Photobiomodulation with 630-nm LED Inhibits M1 Macrophage Polarization via STAT1 Pathway Against Sepsis-Induced Acute Lung Injury.

Background: Sepsis-induced acute lung injury (ALI) is a clinical syndrome characterized by excessive uncontrolled inflammation. Photobiomodulation such as light-emitting diode (LED) irradiation has been used to attenuate inflammatory disease. Objective: The protective effect of 630 nm LED irradiation on sepsis-induced ALI remains unknown. The purpose of this study was to investigate the role of 630 nm LED irradiation in sepsis-induced ALI and its underlying mechanism. Methods and results: C57BL/6 mice were performed cecal ligation and puncture (CLP) for 12 h to generate experimental sepsis models. Histopathology analysis showed that alveolar injury, inflammatory cells infiltration, and hemorrhage were suppressed in CLP mice after 630 nm LED irradiation. The ratio of wet/dry weigh of lung tissue was significantly inhibited by irradiation. The number of leukocytes was reduced in bronchoalveolar lavage fluid. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results and enzyme-linked immunosorbent assay showed that 630 nm LED irradiation significantly inhibited the mRNA and protein levels of M1 macrophage-related genes in the lung of CLP-induced septic mice. Meanwhile, LED irradiation significantly inhibited signal transducer and activator of transcription 1 (STAT1) phosphorylation in the lung of septic mice. In vitro experiments showed that 630 nm LED irradiation significantly inhibited M1 genes mRNA and protein expression in THP-1-derived M1 macrophages without affecting the cell viability. LED irradiation also significantly inhibited the level of STAT1 phosphorylation in THP-1-derived M1 macrophages. Conclusions: We concluded that 630 nm LED is promising as a treatment against ALI through inhibiting M1 macrophage polarization, which is associated with the downregulation of STAT1 phosphorylation.

BMP4 up-regulated by 630 nm LED irradiation is associated with the amelioration of rheumatoid arthritis.

Rheumatoid arthritis (RA) is caused by inflammatory response of joints with cartilage and damage of synovium and bone erosion. In our previous studies, it has showed that irradiation of 630 nm LED reduce inflammation of synovial fibroblasts and cartilage and bone destruction in RA. However, the key genes and mechanism in ameliorating RA by irradiation of 630 nm LED remains unknown. In this study, human fibroblast-like synoviocytes (FLS) cell line MH7A and primary human RA-FLSs were treated with TNF-α and 630 nm LED irradiation with the different energy density. The mRNA sequencing was performed to screen the differentially expressed genes (DEGs). In all datasets, 10 DEGs were identified through screening. The protein interaction network analysis showed that 8 out of the 10 DEGs interacted with each other including IL-6, CXCL2, CXCL3, MAF, PGF, IL-1RL1, RRAD and BMP4. This study focused on BMP4, which is identified as important morphogens in regulating the development and homeostasis. CCK-8 assay results showed that 630 nm LED irradiation did not affect the cell viability. The qPCR and ELISA results showed that TNF-α stimulation inhibited BMP4 mRNA and protein level and irradiation of 630 nm LED increased the BMP4 mRNA and protein level in MH7A cells. In CIA and transgenic hTNF-α mice models, H&E staining showed that irradiation of 630 nm LED decreased the histological scores assessed from inflammation and bone erosion, while BMP4 expression level was up-regulated after 630 nm LED irradiation. Pearson correlation analysis shown that BMP4 protein expression was negatively correlated with the histological score of CIA mice and transgenic hTNF-α mice. These results indicated that BMP4 increased by irradiation of 630 nm LED was associated with the amelioration of RA, which suggested that BMP4 may be a potential targeting gene for photobiomodulation.

LED irradiation at 630 nm alleviates collagen-induced arthritis in mice by inhibition of NF-κB-mediated MMPs production.

Matrix metallopreteinase (MMP), a family of matrix degrading enzyme, plays a significant role in persistent and irreversible joint damage in rheumatoid arthritis (RA). Photobiomodulatory therapy (PBMT) has become an emerging adjunct therapy for RA. However, the molecular mechanism of PBMT on RA remains unclear. The purpose of this study is to explore the effect of 630 nm light emitting diode (LED) irradiation on RA and its underly molecular mechanism. Arthritis clinic scores, histology analysis and micro-CT results show that 630 nm LED irradiation ameliorates collagen-induced arthritis (CIA) in mice with the reduction of the extents of paw swelling, inflammation and bone damage. 630 nm LED irradiation significantly reduces MMP-3 and MMP-9 levels and inhibits p65 phosphorylation level in the paws of CIA mice. Moreover, 630 nm LED irradiation significantly inhibits the mRNA and protein levels of MMP-3 and MMP-9 in TNF-α-treated MH7A cells, a human synovial cell line. Importantly, 630 nm LED irradiation reduces TNF-α-induced the phosphorylated level of p65 but not alters STAT1, STAT3, Erk1/2, JNK and p38 phosphorylation levels. Immunofluorescence result showed that 630 nm LED irradiation blocks p65 nuclear translocation in MH7A cells. In addition, other MMPs mRNA regulated by NF-κB were also significantly inhibited by LED irradiation in vivo and in vitro. These results indicates that 630 nm LED irradiation reduces the MMPs levels to ameliorate the development of RA by inhibiting the phosphorylation of p65 selectively, suggesting that 630 nm LED irradiation may be a beneficial adjunct therapy for RA.Graphical abstract.

The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts.

The FOX family of transcription factors was originally identified in 1989, comprising the FOXA to FOXS subfamilies. FOXO3, a well-known member of the FOXO subfamily, is widely expressed in various human organs and tissues, with higher expression levels in the ovary, skeletal muscle, heart, and spleen. The biological effects of FOXO3 are mostly determined by its phosphorylation, which occurs in the nucleus or cytoplasm. Phosphorylation of FOXO3 in the nucleus can promote its translocation into the cytoplasm and inhibit its transcriptional activity. In contrast, phosphorylation of FOXO3 in the cytoplasm leads to its translocation into the nucleus and exerts regulatory effects on biological processes, such as inflammation, aerobic glycolysis, autophagy, apoptosis, oxidative stress, cell cycle arrest and DNA damage repair. Additionally, FOXO3 isoform 2 acts as an important suppressor of osteoclast differentiation. FOXO3 can also interfere with the development of various diseases, including inhibiting the proliferation and invasion of tumor cells, blocking the production of inflammatory factors in autoimmune diseases, and inhibiting ß-amyloid deposition in Alzheimer's disease. Furthermore, FOXO3 slows down the aging process and exerts anti-aging effects by delaying telomere attrition, promoting cell self-renewal, and maintaining genomic stability. This review suggests that changes in the levels and post-translational modifications of FOXO3 protein can maintain organismal homeostasis and improve age-related diseases, thus counteracting aging. Moreover, this may indicate that alterations in FOXO3 protein levels are also crucial for longevity, offering new perspectives for therapeutic strategies targeting FOXO3.

Gelsolin Inhibits the Proliferation of Colon Cancer Cells by Enhancing the Expression of TNFR2/CASP10 as a Death Receptor Pathway.

BACKGROUND: Colon cancer has the second highest incidence rate of digestive system tumors. It relies on surgical treatment, radiotherapy and chemotherapy, and targeted drug therapy. OBJECTIVE: To study the mechanism of GSN in the proliferation of colon cancer cells. MATERIALS AND METHODS: The expression of gelsolin (GSN) was analyzed with the data of colon cancer patients in the TCGA database. SW620 cells were treated by GSN in vitro and the gene expression was detected by immunoblotting and quantitative PCR. RESULTS: The expression of GSN was found significantly low in colon cancer cells and correlated with the prognosis of patients. The SW620 cell line cultured in vitro was treated with exogenous GSN. SW620 can be significantly inhibited above the concentration of 250 µg/ml. The results of immunoblotting and quantitative PCR showed that exogenous GSN can effectively improve the transcription level of death receptor-related pathway genes such as TNFR2 and CASP10. CONCLUSION: This study found that GSN inhibited the proliferation of SW620 cells in vitro by upregulating the expression of death receptor pathway-related proteins.

Integrated analysis of ferroptosis-related gene signature for overall survival prediction in Asian patients with hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancers in Asia. Accumulating evidence suggests that ferroptosis is a non-apoptotic form of cell death, and has played an important role in cancer biology. METHODS: Based on the manually curated ferroptosis-related gene set and TCGA-LIHC dataset of Asian patients, we used DESeq2, Kaplan-Meier analysis, and univariate Cox regression to identify differentially expressed ferroptosis-related genes with significantly prognostic capacity. A risk signature was constructed based on the selected genes for predicting the survival of HCC patients in Asia. The survival prediction accuracy was confirmed by the time-dependent receiver operating characteristic (ROC) curve analysis. Gene set variation analysis (GSVA) was used to explore the functional associations of the signature. Ferroptosis potential index (FPI) and xCell algorithm was applied to quantify ferroptosis and immune cell infiltration, respectively. Two independent datasets from the GEO and the ICGC database were used for external validation. RESULTS: The ferroptosis-related signature could accurately predict the survival outcomes of HCC patients in Asian (p value < 0.0001). We showed that the signature was an independent factor and was beneficial in elevating risk stratification of current clinicopathologic features, such as the amount of alpha-fetoprotein (AFP) and residual tumor classification. Functional characterization showed that critical processes in tumorigenesis belonged to the high-risk groups, for example inflammatory response, which may be the main driver of HCC. The high-risk group had higher FPIs and infiltrations of macrophages and T-helper cells than the low-risk group. Furthermore, two independent cohorts confirmed the prognostic value of our signature. CONCLUSION: Overall, our results demonstrated potential application of ferroptosis-related genes as independent biomarkers in Asian HCC patients. Targeting ferroptosis may be clinically useful beyond known clinicopathological factors and provide benefit in immunotherapy.

Heat Shock Protein Is Associated with Inhibition of Inflammatory Cytokine Production by 630 nm Light-Emitting Diode Irradiation in Fibroblast-Like Synoviocytes Based on RNA Sequencing Analysis.

Background: Inflammatory cytokine secretion from fibroblast-like synoviocytes (FLS) plays a vital role in the pathological process of rheumatoid arthritis (RA). Photobiomodulation (PBM) has been widely used in the treatment of RA. However, the mechanism of PBM in RA has not been clarified. Objective: In this study, we investigated the underlying mechanism of 630 nm light-emitting diode (LED) irradiation on anti-inflammation using mRNA sequencing analysis. Methods and results: Reverse transcription (RT)-quantitative polymerase chain reaction (RT-qPCR) results showed that 630 nm LED irradiation significantly inhibited interleukin (IL)-1ß, IL-6, and IL-8 mRNA expression in rheumatoid arthritis fibroblast synovial cells (RA-FLS) and MH7A cells. A total of 1730 differentially expressed genes (DEGs) were identified between tumor necrosis factor α (TNF-α)+LED and TNF-α-treated RA-FLS and 1219 DEGs in MH7A cells by mRNA sequencing analysis. A total of 646 intersecting DEGs from the 2 cell models were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Protein-protein interaction (PPI) network of DEGs was used, and 502 nodes and 1452 edges were found. A total of 14 clusters were generated in MCODE, and the top 3 clusters were selected as hub modules. PPI network showed that most of the nodes were DEGs of the heat shock protein (HSP) family. RT-qPCR verified that 630 nm LED irradiation significantly increased HSP70 mRNA expression in FLS. Conclusions: Taken together, our results revealed the correlation between HSP70 and the inhibition of inflammation caused by 630 nm LED irradiation. These findings suggested that HSP may be a novel target of 630 nm LED irradiation to alleviate inflammation in the treatment of RA.

Web Crawling and mRNA Sequencing Analyze Mechanisms of Photobiomodulation.

Background: Photobiomodulation (PBM) is praised as a promising physical therapy, which has many advantages, such as being noninvasive and painless. However, the mechanisms are not fully elucidated. Methods: Using web crawling, mRNA sequence, and bioinformatics analysis, we selected genes, functional annotation, and mechanisms. The expressions of inflammatory cytokines were measured using quantitative real-time PCR (RT-qPCR). Results: A total of 146 human genes and 57 pathways were identified about PBM. The 630 nm light-emitting diode (LED)-stimulated-MH7A cells were sequenced to further analyze the mechanism of PBM. Two thousand nine hundred fifty differentially expressed genes were identified, and the gene ontology term enrichment analysis and Kyoto encyclopedia of genes and genomes pathway analysis were performed to better understand functions and pathways. The 12 pathways were matched with the KEGG results of PBM and MH7A cells. A protein-protein interaction network was performed among genes in 12 pathways, and 10 outstanding proteins were identified. Importantly, the 9 genes were predicted with potential research value. And we also demonstrated that expression of inflammatory factors [interleukin (IL)-6, IL-1ß, IL-8, and matrix metalloproteinase-3 (MMP-3)] was reduced; meanwhile, the expression of anti-inflammatory factor IL-10 was promoted after 630 nm LED. Conclusions: Using web crawling, bioinformatics analysis, and mRNA sequence, we obtained 9 key genes and 12 important pathways about PBM. Importantly, we demonstrated the anti-inflammatory effect of 630 nm LED red light by RT-qPCR.

Dihydroartemisinin Inhibits TGF-ß-Induced Fibrosis in Human Tenon Fibroblasts via Inducing Autophagy.

BACKGROUND: The formation of hypertrophic scars (HS) can result in the failure of glaucoma surgery, and fibrosis is known to be closely associated with the progression of HS. Dihydroartemisinin (DHA) has been reported to inhibit the progression of fibrosis; however, whether DHA can alleviate the formation of HS remains unclear. METHODS: In the present study, in order to examine the effects of DHA on the progression of HS, human Tenon's capsule fibroblasts (HTFs) were isolated from patients who underwent glaucoma surgery. In addition, Western blot analysis, microtubule associated protein 1 light chain 3 α staining and reverse transcription-quantitative PCR were performed to detect protein and mRNA expression levels in the HTFs, respectively. Cell proliferation was detected by Ki67 staining. Flow cytometry was used to examine apoptosis and reactive oxygen species (ROS) levels in the HTFs. RESULTS: The results revealed that TGF-ß promoted the proliferation and fibrosis of HTFs; however, DHA significantly reversed the effects of TGF-ß by increasing cell autophagy. In addition, DHA notably induced the apoptosis of TGF-ß-stimulated HTFs by increasing the ROS levels, while these increases were partially reversed by 3-methyladenine. Furthermore, DHA notably increased the expression of microRNA (miR)-145-5p in HTFs in a dose-dependent manner. CONCLUSION: The present study demonstrated that DHA inhibits the TGF-ß-induced fibrosis of HTFs by inducing autophagy. These findings may aid in the development of novel agents for the prevention of the formation of HS following glaucoma surgery.

The inflammation and reactive oxygen species regulated by Nrf2 and NF-κB signaling pathways in 630-nm light-emitting diode irradiation treated THP-1 monocytes/macrophages.

Because of a large number of macrophages and its secreted pro-inflammatory factors in the synovial fluid of patients with rheumatoid arthritis, the present study aimed to investigate the effect and mechanism of 630-nm LED exposure on monocytes/macrophages and its anti-inflammatory effect. The THP-1 monocytes and PMA-induced THP-1 macrophages (THP-1 macrophages) were employed and irradiated by 630-nm LED for different time and times, and then measure the pro-inflammatory cytokines production by RT-qPCR and Milliplex MAP Multiplex assay, the proteins involved in inflammation pathway and reactive oxygen species (ROS) levels in the cells were detected by Western blot and DCFH-DA method. The exposure dose of red LED (15.3 J/cm2, 30.6 J/cm2) were determined as no-influence on the cell proliferation, the pro-inflammatory factors TNF-α and IL-1ß mRNAs, and secretions in supernatant of THP-1 macrophages were significantly decreased after LED exposure. The ROS production was blocked in THP-1 monocytes and THP-1 macrophages after treatment of LED. Finally, the phosphorylated NF-κB proteins which involved in inflammation pathway significantly decreased, and its inhibitors Nrf2 were slightly upregulated. The effects of LED anti-inflammation response are dependent on the mechanism of inhibiting ROS level and regulating NF-κB signaling pathways by increasing Nrf2 expression in the cells. It is suggested that 630-nm LED could decrease pro-inflammation in immune cells, and it may be a beneficial adjunct therapy in relieving inflammation of patients with rheumatoid arthritis.

Photobiomodulation with 630-nm LED radiation inhibits the proliferation of human synoviocyte MH7A cells possibly via TRPV4/PI3K/AKT/mTOR signaling pathway.

Phototherapy has been used to treat postoperative pain and inflammatory response in rheumatoid arthritis. Confidence in this approach, however, is impaired by lack of understanding of the light-triggered cellular and molecular mechanisms. The purpose of this study was to characterize the response of human synoviocyte MH7A cells to visible LED red light in an attempt to elucidate the associated action mechanism. Human synoviocyte MH7A cells were treated with 630-nm LED light after stimulation of tumor necrosis factor-α (TNF-α). The effects of light radiation on cell proliferation and migration were detected by MTT assay and scratch test. The expressions of inflammatory cytokines were measured using RT-qPCR. This was followed by detection of the levels of extracellular proteins IL-6 and IL-8 after differential radiation. Furthermore, the expression levels and activation of proteins on PI3K/AKT/mTOR signaling pathway were examined with Western blot. In terms of the proliferation and migration, repeated radiation with LED red light (630 nm, 26 and 39 J/cm2) exerted an inhibitory effect on synoviocyte MH7A cells. Expression of inflammatory factors (IL-6, IL-1ß, IL-8, and MMP-3) was reduced; meanwhile, the expression of anti-inflammatory factor IL-10 was promoted. At the protein level, treatment with 39 J/cm2 of LED red light could decrease the level of extracellular protein (IL-6 and IL-8) and affect the expression and phosphorylation of proteins on TRPV4/PI3K/AKT/mTOR signaling pathway induced by TNF-α. These results demonstrated that LED red light (630 nm) inhibits proliferation and migration of MH7A cells. The growth-inhibiting effects of LED red light on human synoviocyte MH7A cells appear to be associated with regulation of the TRPV4/PI3K/AKT/mTOR signaling pathway.

HBV triggers APOBEC2 expression through miR­122 regulation and affects the proliferation of liver cancer cells.

Hepatitis B virus (HBV) infection is responsible for 50% of liver cancer cases globally; this disease is one of the leading causes of cancer­associated mortality. One reported mechanism underlying the development of liver cancer is the mutation of tumor suppressor genes induced by the overexpression of apolipoprotein B mRNA­editing enzyme catalytic subunit 2 (APOBEC2) in hepatocytes. In addition, it has been observed that HBV inhibited microRNA (miR)­122 expression in hepatocytes; however, the molecular mechanisms involved in liver cancer development remain unknown and further investigations are required. In the present study, the mechanistic roles of HBV infection in modulating the expression of miR­122 and APOBEC2, and the development of liver cancer, were investigated. Reverse transcription­quantitative PCR and western blot analyses revealed that APOBEC2 expression was markedly upregulated following HBV infection. Of note, the expression profile of APOBEC2 in the Huh7 and HepG2 liver cancer cell lines opposed that of miR­122; this miR is the most abundant miRNA in the liver and has been associated with hepatocarcinogenesis. Mechanistically, it was demonstrated via a dual­luciferase assay that miR­122 could specifically bind to the 3'­untranslated region (3'UTR) of APOBEC2 mRNA, inhibiting its expression. Collectively, the findings of the present study may provide insight into the mechanistic role of HBV infection in modulating the expression of miR­122, which targets the 3'UTR of APOBEC2 mRNA, subsequently inducing liver carcinogenesis.

Demethylation of SOCS1 mediates its abnormally high expression in ovarian cancer.

The present study aimed to investigate the association between methylation and the high expression of the suppressor of cytokine signaling 1 (SOCS1) in ovarian cancer by detecting the methylation rate and the degree of expression. The present study investigated the expression of SOCS1 mRNA and SOCS1 protein in ovarian cancer and normal ovary tissues using reverse transcription-quantitative polymerase chain reaction (PCR) and immunohistochemistry, and the methylation status of the CpG islands of SOCS1 mRNA in ovarian cancer tissue were examined using a methylation-specific PCR. The expression levels of SOCS1 mRNA in ovarian cancer specimens were significantly increased compared with that in the normal ovary tissues (P=0.0215). Consistent with this, the expression levels of SOCS1 protein in ovarian cancer specimens were significantly increased, while the methylation rate of SOCS1 mRNA was significantly decreased compared with that in the normal ovary tissues. Therefore, it may be concluded that the low methylation rate of SOCS1 mRNA in ovarian cancer increased the expression of SOCS1 mRNA, which may serve a role in the development of ovarian cancer.

miR­17­5p regulates the proliferation and apoptosis of human trabecular meshwork cells by targeting phosphatase and tensin homolog.

Glaucoma is one of the leading causes of blindness. Previous studies have indicated that the oxidative stress­induced apoptosis of trabecular meshwork cells (TMCs) may serve a key role in the pathogenesis of glaucoma, and that micro RNA(miR)­17­5p may be involved in this process. However, the specific mechanisms require further investigation. The aim of the present study was to investigate the effects of miR­17­5p on the proliferation and apoptosis of human TMCs (HTMCs) in response to oxidative stress. It was observed that exposure to H2O2 induced a significant decrease in the proliferation and a marked increase in the apoptosis of HTMCs. H2O2 exposure also suppressed the expression of miR­17­5p and promoted the expression of phosphatase and tensin homolog (PTEN). Furthermore, transient overexpression of miR­17­5p induced a significant increase in the proliferation and a significant decrease in the apoptosis of HTMCs by affecting the expression of PTEN, and the apoptosis­related proteins B­cell lymphoma­associated X protein (Bax), B­cell lymphoma­extra large (Bcl­xL) and B­cell lymphoma­2 (Bcl­2). However, knockdown of miR­17­5p demonstrated the opposite results. The results of a dual luciferase reporter assay demonstrated that PTEN may be a direct target of miR­17­5p. In conclusion, miR­17­5p was downregulated in HTMCs under oxidative conditions, and miR­17­5p may regulate the apoptosis of HTMCs by targeting PTEN. These results provide a novel theoretical basis and potential therapeutic target for the treatment of glaucoma.

Novel biomarkers containing citrullinated peptides for diagnosis of systemic lupus erythematosus using protein microarrays.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoantibody production. This study aims to identify biomarkers involving citrullinated peptides that can be used for SLE diagnosis. METHODS: After a negative selection step with serum from healthy controls (HCs), a phage library of 12 peptides was used for three rounds of screening with sera from 30 SLE patients. After four rounds of biopanning, 21 positive peptides were sequenced. We produced 37-feature arrays containing 16 recombinant citrullinated peptides. The microarrays were tested with an independent validation set of serum samples from 50 HCs, 60 SLE patients, and 60 rheumatoid arthritis (RA) patients. RESULTS: Microarray analysis showed that the positive rates of 13S1212Cit3-IgM (60.0%), 13S1210-IgG (43.33%), and 13S1212Cit3-IgG (41.67%) were increased in SLE patients compared with HCs and RA patients. The area under the receiver operating characteristic curve (AUC) was 0.770, 0.687 and 0.698, respectively. The combination of 13S1212Cit3-IgM and 13S1210-IgG (termed COPSLE, for combination of peptides for SLE) was more efficient for SLE diagnosis, with a larger AUC (0.830) and a positive rate of 73.33%. COPSLE could be used to identify 80.0% of SLE patients who were negative for anti-Smith (Sm), anti-double-stranded DNA (ds-DNA), and anticardiolipin (ACA). The Spearman rank correlation indicated that COPSLE increased with albumin, serum level of C3 and platelet distribution width, but had negative correlations with decreased C3 and discoid lupus. CONCLUSIONS: A citrullinated/non-citrullinated peptide panel is a valuable diagnostic marker of SLE, even for patients who are negative for anti-Sm, anti-ds-DNA and ACA.

The roles and applications of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours.

The existence of autoantibodies towards an individual's own proteins or nucleic acids has been established for more than 100years, and for a long period, these autoantibodies have been believed to be closely associated with autoimmune diseases. However, in recent years, researchers have become more interested in the role and application of autoantibodies in progression, diagnosis, treatment and prognosis of human malignant tumours. Over the past few decades, numerous epidemiological studies have shown that the risk of certain cancers is significantly altered (increased or decreased) in patients with autoimmune diseases, which suggests that autoantibodies may play either promoting or suppressing roles in cancer progression. The idea that autoantibodies are directly involved in tumour progression gains special support by the findings that some antibodies secreted by a variety of cancer cells can promote their proliferation and metastasis. Because the cancer cells generate cell antigenic changes (neoantigens), which trigger the immune system to produce autoantibodies, serum autoantibodies against tumour-associated antigens have been established as a novel type of cancer biomarkers and have been extensively studied in different types of cancer. The autoantibodies as biomarkers in cancer diagnosis are not only more sensitive and specific than antigens, but also could appear before clinical evidences of the tumours, thus disclosing them. The observations that cancer risk is lower in patients with some autoimmune diseases suggest that certain autoantibodies may be protective from certain cancers. Moreover, the presence of autoantibodies in healthy individuals implies that it could be safe to employ autoantibodies to treat cancer. Of note, an autoantibodies derived from lupus murine model received much attention due to their selective cytotoxicity for malignant tumour cell without harming normal ones. These studies showed the therapeutic value of autoantibodies in cancer. In this review, we revisited the pathological or protective role of autoantibodies in cancer progression, summarize the application of autoantibodies in cancer diagnosis and prognosis, and discuss the value of autoantibodies in cancer therapy. The studies established to date suggest that autoantibodies not only regulate cancer progression but also promise to be valuable instruments in oncological diagnosis and therapy.

Chlorpromazine inhibits mitochondrial apoptotic pathway via increasing expression of tissue factor.

Chlorpromazine (CPZ) is a widely used antipsychotic drug with antagonistic effect on dopamine receptors. Accumulating evidence has shown that CPZ plays a neuroprotective role in various models of toxicity and apoptosis. However, the underlying mechanism contributing to this protective effect remains unclear. Here, we evaluate the effect of CPZ on mitochondrial apoptotic pathway in the neuron system. Higher levels of B-cell lymphoma-2 (Bcl-2) and tissue factor (TF) but lower apoptotic rate were found in hippocampus of CPZ-treated schizophrenic patients compared with non-antipsychotic treated controls. Additionally, both short-term and long-term treatment of CPZ in rats could up-regulate the levels of Bcl-2 and TF with no cytotoxic effects. In the in vitro experiment, expression of Bcl-2 was up-regulated in the C6 glioma cells transfected with pEGFP-N1-TF recombinant plasmid. Furthermore, in another independent rat model of apoptosis, compared with the group administrated with alcohol only, the brains of the CPZ-pretreated rats showed lower expression of cleaved caspase-3, cytochrome c and Bax, but higher expression of Bcl-2 and TF. Our data demonstrate that CPZ exerts its neuronal protective effects through inhibiting the activation of mitochondrial apoptotic pathway by up-regulating TF expression, thus providing new insight into CPZ function and application.

Down-regulation of suppressor of cytokine signaling 3 by miR-122 enhances interferon-mediated suppression of hepatitis B virus.

MicroRNA-122 (miR-122) is involved in the pathogenesis of several liver diseases, including chronic hepatitis B infection and hepatocellular carcinoma. This study aimed to explore the potential role of miR-122 in the interferon (IFN)-mediated suppression of hepatitis B virus (HBV) in hepatocytes. We found that elevated expression of suppressor of cytokine signaling 3 (SOCS3) following HBV infection, contributed to the inactivation of the IFN signaling pathway. Based on previous studies from our laboratory showing that miR-122 can modulate type I IFN expression by inhibiting SOCS1 expression, we analyzed the SOCS3 mRNA sequence for putative miR-122 binding sites. We demonstrate that miR-122 inhibits SOCS3 expression by targeting the 3'-untranslated region of the SOCS3 mRNA within the region 1887-1910 nucleotides. Finally, we demonstrate that significantly increased levels of IFN lead to decreased HBV expression in miR-122 mimic-treated Huh7 cells, whereas inhibition of endogenous miR-122 leads to enhanced viral production, owing to a marked decrease in IFN expression. Taken together, our results demonstrate that miR-122 down-regulates SOCS3, thus positively affecting the anti-HBV efficiency of endogenous type I IFN. Our study suggests that suppression of miR-122 induced by HBV infection, leads to the inactivation of IFN expression, which in turn enhances HBV replication, contributing to viral persistence and hepatocarcinogenesis.

MiR-122 directly inhibits human papillomavirus E6 gene and enhances interferon signaling through blocking suppressor of cytokine signaling 1 in SiHa cells.

Human Papillomavirus (HPV) 16 infection is considered as one of the significant causes of human cervical cancer. The expression of the viral oncogenes like E6 and E7 play an important role in the development of the cancer. MiR-122 has been reported to exhibit a strong relationship with hepatitis viruses and take part in several tumor development, while the effects of miR-122 on HPV infection and the HPV viral oncogenes expression still remain unexplored. In this study, using RNAhybrid software, the potential binding sites between miR-122 and HPV16 E6 and E7 mRNAs were identified. Over and loss of miR-122 function showed that miR-122 could directly bind with HPV16 E6 mRNA and significantly inhibit its expression in SiHa cells, which was further confirmed by constructing the miR-122-E6-mu to eliminate the miR-122 binding effects with E6. The increase of the expression of type I interferon (IFN) and its classical effective molecules and the phosphorylation of signal transducers and activators of transcription (STAT1) protein indicated that miR-122 might enhance type I interferon in cervical carcinoma cells, which explained the significant reduction of HPV16 E7 and E6*I mRNA expression. This might be due to the binding between miR-122 and suppressor of cytokine signaling 1 (SOCS1) mRNA, which is the suppressor of interferon signaling pathway. Moreover, it was identified that the miR-122 binding position was nt359-nt375 in SOCS1 mRNA. Taken together, this study indicated that HPV16 could be effectively inhibited by miR-122 through both direct binding with E6 mRNA and promoting SOCS1-dependent IFN signaling pathway. Thus, miR-122 may serve as a new therapeutic option for inhibiting HPV infection.

Borna disease virus encoded phosphoprotein inhibits host innate immunity by regulating miR-155.

It has been reported that the Borna disease virus (BDV) encoded phosphoprotein (P protein) can inhibit the activity of Traf family member-associated NF-kappaB activator (TANK)-binding kinase 1 (TBK-1), thus preventing the induction of type I interferon (IFN). However, the effects of microRNA on the regulation of BDV infection and the host's immune response have not been characterized. miR-155 was predicted to be complementary to the BDV P mRNA by RNAhybrid software. Here, we showed that miR-155 was down-regulated in BDV persistently infected human oligodendroglial (OL/BDV) cells and that the BDV P protein, but not the X protein, directly inhibited miR-155 expression in cells. When miR-155 was over-expressed, the inhibition of type I IFNs by BDV in cells was reversed, and the expression of type I IFNs was increased. When miR-155 expression was specifically blocked, cellular IFN expression and the induction of IFN by poly I:C treatment were suppressed. Furthermore, miR-155 promoted type I IFN production by targeting suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Mutations in the nt1138-nt1158 region of SOCS3 abandoned the impact of miR-155 on the expression of SOCS3-enhanced green fluorescent protein (EGFP). The levels of BDV P mRNA and protein were significantly decreased in OL/BDV cells when miR-155 was over-expressed; however, miR-155-mutation did not affect the expression of BDV P-EGFP. Thus, BDV persistent infection inhibited the expression of type I IFNs through the suppression of miR-155, and miR-155 played an important immune regulatory role in BDV persistent infection.