Identification of a metabolism-linked genomic signature for prognosis and immunotherapeutic efficiency in metastatic skin cutaneous melanoma.

Metastatic skin cutaneous melanoma (MSCM) is the most rapidly progressing/invasive skin-based malignancy, with median survival rates of about 12 months. It appears that metabolic disorders accelerate disease progression. However, correlations between metabolism-linked genes (MRGs) and prognosis in MSCM are unclear, and potential mechanisms explaining the correlation are unknown. The Cancer Genome Atlas (TCGA) was utilized as a training set to develop a genomic signature based on the differentially expressed MRGs (DE-MRGs) between primary skin cutaneous melanoma (PSCM) and MSCM. The Gene Expression Omnibus (GEO) was utilized as a validation set to verify the effectiveness of genomic signature. In addition, a nomogram was established to predict overall survival based on genomic signature and other clinic-based characteristics. Moreover, this study investigated the correlations between genomic signature and tumor micro-environment (TME). This study established a genomic signature consisting of 3 genes (CD38, DHRS3, and TYRP1) and classified MSCM patients into low and high-risk cohorts based on the median risk scores of MSCM cases. It was discovered that cases in the high-risk cohort had significantly lower survival than cases in the low-risk cohort across all sets. Furthermore, a nomogram containing this genomic signature and clinic-based parameters was developed and demonstrated high efficiency in predicting MSCM case survival times. Interestingly, Gene Set Variation Analysis results indicated that the genomic signature was involved in immune-related physiological processes. In addition, this study discovered that risk scoring was negatively correlated with immune-based cellular infiltrations in the TME and critical immune-based checkpoint expression profiles, indicating that favorable prognosis may be influenced in part by immunologically protective micro-environments. A novel 3-genomic signature was found to be reliable for predicting MSCM outcomes and may facilitate personalized immunotherapy.

MiRNA-224-5p regulates the defective permeability barrier in sensitive skin by targeting claudin-5.

BACKGROUND: Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression. MATERIALS AND METHODS: A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin. RESULTS: Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures. CONCLUSION: These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin.

DTL promotes head and neck squamous cell carcinoma progression by mediating the degradation of ARGLU1 to regulate the Notch signaling pathway.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with a high incidence in squamous epithelium. The E3 ubiquitin ligase DTL is a component of the CRL4A complex and is widely involved in tumor progression. We aimed to analyze the role of DTL in HNSCC and to explore its mechanism of action. Through clinical analysis, we found that DTL is upregulated in HNSCC tissues and is associated with the tumor microenvironment and poor survival in patients. Through gain-of-function and loss-of-function assays, we showed that DTL promotes cell proliferation and migration in vitro and tumor growth in vivo. Mass spectrometry analysis and immunoprecipitation assays showed that DTL interacts with ARGLU1 to promote K11-linked ubiquitination-mediated degradation of ARGLU1, thereby promoting the activation of the CSL-dependent Notch signaling pathway. Furthermore, siARGLU1 blocks the inhibitory effects of DTL knockdown on HNSCC cells. In this study, we showed that DTL promotes HNSCC progression through K11-linked ubiquitination of ARGLU1 to activate the CSL-dependent Notch pathway. These findings identify a promising therapeutic target for HNSCC.

Nanocarrier-Mediated Delivery of MicroRNAs for Fibrotic Diseases.

MicroRNAs (miRNAs) are endogenous noncoding RNAs that mediate the fibrotic process by regulating multiple targets. MicroRNA-based therapy can restore or inhibit miRNA expression and is expected to become an effective approach to prevent and alleviate fibrotic diseases. However, the safe, targeted, and effective delivery of miRNAs is a major challenge in translating miRNA therapy from bench to bedside. In this review, we briefly describe the pathophysiological process of fibrosis and the mechanism by which miRNAs regulate the progression of fibrosis. Additionally, we summarize the miRNA nanodelivery tools for fibrotic diseases, including chemical modifications and polymer-based, lipid-based, and exosome-based delivery systems. Further clarification of the role of miRNAs in fibrosis and the development of a novel nanodelivery system may facilitate the prevention and alleviation of fibrotic diseases in the future.

The ubiquitin-proteasome system in melanin metabolism.

BACKGROUND: The ubiquitin-proteasome system (UPS) is a highly conserved way of regulating intracellular protein balance. UPS mediates proteolysis and disruption of variation or misfolding, while finely regulating proteins involved in differentiation and other biological processes. AIMS: The aim of this review is to systematically introduce UPS as a key regulator of melanin metabolism. METHODS: Systematic search and retrospective review were performed on the published data. RESULTS: Melanocyte-inducing transcription factor (MITF) is a substrate of the ubiquitin ligase VCHL1 and acts as a transcription factor to regulate the expression of key enzymes in melanin synthesis such as tyrosinase (TYR). The rate-limiting enzyme TYR is modified by the ubiquitin ligase Hrd1 during melanosynthesis. Melanin itself is also regulated by multiple ubiquitin ligases including Fbp1 and Vhl. By regulating the ubiquitination modification to target each link of melanin synthesis, it plays an important role in correcting the disorder of melanin metabolism. A number of chemical agents have been proven to inhibit the activity of ubiquitin ligase. CONCLUSIONS: Drugs targeting E3 ligase and deubiquitinating enzymes have great potential in the treatment of melanin metabolism disorders.

Deletion of YJL218W reduces salt tolerance of Saccharomyces cerevisiae.

The YJL218W open reading frame may be involved in peroxisomal biogenesis. However, whether it mediates salt tolerance is unclear. We found that after knockdown of YJL218W in Saccharomyces cerevisiae (S. cerevisiae), its salt tolerance was reduced and cell death was increased. Transcriptome sequencing and analysis further revealed that YJL218W knockdown mediated significant changes in the expression of 1432 messenger RNA (mRNAs), of which 603 were upregulated. KEGG enrichment analysis and polymerase chain reaction (PCR) assay indicated that YJL218W mediated the regulation of peroxisome-related genes. Therefore, YJL218W may regulate salt stress in S. cerevisiae by regulating peroxisome assembly.

Localized delivery of curcumin by thermosensitive hydrogels for promoting wound healing.

BACKGROUND: Curcumin can promote wound healing, but its drug delivery medium needs to be improved further. OBJECTIVES: A curcumin-loaded thermosensitive hydrogel was prepared, its characterization was evaluated, and its promoting effect on wound healing was observed. METHODS: Curcumin-loaded thermosensitive hydrogels were prepared with different percentages of poloxamer 188 and poloxamer 407. A small tube inversion assay was used to observe the sol-gel transition temperature, and a rotational rheometer was used to detect the sol viscosity, sol-gel phase transition temperature, and phase transition time. The microstructure of the gel was observed by scanning electron microscopy, and Fourier infrared spectroscopy was used to evaluate whether curcumin was successfully loaded. Finally, its promoting effect on wound healing was observed in vivo and in vitro. RESULTS: Poloxamer 407 24% and poloxamer 188 1% were selected to prepare curcumin-loaded thermosensitive hydrogels. After 60 ± 15 s at 32°C, the sol-gel transition process was completed, with certain elastic behavior and solid-like rheological properties. Scanning electron microscopy showed that the pores of the curcumin-P407/P188 thermosensitive hydrogel were interconnected, with an average pore size ranging from 5 to 10 µm. Hydrogels showed a higher swelling ratio. Fourier transform infrared spectroscopy showed that curcumin had been incorporated into the hydrogel. Live/dead cell assays suggested that the hydrogel was not toxic to fibroblasts. Curcumin-loaded thermosensitive hydrogels can promote an increase in S-phase fibroblasts and improve wound healing. CONCLUSIONS: Curcumin-loaded P407/P188 thermosensitive hydrogel improves wound healing. More in-depth research is needed in the future.

Transcriptome Analysis Reveals that MAPK Signaling Pathway Mediates Salt Tolerance of YMR253C ORF in Saccharomyces cerevisiae.

The YMR253C open reading frame encodes a membrane protein that is highly expressed in NaCl-resistant Saccharomyces cerevisiae mutants. Whether it mediates NaCl tolerance is unclear. By knocking out YMR253C in S. cerevisiae, we found that the salt tolerance of yeast was reduced, the integrity of the cell wall was impaired, and cell death was induced; transcriptome analysis further revealed that YMR253C gene knockout mediates significant changes of 1291 genes, and YMR253C mediates the regulation of MAPK signal pathways. Therefore, the transmembrane protein YMR253C may regulate the MAPK signaling pathway to regulate the salt stress of S. cerevisiae.

Role of miRNAs in melanin metabolism: Implications in melanin-related diseases.

BACKGROUND: MicroRNAs (miRNAs) are short single-stranded non-coding RNAs that regulate degradation and expression of messenger RNA (mRNA) and play a wide range of key roles in different biological processes. They mediate different stages of melanocyte differentiation, growth, and apoptosis through a variety of pathways and can mediate melanin production by targeting key enzymes. AIMS: This article was aimed to review the role of miRNAs in melanin metabolism and to introduce the role and significance of miRNAs in melanin-related diseases. MATERIALS & METHODS: Systematic search and retrospective review were performed on the published data. RESULTS: This paper reviews the process of melanin synthesis and the regulatory mechanism, explores the miRNA expression profiles in different model organisms, and introduces the mechanisms of several key miRNAs participating in melanin metabolism through target genes. We also explore the potential role of miRNA as a new target for the treatment of melanin metabolism disease, including vitiligo, melanoma, and chloasma. CONCLUSION: miRNAs play a key role in melanin-related diseases, and the miRNAs involved may be potential therapeutic targets.

The Ubiquitin Proteasome System and Skin Fibrosis.

The ubiquitin proteasome system (UPS) is a highly conserved way to regulate protein turnover in cells. The UPS hydrolyzes and destroys variant or misfolded proteins and finely regulates proteins involved in differentiation, apoptosis, and other biological processes. This system is a key regulatory factor in the proliferation, differentiation, and collagen secretion of skin fibroblasts. E3 ubiquitin protein ligases Parkin and NEDD4 regulate multiple signaling pathways in keloid. Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) binding with deubiquitinase USP10 can induce p53 destabilization and promote keloid-derived fibroblast proliferation. The UPS participates in the occurrence and development of hypertrophic scars by regulating the transforming growth factor (TGF)-ß/Smad signaling pathway. An initial study suggests that TNFα-induced protein 3 (TNFAIP3) polymorphisms may be significantly associated with scleroderma susceptibility in individuals of Caucasian descent. Sumoylation and multiple ubiquitin ligases, including Smurfs, UFD2, and KLHL42, play vital roles in scleroderma by targeting the TGF-ß/Smad signaling pathway. In the future, drugs targeting E3 ligases and deubiquitinating enzymes have great potential for the treatment of skin fibrosis.

Current insight into the roles of microRNA in vitiligo.

Vitiligo is a common chronic depigmented skin disease characterized by melanocyte loss or dysfunction in the lesion. The pathogenesis of vitiligo has not been fully clarified. Most studies have suggested that the occurrence and progression of vitiligo are due to multiple factors and gene interactions in which noncoding RNAs contribute to an individual's susceptibility to vitiligo. Noncoding RNAs, including microRNAs (miRNAs), are a hot topic in posttranscriptional regulatory mechanism research. miRNAs are noncoding RNAs with a length of approximately 22 nucleotides and play a negative regulatory role by binding to the 3'-UTR or 5'-UTR of the target mRNA to inhibit translation or initiate mRNA degradation. Previous studies have screened the differential expression profiles of miRNAs in the skin lesions, melanocytes, peripheral blood mononuclear cells (PBMCs) and sera of patients and mouse models with vitiligo. Moreover, several studies have focused on miRNA-25, miRNA-155 and other miRNAs involved in melanin metabolism, oxidative stress, and melanocyte proliferation and apoptosis. These miRNAs and regulatory processes further illuminate the pathogenesis of vitiligo and provide hope for the application of small molecules in the treatment of vitiligo. In this review, we summarize miRNA expression profiles in different tissues of vitiligo patients and the mechanisms by which key miRNAs mediate vitiligo development.

Transgelin-2 contributes to proliferation and progression of hepatocellular carcinoma via regulating Annexin A2.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, but its pathogenesis is not clear. This study found that the expression of TAGLN2 mRNA and protein in HCC was higher than that in adjacent tissues. TCGA database analysis further confirmed this result, and found that the expression of TAGLN2 was positively correlated with the prognosis of HCC, suggesting that TAGLN2 may be a tumor promoter gene. Then the TAGLN2-Annexin A2 (ANXA2) interaction and NF-κB signaling pathway were further clarified during the invasion and metastasis of HCC. This mechanism provides a theoretical basis for further finding molecular targets and drug targets related to HCC metastasis.

The integrative regulatory network of circRNA and microRNA in keloid scarring.

Circular RNA (circRNA), a novel type of non-coding RNA that consists of a circular loop, has been demonstrated to act as a "sponge" for microRNAs (miRNAs). However, the role of circRNAs in keloid remains unknown. In this study, we investigated circRNA expression profiles in keloid to identify potential diagnostic and therapeutic circRNAs. We performed a circRNA microarray assay to determine circRNA expression in keloid and paired normal skin tissues. Quantitative reverse transcription polymerase chain reaction was used to evaluate the expression levels of candidate circRNAs. The most significantly over-expressed circRNA was used to predict putative miRNA targets and the binding sites of miRNAs with this circRNA. Finally, we constructed a circRNA-miRNA interaction network and carried out gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. We found 52 significantly upregulated and 24 downregulated circRNAs in keloid compared with normal skin tissue. We confirmed that hsa_circ_0057452, hsa_circ_0007482, hsa_circ_0020792, hsa_circ_0057342, and hsa_circ_0043688 were significantly upregulated in keloid tissues. Analysis of the circRNA-miRNA interaction network revealed that circRNAs could interact with miRNAs, including miRNA-29a, miRNA-23a-5p and miRNA-1976. GO and KEGG analyses indicated that these target genes were involved in biological functions and signaling pathways that may play vital roles in the pathogenesis of keloid. This study revealed that circRNAs are potentially implicated in the development of keloid and could serve as novel diagnostic and therapeutic targets.

Gastrodin ameliorates microvascular reperfusion injury-induced pyroptosis by regulating the NLRP3/caspase-1 pathway.

Inflammation is a pivotal feature of myocardial reperfusion-induced microvascular injury and dysfunction. However, the molecular mechanisms by which myocardial reperfusion triggered inflammation remain incurable. The NLRP3 inflammasome is a key intracellular sensor that detection of cellular stress to activation of caspase-1, and consequent IL-1ß maturation and pyroptotic cell death. Here, we showed that NLRP3 inflammasome played a key role in myocardial reperfusion-induced microvascular injury. We observed NLRP3 inflammasome activation and pyroptosis in both cardiac microvascular endothelial cells and myocardial I/R animal model. Gastrodin, an effective monomeric component extracted from the herb Gastrodia elata BIume, blocked cardiac microvascular endothelial cell pyroptosis via inhibiting NLRP3/caspase-1 pathway. Gastrodin also reduced interleukin-1ß (IL-1ß) production in vivo and in vitro. Furthermore, gastrodin treatment attenuated infarct size and inflammatory cells infiltration and increased capillary formation. Gastrodin is thus a potential therapeutic for NLRP3-associated inflammatory disease.

Integrated Interaction Network of MicroRNA Target Genes in Keloid Scarring.

Keloids are a common dermal pathological disorder characterized by the excessive deposition of extracellular matrix components; however, the exact pathogenesis of the disease is still not clear. Studies increasingly suggest that microRNAs (miRNAs) can play a key role in the process of keloid scarring. In this study, the valuable miRNAs and target genes were screened and the interaction network was constructed. We also predicted target genes of reported miRNAs using TargetScan and miRTarBase software. Cytoscape 3.0.1 further showed the interaction network of miRNA and target genes. Among the various miRNAs involved in keloid pathogenesis, miRNA-21, miRNA-141-3p, miRNA-181a, and miRNA-205 were thought to up-regulate the proliferation and decrease apoptosis of keloid-derived fibroblasts through the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. miRNA-637 and miRNA-1224 inhibited keloid fibroblasts proliferation and promoted apoptosis via the transforming growth factor (TGF)-ß1/Smad3 signaling pathway. miRNA-21 was also involved in mitochondrial-mediated apoptosis and miRNA-31 targeted vascular endothelial growth factor (VEGF) signaling pathway. miRNA-199a may be one key factor in the cell cycle checkpoint signal pathway of keloid-derived fibroblasts. It was also found that miRNA-29a and miRNA-196a mediated collagen metabolism. These pivotal miRNAs and regulatory processes further improve the data on the epigenetic mechanisms of keloids and provide hope for the use of small molecules in the treatment of keloids.

Identification and integrated analysis of microRNA expression profiles in keloid.

BACKGROUND: Keloid is a common abnormal cutaneous fibroproliferative disorder. However, the process underlying keloid pathogenesis still remains to be unclear. OBJECTIVE: To integrated analyse the miRNA expression profiles of keloid. METHODS: We performed miRNA expression profiles analysis of 3 paired keloid and normal tissue samples by miRNA microarray. Differentially expressed miRNAs were further performed integrative analysed and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). After predicting target genes, we constructed the miRNA-target genes interaction network and carried out bioinformatics analysis. RESULTS: The results revealed that 264 miRNAs were significantly altered. The expression of high frequency miRNAs which included miRNA-199a-5p, miRNA-21-5p, miRNA-214-5p, miRNA-424-5p, and miRNA-205-5p was further evaluated. The gene ontology (GO) analyses and the top enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed these target genes were associated with MAPK signaling pathway and HIF-1 signaling pathway. CONCLUSION: This study revealed the profiling of miRNAs in keloid that are potentially implicated in the development of this disease and could serve as novel diagnostic and therapeutic target of keloid.

Downregulation of microRNA-31 inhibits proliferation and induces apoptosis by targeting HIF1AN in human keloid.

microRNAs (miRNAs) play a pivotal role in the regulation of cell proliferation and apoptosis in keloid scarring. Integrative analysis of the previous miRNA microarray revealed miRNA-31 was among the most frequently altered miRNAs in keloid and hypertrophic scar. Using qRT-PCR, we further validated miRNA-31 was increased in keloid tissues and keloid-derived fibroblasts. Moreover, downregulation of miRNA-31 inhibited the cell proliferation, induced the cell apoptosis and disturbed the cell cycle progression by targeting HIF1AN, a negative modulator of hypoxia inducible factor 1. Through the luciferase reporter assay, HIF1AN was confirmed to be a target of miRNA-31. Further studies demonstrated that miRNA-31 regulated proliferation, apoptosis and cell cycle of keloid-derived fibroblasts by mediating HIF1AN/VEGF signaling pathway. Overall, our findings shed new light on miRNA-31 as a promising therapeutic target in keloid scarring.

MicroRNA-21 in Skin Fibrosis: Potential for Diagnosis and Treatment.

Skin fibrosis is a common pathological process characterized by fibroblast proliferation and excessive deposition of extracellular matrix. However, the pathogenesis of the disease is still not clear. Previous studies have shown that microRNA-21 may play pivotal roles in the regulation of a variety of skin fibrosis, including keloid, scleroderma, and hypertrophic scar. In this review, we outline the structure, expression, and regulation of microRNA-21 and its role in fibrotic skin diseases. In future, it may be useful as a prognostic or diagnostic marker. However, there is a significant amount of work required to increase our current understanding of the role of microRNA-21 in skin fibrosis.

Insight into immunocytes infiltrations in polymorphous light eruption.

Polymorphous light eruption (PLE) which is one of the most common photodermatoses has been demonstrated to be immune-mediated disorder. Resistance to UV-induced immunosuppression resulting from differential immune cells infiltration and cytokines secretion has been highlighted in the pathogenesis of PLE. In this study, we reviewed differential patterns of immune cells infiltrations and cytokines secretion that may contribute to PLE occurrence and development.