Jingjun Zhao

Granular parakeratosis (GP) is an uncommon keratinization disorder that predominantly affects intertriginous areas and may clinically mimic atopic dermatitis or psoriasis. Histologically, GP is characterized by compact hyperkeratosis, parakeratosis, and retention of keratohyalin granules within the stratum corneum, although its histopathological spectrum is heterogeneous. Previous studies have consisted mainly of case reports, while mechanistic investigations remain limited, and whether GP represents a purely cornification-related abnormality is unclear. During and after the coronavirus disease 2019 (COVID-19) pandemic, increased use of benzalkonium chloride (BAC)-containing laundry disinfectants coincided with more patients presenting with recurrent erythema and scaling that responded poorly to conventional treatment, prompting renewed attention to this disease. We performed single-cell RNA sequencing of lesional skin from three patients with GP and matched skin samples from three healthy controls, followed by keratinocyte subclustering, pseudotime analysis, and cell–cell communication analysis. Key findings were further validated by immunofluorescence in an independent cohort of four patients with GP and three healthy controls. HaCaT cells were exposed to BAC and analyzed by the Cell Counting Kit-8 (CCK-8) assay and bulk RNA sequencing. Single-cell analysis revealed the expansion of inflammatory keratinocytes in GP lesions. Pathway enrichment showed the activation of innate immune and antimicrobial responses and dysregulation of keratinocyte differentiation. S100A8/S100A9 were increased in GP keratinocytes and validated at the protein level. BAC induced interleukin-1 (IL-1)-related inflammatory activation and cellular stress responses, suggesting that GP is an exposure-associated inflammatory epidermal differentiation disorder.

Third-degree, large-area skin injuries impose a significant socioeconomic burden on victims each year. The liver demonstrates extensive regenerative properties, and its exosomes are rich in organic selenium protein (SELENOP) with a high bioavailability. In this study, we established hepatic exosomes as a distinct biological nanoparticle and considering its unique cargo to investigate their regenerative effects on skin cells, including upregulation of cell growth, antioxidant molecules, and angiogenic properties, which have not been previously explored. Building on these promising findings, we designed a novel three-dimensional (3D) bio-printed multicellular skin organoid scaffold using hepatic exosome-encapsulated GECM (GelMa-ECM) bio-ink to mimic native skin structure. In vivo, the skin construct orchestrates wound healing by boosting key tissue regenerative markers, biological processes, and signaling pathways, while also downregulating various pro-inflammatory pathways during the proliferative stage of healing. Our study highlights a new strategy for wound healing and offers potential insights into the treatment of other chronic and recalcitrant skin diseases.

Background: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by extensive skin fibrosis. There are no effective treatments due to the severity, multiorgan presentation, and variable outcomes of the disease. Here, integrated bioinformatics was employed to discover tissue-specific expressed hub genes associated with SSc, determine potential competing endogenous RNAs (ceRNA) regulatory networks, and identify potential targeted drugs.Methods: In this study, four datasets of SSc were acquired. To identify the genes specific to tissues or organs, the BioGPS web database was used. For differentially expressed genes (DEGs), functional and enrichment analyses were carried out, and hub genes were screened and shown in a network of protein-protein interactions (PPI). The potential lncRNA–miRNA–mRNA ceRNA network was constructed using the online databases. The specifically expressed hub genes and ceRNA network were validated in the SSc mouse and in normal mice. We also used the receiver operating characteristic (ROC) curve to determine the diagnostic values of effective biomarkers in SSc. Finally, the Drug-Gene Interaction Database (DGIdb) identified specific medicines linked to hub genes.Results: The pooled datasets identified a total of 254 DEGs. The tissue/organ-specifically expressed genes involved in this analysis are commonly found in the hematologic/immune system and bone/muscle tissue. The enrichment analysis of DEGs revealed the significant terms such as regulation of actin cytoskeleton, immune-related processes, the VEGF signaling pathway, and metabolism. Cytoscape identified six gene cluster modules and 23 hub genes. And 4 hub genes were identified, including Serpine1, CCL2, IL6, and ISG15. Consistently, the expression of Serpine1, CCL2, IL6, and ISG15 was significantly higher in the SSc mouse model than in normal mice. Eventually, we found that MALAT1-miR-206-CCL2, let-7a-5p-IL6, and miR-196a-5p-SERPINE1 may be promising RNA regulatory pathways in SSc. Besides, ten potential therapeutic drugs associated with the hub gene were identified.Conclusions: This study revealed tissue-specific expressed genes, SERPINE1, CCL2, IL6, and ISG15, as effective biomarkers and provided new insight into the mechanisms of SSc. Potential RNA regulatory pathways, including MALAT1-miR-206-CCL2, let-7a-5p-IL6, and miR-196a-5p-SERPINE1, contribute to our knowledge of SSc. Furthermore, the analysis of drug-hub gene interactions predicted TIPLASININ, CARLUMAB and BINDARIT as candidate drugs for SSc.

Cutaneous melanoma is an aggressive malignant cancer associated with poor prognosis. Identification of reliable biomarkers for predicting prognosis of melanoma contributes to improved clinical outcome and disease management. Long non‑coding RNAs (lncRNAs) serve a crucial regulatory role of oncogenesis and tumor suppression in melanoma. Using data from The Cancer Genome Atlas database, novel lncRNA 11β‑hydroxysteroid dehydrogenase type 1‑antisense RNA 1 (HSD11B1‑AS1) was identified, which was significantly downregulated in malignant melanoma and its downregulation was significantly associated with poor clinicopathological characteristics, including advanced T and pathological stage, Clark level, Breslow depth and ulceration and worse prognosis. Multivariate analysis showed that HSD11B1‑AS1, as well as N stage and Breslow depth, were independent prognostic factors in cutaneous melanoma, and nomograms suggested a good predictive value of 1‑, 3‑ and 5‑year overall survival, progression‑free interval and disease‑specific survival. In vitro experiments verified the decreased HSD11B1‑AS1 expression in melanoma cell lines compared with human epidermal melanocytes. Moreover, cell experiments in vitro, including Cell Counting Kit‑8, colony formation, wound healing and Transwell assay, suggested that overexpression of HSD11B1‑AS1 significantly inhibited melanoma cell proliferation, migration and invasion. Functional enrichment showed significantly enriched pathways in IFN‑γ and ‑α response, TNF‑α signaling via NF‑κB and IL‑2/STAT‑5 and IL‑6/JAK/STAT‑3 signaling. In addition, immune infiltration analysis demonstrated that HSD11B1‑AS1 may function by accelerating immune response regulation and the immune cell infiltration of various immunocytes, especially T, T helper 1, activated dendritic and B cells. The present study revealed HSD11B1‑AS1 as a potential therapeutic target and promising biomarker for diagnosis and prognosis of cutaneous melanoma.

Aim: To explore the N6-methyladenosine (m6A) methylation of mRNAs and its roles in a mouse model of scleroderma. Materials & methods: To evaluate whether the mouse model of scleroderma could meet t... Lay abstract Scleroderma is an autoimmune disease with an unknown etiology. At present there is no effective treatment, and the prognosis is poor. Although m6A methylation is the most common RNA mo...

Background: Scleroderma is a multisystem disease in which tissue fibrosis is caused by inflammation and vascular damage. The mortality of scleroderma has remained high due to a lack of effective treatments. However, exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs)-Ex have been regarded as potential treatments for various autoimmune diseases, and may also act as candidates for treating scleroderma. Methods: Mice with scleroderma received a single 50 μg HUMSCs-Ex. HUMSCs-Ex was characterized using transmission electron microscopy, nanoparticle tracking analysis and nanoflow cytometry. The therapeutic efficacy was assessed using histopathology, immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay and western blot. Results: HUMSCs-Ex ameliorated the deposition of extracellular matrix and suppressed the epithelial-mesenchymal transition process, and the effects lasted at least three weeks. In addition, HUMSCs-Ex promoted M1 macrophage polarization and inhibited M2 macrophage polarization, leading to the restoration of the balance of M1/M2 macrophages. Conclusion: We investigated the potential antifibrotic and anti-inflammatory effects of HUMSCs-Ex in a bleomycin-induced mouse model of scleroderma. So HUMSCs-Ex could be considered as a candidate therapy for scleroderma.

The fungus Cryptococcus neoformans is considered the leading cause of death in immunocompromised patients. Despite numerous investigations concerning its molecular epidemiology, there are only a few studies addressing the impacts of varying factors on genotype-phenotype correlations. It remains largely unknown whether genetic and environmental variabilities among isolates from different sources may have dramatic consequences on virulence. In this study, we analyzed 105 Chinese C. neoformans isolates, including 54 from HIV-infected patients, 44 from HIV-uninfected individuals and 7 from a natural environment, to investigate factors influencing the outcome of C. neoformans infection. MLST analysis clearly identified sequence type (ST) 5 as the prevalent sequence type in all clinical isolates and interestingly, genotypic diversities were observed in isolates from both HIV-uninfected individual and natural environment but not those from HIV-infected patients. Moreover, we found that compared to those from HIV-infected patients, the isolates from HIV-uninfected individuals exhibited enhanced virulence-associated traits including significantly elevated capsule production and melanin formation, increases in survival in human cerebrospinal fluid (CSF), less effective uptake by host phagocytes, and higher mortality in a mouse model of cryptococcosis. Consistently, pathogenic phenotypes were associated with CD4 counts of patients, implying environmental impact on within-host C. neoformans virulence. Importantly, a large-scale whole-genome sequencing analysis revealed that genomic variations within genes related to specific functions may act as a vital driving force of host intrinsic virulence evolution. Taken together, our results support a strong genotype-phenotype correlation suggesting that the pathogenic evolution of C. neoformans could be heavily affected by both genetic and environmental factors.

Wickerhamomyces anomalusis an emerging pathogen, which has been associated with clonal outbreaks and poor clinical outcomes. Despite being an important emerging yeasts species, our understanding concerning the microbiological and clinical characteristics of infections due to this species is limited. Herein, we are reporting a retrospective analysis of fungemia patients withW. anomalusfrom a 2,100-bed hospital in Shanghai during 2014–2016. Moreover, we conducted an extensive literature review to gain a deeper clinical and microbiological insights. Detailed clinical data were recorded. Antifungal susceptibility testing (AFST) followed CLSI M27-A3, and isolates were identified using MALDI-TOF MS. In total, 13 patients were identified with a mortality rate of 38.5% (5/13). Central venous catheter (CVC), broad-spectrum antibiotic therapy, total parenteral nutrition (TPN), surgery, and mechanical ventilation were the most frequently observed risk factors. Eight patients (61.5%) experienced mixed bacterial/Candida bloodstream infections, and four patients developed mixed candidemia (MC).W. anomalusisolates showed high minimum inhibitory concentrations (MICs) against all azoles tested and flucytosine, while AMB showed the highestin vitroactivity. Azoles were used for 84.6% (11/13) of the cases, while 36.4% (4/11) of them died. When combining with the AFST data and the literature review, our study highlights the poor efficacy of azoles and optimal efficacy of AMB and LAMB against infections caused byW. anomalus. In conclusion, our study highlights the emerging threat ofW. anomalusaffecting both neonates and adults. Furthermore, our results advocate the use of AMB formulations rather than azoles among patients infected withW. anomalus. Future studies are warranted to reach a definitive consensus regarding the utility of echinocandins among such patients.