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.

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.

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.

A randomized-controlled trial of ischemia-free liver transplantation for end-stage liver disease.

BACKGROUND & AIMS: Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes. METHODS: In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI. RESULTS: Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025). CONCLUSIONS: Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach. CLINICAL TRIAL REGISTRATION: chictr.org. ChiCTR1900021158. IMPACT AND IMPLICATIONS: Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.

Fascinating Immobilization-Free Electrochemical Immunosensing Strategy Based on the Cooperation of Buoyancy and Magnetism.

Rapid and accurate detection of biomolecules is of vital importance for the diagnosis of disease and for performing timely treatments. The point-of-care analysis of cancer biomarkers in the blood with low cost and easy processing is still challenging. Herein, an advanced and robust strategy, which integrates the buoyant recognition probe with the magnetic reporter probe in one solution, was first proposed for immobilization-free electrochemical immunosensing. The tumor marker of alpha fetoprotein (AFP) can be captured immune-buoyantly, and then a multifunctional magnetic reporter probe in pseudo-homogeneous solution was further captured to fulfill a sandwich-type immunoreaction. The residual magnetic reporter probe can be firmly and efficiently attracted on a magnetic glassy carbon electrode to fulfill the conversion of the target AFP amount into the residual magnetic electrochemical signal indicator. As a result, the electrochemical signal of methylene blue can accurately reflect the original level of target antigen AFP concentration. By integrating buoyancy-driven quasi-homogenous biorecognition with magnetism-mediated amplification and signal output, the proposed immobilization-free electrochemical immunosensing strategy displayed a wide range of linear response (100 fg mL-1 to 10 ng mL-1), low detection limit (14.52 fg mL-1), and good reproducibility, selectivity, and stability. The designed strategy manifests remarkable advantages including assay simplicity, rapidness, and high sensitivity owing to the in-solution instead of on-electrode biorecognition that could accelerate and improve the biorecognition efficiency. To the best of our knowledge, this is the first cooperation of buoyancy-driven biorecognition with magnetism-mediated signal output in bioanalysis, which would be attractive for rapid clinic biomedical application. Thus, this work provides a fresh perspective for convenient and favorable immobilization-free electrochemical biosensing of universal biomolecules.

Application of starch-based nanoparticles and cyclodextrin for prebiotics delivery and controlled glucose release in the human gut: a review.

Starches are a major constituent of staple foods and are the main source of energy in the human diet (55-70%). In the gastrointestinal tract, starches are hydrolyzed into glucose by α-amylase and α-glucosidase, which leads to a postprandial glucose elevation. High levels of blood glucose levels over sustained periods may promote type 2 diabetes mellitus (T2DM) and obesity. Increasing consumption of starchy foods with a lower glycemic index may therefore contribute to improved health. In this paper, the preparation and properties of several starch-based nanoparticles (SNPs) and cyclodextrins (CDs) derivatives are reviewed. In particular, we focus on the various mechanisms responsible for the ability of these edible nanomaterials to modulate glucose release and the gut microbiome in the gastrointestinal tract. The probiotic functions are achieved through encapsulation and protection of prebiotics or bioactive components in foods or the human gut. This review therefore provides valuable information that could be used to design functional foods for improving human health and wellbeing.

Recent advances in natural gums as additives to help the construction and application of edible biopolymer gels: the example of hydrogels and oleogels.

Novel, innovative approaches like edible gels (hydrogels and oleogels) are important food materials with great scientific interest due to their positive impacts on structural and functional foods and other unique properties. Biopolymers (protein, starch and other polysaccharides) can be excellent and cost-effective materials for the formed edible gels. Recently, natural gums, although also as biopolymers, are preferred as additives to further improve the textural and functional properties of edible gels, which have received extensive attention. However, these studies have not been outlined in previous reviews. In this review, we highlighted the advantages of gums as additives to construct edible gels. Moreover, the various roles (including electrostatic or covalent interactions) for natural gums in regulation of food gel properties (solvent-holding and rheological properties) are highlighted. Finally, the use of natural gums as additives to improve the stability and targeted delivery of phytochemicals in food gels and their application in food systems are summarized. The information covered in this article may be useful for the design of functional foods that can better meet personalized needs of people.

Performance Baseline of Phase Transfer Entropy Methods for Detecting Animal Brain Area Interactions.

Objective: Phase transfer entropy (TEθ) methods perform well in animal sensory-spatial associative learning. However, their advantages and disadvantages remain unclear, constraining their usage. Method: This paper proposes the performance baseline of the TEθ methods. Specifically, four TEθ methods are applied to the simulated signals generated by a neural mass model and the actual neural data from ferrets with known interaction properties to investigate the accuracy, stability, and computational complexity of the TEθ methods in identifying the directional coupling. Then, the most suitable method is selected based on the performance baseline and used on the local field potential recorded from pigeons to detect the interaction between the hippocampus (Hp) and nidopallium caudolaterale (NCL) in visual-spatial associative learning. Results: (1) This paper obtains a performance baseline table that contains the most suitable method for different scenarios. (2) The TEθ method identifies an information flow preferentially from Hp to NCL of pigeons at the θ band (4-12 Hz) in visual-spatial associative learning. Significance: These outcomes provide a reference for the TEθ methods in detecting the interactions between brain areas.

Activation of adenosine A3 receptor attenuates progression of osteoarthritis through inhibiting the NLRP3/caspase-1/GSDMD induced signalling.

The specific adenosine A3 receptor (A3AR) agonist (CF101) has potential for inflammation and pain in various disease, such as arthritis, cancer and neuropathic pain, while the role of A3AR in post-traumatic OA and the underlying mechanism is largely unknown. CF101 was orally administrated in OA rats induced by anterior cruciate ligament transection (ACLT) surgery, and the rat primary chondrocytes were stimulated by hydrogen peroxide (H2 O2 , 300 µM). Histologic grading system was performed for detecting cartilage degeneration and immunohistochemistry for determining pyroptosis. The moleculars associated with cartilage homeostasis and inflammatory cytokines were analysed; moreover, the activation of NLRP3 inflammasome was determined. CF101 treatment significantly attenuated OA cartilage damage, OA-related pain and cartilage pyroptosis. Chondrocytes stimulated by H2 O2 evoked ROS release, thereby promoting the activation of NLRP3 inflammasome and facilitating the cleavage of GSDMD, which ultimately resulted in the mass release of pro-inflammatory cytokines including IL-1ß and IL-18, and production of matrix hydrolase. The pre-treatment with CF101 powerfully inhibited the above process both in vivo and in vitro. Our findings demonstrated that activation of A3AR attenuates OA progression and relieves pain perception through suppression of cartilage degradation and inhibition of ROS/NLRP3/GSDMD signalling, indicating pyroptosis is a potential candidate for OA treatment.

mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote KrasG12D-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis.

BACKGROUND & AIMS: Oncogenic KrasG12D induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of KrasG12D, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively. RESULTS: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote KrasG12D-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents KrasG12D-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation. CONCLUSIONS: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53.

BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.

PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.

Cancer cells rely on glycolysis to generate ATP for survival. However, inhibiting glycolysis is insufficient for the eradication of cancer cells because glycolysis-suppressed cells undergo metabolic reprogramming toward mitochondrial oxidative phosphorylation. We previously described that upon glycolytic suppression in pancreatic cancer cells, intracellular glycometabolism is shifted toward mitochondrial oxidative phosphorylation in an autophagy-dependent manner for cellular survival. Here, we hypothesized that mitophagy, which selectively degrades mitochondria via autophagy, is involved in mitochondrial activation under metabolic reprogramming. We revealed that glycolytic suppression notably increased mitochondrial membrane potential and mitophagy in a pancreatic cancer cell model (PANC-1). PTEN-induced kinase 1 (PINK1), a ubiquitin kinase that regulates mitophagy in healthy cells, regulated mitochondrial activation through mitophagy by glycolytic suppression. However, Parkin, a ubiquitin ligase regulated by PINK1 in healthy cells to induce mitophagy, was not involved in the PINK1-dependent mitophagy of the cancer glycometabolism. These results imply that cancer cells and healthy cells have different regulatory pieces of machinery for mitophagy, and inhibition of cancer-specific mechanisms may be a potential strategy for cancer therapy targeting metabolic reprogramming.

Combined lethal toxicity, biochemical responses, and gene expression variations induced by tebuconazole, bifenthrin and their mixture in zebrafish (Danio rerio).

Pesticides commonly occur as mixtures in an aqueous environment, causing deleterious effects on human health and the environment. However, the mechanism underlying the combined effects on aqueous organisms remains largely unknown, especially at low concentrations. In the current study, we inspected the interactive toxicity of tebuconazole (TEB), a triazole fungicide, and bifenthrin (BIF), a pyrethroid insecticide, to zebrafish (Danio rerio) using various toxicological assays. Our data revealed that the 96 h-LC50 (lethal concentration 50) values of BIF to fish at different life periods (embryonic, larval, juvenile, and adult periods) ranged from 0.013 (0.011-0.016) to 0.41 (0.35-0.48) mg a.i. L-1, which were lower than that of TEB ranging from 1.1 (0.88-1.3) to 4.8 (4.1-5.7) mg a.i. L-1. Combination of TEB and BIF induced synergetic acute toxicity to embryonic fish. Activities of T-SOD, POD, and GST were distinctly altered in most individual and joint administrations. Expressions of 16 genes associated with oxidative stress, cellular apoptosis, immune system, and endocrine system at the mRNA level were evaluated, and the information revealed that embryonic zebrafish were impacted by both individual compounds and their combinations. Six genes (cas9, P53, gr, TRα, IL-8, and cxcl-clc) exhibited greater changes when exposed to pesticide mixtures. Therefore, the joint effects induced by the pesticides at low concentrations should be considered in the risk assessment of mixtures and regulated as priorities for mixture risk management in the aqueous ecosystem. More research is needed to identify the threshold concentrations of the realistic pesticide mixtures above which synergistic interactions occur.

Downregulation of the NLRP3/Caspse-1 Pathway Ameliorates Ketamine-Induced Liver Injury and Inflammation in Developing Rats.

Ketamine is an anesthetic drug that is widely used in human and veterinary medicine. In the developmental stage, long-term exposure to ketamine may cause serious side effects. MCC950 and VX765 play protective roles in many disease models by regulating the NLRP3/Caspase-1 pathway. This study aims to explore the potential protective effect of MCC950 and VX765 on ketamine-induced liver injury in neonatal rats and clarify its underlying mechanism. After administration of MCC950 and VX765 in a ketamine-induced liver injury rat model, liver function and inflammatory factors were determined, and immunohistochemistry and western blotting were performed. We found that ketamine caused liver injury in 7-day-old SD rats, decreased liver function indexes, and increased inflammation. MCC950 and VX765 effectively alleviated liver damage and inflammation, and downregulated the expression of proteins such as NLRP3, Caspase-1, and GSDMD-N. In summary, these results indicated that MCC950 and VX765 could have potential protective effects on ketamine-induced liver injury through inhibiting the NLRP3/Caspase-1 pathway.

A Fast and Efficient Ensemble Transfer Entropy and Applications in Neural Signals.

The ensemble transfer entropy (TEensemble) refers to the transfer entropy estimated from an ensemble of realizations. Due to its time-resolved analysis, it is adapted to analyze the dynamic interaction between brain regions. However, in the traditional TEensemble, multiple sets of surrogate data should be used to construct the null hypothesis distribution, which dramatically increases the computational complexity. To reduce the computational cost, a fast, efficient TEensemble with a simple statistical test method is proposed here, in which just one set of surrogate data is involved. To validate the improved efficiency, the simulated neural signals are used to compare the characteristics of the novel TEensemble with those of the traditional TEensemble. The results show that the time consumption is reduced by two or three magnitudes in the novel TEensemble. Importantly, the proposed TEensemble could accurately track the dynamic interaction process and detect the strength and the direction of interaction robustly even in the presence of moderate noises. The novel TEensemble reaches its steady state with the increased samples, which is slower than the traditional method. Furthermore, the effectiveness of the novel TEensemble was verified in the actual neural signals. Accordingly, the TEensemble proposed in this work may provide a suitable way to investigate the dynamic interactions between brain regions.

A Photoinduced Dual-Wavelength Approach for 3D Printing and Self-Healing of Thermosetting Materials.

Vat photopolymerization-based 3D printing techniques have been widely used to produce high-resolution 3D thermosetting materials. However, the lack of repairability of these thermosets leads to the production of waste. In this study, reversible addition fragmentation chain transfer (RAFT) agents are incorporated into resin formulations to allow visible light (405 nm) mediated 3D printing of materials with self-healing capabilities. The self-healing process is based on the reactivation of RAFT agent embedded in the thermosets under UV light (365 nm), which enables reformation of the polymeric network. The self-healing process can be performed at room temperature without prior deoxygenation. The impact of the type and concentration of RAFT agents in the polymer network on the healing efficiency is explored. Resins containing RAFT agents enable 3D printing of thermosets with self-healing properties, broadening the scope of future applications for polymeric thermosets in various fields.

Oxidative Polymerization in Living Cells.

Intracellular polymerization is an emerging technique that can potentially modulate cell behavior, but remains challenging because of the complexity of the cellular environment. Herein, taking advantage of the chemical properties of organotellurides and the intracellular redox environment, we develop a novel oxidative polymerization reaction that can be conducted in cells without external stimuli. We demonstrate that this polymerization reaction is triggered by the intracellular reactive oxygen species (ROS), thus selectively proceeding in cancer cells and inducing apoptosis via a unique self-amplification mechanism. The polymerization products are shown to disrupt intracellular antioxidant systems through interacting with selenoproteins, leading to greater oxidative stress that would further the oxidative polymerization and eventually activate ROS-related apoptosis pathways. The selective anticancer efficacy and biosafety of our strategy are proven both in vitro and in vivo. Ultimately, this study enables a new possibility for chemists to manipulate cellular proliferation and apoptosis through artificial chemical reactions.

Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats.

BACKGROUND: Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain. METHODS: To evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction. RESULTS: Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction. CONCLUSION: NLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.

Facile Synthesis of Two-Dimensional Iron/Cobalt Metal-Organic Framework for Efficient Oxygen Evolution Electrocatalysis.

A facile synthesis is reported of two-dimensional (2D) bimetallic (Fe/Co=1:2) metal-organic frameworks (MOF, ca. 2.2 nm thick) via simple stirring of the reaction mixture of Fe/Co salts and 1,4-benzene dicarboxylic acid (1,4-BDC) in the presence of triethylamine and water at room temperature. The mechanism of the 2D, rather than bulk, MOF was revealed by studying the role of each component in the reaction mixture. It was found that these 2D MOF-Fe/Co(1:2) exhibited excellent electrocatalytic activity for the oxygen evolution reaction (OER) under basic conditions. The electrocatalytic mechanism was disclosed via both experimental results and density functional theory (DFT) calculation. The 2D morphology and co-doping of Fe/Co contributed to the superior OER performance of the 2D MOF-Fe/Co(1:2). The simple and efficient synthetic method is suitable for the mass production and future commercialization of functional 2D MOF with low cost and high yield.

Porphyrinic Zirconium Metal-Organic Frameworks (MOFs) as Heterogeneous Photocatalysts for PET-RAFT Polymerization and Stereolithography.

In this study, porphyrinic zirconium (Zr) MOFs were investigated as heterogeneous photocatalysts for photoinduced electron transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization of various monomers under a broad range of wavelengths, producing polymers with high monomer conversions, narrow molecular weight distributions, low dispersity and good chain-end fidelity. Screening of various porphyrinic Zr-MOFs (Zn) containing Zn-metalled porphyrinic ligands demonstrated that MOF-525 (Zn) with the smallest size had the best photocatalytic activity in PET-RAFT polymerization, due to enhanced dispersion and light penetration. Oxygen tolerance and temporal control were also demonstrated during MOF catalysed PET-RAFT. Results suggested that the polymerization rates were significantly affected by changing the size and surface area of MOFs, and the heterogeneous MOF photocatalysts could be easily separated and recycled for up to five independent PET-RAFT polymerizations without an obvious decrease in efficiency. Finally, the MOF photocatalysts were utilized to create three-dimensional polymeric objects with high resolution via visible light mediated stereolithography in an open-air environment.