Disulfide stress and its role in cardiovascular diseases.

Cardiovascular disease (CVD) is one of the leading causes of mortality in humans, and oxidative stress plays a pivotal role in disease progression. This phenomenon typically arises from weakening of the cellular antioxidant system or excessive accumulation of peroxides. This review focuses on a specialized form of oxidative stress-disulfide stress-which is triggered by an imbalance in the glutaredoxin and thioredoxin antioxidant systems within the cell, leading to the accumulation of disulfide bonds. The genesis of disulfide stress is usually induced by extrinsic pathological factors that disrupt the thiol-dependent antioxidant system, manifesting as sustained glutathionylation of proteins, formation of abnormal intermolecular disulfide bonds between cysteine-rich proteins, or irreversible oxidation of thiol groups to sulfenic and sulfonic acids. Disulfide stress not only precipitates the collapse of the antioxidant system and the accumulation of reactive oxygen species, exacerbating oxidative stress, but may also initiate cellular inflammation, autophagy, and apoptosis through a cascade of signaling pathways. Furthermore, this review explores the detrimental effects of disulfide stress on the progression of various CVDs including atherosclerosis, hypertension, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, cardiac hypertrophy, and heart failure. This review also proposes several potential therapeutic avenues to improve the future treatment of CVDs.

Facilitating safe and sustained submucosal lift through an endoscopically injectable shear-thinning carboxymethyl starch sodium hydrogel.

Traditional submucosal filling materials frequently show insufficient lifting height and duration during clinical procedures. Here, the anionic polysaccharide polymer sodium carboxymethyl starch and cationic Laponite to prepare a hydrogel with excellent shear-thinning ability through physical cross-linking, so that it can achieve continuous improvement of the mucosal cushion through endoscopic injection. The results showed that the hydrogel (56.54 kPa) had a lower injection pressure compared to MucoUp (68.56 kPa). The height of submucosal lifting height produced by hydrogel was higher than MucoUp, and the height maintenance ability after 2 h was 3.20 times that of MucoUp. At the same time, the hydrogel also showed satisfactory degradability and biosafety, completely degrading within 200 h. The hemolysis rate is as low as 0.76 %, and the cell survival rate > 80 %. Subcutaneous implantation experiments confirmed that the hydrogel showed no obvious systemic toxicity. Animal experiments clearly demonstrated the in vivo feasibility of using hydrogels for submucosal uplift. Furthermore, successful endoscopic submucosal dissection was executed on a live pig stomach, affirming the capacity of hydrogel to safely and effectively facilitate submucosal dissection and mitigate adverse events, such as bleeding. These results indicate that shear-thinning hydrogels have a wide range applications as submucosal injection materials.

FGF21 Inhibits Hypoxia/Reoxygenation-induced Renal Tubular Epithelial Cell Injury by Regulating the PPARγ/NF-κB Signaling Pathway.

As a predominant trigger of acute kidney injury, renal ischemia-reperfusion injury can cause permanent renal impairment, and the effective therapies are lacking. Fibroblast growth factor 21 (FGF21) plays a critical regulatory role in a variety of biological activities. This study was conducted to explore the functional of FGF21 in renal ischemia-reperfusion injury and to discuss the hidden reaction mechanism. To simulate renal ischemia-reperfusion injury in vitro, HK2 cells were induced by hypoxia/reoxygenation (H/R). The effects of FGF21 on H/R-induced HK2 cell viability were evaluated utilizing cell counting kit-8 (CCK-8). The levels of lactate dehydrogenase (LDH) and inflammatory cytokines in H/R-induced HK2 cells were assessed by means of LDH assay and enzyme-linked immunosorbent assay (ELISA). The levels of oxidative stress markers were appraised with corresponding assay kits and western blot was applied to estimate the expressions of oxidative stress-related proteins. The apoptosis of H/R-induced HK2 cells was assessed by virtue of flow cytometry. The expressions of apoptosis- and PPARγ/NF-κB signaling pathway-related proteins were evaluated with western blot. To discuss the reaction mechanism of PPARγ/NF-κB pathway in H/R-induced HK2 cells, PPARγ inhibitor GW9662 was employed to treat cells and the above experiments were then conducted again. This study found that FGF21 treatment inhibited the inflammatory response, oxidative stress and apoptosis in H/R-induced HK2 cells. Moreover, FGF21 regulated PPARγ/NF-κB signaling pathway and GW9662 partially reversed the impacts of FGF21 on the inflammatory response, oxidative stress and apoptosis in H/R-exposed HK2 cells. Collectively, FGF21 protected against H/R-induced renal tubular epithelial cell injury by regulating the PPARγ/NF-κB signaling pathway.

LncRNA FOXD3-AS1 Contributes to Glioblastoma Progression Via Sponging miR-3918 to Upregulate CCND1.

AIM: To elucidate the pro-tumorigenic role of IncRNA FOXD3-AS1 in glioblastoma. MATERIAL AND METHODS: The expression of miR-3918, FOXD3-AS1, and CCND1 was measured in glioblastoma cells and tissues using reverse transcriptase quantitative PCR (RT-qPCR). The effect of FOXD3-AS1 silencing on the proliferation of glioblastoma cells was assessed in vitro using CCK-8 and colony formation assays and in vivo using xenograft mouse models. Additionally, the expression levels of the apoptosis-related proteins, Bcl-2 and Bax, were assessed using western blotting. Bioinformatic analysis and luciferase reporter assays assisted by RNA immunoprecipitation (RIP) and RNA pull-down experiments were conducted to validate the interactions among FOXD3-AS1, CCND1, and miR-3918. RESULTS: FOXD3-AS1 and CCND1 were highly expressed in glioblastoma tissues and cells, whereas miR-3918 was poorly expressed. The expressions of FOXD3-AS1 and CCND1 were inversely associated with miR-3918 levels in glioblastoma tissues. FOXD3-AS1 silencing weakened the proliferative capacity and accelerated apoptosis of glioblastoma cells in vitro and hampered tumor growth in vivo. Mechanical investigations showed that FOXD3-AS1 knockdown increased miR-3918 expression and inhibited glioblastoma cell growth. Meanwhile, the miR-3918 inhibitor restored CCND1 expression and induced the opposite outcome. CONCLUSION: FOXD3-AS1 facilitates the CCND1-driven progression of glioblastoma by serving as a competing endogenous RNA (ceRNA) for miR-3918. This suggests that FOXD3-AS1 may be a potential therapeutic target for the management of glioblastoma development.

Alveolar Bone Morphologic Predictors for Guided Bone Regeneration Outcome in Anterior Maxilla.

OBJECTIVES: This study aimed to explore the influence of alveolar bone morphologic variables on the outcome of guided bone regeneration (GBR) in the anterior maxilla region. METHODS: Twenty-eight patients who received single maxillary anterior tooth delayed implant placed simultaneously with GBR were recruited. Baseline data including age, gender, implant site, implant brand, and bone graft materials were recorded. The resorption rate of the grafted bone (RRGB), labial bone width at 0 mm, 2 mm, and 4 mm apical to the implant platform at Tn (LBW0Tn, LBW2Tn, LBW4Tn), implant angulation (IA), maximum bone graft thickness (MBGT), bone graft volume (BGV), and the initial bone morphologic variables bone concavity depth (BCD) and bone concavity angulation (BCA) were measured. The Pearson correlation analysis, analysis of variance (ANOVA), and optimal binning method were used to explore the potential predictors for GBR. RESULTS: Among 28 patients, the labial bone width of implant and bone graft volume decreased significantly when measured 6 months after surgery. The mean percentage of RRGB was 49.78%. RRGB was not correlated with gender, age, bone graft material, IA, MBGT, bone graft volume at T1, implant site, and implant brand (P > .05). BCD and BCA were each moderately correlated with RRGB (r = -0.872 [P < .001] and r = 0.686 [P < .001], respectively). A BCD ≥1.03 mm and a BCA <155.30° resulted in a significantly lower percentage of RRGB (P < .001). CONCLUSIONS: A significant grafted bone materials volume reduction was detected after GBR with collagen membrane and deproteinized bovine bone mineral (DBBM). The initial bone morphology can influence GBR outcome, and a bone concavity with a depth ≥1.03 mm and an angulation <155.30° led to a lower RRGB. BCD and BCA can be used as variables to predict the outcome of GBR.

Targeting DDX11 promotes PARP inhibitor sensitivity in hepatocellular carcinoma by attenuating BRCA2-RAD51 mediated homologous recombination.

Homologous recombination (HR) is a major DNA double-strand break (DSB) repair pathway of clinical interest because of treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). Cooperation between RAD51 and BRCA2 is pivotal for DNA DSB repair, and its dysfunction induces HR deficiency and sensitizes cancer cells to PARPi. The depletion of the DEAD-box protein DDX11 was found to suppress HR in hepatocellular carcinoma (HCC) cells. The HR ability of HCC cells is not always dependent on the DDX11 level because of natural DDX11 mutations. In Huh7 cells, natural DDX11 mutations were detected, increasing the susceptibility of Huh7 cells to olaparib in vitro and in vivo. The HR deficiency of Huh7 cells was restored when CRISPR/Cas9-mediated knock-in genomic editing was used to revert the DDX11 Q238H mutation to wild type. The DDX11 Q238H mutation impeded the phosphorylation of DDX11 by ATM at serine 237, preventing the recruitment of RAD51 to damaged DNA sites by disrupting the interaction between RAD51 and BRCA2. Clinically, a high level of DDX11 correlated with advanced clinical characteristics and a poor prognosis and served as an independent risk factor for overall and disease-free survival in patients with HCC. We propose that HCC with a high level of wild-type DDX11 tends to be more resistant to PARPi because of enhanced recombination repair, and the key mutation of DDX11 (Q238H) is potentially exploitable.

Identification of ORF1B as a unique nonstructural protein for fowl adenovirus serotype 4.

Fowl adenovirus serotype 4 (FAdV-4), the causative agent of hepatitis-hydropericardium syndrome (HHS), is a double-stranded DNA virus. Although many structural proteins have been deeply studied, the coding potential of some other open reading frames (ORFs) and the biological functions of their products during virus infection have not been fully elucidated. Here, a unique nonstructural protein ORF1B of FAdV-4 was identified and its expression kinetics along infection was analyzed. Except that of FAdV-10, a member of the same genus as FAdV-4, FAdV-4 ORF1B shared as low homologous identity as 29.2% in amino acid sequence with the other ten counterparts. Structurally, ORF1B was mapped on the N-terminal region of the genome between 1485 nt to 1808 nt and predicted to only contain two α-helix. Confocal immunofluorescence assay with homemade rabbit polyclonal antibody demonstrated that ORF1B could be simultaneously observed with structural protein Fiber 1 in FAdV-4-infected cells. Western blot further showed that ORF1B could only be detected in the infected cells but not mature virions, suggesting ORF1B was a nonstructural protein. Subsequently, the expression level of ORF1B detected by qRT-PCR and IFA was gradually decreased along with FAdV-4 infection, suggesting ORF1B was an early gene transcript. These results will lay a solid foundation to further study the biological effect of ORF1B on the replication and pathogenicity of FAdV-4.

Sex-modified association between grip strength and mild cognitive impairment: a cross-sectional and follow-up study in rural China.

BACKGROUND: The sex difference in the association between grip strength and mild cognitive impairment (MCI) remains controversial and unclear. METHODS: This is a part of a chronic disease cohort study conducted in rural areas, Fuxin, Liaoning Province, China. At the baseline survey, a total of 2633 participants aged 35- 85 were included in the cross-sectional study. Handgrip strength (HGS, kg) was measured by a dynamometer (Jamar +). MCI were assessed using the Chinese version of the Montreal Cognitive Assessment-Basic (MOCA-BC). Then, a total of 1667 cognitively normal individuals (NCs) were planed to follow up and to assess the incident MCI after two years. We used logistic regression to examine the association between HGS (as a continuous variable and quintiles) and MCI and analyzed the interaction between sex and HGS on MCI. Models stratified by sex were adjusted for demographic information (age, ethnicity, education, marital status, income, physical labor level), modifiable risk factors (body mass index, smoking, drinking) and disease history (hypertension, diabetes, dyslipidemia and coronary heart disease). Baseline MOCA-BC scores were additionally adjusted in the longitudinal study. RESULTS: In the cross-sectional study, participants were on average 56.6 ± 9.8 years, and 1713 (65.1%) were females. In the cohort study, 743 individuals were followed up with an average age of 55.9 ± 9.6 years, which included 530 (71.3%) females. The cumulative incidence of MCI over a two-year period was 17.1%. In the cross-sectional study, compared to the highest quintile of HGS, the lowest HGS was associated with higher risk of MCI in males (odds ratio [OR]: 2.66; 95% confidence interval [CI]: 1.54, 4.64) and females (OR: 1.70; 95% CI: 1.17, 2.49) with adjustment of potential confounding factors. In the cohort study, compared to the highest quintile of HGS, the lowest HGS was associated with an increased risk of incident MCI in females (OR: 3.93; 95% CI: 1.39, 13.01) but not in males (OR: 0.56; 95% CI: 0.11, 2.94, P for interaction = 0.015). CONCLUSIONS: Lower grip strength is a risk factor for mild cognitive impairment and predicts a higher risk of MCI in females.

CSNK1G2-AS1 promotes metastasis, colony formation and serves as a biomarker in testicular germ cell tumor cells.

Background/Aim: Some long non-coding RNAs (lncRNAs) have been found to significantly participate in the progression of TGCTs. In comparison to the normal testis, the TGCT tissues showed significantly decreased CSNK1G2-AS1 expression, however, its effect on TGCTs and its mechanism are still unclear. The aim of this study is to investigate the effect of CSNK1G2-AS1 on TGCTs and explore the mechanism underlying its effect on TGCTs. Materials and Methods: In this study, to evaluate the expression of CSNK1G2-AS1 in tissue samples from TGCTs, the UCSC and GEPIA databases were applied and qRT-PCR was conducted. The Kaplan-Meier Plotter was applied to analyze the correlation between CSNK1G2-AS1 methylation levels and the prognosis of TGCTs patients. The assays of MTS, clone formation, transwell, and flow cytometry were performed to investigate the effect of CSNK1G2-AS1 overexpression on the proliferation, metastasis, and apoptosis of TGCT cells, respectively. Finally, western blotting was conducted to determine the expressions of the proteins associated with EMT and AKT. Results: Our study first found that, compared to the normal testis, TGCTs tissue showed significantly decreased CSNK1G2-AS1 expression, and hypomethylation of CSNK1G2-AS1 was significantly correlated with a better prognosis with TGCTs patients. In vitro, we found that overexpression of CSNK1G2-AS1 dramatically promoted the clone formation, invasion, and migration of TGCT cells, but inhibited apoptosis. And CSNK1G2-AS1 overexpression significantly decreased the expression of EMT-associated proteins ZO-1 but increased the expression and phosphorylation of AKT. Conclusions: CSNK1G2-AS1 may play an essential role in the pathogenesis and metastasis of TGCTs through the EMT- and AKT-mediated signal pathways.

ERO1α promotes the proliferation and inhibits apoptosis of colorectal cancer cells by regulating the PI3K/AKT pathway.

Endoplasmic reticulum oxidoreductin 1α (ERO1α) is an oxidase that exists in the endoplasmic reticulum and plays an important role in regulating oxidized protein folding and tumor malignant progression. However, the specific role and mechanism of ERO1α in the progression of colorectal cancer (CRC) have not yet been fully elucidated. In this study, 280 specimens of CRC tissues and adjacent noncancerous tissues were collected to detect the expression of ERO1α and analyze the clinical significance. ERO1α was stably knocked-down in RKO and HT29 CRC cells to investigate its function and mechanism in vitro and in vivo. We found that ERO1α was remarkably upregulated in CRC tissues and high ERO1α expression is associated with N stage and poor prognosis of CRC patients. ERO1α knockdown in CRC cells significantly inhibited the proliferation and induced apoptosis while inactivating the PI3K/AKT pathway. Rescue assays revealed that AKT activator 740Y-P could reverse the effects on proliferation and apoptosis of ERO1α knockdown in CRC cells. In vivo tumorigenicity assay also confirmed that ERO1α knockdown suppressed tumor growth. Taken together, our findings demonstrated ERO1α promotes the proliferation and inhibits apoptosis of CRC cells by regulating the PI3K/AKT pathway. High expression of ERO1α is associated with poor prognosis in CRC patients, and ERO1α could be a potential therapeutic target for CRC.

The diagnostic significance of the ZNF gene family in pancreatic cancer: a bioinformatics and experimental study.

Background: Pancreatic adenocarcinoma (PAAD) is among the most devastating of all cancers with a poor survival rate. Therefore, we established a zinc finger (ZNF) protein-based prognostic prediction model for PAAD patients. Methods: The RNA-seq data for PAAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Differentially expressed ZNF protein genes (DE-ZNFs) in PAAD and normal control tissues were screened using the "lemma" package in R. An optimal risk model and an independent prognostic value were established by univariate and multivariate Cox regression analyses. Survival analyses were performed to assess the prognostic ability of the model. Results: We constructed a ZNF family genes-related risk score model that is based on the 10 DE-ZNFs (ZNF185, PRKCI, RTP4, SERTAD2, DEF8, ZMAT1, SP110, U2AF1L4, CXXC1, and RMND5B). The risk score was found to be a significant independent prognostic factor for PAAD patients. Seven significantly differentially expressed immune cells were identified between the high- and low-risk patients. Then, based on the prognostic genes, we constructed a ceRNA regulatory network that includes 5 prognostic genes, 7 miRNAs and 35 lncRNAs. Expression analysis showed ZNF185, PRKCI and RTP4 were significantly upregulated, while ZMAT1 and CXXC1 were significantly downregulated in the PAAD samples in all TCGA - PAAD, GSE28735 and GSE15471 datasets. Moreover, the upregulation of RTP4, SERTAD2, and SP110 were verified by the cell experiments. Conclusion: We established and validated a novel, Zinc finger protein family - related prognostic risk model for patients with PAAD, that has the potential to inform patient management.

Association between handgrip strength asymmetry and cognitive function across ethnicity in rural China: a cross-sectional study.

Background: Recently, the association between handgrip strength (HGS) asymmetry and cognition has been revealed, but evidences are still scarce. Particularly, the association between asymmetric HGS and cognitive performance in various cognitive domains is unclear and whether this association is stable across ethnic groups is unknown. Method: The population was from a longitudinal study in rural areas of Fuxin, Liaoning, China. The Chinese version of Montreal Cognitive Assessment-Basic (MOCA-BC) was used to evaluate the cognitive function. The HGS ratio was calculated as maximal non-dominant HGS divided by maximal dominant HGS. HGS ratio <0.9 or >1.1 was classified as asymmetric dominant/non-dominant HGS, respectively. Generalized linear models were used to analyze the relationship between asymmetric HGS and cognitive function adjusted for HGS, handedness, wave, age, sex, education, ethnicity, smoking, drinking, physical labor level, BMI, hypertension, diabetes and dyslipidemia. Result: A total of 2,969 participants ≥50 years were included in this study. Adjusted for HGS and other confunding variables, there was an inverted U-shaped association between HGS ratio and MoCA-BC scores (P non-linear = 0.004). The association between HGS ratio and MoCA-BC scores was inconsistent among ethnic groups (P interaction = 0.048). In Han, only asymmetric non-dominant HGS was associated with lower cognitive scores [ß = -0.67, 95% confidence interval (CI): -1.26 ∼-0.08, P = 0.027]; in Mongolians, asymmetric dominant HGS(ß = -0.60, 95% CI: -1.35 ∼ 0.15, P = 0.115) and asymmetric non-dominant HGS (ß = -0.56, 95% CI: -1.42 ∼ 0.31, P = 0.206) were all associated with lower cognitive scores, although no statistical significance was found. Asymmetric non-dominant HGS and lower HGS, but not asymmetric dominant HGS were all independently associated with impairment of Delayed Recall (OR = 1.35, 95% CI: 1.05 ∼ 1.74; OR per 5 kg decrease = 1.10, 95% CI: 1.01 ∼ 1.21) and Fluency (OR = 1.43, 95% CI: 1.15 ∼ 1.78; OR per 5 kg decrease = 1.10, 95% CI: 1.02 ∼ 1.19). Both asymmetric dominant HGS (OR = 1.34, 95% CI: 1.07 ∼ 1.67) and lower HGS (OR per 5 kg decrease = 1.21, 95% CI: 1.10 ∼ 1.32) were associated with impairment of visuoperception. Conclusion: HGS and HGS asymmetry were all independently related to lower global cognitive performance. The association between HGS asymmetry and cognitive function varies among ethnic groups.

Study on the Interface Microstructure of TaC/GCr15 Steel Surface Reinforced Layer Formed by In-Situ Reaction.

In this study, a micro-nano TaC ceramic steel matrix reinforced layer was prepared by an in situ reaction between a pure tantalum plate and GCr15 steel. The microstructure and phase structure of the in situ reaction reinforced layer of the sample at 1100 °C and reaction time 1 h were characterized with FIB micro-section, TEM transmission, SAED diffraction pattern, SEM and EBSD. The phase composition, phase distribution, grain size, grain orientation and grain boundary deflection, phase structure and lattice constant of the sample were characterized in detail. The results show that the phase composition of the Ta sample is Ta, TaC, Ta2C and α-Fe. TaC is formed after Ta and carbon atoms meet, and the orientation changes in the X and Z directions. The grain size of TaC is widely in the range of 0~0.4 µm, and the angular deflection of TaC grain is not obvious. The high-resolution transmission structure, diffraction pattern and interplanar spacing of the phase were characterized, and the crystal planes of different crystal belt axes were determined. The study provides technical and theoretical support for further research on the preparation technology and microstructure of the TaC ceramic steel matrix reinforcement layer.

Analysis of risk factors for postoperative bleeding and polyp recurrence in adolescents with gastric polyps treated with endoscopic mucosal resection: a retrospective cohort study.

Background: The incidence of gastric polyps in adolescents has been increasing every year in recent years. Endoscopic mucosal resection (EMR) is one of the most common treatments for adults, but there are few reports on the association between EMR of gastric polyps and the occurrence of bleeding and recurrence after the procedure in adolescents. This study sought to analyze the independent risk factors for postoperative bleeding and polyp recurrence after EMR to provide a reference for reducing the occurrence of postoperative complications. Methods: We retrospectively analyzed the data of 579 adolescent patients who developed gastric polyps from June 2016 to June 2021. Postoperative follow-up was conducted for 1 year by telephone, e-mail, and outpatient review. The general characteristics of the study population were compiled using a general information questionnaire designed by the investigators. The relationship between the patients' clinical characteristics and postoperative bleeding or recurrence was analyzed using the chi-square test. A binary logistic regression analysis was conducted to analyze the independent risk factors for the occurrence of postoperative bleeding and polyp recurrence in patients. Results: The results of the binary logistic regression analysis showed that being female [odds ratio (OR) =0.306, P=0.009], polyps >1 cm in diameter (OR =2.557, P=0.029), polyps in gastric sinus (OR =3.889, P=0.032), sessile lesions (OR =0.398, P=0.036), the need for additional intraoperative sedation (OR =3.469, P=0.005), concurrent diverticulum (OR =3.570, P=0.004), and intraoperative bleeding (OR =4.855, P=0.001) were independent risk factors for postoperative bleeding. We also found that polyps >1 cm in diameter (OR =2.134, P=0.003), multiple polyps (OR =2.117, P=0.005), adenomatous polyps (OR =2.684, P=0.041), combined Helicobacter pylori infection (OR =2.036, P=0.009), the occurrence of postoperative gastrointestinal reflux (OR =1.998, P=0.015), and an operative time ≥40 min (OR =2.021, P=0.010) were independent risk factors for the recurrence of polyps. Conclusions: There is still a high probability of postoperative bleeding and polyp recurrence after EMR in adolescents with gastric polyps. Clinicians should pay close attention to the clinical features of polyps, such as polyp size, number, morphology, and pathological type, to identify the related risk factors as early as possible and reduce the probability of postoperative bleeding and polyp recurrence in patients.

VE-822 Enhanced Cisplatin Chemotherapy Effects on Head and Neck Squamous Cell Carcinoma Drug-resistant Cells.

PURPOSE: The study aimed to assess the effect of p-ATR inhibitor VE-822 in the combination chemotherapy with cisplatin of head and neck squamous cell carcinoma and to explore the possible mechanism. METHODS: The DNA damage levels were determined by comet assay and western blot experiments in cisplatin-resistant and sensitive cell lines. The IC50 value changes after combination treatment with VE-822 in cisplatin sensitive and resistant cell lines were detected by the CCK-8 test. The effects of VE-822 combined with cisplatin on proliferation ability, colony formation ability, migration ability, cell apoptosis and cell cycle changes were observed in vitro. In vivo, the combination treatment effect was verified in the subcutaneous xenograft models of nude mice. Besides, the mechanism of VE-822 assisting cisplatin in chemotherapy was explored by comet assay, western blotting and immunohistochemical experiments. RESULTS: The increased expression of the p-ATR protein was related to the DNA damage repair pathway in head and neck squamous cell carcinoma cisplatin-resistant cells. VE-822 inhibited cell proliferation, colony formation and migration abilities and improved the cisplatin chemotherapeutic effects in subcutaneous xenograft models of nude mice by inhibiting the p-ATR expression and blocking DNA damage repair pathway. CONCLUSIONS: The p-ATR expression increased in head and neck squamous cell carcinoma cisplatinresistant cells. VE-822 significantly enhanced the therapeutic effect in cisplatin resistant head and neck squamous cell carcinoma by inhibiting p-ATR expression in vivo and in vitro.

Dioscin reduced chemoresistance for colon cancer and analysis of sensitizing targets.

Chemotherapy resistance is the primary cause of high mortality in patients with advanced colon cancer. The combination of small molecule compound dioscin (DIO) and traditional medicine may have a chemosensitizing effect. In this study, we reported that DIO, in combination with Oxaliplatin (L-OHP) and 5-fluorouracil (5-Fu), can effectively inhibit colon cancer cell proliferation, and co-treatment was positively related to the DIO concentration. HCT116 co-treatment with 6.4 µM L-OHP and 0.8 µM DIO significantly reduced colony formation and migration, increased apoptosis, and cell-cycle arrest in the G0/G1 and G2/M phase. DIO-assisted L-OHP significantly inhibited the xenograft model growth and exhibited low toxicity.The mRNA-sequencing combined with network pharmacological analysis suggested that the DIO sensitivity may be related to the active targets FAS, CDKN1A, ABCA1, and PPARA, which are primarily involved in regulating the cell cycle and apoptosis. Finally, our experiments suggest that DIO may enhance the L-OHP sensitivity by regulating the cell cycle through the Notch pathway.

LncRNA ZFAS1 promotes laryngeal cancer progression through RBFOX2-mediated MENA alternative splicing.

Laryngeal cancer (LC) is the most common aggressive malignancy of the head and neck. LncRNA ZNFX1 antisense RNA 1 (ZFAS1) displays oncogenic properties in head and neck squamous cell carcinoma, but its regulatory role in laryngeal cancer progression remains obscure. Here, we found that ZFAS1 expression in laryngeal cancer tissues and cells was higher than that in adjacent normal tissues and normal nasopharyngeal epithelial cells. Highly expressed ZFAS1 was associated with advanced lymph node metastasis stages and clinical stages. ZFAS1 overexpression promoted LC cell proliferation, invasion, and N-cadherin and Vimentin expression, and suppressed E-cadherin expression. While ZFAS1 knockdown played an opposite role. Mechanistically, ZFAS1 stabilized RNA binding fox-1 homolog 2 (RBFOX2) protein expression by binding to RBFOX2, and RBFOX2 overexpression reversed the effect of ZFAS1 silence on cell functions. Moreover, highly expressed RBFOX2 led to skipping of MENA exon 11a and generating a pro-invasive isoform (MENAINV ). MENAINV overexpression effectively abolished the inhibitory effect of RBFOX2 knockdown on cell malignant progression. Furthermore, Hep2 cells infected with lentivirus-mediated ZFAS1 shRNA or negative control shRNA were subcutaneously injected into mice to assess the role of ZFAS1 in tumor growth. And the data showed that silencing ZFAS1 in vivo hindered xenograft tumor growth. In conclusion, silencing ZFAS1 alleviated malignant progression of laryngeal cancer cells and mouse xenograft tumor growth by regulating RBFOX2-mediated alternative splicing of MENA.

Crystal structure and cap binding analysis of the methyltransferase of langat virus.

Tick-borne encephalitis virus (TBEV) is a major dangerous human pathogen, as TBEV infection can cause serious illness that can lead to irreversible neurological sequelae and even death. Langat virus (LGTV), a member of the tick-borne encephalitis virus (TBEV) serogroup, belongs to the family Flaviviridae, genus Flavivirus. Its nonstructural protein 5 (NS5) protein contains a methyltransferase (MTase) domain that can methylate RNA cap structures, which is critical for viral replication. We determined the structure of LGTV NS5 methyltransferase bound to S-adenosyl-L-homocysteine (SAH) at a 1.70 Å resolution. Sequence analysis and structural comparison of homologous MTases suggests that folds and structures are closely conserved throughout Flavivirus species and play important roles. This study provides the key structural information on LGTV MTase and the foundation for research on antiviral drugs targeting LGTV MTase.

DDX59-AS1 is a prognostic biomarker and correlated with immune infiltrates in OSCC.

Background: lncRNAs play a critical role in multiple steps of gene regulation associated with tumor progression. However, the engagement of DDX59-AS1, a lncRNA, remains equivocal, particularly in oral squamous cell carcinoma (OSCC). In this study, the expression of DDX59-AS1 and its association with immune infiltration were investigated, and its prognostic value in OSSC was evaluated. Methods: OSCC patients were collected from The Cancer Genome Atlas (TCGA) database. The expression of DDX59-AS1 in OSCC and healthy tissue was compared using Wilcoxon rank sum test. The relationship between DDX59-AS1 and clinicopathological features was analyzed using Logistic regression. Gene ontology (GO) terminology analysis, gene set enrichment analysis (GSEA), and single sample GSEA (ssGSEA) were utilized to interpret the enrichment pathway and functionality and to quantify the immune cell infiltration of DDX59-AS1. The correlation between survival and DDA59-AS1 was evaluated by Kaplan-Meier analysis and Cox regression. The prognostic impact of DDX59-AS1 was predicted by the nomogram based on Cox multivariate analysis. Results: High expression of DDX59-AS1 was significantly correlated with T stage, clinical stage, race, and age (p < 0.05). Multivariate survival analysis demonstrated that the high expression of DDX59-AS1 was associated with lower overall and specific survival rates. The prognosis prediction was validated by the nomogram and calibration curves. The expression of DDX59-AS1 was negatively correlated with Mast cells, Tfh, T cells, Treg, and B cells, and positively related with the Tgd infiltration level. Conclusion: DDX59-AS1 played a crucial role in the progression and prognosis of OSCC and was potentially a predictive biomarker for OSCC.