Long Noncoding RNA 00472: A Novel Biomarker in Human Diseases.

Long non-coding RNAs (lncRNAs) play important roles in human diseases. They control gene expression levels and influence various biological processes through multiple mechanisms. Functional abnormalities in lncRNAs are strongly associated with occurrence and development of various diseases. LINC00472, which is located on chromosome 6q13, is involved in several human diseases, particularly cancers of the breast, lung, liver, osteosarcoma, bladder, colorectal, ovarian, pancreatic and stomach. Importantly, LINC00472 can be used as a biomarker for breast cancer cell sensitivity to chemotherapeutic regimens, including doxorubicin. LINC00472 is regulated by microRNAs and several signaling pathways. However, the significance of LINC00472 in human diseases has not been clearly established. In this review, we elucidate on the significance of LINC00472 in various human diseases, indicating that LINC00472 may be a diagnostic, prognostic as well as therapeutic target for these diseases.

Characteristics of peripheral blood CD4+CD25+ regulatory T cells and related cytokines in severe atopic dermatitis.

Regulatory T cells (Tregs) have been suggested to play a role in the pathogenesis of atopic dermatitis (AD). However, alterations in the ability of Tregs remain to be determined. To investigate the expression of various surface receptors on CD4(+)CD25(high) regulatory T cells and to investigate their capacity for inhibiting the proliferation of CD4(+) CD25(-) effector T cells (Teffs). Peripheral blood samples were obtained from 15 patients with severe atopic dermatitis (AD) and 20 control subjects. FACs was then carried out to analyze the expression levels of FoxP3, CD152 (CTLA-4), CD39, CD73, CD223 (LAG-3), CCR4, CCR5, and CCR10 on Tregs. The proliferative responses of Teffs were assessed in the absence or presence of autologous Tregs and the TGF-ß1 and IL-10 levels in the culture supernatant and sera were detected by enzyme-linked immunosorbent assay (ELISA). The CD152, CD39, CD73, CCR4, and CCR5 expression levels on Tregs were higher in patients with severe AD than in the controls. Tregs showed an attenuated suppressive function of the proliferation of autologous Teffs in severe AD. The concentrations of IL-10 and TGF-ß in the culture supernatants of Tregs were lower in the AD group than in the control. The attenuated ability of Tregs to suppress Teff proliferation may be responsible for the autoimmune reaction of severe AD.

Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes.

Sanguinarine (SAG) has been recognized as an anticancer drug candidate. However, the drug-drug interactions (DDI) potential for SAG via the inhibition against human cytochrome P450 (CYP) enzymes remains unclear. In the present study, the inhibitory effects of SAG on seven major human CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C8, 2C9 and 3A4 were investigated with human liver microsomes (HLM). The results showed that SAG was a potent noncompetitive inhibitor of CYP2C8 activity (Ki=8.9 µM), and competitive inhibitor of CYP1A2, CYP2C9 and CYP3A4 activities (Ki=2.7, 3.8 and 2.0 µM, respectively). Furthermore, SAG exhibited time- and NADPH-dependent inhibition towards CYP1A2 and CYP3A4 with KI/kinact values of 13.3/0.087 and 5.58/0.029 min(-1) µM(-1), respectively. Weak inhibition of SAG against CYP2E1, CYP2D6 and CYP2A6 was also observed. In vitro-in vivo extrapolation (IV-IVE) from HLM data showed that more than 35.9% of CYP1A2, CYP2C9, CYP2C8 and CYP3A4 activities in vivo could be inhibited by SAG, suggesting that harmful DDIs could occur when SAG or its medical preparations are co-administered with drugs primarily cleared by these CYP isoforms. Further in vivo studies are needed to evaluate the clinical significance of the data presented herein.

Association analyses identify three susceptibility Loci for vitiligo in the Chinese Han population.

To identify susceptibility loci for vitiligo, we extended our previous vitiligo genome-wide association study with a two-staged replication study that included 6,857 cases and 12,025 controls from the Chinese Han population. We identified three susceptibility loci, 12q13.2 (rs10876864, P(combined)=8.07 × 10(-12), odds ratio (OR)=1.18), 11q23.3 (rs638893, P(combined)=2.47 × 10(-9), OR=1.22), and 10q22.1 (rs1417210, P(combined)=1.83 × 10(-8), OR=0.88), and confirmed three previously reported loci for vitiligo, 3q28 (rs9851967, P(combined)=8.57 × 10(-8), OR=0.88), 10p15.1 (rs3134883, P(combined)=1.01 × 10(-5), OR=1.11), and 22q12.3 (rs2051582, P(combined)=2.12 × 10(-5), OR=1.14), in the Chinese Han population. The most significant single-nucleotide polymorphism in the 12q13.2 locus is located immediately upstream of the promoter region of PMEL, which encodes a major melanocyte antigen and has expression loss in the vitiligo lesional skin. In addition, both 12q13.2 and 11q23.3 loci identified in this study are also associated with other autoimmune diseases such as type 1 diabetes and systemic lupus erythematosus. These findings provide indirect support that vitiligo pathogenesis involves a complex interplay between immune regulatory factors and melanocyte-specific factors. They also highlight similarities and differences in the genetic basis of vitiligo in Chinese and Caucasian populations.

Infliximab monotherapy for Chinese patients with moderate to severe plaque psoriasis: a randomized, double-blind, placebo-controlled multicenter trial.

BACKGROUND: Tumor necrosis factor-α is a key mediator in the pathogenesis of psoriasis. Infliximab is a monoclonal antibody that specifically binds to tumor necrosis factor-α. The purpose of this study was to validate the efficacy and safety of 5 mg/kg infliximab therapy in Chinese patients with moderate to severe plaque psoriasis. METHODS: In this multicenter, double-blind, placebo-controlled trial, 129 patients with moderate-to-severe psoriasis were randomized to the induction therapy (weeks 0, 2 and 6) with infliximab 5 mg/kg (n = 84) or placebo (n = 45), followed with infliximab 5 mg/kg scheduled at week 14 and week 22 in the infliximab group, and infliximab 5 mg/kg scheduled at weeks 10, 12 and 16 in the placebo group. The primary end point was the proportion of patients who achieved at least 75% improvement in Psoriasis Area and Severity Index (PASI 75 response rate) from baseline at week 10. RESULTS: At week 10, 81.0% of patients treated with infliximab (5 mg/kg) achieved a 75% or greater improvement compared with 2.2% of patients treated with placebo (P < 0.001). A significant improvement in PASI, Physician's Global Assessment (PGA) and Dermatology Life Quality Index (DLQI), was seen from week 6 through week 14 in the infliximab group compared with the placebo group. Through week 22, PASI, PGA, DLQI were well maintained. The incidence of adverse events for the infliximab treatment group was slightly higher in comparison to the placebo treatment group during the first 10 weeks without statistical significance. However, there were 3 cases of tuberculosis that developed during the 26 weeks treatment with infliximal. CONCLUSIONS: Infliximab treatment was effective as induction and maintenance treatments for Chinese patients with moderate to severe plaque psoriasis. Most drug-induced adverse events were mild to moderate, and well tolerated. Screening for tuberculosis is essential and prophylactic treatment should be given if necessary.

Curcumin inhibits melanogenesis in human melanocytes.

Plant derived compounds, as potentially safe and effective skin lightening agents (SLAs), have attracted great attention from many researchers. Curcumin is a plant-derived polyphenol, which has been reported to suppress melanogenesis in B16 melanoma cells. However, little is known about whether curcumin affects melanogenesis in cultured human melanocytes. In addition, the molecular mechanism for the antimelanogenic effects of curcumin remains largely unknown. The present study assessed the effects of curcumin on melanin synthesis, cellular tyrosinase activity, the expression of melanogenesis-related proteins (microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein 1 and 2 (TRP-1, TRP-2)), and activation of melanogenesis-regulating signals including phosphatidylinositol 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3 (GSK 3ß), extracellular signal-regulated kinase (ERK) and p38 MAPK in human melanocytes. The results showed that the melanin content and tyrosinase activity, as well as the expression of melanogenesis-related proteins in human melanocytes, were significantly inhibited by curcumin in a dose dependent manner. In addition, PI3K/Akt/ GSK 3ß, ERK and p38 MAPK were activated by curcumin, while inhibitors of these signals attenuated the inhibitory effects of curcumin on melanogenesis. These results suggest that curcumin inhibits melanogenesis in human melanocytes through activation of Akt/GSK 3ß, ERK or p38 MAPK signaling pathways.

Apigenin attenuates dopamine-induced apoptosis in melanocytes via oxidative stress-related p38, c-Jun NH2-terminal kinase and Akt signaling.

BACKGROUND: Accumulating evidence suggests that the occurrence of oxidative stress leads to melanocyte degeneration in vitiligo. Elevated level of dopamine (DA), an initiator of oxidative stress, reportedly is found in patients with vitiligo and induces melanocyte death in vitro. DA-treated melanocytes have been used as a model to search for antioxidants for treating vitiligo. OBJECTIVE: We investigated the protective effects of apigenin against DA-induced apoptosis in melanocytes and the molecular mechanism underlying those effects. METHODS: Melanocytes with or without pretreatment with apigenin were exposed to DA. Then cell viabilities were measured by MTT assay. Cellular reactive oxygen species (ROS) levels and the percentage of apoptotic cells were detected by flow cytometry analysis. Activation of caspase 3, poly(ADP-ribose) polymerase (PARP) and oxidative stress-related signaling, including p38, c-Jun NH2-terminal kinase (JNK) and Akt, were assessed by Western blotting. RESULTS: Apigenin attenuated DA-induced apoptotic cell death, relieved ROS accumulation and activated caspase 3 and PARP, suggesting the protective effects of apigenin against DA-induced oxidative stress and apoptosis in melanocytes. Moreover, DA induced phosphorylation of p38, JNK and Akt, while inhibitors of p38, JNK and Akt significantly decreased DA-induced apoptosis. However, pretreatment with apigenin significantly inhibited DA-triggered activation of p38, JNK and Akt, suggesting the involvement of p38, JNK and Akt in the protective effects of apigenin against DA-induced cytotoxicity. CONCLUSION: These results suggest that apigenin attenuates dopamine-induced apoptosis in melanocytes via oxidative stress-related p38, JNK and Akt signaling and therefore could be a potential agent in treating vitiligo.

Exogenous N-acetylglucosamine increases hyaluronan production in cultured human dermal fibroblasts.

Application of hyaluronan (HA) containing cosmetic products to the skin is reported to moisturize and restore elasticity thereby achieving an antiwrinkle effect. In the skin, HA can be synthesized by dermal fibroblasts and N-acetylglucosamine (NAG) is a precursor for HA biosynthesis in the body. To study the effects of exogenous NAG on HA production in human dermal fibroblasts, HA production and HA-synthesizing enzymes 1, 2 and 3 mRNA expression in cultured human dermal fibroblasts were measured by ELISA and RT-PCR, respectively. The results showed that NAG promoted HA production while had no effect on the expression of HA-synthesizing enzymes 1, 2 and 3 mRNA in human dermal fibroblasts.

Increased interleukin-6 and granulocyte-macrophage colony stimulating factor levels in the sera of patients with non-segmental vitiligo.

BACKGROUND: Although the cause of vitiligo is unknown, an autoimmune theory has been proposed, and there is now convincing evidence that cytokines have an important role in pathogenesis of autoimmunity. OBJECTIVE: To study the possible role of interleukin-1, beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of vitiligo. METHODS: The authors measured the serum levels of the above-mentioned cytokines from 50 patients with the vitiligo compared with 20 healthy volunteers, employing the method of radioimmunoassay. RESULTS: The results showed that the serum levels of both IL-6 and GM-CSF of the patients with both focal type and generalized type of vitiligo, and the serum level of IL-1 beta of the generalized type,were significantly, higher than those of normal controls in the patients with segmental vitiligo, the serum levels of all the cytokines tested were not significantly different from those of the normal controls. The GM-CSF levels of both focal type and generalized type, and the IL-6 level of the generalized type in progressive stage were significantly higher than those in stable state. CONCLUSION: It is speculated that IL-6 and GM-CSF may be involved in the autoimmune mechanism of non-segmental vitiligo. However, more evidence is required before a definite conclusion can be drawn.