, this novel approach could potentially reduce the time and resources involved in drug development, thus making it more cost-effective and efficient.

Over the last decade, applications of ion mobility-mass spectrometry (IM-MS) have exploded due primarily to the widespread commercialization of robust instrumentation from several vendors. Unfortunately, the modest resolving power of many of these platforms (~40-60) has precluded routine separation of constitutional and stereochemical isomers. While instrumentation advances have pushed resolving power to >150 in some cases, chemical approaches offer an alternative for increasing resolution with existing IM-MS instrumentation. Herein we explore the utility of two reactions, derivatization by Girard's reagents and 1,1-carbonyldiimidazole (CDI), for improving IM separation of steroid hormone isomers. These reactions are fast (≤30 min), simple (requiring only basic lab equipment/expertise), and low-cost. Notably, these reactions are structurally selective in that they target carbonyl and hydroxyl groups, respectively, which are found in all naturally occurring steroids. Many steroid hormone isomers differ only in the number, location, and/or stereochemistry of these functional groups, allowing these reactions to "amplify" subtle structural differences and improve IM resolution. Our results show that resolution was significantly improved amongst CDI-derivatized isomer groups of hydroxyprogesterone (two-peak resolution of Rpp = 1.10 between 21-OHP and 11B-OHP), deoxycortisone (Rpp = 1.47 between 11-DHC and 21-DOC), and desoximetasone (Rpp = 1.98 between desoximetasone and fluocortolone). Moreover, characteristic collision cross section ([DT]CCSN2) measurements can be used to increase confidence in the identification of these compounds in complex biological mixtures. To demonstrate the feasibility of analyzing the derivatized steroids in complex biological matrixes, the reactions were performed following steroid extraction from urine and yielded similar results. Additionally, we applied a software-based approach (high-resolution demultiplexing) that further improved the resolving power (>150). Overall, our results suggest that targeted derivatization reactions coupled with IM-MS can significantly improve the resolution of challenging isomer groups, allowing for more accurate and efficient analysis of complex mixtures.

(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism of cytochrome P450 3A4 substrate drugs. Desoximetasone, a topical corticosteroid and cytochrome P450 3A4 substrate, is used to treat skin conditions such as skin allergies, atopic dermatitis, and psoriasis. In this study, we aimed to investigate the anti-psoriatic effect of a low dose of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the epidermis. (2) Methods: Psoriasis-like skin was induced in BALB/c mice via the topical administration of imiquimod. The mice were then topically treated with 0.01-0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient microemulsion, 0.25% commercial desoximetasone ointment, or 0.5 mg/gm clobetasol ointment. (3) Results: The topical application of 0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation restored the imiquimod-induced skin barrier disruption and resulted in fewer severe clinical and pathological features compared with the treatments with 0.25% commercial desoximetasone ointment and 0.5 mg/gm clobetasol ointment. (4) Conclusions: The cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation improved and prolonged the therapeutic effect of cytochrome P450 3A4 substrate drugs and may be a promising approach for psoriasis treatment.

Physiologically based pharmacokinetic (PBPK) models are widely accepted tools utilised to describe and predict drug pharmacokinetics (PK). This includes the use of dermal PBPK models at the regulatory level including virtual bioequivalence (VBE) studies. The current work considers the Topicort® Spray formulation, which contains 0.25% desoximetasone (DSM), as an example formulation. Quantitative formulation composition and in vitro permeation testing (IVPT) data were obtained from the public literature to develop a mechanistic model using the multi-phase, multi-layer (MPML) MechDermA IVPT module in the Simcyp Simulator. In vitro-in vivo extrapolation functionality was used to simulate in vivo PK for various scenarios and predict a 'safe space' for formulation bioequivalence using the VBE module. The potential effect of vasoconstriction, impaired barrier function, and various dosing scenarios on the formulation safe space was also assessed. The model predicted 'safe space' for formulation solubility suggesting that a 50% change in solubility may cause bio-in-equivalence, whereas viscosity could deviate by orders of magnitude and the formulation may still remain bioequivalent. Evaporation rate and fraction of volatile components showed some sensitivity, suggesting that large changes in the volume or composition of the volatile fraction could cause bio-in-equivalence. The tested dosing scenarios showed decreased sensitivity for all formulation parameters with a decreased dose. The relative formulation bioequivalence was insensitive to vasoconstriction, but the safe space became wider with decreased barrier function for all parameters, except viscosity that was unaffected.

The article description and significance to dermatologists: bleomycin flagellate dermatitis is a rare cutaneous manifestation, believed to be due to the lack of bleomycin hydrolase enzyme in the skin, which inactivates bleomycin, resulting in its accumulation. This is thought to be a dose-dependent reaction, and doses over 200 U and higher may increase risk. This case describes a male developing a pruritic, erythematous linear flagellated dermatitis to the lower back after his third cycle of bleomycin, etoposide and cisplatin for a stage 3 seminoma. Pruritis resolved and erythema improved with the treatment of bilastine and desoximetasone cream. It is important to recognize this condition because untreated pruritis may lead to increased impairment of the skin barrier in already immunocompromised patient populations. This may also give further evidence to having ongoing and continuing collaboration between Dermatology and Medical Oncology for any patients presenting with a new rash undergoing chemotherapy treatments.

Hypopigmented mycosis fungoides (HMF) is a rare variant of patch stage MF, which is often misdiagnosed. A 35-year-old male presented with non-pruritic white patches on his chest that had been present for 10 years. The patient had previously been treated for leprosy without any improvement. Physical examination showed well-defined multiple hypopigmented patches and macules on the chest, posterior trunk, and gluteus, with some lesions exhibiting anhidrosis and central erythema. The result of sensibility examination was unclear. Slit-skin-smear examination for acid-fast bacilli and anti-phenolic-glycolipid-1 examination were negative. Histopathological examination showed Pautrier microabscesses. The patient was diagnosed with HMF and was treated with 16 mg methylprednisolone b.i.d., topical application of desoximetasone, and 1% methoxsalen lotion followed by sun exposure. A significant improvement was observed during the following 6 months. This case shows that HMF needs to be considered in patients presenting with chronic unexplained hypopigmented patches to avoid unnecessary treatment and progression to more advanced stages.

Psoriasis is a chronic, recurrent, immune-mediated disease involving the skin and joints. Epidermal hyperproliferation, abnormal keratinocyte differentiation, angiogenesis with blood vessel dilatation, and excess T helper type-1 (Th-1) and Th-17 cell infiltration are the main histopathological features of psoriasis. Magnolol is a polyphenolic compound that exerts its biological properties through a variety of mechanisms such as the NF-κB/MAPK, Nrf2/HO-1 and PI3K/Akt pathways. Magnolol has been demonstrated to exert a number of therapeutic effects on dermatological processes, including acting as an anti-inflammation, antiproliferation and antioxidation agent. However, few studies have been published on the effect of magnolol on psoriasis. Therefore, the present study aimed to elucidate the mechanism of action of magnolol on psoriasis. BALB/c mice were treated topically with imiquimod (IMQ) to induce psoriasis-like dermatitis, and were randomly assigned to the control, vehicle control, low- and high-dose magnolol, and 0.25% desoximetasone ointment treatment groups in order to investigate skin barrier function, any changes in the levels of cytokines and for the histological assessment. High doses of magnolol were indicated to be able to improve the barrier function following IMQ-induced barrier disruption. Magnolol activated peroxisome proliferator-activated receptor-γ, and also significantly inhibited the protein expression of interleukin (IL)-23, IL-1β, IL-6, tumor necrosis factor-α and interferon-γ. However, administering a high dose of magnolol did not lead to any improvement in the clinical and pathological features of the psoriasis severity Taken together, these results demonstrated that downregulation of IL-23 may contribute to barrier function improvement in a psoriatic skin model.

Psoriasis is a chronic autoimmune skin disease impacting the population globally. Pharmaceutical products developed to combat this condition commonly used in clinical settings are IV bolus or oral drug delivery routes. There are some major challenges for effectively developing new dosage forms for topical use: API physicochemical nature, the severity of the disease state, and low bioavailability present challenges for pharmaceutical product developers. For non-severe cases of psoriasis, topical drug delivery systems may be preferred or used in conjunction with oral or parenteral therapy to address local symptoms. Elastic vesicular systems, termed "niosomes", are promising drug delivery vehicles developed to achieve improved drug delivery into biological membranes. This study aimed to effectively incorporate a corticosteroid into the niosomes for improving the drug bioavailability of desoximetasone, used to treat skin conditions via topical delivery. Niosomes characterization measurements were drug content, pH, spreadability, specific gravity, content uniformity, rheology, and physicochemical properties. Formulations used a topical gelling agent, Carbomer 980 to test for in vitro skin permeation testing (IVPT) and accelerated stability studies. The developed niosomal test gel provided approximately 93.03 ± 0.23% to 101.84 ± 0.11% drug content with yield stresses ranging from 16.12 to 225.54 Pa. The permeated amount of desoximetasone from the niosomal gel after 24 h was 9.75 ± 0.44 µg/cm2 compared to 24.22 ± 4.29 µg/cm2 released from the reference gel tested. Furthermore, a drug retention study compared the test gel to a reference gel, demonstrating that the skin retained 30.88 ng/mg of desoximetasone while the reference product retained 26.01 ng/mg. A controlled drug release profile was obtained with a niosomal formulation containing desoximetasone for use in a topical gel formulation showing promise for potential use to treat skin diseases like psoriasis.