Nuclear accumulation of KPNA2 impacts radioresistance through positive regulation of the PLSCR1-STAT1 loop in lung adenocarcinoma.

Lung adenocarcinoma (ADC) is the predominant histological type of lung cancer, and radiotherapy is one of the current therapeutic strategies for lung cancer treatment. Unfortunately, biological complexity and cancer heterogeneity contribute to radioresistance development. Karyopherin α2 (KPNA2) is a member of the importin α family that mediates the nucleocytoplasmic transport of cargo proteins. KPNA2 overexpression is observed across cancer tissues of diverse origins. However, the role of KPNA2 in lung cancer radioresistance is unclear. Herein, we demonstrated that high expression of KPNA2 is positively correlated with radioresistance and cancer stem cell (CSC) properties in lung ADC cells. Radioresistant cells exhibited nuclear accumulation of KPNA2 and its cargos (OCT4 and c-MYC). Additionally, KPNA2 knockdown regulated CSC-related gene expression in radioresistant cells. Next-generation sequencing and bioinformatic analysis revealed that STAT1 activation and nuclear phospholipid scramblase 1 (PLSCR1) are involved in KPNA2-mediated radioresistance. Endogenous PLSCR1 interacting with KPNA2 and PLSCR1 knockdown suppressed the radioresistance induced by KPNA2 expression. Both STAT1 and PLSCR1 were found to be positively correlated with dysregulated KPNA2 in radioresistant cells and ADC tissues. We further demonstrated a potential positive feedback loop between PLSCR1 and STAT1 in radioresistant cells, and this PLSCR1-STAT1 loop modulates CSC characteristics. In addition, AKT1 knockdown attenuated the nuclear accumulation of KPNA2 in radioresistant lung cancer cells. Our results collectively support a mechanistic understanding of a novel role for KPNA2 in promoting radioresistance in lung ADC cells.

Vitamin B12 deficiency may play an etiological role in atrophic glossitis and its grading: A clinical case-control study.

BACKGROUND: Existing studies have reported the significant association between atrophic glossitis (AG) and hematinic deficiencies, including iron, folate and vitamin B12 deficiency. However, these findings were inconsistent. AG can be graded as partial or complete atrophy. It is still unclear whether hematinic deficiencies are associated with the grading of AG. METHODS: 236 AG patients and 208 sex- and age-matched healthy controls were enrolled in this study. Hematological tests including complete blood count, and serum levels of folate, ferritin and vitamin B12 were performed. The AG group was divided into those with partial AG and those with complete AG according to the extent of papillary atrophy. Statistical analysis was performed to assess whether hematinic deficiencies are risk factors for AG and its grading. RESULTS: Compared with the healthy controls, AG patients had significantly higher frequencies of vitamin B12 deficiency (68.22%), ferritin deficiency (13.98%) and anemia (21.61%). The differences in hematinic deficiencies and anemia between AG patients and healthy controls changed according to gender and age. The frequencies of serum vitamin B12 deficiency and anemia in the complete AG subgroup were significantly higher than those in the partial AG subgroup. Logistic regression analysis revealed that vitamin B12 deficiency and anemia were significantly correlated with AG and its grading. The AG patients with vitamin B12 deficiency responded well to supplement therapy. CONCLUSION: AG could be an important clinical indicator for potential vitamin B12 deficiency, especially when the degree of tongue atrophy more than 50% and complete atrophy. Vitamin B12 deficiency might play an etiological role in the development of AG.

TLR4-induced B7-H1 on keratinocytes negatively regulates CD4+ T cells and CD8+ T cells responses in oral lichen planus.

Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4+ T cells and CD8+ T cells. B7-H1 induced by Toll-like receptors (TLRs) can suppress T-cell immune reaction, thereby resulting in immune tolerance. However, the role of TLR-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway downregulated B7-H1 transcriptional expression. Moreover, TLR4-stimulated oral keratinocytes inhibited the proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and simultaneously prompted their apoptosis. Blockade of keratinocyte-associated B7-H1 restored the declined proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and prevented their increased apoptosis. Therefore, TLR4-upregulated B7-H1 on keratinocytes could decelerate immune responses of CD4+ T cells and CD8+ T cells in OLP.

Altered Autophagy-Associated Genes Expression in T Cells of Oral Lichen Planus Correlated with Clinical Features.

Oral lichen planus (OLP) is a T cell-mediated inflammatory autoimmune disease. Autophagy has emerged as a fundamental trafficking event in mediating T cell response, which plays crucial roles in innate and adaptive immunity. The present study mainly investigated the mRNA expression of autophagy-associated genes in peripheral blood T cells of OLP patients and evaluated correlations between their expression and the clinical features of OLP. Five differentially expressed autophagy-associated genes were identified by autophagy array. Quantitative real-time RT-PCR results confirmed that IGF1 expression in the peripheral blood T cells of OLP patients was significantly higher than that in controls, especially in female and middle-aged (30-50 years old) OLP patients. In addition, ATG9B mRNA levels were significantly lower in nonerosive OLP patients. However, no significant differences were found in the expression of HGS, ESR1, and SNCA between OLP patients and controls. Taken together, dysregulation of T cell autophagy may be involved in immune response of OLP and may be correlated with clinical patterns.

Direct reprogramming of stem cell properties in colon cancer cells by CD44.

Cancer progression is commonly segregated into processes of primary tumour growth and secondary metastasis. Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumour growth in cancer. However, the role of CSCs in cancer metastasis is unclear. In this study, we found that the C terminus of CD44 contributes to sphere formation and survival in vitro via the CD44-SRC-integrin axis. In addition, nuclear CD44/acetylated-STAT3 is required for clonal formation in vitro and tumourigenicity in vivo. Nuclear CD44 binds to various promoters identified by chromatin immunoprecipitation-seq, including that of c-myc and Twist1, leading to cell fate change through transcriptional reprogramming. We propose that nuclear CD44/acetylated-STAT3 performs an unexpected tumour-progressing function by enhancing cell outgrowth into structures where cells with properties of CSCs can be generated from differentiated somatic cells in suspension culture, and then exhibit attributes of cells that have undergone an epithelial-mesenchymal transition, leading to tumour metastasis, and a resulting worse prognosis.

Characterization of the structural and molecular interactions of Ferulic acid ethyl ester with human serum albumin and Lysozyme through multi-methods.

Ferulic acid ethyl ester (FAEE) is an essential raw material for the formulation of drugs for cardiovascular and cerebrovascular diseases and leukopenia. It is also used as a fixed aroma agent for food production due to its high pharmacological activity. In this study, the interaction of FAEE with Human serum albumin (HSA) and Lysozyme (LZM) was characterized by multi-spectrum and molecular dynamics simulations at four different temperatures. Additionally, the quenching mechanism of FAEE-HSA and FAEE-LZM were explored. Meanwhile, the binding constants, binding sites, thermodynamic parameters, molecular dynamics, molecular docking binding energy, and the influence of metal ions in the system were evaluated. The results of Synchronous fluorescence spectroscopy, UV-vis spectroscopy, CD, three-dimensional fluorescence spectrum, and resonance light scattering showed that the microenvironment of HSA and LZM and the protein conformation changed in the presence of FAEE. Furthermore, the effects of some common metal ions on the binding constants of FAEE-HSA and FAEE-LZM were investigated. Overall, the experimental results provide a theoretical basis for promoting the application of FAEE in the cosmetics, food, and pharmaceutical industries and significant guidance for food safety, drug design, and development.

Different expression profiles of circulating miR-31 and miR-181a in CD4+ T cells and plasma of patients with oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated inflammatory-immune disease in which CD4+ T cells may be significantly involved in the dysregulated immune response. MicroRNAs (miRNAs) critically control gene expression post-transcriptionally and regulate the immune response and inflammation. Here, we explored the expression profiles of circulating miRs (miR-19b, miR-31, and miR-181a), which can modulate CD4+ T cell activation, differentiation, and immune function. Quantitative real-time PCR showed that miR-31 and miR-181a dramatically decreased in peripheral CD4+ T cells, whereas they markedly increased in the plasma of OLP patients, especially in the erosive form. However, no significant differences were observed in the expression of miR-19b in CD4+ T cells and plasma between OLP patients and healthy controls or between different forms of OLP. Moreover, miR-31 expression positively correlated with the miR-181a expression in the CD4+ T cells and plasma of OLP patients. Furthermore, receiver operating characteristic (ROC) curve analyses indicated that miR-31 and miR-181a, rather than miR-19b, in CD4+ T cells and plasma could discriminate OLP, especially erosive OLP, from healthy controls. In conclusion, there were different expression profiles of circulating miR-31 and miR-181a in CD4+ T cells and plasma of patients with OLP, which could synergistically serve as potential biomarkers for OLP.

MiR-29b interacts with IFN-γ and induces DNA hypomethylation in CD4+ T cells of oral lichen planus.

Oral lichen planus (OLP) is an autoimmune inflammatory disease mediated by T cells, in whose pathogenesis CD4+ T helper cells are supposed to play vital roles. MiR-29b has recently been recognized as a crucial regulator in immune response and inflammation. The current research focuses on exploring how miR-29b functions in the immunopathogenesis of OLP. Our findings showed that miR-29b expression in CD4+ T cells was upregulated in OLP, especially in its erosive form. MiR-29b in CD4+ T cells repressed IFN-γ mRNA and IFN-γ secretion, but not T-bet and EOMES; in turn, IFN-γ increased the expression of STAT1 and miR-29b in CD4+ T cells. Moreover, miR-29b in CD4+ T cells suppressed DNMT1 expression and induced global DNA hypomethylation. In conclusion, elevated miR-29b interacts with IFN-γ via a regulatory feedback loop and induces global DNA hypomethylation in CD4+ T cells, which consequently modulates Type 1 T helper immune response, thus contributing to the immune dysregulation of OLP.

[The spectral properties of an intense lightning return stroke].

The spectrum in the range of 400-600 nm from the first return stroke of an intense cloud-to-ground lightning flash was obtained by a slit-free spectrograph. Applying the atomic structure theory to the research work on lightning spectra, the wavelengths, oscillator strengths and excitation energies of upper levels were calculated for the transitions of related lightning spectrum. Multi-configuration Dirac-Fock method was employed in the calculation. From the results, re-identifications were carried out for the lines of 419.0 and 425.3 nm. It was found by spectral analysis combined with corresponding electrical information finds that the spectrum characteristic is closely related to the intensity of lightning discharge, as during an intense lightning return stroke the lines of O II with high excitation energies are enhanced.

Different Expression of MicroRNA-146a in Peripheral Blood CD4(+) T Cells and Lesions of Oral Lichen Planus.

Oral lichen planus (OLP) is a common T cell-mediated chronic inflammatory disease of unknown etiology. Recent increasing evidence indicates that microRNA-146a (miR-146a) plays a vital role in inflammatory diseases and T cell regulation. This study aimed to investigate the expression of miRNA-146a in peripheral blood CD4(+) T cells and local OLP lesions and to evaluate its relationship with clinical forms of OLP. Sixteen patients with OLP were divided into two groups: erosive OLP and nonerosive OLP. The expression of miR-146a was examined by quantitative real-time polymerase chain reaction. The expression of miR-146a in peripheral blood CD4(+) T cells showed no significant difference between OLP group and control group (P > 0.05), and among erosive OLP, nonerosive OLP, and control groups (P > 0.05 for all). The expression in local lesions of the OLP group was significantly higher than that of the control group (P = 0.003), and it was significantly higher in the erosive OLP group than in the non-erosive OLP (P = 0.010) and control groups (P = 0.007). However, miR-146a expression in the nonerosive OLP group did not significantly differ from that in the control group (P > 0.05). These data indicate that miR-146a might be more involved in the local immune disorder of OLP. MiR-146a might be utilized as a candidate biomarker to estimate the severity of OLP.

MicroRNA-155-IFN-γ Feedback Loop in CD4(+)T Cells of Erosive type Oral Lichen Planus.

Oral lichen planus (OLP) is a T cell-mediated immune disorder, and we have indicated a Th1-dominated immune response in OLP. MicroRNA-155 (miR-155) could promote Th1 cells polarization. The present study aims to determine the role of miR-155 in immune response of OLP. The expression of miR-155 and the target mRNA was tested by Real-Time PCR. The serum levels of IL-2, 4, 10 and IFN-γ were examined with ELISA. Furthermore, in vitro study was built to observe the function of miR-155 in erosive-type OLP (EOLP). Finally, we determined the expression and correlation of miR-155 and SOCS1 in EOLP CD4(+) T cells. The results showed miR-155 was high related with the disease severities. Besides, serum IFN-γ was specifically increased in EOLP group, while IL-4 was decreased. In vitro studies showed miR-155 could reinforce IFN-γ signal transducer, and the induction of IFN-γ could also promote miR-155 expression in EOLP CD4(+) T cells. In addition, miR-155 levels were negatively related with SOCS1 mRNA expression in EOLP CD4(+) T cells. Our study revealed a positive miR-155- IFN-γ feedback loop in EOLP CD4(+) T cell, which might contribute to the Th1-dominated immune response. Furthermore, miR-155 could be used for the evaluation and treatment of OLP.

Detection of IL-20 and its receptors on psoriatic skin.

The aim of this study was to investigate the expression of interleukin-20 (IL-20) and its receptors on psoriatic skin by immunohistochemical analysis and to evaluate the correlation of CD8-positive T lymphocytes with epidermal proliferation. Overexpression of IL-20 and its receptors was detected in the keratinocytes of the lesional skin of psoriasis and spongiotic dermatitis. The expression pattern of IL-20 spreads throughout the whole layer of epidermis, while IL-19 was expressed in up to three or four layers suprabasally. The serum level of IL-20 in psoriatic patients was significantly lower than that in healthy controls. IL-20 upregulated KGF transcripts on CD8-positive T cells. We hypothesize that overexpression of IL-20 is correlated with keratinocyte proliferation that acts through their receptor complex expressed by keratinocytes themselves. Furthermore, IL-20 can stimulate CD8-positive lymphocytes to produce KGF, which may contribute to sustaining the hyperproliferative status of the keratinocytes.