USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.

Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.

Establishment of the prognostic index of lung squamous cell carcinoma based on immunogenomic landscape analysis.

BACKGROUND: The incidence of lung squamous cell carcinoma (LUSC) increased substantially in recent years. Systematical investigation of the immunogenomic pattern is critical to improve the prognosis of LUSC. METHODS: Based on the TCGA and GEO dataset, we integrated the immune-related genes (IRGs) expression profile and the overall survival (OS) of 502 patients with LUSC. The survival-related and differentially-expressed IRGs in LUSC patients were evaluated by univariate cox regression and LASSO regression analysis. By applying multivariate cox analysis, a new prognostic indicator based on IRGs was established. We also used CIBERSORT algorithms and TIMER database to analyze immune infiltration of LUSC. Both gene set enrichment analysis (GSEA) and principal component analysis (PCA) was carried out for functional annotation. With the assist of computational biology, we also investigated the latent properties and molecular mechanisms of these LUSC-specific IRGs. We analyzed the correlation between immune checkpoints and risk score. RESULTS: A novel prognostic model was established based on 11 IRGS, including CXCL5, MMP12, PLAU, ELN, JUN, RNASE7, JAG1, SPP1, AGTR2, FGFR4, and TNFRSF18. This model performed well in the prognostic forecast, and was also related to the infiltration of immune cells. Besides, the high-risk groups and the low-risk groups exhibited distinct layout modes in PCA analysis, and GSEA results showed that different immune status among these groups. CONCLUSIONS: In summary, our researches screened out clinically significant IRGs and proved the significance of IRG-based, individualized immune-related biomarkers in monitoring, prognosis, and discern of LUSC.

An off-on electrochemiluminescence detection for microRNAs based on TiO2 nanotubes sensitized with gold nanoparticles as enhanced emitters.

A sensitive electrochemiluminescence (ECL) assay for microRNAs (miRNAs) based on a semiconductor nanomaterial sensitized with noble-metal Au nanoparticles (NPs) is successfully developed. TiO2 nanotubes (NTs) were equipped with Au NPs to obtain an enhanced ECL emitter. Then, an ECL assay for miRNA-21 was fabricated, which was based on the use of probe 2 DNA-functionalized Pt/PAMAM nanocomposites (NCs) assembled on the surface of Au/TiO2 NT conjugate via DNA hybridization between probe 1 DNA and capture DNA. The Pt/PAMAM NCs act as an ECL quencher of Au/TiO2 NTs via resonance energy transfer. After the binding of target miRNA-21 and the capture DNA, the Pt/PAMAM NCs were released and the ECL signal was recovered. An "off-on" ECL assay was achieved with a linear response from 0.01 to 10,000 pM. Finally, this method has been validated to be sensitive and specific for miRNAs in human serum samples. The ECL enhancement strategy opens a new way for fabricating various sensitive biosensors. Graphical abstract A sensitive "off-on" electrochemiluminescence analysis method was developed, which combined Au NP-enhanced ECL emission of TiO2 nanotubes and an efficient energy-transfer system between Au/TiO2 nanotubes and Pt/PAMAM nanocomposites.

TiO2 nanotubes loaded with CdS nanocrystals as enhanced emitters of electrochemiluminescence: application to an assay for prostate-specific antigen.

An enhanced cathodic electrochemiluminescence (ECL) assay for prostate-specific antigen (PSA) is developed based on the in situ activation of a semiconductor nanomaterial. An excellent ECL emitter (CdS/TiO2 nanotubes) was fabricated by the combination of TiO2 nanotubes (NTs) and thioglycolic acid-capped CdS nanocrystals (NCs). After the activation of the hydrogen peroxide-citric acid solution, the ECL signal was enhanced 265 times compared with that of the original TiO2 NT with H2O2 as co-reactant. For the ECL assay, activated CdS/TiO2 NTs were assembled with complementary DNA, PSA aptamer and probe DNA-functionalized SiO2@Pt nanoparticles (NPs) via DNA hybridization to form the detection platform. The SiO2@Pt NPs acted as ECL quencher of CdS/TiO2 NTs. In the presence of PSA, ECL increased after the release of pDNA-SiO2@Pt NPs because of the binding of PSA to the aptamer. An "off-on" ECL phenomenon appeared. The enhanced ECL signals were used for sensitive determination of PSA. The dynamic range was 0.001 to 50 ng mL-1 with a detection limit of 0.4 pg mL-1 (S/N = 3). This new approach conceivably paves the way for fabricating various other enhanced ECL emitter systems, with good application prospects in clinical practice. Graphical abstract The activated CdS/TiO2 nanotubes and SiO2@Pt nanoparticles were synthesized and used to develop an energy-transfer electrochemiluminescence analysis method with high sensitivity and anti-interference performance.

Effect of cation replacement on the phase stability of formamidinium lead iodide perovskite.

First-principles calculations have been performed to study the effect of cation replacement with methylammonium (MA+), Cs+, and Rb+ on the properties of formamidinium lead iodide (FAPbI3) perovskite. It is found that these dopants could improve the stability of the desired α phase of FAPbI3 at reduced temperature by lowering the transition temperature between the perovskite cubic α phase and nonperovskite hexagonal δ phase. Interestingly, the optical absorption properties and the effective masses of holes of FAPbI3 perovskite are only slightly affected. The nature of the improvement of the phase stability resulting from the cation replacement is revealed. However, the calculated mixing energies indicate that these multication materials still suffer long-term instability. Our results provide theoretical guidance for improving current multication engineering strategies or even developing new approaches.

Attenuation of Oxidative Stress-Induced Osteoblast Apoptosis by Curcumin is Associated with Preservation of Mitochondrial Functions and Increased Akt-GSK3ß Signaling.

BACKGROUND: Osteoblast apoptosis induced by oxidative stress plays a crucial role in the development and progression of osteoporosis. Curcumin, a natural antioxidant isolated from Curcuma longa, has highly protective effects against osteoporosis. However, the effects of curcumin on oxidative stress-induced osteoblast apoptosis remain unclear. This study aimed to explore the effect of curcumin on hydrogen peroxide (H2O2) induced osteoblast apoptosis and the underlying mechanisms. METHODS: An osteoblastic cell line (Saos-2) was exposed to various concentrations of H2O2 with or without curcumin treatment. Cell viability was evaluated by MTT assays. The apoptosis rate was analyzed by flow cytometry and TUNEL assays. Mitochondrial ROS and membrane potential were determined using a fluorescence microscope. Mitochondrial respiratory enzyme activity was measured using a spectrophotometer. Protein levels were detected by western blotting. RESULTS: Curcumin was cytoprotective because it greatly improved the viability of Saos-2 cells exposed to H2O2 and attenuated H2O2-induced apoptosis. Curcumin treatment also preserved the mitochondrial redox potential, decreased the mitochondrial oxidative status, and improved the mitochondrial membrane potential and functions. Furthermore, curcumin treatment markedly increased levels of phosphorylated protein kinase B (Akt) and phosphorylated glycogen synthase kinase-3ß (GSK3ß). CONCLUSION: Curcumin administration ameliorates oxidative stress-induced apoptosis in osteoblasts by preserving mitochondrial functions and activation of Akt-GSK3ß signaling. These data provide experimental evidence supporting the clinical use of curcumin for prevention or treatment of osteoporosis.

Mitochondrial dysfunction is involved in the aggravation of periodontitis by diabetes.

AIM: To elucidate whether mitochondrial dysfunction contributes to aggravated periodontitis in diabetes. MATERIALS AND METHODS: Sixty-four wistar rats were randomly assigned into four groups: control, periodontitis, diabetes, and diabetic periodontitis. Two weeks after induction of diabetes, periodontitis was induced by silk ligation for 2 weeks and thereafter evaluated by assessing alveolar bone loss and apoptosis of periodontium cells. Mitochondrial oxidative stress was detected by MitoSOX staining. Mitochondrial function was determined by measuring ATP production, and by assessing mitochondrial DNA copy number, activities of electron transport chain complexes, and biogenesis with real-time PCR. RESULTS: Significantly severer bone loss, enhanced periodontium cell apoptosis, and mitochondrial oxidative stress were found in the rats with diabetic periodontitis than the others. Furthermore, diabetic rats with periodontitis presented severer mitochondrial dysfunction than lean rats with periodontitis, as reflected by compromised ATP production, decreased mitochondrial DNA copy number, reduced gene expression of electron transport chain complex I subunits, and impaired mitochondrial biogenesis (p < 0.05). Multiple regression analysis further indicated a close correlation between these mitochondrial events and bone loss in diabetic periodontitis. CONCLUSIONS: Mitochondrial dysfunction was positive correlated to aggravated periodontitis in diabetes and might represent a therapeutic target for diabetic periodontitis.

Effect of maleic acid on the bond strength of fibre posts to root dentine.

The aim of this study was to evaluate the effect of maleic acid (MA) on both the bond strength of fibre post to root dentine and smear layer removal after post space preparation. Sixty, single-canal premolars were endodontically treated and randomly assigned to four groups: group 1 [0.9% saline solution (control]); group 2 [2.5% sodium hypochlorite (NaOCl)]; group 3 [17% ethylenediaminetetraacetic acid (EDTA) followed by 2.5% NaOCl]; and group 4 (7% MA followed by 2.5% NaOCl). Self-adhesive resin cement was used to test the adhesion of a glass-fibre post to the root dentine through a micropush-out test. Scanning electron microscopy was performed to examine and score the treated specimens for smear layer removal, and stereomicroscopy was applied to investigate the failure modes of fibre posts. Maleic acid exhibited the highest mean bond-strength values in the apical regions among all the groups. Most failure modes (31.9%) were adhesive-type failures between the dentine and luting materials. Maleic acid performed statistically significantly better than the other groups regarding smear layer removal, especially in the apical region. Maleic acid is an effective irrigant that can remove the smear layer, open dentinal tubules, and act as a high-efficiency final irrigant in activation protocols.

General Strategy for Enhancing Electrochemiluminescence of Semiconductor Nanocrystals by Hydrogen Peroxide and Potassium Persulfate as Dual Coreactants.

Semiconductor nanocrystals usually suffer from weak electrogenerated chemiluminescence (ECL) emissions compared with conventional organic emitters. In this work, we propose, for the first time, a very convenient but effective way to greatly enhance ECL emission of semiconductor TiO2 nanotubes (NTs) by H2O2 and K2S2O8 as dual coreactants, generating ECL emission ca. 6.3 and 107 times stronger than that of K2S2O8 or H2O2 as an individual coreactant, respectively. Scanning electron microscopy, X-ray diffraction, and electron paramagnetic resonance spectral studies were carried out to investigate the ECL enhancement mechanism. The ECL enhancement of TiO2 NTs by the K2S2O8-H2O2 system was supposed to originate from the coordination of H2O2 to the TiO2 surface and the synergy effect between H2O2 and K2S2O8 in the ECL process. The coordination of H2O2 to the surface of TiO2 could stabilize the electrogenerated coreactant-related radical OH(•) (hydroxyl radical), which could obviously promote the amount of sulfate radical anion (SO4(•-)) near the electrode surface by inducing decomposition of K2S2O8 into SO4(•-) or inhibiting the consumption of SO4(•-) by its reaction with H2O. The holes (h(+)) released from SO4(•-) were injected into the valence band of TiO2, resulting in more TiO2(+), which combined with the electrons coming from the conduction band with an enhanced light emission. Moreover, this enhancement effect was also applicable to ECL of a CdS nanocrystal film on a glass carbon electrode, with ca. 2.74- and 148.3-fold enhanced ECL intensity correspondingly, indicating wide applications in the development of semiconductor nanocrystal-based ECL biosensors.

A general strategy for photoelectrochemical immunoassay using an enzyme label combined with a CdS quantum dot/TiO2 nanoparticle composite electrode.

Photoelectrochemical (PEC) immunoassay has received increasing attention owing to its good analytical performance and attractive potential for future protein assay. This Letter represents a novel and general strategy for elegant PEC immunoassay of the important cardiac marker troponin T (cTnT) at neutral conditions. Specifically, we first developed an efficient CdS quantum dots (QDs)/TiO2 nanoparticles (NPs) photoelectrode, on the basis of which an exquisite ß-galactosidase (ß-Gal) catalytic system was integrated with sandwich immunobinding for probing cTnT. In pH 7.4, ß-Gal could catalyze the conversion of p-aminophenyl galactopyranoside (PAPG) to p-aminophenol (PAP), which could be easily photo-oxidized to p-quinone imine (PQI). Because the resulting photocurrent was directly related with the target concentration, an innovative PEC immunoassay could be realized for cTnT detection. The neutral operating condition of this protocol would greatly contribute to its wide applicability for protein assay. This work provides the first PEC immunoassay toward cardiac marker and, more significantly, opens a different perspective for future PEC immunoassay development through a general sensing protocol.

Limosilactobacillus reuteri HCS02-001 Attenuates Hyperuricemia through Gut Microbiota-Dependent Regulation of Uric Acid Biosynthesis and Excretion.

Hyperuricemia is a prevalent metabolic disorder that arises from abnormal purine metabolism and reduced excretion of uric acid (UA). The gut microbiota plays a significant role in the biosynthesis and excretion of UA. Probiotics capable of purine degradation possess the potential to prevent hyperuricemia. Our study aimed to screen probiotics in areas with abundant dairy products and longevity populations in China, which could attenuate the level of UA and explore the underlying mechanism. In this study, twenty-three lactic acid bacteria isolated from healthy Chinese infant feces and traditional fermented foods such as hurood and lump milk were evaluated for the ability to tolerance acid, bile, artificial gastric juice, and artificial intestinal juice to determine the potential of the candidate strains as probiotics. Eight strains were identified as possessing superior tolerance to simulated intestinal conditions and were further analyzed by high-performance liquid chromatography (HPLC), revealing that Limosilactobacillus reuteri HCS02-001 (Lact-1) and Lacticaseibacillus paracasei HCS17-040 (Lact-2) possess the most potent ability to degrade purine nucleosides. The effect of Lact-1 and Lact-2 on hyperuricemia was evaluated by intervening with them in the potassium oxonate and adenine-induced hyperuricemia Balb/c mice model in vivo. Our results showed that the level of serum UA in hyperuricemic mice can be efficiently reduced via the oral administration of Lact-1 (p < 0.05). It significantly inhibited the levels of liver inflammatory cytokines and hepatic xanthine oxidase through a TLR4/MyD88/NF-κB pathway across the gut-liver axis. Furthermore, UA transporters ABCG2 and SLC2A9 were substantially upregulated by the intervention of this probiotic. Fecal ATP levels were significantly induced, while fecal xanthine dehydrogenase and allantoinase levels were increased following probiotics. RNA sequencing of HT-29 cells line treated with Lact-1 and its metabolites demonstrated significant regulation of pathways related to hyperuricemia. In summary, these findings demonstrate that Limosilactobacillus reuteri HCS02-001 possesses a capacity to ameliorate hyperuricemia by inhibiting UA biosynthesis via enhancing gastrointestinal barrier functions and promoting UA removal through the upregulation of urate transporters, thereby providing a basis for the probiotic formulation by targeting the gut microbiota.

Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy.

The tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N6-methyladenosine (m6A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m6A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

A Novel Methacryloyl Chitosan Hydrogel Microneedles Patch with Sustainable Drug Release Property for Effective Treatment of Psoriasis.

Psoriasis is a chronic and recurrent skin disease that often requires long-term treatment, and topical transdermal drug delivery can reduce systemic side effects. However, it is still a challenge in efficient transdermal drug delivery for psoriasis treatment due to low penetration efficiency of most drugs and the abnormal skin conditions of psoriasis patients. Here, a safe and effective methacryloyl chitosan hydrogel microneedles (CSMA hMNs) patch is developed and served as a sustained drug release platform for the treatment of psoriasis. By systematically optimizing the CSMA preparation, CSMA hMNs with excellent morphological characteristics and strong mechanical properties (0.7 N needle-1 ) are prepared with a concentration of only 3% (w/v) CSMA. As a proof-of-concept, methotrexate (MTX) and nicotinamide (NIC) are loaded into CSMA hMNs patch, which can produce a sustained drug release of 80% within 24 h in vitro. In vivo experiments demonstrated that the CSMA hMNs patch can effectively inhibit the skin thickening and spleen enlargement of psoriatic mice and has a good biosafety profile at sufficient therapeutic doses. This study provides a new idea for the preparation of hMN systems using modified CS or other biocompatible materials and offers an effective therapeutic option for psoriasis treatment.

ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.

GPR87 promotes tumor cell invasion and mediates the immunogenomic landscape of lung adenocarcinoma.

The purpose of this study is to examine the association between G protein-coupled receptor 87 (GPR87) and lung adenocarcinoma (LUAD) metastasis and immune infiltration. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets extract clinical data. According to the TCGA database, increased GPR87 expression predicts poor overall survival, progression-free interval, and disease-specific survival in LUAD patients. The meta-analysis also reveals a significant association between high GPR87 expression and poor overall survival. Moreover, functional experiments demonstrate that GPR87 silencing reduces LUAD cell invasion and migration. Immunoblotting shows that GPR87 knockdown decreased Vimentin and N-cadherin expression and increased E-cadherin expression in LUAD cells. GPR87 expression in LUAD is positively correlated with immune infiltration. In addition, GPR87 expression is associated with immune and chemotherapy resistance in LUAD patients. Our findings indicate that GPR87 promotes tumor progression and is correlated with immune infiltration, suggesting GPR87 as a possible biomarker for prognosis prediction in LUAD.

PARP inhibitor plus radiotherapy reshapes an inflamed tumor microenvironment that sensitizes small cell lung cancer to the anti-PD-1 immunotherapy.

Small cell lung cancer (SCLC) is a highly malignant tumor with extremely poor prognosis. The treatment strategy is very limited, and patient outcomes remain dismal with the 5-year survival rate being mere 3-6%. Thus, novel therapeutic strategies for SCLC patients are urgently needed. In this study, we found that the triple-therapy of poly (ADP-ribose) polymerase (PARP) inhibitor, radiotherapy (RT) and anti-PD-1 treatment significantly inhibited tumor growth and prolonged survival in the syngeneic SCLC models in immunocompetent C57BL/6 mice. Mechanistically, we demonstrated that the combination of PARP inhibitor niraparib and RT reshaped an inflamed tumor microenvironment, including activation of the cGAS/STING immune response pathway, induction of immunogenic cell death, and upregulation of PD-L1 on tumor cells. Furthermore, this triple-therapy substantially augmented CD8+ T cell infiltration and activation, and enhanced anti-tumor effects as revealed by increased median survival time and reduced tumor volume without additional myelosuppression or hepatic injury. Together, our studies demonstrated that PARP inhibitor combined with RT potentiated anti-tumor immunity and enhanced the efficacy of anti-PD-1 immunotherapy in preclinical study, which provided a promising therapeutic strategy for SCLC patients in clinic.

Oxidative DNA damage induced by a Copper(II)-1,10-phenanthroline-L-serine complex in the presence of rutin.

The capacity of the ternary complex copper(II)-1,10-phenanthroline-L-serine ([Cu-Phen-Ser]) to induce double-strand scission of DNA was explored by agarose-gel electrophoresis. It was found that the complex exhibited remarkable activity to damage DNA in the presence of rutin. Analysis of the UV and fluorescence spectra clearly demonstrated that the complex was bound to DNA by intercalation. Further, the occurrence of 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, after the treatment of DNA by the complex in presence of rutin was evidenced by an electrochemical method. Finally, the mechanism of oxidative damage to double-stranded DNA by the [Cu-Phen-Ser] complex in the presence of rutin was discussed.

Establishment of the Prognostic Index Reflecting Tumor Immune Microenvironment of Lung Adenocarcinoma Based on Metabolism-Related Genes.

Background: The incidence of lung adenocarcinoma (LUAD) increased substantially in recent years. A systematic investigation of the metabolic genomics pattern is critical to improve the treatment and prognosis of LUAD. This study aimed to analyze the relationship between tumor microenvironment (TME) and metabolism-related genes of LUAD. Methods: The data was extracted from TCGA and GEO datasets. The metabolism-related gene expression profile and the corresponding clinical data of LUAD patients were then integrated. The survival-related genes were screened out using univariate COX regression and lasso regression analysis. The latent properties and molecular mechanisms of these LUAD-specific metabolism-related genes were investigated by computational biology. Results: A novel prognostic model was established based on 8 metabolism-related genes, including TYMS, ALDH2, PKM, GNPNAT1, LDHA, ENTPD2, NT5E, and MAOB. The immune infiltration of LUAD was also analyzed using CIBERSORT algorithms and TIMER database. In addition, the high- and low-risk groups exhibited distinct layout modes in the principal component analysis. Conclusions: In summary, our studies identified clinically significant metabolism-related genes, which were potential signature for LUAD diagnosis, monitoring, and prognosis.

Curcumin Protects Osteoblasts From Oxidative Stress-Induced Dysfunction via GSK3ß-Nrf2 Signaling Pathway.

Osteoblasts dysfunction, induced by oxidative stress (OS), is one of major pathological mechanisms for osteoporosis. Curcumin (Cur), a bioactive antioxidant compound, isolated from Curcumin longa L, was regarded as a strong reactive oxygen species (ROS) scavenger. However, it remains unveiled whether Cur can prevent osteoblasts from OS-induced dysfunction. To approach this question, we adopted a well-established OS model to investigate the preventive effect of Cur on osteoblasts dysfunction by measuring intracellular ROS production, cell viability, apoptosis rate and osteoblastogenesis markers. We showed that the pretreatment of Cur could significantly antagonize OS so as to suppress endogenous ROS production, maintain osteoblasts viability and promote osteoblastogenesis. Inhibiting Glycogen synthase kinase (GSK3ß) and activating nuclear factor erythroid 2 related factor 2 (Nrf2) could significantly antagonize the destructive effects of OS, which indicated the critical role of GSK3ß-Nrf2 signaling. Furthermore, Cur also abolished the suppressive effects of OS on GSK3ß-Nrf2 signaling pathway. Our findings demonstrated that Cur could protect osteoblasts against OS-induced dysfunction via GSK3ß-Nrf2 signaling and provide a promising way for osteoporosis treatment.

Correlation between human leukocyte antigen-G expression and clinical parameters in oral squamous cell carcinoma.

BACKGROUND: Human leukocyte antigen-G (HLA-G) is a tumor-associated molecule, whose expression may help the cancer cells to escape the immune response. AIMS: The aim of this study was to evaluate the diagnostic value of HLA-G level in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: A total of 52 patients who had definite pathological diagnosis and 20 cases of healthy controls were enrolled in this clinical trial. Immunohistochemisty (IHC) and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis were considered for HLA-G identification and multilevel validations. Statistical analysis was performed using SPSS and statistical significance was determined at P < 0.05. RESULTS: IHC results demonstrated that the expression of HLA-G in OSCC was strongly positive and the rate of positive expression was 55.77% (29/52), but the expression of HLA-G in healthy controls was negative (0/20). Furthermore, RT-PCR results showed that the positive expression rate of HLA-G messenger RNA was weak in healthy controls, but strong in OSCC. Besides, HLA-G expression in the tumors was significantly correlated with histological grade. CONCLUSIONS: Our results suggested that HLA-G is associated with the prognosis of OSCC and may serve as a novel therapeutic target.