Recent Developments in Nickel-Based Layered Double Hydroxides for Photo(-/)electrocatalytic Water Oxidation.

Layered double hydroxides (LDHs), especially those containing nickel (Ni), are increasingly recognized for their potential in photo(-/)electrocatalytic water oxidation due to the abundant availability of Ni, their corrosion resistance, and their minimal toxicity. This review provides a comprehensive examination of Ni-based LDHs in electrocatalytic (EC), photocatalytic (PC), and photoelectrocatalytic (PEC) water oxidation processes. The review delves into the operational principles, highlighting similarities and distinctions as well as the benefits and limitations associated with each method of water oxidation. It includes a detailed discussion on the synthesis of monolayer, ultrathin, and bulk Ni-based LDHs, focusing on the merits and drawbacks inherent to each synthesis approach. Regarding the EC oxygen evolution reaction (OER), strategies to improve catalytic performance and insights into the structural evolution of Ni-based LDHs during the electrocatalytic process are summarized. Furthermore, the review extensively covers the advancements in Ni-based LDHs for PEC OER, including an analysis of semiconductors paired with Ni-based LDHs to form photoanodes, with a focus on their enhanced activity, stability, and underlying mechanisms facilitated by LDHs. The review concludes by addressing the challenges and prospects in the development of innovative Ni-based LDH catalysts for practical applications. The comprehensive insights provided in this paper will not only stimulate further research but also engage the scientific community, thus driving the field of photo(-/)electrocatalytic water oxidation forward.

Prognostic significance of Pleural Fluid triglyceride levels based on a low-Fat Diet Management Strategy in patients with Chylothorax following pulmonary resection.

BACKGROUND: Chylothorax is a postoperative complication in patients with lung cancer. Diet-control approaches have been the mainstay for managing this condition. However, a surgical intervention is needed for the patients if conservative treatment is ineffective. Because of the lack of accurate indicators to assess the prognosis of the postoperative complication at an early stage, the criteria of surgical treatment were not consistent. METHODS: We reviewed 2942 patients who underwent pulmonary resection and lymph node dissection for primary lung cancer at our hospital between March 2021 and December 2022. The prognostic implications of clinical indicators were assessed in patients with postoperative chylothorax who were managed with a low-fat diet. Binary logistic regression was used to explore the predictive value of these indicators for patient prognosis. RESULTS: Postoperative chylothorax occurred in 108 patients and 79 patients were treated with a low-fat diet management while 29 patients were managed with TPN. In contrast to drainage volume, the pleural effusion triglyceride level after 2 days of low-fat diet exhibited enhanced predictive efficacy in predicting patient prognosis. When the pleural fluid triglyceride level of 1.33 mmol/L was used as the diagnostic threshold for prognosis, the sensitivity and specificity reached 100% and 80.6%, respectively. CONCLUSIONS: The pleural effusion triglyceride level after 2 days of low-fat diet can serve as a valuable prognostic indicator in patients undergoing lung surgery and experiencing chylothorax. This predictive approach will help thoracic surgeons to identify patients with poor prognosis in a timely manner and make decision to perform necessary surgical interventions.

Serum bile acid profiles are associated with heart failure with preserved ejection fraction in patients with metabolic dysfunction-associated fatty liver disease: An exploratory study.

AIM: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status. CONCLUSIONS: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD.

Improvement of skin wound healing by giant salamander skin mucus gel wrapped with bone marrow mesenchymal stem cells via affecting integrin family molecules.

BACKGROUND: Traditional bandages, gauze, and cotton balls are increasingly insufficient for addressing complex war injuries characterized by severe bleeding and diverse wound conditions. The giant salamander, a species of high medical value, secretes a unique mucus when stimulated, which has potential applications in wound care. MATERIALS: Giant salamander skin mucus gel dressing wrapped with bone marrow mesenchymal stem cells (BMSCs-GSSM-gel) was prepared and validated. Skin wound injury of rabbit and mouse models were established. Hematoxylin and Eosin, Masson's trichrome, and Sirius red staining were performed. The platelet aggregation rate and coagulation items were measured. Transcriptome sequencing was performed to find potential differential expression genes. RESULTS: Preparation and characterization of BMSCs-GSSM-gel were performed, and BMSCs-GSSM-gel particles with a diameter of about 200 nm were obtained. BMSCs-GSSM-gel accelerated wound healing in both rabbit and mouse models. BMSCs-GSSM-gel significantly promoted hemostasis via increasing platelet aggregation rate and fibrinogen, but decreasing activated partial thromboplastin time, thrombin time, and prothrombin time. BMSCs-GSSM-gel treatment significantly impacted several genes associated with cell adhesion, inflammatory response, collagen-containing extracellular matrix, and the positive regulation of cell migration based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Integrin Subunit Beta 4 (ITGB4), Integrin Subunit Alpha 3 (ITGA3), and Laminin Subunit Beta 3 (LAMB3) might be involved in the wound healing process by BMSCs-GSSM-gel. CONCLUSIONS: We proved the BMSCs-GSSM-gel greatly improved the skin wound healing, and it might play a crucial role in the application fields of skin damage repair.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

BACKGROUND: Human adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs. METHODS: haMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model. RESULTS: The quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at - 80°C, 3 months at - 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors. CONCLUSION: haMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease.

BACKGROUND: Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). AIM: To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD. METHODS: We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs. RESULTS: Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2-4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score. CONCLUSIONS: Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.

Microplitis bicoloratus parasitism promotes cyclophilin D-p53 interaction to induce apoptosis of hemocytes in Spodoptera litura.

Microplitis bicoloratus parasitism can induce apoptosis of hemocytes in the M. bicolortus host, Spodoptera litura. However, it is unclear how M. bicolortus parasitism regulates host signaling pathways to induce apoptosis. Expression of cyclophilin D (CypD) and p53 was significantly upregulated in S. litura hemocytes at 6 days postparasitization. In the parasitized hemocytes, there was mitochondrial membrane potential (△Ψm ) loss, cytochrome c (Cyt C) release from mitochondria, and caspase-3 activation. These occurred while hemocytes were undergoing upregulation of CypD and p53. Parasitism also promoted the interaction between CypD and p53. CypD silencing could rescue the apoptotic phenotypes induced by parasitism, but had no effect on apoptosis in unparasitized S. litura. These findings suggest that the CypD-p53 pathway may be an important component of the parasitism-induced immunosuppressive response and establish a basis for further studies of parasitoid/host interactions.

Hydrogel loaded with exosomes from Wharton's Jelly-derived mesenchymal stem cells enhances wound healing in mice. / 负载Wharton's Jelly源间å è´¨å¹²ç»†èƒžæ¥æºå¤–æ³Œä½“çš„æ°´å‡èƒ¶å¯ä¿ƒè¿›å°é¼ åˆ›é¢ä¿®å¤.

OBJECTIVES: To explore the effect of hydrogel loaded with exosomes from Wharton's Jelly-derived mesenchymal stem cell (WJMSC) on wound healing. METHODS: Exosomes were extracted from WJMSC, and the morphology and size of WJMSC-derived exosomes (WEX) were analyzed by transmission electron microscopy and nanoparticle size analyzer, respectively. The surface markers CD9, CD81, and Calnexin of WEX were detected by Western blotting. Exosome-loaded alginate hydrogel (WEX-gel) was prepared; its morphology was studied by scanning electron microscope, and its rheological behavior was examined by a rheometer. The in vitro drug release performance of WEX-gel was investigated by BCA method. RAW264.7 cells were treated with alginate hydrogel, WEX and WEX-gel, respectively; and the expression of CD86 and CD206 in macrophages was detected by flow cytometry. A full-thickness skin wound model was established in mice; the model mice were randomly divided into blank control group, WEX control group and WEX-gel group, and PBS, WEX and WEX-gel were applied to the wound area of mice, respectively. On day 3, the skin tissue of mice was excised, and the antibacterial effect of WEX hydrogel was evaluated by plate counting. On day 15, the mice were euthanized and the percentage of residual wounds was calculated. The histological changes of the skin wound were observed after hematoxylin and eosin (HE) and Masson stainings. The expression of CD86, CD206, CD31 and vascular endothelial growth factor (VEGF) in the skin wound tissue was detected by immunohistochemistry. RESULTS: Exosomes were successfully extracted from WJMSC. WEX-gel presented a regular three-dimensional network structure, good rheology and controlled drug release performance. WEX-gel promoted the polarization of RAW264.7 cells from the M1 phenotype to M2 phenotype in vitro. The residual wound percentage in blank control group, WEX control group and WEX-gel group were (27.5±3.4)%, (15.3±1.2)% and (7.6±1.1)%, respectively (P<0.05). The antibacterial property of WEX-gel is better than that of WEX (P<0.05). The dermis thickness, the number of new hair follicles, and the rate of collagen deposition in the WEX-gel group were significantly higher than those in the other two groups (all P<0.05). The expression of CD206, CD31 and VEGF in skin wound tissue was higher and the expression of CD86 was lower in WEX-gel group than those in other two groups (all P<0.05). CONCLUSIONS: WEX-gel can significantly promote wound healing in mice by regulating the polarization of macrophages.

Sinomenine promotes differentiation of induced pluripotent stem cells into immature dendritic cells with high induction of immune tolerance.

BACKGROUND: Immature dendritic cells (imDCs) play an important role in the induction of donor-specific transplant immunotolerance. However, these cells have limitations, such as rapid maturation and a short lifespan in vivo. In previous studies, induced pluripotent stem cells (iPSCs) differentiated into imDCs, and sinomenine (SN) was used to inhibit the maturation of imDCs. AIM: To study the capacity of SN to maintain iPSC-derived imDCs (SN-iPSCs-imDCs) in an immature state and the mechanism by which SN-iPSCs-imDCs induce immunotolerance. METHODS: In this study, mouse iPSCs were induced to differentiate into imDCs in culture medium without or with SN (iPSCs-imDCs and SN-iPSCs-imDCs). The imDC-related surface markers, endocytotic capacity of fluorescein isothiocyanate-Dextran and apoptosis were analyzed by flow cytometry. The effects of iPSCs-imDCs and SN-iPSCs-imDCs on T-cell stimulatory function, and regulatory T (Treg) cell proliferative function in vitro were analyzed by mixed lymphocyte reaction. Cytokine expression was detected by ELISA. The apoptosis-related proteins of iPSCs-DCs and SN-iPSCs-DCs were analyzed by western blotting. The induced immunotolerance of SN-iPSCs-DCs was evaluated by treating recipient Balb/c skin graft mice. Statistical evaluation of graft survival was performed using Kaplan-Meier curves. RESULTS: Both iPSCs-imDCs and SN-iPSCs-imDCs were successfully obtained, and their biological characteristics and ability to induce immunotolerance were compared. SN-iPSCs-imDCs exhibited higher CD11c levels and lower CD80 and CD86 levels compared with iPSCs-imDCs. Reduced major histocompatibility complex II expression, worse T-cell stimulatory function, higher Treg cell proliferative function and stronger endocytotic capacity were observed with SN-iPSCs-imDCs (P < 0.05). The levels of interleukin (IL)-2, IL-12, interferon-γ in SN-iPSCs-imDCs were lower than those in iPSCs-imDCs, whereas IL-10 and transforming growth factor-ß levels were higher (P < 0.05). The apoptosis rate of these cells was significantly higher (P < 0.05), and the expression levels of cleaved caspase3, Bax and cleaved poly(ADP-ribose) polymerase were higher after treatment with lipopolysaccharides, but Bcl-2 was reduced. In Balb/c mice recipients immunized with iPSCs-imDCs or SN-iPSCs-imDCs 7 d before skin grafting, the SN-iPSCs-imDCs group showed lower ability to inhibit donor-specific CD4+ T-cell proliferation (P < 0.05) and a higher capacity to induce CD4+CD25+FoxP3+ Treg cell proliferation in the spleen (P < 0.05). The survival span of C57bl/6 skin grafts was significantly prolonged in immunized Balb/c recipients with a donor-specific pattern. CONCLUSION: This study demonstrated that SN-iPSCs-imDCs have potential applications in vitro and in vivo for induction of immunotolerance following organ transplantation.

Development and validation of a 4-lncRNA combined prediction model for patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Therefore, it is necessary to develop and validate a novel prognostic model for HCC patients. OBJECTIVES: To establish an innovative and valuable prediction model of long non-coding RNAs (lncRNAs) for HCC. MATERIAL AND METHODS: Transcriptome and clinical data from The Cancer Genome Atlas (TCGA) were analyzed globally using bioinformatic approaches. We used Cox and least absolute shrinkage and selection operator (LASSO) regression analyses to screen for prognostic lncRNAs, while receiver operating characteristic (ROC) and Kaplan-Meier curve analyses were used to evaluate the effectiveness of the models. Clinical data from our center were used as a validation set. RESULTS: In the training set, a prediction model was established based on the expression of AP000844.2, LINC00942, SRGAP3-AS2, and AC010280.2 Hepatocellular carcinoma patients were divided into 2 groups (high-risk group and low-risk group) according to their risk score, and differences in survival were compared between the groups. The clinical data from our center served as a validation set to re-evaluate the effectiveness of the predictive model. The model had an excellent performance. The area under the curve (AUC) of 3-year survival was 0.771, while for 5-year survival it was 0.741, and the concordance index (C-index) was 0.756 (standard error (SE) = 0.023, 95% confidence interval (95% CI) = 0.620-0.891). CONCLUSIONS: The 4-lncRNA combination model is critically important in evaluating the prognosis of HCC. It is an effective independent prognostic factor, although prospective, multi-center studies are needed to validate our findings.

Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study.

BACKGROUND: Existing clinical studies supported the potential efficacy of mesenchymal stromal cells as well as derived exosomes in the treatment of COVID-19. We aimed to explore the safety and efficiency of aerosol inhalation of the exosomes derived from human adipose-derived MSCs (haMSC-Exos) in patients with COVID-19. METHODS: The MEXCOVID trial is a phase 2a single-arm, open-labelled, interventional trial and patients were enrolled in Jinyintan Hospital, Wuhan, China. Eligible 7 patients were assigned to receive the daily dose of haMSCs-Exos (2.0 × 108 nano vesicles) for consecutively 5 days. The primary outcomes included the incidence of prespecified inhalation-associated events and serious adverse events. We also observed the demographic data, clinical characteristics, laboratory results including lymphocyte count, levels of D-dimer and IL-6 as well as chest imaging. RESULTS: Seven severe COVID-19 related pneumonia patients (4 males and 3 females) were enrolled and received nebulized haMSC-Exos. The median age was 57 year (interquartile range (IQR), 43 year to 70 year). The median time from onset of symptoms to hospital admission and administration of nebulized haMSC-Exos was 30 days (IQR, 15 days to 40 days) and 54 d (IQR, 34 d to 69 d), respectively. All COVID-19 patients tolerated the haMSC-Exos nebulization well, with no evidence of prespecified adverse events or clinical instability during the nebulization or during the immediate post-nebulization period. All patients presented a slight increase of serum lymphocyte counts (median as 1.61 × 109/L vs. 1.78 × 109/L). Different degrees of resolution of pulmonary lesions after aerosol inhalation of haMSC-Exos were observed among all patients, more obviously in 4 of 7 patients. CONCLUSIONS: Our trial shows that a consecutive 5 days inhalation dose of clinical grade haMSC-Exos up to a total amount of 2.0 × 109 nano vesicles was feasible and well tolerated in seven COVID-19 patients, with no evidence of prespecified adverse events, immediate clinical instability, or dose-relevant toxicity at any of the doses tested. This safety profile is seemingly followed by CT imaging improvement within 7 days. Further trials will have to confirm the long-term safety or efficacy in larger population. TRIAL REGISTRATION: MEXCOVID, NCT04276987.

Value of Intravoxel Incoherent Motion (IVIM) Imaging for Differentiation between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma.

Efficient noninvasive imaging techniques in the differentiation of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are very important because of their different management and prognosis. Our purpose was to evaluate the difference of parameters extracted from intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) between the two groups and their performance for the differentiation, as well as the significance of perfusion information. IVIM studies (9 b-values) in 41 patients with either ICC or HCC were reviewed retrospectively by two observers. Diffusion coefficient (D), pseudodiffusion coefficient (D∗), perfusion fraction (f), ADC, and the mean percentage of parenchymal enhancement (MPPE) at 30 s after contrast-enhancement were calculated and compared between ICC and HCC. The relationship between D∗, f values, and MPPE was evaluated by Spearman's correlation test. The diagnostic efficacy of all parameters was analyzed by the receiver operating characteristic (ROC) curve. Interobserver and intraobserver agreements were analyzed. The parameters (D and ADC) of ICC were distinctly higher than those of HCC; whereas the parameters (f and MPPE of arterial phase) were distinctly lower (all false discovery rate [FDR]-corrected P < 0.05). The metric D∗ value of ICC was slightly higher than that of HCC (71.44 vs 69.41) with FDR-corrected P > 0.05. Moreover, the value of parameter D was significantly lower than that of ADC (FDR-corrected P < 0.05). The parameters (D and f values) extracted from IVIM showed excellent diagnostic efficiency in the identification, and the diagnostic efficiency of D value was significantly higher than that of the ADC. There were positive correlations between perfusion-related parameters (D∗, f values) and MPPE. Interobserver and intraobserver agreements were excellent or perfect in measurements of all parameters. Parameters derived from IVIM were valuable for distinguishing ICC and HCC. Moreover, the D value showed better diagnostic efficiency for the differential diagnosis than monoexponential fitting-derived ADC value. Meanwhile, the significant correlation between perfusion-related parameters and MPPE demonstrates that specific IVIM metrics may serve as a noninvasive indicator for the vascular perfusion information of ICC and HCC.

Long-term outcomes of arthroscopic debridement of the knee in adults with Kashin-Beck disease: an 18-year follow-up.

OBJECTIVE: Kashin-Beck disease (KBD) is an endemic degenerative joint disease with a high disability rate. We retrospectively evaluated the 18-year clinical follow-up outcomes of adult patients with KBD who underwent arthroscopic debridement for knee osteoarthritis. METHODS: Thirty-one patients with KBD (31 knees) underwent arthroscopy for knee osteoarthritis. The visual analog scale (VAS) score, walking distance, knee mobility, and patients' self-evaluated improvement in clinical symptoms were retrospectively evaluated before and 18 years after the operation. RESULTS: The patients' self-evaluated clinical symptoms showed considerable improvement at 2, 6, and 8 years after surgery but deteriorated at 10 and 18 years after surgery. Knee mobility was greater after than before arthroscopy but decreased from 6 to 18 years postoperatively. The VAS score for knee pain was high before the operation, decreased at 2 years postoperatively, increased at 6 years postoperatively, and was significantly lower at 18 years postoperatively than before surgery. The walking distance was significantly longer at 2, 6, and 8 years postoperatively than preoperatively. CONCLUSIONS: Arthroscopic treatment may be an effective therapy for adult patients with KBD who develop knee osteoarthritis. In this study, arthroscopy had a long-term effect on patients with KBD who had Kellgren-Lawrence grade

Up-regulation of VANGL1 by IGF2BPs and miR-29b-3p attenuates the detrimental effect of irradiation on lung adenocarcinoma.

Accumulating evidence suggests that radiation treatment causes an adaptive response of lung adenocarcinoma (LUAD), which in turn attenuates the lethal effect of the irradiation. Previous microarray assays manifested the change of gene expression profile after irradiation. Bioinformatics analysis of the significantly changed genes revealed that VANGL1 may notably influence the effect of radiation on LUAD. To determine the role of VANGL1, this study knocked down or overexpressed VANGL1 in LUAD. M6A level of VANGL1 mRNA was determined by M6A-IP-qPCR assay. Irradiation caused the up-regulation of VANGL1 with the increase of VANGL1 m6A level. Depletion of m6A readers, IGF2BP2/3, undermined VANGL1 mRNA stability and expression upon irradiation. miR-29b-3p expression was decreased by irradiation, however VANGL1 is a target of miR-29b-3p which was identified by Luciferase report assay. The reduction of miR-29b-3p inhibited the degradation of VANGL1 mRNA. Knockdown of VANGL1 enhanced the detrimental effect of irradiation on LUAD, as indicated by more severe DNA damage and increased percentage of apoptotic cells. Immunocoprecipitation revealed the interaction between VANGL1 with BRAF. VANGL1 increased BRAF probably through suppressing the protein degradation, which led to the increase of BRAF downstream effectors, TP53BP1 and RAD51. These effectors are involved in DNA repair after the damage. In summary, irradiation caused the up-regulation of VANGL1, which, in turn, mitigated the detrimental effect of irradiation on LUAD by protecting DNA from damage probably through activating BRAF/TP53BP1/RAD51 cascades. Increased m6A level of VANGL1 and reduced miR-29b-3p took the responsibility of VANGL1 overexpression upon irradiation.

MiR-10b inhibits migration and invasion of pancreatic ductal adenocarcinoma via regulating E2F7.

BACKGROUND: Abnormal microRNAs (miRNAs) expression is closely related to the development and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). We aimed to elucidate the invasive mechanism and clinical significance of miR-10b in PDAC. METHODS: The RNA sequence data of pancreatic cancer were extracted from the TCGA database. R packages were performed to analyze the differential expression of RNAs. TargetScan, picTar, and miRanda were used to predict the target gene of miRNA. The expression level of the selected candidate was tested by western blot and RT-PCR in PDAC cells and tissues. Scrape and Transwell assays were determined the effect of candidate molecules on cell migration and invasion. The gain of function and loss of function was achieved by co-culture with mimics and vector. Luciferase reporters were generated based on the psiCHECK2 vector. The relative luciferase activity was measured with the Dual-Luciferase Reporter Assay System and Infinate M200 PRO microplate reader. RESULTS: Based on the TCGA data and bioinformatics analysis, we obtained seven differentially expressed miRNAs. Both TCGA data and our center clinical date indicated that miR-10b was contributed to the poor survival of PDAC. Based on the target gene prediction database, we found that E2F7 was a target mRNA of miR-10b. In subsequent experiments in molecular biology, miR-10b expression was downregulated in PDAC cells and tissues, while E2F7 was upregulated. Scrape and Transwell assay indicated that miR-10b could inhibit the invasion and migration of PDAC. MiR-10b was confirmed to be by the E2F7 targeting site by dual-luciferase report. Moreover, rescue experiments prove that miR-10b could inhibit the invasion and migration of PDAC cells by regulating E2F7 expression. CONCLUSION: Our results suggest that miR-10b could inhibit the progression of PDAC by regulating E2F7 expression and acts as an independent prognostic risk factor for PDAC.

Two novel fan-shaped trinuclear Pt(ii) complexes act as G-quadruplex binders and telomerase inhibitors.

Two new trinuclear Pt(ii) complexes {[Pt(dien)]3(tib)}(NO3)6 (1) and {[Pt(dpa)]3(tib)}(NO3)6 (2) (dien: diethylenetriamine, dpa: bis-(2-pyridylmethyl)amine, tib: 1,3,5-tris(1H-imidazol-1-yl)benzene) have been designed, synthesized, characterized and applied to a series of biochemical studies. We found that both of the Pt(ii) complexes exhibited much better selectivity for human telomeric G-quadruplex sequence than promoter G-quadruplexes (c-kit, c-myc, and bcl2) or duplex DNA. Both complexes displayed comparative stability and affinity towards human telomeric G-quadruplex by the studies from surface plasmon resonance, fluorescence resonance energy transfer and polymerase chain reaction stop assays. The circular dichroism indicated that both complexes could induce and stabilize anti-parallel G-quadruplex structures. Molecule docking presented that Pt(ii) complex intercalated into the large groove of human telomeric G-quadruplex (PDB ID: 143D). Furthermore, telomeric repeat amplification protocol assays quantitatively evaluated the inhibition of telomerase activity caused by the Pt(ii) complexes. The obtained IC50 values of 6.41 ± 0.042 µM and 2.67 ± 0.035 µM for 1 and 2, respectively, exhibited strong telomerase inhibitions. All results suggest that such fan-shaped trinuclear Pt(ii) complexes are effective and selective G-quadruplex binders, as well as strong telomerase inhibitors. This study provides insight into the development of human telomeric G-quadruplex targeted anticancer drugs based on the metal complex.

Mitochondria-targeted phosphorescent cyclometalated iridium(III) complexes: synthesis, characterization, and anticancer properties.

Cyclometalated iridium(III) complexes represent a promising approach to developing new anticancer metallodrugs. In this work, three phosphorescent cyclometalated iridium(III) complexes Ir1-Ir3 have been explored as mitochondria-targeted anticancer agents. All three complexes display higher antiproliferative activity than cisplatin against the cancer cells screened, and with the IC50 values ranging from 0.23 to 5.6 µM. Colocalization studies showed that these complexes are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy through initiating a series of events related to mitochondrial dysfunction, including depolarization of mitochondrial membrane potential (MMP), elevation of intracellular reactive oxygen species (ROS) levels, and induction of apoptosis. Mitochondria-targted cyclometalated iridium complexes induce apoptosis through depolarized mitochondria, elevation of intracellular ROS and activated caspase.

Different roles of bortezomib and ONX 0914 in acute kidney injury.

Proteasome inhibitor bortezomib offers one more option for acute or chronic antibody-mediated rejection after kidney transplantation, but aggravated acute kidney injury (AKI) in some cases early after surgery using bortezomib bring new problem. Here, we evaluated the effects of bortezomib and ONX-0914 on renal tubule injury in a mouse model of ischemia-reperfusion injury. After treated with bortezomib, serum creatinine, usea nitrogen and tubular necrosis significantly increased compared with vehicle-treated mice, but decreased in ONX-0914 group mildly. Infiltration of neutrophil and macrophage were less in bortezomib and ONX-0914-treated mice than vehicle-treated group, and the same was observed on oxidative stress in the kidneys. Furthermore, the apoptosis of renal tubular epithelial cells increased in bortezomib-treated mice' kidneys compared with ONX-0914 and vehicle-treated controls. In vitro HK2 cell experiments also demonstrated the proapoptotic effect of bortezomib. The mRNA expression of several proapoptotic factors increased in kidneys of bortezomib-treated mice. In brief, bortezomib, as a proteasome inhibitor, shows a certain cytotoxicity to renal tubular epithelial cell during ischemia/reperfusion injury (IRI) through increased apoptosis. ONX-0914, as an immunoproteasome inhibitor, showed equal potency on anti-inflammation and oxidative stress relieving compared with bortezomib, while less cytotoxicity. The results render the immunoproteasome is a better target for anti-rejection and protecting kidney function in the field of organ transplantation.

TRIAP1 knockdown sensitizes non-small cell lung cancer to ionizing radiation by disrupting redox homeostasis.

BACKGROUND: Radioresistance of some non-small cell lung cancer (NSCLC) types increases the risk of recurrence or metastasis in afflicted patients, following radiotherapy. As such, further improvements to NSCLC radiotherapy are needed. The expression of oncogene TP53-regulated inhibitor of apoptosis 1 (TRIAP1) in NSCLC is increased following irradiation. Furthermore, gene set enrichment analysis (GSEA) has suggested that TRIAP1 might be involved in maintaining redox homeostasis. This in turn might enhance cell radioresistance. METHODS: In this study we irradiated human NSCLC cell lines (A549 and H460), while knocking down TRIAP1, to determine whether a disrupted redox homeostasis could attenuate radioresistance. RESULTS: Irradiation notably increased both mRNA and protein levels of TRIAP1. In addition, TRIAP1 knockdown decreased the expression of several antioxidant proteins, including thioredoxin-related transmembrane protein (TMX) 1, TMX2, thioredoxin (TXN), glutaredoxin (GLRX) 2, GLRX3, peroxiredoxin (PRDX) 3, PRDX4, and PRDX6 in A549 and H460 cells. In addition, silencing TRIAP1 impaired the radiation-induced increase of the aforementioned proteins. Continuing along this line, we observed a radiation-induced reduction of cell viability and invasion, as well as increased apoptosis and intracellular reactive oxygen species following TRIAP1 knockdown. CONCLUSIONS: In summary, we identified TRIAP1 as a key contributor to the radioresistance of NSCLC by maintaining redox homeostasis.