Multi-omics analyses reveal interactions between the skin microbiota and skin metabolites in atopic dermatitis.

Introduction: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. Skin microecological imbalance is an important factor in the pathogenesis of AD, but the underlying mechanism of its interaction with humans remains unclear. Methods: 16S rRNA gene sequencing was conducted to reveal the skin microbiota dynamics. Changes in skin metabolites were tracked by LC-MS metabolomics. We then explored the potential mechanism of interaction by analyzing the correlation between skin bacterial communities and metabolites in corresponding skin-associated samples. Results: Samples from 18 AD patients and 18 healthy volunteers (HVs) were subjected to 16S rRNA gene sequencing and LC-MS metabolomics. AD patients had dysbiosis of the skin bacterial community with decreased species richness and evenness. The relative abundance of the genus Staphylococcus increased significantly in AD, while the abundances of the genera Propionibacterium and Brevundimonas decreased significantly. The relative abundance of the genera Staphylococcus in healthy females was significantly higher than those in healthy males, while it showed no difference in AD patients with or without lesions. The effects of AD status, sex and the presence or absence of rashes on the number of differentially abundant metabolites per capita were successively reduced. Multiple metabolites involved in purine metabolism and phenylalanine metabolism pathways (such as xanthosine/xanthine and L-phenylalanine/trans-cinnamate) were increased in AD patients. These trends were much more obvious between female AD patients and female HVs. Spearman correlation analysis revealed that the genus Staphylococcus was positively correlated with various compounds involved in phenylalanine metabolism and purine metabolic pathways. The genera Brevundimonas and Lactobacillus were negatively correlated with various compounds involved in purine metabolism, phenylalanine metabolism and sphingolipid signaling pathways. Discussion: We suggest that purine metabolism and phenylalanine metabolism pathway disorders may play a certain role in the pathogenic mechanism of Staphylococcus aureus in AD. We also found that females are more likely to be colonized by the genus Staphylococcus than males. Differentially abundant metabolites involved in purine metabolism and phenylalanine metabolism pathways were more obvious in female. However, we should notice that the metabolites we detected do not necessarily derived from microbes, they may also origin from the host.

Infection may play an important role in the pathogenesis of alveolar osteonecrosis following facial herpes zoster: a case report and literature review.

BACKGROUND: Herpes zoster (HZ) is one of the most common skin diseases caused by viruses. Facial HZ develops when the varicella-zoster virus affects the trigeminal nerve, and alveolar osteonecrosis is a rare complication. However, the exact pathogenesis of postherpetic alveolar osteonecrosis remains unclear. CASE DESCRIPTION: We encountered a patient who presented to the dermatology clinic with facial HZ and tooth exfoliation in the upper right jaw, and panoramic radiography revealed decreased bone density and poor alveolar socket healing in his right maxilla. Biopsy of the alveolar process revealed fragments of nonvital lamellar bone, which were devoid of osteoblasts and osteocytes and were surrounded by numerous neutrophils and bacterial aggregates. Thus, the diagnosis of alveolar osteonecrosis following facial HZ was confirmed. He then underwent resection of the osteonecrotic tissue. The pathological findings of postoperative tissue were similar to those of previous biopsies. Varicella-zoster virus and multiple types of bacteria were detected through next-generation sequencing, and the species of bacteria were consistent with the results of bacterial culture. Antibiotics and valaciclovir were administered during the perioperative period. The patient showed good recovery at the 9-month follow-up. CONCLUSIONS: The coexistence of bacterial and viral infection may play an important role in the pathogenesis of alveolar osteonecrosis following HZ. To our knowledge, we are the first to directly explore microbial pathogens in a case of postherpetic alveolar osteonecrosis through next-generation sequencing and bacterial culture. We recommend that oral examinations be carefully conducted for patients who are diagnosed with facial HZ, even if their facial rashes have faded away. We suggest that a prolonged and full-dose antiviral therapy course may be beneficial for the treatment of facial HZ with intraoral lesions. The implementation of dental preventive measures should be considered for patients with facial HZ. The application of antibiotics and excision of necrotic bone may reduce the abundance of bacteria in lesions and improve wound healing.

Combination therapy (toripalimab and lenvatinib)-associated toxic epidermal necrolysis in a patient with metastatic liver cancer: A case report.

BACKGROUND: Both programmed cell death-1 (PD-1) inhibitors and lenvatinib, which have a synergistic effect, are promising drugs for tumor treatment. It is generally believed that combination therapy with a PD-1 inhibitor and lenvatinib is safe and effective. However, we report a case of toxic epidermal necrolysis (TEN), a grade 4 toxicity, after this combination therapy. CASE SUMMARY: A 39-year-old male presented with erythema, blisters and erosions on the face, neck, trunk and limbs 1 wk after receiving combination therapy with lenvatinib and toripalimab, a PD-1 inhibitor. The skin injury covered more than 70% of the body surface area. He was previously diagnosed with liver cancer with cervical vertebra metastasis. Histologically, prominent necrotic keratinocytes, hyperkeratosis, liquefaction of basal cells and acantholytic bullae were observed in the epidermis. Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils. Direct immunofluorescence staining was negative. Thus, the diagnosis was confirmed to be TEN (associated with combination therapy with toripalimab and lenvatinib). Full-dose and long-term corticosteroids, high-dose intravenous immunoglobulin and targeted antibiotic drugs were administered. The rashes gradually faded; however, as expected, the tumor progressed. Therefore, sorafenib and regorafenib were given in succession, and the patient was still alive at the 10-mo follow-up. CONCLUSION: Cautious attention should be given to rashes that develop after combination therapy with PD-1 inhibitors and lenvatinib. Large-dose and long-course glucocorticoids may be crucial for the treatment of TEN associated with this combination treatment.

Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3ß-Mediated Keap1/Nrf2/HO-1 Signalling Pathway.

Melanoma is an aggressive malignant skin tumour with an increasing global incidence. However, current treatments have limitations owing to the acquired tumour drug resistance. Ferroptosis is a recently discovered form of programmed cell death characterised by iron accumulation and lipid peroxidation and plays a critical role in tumour growth inhibition. Recently, ferroptosis inducers have been regarded as a promising therapeutic strategy to overcome apoptosis resistance in tumour cells. In this study, we reported that nobiletin, a natural product isolated from citrus peel, and exhibited antitumour activity by inducing ferroptosis in melanoma cells. Subsequently, we further explored the potential mechanism of nobiletin-induced ferroptosis, and found that the expression level of glycogen synthase kinase 3ß (GSK3ß) in the skin tissue of patients with melanoma was significantly reduced compared to that in the skin of normal tissue. Additionally, nobiletin increased GSK3ß expression in melanoma cells. Moreover, the level of Kelch-like Ech-associated protein-1 (Keap1) was increased, while the level of nuclear factor erythroid 2-related factor 2 (Nrf2), and haem oxygenase-1 (HO-1) was decreased in nobiletin-treated melanoma cells, suggesting that the antioxidant defence system was downregulated. Furthermore, knockdown of GSK3ß significantly reduced nobiletin-induced ferroptosis and upregulated the Keap1/Nrf2/HO-1 signalling pathway, while the opposite was observed in cells overexpressing GSK3ß. In addition, molecular docking assay results indicated that nobiletin showed strong binding affinities for GSK3ß, Keap1, Nrf2, and HO-1. Taken together, our results demonstrated that nobiletin could induce ferroptosis by regulating the GSK3ß-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.