A sensitive and specific genetically-encoded potassium ion biosensor for in vivo applications across the tree of life.

Potassium ion (K+) plays a critical role as an essential electrolyte in all biological systems. Genetically-encoded fluorescent K+ biosensors are promising tools to further improve our understanding of K+-dependent processes under normal and pathological conditions. Here, we report the crystal structure of a previously reported genetically-encoded fluorescent K+ biosensor, GINKO1, in the K+-bound state. Using structure-guided optimization and directed evolution, we have engineered an improved K+ biosensor, designated GINKO2, with higher sensitivity and specificity. We have demonstrated the utility of GINKO2 for in vivo detection and imaging of K+ dynamics in multiple model organisms, including bacteria, plants, and mice.

Platinum complexes with aggregation-induced emission.

Transition metal-containing materials with aggregation-induced emission (AIE) have brought new opportunities for the development of biological probes, optoelectronic materials, stimuli-responsive materials, sensors, and detectors. Coordination compounds containing the platinum metal have emerged as a promising option for constructing effective AIE platinum complexes. In this review, we classified AIE platinum complexes based on the number of ligands. We focused on the development and performance of AIE platinum complexes with different numbers of ligands and discussed the impact of platinum ion coordination and ligand structure variation on the optoelectronic properties. Furthermore, this review analyzes and summarizes the influence of molecular geometries, stacking models, and aggregation environments on the optoelectronic performance of these complexes. We provided a comprehensive overview of the AIE mechanisms exhibited by various AIE platinum complexes. Based on the unique properties of AIE platinum complexes with different numbers of ligands, we systematically summarized their applications in electronics, biological fields, etc. Finally, we illustrated the challenges and opportunities for future research on AIE platinum complexes, aiming at giving a comprehensive summary and outlook on the latest developments of functional AIE platinum complexes and also encouraging more researchers to contribute to this promising field.

Structure Responsible for the Superconducting State in La3Ni2O7 at High-Pressure and Low-Temperature Conditions.

Very recently, a new superconductor with Tc = 80 K has been reported in nickelate (La3Ni2O7) at around 15-40 GPa conditions (Nature, 621, 493, 2023), which is the second type of unconventional superconductor, besides cuprates, with Tc above liquid nitrogen temperature. However, the phase diagram plotted in this report was mostly based on the transport measurement under low-temperature and high-pressure conditions, and the assumed corresponding X-ray diffraction (XRD) results were carried out at room temperature. This encouraged us to carry out in situ high-pressure and low-temperature synchrotron XRD experiments to determine which phase is responsible for the high Tc state. In addition to the phase transition from the orthorhombic Amam structure to the orthorhombic Fmmm structure, a tetragonal phase with the space group of I4/mmm was discovered when the sample was compressed to around 19 GPa at 40 K where the superconductivity takes place in La3Ni2O7. The calculations based on this tetragonal structure reveal that the electronic states that approached the Fermi energy were mainly dominated by the eg orbitals (3dz2 and 3dx2-y2) of Ni atoms, which are located in the oxygen octahedral crystal field. The correlation between Tc and this structural evolution, especially Ni-O octahedra regularity and the in-plane Ni-O-Ni bonding angles, is analyzed. This work sheds new light to identify what is the most likely phase responsible for superconductivity in double-layered nickelate.

LncRNA HBL1 is required for genome-wide PRC2 occupancy and function in cardiogenesis from human pluripotent stem cells.

Polycomb repressive complex 2 (PRC2) deposits H3K27me3 on chromatin to silence transcription. PRC2 broadly interacts with RNAs. Currently, the role of the RNA-PRC2 interaction in human cardiogenesis remains elusive. Here, we found that human-specific heart brake lncRNA 1 (HBL1) interacted with two PRC2 subunits, JARID2 and EED, in human pluripotent stem cells (hPSCs). Loss of JARID2, EED or HBL1 significantly enhanced cardiac differentiation from hPSCs. HBL1 depletion disrupted genome-wide PRC2 occupancy and H3K27me3 chromatin modification on essential cardiogenic genes, and broadly enhanced cardiogenic gene transcription in undifferentiated hPSCs and later-on differentiation. In addition, ChIP-seq revealed reduced EED occupancy on 62 overlapped cardiogenic genes in HBL1-/- and JARID2-/- hPSCs, indicating that the epigenetic state of cardiogenic genes was determined by HBL1 and JARID2 at pluripotency stage. Furthermore, after cardiac development occurs, the cytosolic and nuclear fractions of HBL1 could crosstalk via a conserved 'microRNA-1-JARID2' axis to modulate cardiogenic gene transcription. Overall, our findings delineate the indispensable role of HBL1 in guiding PRC2 function during early human cardiogenesis, and expand the mechanistic scope of lncRNA(s) that cytosolic and nuclear portions of HBL1 could coordinate to orchestrate human cardiogenesis.

InSb all-dielectric metasurface for ultrahigh efficient Si-based mid-infrared detection.

Mid-infrared (MIR) Si-based optoelectronics has wide potential applications, and its design requires simultaneous consideration of device performance optimization and the feasibility of heterogeneous integration. The emerging interest in all-dielectric metasurfaces for optoelectronic applications stems from their exceptional ability to manipulate light. In this Letter, we present our research on an InSb all-dielectric metasurface designed to achieve ultrahigh absorptivity within the 5-5.5 µm wavelength range. By integrating an InSb nanodisk array layer on a Si platform using wafer bonding and heteroepitaxial growth, we demonstrate three kinds of metasurface with high absorptivity of 98.36%, 99.28%, and 99.18%. The enhanced absorption is mainly contributed by the Kerker effect and the anapole state and the peak, with the added flexibility of tuning both the peak and bandwidth of absorption by altering the metasurface parameters. Our findings provide an alternative scheme to develop high-performance detectors and absorbers for MIR silicon photonics.

Diclofenac sodium effectively inhibits the biofilm formation of Staphylococcus epidermidis.

Staphylococcus epidermidis is an opportunistic pathogen commonly implicated in medical device-related infections. Its propensity to form biofilms not only leads to chronic infections but also exacerbates the issue of antibiotic resistance, necessitating high-dose antimicrobial treatments. In this study, we explored the use of diclofenac sodium, a non-steroidal anti-inflammatory drug, as an anti-biofilm agent against S. epidermidis. In this study, crystal violet staining and confocal laser scanning microscope analysis showed that diclofenac sodium, at subinhibitory concentration (0.4 mM), significantly inhibited biofilm formation in both methicillin-susceptible and methicillin-resistant S. epidermidis isolates. MTT assays demonstrated that 0.4 mM diclofenac sodium reduced the metabolic activity of biofilms by 25.21-49.01% compared to untreated controls. Additionally, the treatment of diclofenac sodium resulted in a significant decrease (56.01-65.67%) in initial bacterial adhesion, a crucial early phase of biofilm development. Notably, diclofenac sodium decreased the production of polysaccharide intercellular adhesin (PIA), a key component of the S. epidermidis biofilm matrix, in a dose-dependent manner. Real-time quantitative PCR analysis revealed that diclofenac sodium treatment downregulated biofilm-associated genes icaA, fnbA, and sigB and upregulated negative regulatory genes icaR and luxS, providing potential mechanistic insights. These findings indicate that diclofenac sodium inhibits S. epidermidis biofilm formation by affecting initial bacterial adhesion and the PIA synthesis. This underscores the potential of diclofenac sodium as a supplementary antimicrobial agent in combating staphylococcal biofilm-associated infections.

System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.

HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.

Association between lactate dehydrogenase and ventilator-associated pneumonia risk: an analysis of the MIMIC database 2001-2019.

BACKGROUND: Serum lactate dehydrogenase (LDH) is a nonspecific inflammatory biomarker and has been reported to be associated with pneumonia prognosis. This study aimed to evaluate the relationship between LDH levels and ventilator-associated pneumonia (VAP) risk in intensive care unit (ICU) patients. METHODS: This retrospective cohort study used data from the Multiparameter Intelligent Monitoring in Intensive Care database from 2001 to 2019. ICU patients aged ≥ 18 years and receiving mechanical ventilation were included. LDH levels were analyzed as continuous and categorical variables (< 210, 210-279, 279-390, > 390 IU/L), respectively. Restricted cubic spline (RCS) curves and quartiles were used to categorize LDH levels. Logistic regression and linear regression were utilized to assess the relationship of LDH levels with VAP risk and duration of mechanical ventilation, respectively. RESULTS: A total of 9,164 patients were enrolled, of which 646 (7.05%) patients developed VAP. High levels of LDH increased the risk of VAP [odds ratio (OR) = 1.15, 95% confidence interval (CI): 1.06-1.24] and LDH levels were positively correlated with the duration of mechanical ventilation [ß = 4.49, 95%CI: (3.42, 5.56)]. Moreover, patients with LDH levels of 279-390 IU/L (OR = 1.38, 95%CI: 1.08-1.76) and > 390 IU/L (OR = 1.50, 95%CI: 1.18-1.90) had a higher risk of VAP than patients with LDH levels < 210 IU/L. Patients with LDH levels of 279-390 IU/L [ß = 3.84, 95%CI: (0.86, 6.82)] and > 390 IU/L [ß = 11.22, 95%CI: (8.21, 14.22)] (vs. <210 IU/L) had a longer duration of mechanical ventilation. CONCLUSION: Elevated serum LDH levels were related to a higher risk of VAP and longer duration of mechanical ventilation and may be useful for monitoring VAP risk.

Efficient K-Storage of Fe-Coupled Organic Molecule Anode in Ether-Based Electrolytes.

Given these advantages of widely designable structures and environmentally friendly characteristics, organic electrode materials (OEMs) are considered to be promising electrode materials for alkaline metal-ion batteries. However, their large-scale application is hampered by insufficient specific capacity and rate performance. Here, Fe2+ is coupled to the anhydride molecule NTCDA to form a novel K-storage anode Fe-NTCDA. In this way, the working potential of Fe-NTCDA anode is reduced, which makes it more suitable to be used as an anode material. Meanwhile, the electrochemical performance is significantly improved due to the increase in K-storage sites. Moreover, electrolytes regulation is implemented to optimize the K-storage behavior, resulting into a high specific capacity of 167 mAh/g after 100 cycles at 50 mA/g and 114 mAh/g even at 500 mA/g in the 3 M KFSI/DME electrolytes.

Pseudo[n]-pillar[5]arenes: Synthesis, Structures, and Host-Guest Binding Properties.

[1n]Paracyclophane has been known for nearly 40 years, but its derivatives and properties are understudied in comparison to those of other macrocyclic compounds. By the modification of pillar[5]arene, we successfully obtained five electron-rich pentagonal macrocycles (pseudo[n]-pillar[5]arenes, n = 1-4) with the decrease of substituted phenylenes one after another, achieving the partial derivatization of [15]paracyclophane skeleton at its phenylene sites. Pseudo[n]-pillar[5]arenes (P[n]P[5]s) served as a kind of macrocyclic host to form complexes with various guests, such as dinitriles, dihaloalkanes, and imidazolium salt, in a 1:1 host-guest stoichiometric ratio. The binding constants with the guest gradually reduce along the decrease of substituted phenylene segments from host P[1]P[5] to P[4]P[5]. It is worthy to note that P[n]P[5]s can adjust their conformations to the "pillar-like" shape effectively when binding with succinonitrile in the solid state.

Mechanisms of Obesity-Induced Changes in Pharmacokinetics of IgG in Rats.

PURPOSE: To evaluate how obesity affects the pharmacokinetics of human IgG following subcutaneous (SC) and intravenous (IV) administration to rats and the homeostasis of endogenous rat IgG. METHODS: Differences in body weight and size, body composition, and serum concentration of endogenous rat IgG in male Zucker obese (ZUC-FA/FA) and control (ZUC-LEAN) rats were measured from the age of 5 weeks up to 30 weeks. At the age of 23-24 weeks animals received a single IV or SC dose of human IgG (1 g/kg of total body weight), and serum pharmacokinetics was followed for 7 weeks. A mechanistic model linking obesity-related changes in pharmacokinetics with animal growth and changes in body composition was developed. RESULTS: Significant differences were observed in both endogenous and exogenous IgG pharmacokinetics between obese and control groups. The AUC for human IgG was lower in obese groups (57.6% of control after IV and 48.1% after SC dosing), and clearance was 1.75-fold higher in obese animals. The mechanistic population model successfully captured the data and included several major components: endogenous rat IgG homeostasis with age-dependent synthesis rate; competition of human IgG and endogenous rat IgG for FcRn binding and its effect on endogenous rat IgG concentrations following injection of a high dose of human IgG; and the effect of body size and composition (changing over time and dependent on the obesity status) on pharmacokinetic parameters. CONCLUSIONS: We identified important obesity-induced changes in the pharmacokinetics of IgG. Results can potentially facilitate optimization of the dosing of IgG-based therapeutics in the obese population.

Absolute quantification of SARS-CoV-2 with Clarity Plus™ digital PCR.

In recent years, the usage of digital polymerase chain reaction (dPCR) for various clinical applications has increased exponentially. In this study, a dPCR assay optimized on the Clarity Plus™ dPCR system was evaluated for the absolute quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global coronavirus disease 2019 (COVID-19) outbreak. The assay demonstrated good inter- and intra- assay precision, accuracy, as well as excellent linearity across a range of over 6 orders of magnitude for target gene quantification. In addition, a comparison of the assay on both dPCR and qPCR platforms revealed that dPCR exhibited a slightly higher sensitivity compared to its qPCR counterpart when quantifying SARS-CoV-2 at a lower concentration. Overall, the results showed that the dPCR assay is a reliable and effective approach for the absolute quantification of SARS-CoV-2 and can be a valuable molecular tool in clinical applications such as detecting low viral loads in patients as well as in wastewater surveillance of COVID-19.

First-principles studies on the electronic and photocatalytic water splitting properties of surface functionalized Y2C-based MXenes.

Recently, MXenes, an emerging family of two-dimensional (2D) materials, have attracted increasing interest for photocatalytic water splitting due to their various excellent physical and chemical properties, such as large specific surface area, good hydrophilicity, and remarkable light absorption ability. However, the photocatalysts of MXenes with symmetric structures are limited by rapid recombination of photo-generated carriers and the prerequisite of a large band gap no less than 1.23 eV. Differently, Janus MXenes with different surface functional groups facilitate the separation of photo-generated electrons and holes with the help of the intrinsic electric field. And, at the same time, there is no prerequisite for the band gap of Janus MXene photocatalysts as long as they possess appropriate band edge positions. Here, we explored the structural, electronic and photocatalytic water splitting properties of symmetric Y2CT2 and Janus Y2CTT' MXenes (T, T' = H, F, Cl, OH) using the density functional theory (DFT) method. Our calculations show that all the investigated Y2CT2 are not suitable photocatalysts for photocatalytic water splitting at all pH values (pH = 0, 7, and 14). In contrast, all the investigated Janus Y2CTT' MXenes are good water splitting photocatalysts with high optical absorption coefficients and remarkable solar-to-hydrogen (STH) efficiencies larger than 18% at pH = 14. Moreover, the STH efficiencies are larger than 18% even at all investigated pH values for Y2CHCl (18.5-22.6%), Y2 CFCl (∼18.7%), and Y2 C(OH)Cl (∼19.4%). Based on the first-principles calculations, we here for the first time propose an easy strategy to design Janus MXene photocatalyst candidates with possible high STH efficiency according to the electronic properties of their symmetric counterparts. Our study is helpful for the future design of Janus MXenes and more generally Janus 2D photocatalysts for water splitting with high STH efficiency.

Method for establishing soil contaminant discharge inventory: An arsenic-contaminated site case study.

The existing method to survey site pollution is generally based on soil-groundwater sampling and instrumental analysis, which enables us to access the detailed soil pollution status while lacking quantitative association with industrial activities. It is urgent to understand contaminant discharge modes and establish a discharge inventory for achieving process-targeted pollution control. This study took a 40-year phosphate fertilizer-sulfuric acid site as an example and constructed a contaminant tracing method based on on-site investigations and detailed industrial data. These investigations and data were combined to determine the characteristic pollutant of this site, arsenic. And the calculation process of four-pathway pollution modes (atmospheric deposition, wastewater, solid waste leaching, and storage dripping) is derived from the existing acceptance criteria and risk assessment guidelines. They are set to calculate the arsenic's factory-to-soil discharge flux. The absent process contaminant release information and parameters, such as discharge coefficient, were obtained from soil-groundwater pollution control standards and discharge handbooks. It was found that the high concentration of arsenic (around 1930 mg g-1) was preponderantly caused by sulfur-iron slag and tailing leaching (96.19%), while the other pathways accounted for only 0.13% (atmospheric deposition), 3.59% (wastewater) and 0.09% (storage tank). Results were verified by the measured arsenic concentration, and the difference was +16.29%, which was acceptable. Finally, a contaminant discharge inventory was established with high-resolution spatial distribution and time-scale (historical discharge) evolution. The innovation of this study lies in the preliminary construction of a method for formulating soil discharge inventory. This study would contribute to the refined management of site pollution and reduction of source contaminants discharge. In addition, it will help infer the pollution condition of sites that are difficult to sample so as to help the government achieve precise source control.

HSF1 Alleviates Brain Injury by Inhibiting NLRP3-Induced Pyroptosis in a Sepsis Model.

Background: Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient's prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective: NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods: In this study, we used wild-type mice and hsf1 -/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results: The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1 -/- mouse model compared to hsf1 +/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion: These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.

A Mechanism Study of Redox Reactions of the Ruthenium-oxo-polypyridyl Complex.

Over the years, RuIV(bpy)2(py)(O)2+([RuIVO]2+) has garnered considerable interest owing to its extensive use as a polypyridine mono-oxygen complex. However, as the active-site Ru=O bond changes during the oxidation process, [RuIVO]2+ can be used to simulate the reactions of various high-priced metallic oxides. In order to elucidate the hydrogen element transfer process between the Ruthenium-oxo-polypyridyl complex and organic hydride donor, the current study reports on the synthesis of [RuIVO]2+, a polypyridine mono-oxygen complex, in addition to 1H and 3H (organic hydride compounds) and 1H derivative: 2. Through 1H-NMR analysis and thermodynamics- and kinetics-based assessments, we collected data on [RuIVO]2+ and two organic hydride donors and their corresponding intermediates and established a thermodynamic platform. It was confirmed that a one-step hydride transfer reaction between [RuIVO]2+ and these organic hydride donors occurs, and here, the advantages and nature of the new mechanism approach are revealed. Accordingly, these findings can considerably contribute to the better application of the compound in theoretical research and organic synthesis.

Introducing Spiro-locks into the Nitrogen/Carbonyl System towards Efficient Narrowband Deep-blue Multi-resonance TADF Emitters.

The current availability of multi-resonance thermally activated delayed fluorescence (MR-TADF) materials with excellent color purity and high device efficiency in the deep-blue region is appealing. To address this issue in the emerged nitrogen/carbonyl MR-TADF system, we propose a spiro-lock strategy. By incorporating spiro functionalization into a concise molecular skeleton, a series of emitters (SFQ, SOQ, SSQ, and SSeQ) can enhance molecular rigidity, blue-shift the emission peak, narrow the emission band, increase the photoluminescence quantum yield by over 92 %, and suppress intermolecular interactions in the film state. The referent CZQ without spiro structure has a more planar skeleton, and its bluer emission in the solution state redshifts over 40 nm with serious spectrum broadening and a low PLQY in the film state. As a result, SSQ achieves an external quantum efficiency of 25.5 % with a peak at 456 nm and a small full width at half maximum of 31 nm in a simple unsensitized device, significantly outperforming CZQ. This work discloses the importance of spiro-junction in modulating deep-blue MR-TADF emitters.

An AGS-associated mutation in ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the brain.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a severe neurodegenerative disease with clinical features of early-onset encephalopathy and progressive loss of intellectual abilities and motor control. Gene mutations in seven protein-coding genes have been found to be associated with AGS. However, the causative role of these mutations in the early-onset neuropathogenesis has not been demonstrated in animal models, and the mechanism of neurodegeneration of AGS remains ambiguous. METHODS: Via CRISPR/Cas-9 technology, we established a mutant mouse model in which a genetic mutation found in AGS patients at the ADAR1 coding gene (Adar) loci was introduced into the mouse genome. A mouse model carrying double gene mutations encoding ADAR1 and MDA-5 was prepared using a breeding strategy. Phenotype, gene expression, RNA sequencing, innate immune pathway activation, and pathologic studies including RNA in situ hybridization (ISH) and immunohistochemistry were used for characterization of the mouse models to determine potential disease mechanisms. RESULTS: We established a mouse model bearing a mutation in the catalytic domain of ADAR1, the D1113H mutation found in AGS patients. With this mouse model, we demonstrated a causative role of this mutation for the early-onset brain injuries in AGS and determined the signaling pathway underlying the neuropathogenesis. First, this mutation altered the RNA editing profile in neural transcripts and led to robust IFN-stimulated gene (ISG) expression in the brain. By ISH, the brains of mutant mice showed an unusual, multifocal increased expression of ISGs that was cell-type dependent. Early-onset astrocytosis and microgliosis and later stage calcification in the deep white matter areas were observed in the mutant mice. Brain ISG activation and neuroglial reaction were completely prevented in the Adar D1113H mutant mice by blocking RNA sensing through deletion of the cytosolic RNA receptor MDA-5. CONCLUSIONS: The Adar D1113H mutation in the ADAR1 catalytic domain results in early-onset and MDA5-dependent encephalopathy with IFN pathway activation in the mouse brain.

Rhinacanthus nasutus and okara polysaccharides attenuate colitis via inhibiting inflammation and modulating the gut microbiota.

Plant polysaccharides have prebiotic properties for gut microbiota and immune modulation. This study aimed to investigate the prevention abilities of edible Rhinacanthus nasutus polysaccharide (RNP) and okara polysaccharide (OP) in Sprague-Dawley rats with acetic acid-induced colitis. The characterizations of RNP and OP were analyzed, including Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, and monosaccharide composition. The prebiotic properties of RNP and OP were determined in vitro. In addition, the pathological features of colon length and inflammatory cytokine levels in acetic acid-induced colitis were improved by intragastric preadministration of RNP and OP for 3 weeks. There was no nephrotoxicity or hepatotoxicity in rats via histopathological assessment after RNP and OP intake. Moreover, the abundance of short-chain fatty acids-producing bacteria (Lachnospiraceae, Lactobacilli, and Prevotellaceae) were increased after RNP supplementation. In conclusion, intragastric gavage of RNP and OP significantly modulated the gut microbiota and immune response, consequently alleviating the symptoms of colitis. This novel finding provides an alternative strategy and potential application of these two polysaccharides for colitis prevention and treatment.

Lucidone inhibits autophagy and MDR1 via HMGB1/RAGE/PI3K/Akt signaling pathway in pancreatic cancer cells.

Gemcitabine (GEM) drug resistance remains a difficult challenge in pancreatic ductal adenocarcinoma (PDAC) treatment. Therefore, identifying a safe and effective treatment strategy for PDAC is urgent. Lucidone is a natural compound extracted from the fruits of Lindera erythrocarpa Makino. However, the role of lucidone in PDAC inhibition remains unclear. In addition, high-mobility group box 1 (HMGB1) and receptor for advanced glycation end products (RAGE) are involved in multidrug resistance protein 1 (MDR1) regulation and GEM resistance. Thus, this study aimed to explore the function of lucidone in tumor cytotoxicity and chemosensitivity through the suppression of RAGE-initiated signaling in PDAC cells. The data showed that lucidone significantly promoted apoptotic cell death and inhibited the expression of autophagic proteins (Atg5, Beclin-1, LC3-II, and Vps34) and MDR1 by inhibiting the HMGB1/RAGE/PI3K/Akt axis in both MIA Paca-2 cells and MIA Paca-2GEMR cells (GEM-resistant cells). Notably, convincing data were also obtained in experiments involving RAGE-specific siRNA transfection. In addition, remarkable cell proliferation was observed after treatment with lucidone combined with GEM, particularly in MIA Paca-2GEMR cells, indicating that lucidone treatment enhanced chemosensitivity. Collectively, this study provided the underlying mechanism by which lucidone treatment inhibited HMGB1/RAGE-initiated PI3K/Akt/MDR1 signaling and consequently enhanced chemosensitivity in PDAC.