Iron Drives T Helper Cell Pathogenicity by Promoting RNA-Binding Protein PCBP1-Mediated Proinflammatory Cytokine Production.

Iron deposition is frequently observed in human autoinflammatory diseases, but its functional significance is largely unknown. Here we showed that iron promoted proinflammatory cytokine expression in T cells, including GM-CSF and IL-2, via regulating the stability of an RNA-binding protein PCBP1. Iron depletion or Pcbp1 deficiency in T cells inhibited GM-CSF production by attenuating Csf2 3' untranslated region (UTR) activity and messenger RNA stability. Pcbp1 deficiency or iron uptake blockade in autoreactive T cells abolished their capacity to induce experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis. Mechanistically, intracellular iron protected PCBP1 protein from caspase-mediated proteolysis, and PCBP1 promoted messenger RNA stability of Csf2 and Il2 by recognizing UC-rich elements in the 3' UTRs. Our study suggests that iron accumulation can precipitate autoimmune diseases by promoting proinflammatory cytokine production. RNA-binding protein-mediated iron sensing may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.

Versatile, modular, and customizable magnetic solid-droplet systems.

Magnetic miniature robotic systems have attracted broad research interest because of their precise maneuverability in confined spaces and adaptability to diverse environments, holding significant promise for applications in both industrial infrastructures and biomedical fields. However, the predominant construction methodology involves the preprogramming of magnetic components into the system's structure. While this approach allows for intricate shape transformations, it exhibits limited flexibility in terms of reconfiguration and presents challenges when adapting to diverse materials, combining, and decoupling multiple functionalities. Here, we propose a construction strategy that facilitates the on-demand assembly of magnetic components, integrating ferrofluid droplets with the system's structural body. This approach enables the creation of complex solid-droplet robotic systems across a spectrum of length scales, ranging from 0.8 mm to 1.5 cm. It offers a diverse selection of materials and structural configurations, akin to assembling components like building blocks, thus allowing for the seamless integration of various functionalities. Moreover, it incorporates decoupling mechanisms to enable selective control over multiple functions, leveraging the fluidity, fission/fusion, and magneto-responsiveness properties inherent in the ferrofluid. Various solid-droplet systems have validated the feasibility of this strategy. This study advances the complexity and functionality achievable in small-scale magnetic robots, augmenting their potential for future biomedical and other applications.

Multiple Magneto-Optical Microrobotic Collectives with Selective Control in Three Dimensions Under Water.

Inspired by natural swarms, various methods are developed to create artificial magnetic microrobotic collectives. However, these magnetic collectives typically receive identical control inputs from a common external magnetic field, limiting their ability to operate independently. And they often rely on interfaces or boundaries for controlled movement, posing challenges for independent, three-dimensional(3D) navigation of multiple magnetic collectives. To address this challenge, self-assembled microrobotic collectives are proposed that can be selectively actuated in a combination of external magnetic and optical fields. By harnessing both actuation methods, the constraints of single actuation approaches are overcome. The magnetic field excites the self-assembly of colloids and maintains the self-assembled microrobotic collectives without disassembly, while the optical field drives selected microrobotic collectives to perform different tasks. The proposed magnetic-photo microrobotic collectives can achieve independent position and path control in the two-dimensional (2D) plane and 3D space. With this selective control strategy, the microrobotic collectives can cooperate in convection and mixing the dye in a confined space. The results present a systematic approach for realizing selective control of multiple microrobotic collectives, which can address multitasking requirements in complex environments.

Multi-Enzyme Activity of MIL-101 (Fe)-Derived Cascade Nano-Enzymes for Antitumor and Antimicrobial Therapy.

The clinical application of oncology therapy is hampered by high glutathione concentrations, hypoxia, and inefficient activation of cell death mechanisms in cancer cells. In this study, Fe and Mo bimetallic sulfide nanomaterial (FeS2@MoS2) based on metal-organic framework structure is rationally prepared with peroxidase (POD)-, catalase (CAT)-, superoxide dismutase (SOD)-like activities and glutathione depletion ability, which can confer versatility for treating tumors and mending wounds. In the lesion area, FeS2@MoS2 with SOD-like activity can facilitate the transformation of superoxide anions (O2 -) to hydrogen peroxide (H2O2), and then the resulting H2O2 serves as a substrate for the Fenton reaction with FMS to produce highly toxic hydroxyl radicals (∙OH). Simultaneously, FeS2@MoS2 has an ability to deplete glutathione (GSH) and catalyze the decomposition of nicotinamide adenine dinucleotide phosphate (NADPH) to curb the regeneration of GSH from the source. Thus it can realize effective tumor elimination through synergistic apoptosis-ferroptosis strategy. Based on the alteration of the H2O2 system, free radical production, glutathione depletion and the alleviation of hypoxia in the tumor microenvironment, FeS2@MoS2 NPS can not only significantly inhibit tumors in vivo and in vitro, but also inhibit multidrug-resistant bacteria and hasten wound healing. It may open the door to the development of cascade nanoplatforms for effective tumor treatment and overcoming wound infection.

Maternal Vitamin D3 Supplementation in an Oxidized-Oil Diet Protects Fetus from Developmental Impairment and Ameliorates Oxidative Stress in Mouse Placenta and Fetus.

BACKGROUND: Fried food has increased in popularity worldwide. However, deep frying can increase the production of peroxidative toxins in food, which might be harmful to fetal development. The antioxidative effect of vitamin D3 (VD3) has been reported previously. OBJECTIVES: This study aimed to explore how maternal VD3 supplementation in an oxidized-oil diet during gestation affects fetal antioxidative ability and development. METHODS: Pregnant mice were randomly assigned into 3 groups: Control group (diet with fresh soybean oil), OSO group [diet with oxidized soybean oil (OSO)], and OSOV group (diet with OSO and 10,000 IU/Kg VD3). Mice were fed with the corresponding diet during gestation. On day 16.5 of gestation, the placenta and fetus were harvested to analyze antioxidative status. RESULTS: Maternal oxidized-oil diet during gestation significantly reduced placental vessel abundance, labyrinth zone area, and fetal body weight. However, dietary VD3 supplementation prevented these negative effects of oxidized-oil diet. Maternal intake of oxidized-oil diet increased serum concentrations of malondialdehyde, total-nitric oxide synthase, and inducible nitric oxide synthase, whereas VD3 supplementation showed a protection effect on it. Additionally, maternal VD3 supplementation increased the levels of antioxidative enzymes and the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), thereby protecting placenta and fetus from apoptosis and oxidative stress caused by an oxidized-oil diet. The gene expression and protein levels of a fatty acid transporter solute carrier family 27 member 1 in the fetal liver were increased by maternal VD3 supplementation under oxidized-oil diet. Notably, NRF2 could be co-immunoprecipitated with the VD receptor in the placenta. CONCLUSIONS: Maternal VD3 supplementation could protect fetus from oxidized-oil diet induced developmental impairment by alleviating oxidative stress in the placenta and fetus through the VD receptor/NRF2 pathway, at least partially. Thus, ensuring adequate levels of VD3 through supplementation is often critical during pregnancy.

Liver-derived FGF21 is required for the effect of time-restricted feeding on high-fat diet-induced fatty liver in mice.

Nonalcoholic fatty liver disease (NAFLD), which leads to insulin resistance, steatosis, and even hepatocellular carcinoma, is the most common chronic liver disease worldwide, however, effective treatment is still lacking. This study determined the role of liver FGF21 and the mechanisms underlying the protective effects of time-restricted feeding (TRF) in NAFLD. FGF21 liver knockout (FGF21 LKO) mice and C57BL/6 wild-type (WT) mice were fed either a normal or a high-fat diet (HFD) for 16 weeks. Mice with diet-induced obesity (DIO) were also used. The mice were fed either ad libitum or in a time-restricted manner. Serum FGF21 levels were significantly increased after 16 weeks of TRF. TRF prevented body weight gain, improved glucose homeostasis, and protected against high-fat diet-induced hepatosteatosis and liver damage. The expression of genes related to liver lipogenesis and inflammation was reduced in TRF mice, but the expression of genes involved in fatty acid ß-oxidation was increased. However, those beneficial effects of TRF were blunted in the FGF21 LKO mice. Moreover, TRF promoted improvements in insulin sensitivity and liver damage in DIO mice. Our data show that liver FGF21 signaling was involved in the effect of TRF on high-fat diet-induced fatty liver.

How important is food structure when cats eat mice?

Feeding whole prey to felids has shown to benefit their gastrointestinal health. Whether this effect is caused by the chemical or physical nature of whole prey is unknown. Fifteen domestic cats, as a model for strict carnivores, were either fed minced mice (MM) or whole mice (WM), to determine the effect of food structure on digestibility, mean urinary excretion time (MUET) of 15N, intestinal microbial activity and fermentation products. Faeces samples were collected after feeding all cats a commercially available extruded diet (EXT) for 10 d before feeding for 19 d the MM and WM diets with faeces and urine collected from day 11 to 15. Samples for microbiota composition and determination of MUET were obtained from day 16 to 19. The physical structure of the mice diet (minced or not) did not affect large intestinal fermentation as total SCFA and branched-chain fatty acid (BCFA), and most biogenic amine (BA) concentrations were not different (P > 0·10). When changing from EXT to the mice diets, the microbial community composition shifted from a carbolytic (Prevotellaceae) to proteolytic (Fusobacteriaceae) profile and led to a reduced faecal acetic to propionic acid ratio, SCFA, total BCFA (P < 0·001), NH3 (P = 0·04), total BA (P < 0·001) and para-cresol (P = 0·08). The results of this study indicate that food structure within a whole-prey diet is less important than the overall diet type, with major shifts in microbiome and decrease in potentially harmful fermentation products when diet changes from extruded to mice. This urges for careful consideration of the consequences of prey-based diets for gut health in cats.

Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing.

This study employed a drug repositioning strategy to discover novel PD-L1 small molecule inhibitors. 3D-QSAR pharmacophore models were establishedand subsequently validated through various means to select a robust model, Hypo-1, suitable for virtual screening. Hypo1 was used toscreen a library of 7,475 compounds from the Drugbank database, leading to the identification of 283 molecules following molecular docking with PD-L1.19 compounds underwent HTRF assays, with 15 showing varying degrees of inhibition of the PD-1/PD-L1 interaction. Compounds2202,2204,2207, and2208were further confirmed to bind to PD-L1 using SPR experiments. Among them, compound2204(Daclatasvir, KD = 11.4 µM) showeda higher affinity for human PD-L1 than the control compound BMS-1. In the HepG2/Jurkat cell co-culture model, Daclatasvir effectively activated Jurkat cells to kill HepG2 cells. In the mouse H22 hepatocellular tumor model, Daclatasvir significantly inhibited tumor growth (TGI = 53.4 % at a dose of 100 mg/kg). Its anti-tumor effect was more pronounced when combined with Lenvatinib (TGI = 85.1 %). Flow cytometry analysis of splenocytes and tumor cells indicated that Daclatasvir activated the immune system in both models. In summary, Daclatasvir was identified as a novel PD-L1small molecule inhibitor.

Nerolidol attenuates airway inflammation and airway remodeling and alters gut microbes in ovalbumin-induced asthmatic mice.

Asthma is a common respiratory disease associated with airway inflammation. Nerolidol is an acyclic sesquiterpenoid with anti-inflammatory properties. BALB/C mice were sensitized with ovalbumin (OVA) to induce asthma symptoms and given different doses of Nerolidol. We found that Nerolidol reduced OVA-induced inflammatory cell infiltration, the number of goblet cells and collagen deposition in lung tissue. Nerolidol reduced the OVA-specific IgE levels in serum and alveolar lavage fluid in an asthma model. Immunohistochemical staining of α-SMA (the marker of airway smooth muscle) showed that Nerolidol caused bronchial basement membrane thinning in asthmatic mice. The hyperplasia of airway smooth muscle cells (ASMCs) is an important feature of airway remodeling in asthma. ASMCs were treated with 10 ng/mL TGF-ß to simulate the pathological environment of asthma in vitro and then treated with different doses of Nerolidol. Nerolidol inhibited the activity of TGF-ß/Smad signaling pathway both in the lung tissue of OVA-induced mouse and TGF-ß-stimulated ASMCs. 16s rRNA sequencing was performed on feces of normal mice, the changes of intestinal flora in OVA-induced asthmatic mice and Nerolidol-treated asthmatic mice were studied. The results showed that Nerolidol reversed the reduced gut microbial alpha diversity in asthmatic mice. Nerolidol changed the relative abundance of gut bacteria at different taxonomic levels. At the phylum level, the dominant bacteria were Bacteroidota, Firmicutes, and Proteobacteria. At the genus level, the dominant bacteria were Lactobacillus, Muribaculaceae, Bacteroides, and Lachnospiraceae. We conclude that Nerolidol attenuates OVA-induced airway inflammation and alters gut microbes in mice with asthma via TGF-ß/Smad signaling.

Hollow CoZnSe@CN nanocage with enzymatic activity for determination of tetracycline using smartphone platforms and virtual reality revealing.

Antibiotic residues in the environment pose a serious threat to ecosystems and human health. Therefore, it is important to develop sensitive and rapid in situ detection methods. In this work, the designed nanozymes, with excellent four enzyme activities, were proved to be constituted of unique hollow nanocage structures (CoZnSe@CN HCs). Based on the peroxidase-like enzymes, a portable colorimetric sensor was constructed for the on-site determination of tetracycline (TC) in real samples. The linear range of TC detection was 0.1-100 µM, and the detection limit was 0.02 µM. At the same time, colorimetric detection and smartphones have also been combined for on-site colorimetric detection of TC. In-depth exploration of the detection mechanism showed that TC could be bound with the material, inhibiting the production of oxidized 3,3',5,5'-tetramethylbenzidine. The sensor was also used for the detection of TC in environmental soil and water samples. This study can provide an intelligent detection method for environmental monitoring.

The Simultaneous Efficient Recovery of Ammonia Nitrogen and Phosphate Resources in the Form of Struvite: Optimization and Potential Applications for the Electrochemical Reduction of NO3.

In response to the need for improvement in the utilization of ammonium-rich solutions after the electrochemical reduction of nitrate (NO3--RR), this study combined phosphorus-containing wastewater and adopted the electrochemical precipitation method for the preparation of struvite (MAP) to simultaneously recover nitrogen and phosphorus resources. At a current density of 5 mA·cm-2 and an initial solution pH of 7.0, the recovery efficiencies for nitrogen and phosphorus can reach 47.15% and 88.66%, respectively. Under various experimental conditions, the generated struvite (MgNH4PO4·6H2O) exhibits a typical long prismatic structure. In solutions containing nitrate and nitrite, the coexisting ions have no significant effect on the final product, struvite. Finally, the characterization of the precipitate product by X-ray diffraction (XRD) revealed that its main component is struvite, with a high purity reaching 93.24%. Overall, this system can effectively recover ammonium nitrogen from the NO3--RR solution system after nitrate reduction, with certain application prospects for the recovery of ammonium nitrogen and phosphate.

Carbon footprints and health security: A comparative assessment of the Sustainable Development Goals 3 and 13 in East Asian countries.

In East Asia, where several countries are among the top emitters of carbon dioxide globally, the need to address the dual challenges of reducing carbon footprints and ensuring health security is paramount. Against this backdrop, this study used a descriptive analysis to provide a comparative assessment of the carbon footprints and the level of health security in East Asia using secondary data, sourced from the World Development Indicators. The findings from the study show that it is only North Korea that its average carbon footprint of every person is less than 2.3 tons. However, China, Japan, Mongolia and South Korea are currently lagging behind in meeting the SDG 13 target. Meanwhile, North Korea recorded the highest incidence of tuberculosis in the region. Despite the fact that South Korea and Japan were the highest emitter of CO2, the duo had the lowest under five mortality, infant mortality, incidence of TB alongside the highest life expectancies which surpassed the regional performance. In view of the above, the policymakers in Asia and the rest of the countries with health insecurity should emulate the policymakers in Japan and South Korea by making adequate investment in health, education, and standard of living of their citizens.

En Asie de l'Est, où plusieurs pays comptent parmi les plus grands émetteurs de dioxyde de carbone au monde, la nécessité de relever le double défi de réduire l'empreinte carbone et d'assurer la sécurité sanitaire est primordiale. Dans ce contexte, cette étude a utilisé une analyse descriptive pour fournir une évaluation comparative des empreintes carbone et du niveau de sécurité sanitaire en Asie de l'Est à l'aide de données secondaires provenant des indicateurs de développement mondial. Les résultats de l'étude montrent que seule la Corée du Nord a une empreinte carbone moyenne par personne inférieure à 2,3 tonnes. Cependant, la Chine, le Japon, la Mongolie et la Corée du Sud sont actuellement à la traîne dans la réalisation de l'ODD 13. Pendant ce temps, la Corée du Nord a enregistré la plus forte incidence de tuberculose dans la région. Bien que la Corée du Sud et le Japon soient les plus grands émetteurs de CO2, ces deux pays ont les taux de mortalité des moins de cinq ans, de mortalité infantile et d'incidence de tuberculose les plus faibles, ainsi que les espérances de vie les plus élevées, dépassant les performances régionales. Compte tenu de ce qui précède, les décideurs politiques d'Asie et du reste des pays souffrant d'insécurité sanitaire devraient imiter les décideurs politiques du Japon et de la Corée du Sud en investissant de manière adéquate dans la santé, l'éducation et le niveau de vie de leurs citoyens.

Bipolar membrane electrodialysis integrated with in-situ CO2 absorption for simulated seawater concentrate utilization, carbon storage and production of sodium carbonate.

In the context of carbon capture, utilization, and storage, the high-value utilization of carbon storage presents a significant challenge. To address this challenge, this study employed the bipolar membrane electrodialysis integrated with carbon utilization technology to prepare Na2CO3 products using simulated seawater concentrate, achieving simultaneous saline wastewater utilization, carbon storage and high-value production of Na2CO3. The effects of various factors, including concentration of simulated seawater concentrate, current density, CO2 aeration rate, and circulating flow rate of alkali chamber, on the quality of Na2CO3 product, carbon sequestration rate, and energy consumption were investigated. Under the optimal condition, the CO32- concentration in the alkaline chamber reached a maximum of 0.817 mol/L with 98 mol% purity. The resulting carbon fixation rate was 70.50%, with energy consumption for carbon sequestration and product production of 5.7 kWhr/m3 CO2 and 1237.8 kWhr/ton Na2CO3, respectively. This coupling design provides a triple-win outcome promoting waste reduction and efficient utilization of resources.

2-Undecanone alleviates asthma by inhibiting NF-κB pathway.

Asthma is characterized by airway inflammation and remodeling. 2-Undecanone (methyl nonyl ketone), a volatile organic compound originating from Houttuynia cordata, has the potential to ameliorate inflammatory diseases. This study aimed to explore potential benefits of 2-undecanone in asthma. 2-Undecanone (100, 200, or 400 mg/kg) was administered intragastrically to ovalbumin (OVA)-challenged BALB/c mice. Lung tissues were collected to observe histopathological changes, and bronchoalveolar lavage fluid (BALF) was collected for the detection of inflammatory cells and cytokine production. The results showed that 2-undecanone ameliorated OVA-induced pathologic changes of lungs, including reducing inflammatory cell infiltration, goblet cell hyperplasia, and airway smooth muscle thickness. The number of inflammatory cells and the levels of IL-4, IL-5, IL-13, and IgE in BALF were decreased by 2-undecanone in asthmatic mice. Furthermore, abnormal activation of NF-κB pathway in lung tissues of asthmatic mice was impeded by 2-undecanone. In vitro, 2-undecanone (12.5, 25, or 50 µM) suppressed platelet-derived growth factor-BB-induced proliferation and migration of primary airway smooth muscle cells (ASMCs), and inhibited the switching of ASMCs from contractile phenotype to synthetic phenotype. Consistently, 2-undecanone blocked NF-κB activation in ASMCs. Collectively, 2-undecanone relieves asthma through alleviating airway inflammation and remodeling, and this beneficial effect is achieved by inhibiting NF-κB pathway.

Time-Restricted Feeding Ameliorates Uterine Epithelial Estrogen Receptor α Transcriptional Activity at the Time of Embryo Implantation in Mice Fed a High-Fat Diet.

BACKGROUND: More than 30% of reproductive-age women are obese or overweight. Obesity and exposure to a high-fat diet (HFD) detrimentally affect endometrial development and embryo implantation. We previously reported that time-restricted feeding (TRF) improved ovarian follicular development, but whether and how TRF modulates embryo implantation are poorly understood. OBJECTIVE: We investigated the effect of TRF on embryo implantation. METHODS: In TRF group, mice had 10 h of food free access from 9 pm to 7 am, and fed a normal diet or a HFD. Tail vein injection of Chicago blue dye was used to examine embryo implantation sites at day 5.5 (D5.5) of pregnancy. Serum collected at D0.5 and D4.5 of pregnancy was used to examine the level of estradiol (E2) and progesterone. Uterine estrogen receptor (ER) and progesterone receptor levels and their targeted aquaporins (AQPs) were measured. LC-MS was used to analyze bile acid (BA) composition, and primary hepatocytes were used to test the effects of BA on the expression level of SULT1E1, a key enzyme in estrogen inactivation and elimination. RESULTS: We found that TRF prevented HFD-induced embryo loss and alleviated the defect in luminal closure on D4.5 of pregnancy. The cyclic changes of E2 level were lost in mice fed ad libitum but not in TRF mice on the HFD. The HFD increased ER-α expression and transcriptional activity, which induced AQP3 and AQP5 expression on D4.5 of pregnancy. TRF prevented the negative effect of the HFD on uterine luminal closure. Furthermore, in vitro and in vivo results showed that BA suppressed estrogen degradation by activating liver SULT1E1 expression. CONCLUSIONS: Our findings demonstrated that TRF prevented HFD-induced defects in luminal closure, thereby improving embryonic implantation, and provide novel insights into the effects of dietary intervention on obesity and associated infertility.

Efficacy and safety of macrolides in the treatment of children with bronchiectasis: a meta-analysis.

BACKGROUND: This study summarized the available randomized controlled trials (RCTs) to assess the efficacy and safety of macrolides on pathogens, lung function, laboratory parameters, and safety in children with bronchiectasis. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for available papers published up to June 2021. The outcomes were the pathogens, adverse events (AEs), and the forced expiratory volume in one second (FEV1%) predicted. RESULTS: Seven RCTs (633 participants) were included. The long-term use of macrolides reduced the risk of the presence of Moraxella catarrhalis (RR = 0.67, 95% CI: 0.30-1.50, P = 0.001; I2 = 0.0%, Pheterogeneity = 0.433), but not Haemophilus influenza (RR = 0.19, 95% CI: 0.08-0.49, P = 0.333; I2 = 57.0%, Pheterogeneity = 0.040), Streptococcus pneumonia (RR = 0.91, 95% CI: 0.61-1.35, P = 0.635; I2 = 0.0%, Pheterogeneity = 0.515), Staphylococcus aureus (RR = 1.01, 95% CI: 0.36-2.84, P = 0.986; I2 = 61.9%, Pheterogeneity = 0.033), and any pathogens present (RR = 0.61, 95% CI: 0.29-1.29, P = 0.195; I2 = 80.3%, Pheterogeneity = 0.006). Long-term macrolides had no effect on FEV1% predicted (WMD = 2.61, 95% CI: -1.31, 6.53, P = 0.192; I2 = 0.0%, Pheterogeneity = 0.896). Long-term macrolides did not increase the risk of AEs or serious AEs. CONCLUSION: Macrolides do not significantly reduce the risk of pathogens present (except for Moraxella catarrhalis) or increase FEV1% predicted among children with bronchiectasis. Moreover, macrolides were not associated with AEs. Considering the limitations of the meta-analysis, further larger-scale RCTs are needed to confirm the findings. IMPACT: Macrolides do not significantly reduce the risk of pathogens present (except for Moraxella catarrhalis) among children with bronchiectasis. Macrolides do not significantly increase FEV1% predicted among children with bronchiectasis. This meta-analysis reports on the efficacy and safety of macrolides in the treatment of children with bronchiectasis, providing evidence for the management of children with bronchiectasis. This meta-analysis does not support the use of macrolides in the management of children with bronchiectasis unless the presence of Moraxella catarrhalis is provenor suspected.

Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation.

Drug-induced liver injury (DILI) is a widespread and harmful disease, and is closely linked to acute endoplasmic reticulum (ER) stress. Previous reports have shown that acute ER stress can suppress hepatic gluconeogenesis and even leads to hypoglycemia. However, the mechanism is still unclear. MAPK phosphatase 3 (MKP-3) is a positive regulator for gluconeogenesis. Thus, this study was conducted to investigate the role of MKP-3 in the suppression of gluconeogenesis by acute ER stress, as well as the regulatory role of acute ER stress on the expression of MKP-3. Results showed that acute ER stress induced by tunicamycin significantly suppressed gluconeogenesis in both hepatocytes and mouse liver, reduced glucose production level in hepatocytes, and decreased fasting blood glucose level in mice. Additionally, the protein level of MKP-3 was reduced by acute ER stress in both hepatocytes and mouse liver. Mkp-3 deficiency eliminated the inhibitory effect of acute ER stress on gluconeogenesis in hepatocytes. Moreover, the reduction effect of acute ER stress on blood glucose level and hepatic glucose 6-phosphatase (G6pc) expression was not observed in the liver-specific Mkp-3 knockout mice. Furthermore, activation of protein kinase R-like ER kinase (PERK) decreased the MKP-3 protein level, while inactivation of PERK abolished the reduction effect of acute ER stress on the MKP-3 protein level in hepatocytes. Taken together, our study suggested that acute ER stress could suppress hepatic gluconeogenesis by stimulating MKP-3 degradation via PERK, at least partially. Thus, MKP-3 might be a therapeutic target for DILI-related hypoglycemia.

Selective electrodialysis process for the recovery of potassium from multicomponent solution systems.

Selective electrodialysis is a promising approach to recovering K+ from complex coexisting ionic systems. In this study, the effects of current density, the concentration of K+ and Mg2+, as well as the operating temperature on the separation process of K+ and Mg2+ were explored to investigate the competitive migration of mono- and multivalent ions, offering a guide for the design of selective electrodialysis process, and therefore obtain the desired aqueous solutions containing K+ and Mg2+. The results show that ion concentration played a critical role in determining the selectivity of separation between K+ and Mg2+. High concentrations of K+ and Mg2+ led to a decrease in selectivity but the effect of concentration of K+ on selectivity was more pronounced. Although higher current density increased the flux of ions, their impact on separation selectivity was minimal. Furthermore, higher temperature increased the flux of ions but resulted in a decrease of K+ proportion in the solution. Overall, this study provides good guidance for studying the competitive migration of mono- and multivalent ions and the high-value recycling of potassium resources.

Infiltration and Polarization of Tumor-associated Macrophages Predict Prognosis and Therapeutic Benefit in Muscle-Invasive Bladder Cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is an aggressive and heterogeneous malignancy. Tumor-associated macrophages (TAMs) are key infiltrating cell populations in the inflammatory microenvironment of malignant tumors including MIBC. It intrigues us to explore the clinical significance and immunoregulatory role of TAMs infiltration and polarization in MIBC. METHODS: A total of 141 patients with MIBC from Zhongshan Hospital and 391 patients with MIBC from The Cancer Genome Atlas (TCGA) database were included in this study. Moreover, 195 patients who received anti-PD-L1 therapy from the IMvigor210 trial were enrolled. Patients were categorized into three subtypes considering the infiltration level and polarization status of TAMs, denoted as TAMlow (Subtype I), TAMhigh&M2/M1low (Subtype II), and TAMhigh&M2/M1high (Subtype III). RESULTS: Subtype III suffered inferior prognosis, and Subtype II could benefit more from adjuvant chemotherapy (ACT). Subtype III was featured with increased pro-tumor cells and immunosuppressive cytokines, while Subtype II possessed more immunogenic cells infiltration with activated and tumoricidal properties. Subtype II and Subtype III presented basal/squamous-like characterization and showed additional prognostic merit beyond molecular classification. Subtype I exhibited elevated level of FGFR3 signature, while Subtype II had EGFR signaling activation and immunotherapeutic indication. Additionally, Subtype II patients were indeed highly sensitive to PD-L1 blockade therapy in IMvigor210 trial. CONCLUSION: The infiltration and polarization status of TAMs shaped distinct immune microenvironment with predictive significance for survival outcome, ACT benefit, and PD-L1 blockade therapy sensitivity in MIBC. Immune classification based on TAMs polarization and infiltration might provide tools to tailor chemotherapy and immunotherapy.

Polymorphism of rs12294045 in EAAT2 gene is potentially associated with schizophrenia in Chinese Han population.

BACKGROUND: Recent studies have shown that the excitatory amino acid transporters (EAATs) are associated with schizophrenia. The aim of this study was to investigate the relationship between the polymorphism of EAAT1 and EAAT2 genes and schizophrenia in Chinese Han population. METHODS: A total of 233 patients with schizophrenia and 342 healthy controls were enrolled. Two SNPs in EAAT1 gene (rs2269272, rs2731880) and four SNPs in EAAT2 gene (rs12360706, rs3088168, rs12294045, rs10836387) were genotyped by SNaPshot. Clinical features were collected using a self-made questionnaire. Psychotic symptoms of patients were measured by the Positive and Negative Syndrome Scale (PANSS), and patients' cognitive function was assessed by Matrics Consensus Cognitive Battery (MCCB). RESULTS: Significant difference in allelic distributions between cases and controls was confirmed at locus rs12294045 (Ρ = 0.004) of EAAT2 gene. Different genotypes of rs12294045 were associated with family history (P = 0.046), in which patients with CT genotype had higher proportion of family history of psychosis. The polymorphism of rs12294045 was related to working operational memory (LNS: P = 0.016) and verbal learning function (HVLT-R: P = 0.042) in patients in which CT genotype had lower scores. However, these differences were no longer significant after Bonferroni correction. CONCLUSIONS: Our study showed that the polymorphism of rs12294045 in EAAT2 gene may be associated with schizophrenia in Chinese Han population. CT genotype may be one of the risk factors for family history and cognitive deficits of patients.