Exosomal NAMPT from chronic lymphocytic leukemia cells orchestrate monocyte survival and phenotype under endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress has been reported to be transmitted from tumor cells to immune cells via exosome and implicated in immune escape. However, the influence of ER stress on monocytes in chronic lymphocytic leukemia (CLL) cells is largely unknown. Here, we observed the expression of ER stress markers (GRP78, ATF6, PERK, IRE1a, and XBP1s) in CLL cells. The increasing mRNA expression of these ER stress response components was positively correlated with more aggressive disease. Exosome from ER stress inducer tunicamycin (TM)-primed CLL cells (ERS-exo) up-regulated the expression of ER stress marker on monocytes, indicating ER stress is transmissible in vitro via exosome. Treatment with ERS-exo promoted the survival of monocytes and induced phenotypic changes with a significantly larger percentage of CD14+ CD16+ monocytes. Finally, we identified exosome-mediated transfer of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) from ER stressed CLL cells into monocytes as a novel mechanism through which ERS-exo regulated monocytes. Exosomal eNAMPT up-regulated nicotinamide adenine dinucleotide (NAD+ ) production which subsequently activated SIRT1-C/EBPß signaling pathway in monocytes. Our results suggest the role of ER stress in mediating immunological dysfunction in CLL.

miR-143-null Is against Diet-Induced Obesity by Promoting BAT Thermogenesis and Inhibiting WAT Adipogenesis.

Excessive energy intake is the main cause of obesity, and stimulation of brown adipose tissue (BAT) thermogenesis has emerged as an attractive tool for anti-obesity. Although miR-143 has been reported to promote white adipocyte differentiation, its role in BAT remains unclear. In our study, we found that during HFD-induced obesity, the expression of miR-143 in BAT was significantly reduced, and the expression of miR-143 in WAT first increased and then decreased. Knockout (KO) of miR-143 with CRISPR/Cas9 did not affect the energy metabolism of normal diet fed mice and brown adipocyte differentiation but inhibited the differentiation of white adipocytes. Importantly, during high fat diet-induced obesity, miR-143KO significantly reduced body weight, and improved energy expenditure, insulin sensitivity, and glucose tolerance. Further exploration showed that miR-143KO reduced the weight of adipose tissue, promoted mitochondrial number and functions, induced thermogenesis and lipolysis of BAT, increased lipolysis, and inhibited lipogenesis of white adipose tissue (WAT). Our study considerably improves our collective understanding of the function of miR-143 in adipose tissue and its potential significance in anti-obesity and provides a new avenue for the management of obesity through the inhibition of miR-143 in BAT and WAT.

Endoplasmic Reticulum Stress Causes Liver Cancer Cells to Release Exosomal miR-23a-3p and Up-regulate Programmed Death Ligand 1 Expression in Macrophages.

Endoplasmic reticulum (ER) stress promotes tumor cell escape from immunosurveillance. However, the underlying mechanisms remain unknown. We hypothesized that ER stress induces hepatocellular carcinoma (HCC) cells to release exosomes, which attenuate antitumor immunity by modulating the expression of programmed death ligand 1 (PD-L1) in macrophages. In this study, we demonstrated that expression of several ER stress markers (glucose-regulated protein 78, activating transcription factor 6, protein kinase R-like ER kinase, and inositol-requiring enzyme 1α) was up-regulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores in patients with HCC. Expression of ER stress-related proteins positively correlated with CD68+ macrophage recruitment and PD-L1 expression in HCC tissues. High-throughput sequencing analysis identified miR-23a-3p as one of the most abundant microRNAs in exosomes derived from tunicamycin (TM)-treated HCC cells (Exo-TMs). miR-23a-3p levels in HCC tissues negatively correlated with overall survival. Treatment with Exo-TMs up-regulated the expression of PD-L1 in macrophages in vitro and in vivo. Bioinformatics analysis suggests that miR-23a-3p regulates PD-L1 expression through the phosphatase and tensin homolog (PTEN)-phosphatidylinositol 3-kinase-protein kinase B (AKT) pathway. This notion was confirmed by in vitro transfection and coculture experiments, which revealed that miR-23a-3p inhibited PTEN expression and subsequently elevated phosphorylated AKT and PD-L1 expression in macrophages. Finally, coculture of T cells with Exo-TM-stimulated macrophages decreased CD8+ T-cell ratio and interleukin-2 production but increased T-cell apoptosis in vitro. Conclusion: ER-stressed HCC cells release exosomes to up-regulate PD-L1 expression in macrophages, which subsequently inhibits T-cell function through an exosome miR-23a-PTEN-AKT pathway. Our findings provide insight into the mechanism how tumor cells escape from antitumor immunity.

FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer.

BACKGROUND: This study investigated the role of fibrinogen-like protein 1 (FGL1) in regulating gefitinib resistance of PC9/GR non-small cell lung cancer (NSCLC). METHODS: The effect of different concentrations of gefitinib on cell proliferation were evaluated using the CCK-8 assay. FGL1 expression in the normal human bronchial epithelial cell line Beas-2B, as well as four lung tumor cell lines, H1975, A549, PC9, and PC9/GR, was investigated by using western blotting and qRT-PCR. FGL1 was knocked down using small interfering RNA to evaluate the effects of FGL1 on PC9 and PC9/GR. The correlation between FGL1 expression and gefitinib resistance was determined in vitro via CCK-8 and colony formation assays, and flow cytometry and in vivo via flow cytometry and immunohistochemistry. RESULTS: FGL1 expression was significantly upregulated in non-small cell lung cancer cells with EGFR mutation and higher in the gefitinib-resistant NSCLC cell line PC9/GR than in the gefitinib-sensitive NSCLC cell line PC9. Further, FGL1 expression in PC9 and PC9/GR cells increased in response to gefitinib treatment in a dose-dependent manner. Knockdown of FGL1 suppressed cell viability, reduced the gefitinib IC50 value, and enhanced apoptosis in PC9 and PC9/GR cells upon gefitinib treatment. Mouse xenograft experiments showed that FGL1 knockdown in PC9/GR tumor cells enhanced the inhibitory and apoptosis-inducing actions of gefitinib. The potential mechanism of gefitinib in inducing apoptosis of PC9/GR cells involves inhibition of PARP1 and caspase 3 expression via suppression of FGL1. CONCLUSIONS: FGL1 confers gefitinib resistance in the NSCLC cell line PC9/GR by regulating the PARP1/caspase 3 pathway. Hence, FGL1 is a potential therapeutic target to improve the treatment response of NSCLC patients with acquired resistance to gefitinib.

Exploring the reaction mechanism of ethanol synthesis from acetic acid over a Ni2In(100) surface.

A low-cost and high-efficiency nickel-indium bimetallic catalyst is designed to improve the activity of acetic acid hydrogenation to ethanol, which can make full use of the overproduced acetic acid. In this work, density functional theory (DFT) calculations are carried out to explore the mechanism of ethanol synthesis from acetic acid on the Ni2In(100) surface and tailor the catalyst to acquire enhanced properties. The results show that the most feasible pathway is CH3COOH → CH3CO → CH3CHO → CH3CHOH → CH3CH2OH, and the rate-determining step is the hydrogenation of CH3CHOH* to CH3CH2OH, with an activation barrier of 1.20 eV and an endothermic energy of 0.15 eV. Compared with the Cu2In(100) surface, the Ni2In(100) surface converts the reaction pathway to the acetyl species direction, which shows great advantages for the following CH3CHO* formation. Furthermore, the effects of indium doping in the nickel catalyst on the side reaction is also discussed by comparing with the monometallic Ni(111) surface. The addition of indium turns out to cause a significant inhibition on the C-C bond breaking and is beneficial for promoting the acetic acid hydrogenation to ethanol. Electronic analysis proves that the role of In is to donate electrons, which can increase the electron density of Ni and enhance the catalytic activity.

A sensitive LC-MS/MS method to determine ginkgolide B in human plasma and urine: application in a pharmacokinetics and excretion study of healthy Chinese subjects.

1. Ginkgolide B (GB), the most active of the ginkgolides, has been developed as a new drug for the treatment of vascular insufficiency; however, the pharmacokinetics of GB remain unclear. Here, we investigated the pharmacokinetics and urine excretion properties of GB in healthy Chinese subjects administered single- and multiple-dose injectable GB based on a new LC-MS/MS method.2. GB pharmacokinetics were found to be dose-dependent from 20 to 60 mg. GB reached a steady state by day 6 with once-daily dosing at 40 mg. Systemic exposure to GB, as characterised by AUC0-∞, indicated accumulation following repeated once-daily dosing for seven consecutive days. The mean urinary cumulative excretion rate of GB in response to 20, 40, and 60 mg GB was 41.9 ± 18.5%, 32.9 ± 12.2%, and 43.9 ± 8.5%, respectively.3. Dose-proportional pharmacokinetics of GB were observed after intravenous administration in healthy subjects. A gradual reduction in the volume of distribution and slight change in mean resistance time led us to conjecture the limited accumulation of GB based on distribution equilibrium in vivo.4. This comprehensive study of the clinical pharmacokinetics of GB will provide useful information for its application and further development.

The synergistic effects of Cu clusters and In2O3 on ethanol synthesis from acetic acid hydrogenation.

The development of high efficiency catalysts for acetic acid hydrogenation to ethanol could ameliorate the petroleum crisis and acetic acid overproduction. Cu and In2O3 catalysts both show catalytic activity for acetic acid hydrogenation. However, monometallic Cu catalysts are less active in the dissociative adsorption of acetic acid through C-O bond breaking, while the H2 adsorption and dissociation ability of In2O3 is weak. In this work, Cu4/In2O3 is designed to enhance the dissociation of both acetic acid and H2. The detailed mechanism of acetic acid hydrogenation to ethanol on Cu4/In2O3 is explored using periodic density functional theory (DFT). The results show that the H2 adsorption and dissociation are enhanced by the Cu cluster, while the H atom spillover from Cu to In2O3 is favorable on the Cu4/In2O3(110) surface. Additionally, a synergistic effect exists between the Cu cluster and In2O3 surface: H2 adsorbs on the Cu cluster and the dissociated H atoms react with acetic acid activated by the In2O3 oxygen vacancy. Finally, compared with a Cu2In(100) surface, the Cu4/In2O3(110) surface possesses higher catalytic activity owing to the reduced energy barriers of acetic acid dissociation and hydrogenation of the intermediates (CH3COO*, CH3CHO*, and CH3CH2O*). The Cu4/In2O3 catalyst proposed in this work can provide promising guidance for related catalyst design.

Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 16 (SNHG16) Predicts Poor Prognosis and Sorafenib Resistance in Hepatocellular Carcinoma.

BACKGROUND Long noncoding RNAs (lncRNAs) play important roles in cancer development and therapeutic resistance. However, the role of small nucleolar RNA host gene 16 (SNHG16) in the development of hepatocellular carcinoma (HCC) remains largely unknown. MATERIAL AND METHODS In situ hybridization (ISH) staining was performed to detect the expression level of SNHG16 in HCC tissues and adjacent non-cancerous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the level of SNHG16 in HCC samples, adjacent non-cancerous tissues and HCC cell lines. Transwell assay was performed to investigate the migration and invasion ability of HCC cells. Cell viability assays were performed to determine the ability of proliferation and sorafenib resistance of HCC cells. RESULTS We found that SNHG16 was upregulated in HCC tissues and cell lines and that it was negatively correlated with survival time in HCC patients. Univariate and multivariate analyses revealed that SNHG16 was a significant and independent predictor for the overall survival of HCC patients. Furthermore, downregulation of SNHG16 inhibited proliferation, migration, invasion, and sorafenib resistance in hepatocellular carcinoma cell lines. CONCLUSIONS Our findings revealed that lncRNA SNHG16 could be used as an oncogene to predict the outcome of hepatocellular carcinoma.

Effect of surface oxygen vacancy sites on ethanol synthesis from acetic acid hydrogenation on a defective In2O3(110) surface.

Developing a new type of low-cost and high-efficiency non-noble metal catalyst is beneficial for industrially massive synthesis of alcohols from carboxylic acids which can be obtained from renewable biomass. In this work, the effect of active oxygen vacancies on ethanol synthesis from acetic acid hydrogenation over defective In2O3(110) surfaces has been studied using periodic density functional theory (DFT) calculations. The relative stabilities of six surface oxygen vacancies from Ov1 to Ov6 on the In2O3(110) surface were compared. D1 and D4 surfaces with respective Ov1 and Ov4 oxygen vacancies were chosen to map out the reaction paths from acetic acid to ethanol. A reaction cycle mechanism between the perfect and defective states of the In2O3 surface was found to catalyze the formation of ethanol from acetic acid hydrogenation. By H2 reduction the oxygen vacancies on the In2O3 surface play key roles in promoting CH3COO* hydrogenation and C-O bond breaking in acetic acid hydrogenation. The acetic acid, in turn, benefits the creation of oxygen vacancies, while the C-O bond breaking of acetic acid refills the oxygen vacancy and, thereby, sustains the catalytic cycle. The In2O3 based catalysts were shown to be advantageous over traditional noble metal catalysts in this paper by theoretical analysis.

Insights into the mechanism of ethanol synthesis and ethyl acetate inhibition from acetic acid hydrogenation over Cu2In(100): a DFT study.

Developing low-cost and high-efficiency non-noble metal catalysts is beneficial for industrially massive synthesis of ethanol from acetic acid, which can be obtained from renewable biomass. Understanding the detailed mechanism of the reaction from a molecular level provides insights that can be used to tailor catalysts to improve their performance. In this study, alternative mechanisms for ethanol synthesis from acetic acid hydrogenation over Cu2In(100) have been investigated using periodic density functional theory (DFT) calculations. The pathway of CH3COOH → CH3COO → CH3CHOO → CH3CHO → CH3CH2O → CH3CH2OH was found to be most favorable. The high activation barriers for CH3COO hydrogenation to CH3CHOO (1.33 eV) and CH3CH2O hydrogenation to CH3CH2OH (1.04 eV) indicate that these two steps are the rate-limiting steps. In addition, the results also show that there are probably two more active intermediate species of CH3CO and CH3CH(OH)O besides CH3COO. Furthermore, the synergy and the role of copper and indium in the Cu-In bimetallic catalyst were discussed. The adsorption strength of copper will be improved by indium. Indium, however, has high chemical inertness in Cu2In. They evenly divided the surface into small reaction areas which could significantly inhibit ethyl acetate formation through the hindrance effect.

GTMNet: a vision transformer with guided transmission map for single remote sensing image dehazing.

Existing dehazing algorithms are not effective for remote sensing images (RSIs) with dense haze, and dehazed results are prone to over-enhancement, color distortion, and artifacts. To tackle these problems, we propose a model GTMNet based on convolutional neural networks (CNNs) and vision transformers (ViTs), combined with dark channel prior (DCP) to achieve good performance. Specifically, a spatial feature transform (SFT) layer is first used to smoothly introduce the guided transmission map (GTM) into the model, improving the ability of the network to estimate haze thickness. A strengthen-operate-subtract (SOS) boosted module is then added to refine the local features of the restored image. The framework of GTMNet is determined by adjusting the input of the SOS boosted module and the position of the SFT layer. On SateHaze1k dataset, we compare GTMNet with several classical dehazing algorithms. The results show that on sub-datasets of Moderate Fog and Thick Fog, the PSNR and SSIM of GTMNet-B are comparable to that of the state-of-the-art model Dehazeformer-L, with only 0.1 times of parameter quantity. In addition, our method is intuitively effective in improving the clarity and the details of dehazed images, which proves the usefulness and significance of using the prior GTM and the SOS boosted module in a single RSI dehazing.

Effect of Post-Welding Aging Treatment on the Microstructure and High-Temperature Properties of Inertia Friction Welded GH4065A Joint.

In this study, post-welding aging treatments were applied to a novel Ni-based superalloy GH4065A inertia friction welding (IFW) joint to improve its high-temperature properties. The effect of aging treatment on the microstructure and creep resistance of the IFW joint was systematically investigated. The results indicated that the original γ' precipitates in the weld zone almost completely dissolved during the welding process, and fine tertiary γ' precipitated during the subsequent cooling process. Aging treatment did not significantly change the characteristics of grain structures and primary γ' in the IFW joint. After aging, the size of tertiary γ' in the weld zone and secondary γ' in the base material increased, but their morphology and volume fraction did not change evidently. After 760 °C, 5 h aging treatment, the tertiary γ' in the weld zone of the joint grew from 12.4 nm to 17.6 nm. Correspondingly, the creep rupture time of the joint at 650 °C and 950 MPa increased from 7.51 h to 147.28 h, which is about 19.61 times higher than that of the as-welded joint. The creep rupture was more likely to occur in the base material instead of the weld zone for the IFW joint. This revealed that the creep resistance of the weld zone was significantly improved after aging due to the growth of tertiary γ'. However, increasing the aging temperature or extending the aging time promoted the growth of secondary γ' in the base material, and meanwhile, M23C6 carbides tended to continuously precipitate at the grain boundaries of the base material. It might decrease the creep resistance of the base material.

Nanoparticles alleviate non-alcoholic steatohepatitis via ER stress sensor-mediated intestinal barrier damage and gut dysbiosis.

Introduction: The gut microbiota plays an important role in the development of non-alcoholic steatohepatitis (NASH), but the underlying mechanism is unclear. It has been found that the transcription factor XBP1s plays an important role in regulating inflammation and lipid metabolism and maintaining the integrity of intestinal barrier. However, whether XBP1s modulates the development of NASH by regulating the integrity of the intestinal barrier and altering the composition of the gut microbiota remains unknown. Methods: Mice fed with a fat-, fructose-, cholesterol-rich (FFC) diet for 24 weeks successfully established the NASH model, as demonstrated by significant hepatic steatosis, inflammation, hepatocyte injury and fibrosis. The profile of gut microbiota dynamically changed with the different stages of NAFLD via 16S rDNA sequencing the feces from mice fed with FFC diet for 0, 12, or 24 weeks or NASH mice treated with siRNA-loaded folic acid-modified TPGS (hereafter named FT@XBP1). Results: NASH mice had significantly higher abundance of Firmicutes, Blautia and Bacteroides, and lower abundance of Bifidobacterium and GCA-900066575. FT@XBP1 supplementation had a significantly attenuated effect on FFC diet-induced weight gain, hepatic fat accumulation, dyslipidemia, inflammatory cytokines, ER stress and fibrosis. In particularly, FT@XBP1 modulates the composition of the intestinal flora; for example, NASH mice demonstrated higher abundance of Blautia and Bacteroides, and lower abundance of Actinobacteriota, Muribaculaceae and Bifidobacterium, which were partially restored by FT@XBP1 treatment. Mechanistically, FT@XBP1 increased the expression of ZO-1 in the intestine and had the potential to restore intestinal barrier integrity and improve antimicrobial defense to alleviate enterogenic endotoxemia and activation of inflammatory signaling pathways. Discussion: Regulation of the key transcription factor XBP1s can partially restore the intestinal microbiota structure, maintain the integrity of intestinal mucosal barrier, and prevent the progression of NASH, providing new evidence for treating NASH.

High quality monocular depth estimation with parallel decoder.

Monocular depth estimation aims to recover the depth information in three-dimensional (3D) space from a single image efficiently, but it is an ill-posed problem. Recently, Transformer-based architectures have achieved excellent accuracy in monocular depth estimation. However, due to the characteristics of Transformer, the model parameters are huge and the inference speed is slow. In traditional convolutional neural network-based architectures, many encoder-decoders perform serial fusion of the multi-scale features of each stage of the encoder and then output predictions. However, in these approaches it may be difficult to recover the spatial information lost by the encoder during pooling and convolution. To enhance this serial structure, we propose a structure from the decoder perspective, which first predicts global and local depth information in parallel and then fuses them. Results show that this structure is an effective improvement over traditional methods and has accuracy comparable with that of state-of-the-art methods in both indoor and outdoor scenes, but with fewer parameters and computations. Moreover, results of ablation studies verify the effectiveness of the proposed decoder.

Cost-Effectiveness Analysis of Dapagliflozin Plus Standard Treatment for Patients With Type 2 Diabetes and High Risk of Cardiovascular Disease in China.

Purpose: To evaluate the long-term cost-effectiveness of dapagliflozin, in addition to standard treatment, for the treatment of adult patients with type 2 diabetes (T2DM) at high cardiovascular risk from the Chinese healthcare system perspective. Methods: A decision-analytic Markov model with one-year cycles was developed to evaluate the health and economic outcomes in patients with T2DM and high risk of cardiovascular disease (CVD) treated with standard treatment and dapagliflozin plus standard treatment for 30 years. Clinical data, cost, and utility data were extracted from databases or published literature. Quality-adjusted life-years (QALYs), costs (€/¥ 2021) as well as incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic and probabilistic sensitivity analyses were performed to assess the uncertainty in the results. Results: Compared with standard treatment, dapagliflozin plus standard treatment was predicted to result in an additional 0.25 QALYs (12.26 QALYs vs. 12.01 QALYs) at an incremental cost of €4,435.81 (¥33,875.83) per patient. The ICER for dapagliflozin plus standard treatment vs. standard treatment was €17,742.07 (¥135,494.41) per QALY gained, which was considered cost-effective in China compared to three times the GDP per capita in 2021 (€31,809.77/¥242,928). The deterministic and probabilistic sensitivity analyses showed the base-case results to be robust. Conclusions: The study suggests that, from the perspective of the Chinese health system, dapagliflozin plus standard treatment is a cost-effective option for patients with T2DM at high cardiovascular risk. These findings may help clinicians make the best treatment decisions for patients with T2DM at high cardiovascular risk.

Increased Serum Trimethylamine N-Oxide Level in Type 2 Diabetic Patients with Mild Cognitive Impairment.

Purpose: Trimethylamine N-oxide (TMAO) is a metabolite of phosphatidylcholine in red meat and other diets, which is associated with cardiovascular and other diseases. The aim of this study is to evaluate the associations of serum TMAO with mild cognitive impairment (MCI) in the Chinese type 2 diabetes mellitus (T2DM) population. Materials and Methods: A total of 253 hospitalized T2DM patients and 150 healthy controls were included in this cross-sectional study. Montreal Cognitive Assessment (MoCA) assessed the cognition function, and the 253 T2DM patients were divided into 74 subjects with MCI and 179 with non-MCI. Demographic data and biochemical test results were evaluated. Serum TMAO level was measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results: A higher serum TMAO level was observed in T2DM patients compared with the healthy controls (P < 0.001). Among all T2DM patients, the MCI group (n = 74) showed higher serum TMAO levels than the non-MCI group. Spearman correlation test showed that TMAO levels were significantly positively correlated with age (r = 0.147, P = 0.019), body mass index (BMI) (r = 0.153, P = 0.015), diabetes duration (r = 0.160, P = 0.011), HbA1c (r = 0.138, P = 0.029), triglyceride (TG) (r = 0.138, P = 0.029), creatinine (r = 0.184, p = 0.003), hs-CRP (r = 0.243, P < 0.001), and were negatively correlated with HDL-C (r = -0.144, P = 0.022), BDNF (r = -0.165, p = 0.009), and MoCA (r = -0.386, P < 0.001) score (all P < 0.05). Multivariable Logistic regression identified high serum TMAO level as a significant independent factor of MCI in the T2DM patients (OR = 1.404, 95% CI = 1.255-1.571; P < 0.001). Conclusion: Our study showed that T2DM patients with MCI have elevated serum TMAO levels.

ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation.

Endoplasmic reticulum (ER) stress is widely involved in the drug resistance of hepatocellular carcinoma (HCC), but the mechanism of ER stress-induced drug resistance involves multiple signaling pathways that cannot be fully explained. Exploring genes associated with ER stress could yield a novel therapeutic target for ER stress-induced drug resistance. By analyzing RNA-sequencing, ATAC-sequencing, and Chip-sequencing data of Tunicamycin (TM)-treated or untreated HCC cells, we found that Rho guanine nucleotide exchange factor 2 (ARHGEF2) is upregulated in HCC cells with ER stress. ARHGEF2 plays an active role in tumor malignant progression. Notwithstanding, no research has been done on the link between ER stress and ARHGEF2. The function of ARHGEF2 as a novel downstream effector of ER stress in the angiogenesis and treatment resistance of HCC was revealed in this work. ARHGEF2 overexpression was linked to malignant development and a poor prognosis in HCC. ER stress stimulates the expression of ARHGEF2 through upregulation of ZNF263. Elevated ARHGEF2 accelerates HCC angiogenesis via the EDN1 pathway, enhances HCC cell proliferation and tumor growth both in vitro and in vivo, and contributes to ER stress-related treatment resistance. HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.

Surface Treatment of Zn-Mn-Mg Alloys by Micro-Arc Oxidation in Silicate-Based Solutions with Different NaF Concentrations.

Newly developed Zn-Mn-Mg alloys can be invoked as biomedical materials because of their excellent mechanical properties. However, the corrosion behavior of Zn-Mn-Mg alloys was still lacking in research. It had grown to be a hot research topic to improve the corrosion behavior of Zn alloys by surface treatment to meet the application of degradable Zn alloys in biomedical applications. Micro arc oxidation (MAO) is a simple and effective method to improve the corrosion behavior of the alloy. MAO coatings were successfully prepared on the surface of Zn-Mn-Mg alloys by MAO in silicate-based solutions with different NaF concentrations. The microstructure and phase composition of MAO coatings prepared on Zn-Mn-Mg alloys with different NaF concentrations in the electrolyte was examined by a scanning electron microscope and X-ray diffraction. The results showed that the MAO coatings are porous and mainly composed of ZnO. With the increasing NaF concentration in the electrolyte, the average thickness increases. The distribution of the micro/nanopores was uniform, and the pore size ranged from the submicron scale to several micrometers after MAO treatment in the electrolyte containing different concentrations of NaF. Potential dynamic polarization curves and electrochemical impedance spectroscopy were employed to assess the corrosion behavior of MAO coatings in Hank's solution. The highest corrosion rate can be achieved after MAO treatment, with an electrolyte concentration of 1.5 g/L NaF in Hank's solution. These results indicated that MAO coating can accelerate the corrosion resistance of a Zn-Mn-Mg alloy.

Endoplasmic reticulum stress promotes sorafenib resistance via miR-188-5p/hnRNPA2B1-mediated upregulation of PKM2 in hepatocellular carcinoma.

Emerging evidence has shown that endoplasmic reticulum (ER) stress promotes sorafenib resistance in hepatocellular carcinoma (HCC). However, the underlying mechanisms are poorly understood. The purpose of this study was to explore the mechanism by which ER stress promotes sorafenib resistance in HCC. We found that pyruvate kinase isoform M2 (PKM2) was highly expressed in human HCC tissues and co-related with worse clinicopathologic features and overall survival. Activation of ER stress positively correlated with PKM2 expression both in HCC tissue samples and tunicamycin (TM)-induced HCC cell lines. PKM2 knockdown increased sorafenib-induced apoptosis and decreased the ability of colony formation, while upregulation of PKM2 reverses this phenomenon. Furthermore, high-throughput sequencing identified that activation of ER stress significantly downregulated the expression of miR-188-5p in HCC cells. According to bioinformatics analysis and dual-luciferase assays, we further confirmed that hnRNPA2B1 is the target gene of miR-188-5p. Downregulating the expression of hnRNPA2B1 with siRNA could decrease the expression of PKM2 and enhance sorafenib-induced apoptosis in HepG2 cells. Our study demonstrated that ER stress could promote sorafenib resistance through upregulating PKM2 via miR-188-5p/hnRNPA2B1. Therefore, targeting the miR-188-5p/hnRNPA2B1/PKM2 pathway and ER stress may prove instrumental in overcoming sorafenib resistance in HCC treatment.

Sp2 promotes invasion and metastasis of hepatocellular carcinoma by targeting TRIB3 protein.

OBJECTIVE: To explore the biological function and molecular mechanism of Sp2 in hepatocellular carcinoma (HCC). METHODS: Tissue microarray immunohistochemistry and western blot were used to study the expression of Sp2 in hepatocellular tissue and adjacent non-neoplastic tissues (ANT). In HCC cell lines, the role of Sp2 was determined by in vitro experiments such as CCK8, clone formation test, Transwell assay, wound-healing assay, and flow cytometry apoptotic analysis, and its possible mechanism was analyzed. RESULTS: Compared with ANT, Sp2 expression in HCC tissues was significantly up-regulated, which was strongly associated with stage of tumor and poor prognosis of patients. TCGA database were further confirmed these results. Besides, functional studies had shown that Sp2 knockdown not only leads to a decrease in cell proliferation and an increase in cell apoptosis but also inhibits the cells' abilities of migration and invasion. Sp2 silencing could inhibit the expression of TRIB3 protein and down-regulate the endoplasmic reticulum stress (ERS) level of HCC. CONCLUSION: Sp2 may play a part in promoting cancer by regulating TRIB3 protein, which may be a factor of prognostic and a potential new therapeutic target for HCC.