Application of biomacromolecule-based passive penetration enhancement technique in superficial tumor therapy: A review.

Transdermal drug delivery (TDD) has shown great promise in superficial tumor therapy due to its noninvasive and avoidance of the first-pass effect. Especially, passive penetration enhancement technique (PPET) provides the technical basis for TDD by temporarily altering the skin surface structure without requiring external energy. Biomacromolecules and their derived nanocarriers offer a wide range of options for PPET development, with outstanding biocompatibility and biodegradability. Furthermore, the abundant functional groups on biomacromolecule surfaces can be modified to yield functional materials capable of targeting specific sites and responding to stimuli. This enables precise drug delivery to the tumor site and controlled drug release, with the potential to replace traditional drug delivery methods and make PPET-related personalized medicine a reality. This review focuses on the mechanism of biomacromolecules and nanocarriers with skin, and the impact of nanocarriers' surface properties of nanocarriers on PPET efficiency. The applications of biomacromolecule-based PPET in superficial tumor therapy are also summarized. In addition, the advantages and limitations are discussed, and their future trends are projected based on the existing work of biomacromolecule-based PPET.

Effectiveness and safety of glucagon-like peptide 1 receptor agonists in patients with type 2 diabetes: evidence from a retrospective real-world study.

Introduction: Global phase III clinical trials have shown superior hypoglycemic efficacy to insulin and other oral hypoglycemic agents. However, there is a scarcity of real-world data comparing different glucagon-like peptide 1 receptor agonist (GLP-1RA) directly. This study aimed to assess the safety and effectiveness of various GLP-1RA in treating type 2 diabetes mellitus (T2DM) in a real-world clinical setting and identify predictive factors for favorable treatment outcomes. Methods: This was a retrospective, single-center, real-world study. The changes in HbA1c, fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and the percentage of participants who achieved HbA1c of <7%, 7%-8%, and ≥ 8% after GLP-1RA treatment was analyzed. The clinical factors that affect the effectiveness of GLP-1RA were analyzed. Results: At baseline, the 249 participants had a mean baseline HbA1c of 8.7 ± 1.1%. After at least three months of follow-up, the change in HbA1c was -0.89 ± 1.3% from baseline. Dulaglutide exerted a more significant hypoglycemic effect than immediate-release exenatide. The percentage of participants who achieved HbA1c<7% was substantial, from 6.0% at baseline to 28.9%. Average body weight decreased by 2.02 ± 3.8 kg compared to baseline. After GLP-1RA treatment, the reduction in SBP was 2.4 ± 7.1 mmHg from baseline. A shorter duration of diabetes and a higher baseline HbA1c level were more likely to achieve a good response in blood glucose reduction. Conclusions: This study provided real-world evidence showing that GLP-1RA significantly improved HbA1c, body weight, and SBP. The results can inform the decision-making about GLP-1RA treatment in daily clinical practice.

Optimization strategy of community planning for environmental health and public health in smart city under multi-objectives.

As population density increases, environmental hygiene and public health become increasingly severe. As the space where residents stay for the longest time and have the most profound impact on their physical and mental health, the quality of the environment in urban communities largely determines the degree to which residents engage in physical activity, bear the risk of pollution exposure, and obtain healthy food. Therefore, in order to ensure the physical and mental health of residents, this study proposes community planning guided by environmental hygiene and public health, and establishes an environmental health assessment system for this purpose. This system evaluates the community environment from four aspects: land use, service facilities, site convenience, and environmental quality. Established the diversity, density, road network connectivity and facilities accessibility nine criteria, as well as the land function of mix, plot ratio, food environment, network ring α and connected ß index, pavement risk level, green configuration and neighborhood material environment disorder degree of 27 indicators of community built environmental evaluation index system. The data is collected through field survey, questionnaire distribution, resident interview and data mapping, and the established evaluation index system is used to evaluate the construction environment of the community. The experimental research data included population data, CAD plan, land use data, street data, POI point data, building data and bus station data, etc. 273 questionnaires were distributed, 264 were recovered, 8 invalid questionnaires were removed, and 256 valid questionnaires were obtained. These experiments confirm that land use, service facilities, site convenience, and environmental quality have a significant impact on the built environment of communities, with impact weights of 0.513, 0.227, 0.135, and 0.125, respectively. The above weights are calculated based on the index judgment matrix and the eigenvectors. The scores of land use, service facilities, site convenience, and environmental quality for the study subjects were 3.44, 1.46, 0.94, and 0.51, respectively, among them, the land use score is less than 3.85, the 1 service facility score is less than 1.71, the site convenience score is less than 1.01, and the environmental quality score is less than 0.94; indicating that the community has serious problems such as single land use types, pollution exposure, and difficulty in obtaining healthy food. Therefore, community planning and transformation based on land use, service facilities, venue convenience, and environmental quality can effectively improve the physical and mental health of residents. In the specific community transformation plan, artificial intelligence and data-driven methods can be used to optimize the land use plan, service facility configuration, site convenience transformation and environmental quality improvement, so as to formulate the optimal community transformation plan and improve the comfort and happiness of community residents. In the future, on the basis of the existing research, the selection of community types will be further enriched and the research cases will be expanded. And through the in-depth practical study of the case, the constructed evaluation index system is optimized and improved to make it more scientific. At the same time, as urban renewal and design have entered the era of stock planning, based on the more perfect evaluation index system, more specific and detailed system discussion of the built communities with public health problems, in order to provide more detailed services for the construction of a better and healthy living environment in the future.

High performance production process development and scale-up of an anti-TSLP nanobody.

Nanobodies (Nbs) represent a class of single-domain antibodies with great potential application value across diverse biotechnology fields, including therapy and diagnostics. Thymic Stromal Lymphopoietin (TSLP) is an epithelial cell-derived cytokine, playing a crucial role in the regulation of type 2 immune responses at barrier surfaces such as skin and the respiratory/gastrointestinal tract. In this study, a method for the expression and purification of anti-TSLP nanobody (Nb3341) was established at 7 L scale and subsequently scaled up to 100 L scale. Key parameters, including induction temperature, methanol feed and induction pH were identified as key factors by Plackett-Burman design (PBD) and were optimized in 7 L bioreactor, yielding optimal values of 24 °C, 8.5 mL/L/h and 6.5, respectively. Furthermore, Diamond Mix-A and Diamond MMC were demonstrated to be the optimal capture and polishing resins. The expression and purification process of Nb3341 at 100L scale resulted in 22.97 g/L titer, 98.7% SEC-HPLC purity, 95.7% AEX-HPLC purity, 4 ppm of HCP content and 1 pg/mg of HCD residue. The parameters of the scaling-up process were consistent with the results of the optimized process, further demonstrating the feasibility and stability of this method. This study provides a highly promising and competitive approach for transitioning from laboratory-scale to commercial production-scale of nanobodies.

NAT10 mediated ac4C acetylation driven m6A modification via involvement of YTHDC1-LDHA/PFKM regulates glycolysis and promotes osteosarcoma.

The dynamic changes of RNA N6-methyladenosine (m6A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m6A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m6A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m6A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m6A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m6A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m6A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m6A-LDHA/PFKM in osteosarcoma. Video Abstract.

Vitamin C enhances the sensitivity of osteosarcoma to arsenic trioxide via inhibiting aerobic glycolysis.

Osteosarcoma (OS) is a common malignant tumor disease in the department of orthopedics, which is prone to the age of adolescents and children under 20 years old. Arsenic trioxide (ATO), an ancient poison, has been reported to play a critical role in a variety of tumor treatments, including OS. However, due to certain poisonous side effects such as cardiotoxicity and hepatotoxicity, clinical application of ATO has been greatly limited. Here we report that low doses of ATO (1 µM) observably reduced the half-effective inhibitory concentration (IC50) of vitamin C on OS cells. Compared with the treatment alone, the synthetic application of vitamin C (VitC, 800 µM) and ATO (1 µM) significantly further inhibited the proliferation, migration, and invasion of OS cells and promoted cell apoptosis in vitro. Meanwhile, we observed that the combined application of VitC and ATO directly suppresses the aerobic glycolysis of OS cells with the decreased production of pyruvate, lactate, and ATP via inhibiting the expression of the critical glycolytic genes (PGK1, PGM1, and LDHA). Moreover, the combination of VitC (200 mg/kg) and ATO (1 mg/kg) with tail vein injection significantly delayed OS growth and migration of nude mice by inhibiting aerobic glycolysis of OS. Thus, our results demonstrate that VitC effectively increases the sensitivity of OS to low concentrations of ATO via inhibiting aerobic glycolysis to alleviate the toxic side effects of high doses of arsenic trioxide, suggesting that synthetic application of VitC and ATO is a promising approach for the clinical treatment of human OS.

Quality evaluation of ground improvement by deep cement mixing piles via ground-penetrating radar.

Deep cement mixing piles are a key technology for treating settlement distress of soft soil subgrade. However, it is very challenging to accurately evaluate the quality of pile construction due to the limitations of pile material, large number of piles and small pile spacing. Here, we propose the idea of transforming defect detection of piles into quality evaluation of ground improvement. Geological models of pile group reinforced subgrade are constructed and their ground-penetrating radar response characteristics are revealed. We have also developed ground-penetrating radar attribute analysis technology and established ground-penetrating radar technical system for evaluating the quality of ground improvement. We further prove that the ground-penetrating radar results integrating single-channel waveform, multi-channel section and attributes can effectively detect the defects and stratum structure after ground improvement. Our research results provide a rapid, efficient and economic technical solution for the quality evaluation of ground improvement in soft soil subgrade reinforcement engineering.

Uptake and Biotransformation of Spirotetramat and Pymetrozine in Lettuce (Lactuca sativa L. var. ramosa Hort.).

Here, we investigated the uptake, transport, and subcellular distribution of the pesticides pymetrozine and spirotetramat, and spirotetramat metabolites B-enol, B-glu, B-mono, and B-keto, under hydroponic conditions. Spirotetramat and pymetrozine exhibited high bioconcentrations in lettuce roots, with both having root concentration factor (RCF) values >1 after exposure for 24 h. The translocation of pymetrozine from roots to shoots was higher than that of spirotetramat. Pymetrozine is absorbed in roots mainly via the symplastic pathway and is primarily stored in the soluble fraction of lettuce root and shoot cells. The cell wall and soluble fractions were the major enrichment sites of spirotetramat and its metabolites in root cells. Spirotetramat and B-enol were mainly enriched in the soluble fractions of lettuce shoot cells, whereas B-keto and B-glu accumulated in cell walls and organelles, respectively. Both symplastic and apoplastic pathways were involved in spirotetramat absorption. Pymetrozine and spirotetramat uptake by lettuce roots was passive, with no aquaporin-mediated dissimilation or diffusion. The findings of this study enhance our understanding of the transfer of pymetrozine, spirotetramat, and spirotetramat metabolites from the environment to lettuce, and their subsequent bioaccumulation. This study describes a novel approach for the efficient management of lettuce pest control using spirotetramat and pymetrozine. At the same time, it is of great significance to evaluate the food safety and environmental risks of spirotetramat and its metabolites.

Multisubcellular organelle-targeting nanoparticle for synergistic chemotherapy and photodynamic/photothermal tumor therapy.

Background: The subcellular organelle-targeting strategy has attracted wide attention for a variety of reasons, including strong specificity, high accuracy, low dose administration and few side effects. It is an important and challenging task to explore the multisubcellular organelle-targeting strategy to achieve effective tumor treatment. Materials & methods: Using bovine serum albumin as a nanoreactor, BSA/Cu/NQ/IR780/DOX nanoparticles (NPs) were constructed via drug-induced protein self-assembly. Folic acid was then coupled to the surface of NPs to prepare folate receptor-targeted FA-BSA/Cu/NQ/IR780/DOX NPs. Results & conclusion: The FA-BSA/Cu/NQ/IR780/DOX NPs exhibit multifunctional properties, including multisubcellular organelle-targeting, induction of response release in the tumor microenvironment, fluorescence imaging capabilities and potential for synergistic chemotherapy and photodynamic/photothermal tumor therapy.

The subcellular organelle-targeting strategy has attracted wide attention for a variety of reasons, including strong specificity, high accuracy, low dose administration and few side effects. Previous research has been mostly restricted to one or two subcellular organelle therapies. Despite promising results, the impact of these studies is limited by the hostile conditions of lysosomes, drug efflux facilitated by P-glycoprotein (P-gp), and the expression of antiapoptotic factors, all of which undermine the effectiveness of the treatments. Therefore, it is an important and challenging task to explore the multisubcellular organelle-targeting strategy to achieve effective tumor treatment. Herein, a versatile nanoparticle was designed and constructed to target multiple subcellular organelles, respond to stimuli in the tumor microenvironment, enable fluorescence imaging and facilitate synergistic chemotherapy and photodynamic/photothermal tumor therapy.

Advances in Natural Polymer-Based Transdermal Drug Delivery Systems for Tumor Therapy.

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.

Research progress of physical transdermal enhancement techniques in tumor therapy.

The advancement and popularity of transdermal drug delivery (TDD) based on the physical transdermal enhancement technique (PTET) has opened a new paradigm for local tumor treatment. The drug can be directly delivered to the tumor site through the skin, thus avoiding the toxic side effects caused by the first-pass effect and achieving high patient compliance. Further development of PTETs has provided many options for antitumor drugs and laid the foundation for future applications of wearable closed-loop targeting drug delivery systems. In this highlight, the different types of PTETs and related mechanisms, and applications of PTET-related tumor detection and therapy are highlighted. According to their type and characteristics, PTETs are categorized as follows: (1) iontophoresis, (2) electroporation, (3) ultrasound, (4) thermal ablation, and (5) microneedles. PTET-related applications in the local treatment of tumors are categorized as follows: (1) melanoma, (2) breast tumor, (3) squamous cell carcinoma, (4) cervical tumor, and (5) others. The challenges and future prospects of existing PTETs are also discussed. This highlight will provide guidance for the design of PTET-based wearable closed-loop targeting drug delivery systems and personalized therapy for tumors.

Uptake, Translocation, and Subcellular Distribution of Oxathiapiprolin and Famoxadone in Tomato Plants (Lycopersicon esculentum Miller).

The uptake, translocation, and subcellular distribution of oxathiapiprolin and famoxadone in tomato plants were investigated using hydroponic experiments. Oxathiapiprolin and famoxadone mainly accumulated in the tomato roots with limited translocation capacity from the roots to the upper part. The root absorption and inhibitor results noted the dominance of the apoplastic and symplastic pathways in the oxathiapiprolin and famoxadone uptake by the tomato roots, respectively. Furthermore, the uptake process for the two fungicides followed passive and aquaporin-dependent transport. Insoluble cell components (cell organelles and walls) were the dominant storage compartments for oxathiapiprolin and famoxadone. In the protoplast, oxathiapiprolin in the soluble fraction had a higher proportion than that of famoxadone. Finally, the uptake and distribution of the two fungicides by the tomato plants was accurately predicted using a partition-limited model. Thus, this study provides an in-depth understanding of the transfer of oxathiapiprolin and famoxadone from the environment to tomato plants.

Leading for Innovation: Self-Efficacy and Work Engagement as Sequential Mediation Relating Ethical Leadership and Innovative Work Behavior.

This research investigated the link between ethical leadership and innovative work behavior by examining the role of self-efficacy as a mediating factor and the sequential mediation of self-efficacy and work engagement. Using a survey approach, data were collected from 441 bank employees in the southern region of Thailand. The findings of the structural equation modeling (SEM) analysis revealed an association between ethical leadership and innovative work behavior and self-efficacy, respectively. Work engagement and innovative work behavior were both linked to self-efficacy. Work engagement was associated with innovative work behavior. According to the mediation analysis results, self-efficacy appeared to mediate the relationship between ethical leadership and innovative work behavior. Ultimately, it was shown that self-efficacy and work engagement were sequentially mediated by ethical leadership and innovative work behavior. This research provides insight into the understanding of the connection between ethical leadership and innovative work behavior. The key contributions of this research are the exploration-mediating function of self-efficacy and the sequential mediation roles of self-efficacy and work engagement.

Natural Occurrence of Mycotoxins in Maize in North China.

Mycotoxins seriously threaten the quality of maize seriously around the world. A total of 426 samples of maize kernel from northeast and northwest China were analyzed in this study. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was performed to analyze the mycotoxin contamination of maize samples. The results showed that it was contaminated by mycotoxins in maize. The average contamination levels of fumonisins, deoxynivalenol, aflatoxins, zearalenone, ochratoxin A, T-2 and HT-2 were 937, 431, 22, 27, 2 and 12 µg/kg, respectively. Concentration of mycotoxins in some samples exceeded their limit, but most were still at safe levels. The contamination level of FBs and DON were most significative. The proportion of mycotoxins exceeding the maximum limit standard was in the following order: 8.0%, 8.0%, 7.0%, 1.6%, 1.4% and 0.0%. The contamination of mycotoxins in maize varies from region to region.

Tracing sources of oilfield wastewater based on excitation-emission matrix fluorescence spectroscopy coupled with chemical pattern recognition techniques.

In order to prevent the illegal discharge of oilfield wastewater, this work proposed excitation-emission matrix fluorescence (EEMF) spectroscopy coupled with two kinds of chemical pattern recognition methods for tracing the sources of oilfield wastewater. The first pattern recognition method was built from the relative concentrations extracted by alternating trilinear decomposition (ATLD) based on partial least squares-discriminant analysis (PLS-DA) algorithm, and the other one was modeled based on strictly multi-way partial least squares-discriminant analysis (N-PLS-DA). Both methods showed good discrimination abilities for oilfield wastewater samples from three different sources. The total recognition rates of the training and prediction sets are 100%, the values of sensitivity and selectivity are 1. This study showed that EEMF spectroscopy combined with chemical pattern recognition techniques could be used as a potential tool for tracing the sources of oilfield wastewater.

Uptake, translocation, and degradation of spirotetramat in tomato (Lycopersicon esculentum Miller): Impact of the mixed-application with pymetrozine.

In this study, we investigated the impact of the mixed-application with pymetrozine on the behavior (i.e., uptake, translocation, and degradation) of spirotetramat in tomatoes under laboratory conditions. Results showed that pymetrozine promoted the uptake of spirotetramat from the nutrition solution after root application. The root concentration factor was 0.290 and 1.566 after spirotetramat single application and mixed-application with pymetrozine, respectively. It had little effect on the degradation of spirotetramat, with the metabolites of M-keto, M-enol, and M-glu in tomato issue (root, stems, and leaves). After foliar treatments, pymetrozine accelerated the translocation of spirotetramat from leaves to stems, with the translocation factor of 0.145 and 0.402 after spirotetramat single application and mixtures with pymetrozine, respectively. Pymetrozine also promoted the degradation of spirotetramat to M-kto and M-enol in leaves. Besides, a partition-limited model was used to describe the distribution processes of spirotetramat in the tomato-water system after root application. It showed that pymetrozine accelerated the distribution balance of spirotetramat in the whole system. Our result indicates that the interaction among pesticides should be considered when studied for the uptake, translocation, and degradation of pesticides in crops.

The Chinese automobile industry's research and development capability and innovative performance.

The Report of China's Automobile Industry Development 2016 points out that China's automobile industry faces increasingly fierce competition from global peers, and domestic automobile manufacturers shall continuously improve independent innovation and industry innovative performance. Automobile manufacturers' participation in distributed innovation and their research & development (R&D) capability play a key role in the growth of innovative performances of China's automobile industry. With development of China's automobile industry as the background, this study presents a theoretical framework of correlation of distributed innovation embedment, R&D capability and innovative performances of China's automobile industry from the microscopic perspective of single industry. Several hypotheses were proposed and then verified by empirical method. Specifically, 117 effective questionnaires were collected through non-probability sampling and analyzed quantitatively, followed by hypothesis test. The results clarify the working principles of the three dimensions of distributed innovation embedment influencing innovative performances of China's automobile industry and improvement of R&D capability of enterprises by distributed innovation. This study provides references to improvements of innovative performances of China's automobile industry.

Peroxiredomin-4 ameliorates lipotoxicity-induced oxidative stress and apoptosis in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), one severe complication in the diabetes, leads to high mortality in the diabetic patients. However, the understanding of molecular mechanisms underlying DCM is far from completion. Herein, we investigated the disease-related differences in the proteomes of DCM based on db/db mice and verified the protective roles of peroxiredoxin-4 (Prdx4) in H9c2 cardiomyocytes treated by palmitic acid (PA). Fasting blood glucose (FBG) and cardiac function was detected in the 6-month-old control and diabetic mice. The hearts were then collected and analyzed by a coupled label-free and mass spectrometry approach. In vivo investigation indicated that body weight and FBG of db/db mice markedly increased, and diabetic heart exhibited obvious cardiac hypertrophy and lipid droplet accumulation, and cardiac dysfunction as is indicated by the increases of left ventricle posterior wall thickness in systole (LVPWd) and diastole (LVPWs), and reduction of fractional shortening (FS). We used proteomic analysis and then detected a grand total of 2636 proteins. 175 differentially expressed proteins (DEPs) were markedly detected in the diabetic heart. Thereinto, Prdx4 was markedly down-regulated in the diabetic heart. In vitro experiments revealed that 250 µM PA significantly inhibited viability of H9c2 cell. PA induced much accumulation of lipid droplet in cardiomyocytes and resulted in an increase of mRNA expressions of lipogenic genes (FASN and SCD1) and cardiac hypertrophic genes. Additionally, protein level of Prdx4 evidently reduced in the PA-treated H9c2 cell. It was further found that shRNA-mediated Prdx4 knockdown exacerbated PA-induced oxidative stress and cardiomyocyte apoptosis, whereas overexpressing Prdx4 in the H9c2 cells noteworthily limited PA-induced ROS generation and cardiomyocytes apoptosis. These data collectively reveal the essential role of abnormal Prdx4 in pathological alteration of DCM, and provide potentially therapeutic target for the prevention of DCM.

METTL3 induces bone marrow mesenchymal stem cells osteogenic differentiation and migration through facilitating M1 macrophage differentiation.

Despite the crucial role of m6A methyltransferase METTL3 in multiple diseases onset and progression, there are still lacking hard evidence proving that METTL3 could affect macrophage polarization in the stage of bone repair. Here, we aimed to explore the potential involvement of METTL3 in bone repair through modulating macrophage polarization and decipher the underlying cellular/molecular mechanisms. Here we treated RAW 264.7 cells and BM-derived primary macrophages (BMDM) with lipopolysaccharide (LPS) to induce M1 differentiation. METTL3 expression was upregulated in pro-inflammatory macrophages (M1) as compared with macrophages (M0). And overexpression of METTL3 promoted the expression of IL-6 and iNOS secretion by M1 macrophage. In the coculture condition, M1 macrophages with forced expression of METTL3 significantly enhanced migration ability of BMSCs, and also remarkably facilitated osteogenesis ability of BMSCs; the opposite was true when expression of METTL3 was knockdown. In addition, the m6A-RIP microarray suggested that METTL3 silencing significantly reduce the m6A modification of DUSP14, HDAC5 and Nfam1. Furthermore, the findings showed that expression of HADC5 was downregulated in M1 macrophages with METTL3 knockdown, while the DUSP14 expression had slight change and Nfam1 expression was very low. In contrast, METTL3 overexpression promoted HDAC5 expression, indicating that HDAC5 is the critical target gene of METTL3. Under such a theme, we proposed that METTL3 overexpression might be a new approach of replacement therapy for the treatment of bone repair.

AB4 inhibits Notch signaling and promotes cancer cell apoptosis in liver cancer.

The etiology for liver cancer has been clearly defined. Unfortunately, therapeutic approaches for liver cancer are rather limited, and liver cancer is insensitive to chemotherapy and radiotherapy. Traditional Chinese medicine (TCM) has become a promising strategy for cancer treatment as TCM elicits broad spectrum anticancer activity. In the present study, we evaluated the anticancer efficacy of AB4, an extract from the medical herb Pulsatilla chinensis (Bunge) Regel, in liver cancer in vitro and in vivo. We found that AB4 readily dose­ and time­dependently inhibited liver cancer HepG2 and Huh­7 cell proliferation and colony formation. Western blot and flow cytometry analyses suggested that AB4 treatment induced liver cancer cell apoptosis. Moreover, these findings could be readily recaptured in vivo, in which the AB4 regimen resulted in tumor suppression and cancer cell apoptosis in xenograft tumor­bearing nude mice. Importantly, we noted that treatment with a Notch signaling inhibitor DAPT produced very similar anticancer efficacy in both HepG2 and Huh­7 cell lines, and administration of DAPT also efficiently suppressed HepG2 xenograft outgrowth. To this end, we anticipated that AB4 and DAPT may act on the same signaling pathway, probably through inhibition of the Notch pathway. Indeed, we found decreased expression of Notch1 protein, as well as downstream targets Hes1 and Hey1, after AB4 treatment. Immunohistochemistry analysis further confirmed the suppression of Notch signaling in HepG2 xenograft­bearing mice. Taken together, our study highlighted the anticancer efficacy of AB4 in liver cancer. We also provided preliminary data showing Notch as a therapeutic target of AB4. It would be interesting to investigate the anticancer efficacy of AB4 in other types of cancer with elevated Notch activity.