UBXN1 promotes liver tumorigenesis by regulating mitochondrial homeostasis.

BACKGROUND: The maintenance of mitochondrial homeostasis is critical for tumor initiation and malignant progression because it increases tumor cell survival and growth. The molecular events controlling mitochondrial integrity that facilitate the development of hepatocellular carcinoma (HCC) remain unclear. Here, we report that UBX domain-containing protein 1 (UBXN1) hyperactivation is essential for mitochondrial homeostasis and liver tumorigenesis. METHODS: Oncogene-induced mouse liver tumor models were generated with the Sleeping Beauty (SB) transposon delivery system. Assessment of HCC cell growth in vivo and in vitro, including tumour formation, colony formation, TUNEL and FACS assays, was conducted to determine the effects of UBXN1 on HCC cells, as well as the involvement of the UBXN1-prohibitin (PHB) interaction in mitochondrial function. Coimmunoprecipitation (Co-IP) was used to assess the interaction between UBXN1 and PHB. Liver hepatocellular carcinoma (LIHC) datasets and HCC patient samples were used to assess the expression of UBXN1. RESULTS: UBXN1 expression is commonly upregulated in human HCCs and mouse liver tumors and is associated with poor overall survival in HCC patients. UBXN1 facilitates the growth of human HCC cells and promotes mouse liver tumorigenesis driven by the NRas/c-Myc or c-Myc/shp53 combination. UBXN1 interacts with the inner mitochondrial membrane protein PHB and sustains PHB expression. UBXN1 inhibition triggers mitochondrial damage and liver tumor cell apoptosis. CONCLUSIONS: UBXN1 interacts with PHB and promotes mitochondrial homeostasis during liver tumorigenesis.

Porosity and pore structure evolution during the weathering of black shale.

Pore type and pore structure evolves systematically across continuous black shale weathering profile. However, the extend and process of pore structure change is still an enigma. In this study, we try to unveil the pore structure evolution during weathering process through studying Cambrian Hetang shales in southern China. Fourteen shale samples, from protolith zone (PZ), fractured and weathered shale zone (FWZ), and saprolite zone (SZ), were collected to elucidate how porosity and pore structure develop during black shale weathering under subtropical condition. Through low pressure argon (Ar) gas adsorption (LP-ArGA), high pressure mercury intrusion (HPMI), nuclear magnetic resonance(NMR) and field emission scanning electron microscope (FESEM) observation, the results reveal significant differences in physical properties and pore structures among the PZ, FWZ, and SZ samples. Specifically, compared to PZ, FWZ and SZ samples are characterized by higher clay mineral content, lower organic matter (OM), and the absence of carbonates and pyrite. Total porosity, determined through HPMI and NMR, exhibits a gradual increase from PZ (6.70 % and 6.41 %) to FWZ (20.47 % and 13.45 %) and SZ (23.22 % and 12.48 %). Ar adsorption isotherms indicate a change in pore type from predominantly ink-bottle and slit-shaped in the PZ to mainly slit-shaped in FWZ and SZ. Integrated analysis of LP-ArGA, HPMI, NMR and SEM observation suggests a substantial decrease in the contribution of micropores to total pore volume (PV) and a concurrent increase in larger pores (meso-macropores) with the increase of weathering intensity. This results in smoother surfaces of micro-transition pores but rougher surfaces of macropores. Changes in mineralogy composition during weathering play a crucial role in influencing pore structure of shales and further accelerating the release and migration of toxic elements in black shale. Our study provides the essential theoretical foundation for the remediation of soil and water environmental pollution caused by black shale weathering.

Characteristics of the Blockage from Air Nozzle Guide Duct in Circulating the Fluidized-Bed Coal Gasifier and Its Formation Mechanism.

Blockage is often generated in the air nozzle guide duct in a circulating fluidized-bed coal gasifier (CFBG), especially with Zhundong sub-bituminous coal (ZSBC) as the raw material. A typical example is found in one CFBG sample from Xinjiang Yihua Chemical Industry Co, Ltd. The serious blockage can be observed obviously. As so far, it is not clear for the characteristics and generation mechanism of the blockage. For analysis, the blockage can be classified into two parts, wall-layer blockage (WLB) and center-layer blockage (CLB). To inhibit its formation, it is of significance to analyze the composition, surface morphology, and formation mechanism of the two blockages. In our experiments, WLB and CLB were tested by XRF, XRD, FTIR, SEM-EDS, and SEM-mapping methods. Results showed that WLB presents high content of Fe, Cr, and Ni, and Fe mainly existed in the form of metal oxides. CLB is dominated by Si (43.04%), derived from silica and alkali and alkaline-earth metals silicates, and the migration of Fe, Cr, and Ni elements from the duct material was observed. Compared with WLB, from FTIR analysis, CLB contains more inorganic minerals, and the absorption peak of inorganic minerals is mainly attributed to asymmetric Si-O-Si. Many fine particles are attached to the surface of the WLB, while the surface of the CLB is smooth, and there is noticeable raised texture, which is presumed to be the result of particle melting and agglomerating as the bottom ash enters the duct in the gasification process. For the formation of the blockage, this paper speculates that it is mainly due to the difference in flow resistance near the air nozzle outlet, resulting in the formation of a flow dead zone at the bottom of the gasifier, which leads to large amounts of ash overcoming the outlet resistance and leaking into the air nozzle, and next, the ash corrodes in the tube, resulting in wall deposition and ultimately blocking the air guide duct. Two methods can be tried to avoid or inhibit the formation of blockage in the duct, including optimizing air nozzle with more wear-resistant and heat-resistant materials and adjusting the distance between air nozzles to avoid mutual interference from ash particles.

UBXN9 inhibits the RNA exosome function to promote T cell control of liver tumorigenesis.

BACKGROUND AND AIMS: Liver tumorigenesis encompasses oncogenic activation and self-adaptation of various biological processes in premalignant hepatocytes to circumvent the pressure of cellular stress and host immune control. Ubiquitin regulatory X domain-containing proteins (UBXNs) participate in the regulation of certain signaling pathways. However, whether UBXN proteins function in the development of liver cancer remains unclear. APPROACH AND RESULTS: Here, we demonstrated that UBXN9 (Alveolar Soft Part Sarcoma Chromosomal Region Candidate Gene 1 Protein/Alveolar Soft Part Sarcoma Locus) expression was decreased in autochthonous oncogene-induced mouse liver tumors and ~47.7% of human HCCs, and associated with poor prognosis in patients with HCC. UBXN9 attenuated liver tumorigenesis induced by different oncogenic factors and tumor growth of transplanted liver tumor cells in immuno-competent mice. Mechanistically, UBXN9 significantly inhibited the function of the RNA exosome, resulting in increased expression of RLR-stimulatory RNAs and activation of the retinoic acid-inducible gene-I-IFN-Ι signaling in tumor cells, and hence potentiated T cell recruitment and immune control of tumor growth. Abrogation of the CD8 + T cell response or inhibition of tumor cell retinoic acid-inducible gene-I signaling efficiently counteracted the UBXN9-mediated suppression of liver tumor growth. CONCLUSIONS: Our results reveal a modality in which UBXN9 promotes the stimulatory RNA-induced retinoic acid-inducible gene-I-interferon signaling that induces anti-tumor T cell response in liver tumorigenesis. Targeted manipulation of the UBXN9-RNA exosome circuit may have the potential to reinstate the immune control of liver tumor growth.

Carbon Nanotube-Directed 7 GPa Heterocyclic Aramid Fiber and Its Application in Artificial Muscles.

Poly(p-phenylene-benzimidazole-terephthalamide) (PBIA) fibers with excellent mechanical properties are widely used in fields that require impact-resistant materials such as ballistic protection and aerospace. The introduction of heterocycles in polymer chains increases their flexibility and makes it easier to optimize the fiber structure. However, the inadequate orientation of polymer chains is one of the main reasons for the large difference between the measured and theoretical mechanical properties of PBIA fibers. Herein, carbon nanotubes (CNTs) are selected as an orientation seed. Their structural features allow CNTs to orient during the spinning process, which can induce an orderly arrangement of polymers and improve the orientation of the fiber microstructure. To ensure the complete 1D topology of long CNTs (≈10 µm), PBIA is used as an efficient dispersant to overcome dispersion challenges. The p-CNT/PBIA fibers (10 µm single-walled carbon nanotube 0.025 wt%) exhibit an increase of 22% in tensile strength and 23% in elongation, with a maximum tensile strength of 7.01 ± 0.31 GPa and a reinforcement efficiency of 893.6. The artificial muscle fabricated using CNT/PBIA fibers exhibits a 34.8% contraction and a 25% lifting of a 2 kg dumbbell, providing a promising paradigm for high-performance organic fibers as high-load smart actuators.

Microneedle/CD-MOF-mediated transdural controlled release of methylprednisolone sodium succinate after spinal cord injury.

A new method of transdural delivering drugs to the spinal cord has been developed, involving the use of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). This epidural microneedle array, dubbed MNs@CD-MOF@MPSS, can be utilized to deliver methylprednisolone sodium succinate (MPSS) to the site of spinal cord injury (SCI) in a controlled manner. MNs allows to generate micropores in the dura for direct drug delivery to the spinal cord, overcoming tissue barriers and targeting damaged regions. Additionally, the CD-MOF provides a secondary extended release after separating from the MNs. In in vitro study, inward MNs increased cellular absorption of MPSS and then reduced LPS-induced M1 polarization of microglia. And animal studies have shown that this method of drug delivery results in improved BMS scores and a reduction in M1 phenotype microphage and glial scar formation. Furthermore, the downregulation of the NLRP3-positive inflammasome and related pro-inflammatory cytokines was observed. In conclusion, this new drug platform has potential for clinical application in spinal cord diseases and is a valuable composite for minimally transdural controlled drug delivery. STATEMENT OF SIGNIFICANCE: This research presents a new epidural microneedle patch made up of microneedles (MNs) and a ß-cyclodextrin metal-organic framework (CD-MOF). The epidural microneedle patch boasts high drug loading capacity, the ability to penetrate the dura, and controlled release. When loaded with methylprednisolone sodium succinate (MPSS), it effectively reduces inflammation and improves neurological function after spinal cord injury. Therefore, it is a novel and promising drug platform for the treatment of spinal cord diseases in a clinical setting.

Development and validation of a newly developed nomogram for predicting the risk of deep vein thrombosis after surgery for lower limb fractures in elderly patients.

Background: Prevention of deep vein thrombosis (DVT) is indispensable in the treatment of lower limb fractures during the perioperative period. This study aimed to develop and validate a novel model for predicting the risk of DVT in elderly patients after orthopedic surgeries for lower limb fractures. Methods: This observational study included 576 elderly patients with lower limb fractures who were surgically treated from January 2016 to December 2018. Eleven items affecting DVT were optimized by least absolute shrinkage and selection operator regression analysis. Multivariable logistic regression analysis was performed to construct a predictive model incorporating the selected features. C-index was applied to evaluate the discrimination. Decision curve analysis was employed to determine the clinical effectiveness of this model and calibration plot was applied to evaluate the calibration of this nomogram. The internal validation of this model was assessed by bootstrapping validation. Results: Predictive factors that affected the rate of DVT in this model included smoking, time from injury to surgery, operation time, blood transfusion, hip replacement arthroplasty, and D-dimer level after operation. The nomogram showed significant discrimination with a C-index of 0.919 (95% confidence interval: 0.893-0.946) and good calibration. Acceptable C-index value could still be reached in the interval validation. Decision curve analysis indicated that the DVT risk nomogram was useful within all possibility threshold. Conclusion: This newly developed nomogram could be used to predict the risk of DVT in elderly patients with lower limb fractures during the perioperative period.

FGFR2 modulates the Akt/Nrf2/ARE signaling pathway to improve angiotensin II-induced hypertension-related endothelial dysfunction.

BACKGROUND: Fibroblast growth factor receptor (FGFR)2 expression was decreased in hypertension patients while its role in hypertension was not explored. This experiment aimed to investigate the expression ofFGFR2 in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs) and the role of FGFR2 in improving AngII-induced hypertension-related endothelial dysfunction. METHODS: AngII-induced HUVECs simulated the hypertension model in vitro. The expression of FGFR2 in Ang II-induced HUVECs and transfected HUVECswas detected by RT-qPCR and western blot. The viability, apoptosis, migration and tube formation ability of Ang II-induced HUVECs were analyzed by Methyl Thiazolyl Tetrazolium (MTT) assay, flow cytometry analysis, wound healing assay and tube formation assay.Detectionof lactate dehydrogenase (LDH), caspase 3, Nitric Oxide (NO) and oxidative stress levels was conducted by assay kits and reactive oxygen species (ROS) level was detected by DCFH-DA assay. The expression of apoptosis-related proteins, protein kinase B(Akt)/nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway-related proteins, phospho(p)-endothelial nitric oxide synthase (eNOS) and eNOS was determined by western blot. RESULTS: The expression of FGFR2 was decreased in Ang II-induced HUVECs. FGFR2overexpression increased viability, suppressed apoptosis and oxidative stress, and improve endothelial dysfunction of AngII-induced HUVECs through activating the Akt/Nrf2/ARE signaling pathway. MK-2206 (Akt inhibitor) could weaken the effect of FGFR2overexpression to reduce viability, promote apoptosis and oxidative stress, and aggravate endothelial dysfunction of Ang II-inducedHUVECs. CONCLUSION: Inconclusion, FGFR2activated the Akt/Nrf2/ARE signaling pathway to improve AngII-induced hypertension-related endothelial dysfunction.

Fabricating strong and tough aramid fibers by small addition of carbon nanotubes.

Synthetic high-performance fibers present excellent mechanical properties and promising applications in the impact protection field. However, fabricating fibers with high strength and high toughness is challenging due to their intrinsic conflicts. Herein, we report a simultaneous improvement in strength, toughness, and modulus of heterocyclic aramid fibers by 26%, 66%, and 13%, respectively, via polymerizing a small amount (0.05 wt%) of short aminated single-walled carbon nanotubes (SWNTs), achieving a tensile strength of 6.44 ± 0.11 GPa, a toughness of 184.0 ± 11.4 MJ m-3, and a Young's modulus of 141.7 ± 4.0 GPa. Mechanism analyses reveal that short aminated SWNTs improve the crystallinity and orientation degree by affecting the structures of heterocyclic aramid chains around SWNTs, and in situ polymerization increases the interfacial interaction therein to promote stress transfer and suppress strain localization. These two effects account for the simultaneous improvement in strength and toughness.

Bioinformatics analysis and identification of hub genes associated with female acute myocardial infarction patients by using weighted gene co-expression networks.

To explore potential biomarkers of acute myocardial infarction (AMI) in females by using bioinformatics analysis. In this study, we explored potential biomarkers of AMI in females using bioinformatics analysis. We screened a total of 186 differentially expressed genes from the Gene Expression Omnibus. In the study, we found that weighted gene co-expression network analysis explored the co-expression network of genes and identified key modules. Simultaneously, we chose brown modules as key modules related to AMI. In this study, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that genes in the brown module were mainly enriched in "heparin" and 'complementation and coagulation cascade. Based on the protein-protein interaction network, we identified S100A9, mitogen-activated protein kinase (MAPK) 3, MAPK1, MMP3, interleukin (IL)-17A, and HSP90AB1 as hub gene sets. Whereas, polymerase chain reaction results showed that S100A9, MAPK3, MAPK1, MMP3, IL-17A, and HSP90AB1 were highly expressed compared with the control group. The IL-17 signaling pathway associated with an inflammatory response may be a potential biomarker and target for the treatment of women with myocardial infarction.

A new immune signature for survival prediction and immune checkpoint molecules in non-small cell lung cancer.

Background: Immune checkpoint blockade (ICB) therapy has brought remarkable clinical benefits to patients with advanced non-small cell lung carcinoma (NSCLC). However, the prognosis remains largely variable. Methods: The profiles of immune-related genes for patients with NSCLC were extracted from TCGA database, ImmPort dataset, and IMGT/GENE-DB database. Coexpression modules were constructed using WGCNA and 4 modules were identified. The hub genes of the module with the highest correlations with tumor samples were identified. Then integrative bioinformatics analyses were performed to unveil the hub genes participating in tumor progression and cancer-associated immunology of NSCLC. Cox regression and Lasso regression analyses were conducted to screen prognostic signature and to develop a risk model. Results: Functional analysis showed that immune-related hub genes were involved in the migration, activation, response, and cytokine-cytokine receptor interaction of immune cells. Most of the hub genes had a high frequency of gene amplifications. MASP1 and SEMA5A presented the highest mutation rate. The ratio of M2 macrophages and naïve B cells revealed a strong negative association while the ratio of CD8 T cells and activated CD4 memory T cells showed a strong positive association. Resting mast cells predicted superior overall survival. Interactions including protein-protein, lncRNA and transcription factor interactions were analyzed and 9 genes were selected by LASSO regression analysis to construct and verify a prognostic signature. Unsupervised hub genes clustering resulted in 2 distinct NSCLC subgroups. The TIDE score and the drug sensitivity of gemcitabine, cisplatin, docetaxel, erlotinib and paclitaxel were significantly different between the 2 immune-related hub gene subgroups. Conclusions: These findings suggested that our immune-related genes can provide clinical guidance for the diagnosis and prognosis of different immunophenotypes and facilitate the management of immunotherapy in NSCLC.

Design of Cross-Platform Information Retrieval System of Library Based on Digital Twins.

In order to improve the library's ability of cross-platform information retrieval and data scheduling and distribution, a library cross-platform information retrieval system based on digital twin technology is designed. Using data warehouse decision support and data source structured query methods, the spectral characteristics of Library cross-platform information resources are extracted. Using the method of Hadoop data parallel loading, the library cross-platform operation data is divided into decision-making data, computing resource pool data, and Hadoop parallel loading data. A library cross-platform information digital twin parallel retrieval and information fusion feature matching model is established, and the retrieval channels are allocated through multiple complex and balanced task scheduling sequences. According to the queue configuration model of Library cross-platform information retrieval, the optimization design of Library cross-platform information retrieval system is realized. The simulation test results show that the designed system has good recall ability of cross-platform information retrieval data, and improves the utilization rate of cross-platform resources and the dynamic scheduling ability of online resources.

Ultrasound-guided erector spinae plane block improve opioid-sparing perioperative analgesia in pediatric patients undergoing thoracoscopic lung lesion resection: a prospective randomized controlled trial.

Background: Pediatric patients often experience severe pain after thoracic surgery, especially in the early postoperative period. Recently, the focus has been on regional analgesia with the introduction of ultrasound-guided erector spinae plane blocks. We assumed that preoperative erector spinae plane block (ESPB) in children undergoing video-assisted thoracoscopic surgery (VATS) would reduce the consumption of perioperative opioids. Methods: This randomized, double-blind study enrolled 60 children aged 1-3 years who underwent thoracoscopic lung lesion resection. The patients were enrolled in the study and randomly divided into two groups. The general anesthesia (GA) group received GA alone, and the GA + ESPB group received ESPB. The consumptions of remifentanil and sufentanil were recorded, and the children's face, legs, activity, cry, consolability (FLACC) scores were assessed after awakening. The time to first rescue analgesia, length of hospital stay, parental satisfaction and adverse events were also recorded. Results: The consumptions of remifentanil and sufentanil in the GA + ESPB group were significantly lower than those in the GA group, mean difference [95% confidence interval (CI)]: -26.57 (-31.98 to -21.17) and -0.21 (-0.27 to -0.17), respectively, (both P<0.001); while the time to first rescue analgesia and parental satisfaction scores were significantly longer and higher, respectively, in the GA + ESPB group than those in the GA group, mean difference (95% CI): 2.37 (1.77 to 2.97) and 2.47 (1.79 to 3.15), respectively, (both P<0.001). The FLACC scores in the GA + ESPB group were significantly lower than those in the GA group 1 to 24 hours postoperatively (P=0.023 at 1 h, and P<0.001 at 3 h, 6 h, 12 h, 18 h, 24 h), but not at immediate admission to the post-anesthesia care unit (PACU) (P=0.189 at 0 h). The GA + ESPB group had significantly lower incidence rates of postoperative nausea and vomiting (P=0.037 and P=0.020). Conclusions: In pediatric Thoracoscopic surgery, the results of this study confirm our hypothesis that ESPB decreases the consumptions of intraoperative remifentanil and postoperative sufentanil in 24 hours and demonstrates better postoperative analgesia compared with a control group. Trial Registration: Chinese Clinical Trial Registry ChiCTR2200056166.

ZIF-8 modified multifunctional injectable photopolymerizable GelMA hydrogel for the treatment of periodontitis.

Periodontitis is a chronic inflammatory disease caused by plaque that leads to alveolar bone resorption. In the treatment of periodontitis, it is necessary to reduce the bacterial load and promote alveolar bone regeneration. In this study, zeolitic imidazolate framework-8 (ZIF-8) is used in the treatment of periodontitis, and an injectable photopolymerizable ZIF-8/gelatin methacryloyl (GelMA) composite hydrogel (GelMA-Z) is constructed. We confirm that ZIF-8 nanoparticles are successfully loaded into GelMA, which demonstrates fluidity and photopolymerizability. GelMA-Z continuously releases Zn2+ and shows good cytocompatibility. In vitro, GelMA-Z can effectively upregulate the expression of osteogenesis-related genes and proteins, increase alkaline phosphatase activity, promote extracellular matrix mineralization by rat bone mesenchymal stem cells, and exert an obvious antibacterial effect against Porphyromonas gingivalis. In vivo, GelMA-Z reduces the bacterial load, relieves inflammation and promotes alveolar bone regeneration in a rat model. The above results show that GelMA-Z has potential prospects in the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: Various methods have been explored for the treatment of periodontitis. However, current regiments have difficulty achieving ideal alveolar bone regeneration. In this study, we constructed a zeolitic imidazolate framework-8 (ZIF-8)/gelatin methacryloyl (GelMA) composite hydrogel (GelMA-Z). (1) The injectable and photopolymerizable GelMA-Z showed biocompatibility in vitro and in vivo. (2) GelMA-Z continually released zinc ions to promote the osteogenic differentiation of bone mesenchymal stem cells and kill bacteria in vitro. (3) In a rat model, the GelMA-Z pregel solution was used to fill the periodontal pocket and then crosslinked by UV exposure. GelMA-Z can stably remain in the periodontal pocket to reduce the bacterial load, relieve inflammation and promote alveolar bone regeneration. In conclusion, GelMA-Z has great potential for use in the treatment of periodontitis, especially in promoting alveolar bone regeneration.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial.

BACKGROUND: High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown. OBJECTIVE: The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated. DESIGN, PARTICIPANTS AND INTERVENTION: This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone. MAIN OUTCOME MEASURES: The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3. RESULTS: A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/µL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups. CONCLUSION: STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only. TRIAL REGISTRATION: This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

A periodontal tissue regeneration strategy via biphasic release of zeolitic imidazolate framework-8 and FK506 using a uniaxial electrospun Janus nanofiber.

Guided tissue regeneration (GTR) strategies are an effective approach to repair periodontal defects by using GTR membranes. However, commercial GTR membranes still have limitations in periodontal tissue regeneration owing to lack of antibacterial and osteogenic properties. The development of novel Janus nanofibers with biphasic release characteristics based on the therapeutic needs of GTR is essential to tackle this issue. Here, we developed a multifunctional Janus nanofiber via uniaxial electrospinning, with zeolitic imidazolate framework-8 nanoparticle (ZIF-8 NP) loading in the hydrophilic polyvinylpyrrolidone (PVP) part and FK506 embedding in the hydrophobic polycaprolactone (PCL) part. The release of Zn2+ conformed to the Ritger-Peppas kinetics which could effectively prevent bacterial infection, and the release profile of FK506 was fitted to a first-order equation which could provide persistent osteogenic stimulation for osteogenesis. The periodontal tissue regeneration data from a rat periodontitis model revealed that the multifunctional electrospun Janus nanofibers could be used as an effective bioplatform to restore alveolar bone impairment, compared with the control group. In summary, the Janus nanofibers with biphasic release characteristics quickly exert antibacterial function as well as continuously provide a microenvironment beneficial to the osteogenesis process, demonstrating its great potential for GTR treatment in dental clinic applications.

Deubiquitination of the repressor E2F6 by USP22 facilitates AKT activation and tumor growth in hepatocellular carcinoma.

Dysregulated ubiquitination of tumor-related proteins plays a critical role in tumor development and progression. The deubiquitinase USP22 is aberrantly expressed in certain types of cancer and contributes to aggressive tumor progression. However, the precise mechanism underlying the pro-tumorigenic function of USP22 in hepatocellular carcinoma (HCC) remains unclear. Here, we report that E2F6, a pocket protein-independent transcription repressor, is essential for HCC cell growth, and that its activities are controlled by USP22-mediated deubiquitination. USP22 interacts with and stabilizes E2F6, resulting in the transcriptional repression of phosphatase DUSP1. Moreover, the process involving DUSP1 repression by E2F6 strengthens AKT activation in HCC cells. Therefore, these findings provide mechanistic insights into the USP22-mediated control of oncogenic AKT signaling, emphasizing the importance of USP22-E2F6 regulation in HCC development.

USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade.

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.

The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis.

K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-rasG12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.

Kellerin from Ferula sinkiangensis exerts neuroprotective effects after focal cerebral ischemia in rats by inhibiting microglia-mediated inflammatory responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferula sinkiangensis K. M. Shen is a traditional Chinese medicine that has a variety of pharmacological properties relevant to neurological disorders and inflammations. Kellerin, a novel compound extracted from Ferula sinkiangensis, exerts a strong anti-neuroinflammatory effect by inhibiting microglial activation. Microglial activation plays a vital role in ischemia-induced brain injury. However, the potential therapeutic effect of kellerin on focal cerebral ischemia is still unknown. AIM OF THE STUDY: To explore the effect of kellerin on cerebral ischemia and clarify its possible mechanisms, we applied the middle cerebral artery occlusion (MCAO) model and the LPS-activated microglia model in our study. MATERIALS AND METHODS: Neurological outcome was examined according to a 4-tiered grading system. Brain infarct size was measured using TTC staining. Brain edema was calculated using the wet weight minus dry weight method. Neuron damage and microglial activation were observed by immunofluorescence in MCAO model in rats. In in vitro studies, microglial activation was examined by flow cytometry and the viability of neuronal cells cultured in microglia-conditioned medium was measured using MTT assay. The levels of pro-inflammatory cytokines were measured by qRT-PCR and ELISA. The proteins involved in NF-κB signaling pathway were determined by western blot. Intracellular ROS was examined using DCFH-DA method and NADPH oxidase activity was measured using the NBT assay. RESULTS: We found that kellerin improved neurological outcome, reduced brain infarct size and decreased brain edema in MCAO model in rats. Under the pathologic conditions of focal cerebral ischemia, kellerin alleviated neuron damage and inhibited microglial activation. Moreover, in in vitro studies of LPS-stimulated BV2 cells kellerin protected neuronal cells from being damaged by inhibiting microglial activation. Kellerin also reduced the levels of pro-inflammatory cytokines, suppressed the NF-κB signaling pathway, and decreased ROS generation and NADPH oxidase activity. CONCLUSIONS: Our discoveries reveal that the neuroprotective effects of kellerin may largely depend on its inhibitory effect on microglial activation. This suggests that kellerin could serve as a novel anti-inflammatory agent which may have therapeutic effects in ischemic stroke.