Roles of blood metabolites in mediating the relationship between vitiligo and autoimmune diseases: Evidence from a Mendelian randomization study.

OBJECTIVE: This study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites. METHODS: We performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases. RESULTS: Our findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08-1.27), psoriasis (OR 1.10; 95 % CI 1.04-1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23-1.63), pernicious anemia (OR 1.23; 95 % CI 1.12-1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11-1.26), alopecia areata (OR 1.22; 95 % CI 1.10-1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12-1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated. CONCLUSIONS: We substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities.

Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader.

The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact and influence each other, the specific element that regulates the reprogramming network remains unclear. Dux, a factor known to promote totipotency during the transition from embryonic stem cells (ESC) to 2C-like ESC (2CLC), has not been extensively studied in the context of iPSC reprogramming. In this study, we demonstrate that the modification of H3K18la induced by Dux overexpression controls the metabolism-H3K18la-MET network, enhancing the efficiency of iPSC reprogramming through a metabolic switch and the recruitment of p300 via its C-terminal domain. Furthermore, our proteomic analysis of H3K18la immunoprecipitation experiment uncovers the specific recruitment of Brg1 during reprogramming, with both H3K18la and Brg1 being enriched on the promoters of genes associated with pluripotency and epithelial junction. In summary, our study has demonstrated the significant role of Dux-induced H3K18la in the early reprogramming process, highlighting its function as a potent trigger. Additionally, our research has revealed, for the first time, the binding of Brg1 to H3K18la, indicating its role as a reader of histone lactylation.

Nr5a2 ensures inner cell mass formation in mouse blastocyst.

Recent studies have elucidated Nr5a2's role in activating zygotic genes during early mouse embryonic development. Subsequent research, however, reveals that Nr5a2 is not critical for zygotic genome activation but is vital for the gene program between the 4- and 8-cell stages. A significant gap exists in experimental evidence regarding its function during the first lineage differentiation's pivotal period. In this study, we observed that approximately 20% of embryos developed to the blastocyst stage following Nr5a2 ablation. However, these blastocysts lacked inner cell mass (ICM), highlighting Nr5a2's importance in first lineage differentiation. Mechanistically, using RNA sequencing and CUT&Tag, we found that Nr5a2 transcriptionally regulates ICM-specific genes, such as Oct4, to establish the pluripotent network. Interference with or overexpression of Nr5a2 in single blastomeres of 2-cell embryos can alter the fate of daughter cells. Our results indicate that Nr5a2 works as a doorkeeper to ensure ICM formation in mouse blastocyst.

rDNA Transcription in Developmental Diseases and Stem Cells.

As the first and rate-limiting step in ribosome biogenesis, rDNA transcription undergoes significant dynamic changes during cell pluripotency alteration. Over the past decades, rDNA activity has demonstrated dynamic changes, but most people view it as passive compliance with cellular needs. The evidence for rDNA transcriptional activity determining stem cell pluripotency is growing as research advances, resulting in the arrest of embryonic development and impairment of stem cell lines stemness by rDNA transcription inhibition. The exact mechanism by which rDNA activation influences pluripotency remains unknown. The first objective of this opinion article is to describe rDNA changes in the pathological and physiological course of life, including developmental diseases, tumor genesis, and stem cell differentiation. After that, we propose three hypotheses regarding rDNA regulation of pluripotency: 1) Specialized ribosomes synthesized from rDNA variant, 2) Nucleolar stress induced by the drop of rDNA transcription, 3) Interchromosomal interactions between rDNA and other genes. The pluripotency regulatory center is expected to focus strongly on rDNA. A small molecule inhibitor of rDNA is used to treat tumors caused by abnormal pluripotency activation. By understanding how rDNA regulates pluripotency, we hope to treat developmental diseases and safely apply somatic cell reprogramming in clinical settings.

Development and Validation of a Necroptosis-Related Prognostic Model in Head and Neck Squamous Cell Carcinoma.

Necroptosis is a new regulated cell-death mechanism that plays a critical role in various cancers. However, few studies have considered necroptosis-related genes (NRGs) as prognostic indexes for cancer. As one of the most common cancers in the world, head and neck squamous cell carcinoma (HNSCC) lacks effective diagnostic strategies at present. Hence, a series of novel prognostic indexes are required to support clinical diagnosis. Recently, many studies have confirmed that necroptosis was a key regulated mechanism in HNSCC, but no systematic study has ever studied the correlation between necroptosis-related signatures and the prognosis of HNSCC. Thus, in the current study, we aimed to construct a risk model of necroptosis-related signatures for HNSCC. We acquired 159 NRGs from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and compared them with samples of normal tissue downloaded from The Cancer Genome Atlas (TCGA), ultimately screening 38 differentially expressed NRGs (DE-NRGs). Then, by Cox regression analysis, we successfully identified 7 NRGs as prognostic factors. We next separated patients into high- and low-risk groups via the prognostic model consisting of 7 NRGs. Individuals in the high-risk group had much shorter overall survival (OS) times than their counterparts. Furthermore, using Cox regression analysis, we confirmed the necroptosis-related prognostic model to be an independent prognostic factor for HNSCC. Receiver operating characteristic (ROC) curve analysis proved the predictive ability of this model. Finally, Gene Expression Omnibus (GEO) data sets (GSE65858, GSE4163) were used as independent databases to verify the model's predictive ability, and similar results obtained from two data sets confirmed our conclusion. Collectively, in this study, we first referred to necroptosis-related signatures as an independent prognostic model for cancer via bioinformatics measures, and the necroptosis-related prognostic model we constructed could precisely forecast the OS time of patients with HNSCC. Utilizing the model may significantly improve the diagnostic rate and provide a series of new targets for treatment in the future.

Stabilization of UCA1 by N6-methyladenosine RNA methylation modification promotes colorectal cancer progression.

BACKGROUND: UCA1 is frequently upregulated in a variety of cancers, including CRC, and it can play an oncogenic role by various mechanisms. However, how UCA1 is regulated in cancer is largely unknown. In this study, we aimed to determine whether RNA methylation at N6-methyladenosine (m6A) can impact UCA1 expression in colorectal cancer (CRC). METHODS: qRT-PCR was performed to detect the level of UCA1 and IGF2BP2 in CRC samples. CRISPR/Cas9 was employed to knockout (KO) UCA1, METTL3 and WTAP in DLD-1 and HCT-116 cells, while rescue experiments were carried out to re-express METTL3 and WTAP in KO cells. Immunoprecipitation using m6A antibody was performed to determine the m6A modification of UCA1. In vivo pulldown assays using S1m tagging combined with site-direct mutagenesis was carried out to confirm the recognition of m6A-modified UCA1 by IGF2BP2. Cell viability was measured by MTT and colony formation assays. The expression of UCA1 and IGF2BP2 in TCGA CRC database was obtained from GEPIA ( http://gepia.cancer-pku.cn ). RESULTS: Our results revealed that IGF2BP2 serves as a reader for m6A modified UCA1 and that adenosine at 1038 of UCA1 is critical to the recognition by IGF2BP2. Importantly, we showed that m6A writers, METTL3 and WTAP positively regulate UCA1 expression. Mechanically, IGF2BP2 increases the stability of m6A-modified UCA1. Clinically, IGF2BP2 is upregulated in CRC tissues compared with normal tissues. CONCLUSION: These results suggest that m6A modification is an important factor contributing to upregulation of UCA1 in CRC tissues.

Two-field non-mydriatic fundus photography for diabetic retinopathy screening: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes mellitus. Guidelines for DR screening in different countries vary greatly, including fundus photography, slit-lamp biomicroscopy, indirect ophthalmoscopy, Optical Coherence Tomography (OCT), OCT-A and Fundus Fluorescein Angiography (FFA). Two-field non-mydriatic fundus photography (NMFP) is an effective screening method due to its low cost and less time-consuming process. However, it is controversial due to the sensitivity and specificity of two-field NMFP. This review intends to evaluate the performance of the two-field NMFP in diagnosing DR and helps clinicians determine the most optimal screening method. METHODS AND ANALYSIS: Two reviewers will independently search on the Medline, Embase, Cochrane databases, ProQuest, Opengrey, Chinese National Knowledge Infrastructure, Wanfang Data, VIP China Science and Technology Journal Database, Chinese BioMedical Literature Database, ISRCTN, ClinicalTrials.gov and the WHO ICTRP to identify relevant studies. There is no restriction posed on the language of the study. Included studies focus on the performance of two-field NMFP in detecting DR in diabetes patients. Analysis and evaluation of the studies will be examined by two reviewers independently using the Quality Assessment for Diagnostic Accuracy Studies-2 tool and later evaluated using the Population, Intervention, Comparison, Outcome, Study design criteria. A random-effect model will calculate the diagnostic indicators, including the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic OR, area under the curve and 95% CIs. We will also develop a summary receiver operating characteristic curve. We anticipate analysing subgroups according to the factors, which may lead to heterogeneity, including DR levels of patients, the reference standards, camera models, the interpretation criteria. The data will be analysed by STATA software. This study was registered with PROSPERO. ETHICS AND DISSEMINATION: This review will analyse the published data. Patients/the public were not involved in this research. The results of this study will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020203608.

Brain organoid: a 3D technology for investigating cellular composition and interactions in human neurological development and disease models in vitro.

The study of human brain physiology, including cellular interactions in normal and disease conditions, has been a challenge due to its complexity and unavailability. Induced pluripotent stem cell (iPSC) study is indispensable in the study of the pathophysiology of neurological disorders. Nevertheless, monolayer systems lack the cytoarchitecture necessary for cellular interactions and neurological disease modeling. Brain organoids generated from human pluripotent stem cells supply an ideal environment to model both cellular interactions and pathophysiology of the human brain. This review article discusses the composition and interactions among neural lineage and non-central nervous system cell types in brain organoids, current studies, and future perspectives in brain organoid research. Ultimately, the promise of brain organoids is to unveil previously inaccessible features of neurobiology that emerge from complex cellular interactions and to improve our mechanistic understanding of neural development and diseases.

Functional study of distinct domains of Dux in improving mouse SCNT embryonic development†.

Two-cell-like (2C-like) embryonic stem cells (ESCs) are a small group of ESCs that spontaneously express zygotic genome activation (ZGA) genes and repeats, such as Zscan4 and murine endogenous retrovirus with leucine (MERVL), and are specifically expressed in 2-cell-stage mouse embryos. Although numerous types of treatment and agents elevate the transition of ESCs to 2C-like ESCs, Dux serves as a critical factor in this transition by increasing the expression of Zscan4 and MERVL directly. However, the loss of Dux did not impair the birth of mice, suggesting that Dux may not be the primary transitioning factor in fertilized embryos. It has been reported that for 2-cell embryos derived from somatic cell nuclear transfer (SCNT) and whose expression of ZGA genes and repeats was aberrant, Dux improved the reprogramming efficiency by correcting aberrant H3K9ac modification via its C-terminal domain. We confirmed that the overexpression of full-length Dux mRNA in SCNT embryos improved the efficiency of preimplantation development (62.16% vs. 41.26% with respect to controls) and also increased the expression of Zscan4 and MERVL. Furthermore, we found that the N-terminal double homeodomains of Dux were indispensable for Dux localization and function. The intermediate region was essential for MERVL and Zscan4 activation, and the C-terminal domain was important for elevating level of H3K27ac. Mutant Dux mRNA containing N-terminal double homeodomains with the intermediate region or the C-terminal domain also improved the preimplantation development of SCNT embryos. This is the first report focusing on distinguishing functional domains of Dux in embryos derived from SCNT.

The Immune Atlas of Human Deciduas With Unexplained Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is a common fertility problem that affects 1%-2% of couples all over the world. Despite exciting discoveries regarding the important roles of the decidual natural killer cell (dNK) and regulatory T cell in pregnancy, the immune heterogeneity in patients with unexplained recurrent pregnancy loss (URPL) remains elusive. Here, we profiled the transcriptomes of 13,953 CD45+ cells from three normal and three URPL deciduas. Based on our data, the cellular composition revealed three major populations of immune cells including dNK cell, T cell, and macrophage, and four minor populations including monocytes, dendritic cell (DC), mast cell, and B cell. Especially, we identified a subpopulation of CSF1+ CD59+ KIRs-expressing dNK cells in normal deciduas, while the proportion of this subpopulation was decreased in URPL deciduas. We also identified a small subpopulation of activated dDCs that were accumulated mainly in URPL deciduas. Furthermore, our data revealed that in decidua at early pregnancy, CD8+ T cells exhibited cytotoxic properties. The decidual macrophages expressed high levels of both M1 and M2 feature genes, which made them unique to the conventional M1/M2 classification. Our single-cell data revealed the immune heterogeneity in decidua and the potentially pathogenic immune variations in URPL.

Tumorigenic and Immunogenic Properties of Induced Pluripotent Stem Cells: a Promising Cancer Vaccine.

Induced pluripotent stem cells (iPSCs) are mainly characterized by their unlimited proliferation abilities and potential to develop into almost any cell type. The creation of this technology has been of great interest to many scientific fields, especially regenerative biology. However, concerns about the safety of iPSC application in transplantation have arisen due to the tumorigenic and immunogenic properties of iPSCs. This review will briefly introduce the developing history of somatic reprogramming and applications of iPSC technology in regenerative medicine. In addition, the review will highlight two challenges to the efficient usage of iPSCs and the underlying mechanisms of these challenges. Finally, the review will discuss the expanding application of iPSC technology in cancer immunotherapy as a potential cancer vaccine and its advantages in auxiliary treatment compared with oncofetal antigen-based and embryonic stem cell (ESC)-based vaccines.

Histone demethylase KDM6A promotes somatic cell reprogramming by epigenetically regulating the PTEN and IL-6 signal pathways.

Aberrant epigenetic reprogramming is one of the major barriers for somatic cell reprogramming. Although our previous study has indicated that H3K27me3 demethylase KDM6A can improve the nuclear reprogramming efficiency, the mechanism remains unclear. In this study, we demonstrate that the overexpression of Kdm6a may improve induced pluripotent stem cell (iPSC) reprogramming efficiency in a demethylase enzymatic activity-dependent manner. KDM6A erased H3K27me3 on pluripotency- and metabolism-related genes, and consequently facilitated changing the gene expression profile and metabolic pattern to an intermediate state. Furthermore, KDM6A may promote IL-6 expression, and the secreted IL-6 may further improve iPSC reprogramming efficiency. In addition, KDM6A may promote PTEN expression to decrease p-AKT and p-mTOR levels, which in turn facilitates reprogramming. Overall, our results reveal that KDM6A may promote iPSC reprogramming efficiency by accelerating changes in the gene expression profile and the metabolic pattern in a demethylation-activity-dependent manner. These results may provide an insight into the relationship between epigenomics, transcriptomics, metabolomics, and reprogramming.

The Effects of Daxx Knockout on Pluripotency and Differentiation of Mouse Induced Pluripotent Stem Cells.

Induced pluripotent stem cell (iPSC) technology refers to the reprogramming of terminally differentiated somatic cells into pluripotent stem cells by introducing specific transcription factors that are known to regulate pluripotency, including Oct4, Sox2, Klf4, and c-Myc. In this study, we reprogrammed the primary fibroblasts isolated from the Daxxflox/flox mice, which carry the Oct4-green fluorescent protein reporter, and employed wild-type littermates as a control to induce iPSCs, then knocked out Daxx by infecting with Cre virus at the cellular level. The pluripotency and self-renewal capacity of iPSCs were determined. In addition, Daxx deletion altered the pluripotency marker (Nanog, Oct4) expression and displayed neural differentiation defects. Particularly, by performing transcriptome analysis, we observed that numerous ribosome biogenesis-related genes were altered, and quantitative polymerase chain reaction revealed that the expression of rDNA-related genes, 47S and 18S, was elevated after Daxx deletion. Finally, we illustrated that the expression of the neurodevelopment-related gene was upregulated both in iPSCs and differentiated neurospheres. Taken together, we demonstrated that Daxx knockout promotes the expression of rDNA, pluripotency, and neurodevelopment genes, which may improve the differentiation abilities of mouse iPSCs (miPSCs).

AKR1B10 promotes breast cancer cell migration and invasion via activation of ERK signaling.

BACKGROUND: Aldo-keto reductase family 1, member B10 (AKR1B10), is known to be significantly induced in the cells of various cancers such as breast cancer. However, the mechanisms of AKR1B10 promoting tumorigenesis in breast cancer remain unclear. In the present study, we demonstrated the potential role and mechanism of AKR1B10 in the invasion and migration of breast cancer cells. METHODS: The expression level of AKR1B10 in breast carcinoma, para-carcinoma and cancer tissues were detected by immunohistochemical evaluation and real-time polymerase chain reaction (RT-PCR), and the correlationships between AKR1B10 expression and clinicopathological features in breast cancer patients (n=131) were investigated. AKR1B10 was ectopically expressed in MCF-7 cells or silenced in BT-20 cells. The roles of AKR1B10 expression in the migration and invasion of MCF-7 cells and BT-20 cells were explored by wound healing assay, transwell migration assay and transwell matrigel invasion assay, and finally the activation level of extracellular signal-regulated kinase 1/2 (EKR1/2) activation and the expression level of matrix metalloproteinase-2 (MMP2) and vimentin in MCF-7 and BT-20 cells were measured by western blot. RESULTS: We found that AKR1B10 expression was increased in malignant tissues, which was correlated positively with tumor size, lymph node metastasis (p<0.05). MCF-7/AKR1B10 cells displayed a higher ability of migration (43.57±1.04%) compared with MCF-7/vector cells (29.12±1.34%) in wound healing assay, and the migrated cell number of MCF-7/AKR1B10 was more (418.43±9.62) than that of MCF-7/vector (222.43±17.75) in transwell migration assay without matrigel. We furtherly confirmed MCF-7/AKR1B10 cells invaded faster compared with MCF-7/vector cells by transwell matrigel invasion assay. Finally, we found AKR1B10 induced the migration and invasion of MCF-7 and BT-20 cells by activating EKR signaling, which promoted the expressions of MMP2 and vimentin. PD98059, a specific inhibitor of the activation of MEK, blocked the migration and invasion by inhibiting the expression of MMP2 and vimentin. CONCLUSIONS: AKR1B10 is overexpressed in breast cancer, and promotes the migration and invasion of MCF-7 and BT-20 cells by activating ERK signaling pathway.

G protein-coupled estrogen receptor enhances melanogenesis via cAMP-protein kinase (PKA) by upregulating microphthalmia-related transcription factor-tyrosinase in melanoma.

OBJECTIVE: This study investigated the role and mechanism of action of G protein-coupled estrogen receptor (GPER) in melanogenesis. METHODS: GPER expression was detected in the A375 human melanoma cell line and B16 mouse melanoma cell line. Cell proliferation, melanin content, tyrosinase (TYR) activity, cyclic adenosine monophosphate (cAMP) level, and TYR and microphthalmia-related transcription factor (MITF) expression were measured. GPER activation was altered by agonist and antagonist treatment and its expression was downregulated by gene silencing. Estradiol-induced melanin synthesis and the activation of related signaling pathways were suppressed by inhibiting GPER via antagonist treatment. The relationship between GPER and TYR was evaluated in clinical chloasma samples by immunohistochemistry. RESULTS: Upregulation of GPER in A375 cells promoted melanogenesis, favored as indicated by increases in TYR and MITF expression and TYR activity. GPER activated melanin production via the cAMP-protein kinase (PK) A pathway, suggesting that GPER plays an important role in estrogen-induced melanin synthesis. The effect of GPER activation on cAMP-MITF-TYR signaling was also demonstrated in B16 cells. A significant association was observed between GPER and TYR expression in chloasma skin lesions relative to normal skin. CONCLUSION: GPER enhances melanin synthesis via cAMP-PKA-MITF-TYR signaling and modulates the effects of estrogen in melanogenesis. GPER is therefore a potential drug target for chloasma treatment.

Diethylstilbestrol enhances melanogenesis via cAMP-PKA-mediating up-regulation of tyrosinase and MITF in mouse B16 melanoma cells.

BACKGROUND: It is well known that melanin synthesis in melanoma cells is controlled by melanogenic enzymes, which regulate the cAMP-PKA signaling pathway. Estrogen was previously reported to upregulate melanogenesis that is associated with human skin pigmentation. OBJECTIVE: To investigate the influence and mechanism of diethylstilbestrol (DES) on melanogenesis in mouse B16 melanoma cells. METHODS: The effects of diethylstilbestrol on cell viability, melanin content, tyrosinase activity, cAMP level, expression of the tyrosinase family and microphthalmia related transcription factor (MITF) were measured in B16 melanoma. Estrogen receptor (ER) expression were detected in B16 melanoma and A375 melanoma. Diethylstilbestrol-induced melanin synthesis were evaluated in the presence and absence of H89 (a PKA-specific inhibitor) and ICI182, 780 (a pure ER antagonist). Tyrosinase activity, the mRNA levels of tyrosinase and MITF were evaluated in the presence and absence of H89. RESULTS: In B16 cells, diethylstilbestrol increased cell proliferation, melanin synthesis, tyrosinase activity and expression of the tyrosinase family and MITF. ER expression have not difference in human and mouse melanoma. When ER were inhibited by ICI182, 780, DES-induced melanogenesis was significantly reduced. Diethylstilbestrol enhanced the level of cAMP. The upregulation of melanin content and tyrosinase activity stimulated by diethylstilbestrol was significantly attenuated in the presence of H89. Further, diethylstilbestrol-induced upregulation of tyrosinase and MITF were significantly attenuated when the PKA pathway was blocked. CONCLUSIONS: Diethylstilbestrol can enhance melanin synthesis in melanoma cells. This effect is associated with activation of the cAMP-PKA pathway and upregulation of expression and activity of the melanogenesis-related enzyme tyrosinase and MITF.

Aquaporin-3 gene and protein expression in sun-protected human skin decreases with skin ageing.

BACKGROUND/OBJECTIVES: Aquaporin 3 (AQP3) is a protein implicated in skin hydration. AQP3 null mice have relatively dry skin, reduced skin elasticity, and delayed recovery of barrier function after removal of the stratum corneum which is also present in skin of old people. A feature of skin aging is the change in both water content and barrier function of the skin. We investigated the expression of aquaporin 3 in non sun-exposed human skin, normal human keratinocytes and fibroblasts from different age groups to further understand the relationship between AQP3 and intrinsic skin aging. METHODS: We investigated the expression of aquaporin3 (AQP3) in normal human skin, normal human epidermal keratinocytes (NHEK) and skin fibroblast of different ages by immunohistochemistry, immunocytochemistry, the reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. The samples were derived from 60 patients of varying ages: <20 years of age, 30-45 years and >60 years of age. Twenty skin biopsies, 6 for keratinocyte/fibroblast cultures, were taken from each age group. RESULTS: AQP3 decreased with increasing age in both skin and NHEK samples. We demonstrated significant differences in AQP3 expression between the 3 age groups (P < 0.05). In fibroblasts, AQP3 expression levels were significantly lower in the >60 year olds compared to 30-45 year olds (P < 0.05) and <20 year olds (P < 0.05), there was no significant difference between the two younger groups (P > 0.05). CONCLUSIONS: AQP3 may be involved in the intrinsic aging process of non sun-exposed human skin.

Depletion of CD147 sensitizes human malignant melanoma cells to hydrogen peroxide-induced oxidative stress.

BACKGROUND: Increased sensitivity to reactive oxygen species (ROS) contributes to the effectiveness of therapeutic strategies in patients with malignant melanoma (MM). CD147, a cell surface receptor for cyclophilin A (CypA), is thought to exert antioxidant activities. OBJECTIVE: To understand the influences and mechanisms of CD147 on proliferation, apoptosis and redox state of A375 cells under H(2)O(2)-induced oxidative stress. METHODS: The effect of CD147 silencing on cell viability, apoptosis, the generation of ROS, superoxide dismutase (SOD) activity, and the malondialdehyde (MDA) level that reflects oxidative damage, was measured in human malignant melanoma cell line A375 treated or untreated with hydrogen peroxide (H(2)O(2)). RESULTS: In A375 cells, CD147 silencing increased the H(2)O(2)-induced inhibition of cell viability, H(2)O(2)-induced apoptosis, H(2)O(2)-mediated ROS- and MDA generation, and the H(2)O(2)-triggered decrease in SOD activity. CONCLUSIONS: Our results demonstrated that CD147 silencing increased cellular ROS and destroyed the intrinsic antioxidant defenses in A375, indicating that CD147 exerts a cytoprotective effect against H(2)O(2)-induced oxidative damage.