Diabetic vascular complications remain a major cause of morbidity and mortality, yet the molecular mechanisms underlying endothelial dysfunction in diabetes remain incompletely understood. Endothelial dysfunction is a key contributor to vascular pathology, and patient-derived induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) provide a human platform to investigate disease-associated endothelial phenotypes under controlled conditions. Here, we identify the RNA-binding protein Quaking-7 (QKI-7) as a key regulatory factor associated with endothelial dysfunction in patient-derived iPSC-ECs. Using cells derived from diabetic and non-diabetic donors maintained under standard culture conditions, we demonstrate that elevated QKI-7 expression is associated with reduced expression of endothelial homeostatic genes (COL4A2, JUN, TMEM184A, and PPP1R15A) and impaired angiogenic capacity, including reduced tube formation. Importantly, these findings were further validated in three-dimensional blood vessel organoid models, supporting the relevance of QKI-7-associated endothelial phenotypes in a more physiologically complex vascular system. Connectivity mapping identified FDA-approved compounds, including simvastatin, halcinonide, and retinoic acid, as potential modulators of QKI-7-associated pathways. Functional validation in iPSC-ECs demonstrated that these compounds reduce QKI-7 expression and improve endothelial functional readouts. Together, these findings identify QKI-7 as a regulatory node associated with endothelial dysfunction in patient-derived iPSC-ECs and highlight the utility of human iPSC-based vascular models for identifying candidate therapeutic strategies. While these models capture endothelial phenotypes associated with diabetic donor origin, further studies in more complex in vivo systems will be required to establish causal relevance to vascular disease.

Atopic dermatitis is a typical chronic inflammatory disease with pathological characteristics of persistent immune activation and oxidative stress. Combined anti-inflammatory and antioxidant treatment can effectively block the inflammatory cascade while reducing oxidative damage. Halloysite nanotubes (HNTs) are the main components of the traditional Chinese medicine "Chishizhi", which shows the medicinal functions of hemostasis and astringency. However, the efficacy of HNTs alone in treating diseases is relatively weak, and their therapeutic effect can be improved by surface modification and drug loading. Herein, CuO-Fe3O4 nanoparticles were synthesized on the outer surfaces of HNTs by a hydrothermal reaction. CuO-Fe3O4@HNTs have high SOD and CAT enzyme activities under neutral conditions. Then, the nanozyme-modified HNT powder was prepared into sprayable hydrogels by introduction of sodium alginate (SA) and aloe vera extracts. Cell experiments confirmed that the hydrogel can promote HacaT cell proliferation within 0-200 μg mL-1 concentration. Through the mouse dermatitis model, it was seen that a CuO-Fe3O4@HNTs-SA composite hydrogel has a good therapeutic effect on atopic dermatitis. Compared with the positive drug halcinonide solution, the CuO-Fe3O4 nanozyme-incorporated hydrogel showed an enhanced therapeutic effect, which shows promising prospects for the clinical treatment of atopic dermatitis.

Atopic dermatitis (AD) is one of the most common allergic skin disorders affecting over 230 million people worldwide, while safe and efficient therapeutic options for AD are currently rarely available. Reactive oxygen species (ROS) accumulation plays a key role in AD's disease progression. Therefore, a novel single-atom catalyst is designed with isolated Cu1-N4 sites anchored on carbon support (Cu1-N4 ISAC), featuring triple antioxidant enzyme-mimicking activities, for efficient AD cascade catalytic therapy (CCT). The excellent superoxide dismutase (SOD)-, glutathione peroxidase (GPx)-, and ascorbate peroxidase (APx)-like activities of Cu1-N4 ISACs enable the sequential conversion of O2•[-] to H2O2 and then to harmless H2O, thereby protecting keratinocytes from oxidative stress damage. Notably, two novel experimental methods are developed to directly prove the SOD-GPx and SOD-APx cascade catalytic activities for the first time. In vivo experiments show that Cu1-N4 ISACs are more potent than a recommended typical medicine (halcinonide solution). Additionally, RNA sequencing and bioinformatic analysis reveal that Cu1-N4 ISACs reduce inflammation and inhibit ROS production by activating PPAR signaling, which is aberrantly reduced in AD. Therefore, the synthesized catalytic medicine offers an alternative to alleviate AD and has the potential to serve as PPAR agonists for treating similar diseases.

Synthetic steroid hormones are an emerging class of environmental pollutants, but their influence on pubertal timing remains unclear. This case-control study explored the association between synthetic steroid hormone exposure and precocious puberty. Using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), synthetic steroid hormones were detected in urine samples from 229 Chinese girls, aged 6-9 years. Puberty status was assessed using Tanner staging by professional pediatricians. We conducted the least absolute shrinkage and selection operator (LASSO) regression combined with logistic regression. Besides, we evaluated the joint effects of steroid hormone mixture and identified the main contributor using the Weighted quantile sum (WQS) model and Bayesian kernel machine regression (BKMR) model. The logistic regression model reflected an inverse individual association between precocious puberty and halcinonide [OR (95 %CI): 0.20 (0.07, 0.46)], and budesonide [OR (95 %CI): 0.77 (0.62, 0.95)]. In the joint effects utilizing the WQS model, precocious puberty showed a marginal association with steroid hormone mixture, but was not significant [OR (95 %CI): 0.88 (0.75, 1.04)]. Prednisolone (0.31), fluorometholone acetate (0.24), and dexamethasone acetate (0.12) had the highest weight. Consistently, mixture exposure was not associated with precocious puberty in the BKMR model. In conclusion, precocious puberty was associated with halcinonide and budesonide exposure, but not steroid hormone mixture among girls. It highlighted the management of the residual synthetic steroid hormones in the environment and provided a direction for the prevention of precocious puberty.

Atopic dermatitis (AD) is a prevalent chronic inflammatory skin disease that carries a significant global economic burden. Elevated levels of reactive oxygen species (ROS) have been recognized as contributing to AD exacerbation, making them a potential therapeutic target for AD treatment. Here, we introduce a dual-site biomimetic copper/zinc metal-organic framework (Cu/Zn-MOF) featuring four types of enzyme-like activities for AD treatment via suppressing the Fcγ receptor (FcγR)-mediated phagocytosis signal by mimicking the bimetallic sites of natural copper-zinc superoxide dismutase (CuZn-SOD). Interestingly, the neighboring Cu and Zn sites in both Cu/Zn-MOF and CuZn-SOD are at similar distances of ∼5.98 and ∼6.3 Å from each other, respectively, and additionally, both Cu and Zn sites are coordinated to nitrogen atoms in both structures, and the coordinating ligands to Cu and Zn are both imidazole rings. Cu/Zn-MOF exhibits remarkable SOD-like activity as well as its glutathione peroxidase (GPx)-, thiol peroxidase (TPx)-, and ascorbate peroxidase (APx)-like activities to continuously consume ROS and mitigate oxidative stress in keratinocytes. Animal experiments show that Cu/Zn-MOF outperforms halcinonide solution (a potent steroid medication) in terms of preventing mechanical injuries, reducing cutaneous water loss, and inhibiting inflammatory responses while presenting favorable biosafety. Mechanistically, Cu/Zn-MOF functions through an FcγR-mediated phagocytosis signal pathway, decreasing the continuous accumulation of ROS in AD and ultimately suppressing disease progression. These findings will provide an effective paradigm for AD therapy and contribute to the development of two-site bionics (TSB).

Halcinonide is a topical corticosteroid approved by the US Food and Drug Administration (FDA), known for its anti-inflammatory and antipruritic properties. The therapeutic benefits of halcinonide have rendered it an effective treatment regimen for various dermatological conditions such as psoriasis, dermatitis, and eczema. However, stability of the drug substance is a prerequisite in determining the therapeutic efficacy and plays a crucial role during formulation development and long-term storage. As corticosteroids are highly susceptible to degradation, the current study aims to expose halcinonide to different stress conditions and understand its stability behavior. An HPLC method was developed for the separation of halcinonide and its degradation products. Separation was accomplished in gradient mode using an Eclipse Plus C18 column (250 × 4.5 mm, 5 μm) with ammonium formate (10 mM, pH 6.5) and acetonitrile as the mobile phases. LC-Q-TOF/MS/MS studies were conducted on halcinonide, which led to the identification of degraded products using optimized mass parameters. A potential mechanistic degradation pathway for halcinonide, along with the major identified degradation products has been established. The chromatographic method that was developed has been validated in compliance with the Q2(R1) guideline of the International Council for Harmonization. ProTox-II was used to perform in silico toxicity studies in order to evaluate the toxicity potential of both halcinonide and the identified degradation products.

Lichen sclerosis (LS) is an insidious, chronic, relapsing skin disease characterized by atrophic, porcelain-appearing plaques. It usually arises in the anogenital area, but some cases can present in extragenital regions with a variety of presentations, including a bullous variant. Topical corticosteroids are a first-line therapy and are usually the most effective treatment to induce remission of LS. However, there is a subset of patients that does not respond well to topical steroids. Herein, we report an extragenital bullous LS case successfully treated with a fractional CO2 laser (FxCO2) and subsequent wet dressing of halcinonide solution.

The potencies of topical corticosteroid products have mainly been classified using clinical data but in some instances, the US Food and Drug Administration's (FDA's) vasoconstrictor assay (VCA) to assess the skin blanching response has also been used. However, the reported skin blanching response data were often based on a single visual reading and lack information on the dose (amount/quantity) or dose duration. Although several lists classifying potencies of various topical corticosteroid products have been published, the inherent potencies of topical corticosteroid raw materials used as active pharmaceutical ingredients (APIs) have not been investigated. The objective was to rank the inherent potencies of topical corticosteroid APIs and to standardize dosing such that the relevant compounds could be compared on a normalized molar basis. The potencies of clobetasol propionate, halcinonide, mometasone furoate, and fluocinolone acetonide were compared using the resulting Emax data following the fitting of the relevant response data to the Emax model where mometasone furoate > fluocinolone acetonide = clobetasol propionate > halcinonide. This ranking lists the respective inherent potencies of the APIs, which will facilitate the choice of a suitable candidate for incorporation into an appropriate topical corticosteroid product for a specific clinical indication.

The recent outbreak of COVID-19 has become a global health concern. There are currently no effective treatment strategies and vaccines for the treatment or prevention of this fatal disease. The current study aims to determine promising treatment options for the COVID-19 through a computational drug repurposing approach.

Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug-gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.