Taz/Tead1 Promotes Alternative Macrophage Activation and Kidney Fibrosis via Transcriptional Upregulation of Smad3.

Macrophage alternative activation is involved in kidney fibrosis. Previous researches have documented that the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz) are linked to organ fibrosis. However, limited knowledge exists regarding the function and mechanisms of their downstream molecules in regulating macrophage activation and kidney fibrosis. In this paper, we observed that the Hippo pathway was suppressed in macrophages derived from fibrotic kidneys in mice. Knockout of Taz or Tead1 in macrophages inhibited the alternative activation of macrophages and reduced kidney fibrosis. Additionally, by using bone marrow-derived macrophages (BMDMs), we investigated that knockout of Taz or Tead1 in macrophages impeded both cell proliferation and migration. Moreover, deletion of Tead1 reduces p-Smad3 and Smad3 abundance in macrophages. And chromatin immunoprecipitation (ChIP) assays showed that Tead1 could directly bind to the promoter region of Smad3. Collectively, these results indicate that Tead1 knockout in macrophages could reduce TGFß1-induced phosphorylation Smad3 via transcriptional downregulation of Smad3, thus suppressing macrophage alternative activation and IRI-induced kidney fibrosis.

Interaction of zein/HP-ß-CD nanoparticles with digestive enzymes: Enhancing curcumin bioavailability.

The low bioavailability of polyphenolic compounds due to poor solubility and stability is a major challenge. Encapsulation of polyphenols in zein-based composite nanoparticles can improve the water dispersion, stability, targeted delivery, and controlled release of polyphenols in the gastrointestinal tract. In this study, we investigated the fluorescence properties, bioactivity, and microstructural characteristics of polyphenols during digestion, revealing that zein nanoparticles protect polyphenols from gastric degradation and promote their sustained release in the small intestine. The effects of different ionic species and salt ion concentrations on the digestive properties of polyphenol complex delivery systems have also been explored. In addition, the formation of "protein corona" structures during digestion may affect bioavailability. These findings highlight the potential of nanoparticle formulations to improve polyphenol stability and absorption. The results of this study may provide new insights and references for the study of polyphenol bioavailability enhancement.

Preparation of ß-Cyclodextrin(CD)/Flavour CD Powder and Its Application on Flavour Improvement of Regular Coffee.

To improve the overall sensory evaluation of regular coffee, a mixture of ß-CD/flavour CD powder was prepared by a freeze-drying method. Cyclodextrin inclusion complexes consist of eight compounds that are naturally present in coffee, specifically: 2,5-dimethylpyrazine, benzaldehyde, citral, linalool, limonene, phenethyl acetate, furfural, and ethyl acetate. These eight compounds naturally occur in coffee, making them safer than using other compounds. Moreover, these eight compounds are the primary active ingredients in coffee, significantly influencing its flavour profile. Therefore, choosing to complex these eight compounds with cyclodextrins can effectively enhance the taste of the coffee. XRD, FT-IR, and SDE-GC-FID were presented to study the formation of inclusion CD powder, the storage stability, chemical composition changes, and safety. Results show that by the cyclodextrin method of freeze-drying, the CD powder showed a stable encapsulated structure and increased stability of flavour compounds. Based on the coffee aroma analysis results, prepared CD powder can enhance the coffee's aroma score by 3.0-4.0 points and increase the flavour score by 2.1-3.5 points, and it can achieve preservation for a minimum of 181 days at 25 °C. Furthermore, under the requirements of the China national standard for additives, the mixture of ß-CD/flavour CD powder was used for the cup testing with four regular coffees to obtain improved coffees. With the full score is 10, improved coffees could score extra 3.0-4.0 points on aroma and 2.1-3.5 on flavour compared to regular coffee. In addition, the CD powder also improves the quality of the coffee in terms of aftertaste, body, and sweetness. Overall, ß-CD/flavour CD powders provide several advantages over the currently popular coffee bean processing methods, including improved reproducibility, enhanced controllability, and increased flexibility, while prioritizing safety. And it should be explored further with appropriate compounds given its potential for coffee aroma modulation.

A Review of Whey Protein-Based Bioactive Delivery Systems: Design, Fabrication, and Application.

The efficacy of many edible bioactive agents is limited by their low water dispersibility and chemical instability in foods, as well as by their poor bioaccessibility, low absorption, and metabolism within the human gastrointestinal tract. Whey proteins are amphiphilic molecules that can be used to construct a variety of edible carrier systems that can improve the performance of bioactive ingredients. These carrier systems are being used by the food and biomedical industries to encapsulate, protect, and deliver a variety of bioactive agents. In this article, we begin by providing an overview of the molecular and functional characteristics of whey proteins, and then discuss their interactions with various kinds of bioactive agents. The ability of whey proteins to be used as building blocks to assemble different kinds of carrier systems is then discussed, including nanoparticles, hydrogels, oleogels, bigels, nanofibers, nanotubes, and nanoemulsions. Moreover, applications of these carrier systems are highlighted. Different kinds of whey protein-based carriers can be used to encapsulate, protect, and deliver bioactive agents. Each kind of carrier has its own characteristics, which make them suitable for different application needs in foods and other products. Previous studies suggest that whey protein-based carriers are particularly suitable for protecting chemically labile bioactive agents and for prolonging their release profiles. In the future, it is likely that the applications of whey protein-based carriers in the food and pharmaceutical fields will expand.

EGaIn-Modified ePADs for Simultaneous Detection of Homocysteine and C-Reactive Protein in Saliva toward Early Diagnosis of Cardiovascular Disease.

Homocysteine (Hcy) and C-reactive protein (CRP) are critical biomarkers for numerous chronic diseases, with cardiovascular disease (CVD) being the most prevalent. The ability to simultaneously detect both biomarkers in point-of-care settings is in high demand for CVD early diagnosis and prevention. Herein, we prepared the eutectic gallium indium (EGaIn) nanoparticles decorated with p-phenylenediamine (PPD) on the surface to facilitate the subsequent attachment of gold nanoparticles (AuNPs) to achieve EGaIn-PPD@Au, which was modified on the screen-printed electrochemical paper-based analytical devices (ePADs). Aptamers that are specific to Hcy and CRP were then immobilized on the EGaIn-PPD@Au surface to achieve the sensing interface on ePADs. The presence of EGaIn-PPD@Au significantly enhanced the electrical conductivity, leading to amplified electrochemical signals. This aptasensor demonstrated high specificity, capable of detecting Hcy in a range of 1-50 µM with a detection limit of 0.22 µM, and the detection range for CRP was 1-100 ng/mL with a detection limit of 0.039 ng/mL. The aptasensor also effectively detected Hcy and CRP in clinical saliva samples, yielding an area under the curve (AUC) of about 0.80 when the individual biomarker was considered and 0.93 when both biomarkers were taken into account. The positive correlation observed between salivary and blood concentrations of Hcy and CRP, coupled with their association with cardiovascular disease (CVD), suggested the potential of this methodology as a noninvasive point-of-care strategy for the early diagnosis of CVD.

A Chemical Reaction Network Drives Complex Population Dynamics in Oscillating Self-Reproducing Vesicles.

We report chemically fueled oscillations of vesicles. The population cycling of vesicles is driven by their self-reproduction and collapse within a biphasic reaction network involving the interplay of molecular and supramolecular events. We studied the oscillations on the molecular and supramolecular scales and tracked vesicle populations in time by interferometric scattering microscopy and dynamic light scattering. Complex supramolecular events were observed during oscillations─including vesicle reproduction, growth, and decomposition─and differences in the number, size, and mass of aggregates can often be observed within and between pulses. This system's dynamic behavior is reminiscent of a reproductive cycle in living cells.

Impact of Nitrate on the Removal of Pollutants from Water in Reducing Gas-Based Membrane Biofilm Reactors: A Review.

The membrane biofilm reactor (MBfR) is a novel wastewater treatment technology, garnering attention due to its high gas utilization rate and effective pollutant removal capability. This paper outlines the working mechanism, advantages, and disadvantages of MBfR, and the denitrification pathways, assessing the efficacy of MBfR in removing oxidized pollutants (sulfate (SO4-), perchlorate (ClO4-)), heavy metal ions (chromates (Cr(VI)), selenates (Se(VI))), and organic pollutants (tetracycline (TC), p-chloronitrobenzene (p-CNB)), and delves into the role of related microorganisms. Specifically, through the addition of nitrates (NO3-), this paper analyzes its impact on the removal efficiency of other pollutants and explores the changes in microbial communities. The results of the study show that NO3- inhibits the removal of other pollutants (oxidizing pollutants, heavy metal ions and organic pollutants), etc., in the simultaneous removal of multiple pollutants by MBfR.

Distinguishable Magnetic Reporter Coordination with Buoyancy-Magnetism Separation for Immobilization-Free Dual-Target Electrochemical Immunosensing.

Simultaneous sensitive and precise determination of multibiomarkers is of great significance for improving detection efficiency, reducing diagnosis and treatment expenses, and elevating survival rates. However, the development of simple and portable biosensors for simultaneous determination of multiplexed targets in biological fluids still faces challenges. Herein, a unique and versatile immobilization-free dual-target electrochemical biosensing platform, which combines distinguishable magnetic signal reporters with buoyancy-magnetism separation, was designed and constructed for simultaneous detection of carcinoembryonic (CEA) and α-fetoprotein (AFP) in intricate biological fluids. To construct such distinguishable magnetic signal reporters with signal transduction, amplification, and output, secondary antibodies of CEA and AFP were respectively functionalized on methylene blue (MB) and 6-(ferrocenyl)hexanethiol (FeC) modified Fe3O4@Au magnetic nanocomposites. Meanwhile, a multifunctional flotation probe with dual target recognition, capture, and isolation capability was prepared by conjugating primary antibodies (Ab1-CEA, Ab1-AFP) to hollow buoyant microspheres. The target antigens of CEA and AFP can trigger a flotation-mediated sandwich-type immunoreaction and capture a certain amount of the distinguishable magnetic signal reporter, which enables the conversion of the target CEA and AFP quantities to the signal of the potential-resolved MB and FeC. Thus, the MB and FeC currents of magnetically adsorbed distinguishable magnetic reporters can be used to determine the CEA and AFP targets simultaneously and precisely. Accordingly, the proposed strategy exhibited a delightful linear response for CEA and AFP in the range of 100 fg·mL-1-100 ng·mL-1 with detection limits of 33.34 and 17.02 fg·mL-1 (S/N = 3), respectively. Meanwhile, no significant nonspecific adsorption and cross-talk were observed. The biosensing platform has shown satisfactory performance in the determination of real clinical samples. More importantly, the proposed approach can be conveniently extended to universal detection just by simply substituting biorecognition events. Thus, this work opens up a new promising perspective for dual and even multiple targets and offers promising potential applications in clinical diagnosis.

Robust fault detection and isolation for uncertain neutral time-delay systems using a geometric approach.

This paper proposes a new geometric fault detection and isolation (FDI) strategy for uncertain neutral time-delay systems (UNTDS). Firstly, the concept of unobservability subspace is extended to the considered system. Subsequently, utilizing the geometric properties of factor space and canonical projection, the fault is divided into different unobservability subspaces. Therefore, an algorithm for constructing the subspace is developed for fault isolation. Finally, a set of observers is designed for the subsystems, and generates a set of structured residuals which is sensitive only to a specific fault. Additionally, the H∞ technique is utilized to suppress the disturbances and error signals due to time-varying delays on the residual. The simulation examples verify the effectiveness of the proposed approach.

Potential role of lipophagy impairment for anticancer effects of glycolysis-suppressed pancreatic ductal adenocarcinoma cells.

Although increased aerobic glycolysis is common in various cancers, pancreatic ductal adenocarcinoma (PDAC) cells can survive a state of glycolysis suppression. We aimed to identify potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anticancer metabolic compounds, we identified SP-2509, an inhibitor of lysine-specific histone demethylase 1A (LSD1), which dramatically decreased the growth of PDAC PANC-1 cells and showed an anti-tumoral effect in tumor-bearing mice. The growth of glycolysis-suppressed PANC-1 cells was also inhibited by another LSD1 inhibitor, OG-L002. Similarly, the other two PDAC cells (PK-1 and KLM-1) with suppressed glycolysis exhibited anticancer effects against SP-2509. However, the anticancer effects on PDAC cells were unrelated to LSD1. To investigate how PDAC cells survive in a glycolysis-suppressed condition, we conducted proteomic analyses. These results combined with our previous findings suggested that glucose-starvation causes PDAC cells to enhance mitochondrial oxidative phosphorylation. In particular, mitochondrial fatty acid metabolism was identified as a key factor contributing to the survival of PDAC cells under glycolysis suppression. We further demonstrated that SP-2509 and OG-L002 disturbed fatty acid metabolism and induced lipid droplet accumulation through the impairment of lipophagy, but not bulk autophagy. These findings indicate a significant potential association of lipophagy and anticancer effects in glycolysis-suppressed PDAC cells, offering ideas for new therapeutic strategies for PDAC by dual inhibition of glycolysis and fatty acids metabolism.

Development of a Large Animal Model of Ischemia-free Liver Transplantation in Pigs.

Background: In organ transplantation, ischemia, and reperfusion injury (IRI) is considered as an inevitable event and the major contributor to graft failure. Ischemia-free liver transplantation (IFLT) is a novel transplant procedure that can prevent IRI and provide better transplant outcomes. However, a large animal model of IFLT has not been reported. Therefore, we develop a new, reproducible, and stable model of IFLT in pigs for investigating mechanisms of IFLT in IRI. Methods: Ten pigs were subjected to IFLT or conventional liver transplantation (CLT). Donor livers in IFLT underwent 6-h continuous normothermic machine perfusion (NMP) throughout graft procurement, preservation, and implantation, whereas livers in CLT were subjected to 6-h cold storage before implantation. The early reperfusion injury was compared between the 2 groups. Results: Continuous bile production, low lactate, and liver enzyme levels were observed during NMP in IFLT. All animals survived after liver transplantation. The posttransplant graft function was improved with IFLT when compared with CLT. Minimal histologic changes, fewer apoptotic hepatocytes, less sinusoidal endothelial cell injury, and proinflammatory cytokine (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-α) release after graft revascularization were documented in the IFLT group versus the CLT group. Conclusions: We report that the concept of IFLT is achievable in pigs. This innovation provides a potential strategy to investigate the mechanisms of IRI and provide better transplant outcomes for clinical practice.

Fabrication and characterization of polydopamine-mediated zein-based nanoparticle for delivery of bioactive molecules.

In this study, a combination of whey protein (hydrophilic coating) and polydopamine (crosslinking agent) was used to improve the stability and functionality of quercetin-loaded zein nanoparticles. There are two key benefits of the core-shell nanoparticles formed. First, the ability of the polydopamine to bind to both zein and whey protein facilitates the formation of a stable core-shell structure, thereby protecting quercetin from any pro-oxidants in the aqueous surroundings. Second, neutral and hydrophilic whey proteins were used for the surface coating of the nanoparticles to further enhance the sustained and slow release of quercetin, facilitating its sustained release into the body at a slow and steady rate. The results of this study will promote the innovative development of precise nutritional delivery systems for zein and provide a theoretical basis for the design and development of dietary supplements based on hydrophobic food nutrient molecules.

Enhanced Hippocampus-Nidopallium Caudolaterale Interaction in Visual-Spatial Associative Learning of Pigeons.

Learning the spatial location associated with visual cues in the environment is crucial for survival. This ability is supported by a distributed interactive network. However, it is not fully understood how the most important task-related brain areas in birds, the hippocampus (Hp) and the nidopallium caudolaterale (NCL), interact in visual-spatial associative learning. To investigate the mechanisms of such coordination, synchrony and causal analysis were applied to the local field potentials of the Hp and NCL of pigeons while performing a visual-spatial associative learning task. The results showed that, over the course of learning, theta-band (4-12 Hz) oscillations in the Hp and NCL became strongly synchronized before the pigeons entered the critical choice platform for turning, with the information flowing preferentially from the Hp to the NCL. The learning process was primarily associated with the increased Hp-NCL interaction of theta rhythm. Meanwhile, the enhanced theta-band Hp-NCL interaction predicted the correct choice, supporting the pigeons' use of visual cues to guide navigation. These findings provide insight into the dynamics of Hp-NCL interaction during visual-spatial associative learning, serving to reveal the mechanisms of Hp and NCL coordination during the encoding and retrieval of visual-spatial associative memory.

NDRG1 overcomes resistance to immunotherapy of pancreatic ductal adenocarcinoma through inhibiting ATG9A-dependent degradation of MHC-1.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is resistant to immune checkpoint blockade (ICB) therapies. Emerging evidence suggests that NDRG1 may be an important target for the development of new therapies for PDAC. Herein, we investigated the novel roles of NDRG1 and Combretastatin A-4 (CA-4) in the treatment of PDAC ICB resistance. METHODS: Enrichment of MHC class I was detected by RNA sequence and verified by RT-qPCR and immunoblotting in NDRG1-knockdown human pancreatic cancer cell lines. The protein degradation mode was found by stimulation with various inhibitors, and the autophagy degradation pathway was found by immunoprecipitation and immunolocalization. The roles of NDRG1 and MHC-I in immunotherapy were investigated by orthotopic solid tumors, histology, immunohistochemistry, multiplex immunofluorescence staining and flow cytometry. RESULTS: Here, we identified a previously undescribed role of NDRG1 in activating major histocompatibility complex class 1 (MHC-1) expression in pancreatic ductal adenocarcinoma (PDAC) cells through lysosomal-autophagy-dependent degradation. In mouse models of PDAC, either tumor cell overexpression or pharmacologic activation of NDRG1 leads to MHC-1 upregulation in tumor cells, which in turn promotes the infiltration and activity of CD8 + T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. Moreover, combination therapy of CA-4 and ICB overcomes the drug resistance of pancreatic cancer to ICB therapy. In PDAC patients, NDRG1 expression correlates with high MHC-1 expression and better survival. CONCLUSION: Our results reveal NDRG1 in PDAC cancer cells as a tumor suppressor and suggest that pharmaceutically targeting NDRG1 is a promising way to overcome pancreatic cancer resistance to immunotherapy and provides a potential therapeutic strategy for the treatment of pancreatic cancer patients.

Integrated acetic acid and deep eutectic solvent pretreatment on poplar for co-production of xylo-oligosaccharides, fermentable sugars and lignin antioxidants/adsorbents.

Efficient fractionation of lignocellulosic biomass in usable forms of hemicellulose, cellulose and lignin is very important for the sustainable lignocellulosic biorefinery. Herein, poplar sawdust was pretreated with an integrated process composed of acetic acid pre-hydrolysis (170 °C, 60 min) for xylo-oligosaccharides (XOS) production and mild deep eutectic solvent (90-130 °C, 60 min) post-delignification for recovering lignin fractions, resulting in easily hydrolyzed cellulose fraction. Results showed that, after integrated pretreatment and enzymatic hydrolysis, 51 % of xylan and 92 % of glucan in raw biomass could be converted to XOS (DP 2-6) and glucose, respectively, while 71 % of the original lignin could be recovered in DES solvent. The resulting XOS were proven to ensure the growth of probiotics, Bifidobacterium adolescentis. Besides, the lignin macromolecules recovered from DES solvent showed high-purity (around 95 %), low-molecular weight (Mw around 2000), small particle size (270-170 nm) and high-PhOH (3.08 mmol/g) content, which were likely relevant to the excellent antioxidant activity (RSI = 15.16) and adsorbent activity (Pb(II) 461.89 mg/g lignin). Finally, mass balance and energy analysis revealed that the integrated pretreatment could be used as a promising approach for the production of bio-based chemicals and materials from woody biomass.