3D-printed PCL framework assembling ECM-inspired multi-layer mineralized GO-Col-HAp microscaffold for in situ mandibular bone regeneration.

BACKGROUND: In recent years, natural bone extracellular matrix (ECM)-inspired materials have found widespread application as scaffolds for bone tissue engineering. However, the challenge of creating scaffolds that mimic natural bone ECM's mechanical strength and hierarchical nano-micro-macro structures remains. The purposes of this study were to introduce an innovative bone ECM-inspired scaffold that integrates a 3D-printed framework with hydroxyapatite (HAp) mineralized graphene oxide-collagen (GO-Col) microscaffolds and find its application in the repair of mandibular bone defects. METHODS: Initially, a 3D-printed polycaprolactone (PCL) scaffold was designed with cubic disks and square pores to mimic the macrostructure of bone ECM. Subsequently, we developed multi-layer mineralized GO-Col-HAp microscaffolds (MLM GCH) to simulate natural bone ECM's nano- and microstructural features. Systematic in vitro and in vivo experiments were introduced to evaluate the ECM-inspired structure of the scaffold and to explore its effect on cell proliferation and its ability to repair rat bone defects. RESULTS: The resultant MLM GCH/PCL composite scaffolds exhibited robust mechanical strength and ample assembly space. Moreover, the ECM-inspired MLM GCH microscaffolds displayed favorable attributes such as water absorption and retention and demonstrated promising cell adsorption, proliferation, and osteogenic differentiation in vitro. The MLM GCH/PCL composite scaffolds exhibited successful bone regeneration within mandibular bone defects in vivo. CONCLUSIONS: This study presents a well-conceived strategy for fabricating ECM-inspired scaffolds by integrating 3D-printed PCL frameworks with multilayer mineralized porous microscaffolds, enhancing cell proliferation, osteogenic differentiation, and bone regeneration. This construction approach holds the potential for extension to various other biomaterial types.

Undifferentiated sarcomatoid carcinoma of the pancreas-a single-institution experience with 23 cases.

BACKGROUND: The clinical course and surgical outcomes of undifferentiated sarcomatoid carcinoma of the pancreas (USCP) remain poorly characterized owing to its rarity. This study aimed to describe the histology, clinicopathologic features, perioperative outcomes, and overall survival (OS) of 23 resected USCP patients. METHODS: We retrospectively described the histology, clinicopathologic features, perioperative outcomes and OS of patients who underwent pancreatectomy with a final diagnosis of USCP in a single institution. RESULTS: A total of 23 patients were included in this study. Twelve patients were male, the median age at diagnosis was 61.5 ± 13.0 years (range: 35-89). Patients with USCP had no specific symptoms and characteristic imaging findings. The R0 resection was achieved in 21 cases. The En bloc resection and reconstruction of mesenteric-portal axis was undertaken in 9 patients. There were no deaths attributed to perioperative complications in this study. The intraoperative tumor-draining lymph nodes (TDLNs) dissection was undergone in 14 patients. The 1-, 3- and 5-year survival rates were 43.5%, 4.8% and 4.8% in the whole study, the median survival was 9.0 months. Only 1 patient had survived more than 5 years and was still alive at last follow-up. The presence of distant metastasis (p = 0.004) and the presence of pathologically confirmed mesenteric-portal axis invasion (p = 0.007) was independently associated with poor OS. CONCLUSIONS: USCP was a rare subgroup of pancreatic malignancies with a bleak prognosis. To make a diagnose of USCP by imaging was quite difficult because of the absence of specific manifestations. Accurate diagnosis depended on pathological biopsy, and the IHC profile of USCP was mainly characterized by co-expression of epithelial and mesenchymal markers. A large proportion of patients have an early demise, especially for patients with distant metastasis and pathologically confirmed mesenteric-portal axis invasion. Long-term survival after radical resection of USCPs remains rare.

Renal interstitial fibrotic assessment using non-Gaussian diffusion kurtosis imaging in a rat model of hyperuricemia.

BACKGROUND: To investigate the feasibility of Diffusion Kurtosis Imaging (DKI) in assessing renal interstitial fibrosis induced by hyperuricemia. METHODS: A hyperuricemia rat model was established, and the rats were randomly split into the hyperuricemia (HUA), allopurinol (AP), and AP + empagliflozin (AP + EM) groups (n = 19 per group). Also, the normal rats were selected as controls (CON, n = 19). DKI was performed before treatment (baseline) and on days 1, 3, 5, 7, and 9 days after treatment. The DKI indicators, including mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) of the cortex (CO), outer stripe of the outer medulla (OS), and inner stripe of the outer medulla (IS) were acquired. Additionally, hematoxylin and eosin (H&E) staining, Masson trichrome staining, and nuclear factor kappa B (NF-κB) immunostaining were used to reveal renal histopathological changes at baseline, 1, 5, and 9 days after treatment. RESULTS: The HUA, AP, and AP + EM group MKOS and MKIS values gradually increased during this study. The HUA group exhibited the highest MK value in outer medulla. Except for the CON group, all the groups showed a decreasing trend in the FA and MD values of outer medulla. The HUA group exhibited the lowest FA and MD values. The MKOS and MKIS values were positively correlated with Masson's trichrome staining results (r = 0.687, P < 0.001 and r = 0.604, P = 0.001, respectively). The MDOS and FAIS were negatively correlated with Masson's trichrome staining (r = -626, P < 0.0014 and r = -0.468, P = 0.01, respectively). CONCLUSION: DKI may be a non-invasive method for monitoring renal interstitial fibrosis induced by hyperuricemia.

Hollow MnO2-Based Nanoprobes for Enhanced Photothermal/Photodynamic /Chemodynamic Co-Therapy of Hepatocellular Carcinoma.

PURPOSE: The effect of monotherapy in cancer is frequently influenced by the tumor's unique hypoxic microenvironment, insufficient drug concentration at the treatment site, and tumour cells' increased drug tolerance. In this work, we expect to design a novel therapeutic nanoprobe with the ability to solve these problems and improve the efficacy of antitumor therapy. METHODS: We have prepared a hollow manganese dioxide nanoprobes loaded with photosensitive drug IR780 for the photothermal/photodynamic/chemodynamic co-therapy of liver cancer. RESULTS: The nanoprobe demonstrates efficient thermal transformation ability under a single laser irradiation, and under the synergistic influence of photo heat, accelerates the Fenton/ Fenton-like reaction efficiency based on Mn2+ ions to produce more ·OH under the synergistic effect of photo heat. Moreover, the oxygen released under the degradation of manganese dioxide further promotes the ability of photosensitive drugs to produce singlet oxygen (ROS). The nanoprobe has been found to efficiently destroy tumour cells in vivo and in vitro experiments when used in combination with photothermal/photodynamic/ chemodynamic modes of treatment under laser irradiation. CONCLUSION: In all, this research shows that a therapeutic strategy based on this nanoprobe could be a viable alternative for cancer treatment in the near future.

A Molybdenum Disulfide Nanozyme with Charge-Enhanced Activity for Ultrasound-Mediated Cascade-Catalytic Tumor Ferroptosis.

The deficient catalytic activity of nanozymes and insufficient endogenous H2 O2 in the tumor microenvironment (TME) are major obstacles for nanozyme-mediated catalytic tumor therapy. Since electron transfer is the basic essence of catalysis-mediated redox reactions, we explored the contributing factors of enzymatic activity based on positive and negative charges, which are experimentally and theoretically demonstrated to enhance the peroxidase (POD)-like activity of a MoS2 nanozyme. Hence, an acidic tumor microenvironment-responsive and ultrasound-mediated cascade nanocatalyst (BTO/MoS2 @CA) is presented that is made from few-layer MoS2 nanosheets grown on the surface of piezoelectric tetragonal barium titanate (T-BTO) and modified with pH-responsive cinnamaldehyde (CA). The integration of pH-responsive CA-mediated H2 O2 self-supply, ultrasound-mediated charge-enhanced enzymatic activity, and glutathione (GSH) depletion enables out-of-balance redox homeostasis, leading to effective tumor ferroptosis with minimal side effects.

Pyrroloquinoline quinone ameliorates diabetic cardiomyopathy by inhibiting the pyroptosis signaling pathway in C57BL/6 mice and AC16 cells.

PURPOSE: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. METHODS: Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. RESULTS: PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy-(ANP and BNP), myocardial fibrosis-(collagen I and TGF-ß1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. CONCLUSION: PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1ß, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM.

Heterojunction of Vertically Arrayed MoS2 Nanosheet/N-Doped Reduced Graphene Oxide Enabling a Nanozyme for Sensitive Biomolecule Monitoring.

Enzymes are still indispensable for bio-assaying methods in biomolecule detection by far. The unsatisfied long-term instability, high cost, and susceptibility to the physical environment of natural enzymes are obvious weak points. Here, we developed peroxidase-like heterostructured nanozyme, vertically arraying molybdenum disulfide nanosheets on a substrate layer of nitrogen-doped reduced graphene oxide (MoS2/N-rGO), with a well-pleasing stability that is characterized by the retained enzymatic activity and maintained structure after 2 years of casual storage at ambient temperatures or 80 cycles of catalytic reaction. The catalytic kinetics of the as-prepared heterostructured nanozyme was superior to some reported nanozymes and even horse radish peroxidase, which was demonstrated due to the defect-rich MoS2 with Mo and S vacancies and nitrogen-doped rGO experimentally and theoretically. The vertically heterostructured nanozyme exhibited adequate analytical performance in sensitive and quantitative detection of glucose and glutathione (GSH), with a large dynamic sensing range and extremely low limit of detection (0.02 and 0.12 µM (3σ/slope) for glucose and GSH, respectively). We hope this inspired artificial nanozyme will contribute to the future development in sensitive detection of other biomolecules in physiological conditions.

Cyclopentadienone Derivative Dimers as Tunable Photoswitches.

A series of photoswitchable cyclopentadienone derivative dimers bearing bromo, thienyl, 4-(dimethylamino)phenyl, 3-pyridinyl, 4-nitrophenyl and cyano groups was designed and facilely synthesized. Photoswitching properties such as the photoconversions in the photostationary state (PSS), the thermal kinetics and thermal half-lives of photoisomers were systematically investigated. These photoswitches show high fatigue resistance and large photoconversions in the PSS. This work proves that the photoswitching properties of photoswitches based on cyclopentadienone dimers can be tuned by substitution groups and also pave the way to functionalize the cyclopentadienone derivative dimer-based photoswitch, which is important for its future applications.

Tumor-Targeting Multifunctional Nanoprobe for Enhanced Photothermal/Photodynamic Therapy of Liver Cancer.

Numerous researchers have committed to the development of combined therapy strategies for tumors, since their use in the treatment of tumors has more ideal therapeutic outcomes. In the study, we designed and prepared gold nanostars with CD147 modified on the surface and then efficiently loaded a photosensitive drug IR820 to construct a multifunctional nanoprobe. Due to the protection effect of gold, the nanoprobe has oxygen/heat energy generation capability and can also efficiently deliver the loaded drugs inside the tumor cells. Moreover, the nanoprobe has excellent photothermal/photodynamic therapeutic outcomes. The observation by photoacoustic real-time imaging validated the outstanding tumor-targeting characteristics of our nanoprobe. Finally, in the in vivo treatment experiment, the nanoprobe achieved ideal tumor-suppressive effects after the photothermal/photodynamic therapy. In summary, the findings of this experiment are useful in the development of new combined tumor therapy strategies based on nanomaterials.

Multiparametric MRI analysis for the evaluation of renal function in patients with hyperuricemia: a preliminary study.

BACKGROUND: To investigate the renal dysfunction in patients with hyperuricemia by employing a multiparametric MRI protocol, consisting of quantitative water molecule diffusion, microstructure, microscopic perfusion, and oxygenation measurements in kidneys. MATERIALS AND METHODS: A total of 48 patients with hyperuricemia (HU) and 22 age-matched healthy control subjects (HC) were enrolled in the study. For each participant, three different functional magnetic resonance imaging (fMRI) sequences were acquired and analyzed, including intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), and blood-oxygen-level-dependent MRI (BOLD). Thereafter, an independent two-sample t-test was applied to discover the significant differences of MRI indices between the hyperuricemia (HU) and HC groups, and the specific potential biomarkers between two subgroups of HU group (asymptomatic hyperuricemia group (AH) and gouty arthritis group (GA)). Further, multivariate logistic regression analyses were performed to classify the AH from the GA group using the MRI indices with significant between-group differences. The receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated to assess the performance of each MR index for differentiation between the AH and GA groups. RESULTS: Ten parametric values of the HU group were significantly lower than those of the HC group among the 14 fMRI parameters (P < 0.05). The cortical D, D*, and f values and medullary D and R2*values had significant differences between the AH and GA groups (P < 0.05). Combining the cortical D and f values and medullary R2* value gave the best diagnostic efficacy, yielding an AUC, sensitivity, and specificity of 0.967 ± 0.022, 91.67%, and 95.83%, respectively. CONCLUSIONS: A multiparametric MR analysis plays an important role in the evaluation of renal dysfunction in hyperuricemia from multiple perspectives. It could be a promising method for noninvasive detection and identification of the early-stage renal damage induced by hyperuricemia.

Non-invasive investigation of early kidney damage in streptozotocin-induced diabetic rats by intravoxel incoherent motion diffusion-weighted (IVIM) MRI.

BACKGROUND: The current study investigated the performance of intravoxel incoherent motion diffusion (IVIM) technology in monitoring early renal injury in streptozotocin rats. METHODS: Forty-eight Sprague-Dawley (SD) rats were divided into a control group and a diabetic mellitus (DM) group. Six rats in each group were randomly selected for MR scans at four different time points (0, 4, 8, and 12 weeks). The IVIM-derived parameters (D, D*, f and ADC values) of the renal cortex (CO), outer and inner stripe of the outer medulla (OS, IS), and internal medulla (IM) were acquired. Changes in each IVIM-derived parameter over time were analyzed, and differences between the two groups at each point were assessed. The associations between the IVIM parameters and IV collagen expression, urine volume (UV), blood urea nitrogen (BUN), and serum creatinine (Scr) were investigated. RESULTS: The D and D* values of CO and the ADC values of CO, OS, IS and IM displayed significantly different trends between the two groups over time (P<0.05). In addition, significant correlations were discovered between the D* value of CO and UV and BUN (r=0.527, P=0.033; r=0.617, P=0.005), between the ADC value of IM and BUN (r=0.557, P=0.019) and between the f value of IM and BUN (r=0.527, P=0.033). No correlation was found between IVIM parameters and IV collagen expression and Scr. CONCLUSIONS: IVIM is a potential sensitive and noninvasive technology for the simultaneous assessment of early renal cortical and medullary injuries induced by diabetes.

Prevalence of dental caries in the first permanent molar and associated risk factors among sixth-grade students in São Tomé Island.

BACKGROUND: Dental caries is one of the most preventable oral diseases among children in developing countries. This study aims to estimate the prevalence and severity of dental caries in the first permanent molar and analyze the related risk factors among sixth-grade students in São Tomé Island. METHODS: A cross-sectional study with a stratified cluster sampling method was conducted on 1855 sixth-grade school children, mainly aged 11 to 14 years old, from 10 schools in 6 regions of São Tomé Island, from April 17 to June 27, 2021. Dental caries examination was performed by using the CAST criteria (DMFT) index, and the self-administered questionnaires about family background, oral hygiene, and relevant behaviors were collected. Multivariable logistic regression was used to study risk factors related to dental caries of the first permanent molar, and all data analyses were done using SPSS version 25. RESULTS: The prevalence of dental caries in the first permanent molar was 68.79%, without significant difference between gender, age, residence, and whether only child or not. The mean Decayed, Missing, and Filled Teeth (DMFT) index and mean Decayed, Missing, and Filled Surface (DMFS) index were 1.751 ± 1.514 and 3.542 ± 3.941, respectively. The rate of filling teeth was 5.50%, and Pit and Fissure Sealant (PFS) rate was 2.21%. The overall prevalence and DMFT index of dental caries of permanent teeth was 76.01% and 2.753 ± 4.569, respectively. The results of logistic regression analysis indicated that the frequency of candy/chocolate consumption (OR = 1.095) and fair self-assessment of dental health (OR = 1.354) were significantly associated with dental caries (P < 0.05). CONCLUSIONS: The high prevalence of dental caries in the first permanent molar was a public health issue among sixth-grade school children in São Tomé Island. The prevalence of dental caries, mean DMFT and DMFS scores were higher, while the rate of filling and PFS teeth were lower than the average score of other African countries. Thus, oral health education, implement oral health preaching to school children and their parents is crucial to prevent dental caries.

Intravoxel incoherent motion imaging of the kidney: The application in patients with hyperuricemia.

BACKGROUND: Hyperuricemia is an independent risk factor for onset and progression of kidney disease. However, there remains a lack of a reliable and noninvasive biomarker to identify and monitor the changes of renal function in patients with hyperuricemia. PURPOSE: To assess the utility of intravoxel incoherent motion (IVIM) parameters in identifying the early changes of renal function in patients with hyperuricemia. STUDY TYPE: Retrospective case-control study. POPULATION: Eighty-four male participants, including asymptomatic hyperuricemia (AH, 27 cases), gouty arthritis (GA, 31 cases), and 26 age-matched healthy controls. FIELD STRENGTH/SEQUENCE: 3.0T; intravoxel incoherent motion (IVIM). ASSESSMENT: Differences in the IVIM parameters among the three groups were assessed. Pure molecular diffusion (D value); perfusion-related diffusion (D* value); pseudodiffusion fraction (f value); apparent diffusion coefficient (ADC value); estimated glomerular filtration rate (eGFR). Also, they were correlated with eGFR. STATISTICAL TESTS: Bonferroni test, Tamhane's T2 method, and Pearson correlation analysis. RESULTS: The D values in renal cortex and medulla significantly decreased from the control, AH to GA groups (P < 0.05). The GA patients had a significantly lower cortical f value than the controls and AH patients (P < 0.05). The medullary f values in the AH and GA patients were significantly lower than that in the controls (P < 0.05). Also, the cortical and medullary ADC values had similar results across the three groups (P < 0.05), except for the comparison between the AH and GA groups (P = 0.668, P = 0.111, respectively). No significant correlation was found between any IVIM parameters with eGFR. DATA CONCLUSION: IVIM imaging may be helpful for detecting the early changes of renal function induced by hyperuricemia. The D value could be the most sensitive IVIM-derived parameter in the assessment of renal function in patients with hyperuricemia in this study. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:833-840.

Genome-wide analysis of circular RNAs involved in Marek's disease tumourigenesis in chickens.

Marek's disease (MD), induced by Marek's disease virus (MDV), is a lymphotropic neoplastic disease and causes huge economic losses to the poultry industry. Non-coding RNAs (ncRNAs) play important regulatory roles in disease pathogenesis. To investigate host circular RNA (circRNA) and microRNA (miRNA) expression profile, RNA sequencing was performed in tumourous spleens (TS), spleens from the survivors (SS) without any lesion after MDV infection, and non-infected chicken spleens (NS). A total of 2,169 circRNAs were identified and more than 80% of circRNAs were derived from exon. The flanking introns of 1,744 exonic circRNAs possessed 579 reverse complementary matches (RCMs), which mainly overlapped with chicken repeat 1 family (CR1F). It suggested that CR1F mediated the cyclization of exons by intron pairing. Out of 2,169 circRNAs, 113 were differentially expressed circRNAs (DECs). The Q-PCR and Rnase R digestion experiments showed circRNA possessed high stability compared with their linear RNAs. Integrated with previous transcriptome data, we profiled regulatory networks of circRNA/long non-coding RNA (lncRNA)-miRNA-mRNA. Extensive competing endogenous RNA (ceRNA) networks were predicted to be involved in MD tumourigenesis. Interestingly, circZMYM3, an intronic circRNA, interacted with seven miRNAs which targeted some immune genes, such as SWAP70 and CCL4. Gga-miR-155 not only interacted with circGTDC1 and circMYO1B, but also targeted immune-related genes, such as GATA4, which indicated the roles of non-coding RNAs played to mediate immune responsive genes. Collectively, this is the first study that integrated RNA expression profiles in MD model. Our results provided comprehensive interactions of ncRNAs and mRNA in MD tumourigenesis.

Diffusional kurtosis imaging of kidneys in patients with hyperuricemia: initial study.

BACKGROUND: At present, there remains a lack of a reliable indicator for monitoring renal function in patients with hyperuricemia. PURPOSE: This study aimed to evaluate the feasibility of diffusion kurtosis imaging in the assessment of renal function in patients with hyperuricemia. MATERIAL AND METHODS: A total of 75 male participants, including 25 with asymptomatic hyperuricemia, 25 with gouty arthritis, and 25 age-matched male healthy controls, were enrolled in this study. Diffusion kurtosis imaging data were acquired to derive axial (Ka), radial (Kr), and mean kurtosis (MK), fractional anisotropy, axial (Da), radial (Dr), and mean diffusivity (MD) for comparisons among the three groups. They were also correlated with estimated glomerular filtration rate (eGFR). RESULTS: The MK values of the renal cortex and medulla and Kr value of the renal medulla in patients with asymptomatic hyperuricemia and gouty arthritis significantly increased compared with those in the controls (P < 0.05). Patients with gouty arthritis showed significant higher cortical and medullary Ka values compared with the other two groups (P < 0.05). The cortical Kr values of the asymptomatic hyperuricemia and gouty arthritis patients were significantly higher than that of the controls (P < 0.05). The medullary fractional anisotropy value showed a significant difference between the control and gouty arthritis groups (P < 0.05). No correlation was found between any diffusion kurtosis imaging parameters and eGFR value. CONCLUSION: Diffusion kurtosis imaging is feasible in the assessment of the early changes of renal cortex and medulla in patients with hyperuricemia.

The mechanism of ATF3 repression of epithelial-mesenchymal transition and suppression of cell viability in cholangiocarcinoma via p53 signal pathway.

The aim of this research was to determine the underlying mechanism of activating transcription factor 3 (ATF3) on cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT). The differentially expressed mRNAs in cholangiocarcinoma (CC) and its adjacent tissues were screened by microarray analysis, and the expression of ATF3 was detected through Quantitative real time polymerase chain reaction (qRT-PCR) and Western blot. The expression of EMT markers and p53-related proteins was analysed by Western blot. Analyses using the Cell Counting Kit-8 and TUNEL were performed to assess the rate of apoptosis and cell proliferation. Scratch wound and transwell assays were performed to study cell migration and invasion. Activating transcription factor 3 was restrained in CC cell lines and tissues and inhibited EMT while activating the p53 signalling pathway. Knockdown of ATF3 promoted cell proliferation but reduced the rate of apoptosis by inhibiting p53 signalling. Cell migration and invasion can be strengthened by ATF3 through activating the p53 signalling pathway.

Integrated analysis of lncRNA and mRNA repertoires in Marek's disease infected spleens identifies genes relevant to resistance.

BACKGROUND: Marek's disease virus (MDV) is an oncogenic herpesvirus that can cause T-cell lymphomas in chicken. Long noncoding RNA (lncRNA) is strongly associated with various cancers and many other diseases. In chickens, lncRNAs have not been comprehensively identified. Here, we profiled mRNA and lncRNA repertoires in three groups of spleens from MDV-infected and non-infected chickens, including seven tumorous spleens (TS) from MDV-infected chickens, five spleens from the survivors (SS) without lesions after MDV infection, and five spleens from noninfected chickens (NS), to explore the underlying mechanism of host resistance in Marek's disease (MD). RESULTS: By using a precise lncRNA identification pipeline, we identified 1315 putative lncRNAs and 1166 known lncRNAs in spleen tissue. Genomic features of putative lncRNAs were characterized. Differentially expressed (DE) mRNAs, putative lncRNAs, and known lncRNAs were profiled among three groups. We found that several specific intergroup differentially expressed genes were involved in important biological processes and pathways, including B cell activation and the Wnt signaling pathway; some of these genes were also found to be the hub genes in the co-expression network analyzed by WGCNA. Network analysis depicted both intergenic correlation and correlation between genes and MD traits. Five DE lncRNAs including MSTRG.360.1, MSTRG.6725.1, MSTRG.6754.1, MSTRG.15539.1, and MSTRG.7747.5 strongly correlated with MD-resistant candidate genes, such as IGF-I, CTLA4, HDAC9, SWAP70, CD72, JCHAIN, CXCL12, and CD8B, suggesting that lncRNAs may affect MD resistance and tumorigenesis in chicken spleens through their target genes. CONCLUSIONS: Our results provide both transcriptomic and epigenetic insights on MD resistance and its pathological mechanism. The comprehensive lncRNA and mRNA transcriptomes in MDV-infected chicken spleens were profiled. Co-expression analysis identified integrated lncRNA-mRNA and gene-gene interaction networks, implying that hub genes or lncRNAs exert critical influence on MD resistance and tumorigenesis.

CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations.

Pregnant women at risk of preterm labor usually receive synthetic glucocorticoids (sGCs) to promote fetal lung development. Emerging evidence indicates that antenatal sGC increases the risk of affective disorders in offspring. Data from animal studies show that such disorders can be transmitted to the second generation. However, the molecular mechanisms underlying the intergenerational effects of prenatal sGC remain largely unknown. Here we show that prenatal dexamethasone (Dex) administration in late pregnancy induced depression-like behavior in first-generation (F1) offspring, which could be transmitted to second-generation (F2) offspring with maternal dependence. Moreover, corticotropin-releasing hormone (CRH) and CRH receptor type 1 (CRHR1) expression in the hippocampus was increased in F1 Dex offspring and F2 offspring from F1 Dex female rats. Administration of a CRHR1 antagonist to newborn F1 Dex offspring alleviated depression-like behavior in these rats at adult. Furthermore, we demonstrated that increased CRHR1 expression in F1 and F2 offspring was associated with hypomethylation of CpG islands in Crhr1 promoter. Our results revealed that prenatal sGC exposure could program Crh and Crhr1 gene expression in hippocampus across 2 generations, thereby leading to depression-like behavior. Our study indicates that prenatal sGC can cause epigenetic instability, which increases the risk of disease development in the offspring's later life.-Xu, Y.-J., Sheng, H., Wu, T.-W., Bao, Q.-Y., Zheng, Y., Zhang, Y.-M., Gong, Y.-X., Lu, J.-Q., You, Z.-D., Xia, Y., Ni, X. CRH/CRHR1 mediates prenatal synthetic glucocorticoid programming of depression-like behavior across 2 generations.

Synthesis and biological evaluation of nitroxide labeled pyrimidines as Aurora kinase inhibitors.

To find novel effective Aurora kinases inhibitors, a series of structurally interesting nitroxide labeled pyrimidines were synthesized and evaluated their anti-proliferative and Aurora kinases inhibitory activities. Among them, butyl 2-(3-((5-fluoro-2-((4-((1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)carbamoyl) phenyl) amino)pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)acetate (22) possessed the most potent anti-proliferative effects against four carcinoma cell lines with IC50 values in range of 0.89-11.41 µM, and kinases inhibition against Aurora A and B with the IC50 values were 9.3 and 2.8 nM, respectively. Furthermore, compound 22 blocked the phosphorylation of Aurora A (T288), Aurora B (Thr232) and HisH3, decreased the expression of proteins TPX2, Eg5 and Bora, as well as disrupted the mitotic spindle formation in HeLa cells. Molecular docking studies indicated that compound 22 well interact with both Aurora A and B. The results showed that compound 22 is a potential anticancer agent as promising pan-Aurora kinase inhibitor.

Synthesis and identification of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl as potential Aurora A inhibitors.

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.