ß-arrestin1 protects intestinal tight junction through promoting mitofusin 2 transcription to drive parkin-dependent mitophagy in colitis.

Background: Intestinal barrier defect is an essential inflammatory bowel disease (IBD) pathogenesis. Mitochondrial dysfunction results in energy deficiency and oxidative stress, which contribute to the pathogenesis of IBD. ß-arrestin1 (ARRB1) is a negative regulator that promotes G protein-coupled receptors desensitization, endocytosis, and degradation. However, its role in maintaining the intestinal barrier remains unclear. Methods: Dextran sulfate sodium-induced colitis was performed in ARRB1 knockout and wild-type mice. Intestinal permeability and tight junction proteins were measured to evaluate the intestinal barrier. Mitochondria function and mitophagic flux in mice and cell lines were detected. Finally, the interaction between ARRB1 and mitofusin 2 was investigated by co-immunoprecipitation and dual luciferase assay. Results: We identified that ARRB1 protected the intestinal tight junction barrier against experimental colitis in vivo. ARRB1 deficiency was accompanied by abnormal mitochondrial morphology, lower adenosine triphosphate (ATP) production, and severe oxidative stress. In vitro, the knockdown of ARRB1 reduced ATP levels and mitochondrial membrane potential while increasing reactive oxygen species levels and oxidative stress. Upon ARRB1 ablation, mitophagy was inhibited, accompanied by decreased LC3BII, phosphatase and tension homologue-induced protein kinase1 (PINK1), and parkin, but increased p62 expression. Mitophagy inhibition via PINK1 siRNA or mitochondrial division inhibitor 1 impaired ARRB1-mediated tight junction protection. The interaction of ARRB1 with E2F1 activated mitophagy by enhancing the transcription of mitofusin 2. Conclusions: Our results suggest that ARRB1 is critical to maintaining the intestinal tight junction barrier by promoting mitophagy. These results reveal a novel link between ARRB1 and the intestinal tight junction barrier, which provides theoretical support for colitis treatment.

Causal association of inflammatory bowel disease with sarcoidosis and the mediating role of primary biliary cholangitis.

Objectives: Previous observational epidemiological studies have identified a potential association between inflammatory bowel disease (IBD) and sarcoidosis. Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between IBD with genetic susceptibility to sarcoidosis, as well as to explore the potential mediating role. Methods: The genetic associations were obtained from publicly available genome-wide association studies (GWASs) of European ancestry. The IBD dataset has 31,665 cases and 33,977 controls, consisting of 13,768 individuals with ulcerative colitis (UC) and 17,897 individuals with Crohn's disease (CD). The genetic associations of sarcoidosis with 4,854 cases and 446,523 controls. A bidirectional causality between IBD and sarcoidosis was implemented to be determined by a two-sample MR approach. The inverse variance weighted (IVW) method was utilized as the main statistical method, and a series of sensitivity analyses were performed to detect heterogeneity and horizontal pleiotropy. A two-step MR approach was used to investigate whether the mediating pathway from IBD to sarcoidosis was mediated by PBC. Results: The forward MR analysis indicated that genetic predisposition to IBD was significantly linked to an increased risk of sarcoidosis (OR = 1.088, 95% CI: 1.023-1.158, pIBD-sar = 7.498e-03). Similar causal associations were observed in CD (OR = 1.082, 95% CI: 1.028-1.138, pCD-sar = 2.397e-03) and UC (OR = 1.079, 95% CI: 1.006-1.158, pUC-sar = 0.034). Reverse MR analysis revealed that genetic susceptibility to sarcoidosis was correlated with an augmented risk of CD (OR = 1.306, 95% CI: 1.110-1.537, psar-CD = 1.290e-03) but not IBD or UC. The mediation analysis via two-step MR showed that the causal influence of IBD and CD on sarcoidosis effects was partly mediated by PBC, and the mediating effect was 0.018 (95% CI: 0.005-0.031, p = 7.596e-03) with a mediated proportion of 21.397% in IBD, and 0.014 (95% CI: 0.004-0.024, p = 7.800e-03) with a mediated proportion of 17.737% in CD. Conclusions: The MR analysis provided evidence substantiating the causal effect of IBD (CD and UC) on an increased risk of sarcoidosis, with PBC playing a mediating role in IBD and CD. However, sarcoidosis only enhances the risk of developing CD, but not IBD or UC. These findings illuminate the etiology of sarcoidosis and contribute to the management of IBD patients.

Evaluation of Factors Influencing Postoperative Cognitive Dysfunction in Patients After Cranial Tumor Surgery.

BACKGROUND: The authors retrospectively analyzed the perioperative data of 81 patients who underwent cranial tumor surgery to explore the factors influencing POCD in patients after the surgery. METHODS: The authors evaluated preoperative cognitive dysfunction using the Mini-Mental State Examination (MMSE) score measured. For patients whose cognitive function was normal, the authors retrieved the MMSE score on the seventh day after surgery and compared it to determine whether the patients had POCD. The authors used a univariate logistic regression analysis to analyze the perioperative factors in patients, namely, age, gender, history of underlying diseases, tumor size, peritumoral edema, duration of surgery, blood loss, intraoperative fluid infusion, and type of anesthetic drugs. The authors then performed a multivariate logistic regression analysis for the statistically significant factors. RESULTS: The authors found that 23 of 81 patients (28.4%) developed POCD. Univariate logistic analysis showed that a history of diabetes mellitus, peritumoral edema, intraoperative blood loss, and anesthetic drugs were the risk factors for patients developing POCD after cranial tumor surgery. Multivariate logistic regression analysis showed that a history of diabetes mellitus, peritumoral edema, and use of ciprofol as the anesthetic drug were independent risk factors for POCD after cranial tumor surgery. CONCLUSIONS: A history of diabetes mellitus, the degree of brain tumor edema, and the choice of anesthetic drugs significantly influence the occurrence of POCD in patients after cranial tumor surgery.

Casual associations of thyroid function with inflammatory bowel disease and the mediating role of cytokines.

Background: Previous observational epidemiological studies have suggested a potential association between thyroid function and inflammatory bowel disease (IBD). However, the findings remain inconclusive, and whether this association is causal remains uncertain. The objective of this study is to investigate the causal association between thyroid function and IBD. Methods: Genome-wide association studies (GWAS) involving seven indicators of thyroid function, IBD, and 41 cytokines were analyzed. Bidirectional two-sample Mendelian randomization (MR) and multivariable MR were conducted to examine the causal relationship between thyroid function and IBD and to explore the potential mechanisms underlying the associations. Results: Genetically determined hypothyroidism significantly reduced the risk of CD (odds ratio [OR] = 0.761, 95% CI: 0.655-0.882, p < 0.001). Genetically determined reference-range TSH was found to have a suggestive causal effect on IBD (OR = 0.931, 95% CI: 0.888-0.976, p = 0.003), (Crohn disease) CD (OR = 0.915, 95% CI: 0.857-0.977, p = 0.008), and ulcerative colitis (UC) (OR =0.910, 95% CI: 0.830-0.997, p = 0.043). In reverse MR analysis, both IBD and CD appeared to have a suggestive causal effect on the fT3/fT4 ratio (OR = 1.002, p = 0.013 and OR = 1.001, p = 0.015, respectively). Among 41 cytokines, hypothyroidism had a significant impact on interferon-inducible protein-10 (IP-10) (OR = 1.465, 95% CI: 1.094-1.962, p = 0.010). The results of multivariable MR showed that IP-10 may mediate the causal effects of hypothyroidism with CD. Conclusion: Our results suggest that an elevated TSH level reduces the risk of CD, with IP-10 potentially mediating this association. This highlights the pituitary-thyroid axis could serve as a potential therapeutic strategy for CD.

Effects of enhanced biological phosphorus removal on rapid control of sludge bulking and fast formation of aerobic granular sludge.

This study investigated the effects of enhanced biological phosphorus removal (EBPR) on rapid sludge bulking control and fast aerobic granular sludge (AGS) formation by adding 20 % of EBPR activated sludge to the bulking activated sludge (BAS) reactor. The results indicate that activating EBPR activity swiftly improved BAS settleability within 16 days, thus resolving sludge bulking issues. Subsequently, a settling time-based selection was employed, resulting in the BAS granulation within another 16 days. The rapid achievement of EBPR activity improved the BAS settleability and facilitated the formation of sludge aggregates, thereby expediting BAS granulation. Inhibition of filamentous bacteria and enrichment of slow-growing organisms contributed to both sludge bulking control and aerobic granulation. Furthermore, the increase in proteins/polysaccharides ratio facilitated the granulation process. Additionally, total nitrogen removal increased from 59.4 % to 71.7 % because of the mature AGS formation. This study provided an approach to simultaneously control sludge bulking and promote aerobic granulation.

Insight into the role of chitosan in rapid recovery and re-stabilization of disintegrated aerobic granular sludge.

The disintegration and instability of aerobic granular sludge (AGS) systems during long-term operation pose significant challenges to its practical implementation, and rapid recovery strategies for disintegrated AGS are gaining more attention. In this study, the recovery and re-stabilization of disintegrated AGS was investigated by adding chitosan to a sequencing batch reactor and simultaneously adjusting the pH to slightly acidic condition. Within 7 days, chitosan addition under slight acidity led to the re-aggregation of disintegrated granules, increasing the average particle size from 166.4 µm to 485.9 µm. Notably, sludge volume indexes at 5 min (SVI5) and 30 min (SVI30) decreased remarkably from 404.6 mL/g and 215.1 mL/g (SVI30/SVI5 = 0.53) to 49.1 mL/g and 47.6 mL/g (SVI30/SVI5 = 0.97), respectively. Subsequent operation for 43 days successfully re-stabilized previous collapsed AGS system, resulting in an average particle size of 750.2 µm. These mature and re-stabilized granules exhibited characteristics of large particle size, excellent settleability, compact structure, and high biomass retention. Furthermore, chitosan facilitated the recovery of COD and nitrogen removal performances within 17-23 days of operation. It effectively facilitated the rapid aggregation of disintegrated granules by charge neutralization and bridging effects under a slightly acidic environment. Moreover, the precipitated chitosan acted as carriers, promoting the adhesion of microorganisms once pH control was discontinued. The results of batch tests and microbial community analysis confirmed that chitosan addition increased sludge retention time, enriching slow-growing microorganisms and enhancing the stability and pollutant removal efficiency of the AGS system.

Acute muscle wasting rate assessment and long-term mortality in critically ill trauma.

BACKGROUND AND OBJECTIVES: To evaluate the relationship between acute muscle wasting rate and long-term mortality in critically ill trauma. METHODS AND STUDY DESIGN: A single-center, retrospective study was conducted in critically ill trauma. Patients with Computed Tomography scans including the L3 vertebra within 24 hours and at 1 week after trauma were recruited. Acute muscle wasting rate was defined as the mean percent variation per day of skeletal muscle index in the first week after trauma. Multivariate logistic regression analysis and receiver operating characteristic curve analysis were performed to determine whether acute muscle wasting rate could help predict hospital malnutrition and 1-year mortality. RESULTS: Skeletal muscle index was 49.3±10.7 cm2/m2 at baseline and decreased to 45.1±9.6 cm2/m2 (p<0.001) at 1 week and 39.8±10.8cm2/m2 (p<0.001) at 1 month after trauma. A sustained decrease of skeletal muscle index was observed from baseline up to 6 months (33.7±8.4cm2/m2, p<0.001) post trauma, and lasted for 1 year (37.7±5.6cm2/m2, p=0.004). Logistic regression analysis showed that acute muscle wasting rate was an independent risk factor for hospital malnutrition and 1-year mortality. Every 1% absolute increase of acute muscle wasting rate was associated with 1.82-fold higher odds of 1-year mortality in critically ill trauma. The area under curve of acute muscle wasting rate was 0.813 for hospital malnutrition prediction and 0.715 for 1-year mortality prediction. CONCLUSIONS: Acute muscle wasting rate was independently associated with higher 1-year mortality and hospital malnutrition in critically ill trauma.

Manipulation of Spin-Orbit Torque in Tungsten Oxide/Manganite Heterostructure by Ionic Liquid Gating and Orbit Engineering.

Spin-orbit coupling (SOC) is the interaction between electron's spin and orbital motion, which could realize a charge-to-spin current conversion and enable an innovative method to switch the magnetization by spin-orbit torque (SOT). Varied techniques have been developed to manipulate and improve the SOT, but the role of the orbit degree of freedom, which should have a crucial bearing on the SOC and SOT, is still confusing. Here, we find that the charge-to-spin current conversion and SOT in W3O8-δ/(La, Sr)MnO3 could be produced or eliminated by ionic liquid gating. Through tuning the preferential occupancy of Mn/W-d electrons from the in-plane (dx2-y2) to out-of-plane (d3z2-r2) orbit, the SOT damping-like field efficiency is nearly doubled due to the enhanced spin Hall effect and interfacial Rashba-Edelstein effect. These findings not only offer intriguing opportunities to control the SOT for high-efficient spintronic devices but also could be a fundamental step toward spin-orbitronics in the future.

Electrical Control of Spin Hall Efficiency and Field-Free Magnetization Switching in W/Pt/Co/Pt Heterostructures with Competing Spin Currents.

Reversal of magnetization via current-induced spin-orbit torque (SOT) is one of the core issues in spintronics. However, an in-plane assistant field is usually required for the deterministic switching of a perpendicularly magnetized system. Additionally, the efficiency of SOT is low, which is detrimental to device applications. This study achieved a reversible and non-volatile control of the critical current for magnetization switching and spin Hall efficiency in the TaN/W/Pt/Co/Pt/TaN heterostructures by ionic liquid (IL) gating-induced hydrogen ion adsorption and desorption in the upper Pt layer. Furthermore, the thinning of the Pt and TaN capping layers activated the oxygen ion migration toward the Co layer under IL gating, resulting in an exchange bias field and allowing field-free magnetization switching and Boolean logic operation. The results of this study offer an intriguing opportunity to promote the development of SOT-based spintronic devices from the perspective of iontronics with low energy dissipation.

Berberine alleviates liver fibrosis through inducing ferrous redox to activate ROS-mediated hepatic stellate cells ferroptosis.

Berberine (BBR) has been explored as a potential anti-liver fibrosis agent, but the underlying mechanisms are unknown. In the current study, we aimed to investigate the molecular mechanisms underlying the effect of BBR against liver fibrogenesis in thioacetamide (TAA) and carbon tetrachloride (CCl4) induced mouse liver fibrosis. In addition to i.p. injection with TAA or CCl4, mice in the treatment group received BBR intragastrically. Concurrently, combined with TAA and BBR treatment, mice in the inhibitor group were injected i.p. with ferrostatin-1 (Fer-1). Hepatic stellate cells (HSCs) were also used in the study. Our results showed that BBR obviously alleviated mouse liver fibrosis and restored mouse liver function; however, the pharmacological effects of BBR against liver fibrosis were significantly diminished by Fer-1 treatment. Mechanically, BBR impaired the autophagy-lysosome pathway (ALP) and increased cell reactive oxygen species (ROS) production in HSCs. ROS accelerated the breakdown of the iron-storage protein ferritin and sped up iron release from ferritin, which resulted in redox-active iron accumulation in HSCs. Lipid peroxidation and glutathione (GSH) depletion triggered by the Fenton reaction promoted ferroptosis and attenuated liver fibrosis. Furthermore, impaired autophagy enhanced BBR-mediated ferritin proteolysis to increase cellular ferrous overload via the ubiquitin-proteasome pathway (UPS) in HSCs and triggered HSC ferroptosis. Collectively, BBR alleviated liver fibrosis by inducing ferrous redox to activate ROS-mediated HSC ferroptosis. Our findings may be exploited clinically to provide a potential novel therapeutic strategy for liver fibrosis.

Rapid start-up of an aerobic granular sludge system for nitrogen and phosphorus removal through seeding chitosan-based sludge aggregates.

This study presents a novel strategy to accelerate the start-up of aerobic granular sludge (AGS) system and ensure the nutrient removal during cultivation. This new method consists of preparing the chitosan-based sludge aggregates outside the reactor and then seeding the reactor with such sludge aggregates. To prepare chitosan-based sludge aggregates, chitosan was dissolved in acetic acid solution acting as a cationic flocculant to bind negatively charged sludge together, and then the dissolved chitosan was in situ precipitated by readjusting pH to form stable sludge aggregates. The chitosan-induced charge neutralization and water-insolubility of chitosan were the two main reasons for the super-rapid formation of chitosan-based sludge aggregates. The as-prepared chitosan-based sludge aggregates had a much lower sludge volume index at 30 min (SVI30) (90.1 mL/g) than the original sludge (SVI30 = 328.0 mL/g). They also had some AGS-like characteristics such as large particle size (1300 µm) and fast settling velocity (23.8 m/h). Consequently, short settling time can be achieved and excessive biomass wash-out can be avoided in the rapid start-up of AGS system with chitosan-based sludge aggregates as inoculant, which was beneficial to accelerating sludge granulation while maintaining nutrient removal. Additionally, the abundances of filamentous bacteria and Candidatus Accumulibacter and the content of extracellular polymeric substances increased during cultivation, which could also contribute to the AGS formation. By seeding chitosan-based sludge aggregates in the anaerobic/oxic sequencing batch reactor, complete granulation was rapidly achieved in 10 days, and good removals of nitrogen and phosphorus was obtained after 14-18 days of cultivation.

Rapid control of activated sludge bulking and simultaneous acceleration of aerobic granulation by adding intact aerobic granular sludge.

The feasibility of rapidly controlling activated sludge bulking and accelerating aerobic sludge granulation was evaluated by adding intact aerobic granular sludge (AGS) to the bulking activated sludge (BAS) reactor. Two ratios of AGS to BAS (0.2 in the first reactor (R1), and 0.4 in the second reactor (R2)) were tested. The results indicate that the addition of AGS immediately improved the settling ability of BAS (sludge volume index at 30 min (SVI30) in R1 and R2 decreased from 173.1 mL/g to 130.8 and 91.3 mL/g, respectively) and gradually increased the biomass concentration (mixed liquor suspended solids (MLSS) in R1 and R2 increased to 4722 and 5190 mg/L, respectively), thus resolving the sludge bulking problem. Meanwhile, adding AGS not only promoted the BAS growth in aggregates, but also facilitated the selection of well-settling aggregates at an early stage. Consequently, the granulation process was significantly accelerated. The granulation time in R1 and R2 was 14 and 10 days, respectively, indicating that the higher ratio of AGS to BAS can result in the faster granulation. Partial nitrification could be maintained during the BAS granulation process when the initial inoculation of nitritation sludge was large enough. Additionally, the microbial community changed during the BAS granulation process. The genera Thauera and Zoogloea belonging to family Rhodobacteraceae were speculated to play an important role in the BAS granulation.

Cultivating aerobic granular sludge in a developed continuous-flow reactor with two-zone sedimentation tank treating real and low-strength wastewater.

A continuous-flow reactor with two-zone sedimentation tank (CFR-TST) was developed to evaluate the formation of aerobic granular sludge (AGS). Micropowder made of excess sludge was added for a while in the CFR-TST, and selection pressure associated with settling time was created by the two-zone sedimentation tank. To avoid AGS disintegration, an airlift system for sludge return was used. The results show that AGS (mean particle size of 105µm; sludge volume index of approximately 26mL/g) was formed successfully in the CFR-TST. The micropowder induced bacterial attachment by acting as nuclei. The two-zone sedimentation tank made the well settling granules (i.e., heavy sludge) always retained in the CFR and poorly settling flocs (i.e., light sludge) washed away. After granulation, the contents of extracellular polymeric substances and metal precipitations in sludge increased, and the microbial community changed obviously. Additionally, the effluent concentrations of CODCr and NH4+-N were relatively low after granulation.

Synthesis of cationic branched tea polysaccharide derivatives for targeted delivery of siRNA to hepatocytes.

The cationic branched tea polysaccharide (CTPSA) derivative bearing N-acylurea and 3-(dimethylamino)-1-propylamine residues was synthesized and characterized using FTIR and 1H NMR spectroscopy. A nonspecific siRNA (NsiRNA) was used as a model molecule of functional siRNA that could downregulate over-expressed glycometabolism enzymes in the liver. The result from the agarose gel electrophoresis confirmed that the CTPSA and NsiRNA could form stable complexes when their weight ratio was larger than 18. The zeta potentials and sizes of the complexes were in the range of +8-+15 mv and 120-150 nm, respectively. The CTPSA/NsiRNA complex was observed as nanoparticles with a spherical shape of approximately 100 nm using scanning electron microscopy. The CTPSA derivative and the CTPSA/NsiRNA complexes exhibited lower cytotoxicity in HL-7702 cells when compared with the branched PEI (bPEI) and bPEI/NsiRNA complexes assessed by the Cell Counting Kit-8 assay. The results of flow cytometric analysis and laser confocal microscopy indicated that the CTPSA derivative could effectively target the transfer of the NsiRNA to HL-7702 cells. This work provides a potential approach to promote the CTPSA derivative as a nonviral vector for targeted delivery of functional siRNA to hepatocytes.

Optimization of methane-dependent oxygenic denitrification in sequencing batch reactors by insights into the microbial interactions.

Methane-dependent oxygenic denitrification (O2DN) is a promising technology used for reducing greenhouse gas emissions of nitrous oxide (N2O) during wastewater treatment. Heterotrophic bacteria are associated with methane-dependent O2DN bacteria, and it has been proposed that metabolic cross-feeding occurs between the two populations above. In this study, a mathematical model was developed to describe the microbial processes and interactions between methane-dependent O2DN bacteria and associated heterotrophic bacteria in a sequencing batch reactor (SBR). A growth factor-dependent decoupling of metabolism and growth of methane-dependent O2DN bacteria was introduced into the model. Effects of influent substrates, operating parameters, and initial biomass on microbial community and reactor performance were then investigated, and the above parameters were optimized using the model. Results surprisingly show that organic matter in the influent greatly stimulated the growth of methane-dependent O2DN bacteria but slightly limited the increase of heterotrophic bacteria. This effect could be explained by the increased excretion of growth factors by heterotrophic bacteria and the intensified competition for nitrite when methane-dependent O2DN bacteria increased. These results will assist in providing a new understanding of microbial interactions in methane-dependent O2DN systems and offer a new and efficient strategy for operating methane-dependent O2DN reactors.

Nitrifying aerobic granular sludge fermentation for releases of carbon source and phosphorus: The role of fermentation pH.

The effect of fermentation pH (uncontrolled, 4 and 10) on the releases of carbon source and phosphorus from nitrifying aerobic granular sludge (N-AGS) was investigated. Meanwhile, metal ion concentration and microbial community characterization were explored during N-AGS fermentation. The results indicated that N-AGS fermentation at pH 10 significantly promoted the releases of soluble chemical oxygen demand (SCOD) and total volatile fatty acids (TVFAs). However, SCOD and TVFA released from N-AGS were inhibited at pH 4. Moreover, acidic condition promoted phosphorus release (mainly apatite) from N-AGS during anaerobic fermentation. Nevertheless, alkaline condition failed to increase phosphorus concentration due to the formation of chemical-phosphate precipitates. Compared with the previously reported flocculent sludge fermentation, N-AGS fermentation released more SCOD and TVFAs, possibly due to the greater extracellular polymeric substances content and some hydrolytic-acidogenic bacteria in N-AGS. Therefore, N-AGS alkaline fermentation facilitated the carbon source recovery, while N-AGS acidic fermentation benefited the phosphorus recovery.

Oxygenic denitrification for nitrogen removal with less greenhouse gas emissions: Microbiology and potential applications.

Nitrogen pollution is a worldwide problem and has been extensively treated by canonical denitrification (CDN) process. However, the CDN process generates several issues such as intensive greenhouse gas (GHG) emissions. In the past years, a novel biological nitrogen removal (BNR) process of oxygenic denitrification (O2DN) has been proposed as a promising alternative to the CDN process. The classic denitrification four steps are simplified to three steps by O2DN bacteria without producing and releasing the intermediate nitrous oxide (N2O), a potent GHG. In this article, we summarized the findings in previous literatures as well as our results, including involved microorganisms and metabolic mechanisms, functional genes and microbial detection, kinetics and influencing factors and their potential applications in wastewater treatment. Based on our knowledge and experience, the benefits and limitations of the current O2DN process were analyzed. Since O2DN is a new field in wastewater treatment, more research and application is required, especially the development of integrated processes and the quantitative assessment of the contribution of O2DN process in natural habitats and engineered systems.

Folic acid-functionalized polyethylenimine superparamagnetic iron oxide nanoparticles as theranostic agents for magnetic resonance imaging and PD-L1 siRNA delivery for gastric cancer.

Programmed death ligand-1 (PD-L1), which is highly expressed in gastric cancers, interacts with programmed death-1 (PD-1) on T cells and is involved in T-cell immune resistance. To increase the therapeutic safety and accuracy of PD-1/PD-L1 blockade, RNA interference through targeted gene delivery was performed in our study. We developed folic acid (FA)- and disulfide (SS)-polyethylene glycol (PEG)-conjugated polyethylenimine (PEI) complexed with superparamagnetic iron oxide Fe3O4 nanoparticles (SPIONs) as a siRNA-delivery system for PD-L1 knockdown. The characterization, binding ability, cytotoxicity, transfection efficiency, and cellular internalization of the polyplex were determined. At nitrogen:phosphate (N:P) ratios of 10 or above, the FA-PEG-SS-PEI-SPIONs bound to PD-L1 siRNA to form a polyplex with a diameter of approximately 120 nm. Cell-viability assays showed that the polyplex had minimal cytotoxicity at low N:P ratios. The FA-conjugated polyplex showed higher transfection efficiency and cellular internalization in the folate receptor-overexpressing gastric cancer cell line SGC-7901 than a non-FA-conjugated polyplex. Subsequently, we adopted the targeted FA-PEG-SS-PEI-SPION/siRNA polyplexes at an N:P ratio of 10 for function studies. Cellular magnetic resonance imaging (MRI) showed that the polyplex could also act as a T2-weighted contrast agent for cancer MRI. Furthermore, one of four PD-L1 siRNAs exhibited effective PD-L1 knockdown in PD-L1-overexpressing SGC-7901. To determine the effects of the functionalized polyplex on T-cell function, we established a coculture model of activated T cells and SGC-7901 cells and demonstrated changes in secreted cytokines. Our findings highlight the potential of this class of multifunctional theranostic nanoparticles for effective targeted PD-L1-knockdown therapy and MRI diagnosis in gastric cancers.

Immunosuppressive Agents for the Treatment of Primary Sclerosing Cholangitis: A Systematic Review and Meta-Analysis.

OBJECTIVES: Currently, there are no effective therapeutic agents for patients with primary sclerosing cholangitis (PSC). This study aimed to evaluate the safety and efficiency of immunosuppressive agents (IAs) for the treatment of PSC. METHODS: The literatures were searched using the following keywords singly or in combination: PSC, treatments, IAs. The primary outcome was defined as the need for liver transplantation or mortality. RESULTS: Two hundred sixty six patients from 7 eligible studies were analyzed. IAs had no remarkable effects on the rate of mortality or liver transplantation (relative risk, RR 1.02, 95% CI 0.58-1.62, p = 0.92). Subgroup analyses showed no significant effect of IAs co-administration therapy (IAs co-administered with ursodeoxycholic acid, IA co-administered with IA; RR 1.41, 95% CI 0.40-4.95, p = 0.60). IAs caused adverse events (AEs) such as diarrhea, abdominal pain, and pruritus (RR 1.81, 95% CI 1.07-3.07, p = 0.03). IAs therapy did not significantly improve markers of liver function except for aspartate transaminase (weighted mean difference -9.76, 95% CI -12.92 to -6.6, p < 0.001). CONCLUSION: IAs administrated as either monotherapy or combination therapy do not reduce the risk of mortality or liver transplantation. IAs monotherapy is associated with AEs.

Interactions between α-amylase and an acidic branched polysaccharide from green tea.

To understand the mechanism responsible for the α-amylase inhibitory activity of tea polysaccharides, the interaction between α-amylase and an acidic branched tea polysaccharide (TPSA) was investigated using fluorescence spectroscopy and resonance light scattering analysis. TPSA, exhibiting inhibitory activity towards α-amylase (the maximum inhibition percentage of 65%), was isolated from green tea (Camellia sinensis) and characterized by nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, and gas chromatography. Synchronous fluorescence spectroscopy revealed that the binding interaction between the tryptophan residues of α-amylase and TPSA was predominant. Based on the fluorescence quenching effect of tryptophan residues induced by TPSA, the binding constants between α-amylase and TPSA were determined to be 18.6×106, 8.0×106 and 4.6×106 L·mol-1 at 20, 30 and 37°C, respectively. The calculated Gibbs free-energy changes were negative, indicating that the bonding interaction was a spontaneous process. The enthalpy and the entropy changes were -62.13 KJ·mol-1 and -0.0728 KJ·mol-1·K-1, suggesting that hydrogen bonding interactions might play a major role in the binding process. The formation of an α-amylase/TPSA complex was evidenced by fluorescence quenching and resonance light scattering analysis, and this complex could be the main contributor to the α-amylase inhibitory activity of TPSA.