Effect of glabridin combined with bakuchiol on UVB-induced skin damage and its underlying mechanism: An experimental study.

BACKGROUND: Research has demonstrated the anti-photoaging properties of glabridin and bakuchiol. METHODS: The impact of glabridin, glabridin + bakuchiol, and bakuchiol on the levels of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) in mice skin fibroblasts was observed. Furthermore, we investigated the potential roles of fibronectin (FN), interferon-γ (IFN-γ), interleukin-22 (IL-22), and transforming growth factor-ß (TGF-ß) in the tissues, and evaluated their impact on the enzymatic levels in the skin. In conjunction with transcriptomic analysis, metabolomic profiling, and network pharmacology, all samples underwent comprehensive metabolomic and principal component analysis. The Venny2.1 method was utilized to identify variances in shared metabolites between the treatment group and the UVB group, as well as between the UVB group and the control group. Subsequently, a cluster heat map was generated to forecast and analyze metabolic pathways and targets. RESULTS: The outcomes from the hematoxylin and eosin and toluidine blue staining revealed that glabridin and bakuchiol markedly decreased dermal thickness and suppressed mast cell infiltration in photoaged mice. Immunohistochemistry and Elisa analysis revealed that glabridin and bakuchiol effectively attenuated the levels of pro-inflammatory factors, including IL-1ß, tumor necrosis factor-α, IL-22, and IFN-γ. Furthermore, an increase in the levels of anti-inflammatory factors such as FN and TGF-ß was also observed. The determination of the contents of superoxide dismutase, hydroxypropyltransferase and malondialdehyde in mice dorsal skin revealed that glabridin and bakuchiol not only elevated the levels of superoxide dismutase and hydroxyproline, but also reduced malondialdehyde content. Due to the limited number of shared differential metabolites exclusively within Kyoto Encyclopedia of Genes and Genomes, comprehensive pathway enrichment analysis was not feasible. CONCLUSION: This study demonstrates that glabridin and bakuchiol effectively impede photoaging and alleviate skin inflammation in mice.

POH1 induces Smad3 deubiquitination and promotes lung cancer metastasis.

Smad3 is the key mediator of TGF-ß1-triggered signal transduction and the related biological responses, promoting cell invasion and metastasis in various cancers, including lung cancer. However, the deubiquitinase stabilizing Smad3 remains unknown. In this study, we present a paradigm in which POH1 is identified as a novel deubiquitinase of Smad3 that plays a tumor-promoting role in lung adenocarcinoma (LUAD) by regulating Smad3 stability. POH1 markedly increased Smad3 protein levels and prolonged its half-life. POH1 directly interacted and colocalized with Smad3, leading to the removal of poly-deubiquitination of Smad3. Functionally, POH1 facilitated cell proliferation, migration, and invasion by stabilizing Smad3. Importantly, POH1 also promoted liver metastasis of lung cancer cells. The protein levels of both POH1 and Smad3 were raised in the tumor tissues of patients with LUAD, which predicts poor prognosis. Collectively, we demonstrate that POH1 acts as an oncoprotein by enhancing TGF-ß1/Smad3 signaling and TGF-ß1-mediated metastasis of lung cancer.

Systematic pan-cancer analysis of RNF186 with potential implications in progression and prognosis in human cancer.

AIMS: Cancer remains a significant global public health issue. There is growing proof that Ring Finger Protein 186 (RNF186) may play a function in pan-cancer, however, this has not yet been thoroughly determined. This study aims to analyze RNF186 with potential implications in progression and prognosis in human cancer. MATERIALS AND METHODS: A comprehensive bioinformatics approaches combined with experimental verification were used across 33 types of cancers in this study to conduct a pan-cancer investigation of RNF186 from the perspectives of gene expression, prognosis, genomic alterations, immunological markers, gene set, and function. KEY FINDINGS: RNF186 is a valuable prognostic biomarker in several cancer types, especially breast invasive carcinoma (BRCA) and uterine corpus endometrial carcinoma (UCEC). The levels of RNF186 promoter methylation and genetic alterations may be responsible for some cancers' abnormal expression. Furthermore, RNF186 expression was determined to be associated with immune checkpoint genes. Analysis of RNF186-related genes revealed that proteasome and PI3K-AKT signaling pathway were primarily involved in the cellular function of RNF186. Additionally, our research first confirmed that RNF186 may function as an oncogene and contribute to cancer proliferation, migration and invasion in UCEC. In contrast, RNF186 may play an inhibitory role in BRCA progression. This function depends on the ligase activity of RNF186. SIGNIFICANCE: This study suggests that RNF186 is a novel critical target for tumor progression in BRCA and UCEC. It reveals that RNF186 may be associated with tumor immunotherapy, which may provide an effective predictive evaluation of the prognosis of immunotherapy.

Missense Mutations in MAB21L1: Causation of Novel Autosomal Dominant Ocular BAMD Syndrome.

Purpose: Biallelic MAB21L1 variants have been reported to cause autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG), whereas only five heterozygous pathogenic variants have been suspected to cause autosomal dominant (AD) microphthalmia and aniridia in eight families. This study aimed to report an AD ocular syndrome (blepharophimosis plus anterior segment and macular dysgenesis [BAMD]) syndrome based on clinical and genetic findings from patients with monoallelic MAB21L1 pathogenic variants in our cohort and reported cases. Methods: Potential pathogenic variants in MAB21L1 were detected from a large in-house exome sequencing dataset. Ocular phenotypes of the patients with potential pathogenic variants in MAB21L1 were summarized, and the genotype-phenotype correlation was analyzed through a comprehensive literature review. Results: Three heterozygous missense variants in MAB21L1, predicted to be damaging, were detected in 5 unrelated families, including c.152G>T in 2, c.152G>A in 2, and c.155T>G in one. All were absent from gnomAD. The variants were de novo in two families, transmitted from affected parents to offspring in two families, and with an unknown origin in the other family, demonstrating strong evidence of AD inheritance. All patients revealed similar BAMD phenotypes, including blepharophimosis, anterior segment dysgenesis, and macular dysgenesis. Genotype-phenotype analysis suggested that patients with monoallelic MAB21L1 missense variants had only ocular anomalies (BAMD), whereas patients with biallelic variants presented both ocular and extraocular symptoms. Conclusions: Heterozygous pathogenic variants in MAB21L1 account for a new AD BAMD syndrome, which is completely different from COFG caused by homozygous variants in MAB21L1. Nucleotide c.152 is likely a mutation hot spot, and the encoded residue of p.Arg51 might be critical for MAB21L1.

MiR-149-5p inhibits cell proliferation, promotes cell apoptosis and retards cell cycle of IL-22-stimulated HaCaT and NHEK keratinocytes via regulating PDE4D.

BACKGROUND: Psoriasis is a chronic autoimmune skin disease with unclear pathogenesis. It was found that miR-149-5p was significantly decreased in psoriatic lesion tissues. In this study, we aims to investigate the role and related molecular mechanism of miR-149-5p on psoriasis. METHOD: IL-22 was used to stimulate HaCaT and NHEK cells to establish psoriasis model in vitro. The miR-149-5p and phosphodiesterase 4D (PDE4D) expression levels were detected by quantitative real-time PCR. HaCaT and NHEK cells proliferation was determined by Cell Couting Kit-8 assay. The cell apoptosis and cell cycle were detected by flow cytometry. The cleaved Caspase-3, Bax and Bcl-2 protein expressions were detected by western blot. The targeting relationship between PDE4D and miR-149-5p was predicted and confirmed by Starbase V2.0 and dual-luciferase reporter assay, respectively. RESULT: There was a low expression level of miR-149-5p and a high expression of PDE4D in psoriatic lesion tissues. MiR-149-5p could target PDE4D. IL-22 promoted HaCaT and NHEK cells proliferation, while inhibited cell apoptosis and accelerated cell cycle. Moreover, IL-22 decreased the expressions of cleaved Caspase-3 and Bax, and increased the expression of Bcl-2. And the overexpressed miR-149-5p promoted HaCaT and NHEK cells apoptosis, inhibited cell proliferation and retarded cell cycle, meanwhile increased the cleaved Caspase-3 and Bax expressions, decreased the Bcl-2 expression. In addition, PDE4D overexpression has the opposite effect as miR-149-5p. CONCLUSION: The overexpressed miR-149-5p inhibits IL-22-stimulated HaCaT and NHEK keratinocytes proliferation, promotes cell apoptosis and retards cell cycle by down-regulating the expression of PDE4D, which could be the promising therapeutic target of psoriasis.

Follistatin-like 1 deficiency impairs T cell development to promote lung metastasis of triple negative breast cancer.

Our study aims to detect the underlying mechanism of the suppressive effect of Follistatin-like 1 (FSTL1) on lung metastasis of triple negative breast cancer (TNBC). We found that FSTL1 had no effect on the proliferation and metastasis of 4T1 cells in vitro, while in the tumor-bearing Fstl1 heterozygous (Fstl1+/-) mice, the number of anti-tumor T lymphocytes in the lung was significantly reduced with the increase in lung metastasis. Impaired development of T cells can cause dysfunction of adaptive immune system, which promotes cancer metastasis. Therefore the effect of FSTL1 on T cell development was further investigated. Lower population of T cells in periphery and decreased proliferation of CD4- CD8- double negative (DN) thymocytes and impairment development of T cells were found in Fstl1+/- mice. Furthermore, high expression of FSTL1 in medullary thymus epithelial (mTEC) cells and decreased mRNA expression of inducible costimulator on activated T-cell ligand (Icosl) in mTECsh Fstl1 were detected. Combining other studies that the generation of ICOSL by mTEC cells promotes CD4+ single positive (SP) thymocytes to produce IL-2, which promotes T cell development. Our results indicate FSTL1 deficiency in mTEC cells impairs T cell development to promote the lung metastasis of TNBC.

Impact of HLA-B*58:01 allele and allopurinol-induced cutaneous adverse drug reactions: evidence from 21 pharmacogenetic studies.

Allopurinol is widely used for hyperuricemia and gouty arthritis, but is associated with cutaneous adverse drug reactions (CADRs). Recently, HLA-B*58:01 allele was identified as a strong genetic marker for allopurinol-induced CADRs in Han Chinese. However, the magnitude of association and diagnosis value of HLA-B*58:01 in allopurinol-induced CADRs remain inconclusive. To investigate this inconsistency, we conducted a meta-analysis of 21 pharmacogenetic studies, including 551 patients with allopurinol-induced CADRs, and 2,370 allopurinol-tolerant controls as well as 9,592 healthy volunteers. The summary OR for allopurinol-induced CADRs among HLA-B*58:01 carriers was 82.77 (95% CI: 41.63 - 164.58, P < 10-5) and 100.87 (95% CI: 63.91 - 159.21, P < 10-5) in matched and population based studies, respectively. Significant results were also observed when stratified by outcomes and ethnicity. Furthermore, the summary estimates for quantitative analysis of HLA-B*58:01 allele carriers in allopurinol-induced CADRs screening were as follows: sensitivity, 0.93 (95% CI: 0.85 - 0.97); specificity, 0.89 (95% CI: 0.87 - 0.91); positive likelihood ratio, 8.24 (95% CI: 6.92 - 9.81); negative likelihood ratio, 0.084 (95% CI: 0.039 - 0.179); and diagnostic odds ratio, 98.59 (95% CI: 43.31 - 224.41). The AUSROC was 0.92 (95% CI: 0.89-0.94), indicating the high diagnostic performance. Our results indicated that allopurinol-SCAR is strongly associated with HLA-B*58:01, and HLA-B*58:01 is a highly specific and effective genetic marker for the detection allopurinol-induced CADRs, especially for Asian descents.