Cordycepin mitigates dextran sulfate sodium-induced colitis through improving gut microbiota composition and modulating Th1/Th2 and Th17/Treg balance.

BACKGROUND: Imbalances in Th1/Th2 and Th17/Treg immune axes, coupled with disruptions in the gut microbiota (GM), play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). Cordycepin, a natural anti-inflammatory compound, holds promise in mitigating IBD by rebalancing these immune axes in conjunction with modulating the GM. The aim of this experiment is to investigate the potential of cordycepin in mitigating enteritis and elucidate the underlying mechanisms associated with its ameliorative effects on enteritis. METHODS: On the day of inducing experimental colitis with Dextran Sulfate Sodium (DSS), mice in the DSS + Cordycepin and Cordycepin groups received 50 mg/kg/day Cordycepin via intra-gastric administration (i.g.) for seven consecutive days, respectively. Mice in the DSS and control groups were treated with equal volumes of saline. On day 8, all mice were euthanized under pentobarbital sodium anesthesia. RESULTS: In a DSS-induced colitis mouse model, Cordycepin treatment led to a significant reduction in the disease activity index (DAI), splenic weight, and colonic pathological injury while simultaneously improving body weight and colonic length. Furthermore, it positively impacted GM composition, resulting in decreased Th1 and Th17 cells, alongside an increase in Th2 and Treg cells. The contents of the mouse colon were extracted for microbial community analysis. Mouse blood was prepared into a single-cell suspension, and flow cytometry was used to assess the expressio of Treg, Th17, Th1, and Th2 immune cells. CONCLUSIONS: These results underscored the effective intervention of cordycepin in ameliorating DSS-induced colitis by harmonizing the interplay between GM and immune homeostasis.

Naturally-derived modulators of the Nrf2 pathway and their roles in the intervention of diseases.

Cumulative evidence has verified that persistent oxidative stress is involved in the development of various chronic diseases, including pulmonary, neurodegenerative, kidney, cardiovascular, and liver diseases, as well as cancers. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular oxidative stress and inflammatory reactions, making it a focal point for disease prevention and treatment strategies. Natural products are essential resources for discovering leading molecules for new drug research and development. In this review, we comprehensively outlined the progression of the knowledge on the Nrf2 pathway, Nrf2 activators in clinical trials, the naturally-derived Nrf2 modulators (particularly from 2014-present), as well as their effects on the pathogenesis of chronic diseases.

Use of a Microelectromechanical Systems Sensor for Objective Measurements of Abnormal Head Posture in Congenital Superior Oblique Palsy Patients.

Purpose: The purpose of this study was to design an objective method for measurement of head positions as achieved with use of a microelectromechanical systems (MEMS) sensor. In addition, to use this system to observe the abnormal head position (AHP) in patients with congenital superior oblique palsy (SOP) before and after their surgery. Methods: An MEMS sensor was designed for recording of the pitch, roll, and yaw values of the head position in real time. The MEMS sensor was then fixed on the synoptophore from -30 degrees to +30 degrees positions horizontally and vertically to test the accuracy of these measurements. Then, we tested 13 participants with AHP using the MEMS method and the photographic method and compared their correlations. Finally, the pitch, roll, and yaw values of head positions were measured using this MEMS sensor in 31 patients with congenital SOP as performed before and after their surgery. Results: The MEMS sensor (LPMS-B2; Alubi, Guangzhou, China; 400 hertz [Hz]), as based on the theory of a gyroscope, was designed and connected to a smartphone via Bluetooth. It was able to conveniently record the patient's pitch, roll, and yaw head positions in real time, recordings which were consistent with the scales of the synoptophore (P > 0.05) and good correlations with the photographic method (P < 0.001). The main preoperative AHP in patients with SOP was roll (22/31, 71%). Pre- and postoperative vertical deviations were 16.4 ± 7.3 prism diopters (PD) and 4.1 ± 4.2 PD, respectively (P = 0.001). The AHP in patients with SOP was positively correlated with the angle of extorsion in the dominant eye (P = 0.01), rather than that of the vertical deviation. Conclusions: The MEMS sensor described in this report is a simple, practical, and accurate objective device for use in head position measurements. In patients with SOP, the AHP is related to the angle of extorsion in the dominant eye. Translational Relevance: The MEMS sensor was designed as a micro-wireless dynamic high-precision device for AHP measurement, which has the potential for use in a clinic.

A Comprehensive Quality Evaluation for Gentiana rigescens Franch. by Fingerprinting Combined with Chemometrics and Network Pharmacology.

Gentiana rigescens Franch. (G. rigescens) is a unique traditional medicinal herb from southwestern China, and its clinical mechanism for the treatment of hepatitis and the quality differences between different origins are not clear. The research aims to analyze the mechanisms for the treatment of hepatitis and differences in inter-origin differences using analytical techniques, chemometrics, and network pharmacology. Through infrared spectroscopy, spectral images, and high-performance liquid chromatography (HPLC) analysis, it was found that there were differences in absorbance intensity and significant differences in compound content among the samples'origin. G. rigescens iridoids and flavonoids exert therapeutic effects on hepatitis through multiple targets and multiple pathways. The above HPLC, chemometrics, and network pharmacology results revealed that gentiopicroside, and swertiamarine was the best quality marker among origins. The ResNet model could be utilized as an effective tool for tracing G. rigescens's origins. The PLSR model had excellent predictive performance in determining the content of gentiopicroside and swertiamarine, and could quickly, accurately, and effectively predict these two compounds. The research investigates the differences in G. rigescens origins from multiple perspectives, establishes image recognition models and prediction models, and provides new methods and theoretical basis for quality control of G. rigescens.

In Situ Synthesis and Characterizations of a Strontium-Substituted Dicalcium Phosphate Anhydrous/Hydroxyapatite Biphasic Whisker and Its Properties Evaluation.

Dicalcium phosphate anhydrous (DCPA) presents good biomineralization ability, the strontium element is known for superior bone affinity, and a whisker possesses good mechanical strength; all these are beneficial for improving the drawbacks of hydroxyapatite (HAP) like weaker mechanical properties, poor biomineralization, and slower degradation/absorption. Therefore, a homogeneous precipitation was adopted to synthesize Sr-substituted and DCPA and HAP coexisting whiskers. The composition, structure, and morphology based on urea dosage and substitution content were characterized, and the roles of DCPA, Sr, and whisker shape were investigated. It turned out that Sr-DCPA/HAP biphasic products contained about 19% DCPA and 81% HAP, and both phases occupied the outer and inner parts of the whisker, respectively. Increasing the urea dosage made the morphology transform from a sea urchin shape to fiber clusters and then whiskers, while Sr substitution brought the whisker back to the porous microsphere shape. Only 5% of Sr content and 15 g of urea could maintain the whisker shape. Sr could promote the proliferation of MC3T3-E1 cells even at a higher extract concentration of 10 mg/mL. The cells stayed in a healthy state whether cocultured with the whisker or the microsphere. The unstable DCPA combined with the decreased crystallinity brought by Sr doping contributed to shortening the apatite deposition period to within 7 days. The whisker morphology enhanced the compressive strength of acrylic resin, and the apatite layer helped to reduce the strength loss during soaking. The Sr-DCPA/HAP biphasic whisker with enhanced overall properties possessed more promising potential for biomedical application.

Multiomics Reveals a Mechanism: Glycogen Synthesis, Galactose Metabolism, and Ethanol Degradation Pathways, the Durable Role of Neutralizing Antibodies in Preventing COVID-19.

Since the emergence and rapid dissemination of Coronavirus disease 2019 (COVID-19), over 774 million individuals globally have achieved recovery to today. There is some case flashing into here and there all over the world. Neutralizing Antibody (NAb) against Severe Acute Respiratory Syndrome Coronavirus-Type 2 (SARS-CoV-2) play a paramount role in conferring effective and lasting protection for several months. This protective effect decreases with time thus increasing the chance of reinfection. Therefore, we can provide the body with a lasting protective effect by maintaining NAb level. However, how to maintain Nab level remains elusive. To address this question, we recruited 80 patients with confirmed COVID-19 and collected 480 consecutive blood samples and performed NAb testing six months after their recovery. The NAb level were categorized into two groups: a low-titer NAb group (≤20) and a high-titer NAb group (>20). To achieve a comprehensive understanding of the changes in NAb level, 16 serum samples were randomly selected for an untargeted metabolomic analysis, whereas 9 samples were designated for a label-free proteomic analysis. We successfully identified differentially expressed 751 metabolites and 845 proteins. In both the low and high NAb titer groups, we identified three key differential proteins, phosphoglucose translocase 2(PGM2), UDP-Glc 4-epimerase (GALE), and alcohol dehydrogenase 1B (ADH1B), that play important roles in fluctuating NAb level through the glycogen synthesis, galactose metabolism and ethanol degradation pathways. These three key differential proteins may serve as potential biomarkers for maintaining NAb level and enhancing immune protection in patients recovering from COVID-19.

Comparative analysis of chemical elements and metabolites in diverse garlic varieties based on metabolomics and ionomics.

As a plant classified under the "medicine food homology" concept, garlic offers various health benefits and comes in many different varieties. In this study, the metabolite composition of different garlic varieties were analyzed using LC-MS/MS quadrupole-Orbitrap mass spectrometry and ICP-MS. A total of 30 chemical elements and 1256 metabolites were identified. Significant differences in chemical elements and metabolomics profiles were observed among the five garlic groups (VIP > 1.5). Compared to WG, PG contained 5 unique compounds, HG had 15 unique compounds, SCG had 18 unique compounds, and SBG had 26 unique compounds. Furthermore, the results showed that WG had smaller differences with PG and HG, but significant differences with SBG and SCG. KEGG analysis revealed metabolic pathways associated with the formation of differential metabolites. These findings uncover the differences and mechanisms in the composition of various garlic varieties, providing a theoretical foundation for distinguishing the nutritional components of different garlic types.

Simplification algorithm of 3D building model based on triangle folding.

3D building models have a complex structure and a large number of triangular meshes, which can put great pressure on computer real-time rendering. Therefore, the model needs to be simplified to reduce the number of meshes without affecting the overall visual effect of the model. The algorithm in this paper is based on triangle folding, which simplifies more but loses model details. In order to make up for the shortcoming of triangle folding, more constraints need to be introduced for error control. Meanwhile, this paper solves the problem of higher complexity of the algorithm due to the introduction of more constraints by calculating the Mahalanobis distance of each constraint factor introduced. The vertices with obvious sharp features are constrained to keep the structure of the model undeformed. Experiments prove that the algorithm in this paper can better preserve the detailed features and the visual effect of the model.

Rapid Synthesis of Sb2Si2Te6 under High Pressure with a Modulated Microstructure.

Over the past decades, thermoelectric materials have advanced significantly, yet materials such as Sb2Si2Te6, which are challenging to synthesize chemically, often require lengthy and complex preparation processes, hindering their development. In this work, we prepare polycrystalline Sb2Si2Te6 bulk from elemental precursors using a high-pressure synthesis (HPS) method. This method offers significant advantages in efficiency and preparation duration. The applied pressure promotes an isotropic microstructure and regulates the thermoelectric properties by controlling precipitate contents, grain size, and twinning. Although an increase in thermal conductivity, mostly due to the notable increase in electrical conductivity, leads to less favorable thermal conductivity near room temperature compared to samples prepared using conventional methods, a beneficial reversal occurs at high temperatures. The polycrystalline Sb2Si2Te6 sample synthesized at 2 GPa demonstrates a peak ZT value of 1.1 at 773 K, outperforming most pristine Sb2Si2Te6 materials. This work demonstrates an efficient strategy for optimizing Sb2Si2Te6 performance and offers a new synthesis pathway for other challenging thermoelectric materials.

A Novel End-to-End Deep Learning Framework for Chip Packaging Defect Detection.

As semiconductor chip manufacturing technology advances, chip structures are becoming more complex, leading to an increased likelihood of void defects in the solder layer during packaging. However, identifying void defects in packaged chips remains a significant challenge due to the complex chip background, varying defect sizes and shapes, and blurred boundaries between voids and their surroundings. To address these challenges, we present a deep-learning-based framework for void defect segmentation in chip packaging. The framework consists of two main components: a solder region extraction method and a void defect segmentation network. The solder region extraction method includes a lightweight segmentation network and a rotation correction algorithm that eliminates background noise and accurately captures the solder region of the chip. The void defect segmentation network is designed for efficient and accurate defect segmentation. To cope with the variability of void defect shapes and sizes, we propose a Mamba model-based encoder that uses a visual state space module for multi-scale information extraction. In addition, we propose an interactive dual-stream decoder that uses a feature correlation cross gate module to fuse the streams' features to improve their correlation and produce more accurate void defect segmentation maps. The effectiveness of the framework is evaluated through quantitative and qualitative experiments on our custom X-ray chip dataset. Furthermore, the proposed void defect segmentation framework for chip packaging has been applied to a real factory inspection line, achieving an accuracy of 93.3% in chip qualification.

Neoadjuvant envafolimab in a patient with MSI-H/dMMR colon cancer: a case report and literature review.

Clinical evidences of neoadjuvant immunotherapy in patients with mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) colorectal cancer have not been well received. A 36-year-old man complained of recurrent right upper quadrant pain for more than 1 year, and the symptoms were not significantly relieved after 10 days of oral Changyanning tablet. The patient was finally diagnosed as dMMR/MSI-H colon cancer. Tumor regression was achieved after seven cycles of envafolimab treatment, and the patient obtained postoperative pathological complete response (pCR). Here, we report a case of MSI-H/dMMR transverse colon cancer, who obtained pCR after neoadjuvant envafolimab (a novel subcutaneous single-domain anti-PD-L1 antibody) with a favorable safety profile, aiming to enhance the experiences of comprehensive diagnosis and treatment of colon cancer.

Immune checkpoint inhibitors (ICIs) are a type of immunotherapy which can be used in the treatment of colorectal cancer. The authors here report the functions of envafolimab (a type of ICI) used before surgery to shrink tumor volume in colorectal cancer. A 36-year-old man suffered from repeated illness of right upper quadrant for over 1 year, and the illness were not recovered after 10 days of oral Changyanning tablet. The patient was finally diagnosed with colorectal cancer. After seven cycles of envafolimab treatment, tumor volume was significantly decreased, and the patient obtained favorable surgical outcomes with tolerable safety after surgery.

Multi­omics identification of a signature based on malignant cell-associated ligand-receptor genes for lung adenocarcinoma.

PURPOSE: Lung adenocarcinoma (LUAD) significantly contributes to cancer-related mortality worldwide. The heterogeneity of the tumor immune microenvironment in LUAD results in varied prognoses and responses to immunotherapy among patients. Consequently, a clinical stratification algorithm is necessary and inevitable to effectively differentiate molecular features and tumor microenvironments, facilitating personalized treatment approaches. METHODS: We constructed a comprehensive single-cell transcriptional atlas using single-cell RNA sequencing data to reveal the cellular diversity of malignant epithelial cells of LUAD and identified a novel signature through a computational framework coupled with 10 machine learning algorithms. Our study further investigates the immunological characteristics and therapeutic responses associated with this prognostic signature and validates the predictive efficacy of the model across multiple independent cohorts. RESULTS: We developed a six-gene prognostic model (MYO1E, FEN1, NMI, ZNF506, ALDOA, and MLLT6) using the TCGA-LUAD dataset, categorizing patients into high- and low-risk groups. This model demonstrates robust performance in predicting survival across various LUAD cohorts. We observed distinct molecular patterns and biological processes in different risk groups. Additionally, analysis of two immunotherapy cohorts (N = 317) showed that patients with a high-risk signature responded more favorably to immunotherapy compared to those in the low-risk group. Experimental validation further confirmed that MYO1E enhances the proliferation and migration of LUAD cells. CONCLUSION: We have identified malignant cell-associated ligand-receptor subtypes in LUAD cells and developed a robust prognostic signature by thoroughly analyzing genomic, transcriptomic, and immunologic data. This study presents a novel method to assess the prognosis of patients with LUAD and provides insights into developing more effective immunotherapies.

Yttrium-based metal-organic frameworks built on hexanuclear clusters.

Yttrium-based metal-organic frameworks built on hexanuclear clusters (Y6-MOFs) represent an important subgroup of MOFs that are assembled from Y6 clusters and diverse organic linkers, featuring a variety of topologies. Due to the robust Y-O bonds and high connectivity of hexanuclear SBUs, Y6-MOFs are generally thermally stable and resistant to water. Additionally, their pore structures are highly tunable through the practice of the reticular chemistry strategy, resulting in excellent performance in gas adsorption and separation related applications. Y6-MOFs are structurally analogous to Zr6-MOFs; however, the existence of charge-balancing cations in Y6-MOFs serves as an additional pore structure regulator, enhancing their tailorability with respect to pore shape and dimensions. In this Frontier article, we summarize the main advances in the design and synthesis of Y6-MOFs, with a particular focus on the precise engineering of their pore structure for gas separation. Future directions of research efforts in this field are also discussed.

Development of a prognostic model for NSCLC based on differential genes in tumour stem cells.

Non-small cell lung cancer (NSCLC) constitutes a significant portion of lung cancers and cytotoxic drugs (e.g. cisplatin) are currently the first-line treatment. However, NSCLC has developed resistance to this drug, which limits the therapeutic effect and thus affects prognosis. NSCLC sc-RNA-seq data were downloaded from the GEO database and Ku Leuven Laboratory for Functional Epigenetics, and bulk RNA-seq data were obtained from the TCGA database. The "Seurat" package was employed for scRNA-seq data processing, and the uniform manifold approximation and projection (UMAP) were applied for downscaling and cluster identification. Use the FindAllMarkers function to find differential genes (DEGs) for tumor stem cells. Then, we performed univariate regression analyses on the DEGs to identify potential prognostic genes. We created a machine learning framework based on potential prognostic genes, which combines 10 machine learning methods and their 101 combinations to get the optimal prognostic risk model. The model was evaluated in the training set and validation set. A nomogram was developed to provide physicians with a quantitative tool for prognosis prediction. Finally, we evaluated the expression and functionality of SLC2A1. We discovered 22 cell clusters containing 218379 cells by examining single-cell RNA sequencing datasets (GSE148071, KU_lom, GSE131907, GSE136246, GSE127465). Tumour cells were isolated for subpopulation analysis and 162 differential genes from SOX2_cancer were obtained. After univariate Cox analysis, we found 23 genes with prognostic potential prognostic value and utilized them to develop 101­combination machine learning computational framework. We eventually picked the best performing 'StepCox[both] + RSF', which includes 8 genes. The model has a relatively high prediction accuracy in both TCGA and GEO datasets. In in vitro investigations, targeted suppression of the SLC2A1 gene resulted in significant reductions in proliferation, invasion and migration in A549 cells. In addition, a significant reduction in cisplatin resistance was seen in A549/DDP cells. The outcomes demonstrated the precision and credibility of the prognostic model for NSCLC, highlighting its potential significance in the treatment and prognosis of individuals affected by this disease. SLC2A1 may become a promising prognostic marker and a potential therapeutic target, offering valuable insights to inform clinical treatment decisions.

Ethyl acetate fraction of Thesium chinense Turcz. alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis mediated by activating Nrf2/SLC7A11/GPX4 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Thesium chinense Turcz., a traditional Chinese herbal medicine, displays good therapeutic efficiency against respiratory diseases (e.g. pneumonia, pharyngitis) in clinical applications, however, its effects on COPD and the mechanism of action are still unclear. AIM OF THE STUDY: This study aims to investigate the therapeutic effect of the ethyl acetate fraction of Thesium chinense Turcz. (TCEA) on COPD and reveal the underlying mechanism. MATERIALS AND METHODS: A cigarette smoke (CS)-induced mouse COPD model was established, and the efficacy of TCEA was evaluated using peripheral blood testing, HE and Masson staining, qRT-PCR and ELISA assays. TCEA was analyzed for chemical composition by LC-MS/MS and HPLC. Prediction of major signaling pathways and potential targets was performed by network pharmacology. The molecular mechanism of TCEA was explored by immunoblotting, immunofluorescence staining, flow cytometry, and ubiquitination assay. Finally, potential active small molecules in TCEA were identified by molecular virtual screening. RESULTS: TCEA treatment significantly inhibited the secretion of pro-inflammatory factors and attenuated pathological emphysema. The main chemical constituents of TCEA were identified as flavonoids by UPLC-MS/MS. Network pharmacology analysis enriched the Nrf2 signaling pathway closely related to oxidative stress. Our results suggested that TCEA inhibited ferroptosis by activating Nrf2/SLC7A11/GPX4 axis and inhibiting lipid metabolism-related proteins, ACSL4, ALOX5 and COX2 in vivo and in vitro. Noteworthily, the beneficial impact of TCEA on regulation of SLC7A11 and GPX4 vanished after silencing Nrf2. Moreover, Nrf2 ubiquitination was inhibited by TCEA treatment. Finally, several flavonoids modulating Nrf2 were identified by molecular virtual screening. CONCLUSIONS: TCEA significantly alleviated COPD progression by inhibiting ferroptosis primarily through activation of Nrf2/SLC7A11/GPX4 signaling. Flavonoids are the main active components that exert their effects. These findings shed light on the mechanism of action of TCEA and its potential active components, providing a feasible approach for the treatment of COPD.

Causal links between immune cells and asthma: Insights from a Mendelian Randomization analysis.

OBJECTIVES: Recent studies suggest immunophenotypes may play a role in asthma, but their causal relationship has not been thoroughly examined. METHODS: We used single nucleotide polymorphism (SNP)-derived instrumental variables. Summary data from 731 immune cell profiles and asthma cases were analyzed from genome-wide association studies (GWAS) of European populations. Mendelian Randomization (MR) analyses included inverse variance weighted (IVW), weighted median, and MR-Egger methods. Pleiotropy was assessed using the MR-Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Reverse MR analysis explored bidirectional causation between asthma and immunophenotypes. All statistical analyses were conducted using R software. RESULTS: MR analysis identified 108 immune signatures potentially contributing to asthma. Two immunophenotypes were significantly associated with asthma risk: CD4+ secreting Treg cells in allergic asthma (ORIVW = 1.078; 95% CI: 1.036-1.122; PIVW = 0.0002) and IgD + CD38- %lymphocyte cells in non-allergic asthma (ORIVW = 1.123; 95% CI: 1.057-1.194; PIVW = 0.0002). CONCLUSIONS: This study highlights the causal associations between specific immunophenotypes and asthma risk, providing new insights into asthma pathogenesis.

Exploring the Effects and Potential Mechanisms of Hesperidin for the Treatment of CPT-11-Induced Diarrhea: Network Pharmacology, Molecular Docking, and Experimental Validation.

Chemotherapy-induced diarrhea (CID) is a potentially serious side effect that often occurs during anticancer therapy and is caused by the toxic effects of chemotherapeutic drugs on the gastrointestinal tract, resulting in increased frequency of bowel movements and fluid contents. Among these agents, irinotecan (CPT-11) is most commonly associated with CID. Hesperidin (HPD), a flavonoid glycoside found predominantly in citrus fruits, has anti-oxidation properties and anti-inflammation properties that may benefit CID management. Nevertheless, its potential mechanism is still uncertain. In this study, we firstly evaluated the pharmacodynamics of HPD for the treatment of CID in a mouse model, then used network pharmacology and molecular docking methods to excavate the mechanism of HPD in relieving CID, and finally further proved the predicted mechanism through molecular biology experiments. The results demonstrate that HPD significantly alleviated diarrhea, weight loss, colonic pathological damage, oxidative stress, and inflammation in CID mice. In addition, 74 potential targets for HPD intervention in CID were verified by network pharmacology, with the top 10 key targets being AKT1, CASP3, ALB, EGFR, HSP90AA1, MMP9, ESR1, ANXA5, PPARG, and IGF1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the PI3K-Akt pathway, FoxO pathway, MAPK pathway, TNF pathway, and Ras pathway were most relevant to the HPD potential treatment of CID genes. The molecular docking results showed that HPD had good binding to seven apoptosis-related targets, including AKT1, ANXA5, CASP3, HSP90AA1, IGF1, MMP9, and PPARG. Moreover, we verified apoptosis by TdT-mediated dUTP nick-end labeling (TUNEL) staining and immunohistochemistry, and the hypothesis about the proteins above was further verified by Western blotting in vivo experiments. Overall, this study elucidates the potential and underlying mechanisms of HPD in alleviating CID.

[Zhuyu Pills regulate p53/SLC7A11 signaling pathway-mediated oxidative damage and ferroptosis to treat atherosclerosis].

This article aims to investigate the effect of Zhuyu Pills on atherosclerosis(AS) and decipher the underlying mechanism. The mouse model of AS was established by feeding with a high-fat diet for 12 weeks. The 50 successfully modeled mice with the apolipoprotein E knockout(ApoE~(-/-)) were assigned by the random number table method into 5 groups(n=10): model, low-, medium-, and high-dose(130.54, 261.08, 522.16 mg·kg~(-1), respectively) Zhuyu Pills, and atorvastatin calcium(10.40 mg·kg~(-1)). Ten C57BL/6J mice were selected as the blank group. The blank group and model group were administrated with an equal volume of normal saline, and other groups were administrated with corresponding drugs once a day for 12 weeks. At the end of drug intervention, hematoxylin-eosin(HE) staining was employed to observe the pathological changes of fat in the aorta, liver, and epididymis of mice, and the proportion of aortic plaque area, fat area in epididymis, and nonalcoholic fatty liver disease activity score(NAS) were calculated. Lipid and collagen deposition in the aorta was observed by oil red O staining and Masson staining, respectively, and the proportions of lipid and collagen deposition areas were calculated. The serum levels of superoxide dismutase(SOD), malondialdehyde(MDA), glutathione peroxidase(GSH-Px), and iron ion were measured by colorimetry. The expression of cyclooxygenase 2(COX2), ferritin heavy chain 1(FTH1), cystine/glutamate reverse transporter solute carrier family 7 member 11(SLC7A11), and glutathione peroxidase 4(GPX4) in the aorta was detected by the immunofluorescence assay. The level of tumor protein 53(p53) in the aorta was detected by immunohistochemistry. The protein levels of p53 and SLC7A11 in the aorta were determined by Western blot. The mRNA levels of p53, SLC7A11, GPX4, FTH1, prostaglandin G/H synthase 2(PTGS2), and reduced nicotinamide adenine dinucleotide phosphate oxidase 1(NOX1) in mouse aorta were determined by real-time PCR. The results showed that compared with the blank group, the model group showcased enlarged aortic plaque area, increased collagen fiber deposition, liver lipid deposition, and lipid droplets, and enlarged epididymal adipocytes. In addition, the modeling elevated the levels of iron ion and MDA and lowered the levels of SOD and GSH-Px in the serum, promoted the expression of p53 and COX2, down-regulated the protein and mRNA levels of FTH1, SLC7A11, and GPX4, and up-regulated the mRNA levels of PTGS2 and NOX1 in the aorta. Compared with the model group, low-, medium-, and high-dose Zhuyu Pills and atorvastatin calcium reduced the aortic plaque area, collagen deposition, liver lipid deposition, lipid droplets, and epididymal adipocyte volume, lowered the levels of iron ion and MDA and elevated the levels of SOD and GSH-Px in the serum, inhibited the expression of p53 and COX2, up-regulated the protein and mRNA levels of FTH1, SLC7A11, and GPX4, and down-regulated the mRNA levels of PTGS2 and NOX1 in the aorta. In conclusion, Zhuyu Pills exert definite therapeutic effect on aortic plaque in AS mice by regulating the p53/SLC7A11 signaling pathway to alleviate oxidative damage and inhibit ferroptosis.

Gastrointestinal tract organoids as novel tools in drug discovery.

Organoids, characterized by their high physiological attributes, effectively preserve the genetic characteristics, physiological structure, and function of the simulated organs. Since the inception of small intestine organoids, other organoids for organs including the liver, lungs, stomach, and pancreas have subsequently been developed. However, a comprehensive summary and discussion of research findings on gastrointestinal tract (GIT) organoids as disease models and drug screening platforms is currently lacking. Herein, in this review, we address diseases related to GIT organoid simulation and highlight the notable advancements that have been made in drug screening and pharmacokinetics, as well as in disease research and treatment using GIT organoids. Organoids of GIT diseases, including inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, and Helicobacter pylori infection, have been successfully constructed. These models have facilitated the study of the mechanisms and effects of various drugs, such as metformin, Schisandrin C, and prednisolone, in these diseases. Furthermore, GIT organoids have been used to investigate viruses that elicit GIT reactions, including Norovirus, SARS-CoV-2, and rotavirus. Previous studies by using GIT organoids have shown that dasabuvir, gemcitabine, and imatinib possess the capability to inhibit viral replication. Notably, GIT organoids can mimic GIT responses to therapeutic drugs at the onset of disease. The GIT toxicities of compounds like gefitinib, doxorubicin, and sunset yellow have also been evaluated. Additionally, these organoids are instrumental for the study of immune regulation, post-radiation intestinal epithelial repair, treatment for cystic fibrosis and diabetes, the development of novel drug delivery systems, and research into the GIT microbiome. The recent use of conditioned media as a culture method for replacing recombinant hepatocyte growth factor has significantly reduced the cost associated with human GIT organoid culture. This advancement paves the way for large-scale culture and compound screening of GIT organoids. Despite the ongoing challenges in GIT organoid development (e.g., their inability to exist in pairs, limited cell types, and singular drug exposure mode), these organoids hold considerable potential for drug screening. The use of GIT organoids in this context holds great promises to enhance the precision of medical treatments for patients living with GIT diseases.