Effects of acetate-producing Blautia wexlerae on oxidative stress and NLRP3 inflammasome in obesity-associated male infertility.

BACKGROUND: Obesity-associated male infertility is a common complication of obesity and has been increasing in prevalence. Blautia wexlerae has modulation effects on obesity. However, the action of B. wexlerae on obesity-associated male infertility is unclear. The nod-like receptor protein 3 (NLRP3) inflammasome has become a major target for addressing many diseases, including obesity-associated male infertility. This study aims to investigate the action of B. wexlerae on obesity-associated male infertility and the influence of B. wexlerae on NLRP3 inflammasome. MATERIALS AND METHODS: The fecal samples were collected from 60 infertile men with or without obesity and 30 healthy men. The obesity mice model was established through high-fat diet (HFD) induction. The mating assays evaluated the male infertility of obese mice. A mouse-derived spermatogonia (GC-1 spg) cell viability was detected using the Cell Counting Kit-8 assay. The reactive oxygen species (ROS) were assessed using flow cytometry. Furthermore, immunofluorescence, enzyme-linked immunosorbent assay, and western blotting were applied to measure the gene expressions. RESULTS: Blautia wexlerae was decreased and negatively correlated with interleukin-1 beta (IL-1ß) or IL-18 levels in infertile men with obesity. On the other hand, B. wexlerae improved the mating capability of obese male mice and suppressed oxidative stress and NLRP3 inflammasome via the activation of the acetate receptor. Furthermore, sodium acetate regulated oxidative stress and NLRP3 inflammasome via the activation of the acetate receptor in GC-1 spg cells in vitro. CONCLUSION: The administration of Blautia wexlerae improved obesity-associated male infertility and regulated oxidative stress and NLRP3 inflammasome activities. In general, its administration may be an effective strategy for the treatment of obesity-associated male infertility.

Resection of pleural solitary fibrous tumors with distinct feeding vessels arising from the descending aorta: a case report.

BACKGROUND: Pleural solitary fibrous tumors (pSFTs) are rare mesenchymal pleural tumors with rich vascularity. Surgical resection is the cornerstone of pSFTs treatment, requiring careful preoperative imaging to delineate lesion extent and vascular supply including contrast-enhanced computed tomography and other examinations depending on its size and characteristics. CASE PRESENTATION: The patient was a 34-year-old female with a mass measuring approximately 67 × 42 × 65 mm in the left posterior mediastinum. Intraoperatively, the mass demonstrated rich vascularity. Two veins originating from the abdominal cavity entered the lower pole, one converged from the superior pole, draining into the brachiocephalic vein. Additionally, two arteries arose directly from the descending aorta, while several veins drained into the intercostal veins. In response to unexpected intraoperative vascular findings, vascular clips and silk threads were used to ligate them. Subsequently, the tumor was successfully dissected, with approximately 600 ml of blood loss recorded during the 4-hour surgery. The patient exhibited a satisfactory postoperative recovery, and follow-up spanning over six months revealed no indications of recurrence or metastasis. CONCLUSIONS: We firstly present a case of successful resection of a pSFT in a 34-year-old woman with a distinct feeding vessel arising from the descending aorta and describe the related surgical procedures. This case highlights preoperative evaluation of mass vascularity based on contrast-enhanced computed tomography. When blood supply is challenging to clarify, angiography can offer additional details, especially for giant pSFTs. Despite this, thorough intraoperative exploration remains essential to detect unexpected vessels. Appropriate interventions should be customized based on the vascular origins and the surrounding anatomical structures.

Women patients with small-cell lung cancer using immunotherapy in a real-world cohort achieved long-term survival.

BACKGROUND: Usage of immune checkpoint inhibitors (ICIs) has prolonged the overall survival (OS) of patients with extensive-stage small-cell lung cancer (ES-SCLC). In clinical trials, males accounted for a large proportion, leading to the uncertainty of its efficacy in female patients. We therefore conducted this study to explore the efficacy and safety of using ICIs in female patients with ES-SCLC. METHODS: We retrospectively enrolled female SCLC patients and subdivided them into two groups. Group A (n = 40) was defined as ES-SCLC patients who received first-line standard chemotherapy with or without ICIs. Group B (n = 47) included relapsed SCLC patients who were administered with second-line therapies. Kaplan-Meier methodology was used to calculate survival analysis. Chi-squared tests were used to analyze the incidence of adverse events (AEs). RESULTS: Median progression-free survival (PFS) and median OS favored the ICI-contained cohorts (Group A PFS: 8.3 vs. 6.1 months; OS: not reached vs. 11.3 months; Group B PFS: 15.1 vs. 3.3 months; OS: 35.3 vs. 8.3 months), especially in those patients who received second-line immunotherapies. Patients who received immunotherapy had a slightly higher incidence rate of grade ≥3 AEs (Group A: 71.4% vs. 46.2%; Group B: 44.5% vs. 13.2%). Those who developed grade ≥3 AEs in first-line ICIs cohort had a more favorable survival (PFS: 8.3 vs. 3.2 months; OS: not reached vs. 5.1 months). CONCLUSIONS: Our study suggested that female ES-SCLC patients treated with immunotherapy tended to achieve a relatively longer survival. The incidence of AEs (grade ≥3) was higher in women patients receiving ICIs, which requires monitoring more closely.

Diatom cell-size composition as a novel tool for quantitative estimates of the water table in peatlands.

Diatom cell-size composition is an indicator of aquatic environmental changes but has been rarely investigated, especially in semi-terrestrial peatlands. In this study, both taxonomic composition and cell-size composition of diatoms were analysed in 41 samples from two montane peatlands, northeastern China. Redundancy analyses revealed that diatom taxonomic composition was significantly related to the depth to the water table (DWT) and Ca2+, while cell-size composition was significantly associated with DWT and Si. DWT was the most important factor and its sole effect explained 26.2% and 17.9% of the total variance in taxonomic composition and cell-size composition, respectively. Accordingly, diatom-based water-table transfer functions were developed based on taxonomic composition and cell-size composition, respectively. The maximum-likelihood (ML) model based on diatom taxonomic composition had the best performance, with a correlation coefficient value (R2) of 0.78 and the root mean squared error of prediction (RMSEP) of 6.66 cm. The ML model based on cell-size composition had similar performance, with an R2 of 0.78 and the RMSEP of 6.87 cm, suggesting that diatom cell-size composition can be a new quantitative means to track past water-table changes. This method requires further appraisal with palaeoecological data but offers a new option that deserves exploration.

AMFL: Resource-Efficient Adaptive Metaverse-Based Federated Learning for the Human-Centric Augmented Reality Applications.

The emergence of 5G technology has enabled the development of Metaverse applications that provide users with immersive experiences through augmented reality (AR) devices, and the integration of federated learning (FL) with the Metaverse AR (MAR) systems can enable many edge intelligence services in 5G. However, the presence of nonindependent and identically distributed (Non-IID) data across all AR users' devices, coupled with limited edge communication resources, makes it challenging to achieve human-centric Metaverse-related applications such as target detection or image classification that combine virtual content with real-world. To address these challenges, we propose a novel adaptive resource-efficient Metaverse-based FL (AMFL) algorithm for AR applications that mitigates the negative effect of Non-IID data and reduces resource costs as well as improves the quality of experience (QoE). We first analyze the impact of wireless communication factors such as CPU frequency, bandwidth, and transmission power on FL training performance by a toy example in the MAR systems. Based on this analysis, furthermore, we establish a Non-IID degree, model accuracy, and resource consumption-related QoE maximization problem under given resource budgets, which is a stochastic optimization problem with strongly coupled variables, including bandwidth, CPU frequency, and transmission power. Guided by the theoretical analysis, to solve this issue, AMFL employs a deep reinforcement learning (DRL)-based method to adaptively allocate resources. Numerical results demonstrate that AMFL can significantly improve the QoE by up to 30.28 % , and reduce communication round and energy costs by up to 81.08 % and 72.20 % , respectively, even under the worst Non-IID case, compared to benchmarks.

Prognostic prediction of patients having classical papillary thyroid carcinoma with a 4 mRNA-based risk model.

The dysregulation of protein-coding genes involved in various biological functions is closely associated with the progression of thyroid cancer. This study aimed to investigate the effects of dysregulated gene expressions on the prognosis of classical papillary thyroid carcinoma (cPTC). Using expression profiling datasets from the Cancer Genome Atlas (TCGA) database, we performed differential expression analysis to identify differentially expressed genes (DEGs). Cox regression and Kaplan-Meier analysis were used to identify DEGs, which were used to construct a risk model to predict the prognosis of cPTC patients. Functional enrichment analysis unveiled the potential significance of co-expressed protein-encoding genes in tumors. We identified 4 DEGs (SALL3, PPBP, MYH1, and SYNDIG1), which were used to construct a risk model to predict the prognosis of cPTC patients. These 4 genes were independent of clinical parameters and could be functional in cPTC carcinogenesis. Furthermore, PPBP exhibited a strong correlation with poorer overall survival (OS) in the advanced stage of the disease. This study suggests that the 4-gene signature could be an independent prognostic biomarker to improve prognosis prediction in cPTC patients older than 46.

Mitochondrial calcium uniporter knockdown in hippocampal neurons alleviates anxious and depressive behavior in the 3XTG Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca2+ (mCa2+) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa2+ uptake, induces the imbalance of mCa2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABAA receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD.

Active volatile components of the preferred hosts are potential attractants to Hyphantria cunea adults.

The extraordinary adaptability and dispersal abilities have allowed Hyphantria cunea to expand its range, posing a great threat to urban landscapes and natural ecosystems. Searching for safe, efficient, and low-cost control methods may provide new strategies for pest management in H. cunea spread areas. In this study, based on the attraction of insects by preferred hosts, it was found that the response rates of virgin H. cunea female adults to Salix matsudana, Juglans mandshurica and Ulmus pumila were 89.17%, 97.92% and 93.98%, respectively. It was further found that this significant preference was mainly related to the volatiles m-xylene, o-xylene, dodecane and tetradecane found in the three species. Even though all four compounds at 10 µL/mL and 100 µL/mL had significant attractive effects on the virgin H. cunea female adults, m-xylene and dodecane at 100 µL/mL elicited significant EAG responses and tending behaviors by stimulating the olfactory receptor neurons (ORN A) of females, with response rates of 83.13% and 84.17%, while also having significant attractive effects on virgin male adults with rates of 65.74% and 67.51%. Therefore, both m-xylene and dodecane which at concentrations of 100 µL/mL had strong attractions to adults, could be used as the first choice of attractants for both sexes of H. cunea. This has important practical significance in reducing the frequency of H. cunea generations, limiting their population, controlling their spread range, and improving the efficiency of pest management in epidemic areas.

Carboxymethylated Lycium barbarum seed dreg dietary fiber alleviates high fat diet-induced hyperlipidemia in mice via intestinal regulation.

In this study, we investigated the ameliorative gut modulatory effect of carboxymethylated Lycium barbarum seed dreg insoluble dietary fiber (LBSDIDF) on hyperlipidemic mice. After seven weeks of insoluble dietary fiber (IDF) intervention, the results demonstrated that IDFs effectively inhibited body weight gain, with slimming and hypolipidemic effects, and improved liver histopathology by decreasing ALT, AST, TNF-α and IL-6, and increasing short-chain fatty acid (SCFA) levels in hyperlipidemic mice. With the increasing diversity and abundance of intestinal bacteria and decreasing ratio of Firmicutes to Bacteroidetes, intestinal flora facilitated cholesterol lowering effects in hyperlipidemic mice. Our research offers a novel concept for the use of LBSDIDF as a prebiotic to improve intestinal dysbiosis or as a preventive measure against obesity and dyslipidemia.

Reactivation Risk of Latent Tuberculosis or Inactive Hepatitis B Virus Infection and Effectiveness of Ustekinumab in Chinese Plaque Psoriasis Patients: A 28-Week Retrospective, Observational Study.

Introduction: This study observed the effectiveness of ustekinumab and reactivation risk of concurrent latent tuberculosis infection (LTBI) and inactive hepatitis B virus (HBV) infection in Chinese mainland psoriasis patients on ustekinumab treatment. Methods: This retrospective, multicenter, observational study was conducted in three centers in China. Adult patients with moderate to severe plaque psoriasis were treated with ustekinumab for 28 weeks. The effectiveness endpoint included 75% and 90% improvement in Psoriasis Area Severity Index (PASI75/90) response rate, percentage of PASI improvement, change of absolute PASI score and body surface area involvement (BSA) score, absolute PASI ≤1/3 and Physicians' Global Assessment (PGA)=0/1, as well as Dermatology life quality index (DLQI)=0/1 response rate at week 4, 16 and 28. Screening of tuberculosis and hepatitis were performed at baseline and week 28. Results: A total of 82 patients were enrolled between March 2021 and May 2023 and the number of patients combined with LTBI and inactive HBV infection was 20 and 21 respectively. The PASI75 and PASI90 response rate at week 28 was 95.1% and 81.7% respectively. The mean PASI score decreased from 14.93 ± 12.07 at baseline to 0.78 ± 1.86 at week 28, and the mean BSA score decreased from 21% ± 18% at baseline to 1% ± 2% at week 28 (both P<0.001 compared with baseline). DLQI 0/1 response rate at week 28 was 73.2%. No reactivation of LTBI and inactive HBV infection and also no new-onset tuberculosis and hepatitis B occurred in patients without LTBI and inactive HBV infection at baseline. Conclusion: Ustekinumab demonstrated great effectiveness in Chinese plaque psoriasis patients and good safety in psoriasis concurrent with LTBI and inactive HBV infection under the real-world setting.

Amelioration activity of the high bioaccessible chrysanthemum (Gongju) phenolics on alcohol-induced oxidative injury in AML-12 cells.

The main bioavailable phenolics from of Gongju (GJ) and their mechanism for hepato-protection remain unclear. To select the GJ phenolics with high bioavailability, chrysanthemum digestion and Caco-2 cells were used and their hepato-protective potential were examined by using AML-12 cells. The digestive recovery and small intestinal transit rate of the main phenolic compounds ranged from 28.52 to 69.53% and 6.57% âˆ¼ 15.50%, respectively. Among them, chlorogenic acid, 3,5-dicaffeoylquinic acid, and 1,5-dicaffeoylquinic acid, showed higher small intestinal transit rates and digestive recoveries. Furthermore, we found that by increasing intracellular Catalase (CAT) and Superoxide dismutase (SOD) viability and lowering Malondialdehyde (MDA) level (P < 0.05), 3,5-dicaffeoylquinic acid significantly mitigated the oxidative damage of AML-12 liver cells more than the other two phenolics. Our results demonstrated that 3,5-dicaffeoylquninic acid was the primary phenolic compounds in GJ that effectively reduced liver damage, providing a theoretical basis for the development of GJ as a potentially useful resource for hepatoprotective diet.

Dynamic response of a simply supported liquid-crystal elastomer beam under moving illumination.

Optically responsive liquid crystal elastomer (LCE) devices have thriving potential to flourish in soft robots and microdrives, owing to their advantages of remote controllability, structural simplicity, and no power supply. In terms of illumination-driven modes, most research has focused on the dynamic response of LCE devices under continuous and periodic illumination, while the theoretical study of the dynamic response under moving illumination is limited. In this paper, based on the coupling of LCE and mechanical deformation under moving illumination, the dynamic model of a LCE simply supported beam is built to investigate its dynamic response under moving illumination. The analytical solution of the dynamic response of the LCE beam under moving illumination is derived through the modal superposition method and the Duhamel integration, and the solution is programed and analyzed with matlab software. By numerical calculations, the influence of the internal and driving parameters of the structure on the dynamic response of the LCE simply supported beam can be analyzed. The results show that when the moving speed of illumination reaches the first-order critical frequency, the maximum amplitude of the dynamic response at the beam mid-span will reach a peak. Meanwhile, the dynamic response of beam can be improved by increasing the illumination width, increasing the light intensity, increasing the shrinkage coefficient, and reducing the damping coefficient. This work provides theoretical guidance for applying the dynamic response of LCE devices under moving illumination in soft robots, microactuators, energy harvesters, sensors, etc.

Goose IFIT5 positively regulates goose astrovirus replication in GEF cells.

Interferon-induced protein with tetratricopeptide repeats (IFITs), a family of proteins strongly induced by type I interferon (IFN-I), are deeply involved in many cellular and viral processes. IFIT5, the sole protein in this family found in birds, also plays a crucial role in regulating virus infection. In this study, goose IFIT5 (gIFIT5) was first cloned from peripheral blood lymphocyte (PBL) and phylogenetic analysis showed that it was highly homologous with duck IFIT5 (dIFIT5), sharing 94.6% identity in amino acid sequence. Subsequently, the expression kinetics of gIFIT5 during goose astrovirus (GAstV) infection and the regulatory effect of gIFIT5 on GAstV proliferation were evaluated. Results showed that the mRNA and protein expression level of gIFIT5 was greatly induced by GAstV infection, especially at 12 hpi. Importantly, gIFIT5 could conversely promote GAstV replication in GEF cells. Virus titers in gIFIT5 overexpression group were significantly higher than those in control group at 12 and 24 hpi. Western blot and quantitative real-time PCR (qRT-PCR) further demonstrated that the production of viral cap protein was significantly facilitated in gIFIT5-transfected group. Collectively, GAstV facilitates self-replication via promoting gIFIT5 expression.

Polydopamine modified multifunctional carboxymethyl chitosan/pectin hydrogel loaded with recombinant human epidermal growth factor for diabetic wound healing.

The development of a multifunctional wound dressing that can adapt to the shape of wounds and provide controlled drug release is crucial for diabetic patients. This study developed a carboxymethyl chitosan-based hydrogel dressing with enhanced mechanical properties and tissue adherence that were achieved by incorporating pectin (PE) and polydopamine (PDA) and loading the hydrogel with recombinant human epidermal growth factor (rhEGF). This EGF@PDA-CMCS-PE hydrogel demonstrated robust tissue adhesion, enhanced mechanical properties, and superior water retention and vapor permeability. It also exhibited significant antioxidant capacity. The results showed that EGF@PDA-CMCS-PE could effectively scavenge 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate)， (1,1-diphenyl-2-picrylhydrazyl), and superoxide anions and increase superoxide dismutase and catalase levels in vivo. In vitro cytotoxicity and antibacterial assays showed good biocompatibility and antimicrobial properties. The sustained release of EGF by the hydrogel was confirmed, with a gradual release profile over 120 h. In vivo studies in diabetic mice showed that the hydrogel significantly accelerated wound healing, with a wound contraction rate of 97.84% by day 14. Histopathological analysis revealed that the hydrogel promoted fibroblast proliferation, neovascularization, and orderly connective tissue formation, leading to a more uniform and compact wound-healing process. Thus, EGF@PDA-CMCS-PE hydrogel presents a promising tool for managing chronic diabetic wounds, offering a valuable strategy for future clinical applications.

Intrahepatic cholangiocarcinoma detected on 18F-PSMA-1007 PET/MR imaging in a prostate cancer patient: a case report and literature review.

Radionuclide probes-targeted prostate-specific membrane antigen (PSMA) is used in diagnosis and treatment of prostate cancer (PCa). Recent studies have shown that PSMA is expressed in the tumor neovascular endothelium, such as in malignant liver tumors. We report a case of PCa with incidental intrahepatic cholangiocarcinoma (ICC) detection using 18F-PSMA-1007 and 18F-fluorodeoxyglucose (FDG) positron emission topography (PET)/MRI.18F-PSMA-1007 PET/MRI of our patient with PCa showed that one liver lesion had high PSMA uptake. 18F-FDG PET/MRI revealed minimal FDG uptake in the liver lesion. Histopathological examination revealed that the liver lesion was moderately to poorly differentiated cholangiocarcinoma. Our studies, along with others, demonstrated that malignant liver tumors, such as ICC, hepatocellular carcinoma (HCC), and combined hepatocellular-cholangiocarcinoma (CHC), and benign lesions, such as benign liver hemangioma, focal nodular hyperplasia, focal inflammation and steatosis, vascular malformation, and fatty sparing, exhibited elevated PSMA uptake. Moreover, PSMA-PET was superior to FDG-PET in detecting ICC and HCC, indicating that PSMA-PET may be used as alternative staging and to identify patients for PSMA-targeted therapy.

Stretchable poly[2]rotaxane elastomers.

Mechanically interlocked polymers (MIPs) are promising candidates for the construction of elastomeric materials with desirable mechanical performance on account of their abilities to undergo inherent rotational and translational mechanical movements at the molecular level. However, the investigations on their mechanical properties are lagging far behind their structural fabrication, especially for linear polyrotaxanes in bulk. Herein, we report stretchable poly[2]rotaxane elastomers (PREs) which integrate numerous mechanical bonds in the polymeric backbone to boost macroscopic mechanical properties. Specifically, we have synthesized a hydroxy-functionalized [2]rotaxane that subsequently participates in the condensation polymerization with diisocyanate to form PREs. Benefitting from the peculiar structural and dynamic characteristics of the poly[2]rotaxane, the representative PRE exhibits favorable mechanical performance in terms of stretchability (∼1200%), Young's modulus (24.6 MPa), and toughness (49.5 MJ/m3). Moreover, we present our poly[2]rotaxanes as model systems to understand the relationship between mechanical bonds and macroscopic mechanical properties. It is concluded that the mechanical properties of our PREs are mainly determined by the unique topological architectures which possess a consecutive energy dissipation pathway including the dissociation of host-guest interaction and consequential sliding motion of the wheel along the axle in the [2]rotaxane motif.

Effect of κ-carrageenan on the quality of crayfish surimi gels.

The demand for crayfish surimi products has grown recently due to its high protein content. This study examined the effects of varying κ-carrageenan (CAR) and crayfish surimi (CSM) concentrations on the gelling properties of CAR-CSM composite gel and its intrinsic formation process. Our findings demonstrated that with the increasing concentration of carrageenan, the quality of CAR-CSM exhibited rising trend followed by subsequently fall. Based on the textural qualities, the highest quality CAR-CSM was achieved at 0.3% carrageenan addition. With the exception of chewiness, and the cooking loss of the gel system was 1.62%, whiteness was 82.35%, and the percentage of ß-sheets increased to 57.18%. Further increase in CAR (0.4-0.5%) addition resulted in internal build-up of LCAR-CSM, conversion of intermolecular forces into disulfide bonds and gel breakage. This study exudes timely recommendations for extending the CAR application for the continuous development of crayfish surimi and its derivatives and its overall economic worth.

Investigating the physicochemical characteristics and importance of insoluble dietary fiber extracted from legumes: An in-depth study on its biological functions.

Legumes are widely appreciated for their abundant reserves of insoluble dietary fiber, which are characterized by their high fiber content and diverse bioactive compounds. Insoluble dietary fiber in leguminous crops is primarily localized in the structural cell walls and outer integument and exhibits strong hydrophilic properties that enable water absorption and volumetric expansion, resulting in increased food bulk and viscosity. This contributes to enhanced satiety and accelerated gastrointestinal transit. The benefits of legume insoluble dietary fiber extend to its notable antioxidant, anti-inflammatory, and anti-cancer properties, as well as its ability to modulate the composition of the intestinal microbiota, promoting the growth of beneficial bacteria while suppressing the proliferation of harmful pathogens, thereby promoting optimal intestinal health. It is highly valued as a valuable thickening agent, stabilizer, and emulsifier, contributing to the texture and stability of a wide range of food products.

Combination of RNA-seq and proteomics reveals the mechanism of DL0410 treatment in APP/PS1 transgenic mouse model of Alzheimer's disease.

There is a lack of a systematic understanding of the specific mechanism of action of DL0410 in AD treatment. In this study, the combination of RNA-seq and proteomics was firstly employed to uncover the mechanism of action of DL0410 in APP/PS1 transgenic mice. The results of behavioral tests showed that oral administration of DL0410 for 8 weeks improved memory and cognition of APP/PS1 mice. DL0410 significantly reduced ß-amyloid deposition and resulted in significant upregulation of synaptophysin, PSD95 and NMDAR/ CaMKⅡ signaling pathway in the hippocampus and cortex, indicating that DL0410 improved synaptic plasticity in APP/PS1 mice, which agrees with the results of RNA-seq and proteomics. Furthermore, the enrichment results of differentially expressed genes identified by RNA-seq and proteomics demonstrate the potential protective effects of DL0410 against oxidative stress and mitochondrial dysfunction. As expected, DL0410 dose-dependently ameliorated oxidative damage and markedly increased the expression of PGC-1α, TFAM, SOD1 and SOD2. Mitochondrial high-resolution respirometry results revealed that mitochondrial respiratory function was significantly improved in APP/PS1 mice administered with DL0410. In addition, DL0410 treatment reduced oxidative damage, strengthened antioxidant system and improved mitochondrial function in Aß-induced HT22 cells. Altogether, our findings suggest the potential of DL0410 as a novel candidate for AD treatment.

Tryptanthrin suppresses multiple inflammasome activation to regulate NASH progression by targeting ASC protein.

BACKGROUND: The adaptor protein apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain (CARD) can be activated through pyrin domain (PYD) interactions between sensors and ASC, and through CARD interactions between caspase-1 and ASC. Although the majority of ternary inflammasome complexes depend on ASC, drugs targeting ASC protein remain scarce. After screening natural compounds from Isatidis Radixin, we found that tryptanthrin (TPR) could inhibit NLRP3-induced IL-1ß and caspase-1 production, but the underlying anti-inflammatory mechanisms remain to be elucidated. PURPOSE: The purpose of this study was to determine the impact of TPR on the NLRP3, NLRC4, and AIM2 inflammasomes and the underlying mechanisms. Additionally, the efficacy of TPR was analysed in the further course of methionine- and choline-deficient (MCD)-induced NASH and lipopolysaccharide (LPS)-induced sepsis models of mice. METHODS: In vitro studies used bone marrow-derived macrophages to assess the anti-inflammatory activity of TPR, and the techniques included western blot, testing of intracellular K+ and Ca2+, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), co-immunoprecipitation, ASC oligomerization assay, surface plasmon resonance (SPR), and molecular docking. We used LPS-induced sepsis models and MCD-induced NASH models in vivo to evaluate the effectiveness of TPR in inhibiting inflammatory diseases. RESULTS: Our observations suggested that TPR could inhibit NLRP3, NLRC4, and AIM2 inflammasome activation. As shown in a mouse model of inflammatory diseases caused by MCD-induced NASH and LPS-induced sepsis, TPR significantly alleviated the progression of diseases. TPR interrupted the interactions between ASC and NLRP3/NLRC4/AIM2 in the co-immunoprecipitation experiment, and stable binding of TPR to ASC was also evident in SPR experiments. The underlying mechanisms of anti-inflammatory activities of TPR might be associated with targeting ASC, in particular, PYD domain of ASC. CONCLUSION: In general, the requirement for ASC in multiple inflammasome complexes makes TPR, as a novel broad-spectrum inflammasome inhibitor, potentially useful for treating a wide range of multifactorial inflammasome-related diseases.