IGFBP1a is a nutrient deficient response factor that can inhibit fish reproduction through the hypothalamus-pituitary-ovary axis†.

Reproduction is a high energy consuming process, so long-term malnutrition can significantly inhibit gonadal development. However, little is known about the molecular mechanism by which fasting inhibits reproduction. Our present study found that fasting could dramatically induce insulin-like growth factor binding protein 1 (IGFBP1) expression in the liver, hypothalamus, pituitary and ovaries of grass carp. In addition, IGFBP1a in the hypothalamus-pituitary-gonad axis could inhibit the development of gonads. These results indicated that fasting may participate in the regulation of fish gonadal development through the mediation of IGFBP1a. Further studies found that IGFBP1a could markedly inhibit gonadotropin-releasing hormone 3 expressions in hypothalamus cells. At the pituitary level, IGFBP1a could significantly reduce the gonadotropin hormones (LH and FSH) expression by blocking the action of pituitary insulin-like growth factor 1. Interestingly, IGFBP1a could also directly inhibit the expression of lhr, fshr, and sex steroid hormone synthase genes (cyp11a, cyp17a, and cyp19a1) in the ovary. These results indicated that IGFBP1a should be a nutrient deficient response factor that could inhibit fish reproduction through the hypothalamus-pituitary-ovary axis.

Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.

After undergoing metabolic reprogramming, tumor cells consume additional glutamine to produce amino acids, nucleotides, fatty acids, and other substances to facilitate their unlimited proliferation. As such, the metabolism of glutamine is intricately linked to the survival and progression of cancer cells. Consequently, targeting the glutamine metabolism presents a promising strategy to inhibit growth of tumor cell and cancer development. This review describes glutamine uptake, metabolism, and transport in tumor cells and its pivotal role in biosynthesis of amino acids, fatty acids, nucleotides, and more. Furthermore, we have also summarized the impact of oncogenes like C-MYC, KRAS, HIF, and p53 on the regulation of glutamine metabolism and the mechanisms through which glutamine triggers mTORC1 activation. In addition, role of different anti-cancer agents in targeting glutamine metabolism has been described and their prospective applications are assessed.

Solution-processed bilayer InGaZnO/In2O3thin film transistors at low temperature by lightwave annealing.

At low temperatures about 230 °C, bilayer InGaZnO/In2O3thin film transistors (TFTs) were prepared by a solution process with lightwave annealing. The InGaZnO/In2O3bilayer TFTs with SiO2as dielectric layer show high electrical performances, such as a mobility of 7.63 cm2V-1s-1, a threshold voltage (Vth) of 3.8 V, and an on/off ratio higher than 107, which are superior to single-layer InGaZnO TFTs or In2O3TFTs. Moreover, bilayer InGaZnO/In2O3TFTs demonstrated a great bias stability enhancement due to the introduction of top InGaZnO film act as a passivation layer, which could prevent the interaction of ambient air with the bottom In2O3layer. By using high dielectric constant AlOxfilm, the InGaZnO/In2O3TFTs exhibit an improved mobility of 47.7 cm2V-1s-1. The excellent electrical performance of the solution-based InGaZnO/In2O3TFTs shows great application potential for low-cost flexible printed electronics.

Molecular mechanism of Xiaohuoluo wan for rheumatoid arthritis by integrating in vitro and in vivo chemomics and network pharmacology.

The cause of rheumatoid arthritis (RA) is unclear. Xiaohuoluo wan (XHLW) is a classical Chinese medicine that is particularly effective in the treatment of RA. Given the chemical composition of XHLW at the overall level has been little studied and the molecular mechanism for the treatment of RA is not clear, we searched for the potential active compounds of XHLW and explored their anti-inflammatory mechanism in the treatment of RA by flexibly integrating the high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS)-based in vitro and in vivo chemomics, network pharmacology, and other means. The results of the study identified that the active compounds of XHLW, such as alkaloids, nucleosides, and fatty acids, may play an anti-inflammatory role by regulating key targets such as IL-2, STAT1, JAK3, and MAPK8, inducing immune response through IL-17 signaling pathway, T-cell receptor, FoxO, tumor necrosis factor (TNF), and so forth, inhibiting the release of inflammatory factors and resisting oxidative stress and other pathways to treat RA. The results of this study provide referable data for the screening of active compounds and the exploration of molecular mechanisms of XHLW in the treatment of RA.

Extracellular vesicle-cell adhesion molecules in tumours: biofunctions and clinical applications.

Cell adhesion molecule (CAM) is an umbrella term for several families of molecules, including the cadherin family, integrin family, selectin family, immunoglobulin superfamily, and some currently unclassified adhesion molecules. Extracellular vesicles (EVs) are important information mediators in cell-to-cell communication. Recent evidence has confirmed that CAMs transported by EVs interact with recipient cells to influence EV distribution in vivo and regulate multiple cellular processes. This review focuses on the loading of CAMs onto EVs, the roles of CAMs in regulating EV distribution, and the known and possible mechanisms of these actions. Moreover, herein, we summarize the impacts of CAMs transported by EVs to the tumour microenvironment (TME) on the malignant behaviour of tumour cells (proliferation, metastasis, immune escape, and so on). In addition, from the standpoint of clinical applications, the significance and challenges of using of EV-CAMs in the diagnosis and therapy of tumours are discussed. Finally, considering recent advances in the understanding of EV-CAMs, we outline significant challenges in this field that require urgent attention to advance research and promote the clinical applications of EV-CAMs. Video Abstract.

Dietary sources, health benefits, and risks of caffeine.

Dietary intake of caffeine has significantly increased in recent years, and beneficial and harmful effects of caffeine have been extensively studied. This paper reviews antioxidant and anti-inflammatory activities of caffeine as well as its protective effects on cardiovascular diseases, obesity, diabetes mellitus, cancers, and neurodegenerative and liver diseases. In addition, we summarize the side effects of long-term or excessive caffeine consumption on sleep, migraine, intraocular pressure, pregnant women, children, and adolescents. The health benefits of caffeine depend on the amount of caffeine intake and the physical condition of consumers. Moderate intake of caffeine helps to prevent and modulate several diseases. However, the long-term or over-consumption of caffeine can lead to addiction, insomnia, migraine, and other side effects. In addition, children, adolescents, pregnant women, and people who are sensitive to caffeine should be recommended to restrict/reduce their intake to avoid potential adverse effects.

Crossover behavior in stress relaxations of poroelastic and viscoelastic dominant hydrogels.

The mechanical response and relaxation behavior of hydrogels are crucial to their diverse functions and applications. However, understanding how stress relaxation depends on the material properties of hydrogels and accurately modeling relaxation behavior at multiple time scales remains a challenge for soft matter mechanics and soft material design. While a crossover phenomenon in stress relaxation has been observed in hydrogels, living cells, and tissues, little is known about how the crossover behavior and characteristic crossover time depend on material properties. In this study, we conducted systematic atomic-force-microscopy (AFM) measurements of stress relaxation in agarose hydrogels with varying types, indentation depths, and concentrations. Our findings show that the stress relaxation of these hydrogels features a crossover from short-time poroelastic relaxation to long-time power-law viscoelastic relaxation at the micron scale. The crossover time for a poroelastic-dominant hydrogel is determined by the length scale of the contact and diffusion coefficient of the solvent inside the gel network. In contrast, for a viscoelastic-dominant hydrogel, the crossover time is closely related to the shortest relaxation time of the disordered network. We also compared the stress relaxation and crossover behavior of hydrogels with those of living cells and tissues. Our experimental results provide insights into the dependence of crossover time on poroelastic and viscoelastic properties and demonstrate that hydrogels can serve as model systems for studying a wide range of mechanical behaviors and emergent properties in biomaterials, living cells, and tissues.

Extraction of Polysaccharides from Root of Pseudostellaria heterophylla (Miq.) Pax. and the Effects of Ultrasound Treatment on Its Properties and Antioxidant and Immune Activities.

The hydrophilic polysaccharides (PS) were isolated and purified from the tuberous roots of Pseudostellaria heterophylla. The extraction process of PS from Pesudostellariae radix was optimized by single-factor experiments and orthogonal design. The extract was purified by DEAE cellulose column to obtain the pure polysaccharide PHP. Then PHP was treated with different intensities of sonication to study the effect of sonication on PHP's characteristics and its biological activity in vitro and in vivo. The results of this study revealed that ultrasound treatment did not significantly change the properties of PHP. Further, with the increase of ultrasound intensity, PHP enhanced the proliferation and phagocytosis of macrophage RAW264.7. Meanwhile, it could also significantly improve the body's antioxidant activity and immune function. The results of this study demonstrated that PHP has the potential as a food additive with enhanced antioxidant and immune functions, and its biological activities could be enhanced by sonication.

Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications.

Hypoxia is a remarkable trait of the tumor microenvironment (TME). When facing selective pressure, tumor cells show various adaptive characteristics, such as changes in the expression of cancer hallmarks (increased proliferation, suppressed apoptosis, immune evasion, and so on) and more frequent cell communication. Because of the adaptation of cancer cells to hypoxia, exploring the association between cell communication mediators and hypoxia has become increasingly important. Exosomes are important information carriers in cell-to-cell communication. Abundant evidence has proven that hypoxia effects in the TME are mediated by exosomes, with the occasional formation of feedback loops. In this review, we equally focus on the biogenesis and heterogeneity of cancer-derived exosomes and their functions under hypoxia and describe the known and potential mechanism ascribed to exosomes and hypoxia. Notably, we call attention to the size change of hypoxic cancer cell-derived exosomes, a characteristic long neglected, and propose some possible effects of this size change. Finally, jointly considering recent developments in the understanding of exosomes and tumors, we describe noteworthy problems in this field that urgently need to be solved for better research and clinical application.

Multimodal Bubble Microrobot Near an Air-Water Interface.

The development of multifunctional and robust swimming microrobots working at the free air-liquid interface has encountered challenge as new manipulation strategies are needed to overcome the complicated interfacial restrictions. Here, flexible but reliable mechanisms are shown that achieve a remote-control bubble microrobot with multiple working modes and high maneuverability by the assistance of a soft air-liquid interface. This bubble microrobot is developed from a hollow Janus microsphere (JM) regulated by a magnetic field, which can implement switchable working modes like pusher, gripper, anchor, and sweeper. The collapse of the microbubble and the accompanying directional jet flow play a key role for functioning in these working modes, which is analogous to a "bubble tentacle." Using a simple gamepad, the orientation and the navigation of the bubble microrobot can be easily manipulated. In particular, a speed modulation method is found for the bubble microrobot, which uses vertical magnetic field to control the orientation of the JM and the direction of the bubble-induced jet flow without changing the fuel concentration. The findings demonstrate a substantial advance of the bubble microrobot specifically working at the air-liquid interface and depict some nonintuitive mechanisms that can help develop more complicated microswimmers.

Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies.

Programmed cell death 1 ligand 1 (PD-L1) is the ligand for programmed death protein-1 (PD-1), is associated with immunosuppression. Signaling via PD-1/PD-L1 will transmits negative regulatory signals to T cells, inducing T-cell inhibition, reducing CD8+ T-cell proliferation, or promoting T-cell apoptosis, which effectively reduces the immune response and leads to large-scale tumor growth. Accordingly, many antibody preparations targeting PD-1 or PD-L1 have been designed to block the binding of these two proteins and restore T-cell proliferation and cytotoxicity of T cells. However, these drugs are ineffective in clinical practice. Recently, numerous of studies have shown that, in addition to the surface of tumor cells, PD-L1 is also found on the surface of extracellular vesicles secreted by these cells. Extracellular vesicle PD-L1 can also interact with PD-1 on the surface of T cells, leading to immunosuppression, and has been proposed as a potential mechanism underlying PD-1/PD-L1-targeted drug resistance. Therefore, it is important to explore the production, regulation and tumor immunosuppression of PD-L1 on the surface of tumor cells and extracellular vesicles, as well as the potential clinical application of extracellular vesicle PD-L1 as tumor biomarkers and therapeutic targets. Video Abstract.

Sweet tea (Lithocarpus polystachyus rehd.) as a new natural source of bioactive dihydrochalcones with multiple health benefits.

Sweet tea (Lithocarpus polystachyus Rehd.) has been consumed as herbal tea to prevent and manage diabetes for a long time. Recent studies indicate that sweet tea is rich in a variety of bioactive compounds, especially a class of nonclassical flavonoids, dihydrochalcones. In order to provide a better understanding of sweet tea and its main dihydrochalcones on human health, this review mainly summarizes related literature in the recent ten years, with the potential molecular mechanisms emphatically discussed. Phlorizin, phloretin, and trilobatin, three natural sweeteners, are the main dihydrochalcones in sweet tea. In addition, sweet tea and its dihydrochalcones exhibit plenty of health benefits, such as antioxidant, anti-inflammatory, antimicrobial, cardioprotective, hepatoprotective, antidiabetic, and anticancer effects, which are associated with the regulation of different molecular targets and signaling pathways. Therefore, sweet tea, as a rare natural source of dihydrochalcones, can be processed and developed into nutraceuticals or functional foods, with the potential application in the prevention and management of certain chronic diseases.

OCT3/4 enhances tumor immune response by upregulating the TET1-dependent NRF2/MDM2 axis in bladder cancer.

This study aimed to investigate the function of OCT3/4 on tumor immune escape in bladder cancer. Initially, the expression of OCT3/4, TET1, NRF2 and MDM2 was quantified in tumor tissues and cells, followed by gain- or loss-of-function studies to define their roles in cell migration, invasion and apoptosis and tumorigenicity in nude mice. Bladder cancer presented with abundant expression levels of OCT3/4, TET1, NRF2 and MDM2. We found that OCT3/4 promoted TET1 expression via binding to its promoter and that TET1 recruited MLL protein to NRF2 promoter and upregulated its expression, while NRF2 enhanced MDM2 expression. Upregulated MDM2 accelerated tumor immune escape in bladder cancer in mice. OCT3/4 knockdown suppressed the cell migration and invasion while inducing apoptosis, and consequently prevented tumor growth and immune escape in mice. Collectively, OCT3/4 may promote the progression of tumor immune escape in bladder cancer through acting as a promoter of the TET1/NRF2/MDM2 axis.

Mannose Receptor-Mediated Carbon Nanotubes as an Antigen Delivery System to Enhance Immune Response Both In Vitro and In Vivo.

Carbon nanotubes (CNTs) are carbon allotropes consisting of one, two, or more concentric rolled graphene layers. These can intrinsically regulate immunity by activating the innate immune system. Mannose receptors (MR), a subgroup of the C-type lectin superfamily, are abundantly expressed on macrophages and dendritic cells. These play a crucial role in identifying pathogens, presenting antigens, and maintaining internal environmental stability. Utilizing the specific recognition between mannose and antigen-presenting cells (APC) surface mannose receptors, the antigen-carrying capacity of mannose-modified CNTs can be improved. Accordingly, here, we synthesized the mannose-modified carbon nanotubes (M-MWCNT) and evaluated them as an antigen delivery system through a series of in vitro and in vivo experiments. In vitro, M-MWCNT carrying large amounts of OVA were rapidly phagocytized by macrophages and promoted macrophage proliferation to facilitate cytokines (IL-1ß, IL-6) secretion. In vivo, in mice, M-MWCNT induced the maturation of dendritic cells and increased the levels of antigen-specific antibodies (IgG, IgG1, IgG2a, IgG2b), and cytokines (IFN-γ, IL-6). Taken together, M-MWCNT could induce both humoral and cellular immune responses and thereby can be utilized as an efficient antigen-targeted delivery system.

Enhancement of immune responses using ovalbumin-conjugated Eucommia ulmoides leaf polysaccharides encapsulated in a cubic liquid-crystalline phase delivery system.

BACKGROUND: To improve the adjuvant activity of polysaccharides from Eucommia ulmoides leaves (PsEUL) in inducing an effective immune response against ovalbumin (OVA), PsEUL were conjugated to OVA using the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) method. The synthesized PsEUL-OVA was encapsulated using phytantriol and F127 to produce PsEUL-OVA cubosomes (Cubs), a novel delivery system. The physicochemical properties and immune modulation effects of this novel delivery system were explored. RESULTS: In vitro, PsEUL-OVA/Cubs carrying large amounts of OVA were rapidly phagocytized by macrophages and upregulated macrophage proliferation, thereby stimulating cytokine production (interleukin (IL)-6 and IL-4). In vivo, PsEUL-OVA/Cubs increased the titer of OVA-specific antibodies (immunoglobulin (Ig)G, IgG2b, IgG2a and IgG1) and cytokine levels (IL-2, IL-6, IL-4 and interferon-γ). In addition, the cubosomes promoted the differentiation of CD8+ and CD4+ T cells in the spleen and the maturation of dendritic cells (DCs). These results indicated that PsEUL-OVA/Cubs stimulated both cellular and humoral immune responses by enhancing the phagocytic activity of DCs and macrophages and increasing the antigen presentation efficiency. CONCLUSION: Collectively, the findings demonstrate that PsEUL-antigen/Cubs can be a useful delivery vehicle with immune response-promoting effects. Therefore, this study lays the foundation for the development of novel adjuvant-antigen delivery systems with potential applications in vaccine design. © 2022 Society of Chemical Industry.

ECFS-DEA: an ensemble classifier-based feature selection for differential expression analysis on expression profiles.

BACKGROUND: Various methods for differential expression analysis have been widely used to identify features which best distinguish between different categories of samples. Multiple hypothesis testing may leave out explanatory features, each of which may be composed of individually insignificant variables. Multivariate hypothesis testing holds a non-mainstream position, considering the large computation overhead of large-scale matrix operation. Random forest provides a classification strategy for calculation of variable importance. However, it may be unsuitable for different distributions of samples. RESULTS: Based on the thought of using an ensemble classifier, we develop a feature selection tool for differential expression analysis on expression profiles (i.e., ECFS-DEA for short). Considering the differences in sample distribution, a graphical user interface is designed to allow the selection of different base classifiers. Inspired by random forest, a common measure which is applicable to any base classifier is proposed for calculation of variable importance. After an interactive selection of a feature on sorted individual variables, a projection heatmap is presented using k-means clustering. ROC curve is also provided, both of which can intuitively demonstrate the effectiveness of the selected feature. CONCLUSIONS: Feature selection through ensemble classifiers helps to select important variables and thus is applicable for different sample distributions. Experiments on simulation and realistic data demonstrate the effectiveness of ECFS-DEA for differential expression analysis on expression profiles. The software is available at http://bio-nefu.com/resource/ecfs-dea.

LncRNA NEAT1 promotes autophagy via regulating miR-204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma.

Long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually because of the great importance in different cancers. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is a novel lncRNA and has been reported to promote multiple cancer progression. However, the biological roles of NEAT1 in hepatocellular carcinoma (HCC) is not cleared nowadays. In the present research, the level of NEAT1 was found to be upregulated in HCC by The Cancer Genome Atlas. In addition, NEAT1 expression is negatively correlated with the survival rate in HCC. Further investigation revealed that NEAT1 upregulation inhibited sorafenib efficacy and promoted autophagy. We found that NEAT1 could be a sponge for microRNA-204 (miR-204) and inhibits its level to upregulate ATG3 expression. In addition to the above, we demonstrated that miR-204 mimics also attenuated tumor autophagy. And rescue assays demonstrated that NEAT1 promotes HCC autophagy through modulating miR-204/ATG3 pathway. Collectively, this study first demonstrated that a novel NEAT1/miR-204/ATG3 signaling regulates HCC progression.

Focus on the morphogenesis, fate and the role in tumor progression of multivesicular bodies.

Multivesicular bodies (MVBs) are endosome organelles that are gradually attracting research attention. Initially, MVBs were considered as important components of the endosomal-lysosomal degradation pathway. In recent years, with an increase in extracellular vesicle (EV) research, the biogenesis, fate, and pathological effects of MVBs have been increasingly studied. However, the mechanisms by which MVBs are sorted to the lysosome and plasma membrane remain unclear. In addition, whether the trafficking of MVBs can determine whether exosomes are released from cells, the factors are involved in cargo loading and regulating the fate of MVBs, and the roles that MVBs play in the development of disease are unknown. Consequently, this review focuses on the mechanism of MVB biogenesis, intraluminal vesicle formation, sorting of different cargoes, and regulation of their fate. We also discuss the mechanisms of emerging amphisome-dependent secretion and degradation. In addition, we highlight the contributions of MVBs to the heterogeneity of EVs, and their important roles in cancer. Thus, we attempt to unravel the various functions of MVBs in the cell and their multiple roles in tumor progression. Video Abstract.

Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma.

BACKGROUND: Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear. METHODS: We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments. RESULTS: We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling. CONCLUSION: Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.

The role of YAP/TAZ activity in cancer metabolic reprogramming.

In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.