Novel Bifunctional Affibody Molecules with Specific Binding to Both EBV LMP1 and LMP2 for Targeted Therapy of Nasopharyngeal Carcinoma.

Antibodies are considered highly specific therapeutic agents in cancer medicines, and numerous formats have been developed. Among them, bispecific antibodies (BsAbs) have gained a lot of attention as a next-generation strategy for cancer therapy. However, poor tumor penetration is a major challenge because of their large size and thus contributes to suboptimal responses within cancer cells. On the other hand, affibody molecules are a new class of engineered affinity proteins and have achieved several promising results with their applications in molecular imaging diagnostics and targeted tumor therapy. In this study, an alternative format for bispecific molecules was constructed and investigated, named ZLMP110-277 and ZLMP277-110, that targets Epstein-Barr virus latent membrane protein 1 (LMP1) and latent membrane protein 2 (LMP2). Surface plasmon resonance (SPR), indirect immunofluorescence assay, co-immunoprecipitation, and near-infrared (NIR) imaging clearly demonstrated that ZLMP110-277 and ZLMP277-110 have good binding affinity and specificity for both LMP1 and LMP2 in vitro and in vivo. Moreover, ZLMP110-277 and ZLMP277-110, especially ZLMP277-110, significantly reduced the cell viability of C666-1 and CNE-2Z as compared to their monospecific counterparts. ZLMP110-277 and ZLMP277-110 could inhibit phosphorylation of proteins modulated by the MEK/ERK/p90RSK signaling pathway, ultimately leading to suppression of oncogene nuclear translocations. Furthermore, ZLMP110-277 and ZLMP277-110 showed significant antitumor efficacy in nasopharyngeal carcinoma-bearing nude mice. Overall, our results demonstrated that ZLMP110-277 and ZLMP277-110, especially ZLMP277-110, are promising novel prognostic indicators for molecular imaging and targeted tumor therapy of EBV-associated nasopharyngeal carcinoma.

One-Step Gas-Solid-Phase Diffusion-Induced Elemental Reaction for Bandgap-Tunable CuaAgm1Bim2In/CuI Thin Film Solar Cells.

Lead-free inorganic copper-silver-bismuth-halide materials have attracted more and more attention due to their environmental friendliness, high element abundance, and low cost. Here, we developed a strategy of one-step gas-solid-phase diffusion-induced reaction to fabricate a series of bandgap-tunable CuaAgm1Bim2In/CuI bilayer films due to the atomic diffusion effect for the first time. By designing and regulating the sputtered Cu/Ag/Bi metal film thickness, the bandgap of CuaAgm1Bim2In could be reduced from 2.06 to 1.78 eV. Solar cells with the structure of FTO/TiO2/CuaAgm1Bim2In/CuI/carbon were constructed, yielding a champion power conversion efficiency of 2.76%, which is the highest reported for this class of materials owing to the bandgap reduction and the peculiar bilayer structure. The current work provides a practical path for developing the next generation of efficient, stable, and environmentally friendly photovoltaic materials.

MITF Downregulation Induces Death in Human Mast Cell Leukemia Cells and Impairs IgE-Dependent Degranulation.

Activating mutations in KIT (CD117) have been associated with several diseases, including gastrointestinal stromal tumors and mastocytosis. Rapidly progressing pathologies or drug resistance highlight the need for alternative treatment strategies. Previously, we reported that the adaptor molecule SH3 binding protein 2 (SH3BP2 or 3BP2) regulates KIT expression at the transcriptional level and microphthalmia-associated transcription factor (MITF) expression at the post-transcriptional level in human mast cells and gastrointestinal stromal tumor (GIST) cell lines. Lately, we have found that the SH3BP2 pathway regulates MITF through miR-1246 and miR-5100 in GIST. In this study, miR-1246 and miR-5100 were validated by qPCR in the SH3BP2-silenced human mast cell leukemia cell line (HMC-1). MiRNA overexpression reduces MITF and MITF-dependent target expression in HMC-1. The same pattern was observed after MITF silencing. In addition, MITF inhibitor ML329 treatment reduces MITF expression and affects the viability and cell cycle progression in HMC-1. We also examine whether MITF downregulation affected IgE-dependent mast cell degranulation. MiRNA overexpression, MITF silencing, and ML329 treatment reduced IgE-dependent degranulation in LAD2- and CD34+-derived mast cells. These findings suggest MITF may be a potential therapeutic target for allergic reactions and deregulated KIT mast-cell-mediated disorders.

HOTAIR modulates hepatocellular carcinoma progression by activating FUT8/core-fucosylated Hsp90/MUC1/STAT3 feedback loop via JAK1/STAT3 cascade.

BACKGROUND: Glycosylation exhibits crucial effect on hepatocellular carcinoma (HCC) progression. Long non-coding RNAs (lncRNAs) are involved in multilevel regulation of gene transcription during tumor development. The purpose of this study is to clarify the potential mechanism that HOTAIR modulates hepatocellular carcinoma progression by activating FUT8/core-fucosylated Hsp90/MUC1/STAT3 feedback loop via JAK1/STAT3 cascade. METHODS: qRT-PCR was used to show the differential expression of genes. Functional experiments were used to measure the malignancy of HCC cells. ChIP and co-IP assays showed the directly interaction of the key molecules. Xenografts was conducted to show the in vivo effects. RESULTS: Upregulation of FUT8 showed closely correlation with HCC progression. Core-fucosylation of Hsp90 stabilized MUC1 binding to the downstream p-STAT3, which involved in the activation of JAK1/STAT3 cascade. STAT3 was identified as the regulator of FUT8 and MUC1 transcription, while FUT8 and MUC1 impacted STAT3 level both in nuclear and cytoplasm. HOTAIR recruited P300 to efficiently bind with STAT3. The transcript complex co-modulated the transcrption of FUT8 and MUC1. Moreover, highly HOTAIR expression also exhibited closely correlation with HCC progression. CONCLUSIONS: FUT8 triggered core-fucosylated-Hsp90/MUC1/P300-HOTAIR-STAT3 cascade via JAK1/STAT3 pathway, which exhibited as positive feedback loop during HCC progression.

The Traditional Uses, Phytochemistry, Pharmacokinetics, Pharmacology, Toxicity, and Applications of Corydalis saxicola Bunting: A Review.

Background: Corydalis saxicola Bunting (CSB) is a perennial herb belonging to genus Corydalis (Papaveraceae), called "Yan-huang-lian" in the Chinese folk. Traditionally, it is used to treat acute conjunctivitis, corneal pannus, acute abdominal pain, hemorrhoidal bleeding, haematochezia, swelling, hepatitis, cirrhosis and liver cancer based on traditional Chinese medicine (TCM) concepts. Purpose: This review aims to summarize and analyze the pharmacokinetics, pharmacological and toxicological properties of CSB and its extracts; to highlight the relevance of modern pharmacology to traditional pharmacology; also to assess its therapeutic potential. Methods: CSB related literatures were searched and screened from databases including PubMed, Web of Science and CNKI. The selected literatures provided reliable source identification evidences. Results: In traditional medicine concepts, CSB has the effects of clearing away heat and detoxification, eliminating dampness, relieving pain, and stopping bleeding. Its modern pharmacology includes hepatoprotective, anticancer, anti-inflammatory, analgesic, antibacterial, anti-oxidative effects. Further, some pharmacological effects support its traditional uses. The CSB total alkaloids (CSBTA) are the main constituents isolated from this plant, and they exert the major of the pharmacological effects. Toxicological studies have shown that the toxicity of CSBTA is mild and reversible in rodents and beagle dogs. Conclusion: Although the present study summarizes the botany, phytochemistry, pharmacokinetics, pharmacology, toxicity, and applications of this plant, it is still necessary to systemically evaluate the chemistry, safety and parameters related to drug metabolism of the extracts or compounds from this plant before or in clinical trials in the future. Meanwhile, cancers and inflammatory-related diseases may be new research directions of this ethnomedicine.

Automated detection of lung cancer-caused metastasis by classifying scintigraphic images using convolutional neural network with residual connection and hybrid attention mechanism.

BACKGROUND: Whole-body bone scan is the widely used tool for surveying bone metastases caused by various primary solid tumors including lung cancer. Scintigraphic images are characterized by low specificity, bringing a significant challenge to manual analysis of images by nuclear medicine physicians. Convolutional neural network can be used to develop automated classification of images by automatically extracting hierarchal features and classifying high-level features into classes. RESULTS: Using convolutional neural network, a multi-class classification model has been developed to detect skeletal metastasis caused by lung cancer using clinical whole-body scintigraphic images. The proposed method consisted of image aggregation, hierarchal feature extraction, and high-level feature classification. Experimental evaluations on a set of clinical scintigraphic images have shown that the proposed multi-class classification network is workable for automated detection of lung cancer-caused metastasis, with achieving average scores of 0.7782, 0.7799, 0.7823, 0.7764, and 0.8364 for accuracy, precision, recall, F-1 score, and AUC value, respectively. CONCLUSIONS: The proposed multi-class classification model can not only predict whether an image contains lung cancer-caused metastasis, but also differentiate between subclasses of lung cancer (i.e., adenocarcinoma and non-adenocarcinoma). On the context of two-class (i.e., the metastatic and non-metastatic) classification, the proposed model obtained a higher score of 0.8310 for accuracy metric.

LncRNA LEF1-AS1/LEF1/FUT8 Axis Mediates Colorectal Cancer Progression by Regulating α1, 6-Fucosylationvia Wnt/ß-Catenin Pathway.

BACKGROUND: Fucosylation alteration is involved in several steps of human cancer pathogenesis. Dysregulated long non-coding RNA (lncRNA) often leads to malignancy in colorectal cancer (CRC). METHODS: Differential levels of LEF1-AS1, LEF1 and FUT8 are analyzed by qRT-PCR and western blot. Chip, RIP, EMSA and luciferase reporter assay confirm the direct interaction among LEF1-AS1, MLL1, H3K4me3, LEF1 and FUT8. Functionally, CRC cell proliferation, migration and invasion are analyzed by CCK8 assay, colony formation assay, transwell assay and flow cytometry. The xenografts nude mice models, lung metastasis and liver metastasis are established to determine the effect of LEF1-AS1/LEF1/FUT8 axis on CRC progression in vivo. RESULTS: Here, we identify that LEF1-AS1 and LEF1 are higher in CRC tissues than that in adjacent tissues, as well as upregulated in CRC cell lines than that in normal colorectal cells. Altered levels of LEF1-AS1 modulate LEF1 expression, while altered LEF1 could not regulate LEF1-AS1. LEF1-AS1 recruits MLL1 to the promoter region of LEF1, induces H3K4me3 methylation modification and mediates LEF1 transcription. Furthermore, α1-6 fucosyltransferase FUT8 is overexpressed in CRC tissues and positively correlated to LEF1. FUT8 is a direct target of transcription factor LEF1, which regulates FUT8 level. Altered FUT8 also regulates the core fucosylation of CRC cells, and LEF1-AS1 mediates FUT8 level through activation of Wnt/ß-catenin/LEF1 pathway, thereby resulting in ß-catenin nuclear translocation. In addition, LEF1-AS1 mediates the proliferation, migration and invasion of CRC cells in vitro. LEF1-AS1 silence hinders the tumorigenesis, liver and lung metastasis of SW620 cells in vivo, while overexpressed FUT8 abolishes the suppressive impact of LEF1-AS1 repression on the biological behavior of SW620 cells. CONCLUSION: Our studies uncovered a novel mechanism for constitutive LEF1-AS1/LEF1/FUT8 axis in CRC progression by regulating α1, 6-fucosylation via Wnt/ß-catenin pathway, and consequently, as a potential therapeutic target in CRC.

Automated detection of skeletal metastasis of lung cancer with bone scans using convolutional nuclear network.

A bone scan is widely used for surveying bone metastases caused by various solid tumors. Scintigraphic images are characterized by inferior spatial resolution, bringing a significant challenge to manual analysis of images by nuclear medicine physicians. We present in this work a new framework for automatically classifying scintigraphic images collected from patients clinically diagnosed with lung cancer. The framework consists of data preparation and image classification. In the data preparation stage, data augmentation is used to enlarge the dataset, followed by image fusion and thoracic region extraction. In the image classification stage, we use a self-defined convolutional neural network consisting of feature extraction, feature aggregation, and feature classification sub-networks. The developed multi-class classification network can not only predict whether a bone scan image contains bone metastasis but also tell which subcategory of lung cancer that a bone metastasis metastasized from is present in the image. Experimental evaluations on a set of clinical bone scan images have shown that the proposed multi-class classification network is workable for automated classification of metastatic images, with achieving average scores of 0.7392, 0.7592, 0.7242, and 0.7292 for accuracy, precision, recall, and F-1 score, respectively.

EBV LMP1-C terminal binding affibody molecule downregulates MEK/ERK/p90RSK pathway and inhibits the proliferation of nasopharyngeal carcinoma cells in mouse tumor xenograft models.

Nasopharyngeal carcinoma (NPC), is an Epstein-Barr virus (EBV) associated malignancy most common in Southern China and Southeast Asia. In southern China, it is one of the major causes of cancer-related death. Despite improvement in radiotherapy and chemotherapy techniques, locoregional recurrence and distant metastasis remains the major causes for failure of treatment in NPC patients. Therefore, finding new specific drug targets for treatment interventions are urgently needed. Here, we report three potential ZLMP1-C affibody molecules (ZLMP1-C15, ZLMP1-C114 and ZLMP1-C277) that showed specific binding interactions for recombinant and native EBV LMP1 as determined by epitope mapping, co-localization and co-immunoprecipitation assays. The ZLMP1-C affibody molecules exhibited high antitumor effects on EBV-positive NPC cell lines and displayed minimal cytotoxicity towards EBV-negative NPC cell line. Moreover, ZLMP1-C277 showed higher antitumor efficacy than ZLMP1-C15 and ZLMP1-C114 affibody molecules. The ability of ZLMP1-C277 decrease the phosphorylation levels of up-stream activator phospho-Raf-1(Ser338), phospho-MEK1/2(Ser217/Ser221), phospho-ERK1/2(Thr202/Thr204), thereby leading to downstream suppression of phospho-p90RSK(Ser380) and transcription factor c-Fos. Importantly, tumor growth was reduced in tumor-bearing mice treated with ZLMP1-C277 and caused no apparent toxicity. Taken together, our findings provide evidence that ZLMP1-C277 as a promising therapeutic agent in EBV-associated NPC.

Novel EBV LMP1 C-terminal domain binding affibody molecules as potential agents for in vivo molecular imaging diagnosis of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) latent infection and is common in Southern China and Southeast Asia. The viral latent membrane proteins LMP1 and LMP2 are persistently expressed in NPC tissues; the cytoplasmic domain of LMP1 (LMP1 C-terminal) and LMP2A (LMP2A N-terminal) proteins is essential for maintenance of latency and can alter host cell signaling to facilitate tumor growth and progression. Thus, targeting LMP1 or LMP2 oncoprotein has been an increasing interest for diagnosis and targeted therapy of NPC. Affibody molecules, a new class of small-affinity engineered scaffold proteins, have demonstrated high potential for therapeutics, diagnostics, and biotechnological applications. More recently, radiolabelled HER2-specific affibody molecules have demonstrated to be useful in imaging of HER2 expressing tumor. In this study, we report three novel EBV LMP1 C-terminal (EBV LMP1-C) domain affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) were selected by biopanning from a random-peptide displayed phage library and used for molecular imaging in tumor-bearing nude mice. Surface plasmon resonance (SPR), indirect immunofluorescence, and immunohistochemistry (IHC) clearly showed that all three selected affibody molecules have high affinity and specificity in binding to EBV LMP1 protein. Moreover, in vivo tumor imaging revealed that Dylight-755-labeled affibody molecules accumulated rapidly in tumor site after injection (1 h) and then were continuously maintained for 24 h in EBV-positive NPC xenograft mice model. In conclusion, our findings highlight the potential use of ZLMP1-C affibody molecules as tumor-specific molecular imaging agents of EBV-associated NPC.Key points• We screened three novel affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) targeting EBV LMP1-C terminal domain• ZLMP1-C recognize the recombinant and native LMP1-C with high affinity and specificity• ZLMP1-C can be used for molecular imaging.

Phytochemicals: Targeting Mitophagy to Treat Metabolic Disorders.

Metabolic disorders include metabolic syndrome, obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular diseases. Due to unhealthy lifestyles such as high-calorie diet, sedentary and physical inactivity, the prevalence of metabolic disorders poses a huge challenge to global human health, which is the leading cause of global human death. Mitochondrion is the major site of adenosine triphosphate synthesis, fatty acid ß-oxidation and ROS production. Accumulating evidence suggests that mitochondrial dysfunction-related oxidative stress and inflammation is involved in the development of metabolic disorders. Mitophagy, a catabolic process, selectively degrades damaged or superfluous mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial function. It is considered to be one of the major mechanisms responsible for mitochondrial quality control. Growing evidence shows that mitophagy can prevent and treat metabolic disorders through suppressing mitochondrial dysfunction-induced oxidative stress and inflammation. In the past decade, in order to expand the range of pharmaceutical options, more and more phytochemicals have been proven to have therapeutic effects on metabolic disorders. Many of these phytochemicals have been proved to activate mitophagy to ameliorate metabolic disorders. Given the ongoing epidemic of metabolic disorders, it is of great significance to explore the contribution and underlying mechanisms of mitophagy in metabolic disorders, and to understand the effects and molecular mechanisms of phytochemicals on the treatment of metabolic disorders. Here, we investigate the mechanism of mitochondrial dysfunction in metabolic disorders and discuss the potential of targeting mitophagy with phytochemicals for the treatment of metabolic disorders, with a view to providing a direction for finding phytochemicals that target mitophagy to prevent or treat metabolic disorders.

Exosome-derived SNHG16 sponging miR-4500 activates HUVEC angiogenesis by targeting GALNT1 via PI3K/Akt/mTOR pathway in hepatocellular carcinoma.

Accumulating evidence suggests cancer-derived exosomes play an important role in promoting angiogenesis. Long noncoding RNA small nucleolar RNA host gene 16 (SNHG16) is known to aggravate hepatocellular carcinoma (HCC) progression. However, the function of exosomal SNHG16 in HCC angiogenesis remains unclear. In this study, the expression of SNHG16 was significantly upregulated in HCC tissues and cell lines. The proliferative, migratory, and angiogenic abilities of HUVECs were enhanced after exposure to exosomes derived from HCC cells by transmitting SNHG16. In addition, SNHG16 was validated to promote the biological function of HUVECs directly. Exosomal SNHG16 increased GALNT1 expression to promote angiogenesis via sponging miR-4500. SNHG16/miR-4500/GALNT1 axis played an important role in exosome-mediated angiogenesis and tumor growth in vitro and vivo. Furthermore, SNHG16 activated PI3K/Akt/mTOR pathway via competing endogenous miR-4500 and GALNT1. Meanwhile, the expression of plasma exosomal SNHG16 upregulated in the plasma of HCC patients. These data elucidated the essential role of exosomal SNHG16 in communication between HCC cells and endothelial cells. Exosomal SNHG16 could be utilized as a therapeutic target for anti-angiogenesis in HCC progression.

Novel Affibody Molecules Targeting the HPV16 E6 Oncoprotein Inhibited the Proliferation of Cervical Cancer Cells.

Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key viral oncogenes expressed constitutively, inducing carcinogenesis. Thus, E6/E7 have been proposed as ideal targets for HPV-related cancer diagnosis and treatment. In this study, three novel HPV16 E6-binding affibody molecules (ZHPV16E61115, ZHPV16E61171, and ZHPV16E61235) were isolated from a randomized phage display library and cloned for bacterial production. These affibody molecules showed high binding affinity and specificity for recombinant and native HPV16 E6 as determined by surface plasmon resonance, indirect immunofluorescence, immunohistochemistry, and near-infrared small animal optical imaging in vitro and in vivo. Moreover, by binding to HPV16 E6 protein, ZHPV16E61235 blocked E6-mediated p53 degradation, which increased the expression of some key p53 target genes, including BAX, PUMA and p21, and thereby selectively reduced the viability and proliferation of HPV16-positive cells. Importantly, ZHPV16E61235 was applied in combination with HPV16 E7-binding affibody ZHPV16E7384 to simultaneously target the HPV16 E6/E7 oncoproteins, and this combination inhibited cell proliferation more potently than either modality alone. Mechanistic studies revealed that the synergistic antiproliferative activity depends primarily on the induction of cell apoptosis and senescence but not cell cycle arrest. Our findings provide strong evidence that three novel HPV16 E6-binding affibody molecules could form a novel basis for the development of rational strategies for molecular imaging and targeted therapy in HPV16-positive preneoplastic and neoplastic lesions.

The lncRNA MEG3 mediates renal cell cancer progression by regulating ST3Gal1 transcription and EGFR sialylation.

Long noncoding RNAs (lncRNAs) have emerged as important regulators of cancer progression. Abnormal sialylation leads to renal cell carcinoma (RCC) malignancy. However, the mechanism by which the lncRNA maternally expressed gene 3 (MEG3) mediates RCC progression by regulating ST3Gal1 transcription and EGFR sialylation is still unrevealed. Here, we found that the expression of MEG3 was higher in adjacent tissues than in RCC tissues, as well as downregulated in RCC cell lines compared to expression in normal renal cells. The proliferation, migration and invasion of RCC cells transfected with MEG3 was decreased, whereas knockdown of MEG3 had the opposite effect. The proliferative and metastatic abilities of RCC cells in vivo were concordant with their behavior in vitroST3Gal1 expression was dysregulated in RCC and was positively correlated with MEG3 By applying bioinformatics, c-Jun (also known as JUN) was identified as a transcription factor predicted to bind the promoter of ST3Gal1, and altered MEG3 levels resulted in changes to c-Jun expression. Furthermore, ST3Gal1 modulated EGFR sialylation to inhibit EGFR phosphorylation, which affected activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway. Taken together, our findings provide a novel mechanism to elucidate the role of the MEG3-ST3Gal1-EGFR axis in RCC progression.

LncRNA MEG3 contributes to drug resistance in acute myeloid leukemia by positively regulating ALG9 through sponging miR-155.

INTRODUCTION: The development of drug resistance is the main obstacle for successful treatment in acute myeloid leukemia (AML). Noncoding RNAs have been implicated in biological function in AML drug resistance. Aberrant protein glycosylation is associated with AML progression. The aim of the study was to explore the potential regulatory mechanism of lncRNA MEG3/miR-155/ALG9 axis in drug resistance of AML. METHODS: QRT-PCR and Western blot were used for comparison analyses of ALG9, MEG3, and miR-155 levels. CCK-8 and colony formation assays were determined for drug sensitivity and proliferative capability of AML cells. Luciferase reporter assay was used to confirm the targets of miR-155. RESULTS: The mannosyltransferase ALG9 and MEG3 was downregulated in peripheral blood mononuclear cells (PBMCs) of M5/multidrug resistance (MDR) AML patients and adriamycin (ADR)-resistant AML cell lines, which determined a positive correlation in AML patients. Low expression of ALG9 and MEG3 predicted poor prognosis of AML patients. The altered level of ALG9 was found corresponding to the drug-resistant phenotype and sphere formation of AML cells. MiR-155 was overexpressed in M5/MDR patients and ADR-resistant AML cells, as well as inversely correlated to ALG9 expression. MEG3 was a direct target of miR-155 and could sponge miR-155 in AML cells. MEG3 interacted with miR-155 to regulate ALG9 expression, which reversed the effects of ALG9 regulation on proliferation and drug resistance in AML cells. CONCLUSION: MEG3 sponged miR-155 by competing endogenous RNA (ceRNA) mechanism, which further modulated ALG9 expression and AML procession, providing a novel therapeutic target for AML chemoresistance.

Plasma Transforming Ni(OH)2 Nanosheets into Porous Nickel Nitride Sheets for Alkaline Hydrogen Evolution.

Nickel nitride (Ni3N) is a superior hydrogen evolution reaction (HER) catalyst where the nitrogen source is usually ammonia and the reaction temperature is high during the synthesis process. Herein, we employed an innovative method to obtain three-dimensional porous nickel nitride nanosheets on Ni foam (Ni3N/NF) by transforming Ni(OH)2 nanosheets in N2-H2 glow discharge plasma. The obtained Ni3N/NF displays a high HER activity with a small overpotential of 44 mV and a low Tafel slope of 46 mV dec-1, which is competitive to a Pt/C catalyst. Both the test data and simulation results prove that active ions and radicals in plasma play essential roles in achieving the facile nitridation, as well as building a nanostructured morphology over the Ni3N/NF surface. The unique synthesis method opens new avenues for metal nitrides of HER catalysts and beyond.

Plasma enabled non-thermal phosphorization for nickel phosphide hydrogen evolution catalysts.

While nickel phosphide is a highly attractive catalyst for the hydrogen evolution reaction, its preparation requires either high temperature or the use of highly toxic PH3 directly or indirectly. Herein, we demonstrate that H2 plasma activated red phosphorus enables the synthesis of self-supported Ni2P nanosheet (Ni2P/NF) arrays on commercial nickel foam from a NiO/NF precursor at only 250 °C. Highly reactive atomic H in the plasma induces dissociation of the P4 molecules, yielding an acid stable electrode with excellent hydrogen evolution activity and good mechanical strength.

The positive effect of chick embryo and nutrient mixture on bone marrow- derived mesenchymal stem cells from aging rats.

The aging of many mammalian tissues is associated with loss of functional adult stem cells, especially bone marrow-derived mesenchymal stem cells (BMSCs). This study was aimed to analyze the biological effect of chick embryo (CE) and nutrient mixture (NM) on the BMSCs of aging rats. The aging rat model was established to be induced by D-galactose (500 mg/kg/d) for 90 days. Meanwhile, aging rats were fed with CE and NM in different dose manner by intragastric administration. At the end of the experimental period, serum was collected from rats and used for BMSCs culture. Flow cytometric analysis was used to investigate the BMSCs surface markers. Alizarin Red and oil red O staining were performed to evaluate the multi-lineage differentiation of BMSCs. The results showed that CE plus NM increased the telomere length of BMSCs and promoted BMSCs proliferation. Moreover, CE plus NM administration promoted BMSCs differentiation into osteoblasts and suppressed differentiation into adipocytes. High-throughput sequencing analysis revealed that there were 326 genes were up-regulated and 59 genes were down-regulated in BMSCs of aging rats treated with CE plus NM. In conclusion, CE plus NM supplement had potential to delay aging through the recovery of BMSCs senescence and could be used as a safe effective approach for nutritional therapy of anti-aging.

Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD+ reduction.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.

Correlation between liver cancer pain and the HIF-1 and VEGF expression levels.

A possible correlation between liver cancer pain and the hypoxia-inducible factor (HIF)-1 and vascular endothelial growth factor (VEGF) expression levels was examined. From January, 2015 to January, 2016, 30 patients suffering from liver cancer with pain, 30 patients with liver cancer without pain and 30 hepatitis patients with pain were enrolled in the study. Pain level was evaluated by visual analogue scale (VAS), the expression levels of HIF-1 and VEGF mRNA were determined by RT-PCR and the expression levels of HIF-1 and VEGF proteins were examined by ELISA. Before intervention, the VAS in the hepatitis group was significantly higher than that of the liver cancer pain group. However, after intervention the VAS in the two groups was reduced. HIF-1 and VEGF mRNA expression levels in the liver cancer pain group were significantly higher than those in the liver cancer group before and after intervention. The expression levels of HIF-1 and VEGF mRNA in the hepatitis group were the lowest. The expression levels of HIF-1 and VEGF mRNA in the liver cancer pain group considerably increased after intervention. The expression levels of HIF-1 and VEGF mRNA in the other two groups showed no changes before or after intervention. Before and after the intervention, VAS in the liver cancer pain group was positively correlated to the expression levels of HIF-1 and VEGF. Thus, pain occurrence and the pain level in liver cancer patients were correlated with the expression levels of HIF-1 and VEGF. As the regular three-step medicine analgesic ladder is ineffective in these cases, verification of HIF-1 and VEGF expression levels may be considered the new target for pain release.