BACKGROUND:Sporotrichosis is a chronic, deep fungal infection of skin caused by Sporothrix schenckii. Macrophages are predominant in S. schenckii-infected skin and are able to phagocytize and kill the fungus. Local hyperthermia is effective for treating sporotrichosis, but its mechanism of action is still not fully understood. METHODS:Using single-cell RNA sequencing of sporotrichosis lesions, coupled with in vitro and in vivo sporotrichosis models, we investigated the role of tumor necrosis factor receptor-associated factor 1 (TRAF1) and nitric oxide synthase, inducible (NOS2). Mechanistic studies included coimmunoprecipitation, ubiquitination assays, and site-directed mutagenesis. Therapeutic mechanisms of hyperthermia were evaluated in vivo and in vitro. RESULTS:We demonstrated for the first time that TRAF1 could delay the healing of sporotrichosis by inhibiting phagocytosis and killing of macrophages with S. schenckii. This effect of TRAF1 is caused by binding NOS2 to regulate its expression and enzymatic activity, through inhibition of NOS2 ubiquitination and subsequent proteasome-induced degradation. Our team's previous research has demonstrated the efficacy of hyperthermia in treating sporotrichosis. Our experiments indicate that hyperthermia can down-regulate the expression of TRAF1 and NOS2 in macrophages. CONCLUSIONS:We identify TRAF1-mediated stabilization of NOS2 as a key immune evasion mechanism in S. schenckii infection. Local hyperthermia represents a targeted therapy against this pathway, offering a novel strategy for enhancing the therapeutic effect of hyperthermia.

Neutrophils, the most abundant of the circulating leucocytes, play crucial roles in antimicrobial defence, tissue remodelling, and immune regulation. Traditionally regarded as predominantly glycolytic, relying on aerobic glycolysis (the Warburg effect) for rapid ATP generation, neutrophils are now recognised to possess broader metabolic flexibility. Emerging evidence has revealed their capacity for oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glutaminolysis. As a result, mitochondrial metabolism is dynamically reprogrammed during differentiation and activation. These metabolic shifts in mitochondria profoundly influence essential neutrophil functions, including extracellular trap (NET) formation, reactive oxygen species (ROS) generation, chemotaxis, and apoptosis. In inflammatory skin diseases, mitochondrial dysfunction amplifies pathological responses by enhancing ROS production and driving NETosis. Specifically, in conditions such as psoriasis, cutaneous lupus erythematosus, and Behçet's disease, neutrophil mitochondrial activity is markedly increased, and this increase correlates with disease activity and progression. Notably, mitochondrial ROS have emerged as critical mediators of inflammation, triggering pathways such as PAD4 (peptidylarginine deiminase type 4)-dependent NETosis, inflammasome activation, and proinflammatory cytokine release. Accordingly, therapeutic strategies targeting neutrophil mitochondrial pathways, including ROS scavengers, mitophagy inducers, and metabolic modulators, are gaining increasing attention as promising approaches to mitigate neutrophil-driven skin inflammation. In this review recent advances in understanding mitochondrial metabolism in neutrophils, with particular emphasis on the pathological roles and therapeutic potential of this metabolism as related to inflammatory skin disorders are described.

Facial verruca plana can be therapeutically challenging and cosmetically distressing when extensive. Conventional ablative treatments (for example, cryotherapy) often carry risks of scarring and discomfort. We report a novel combination of local hyperthermia and topical interferon alpha-2b gel that achieved rapid, scar‑free clearance of widespread facial warts within 3 weeks. A 49‑year‑old Han Chinese male patient presented with over 60 verruca plana distributed across the cheeks, forehead, and nose. He had no history of immunodeficiency or systemic disease. Previous topical therapies yielded minimal improvement. The patient was treated with a pulsed regimen of local infrared hyperthermia (44 ± 2 °C) targeting representative lesions, combined with twice-daily topical application of interferon alpha-2b gel. By the sixth hyperthermia session (approximately 2 weeks after initiation), significant lesion regression was observed. Near‑complete clearance occurred by the tenth session (3 weeks), with no scarring or adverse effects. At the 16‑week follow‑up, there was no recurrence. The combination of targeted local hyperthermia and topical interferon alpha-2b gel appears to be a safe, effective, and cosmetically favorable treatment for extensive facial verruca plana. This regimen harnesses both immunomodulatory and antiviral mechanisms to accelerate viral lesion clearance while preserving skin integrity. Further studies in larger cohorts are warranted to validate this approach.

Immune‑regulatory dysfunction caused by human papillomavirus (HPV) infection can lead to severe condyloma acuminate (CA), and the treatment is challenged by obstinacy and recurrence. Hyperthermia treatment stimulates the immune response by raising the body temperature locally to fight pathogens. Hyperthermia treatment possesses advantages of low recurrence rate and good efficacy in curing viral warts. However, the exact modulatory mechanism of hyperthermia treatment on immune response remains to be addressed. HPV 16 pseudovirus (HPV.PSV)‑infected HaCaT cells were established to mimic clinical HPV infection. Flow cytometry showed higher major histocompatibility complex class I (MHC‑I) expression in HPV.PSV infected cells. HPV.PSV‑infected cells, CaSki cells and CA tissue demonstrated upregulated MHC‑Ⅰ expression following 44˚C water bath incubation, as detected by flow cytometry and IHC. 4D‑FastDIA quantitative proteomics was used to analyze differential protein expression in CaSki cells following 37‑ or 44˚C incubation. High mobility group box (HMGB)1 was upregulated following 44˚C incubation, as shown by ELISA and western blotting. By applying HMGB1 knockdown cell lines established by small interfering RNA, the present study demonstrated HMGB1 was essential to MHC‑Ⅰ expression, which was detected by flow cytometry and the recombinant HMGB1 protein addition test. Western blotting and ELISA demonstrated that hyperthermia increased heat shock protein family A member 6 (HSPA6) expression and JNK phosphorylation, which resulted in greater secretion of HMGB1. Hyperthermia treatment facilitated HSPA6‑modulated JNK phosphorylation, which lead to HMGB1 secretion and enhanced the expression of MHC‑Ⅰ in HPV‑infected epithelial cells, as well as strengthened the host immune regulation and recognition.

Actinic keratosis is a precancerous skin lesion caused by long-term sun exposure, and may progress to cutaneous squamous cell carcinoma. Bowen disease is a squamous cell carcinoma in situ of the epidermis. Differential diagnosis of actinic keratosis, Bowen disease and cutaneous squamous cell carcinoma, as well as early diagnosis of cutaneous squamous cell carcinoma, has always been research hotspots. This review summarizes biomarkers related to the malignant progression of actinic keratosis, with a view to providing a reference for early clinical diagnosis.

Psoriasis is a recurrent autoimmune disease. No biological factor that is associated with the risk of psoriasis has been definitively identified. The potential role of the immunogen double-stranded (ds)DNA as a trigger of and biomarker for psoriasis warrants exploration. This multicentre case-control study included 3 069 patients with psoriasis and 7 041 healthy controls from 12 regions in China. The associations of the serum dsDNA level with the psoriasis risk and severity were analysed in the overall population. The serum dsDNA level was significantly higher in patients than in controls. Each 0.1 ng/mL increase in serum dsDNA was significantly associated with increased odds of psoriasis (adjusted odds ratio, 1.45; 95% confidence interval, 1.40-1.48; p < 0.001). The optimal serum dsDNA cutoff value for the diagnosis of psoriasis was 1.11 ng/mL, with 61.6% sensitivity and 74.8% specificity. A significant dose-response relationship was observed between the serum dsDNA level and the risk of psoriasis-associated morbidity when using the optimal dsDNA cutoff value as the reference. Serum dsDNA levels were positively associated with higher PASI and BSA scores and the severity of psoriasis. These findings suggest that serum dsDNA level is strongly associated with psoriasis morbidity and severity.

An interest in the production of unilamellar liposomes (ULs) as a drug carrier vector for a wide range of different substances is increasing, in particular for dermatology applications. Formulations of concentrated unilamellar liposomes (ULs) with controlled size below 400 nm enhance the efficiency of drug delivery in topical skin applications, primarily by improving local deposition and retention of the encapsulated compound, rather than penetration of intact vesicles. In a recent work, a spinning disk reactor (SDR) was used to produce UL suspensions. The same method of production was here applied, focusing on encapsulation of Rhodamine as a drug model substance. The production protocol was optimized for dermatological applications, targeting a modal size of 180 nm with a narrow polydispersity index (PDI), chosen to balance stability, payload, and dermal deposition efficiency. After the suspension production, the ULs were concentrated and recovered from the solution by adopting a membrane separation process. The obtained results validate the suggested approach, demonstrating that the adopted SDR is capable of producing ULs of the desired size of 180 nm with a PDI of 0.28, encapsulating 65 % of the Rhodamine at a rate of 14.4 L day-1. Liposomes as small as 60 nm were also produced, but were not selected for dermatological applications due to lower payload and reduced deposition in deeper skin layers. Using ultrafiltration (UF), it was possible to separate the ULs from the bulk liquid, allowing recycling of unencapsulated drug and obtaining concentrated liposomes containing 1.12 mu g mL-1 Rhodamine for topical formulations. Finally, a process scheme is proposed as an example of a possible industrial production of drug-loaded liposomes.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by NF1 gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features, NF1 variant spectrum, and external variant contextualization remain limited. We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and NF1 variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived NF1 variant data. Among 847 patients, the median age was 23 years, 27.5

INTRODUCTION:Clearance of cerebral Aβ was primarily mediated by the brain endothelial transporters including LRP1. The regulatory mechanism of LRP1 expression remained unclear. METHODS:LRP1 in brain endothelial cells treated with pro-CTSD were analyzed by western blot. Transgenic mice with high circulatory pro-CTSD (hCTSDhi) were generated to assess LRP1 levels and brain Aβ deposition by immunostaining and live-imaging. Internalization of pro-CTSD and its co-localization with LRP1 was analyzed using confocal and TIRF microscopy. RESULTS:Circulatory pro-CTSD is increased in the AD models. hCTSDhi mice exhibited reduced endothelial LRP1 and impaired Aβ clearance. Soluble pro-CTSD bound the Cluster II domain of LRP1, triggering LRP1 endocytosis and lysosomal degradation. Crossing hCTSDhi mice with AD models increased brain Aβ deposition and exaggerated cognitive deficit. DISCUSSION:Circulatory pro-CTSD triggered degradation of brain endothelial LRP1 to inhibit brain-to-blood Aβ clearance.

Psoriasis is increasingly recognized as a systemic immune-mediated disorder that extends beyond cutaneous inflammation. Although skin lesions are its most visible manifestation, growing evidence indicates that psoriasis reflects a broader disruption of immune homeostasis accompanied by sustained systemic inflammatory activation. Persistent immune activation, altered myeloid programming, and dysregulated immunometabolic pathways together establish a state of chronic inflammatory priming. This systemic inflammatory state contributes to multi-organ comorbidities and also favors disease relapse through durable immune memory and trained immunity. In this review, we propose that psoriasis reflects maladaptive reprogramming of the systemic immune set-point, such that both spatial multi-organ involvement and temporal disease recurrence arise from shared immunologic mechanisms. Viewing psoriasis in these terms has important implications for comorbidity assessment, long-term maintenance strategies, and the pursuit of disease modification.

Psoriasis is a common immune-mediated skin disease driven largely by interleukin-17A (IL-17A). Although IL-17A plays a key role in disease pathogenesis, the underlying mechanisms remain incompletely understood. Through bioinformatic analysis, we discovered that proline/arginine-rich end leucine-rich repeat protein (PRELP) expression is upregulated in skin lesions from psoriasis patients following treatment with IL-17A inhibitors (secukinumab, ixekizumab, and brodalumab), despite being significantly downregulated in lesional compared to nonlesional skin at baseline. Experimental assays confirmed that IL-17A suppressed PRELP expression in keratinocytes, consistent with its reduced expression in lesional tissues from both murine models and human patients. Functionally, PRELP suppressed keratinocyte proliferation, promoted apoptosis, and attenuated activation of the NF-κB and MAPK pathways, along with downstream proinflammatory cytokine and chemokine production. By downregulating IL6 in keratinocytes, PRELP further attenuated local IL-17A production via IL6 modulation, suggesting a break in the feed-forward loop of psoriatic inflammation. Intradermal administration of AAV-K14-PRELP ameliorated psoriasis-like findings in mice, including erythema, scaling, epidermal hyperplasia, and Th17 cell infiltration. Mechanistically, IL-17A suppressed PRELP transcription by activating STAT3, which directly binds to the PRELP promoter as a transcriptional repressor. Collectively, our findings identify PRELP as a negative regulator of IL-17A signaling in psoriasis, acting through keratinocyte dysregulation and modulation of Th17 cells. Therapeutic strategies aimed at enhancing PRELP expression may represent a novel approach for treating psoriasis and other Th17-driven inflammatory diseases.

Androgenetic alopecia is the most common hair loss disorder, influenced by distinct genetic factors and intricate environmental factors. The exosomes (Exos) from adipose-derived mesenchymal stem cells (ADMSCs) have diverse effects, including the promotion of cell proliferation, inhibition of apoptosis, analgesia, and enhancement of wound healing. MicroRNAs are essential components of the paracrine secretion of ADMSC-derived Exos. This study revealed that ADMSC-derived Exos could counteract the impairment of dermal papilla cells induced by dihydrotestosterone by inhibiting the TGF-β1 signaling pathway`s activation. Two miRNAs-miR-574-3p and miR-125a-5p-were identified as being predominantly expressed and specifically targeting TGF-β1 and SMAD2, respectively. Notably, individually knocking down miR-574-3p or miR-125a-5p did not affect the therapeutic efficacy of ADMSC-derived Exos. Yet, when both miR-574-3p and miR-125a-5p were concurrently knocked down, the efficacy of ADMSC-derived Exos was markedly reduced. Ultimately, our findings indicate that ADMSC-derived Exos target the TGF-β1/SMAD2 signaling pathway through miR-574-3p and miR-125a-5p, which are integral to the therapeutic action of ADMSC-derived Exos on dihydrotestosterone-induced dermal papilla cells and androgenetic alopecia murine models. This discovery offers significant insights into the pathogenesis of androgenetic alopecia and suggests potential therapeutic approaches. Further investigation into the role and interaction of these miRNAs in ADMSC-derived Exos may lead to the development of more precise and efficacious treatments for androgenetic alopecia.

Viral warts, a common dermatological condition caused by human papillomavirus infection (HPV) infection, present a particular challenge for systemic lupus erythematosus (SLE) patients due to their compromised immunity, which increases the susceptibility to HPV infection and complicates treatment efforts. Imiquimod, an immunomodulatory agent, has demonstrated efficacy in managing warts. Furthermore, local hyperthermia, a non-invasive therapeutic modality, has demonstrated significant potential in the management of warts. We report the case of a SLE patient developed recalcitrant and extensive viral warts on limbs. We applied hyperthermia at 45 °C on a target lesion for 1 hour / day with imiquimod cream 3 times/week. All the lesions cleared in 8 months and there was no sign of recurrence.

The fibroblast growth factor (FGF) superfamily comprises 23 structurally related members that play pivotal roles in a wide range of biological and pathophysiological processes. These heparin-binding growth factors exert their functions through paracrine or endocrine signaling, regulating critical processes such as embryonic development, hair regeneration, wound healing, and metabolic homeostasis. FGFs primarily signal through four fibroblast growth factor receptors (FGFRs) and are classified into six subfamilies based on their structural homology and functional similarity. Among these, the FGF9 subfamily—consisting of FGF9, FGF16, and FGF20—exhibits preferential binding to FGFR2 and FGFR3. Initially identified as a glia-activating factor (GAF), FGF9 was first characterized as a potent mitogen in glial cells. Recombinant human FGF 9 (rhFGF9), the engineered expression product of FGF family members, offers significant advantages for clinical research and therapeutic applications, including standardized production, elimination of pathogen contamination risks, and consistent bioactivity. FGF9 has emerged as a key regulator in multiple developmental and physiological processes, including lung morphogenesis, neuronal survival, mammalian gonad differentiation, and sex determination. This review provides a comprehensive overview of the FGF family and subfamilies, with a focus on the purification, expression, and pathophysiological functions of FGF9. By synthesizing current knowledge, we aim to facilitate further research and potential clinical applications of FGF9.

Herpes simplex virus type 1 (HSV-1) is an ubiquitous pathogen that can infect humans through skin or mucous regions. This study was to explore the effects and underlying mechanism of HSV-1 as examined within the human epidermal melanocyte cell line, PIG1. Our results showed that following HSV-1 infection, PIG1 cells shrank and acquired a rounded shape, while the numbers and lengths of their dendrites decreased and melanogenesis was inhibited. Meanwhile, the HSV-1 receptors (nectin-1, herpes virus entry mediator, paired immunoglobulin-like type 2 receptor alpha) and phospho-extracellular signal-regulating kinase (p-ERK) were all substantially decreased, while vomeronasal type-1 receptor 5 (VN1R5) increased. Results of RNA interference and protein inhibitor assays revealed that knockdown of VN1R5 increased the expression of p-ERK and microphthalmia-associated transcription factor (MITF), while an inhibition of ERK decreased VN1R5 expression. Taken together, our study provides the first evidence that HSV-1 can infect human normal melanocytes and inhibit melanogenesis through VN1R5/ERK pathway.