A Marine Natural Product, Harzianopyridone, as an Anti-ZIKV Agent by Targeting RNA-Dependent RNA Polymerase.

The Zika virus (ZIKV) is a mosquito-borne virus that already poses a danger to worldwide human health. Patients infected with ZIKV generally have mild symptoms like a low-grade fever and joint pain. However, severe symptoms can also occur, such as Guillain-Barré syndrome, neuropathy, and myelitis. Pregnant women infected with ZIKV may also cause microcephaly in newborns. To date, we still lack conventional antiviral drugs to treat ZIKV infections. Marine natural products have novel structures and diverse biological activities. They have been discovered to have antibacterial, antiviral, anticancer, and other therapeutic effects. Therefore, marine products are important resources for compounds for innovative medicines. In this study, we identified a marine natural product, harzianopyridone (HAR), that could inhibit ZIKV replication with EC50 values from 0.46 to 2.63 µM while not showing obvious cytotoxicity in multiple cellular models (CC50 > 45 µM). Further, it also reduced the expression of viral proteins and protected cells from viral infection. More importantly, we found that HAR directly bound to the ZIKV RNA-dependent RNA polymerase (RdRp) and suppressed its polymerase activity. Collectively, our findings provide HAR as an option for the development of anti-ZIKV drugs.

Oral abrocitinib in the treatment of granuloma annulare: a case report.

Aim: To evaluate the therapeutic efficacy and safety of JAK inhibitor abrocitinib in patients with localized granuloma annulare (GA) and to review the available cases documented in English.Methods: We presented a patient who had a persistent, localized granuloma anulare (GA) for one year and did not respond to traditional therapies. This patient was treated with oral abrocitinib at a dosage of 150 mg daily.Results: After 6 weeks of treatment with abrocitinib, the patient exhibited notable symptom improvement with no new lesions. No adverse events or recurrences were reported during the 5-month follow-up period.Conclusions: Abrocitinib may be a promising and safe treatment option for patients with localized GA who do not respond to traditional therapies.

RNA-Seq Identifies Marked Th17 Cell Activation and Altered CFTR Expression in Different Atopic Dermatitis Subtypes in Chinese Han Populations.

Background: Patients with atopic dermatitis (AD) exhibit phenotypic variability in ethnicity and IgE status. In addition, some patients develop other allergic conditions, such as allergic rhinitis (AR), in subsequent life. Understanding the heterogeneity of AD would be beneficial to phenotype-specific therapies. Methods: Twenty-eight Chinese AD patients and 8 healthy volunteers were enrolled in the study. High-throughput transcriptome sequencing was conducted on lesional and nonlesional skin samples from 10 AD patients and matched normal skin samples from 5 healthy volunteers. Identification of differentially expressed genes (DEGs), KEGG pathway analyses, and sample cluster analyses were conducted in the R software environment using the DEseq2, ClusterProfiler, and pheatmap R packages, respectively. qRT-PCR, Western blotting, and ELISA were used to detect gene expression levels among subtypes. Correlation analysis was performed to further investigate their correlation with disease severity. Results: A total of 25,798 genes were detected per sample. Subgroup differential expression analysis and functional enrichment analysis revealed significant changes in the IL17 signaling pathway in Chinese EAD patients but not in IAD patients. DEGs enriched in cytokine-cytokine receptor interactions and gland secretion were considered to be associated with atopic march. Further investigations confirmed a marked IL17A upregulation in Chinese EAD with a positive relationship with total IgE level and AD severity. In addition, increased IL17A in AD patients with AR demonstrated a closer association with AR severity than IL4R. Moreover, AQP5 and CFTR were decreased in the lesions of AD patients with AR. The CFTR mRNA expression level was negatively associated with the skin IL17A level and AR severity. Conclusion: Our research characterized marked Th17 activation in Chinese EAD patients, and altered expression of IL17A, IL4R, AQP5, and CFTR in AD patients with AR was associated with AR severity. It partially explained the phenotypic differences of AD subtypes and provided potential references for endotype-targeted therapy.

Circular RNA profiles and the potential involvement of down-expression of hsa_circ_0001360 in cutaneous squamous cell carcinogenesis.

Circular RNAs (circRNAs) act as sponges of noncoding RNAs and have been implicated in many pathophysiological processes, including tumor development and progression. However, their roles in cutaneous squamous cell carcinoma (cSCC) are not yet well understood. This study aimed to identify differentially expressed circRNAs and their potential functions in cutaneous squamous cell carcinogenesis. The expression profiles of circRNAs in three paired cSCC and adjacent nontumorous tissues were detected with RNA sequencing and bioinformatics analysis. The candidate circRNAs were validated by PCR, Sanger sequencing and quantitative RT-PCR in another five matched samples. The biological functions of circRNAs in SCL-1 cells were assessed using circRNA silencing and overexpression, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS), flow cytometry, transwell and colony formation assays. In addition, the circRNA-miRNA-mRNA interaction networks were predicted by bioinformatics. In summary, 1115 circRNAs, including 457 up-regulated and 658 down-regulated circRNAs (fold change ≥ 2 and P < 0.05), were differentially expressed in cSCC compared with adjacent nontumorous tissues. Of four selected circRNAs, two circRNAs (hsa_circ_0000932 and hsa_circ_0001360) were confirmed to be significantly decreased in cSCC using PCR, Sanger sequencing and quantitative RT-PCR. Furthermore, hsa_circ_0001360 silencing was found to result in a significant increase of the proliferation, migration and invasion but a significant decrease of apoptosis in SCL-1 cells in vitro, whereas hsa_circ_0001360 overexpression showed the opposite regulatory effects. hsa_circ_0001360 was predicted to interact with five miRNAs and their corresponding genes. In conclusion, circRNA dysregulation may play a critical role in carcinogenesis of cSCC, and hsa_circ_0001360 may have potential as a biomarker for cSCC.

5-aminolevulinic acid photodynamic therapy and excision surgery for nevoid basal cell carcinoma syndrome with multiple basal cell carcinomas and PTCH1 mutation.

This report describes a PTCH1 c.1804C > T (p.Arg602*) mutation causing a Chinese nevoid basal cell carcinoma syndrome (NBCCS) with multiple basal cell carcinoma (BCC) phenotype. Multiple modalities including microwave ablation, photodynamic therapy, and excision surgery have a good respond to the NBCCS. The current results broaden the spectrum of PTCH1 mutations responsible for NBCCS.

Secukinumab monotherapy successfully treated severe refractory type V (atypical juvenile) pityriasis rubra pilaris: A case report and literature review.

Pityriasis rubra pilaris (PRP) is a rare heterogeneous group of papulosquamous inflammatory disorders with unknown etiology. PRP is often resistant to many conventional therapies which has made more challenging on treatment. More recently, several studies have shown encouraging clinical results of secukinumab in the treatment of PRP in adult, but no studies have explored its effects in children. We herein report a 7-year-old boy with severe type V PRP responded rapidly to secukinumab monotherapy (150 mg once weekly) when conventional therapies have failed. The patient showed rapid and dramatic improvement of erythema, palmoplantar hyperkeratosis, scaling, and itching within only 5 weeks, with no adverse effects. Secukinumab could be considered as a treatment option for refractory PRP in children, as recently reported in adult.

Exome sequencing identifies a KRT9 pathogenic variant in a Chinese pedigree with epidermolytic palmoplantar keratoderma.

BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is a rare skin disorder and its pathogenesis and inheritability are unknown. OBJECTIVE: To investigate the inheritance and pathogenesis of EPPK. METHODS: Two EPPK cases occurred in a three-generation Chinese family. Patient-parents trio EPPK was carried out and the identified candidate variants were confirmed by Sanger sequencing. RESULTS: A heterozygous missense pathogenic variant, c.488G > A (p.Arg163Gln), in the keratin (KRT) 9 gene was detected in the proband and his son via targeted exome sequencing, and then validated by Sanger sequencing. This pathogenic variant cosegregated with the EPPK in extended family members, and was predicted to be pathogenic by SIFT, PolyPhen2, PROVEAN, and Mutation Taster. This heterozygous variation was not evident in 100 healthy controls. CONCLUSION: This report describes a KRT9 c.488G > A (p.Arg163Gln) variant causing a diffuse phenotype of Chinese EPPK. The current results broaden the spectrum of KRT9 pathogenic variants responsible for EPPK and have important implications for molecular diagnosis, treatment, and genetic counseling for this family.

Long-term safety and efficacy of continuous acitretin monotherapy for three children with different severe hyperkeratotic disorders in China.

Long-term systemic treatment with acitretin for severe hyperkeratotic disorders is needed to maintain quality of life of afflicted patients, but treatment has been limited owing to its potential side-effects including skeletal malformations, particularly for children during their growth and development. A retrospective investigation was conducted with three children afflicted with a severe hyperkeratotic disorder, namely Darier's disease, bullous ichthyosiform erythroderma or lamellar ichthyosis, who were continuously maintained on 0.2-0.3 mg/kg per day acitretin for more than 12 years after an initial period at a larger acitretin dose to bring each disease under control. The patients had good responses to acitretin treatment, which was assessed for safety, skeletal abnormalities, growth retardation and other potential side-effects. Acitretin monotherapy was an effective treatment for these children, and maintenance doses were well tolerated with no skeletal or other observable side-effects during the course of the study.

Complete hydatidiform mole and a coexistent fetus following ovulation induction in a patient with Sheehan's syndrome: a first case report and review of literature.

Pregnancy in Sheehan's syndrome (SS) is extremely rare. We present the first reported case of twin pregnancy with complete hydatiform mole (CHM) and a coexistent fetus (CHCF) in a patient with SS. A 29-year-old Chinese patient with SS became pregnant following one cycle of ovulation induction with human menopausal gonadotropin after secondary infertility. A normal live fetus and a low echogenic mass suspected hydatidiform mole (HM) were detected by ultrasound examinations at gestational week 8. The couple highly desired to continue the pregnancy because it is very hard to get pregnant for the patients with SS. However, the pregnancy was terminated for the size of the HM component increased rapidly at gestational week 15. Histological examinations confirmed CHCF. Genetic studies showed that the CHM genome was derived from paternal diploidy, and the normal fetus was from biparental genomes. Furthermore, a literature review on these topics is included. This case highlighted that even in a patient with SS, twin pregnancy with CHCF can still occur after ovulation induction.

[Screening ubiquitin/ribosomal protein S27a by yeast two-hybridization system].

BACKGROUND & OBJECTIVE: Protein kinase CK2, a kind of ubiquitous eukaryotic messenger-independent protein serine/threonine kinase, plays a vital role in cell differentiation and proliferation, signal transduction and procession. Activity of CK2 in hematopoietic cells is 2-8 folds higher than that in relevant normal tissues, moreover changes of CK2 activity are correlated to tumor growth. In order to investigate the mechanism of its effect on hematopoietic cells, we used yeast two-hybridization screening the proteins interacting with protein kinase CK2alpha' subunit from HL-60 cells cDNA library. METHODS: The target CK2alpha' cDNA was obtained by amplifying recombinant plasmid pTHCK2A', containing human protein kinase CK2alpha' subunit cDNA, through polymerase chain reaction (PCR). Pst I/Nde I-digested PCR products were directionally cloned into DNA-BD vector pGBKT7, which had also been digested by Pst I/Nde I. The recombinant plasmid was named yeast two-hybridization BD bait plasmid, and confirmed by DNA sequencing, and auto-activated experiments. Total RNA of HL-60 cells was extracted, CLONTECH switching mechanism at 5' end of RNA transcript method was used to construct a cDNA library in yeast cells. Library plasmid was named AD plasmid. BD plasmid and AD plasmid were co-transformed into competent yeast AH109. Yeast two-hybridization was used to screen positive clones. RESULTS: Six proteins, interacting with human protein kinase CK2alpha' subunit, were screened. DNA sequencing and homology comparison showed that one of the proteins was highly homologous with ubiquitin/ribosomal protein S27a (99.8%). CONCLUSION: Using yeast two-hybridization system could screen out ubiquitin/ribosomal protein S27a, which may interact with human protein kinase CK2alpha' subunit, from HL-60 cells.