Synergistic Regulation of Targeted Organelles in Tumor Cells to Promote Photothermal-Immunotherapy Using Intelligent Core-Satellite-Like Nanoparticles for Effective Treatment of Breast Cancer.

The normal operation of organelles is critical for tumor growth and metastasis. Herein, an intelligent nanoplatform (BMAEF) is fabricated to perform on-demand destruction of mitochondria and golgi apparatus, which also generates the enhanced photothermal-immunotherapy, resulting in the effective inhibition of primary and metastasis tumor. The BMAEF has a core of mesoporous silica nanoparticles loaded with brefeldin A (BM), which is connected to ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) and folic acid co-modified gold nanoparticles (AEF). During therapy, the BMAEF first accumulates in tumor cells via folic acid-induced targeting. Subsequently, the schiff base/ester bond cleaves in lysosome to release brefeldin A and AEF with exposed EGTA. The EGTA further captures Ca2+ to block ion transfer among mitochondria, endoplasmic reticulum, and golgi apparatus, which not only induced dysfunction of mitochondria and golgi apparatus assisted by brefeldin A to suppress both energy and material metabolism against tumor growth and metastasis, but causes AEF aggregation for tumor-specific photothermal therapy and photothermal assisted immunotherapy. Moreover, the dysfunction of these organelles also stops the production of BMI1 and heat shock protein 70 to further enhance the metastasis inhibition and photothermal therapy, which meanwhile triggers the escape of cytochrome C to cytoplasm, leading to additional apoptosis of tumor cells.

The implication of infection with respiratory syncytial virus in pediatric recurrent wheezing and asthma: knowledge expanded post-COVID-19 era.

BACKGROUND: Respiratory syncytial virus (RSV) infection has been identified to serve as the primary cause of acute lower respiratory infectious diseases in children under the age of one and a significant risk factor for the emergence and development of pediatric recurrent wheezing and asthma, though the exact mechanism is still unknown. METHODS AND RESULTS: In this study, we discuss the key routes that lead to recurrent wheezing and bronchial asthma following RSV infection. It is interesting to note that following the coronavirus disease 2019 (COVID-19) epidemic, the prevalence of RSV changes significantly. This presents us with a rare opportunity to better understand the associated mechanism for RSV infection, its effects on the respiratory system, and the immunological response to RSV following the COVID-19 epidemic. To better understand the associated mechanisms in the occurrence and progression of pediatric asthma, we thoroughly described how the RSV infection directly destroys the physical barrier of airway epithelial tissue, promotes inflammatory responses, enhances airway hyper-responsiveness, and ultimately causes the airway remodeling. More critically, extensive discussion was also conducted regarding the potential impact of RSV infection on host pulmonary immune response. CONCLUSION: In conclusion, this study offers a comprehensive perspective to better understand how the RSV infection interacts in the control of the host's pulmonary immune system, causing recurrent wheezing and the development of asthma, and it sheds fresh light on potential avenues for pharmaceutical therapy in the future.

Prediction of Human Liver Microsome Clearance with Chirality-Focused Graph Neural Networks.

In drug candidate design, clearance is one of the most crucial pharmacokinetic parameters to consider. Recent advancements in machine learning techniques coupled with the growing accumulation of drug data have paved the way for the construction of computational models to predict drug clearance. However, concerns persist regarding the reliability of data collected from public sources, and a majority of current in silico quantitative structure-property relationship models tend to neglect the influence of molecular chirality. In this study, we meticulously examined human liver microsome (HLM) data from public databases and constructed two distinct data sets with varying HLM data quantity and quality. Two baseline models (RF and DNN) and three chirality-focused GNNs (DMPNN, TetraDMPNN, and ChIRo) were proposed, and their performance on HLM data was evaluated and compared with each other. The TetraDMPNN model, which leverages chirality from 2D structure, exhibited the best performance with a test R2 of 0.639 and a test root-mean-squared error of 0.429. The applicability domain of the model was also defined by using a molecular similarity-based method. Our research indicates that graph neural networks capable of capturing molecular chirality have significant potential for practical application and can deliver superior performance.

Constructing Innovative Covalent and Noncovalent Compound Libraries: Insights from 3D Protein-Ligand Interactions.

Noncovalent interactions between small-molecule drugs and protein targets assume a pivotal role in drug design. Moreover, the design of covalent inhibitors, forming covalent bonds with amino acid residues, requires rational reactivity for their covalent warheads, presenting a key challenge as well. Understanding the intricacies of these interactions provides a more comprehensive understanding of molecular binding mechanisms, thereby guiding the rational design of potent inhibitors. In this study, we adopted the fragment-based drug design approach, introducing a novel methodology to extract noncovalent and covalent fragments according to distinct three-dimensional (3D) interaction modes from noncovalent and covalent compound libraries. Additionally, we systematically replaced existing ligands with rational fragment substitutions, based on the spatial orientation of fragments in 3D space. Furthermore, we adopted a molecular generation approach to create innovative covalent inhibitors. This process resulted in the recombination of a noncovalent compound library and several covalent compound libraries, constructed by two commonly encountered covalent amino acids: cysteine and serine. We utilized noncovalent ligands in KLIFS and covalent ligands in CovBinderInPDB as examples to recombine noncovalent and covalent libraries. These recombined compound libraries cover a substantial portion of the chemical space present in the original compound libraries and exhibit superior performance in terms of molecular scaffold diversity compared to the original compound libraries and other 11 commercial libraries. We also recombined BTK-focused libraries, and 23 compounds within our libraries have been validated by former researchers to possess potential biological activity. The establishment of these compound libraries provides valuable resources for virtual screening of covalent and noncovalent drugs targeting similar molecular targets.

Parkin deficiency promotes liver cancer metastasis by TMEFF1 transcription activation via TGF-ß/Smad2/3 pathway.

Parkin (PARK2) deficiency is frequently observed in various cancers and potentially promotes tumor progression. Here, we showed that Parkin expression is downregulated in liver cancer tissues, which correlates with poor patient survival. Parkin deficiency in liver cancer cells promotes migration and metastasis as well as changes in EMT and metastasis markers. A negative correlation exists between TMEFF1 and Parkin expression in liver cancer cells and tumor tissues. Parkin deficiency leads to upregulation of TMEFF1 which promotes migration and metastasis. TMEFF1 transcription is activated by Parkin-induced endogenous TGF-ß production and subsequent phosphorylation of Smad2/3 and its binding to TMEFF1 promotor. TGF-ß inhibitor and TMEFF1 knockdown can reverse shParkin-induced cell migration and changes of EMT markers. Parkin interacts with and promotes the ubiquitin-dependent degradation of HIF-1α/HIF-1ß and p53, which accounts for the suppression of TGF-ß production. Our data have revealed that Parkin deficiency in cancer leads to the activation of the TGF-ß/Smad2/3 pathway, resulting in the expression of TMEFF1 which promotes cell migration, EMT, and metastasis in liver cancer cells.

Application progress of deep generative models in de novo drug design.

The deep molecular generative model has recently become a research hotspot in pharmacy. This paper analyzes a large number of recent reports and reviews these models. In the central part of this paper, four compound databases and two molecular representation methods are compared. Five model architectures and applications for deep molecular generative models are emphatically introduced. Three evaluation metrics for model evaluation are listed. Finally, the limitations and challenges in this field are discussed to provide a reference and basis for developing and researching new models published in future.

Myocardial contractility characteristics of hypertrophic cardiomyopathy patients with and without sarcomere mutation.

Hypertrophic cardiomyopathy (HCM) patients with sarcomere mutations have an increased risk of heart failure and left ventricular (LV) systolic dysfunction. We hypothesize that sarcomere mutation carriers have abnormal myocardial contractility before LV dysfunction. Therefore, we aimed to associate myocardial contractility with identified sarcomere mutations and predict genotyped HCM patients with sarcomere mutation by three-dimensional speckle tracking imaging (3D-STI). A retrospective analysis of 117 HCM patients identified 32 genotype-positive (G +) and 85 genotype-negative (G-) patients. Genotype-positive patients had higher globe circumferential strain (GCS), globe longitudinal strain (GLS), and globe radial strain (GRS) (p < 0.05), and multivariate logistic regression revealed that these variables were associated with a positive genetic status (p < 0.05). After the propensity matches other possible influencing factors, we developed three models, named Model GCS, Model GLS, and Model GRS, which could identified genotype-positive HCM patients with excellent performance (AUC of 0.855, 0.833, and 0.870 respectively, all p < 0.001). Genotype-positive HCM patients show a higher myocardial hyper-contractility status than patients without sarcomere mutations. When combined with clinical and echocardiographic markers, the 3D-STI parameters can effectively identify the likelihood of genotype-positive HCM.

Prognostic value of transthoracic echocardiography score for the prognosis of continuous ambulatory peritoneal dialysis patients.

BACKGROUND: We devoted ourselves to proving that the initial transthoracic echocardiography score (TTES) had predictive significance for patients with continuous ambulatory peritoneal dialysis (CAPD). METHODS: In this retrospective analysis, 274 CAPD patients who had PD therapy were recruited sequentially. TTE exams were performed three months following the start of PD therapy. All patients were divided into two groups based on the strength of their TTES levels. TTES's predictive value for CAPD patients was then determined using LASSO regression and Cox regression. RESULTS: During a median of 52 months, 46 patients (16.8%) died from all causes, and 32 patients (11.7%) died from cardiovascular disease (CV). The TTES was computed as follows: 0.109 × aortic root diameter (ARD, mm) - 0.976 × LVEF (> 55%, yes or no) + 0.010 × left ventricular max index, (LVMI, g/m2) + 0.035 × E/e' ratio. The higher TTES value (≥ 3.7) had a higher risk of all-cause death (hazard ratio, HR, 3.70, 95% confidence index, 95%CI, 1.45-9.46, P = 0.006) as well as CV mortality (HR, 2.74, 95%CI 1.15-19.17, P = 0.042). Moreover, the TTES had an attractive predictive efficiency for all-cause mortality (AUC = 0.762, 95%CI 0.645-0.849) and CV mortality (AUC = 0.746, 95%CI 0.640-0.852). The introduced nomogram, which was based on TTES and clinical variables, exhibited a high predictive value for all-cause and CV mortality in CAPD patients. CONCLUSION: TTES is a pretty good predictor of clinical outcomes, and the introduced TTES-based nomogram yields an accurate prediction value for CAPD patients.

Analysis of lncRNA-related studies of ivermectin-sensitive and -resistant strains of Haemonchus contortus.

In this study, 858 novel long non-coding RNAs (lncRNAs) were predicted as sensitive and resistant strains of Haemonchus contortus to ivermectin. These lncRNAs underwent bioinformatic analysis. In total, 205 lncRNAs significantly differed using log2 (difference multiplicity) > 1 or log2 (difference multiplicity) < - 1 and FDR < 0.05 as the threshold for significant difference analysis. We selected five lncRNAs based on significant differences in expression, cis-regulation, and their association with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. These expressions of lncRNAs, namely MSTRG.12610.1, MSTRG.8169.1, MSTRG.6355.1, MSTRG.980.1, and MSTRG.9045.1, were significantly downregulated. These findings were consistent with the results of transcriptomic sequencing. We further investigated the relative expression of target gene mRNAs and the regulation of mRNA and miRNA, starting with lncRNA cis-regulation of mRNA, and constructed a lncRNA-mRNA-miRNA network regulation. After a series of statistical analyses, we finally screened out UGT8, Unc-116, Fer-related kinase-1, GGPP synthase 1, and sart3, which may be involved in developing drug resistance under the regulation of their corresponding lncRNAs. The findings of this study provide a novel direction for future studies on drug resistance targets.

Sulfamethoxazole stress endangers the gut health of sea cucumber (Apostichopus japonicus) and affects host metabolism.

Sulfamethoxazole (SMZ) is a frequently detected antibiotic in the environment, and there is a growing concern about its potential toxic effects on aquatic organisms. sea cucumber (Apostichopus japonicas) is a benthic invertebrate whose gut acts as a primary immune defense and serves critical protective barrier. In this study, growth performance, histology, gut microbiota, and metabolomics analyses were performed to investigate the toxic response in the intestine of sea cucumber effects caused by SMZ stress for 56 d by evaluating with different concentrations of SMZ (0, 1.2×10-3, and 1.2 mg/L). The weight gain rate of sea cucumbers under SMZ stress showed significant decrease, indicating that the growth of sea cucumbers was hindered. Analysis of the intestinal morphological features indicated that SMZ stimulation resulted in atrophy of the sea cucumber gut. In the 1.2×10-3 mg/L concentration, the thickness of muscle and mucosal layers was reduced by 12.40% and 21.39%, while in the 1.2 mg/L concentration, the reductions were 35.08% and 26.98%. The abundance and diversity of sea cucumber intestinal bacteria decreased significantly (P < 0.05) under the influence of SMZ. Notably, the intestinal bacteria of sea cucumber became homogenized with the increase in SMZ concentration, and the relative abundance of Ralstonia reached 81.64% under the stress of 1.2 mg/L concentration. The SMZ stress significantly impacted host metabolism and disrupted balance, particularly in L-threonine, L-tyrosine, neuronic acid, piperine, and docosapentaenoic acid. SMZ leads to dysregulation of metabolites, resulting in growth inhibition and potential inflammatory responses that could adversely affect the normal activities of aquatic organisms. Further metabolic pathway enrichment analyses demonstrated that impaired biosynthesis of unsaturated fatty acids and aminoacyl-tRNA biosynthesis metabolic pathway were major reasons for SMZ stress-induced intestinal bacteria dysbiosis. This research aims to provide some theoretical evidence for the ecological hazard assessment of antibiotics in water.

Ginsenoside Re inhibits non-small cell lung cancer progression by suppressing macrophage M2 polarization induced by AMPKα1/STING positive feedback loop.

Tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT-PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2-like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2-like MΦ and consequently inhibiting the epithelial-mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2-type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC.

[Expansion of the genotypic and phenotypic spectrum and treatment of four children with Steroid-resistant nephrotic syndrome due to variants of TRPC6 gene].

OBJECTIVE: To summarize the clinical and genetic characteristics, treatment and prognosis of four children with Steroid-resistant nephrotic syndrome (SRNS) due to variants of TRPC6 gene. METHODS: Clinical data of four children with SRNS admitted to Children's Hospital Affiliated to Zhengzhou University between May 2020 and August 2022 were collected. Peripheral blood samples were collected from the children and their parents, and whole exome sequencing was carried out. Sanger sequencing was used to verify the pathogenicity of the candidate variants among the children and their parents. RESULTS: All of the four children were found to harbor heterozygous variants of the TRPC6 gene, including c.523C>T (p.R175W), c.1327T>A (p.F443I), c.430G>C (p.E144Q) (unreported previously), and c.523C>T (p.R175W), which were all missense variants. Two of the children have shown a simple type, whilst two have shown a nephritis type, none had extrarenal phenotype. Comprehensive renal pathology of three children revealed focal segmental glomerulosclerosis (FSGS). Two children were treated with steroids combined with calcineurin inhibitors (CNIs), among whom one showed significant improvement in symptoms. CONCLUSION: Discoveries of the novel c.430G>C variant and the new SRNS phenotype of the c.1327T>A variant have expanded the mutational and phenotypic spectrum of the TRPC6 gene, which has provided a reference for clinical diagnosis and genetic counseling for the families.

Highly Efficient Self-Assembly of Heterometallic [2]Catenanes and Cyclic Bis[2]catenanes via Orthogonal Metal-Coordination Interactions.

Although catenated cages have been widely constructed due to their unique and elegant topological structures, cyclic catenanes formed by the connection of multiple catenane units have been rarely reported. Herein, based on the orthogonal metal-coordination-driven self-assembly, we prepare a series of heterometallic [2]catenanes and cyclic bis[2]catenanes, whose structures are clearly evidenced by single-crystal X-ray analysis. Owing to the multiple positively charged nature, as well as the potential synergistic effect of the Cu(I) and Pt(II) metal ions, the cyclic bis[2]catenanes display broad-spectrum antibacterial activity. This work not only provides an efficient strategy for the construction of heterometallic [2]catenanes and cyclic bis[2]catenanes but also explores their applications as superior antibacterial agents, which will promote the construction of advanced supramolecular structures for biomedical applications.

Clinical characteristics and follow-up of a newborn with Dubin-Johnson Syndrome: A clinical case report.

BACKGROUND: Dubin-Johnson syndrome (DJS) is a rare autosomal recessive liver disorder, characterized by conjugated hyperbilirubinemia. This case report investigates the clinical characteristics and longitudinal outcomes of a neonate diagnosed with DJS. METHODS: A newborn presented with elevated bilirubin levels and abnormal liver enzyme readings. Comprehensive genetic evaluation was conducted, which included peripheral blood sample collection from the infant and both parents after obtaining informed consent and high-throughput trio exome sequencing was performed. The genetic analysis revealed 2 significant mutations in the ABCC2 gene on chromosome 10: the insertion mutation c.4237(exon30)_c.4238(exon30)ins CT, inherited from the father, and the missense mutation c.517(exon5)G > A, inherited from the mother. Both mutations were classified as pathogenic according to the ACMG 2015 guidelines, indicating a compound heterozygous inheritance pattern. The patient's treatment regimen included phototherapy, which was initiated to address her jaundice upon admission. To support liver function and regulate gut activity, oral ursodeoxycholic acid (20 mg/kg/dose, twice a day) and probiotics were administered. Additionally, a postdischarge medication plan involving a low-dose regimen of phenobarbital (3.5 mg/kg/dose, twice a day) was implemented for 2 weeks. RESULTS: During a 2-year follow-up after discharge, the infant's bilirubin levels significantly decreased, and liver enzymes, including GGT, progressively normalized. CONCLUSION: This case report enhances the understanding of DJS in neonates by emphasizing the clinical ramifications of compound heterozygous mutations within the ABCC2 gene and documenting the evolution of the disease. The gradual normalization of liver function tests suggests potential compensatory mechanisms in response to the genetic abnormalities in neonates with DJS. The correlation between the patient's genetic profile of compound heterozygosity and her milder clinical phenotype warrants attention, suggesting that this specific genetic configuration may be associated with less severe manifestations of the disease. The necessity for long-term follow-up is highlighted, recognizing that intercurrent stress conditions could influence the hepatic profile and potentially exacerbate symptoms. Such sustained observation is crucial to further delineate the genomic and clinical landscape of DJS, offering opportunities to refine prognostic and therapeutic approaches.

Reassessing type 2 diabetes in adolescents and its management strategies based on insulin resistance.

With changes in lifestyle behaviors, including dietary structure and habits, the prevalence of Youth-onset Type 2 Diabetes Mellitus (YODM) has increased 2 to 3 times compared to 30 years ago. YODM patients experience complications earlier, progress faster, and exhibit more severe symptoms. However, limited and inconclusive direct evidence, coupled with poor patient compliance, poses challenges in the clinical management of YODM. Apart from the continuous decline in pancreatic ß-cell function and quantity, tissue-specific insulin resistance (IR) is also a typical characteristic of YODM. The main mechanisms of IR in YODM involve different aspects such as obesity, dietary imbalance, abnormal substance metabolism, chronic inflammation, oxidative stress, and hormonal fluctuations during adolescence. For the comprehensive management of YODM, besides achieving good control of blood glucose levels, it may be necessary to apply the most appropriate methods considering the uniqueness of the patient population and the specifics of the disease. Early identification and detection of the disease are crucial. Precise screening of patients with well-functioning pancreatic insulin ß-cells, primarily characterized by IR and obesity, represents the population most likely to achieve diabetes remission or reversal through lifestyle modifications, medications, or even surgical interventions. Additionally, considering potential emotional disorders or the impact of adolescent hormones in these patients, health education for patients and caregivers is essential to make them aware of the long-term benefits of well-controlled blood glucose. In conclusion, adopting comprehensive management measures to achieve diabetes remission or reversal is the ideal goal. Controlling high blood glucose, obesity, and other risk factors related to diabetes complications is the next priority to delay the occurrence and progression of complications. A comprehensive perspective on IR provides insights and references for identifying YODM and its management strategies.

The value of lung function assessment and Testin expression detection in clinicopathological features and prognosis of NSCLC patients.

OBJECTIVE: The aim of this study is to investigate the clinical value and potential prognostic significance of lung function assessment and Testin expression in non-small cell lung cancer (NSCLC) patients. METHODS: The NSCLC patients were classified into three groups according to lung function: group of normal lung function, group of PRISm (preserved ratio impaired spirometry) (FEV1, forced expiratory volume during the first second < 80% predicted and FEV1/FVC (forced vital capacity) ≥ 70%) and group of COPD (chronic obstructive pulmonary disease) (FEV1/FVC < 70%). The pre-operational clinicopathological characteristics of these patients were recorded and the markers of systemic inflammatory response, including neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR) and eosinophils (EOS), were compared between three groups. The expression of Testin in NSCLC samples was detected by IHC and we further explored the correlation between Testin expression and clinicopathological characteristics and prognosis of NSCLC patients. Finally, Cox regression analysis was conducted to study the prognostic factors of NSCLC patients. RESULTS: Of the 158 NSCLC patients, percentages of normal lung function, PRISm and COPD were 41.4%, 22.8% and 36.1%, respectively. Patients with tumor in the left lung were more likely to have pulmonary dysfunction (PRISm and COPD) than the right lung. The markers of systemic inflammatory response showed differences to various degree in the three groups and NSCLC patients with PRISm or COPD presented more unfavorable prognosis than patients with normal function. The expression of Testin correlated with lymph node metastasis, TNM stage and tumor invasion of NSCLC patients. Moreover, patients with low Testin expression exhibited poorer disease-free survival and overall survival than those with high Testin expression. In Cox regression analysis, we found that PRISm, COPD and Testin expression served as prognostic factors in NSCLC patients. CONCLUSIONS: The presence of COPD or PRISm influenced systemic inflammatory response and prognosis of NSCLC patients. Testin expression correlated with clinicopathological features and could be potentially used as a prognostic marker in NSCLC.

Hepatoprotective effect of diammonium glycyrrhizinate and neuroprotective effect of piperazine ferulate on AmB-induced liver and kidney injury by suppressing apoptosis in vitro and in vivo.

Amphotericin B (AmB) induced liver and kidney injury is often responsible for hepatic and renal dysfunction. Therefore, the protection strategy on liver and renal functions in patients treated with AmB should be emphasized. In this paper, diammonium glycyrrhizinate (DG) and piperazine ferulate (PF) were taken as the research object to study its hepatoprotective and neuroprotective effect on AmB-induced liver and kidney damage in vitro and in vivo. The microplate method and ELISA kits were employed for the biochemical detection in the serum and urine of mice. Flow cytometric analysis and western blotting analysis were conducted to study the mechanism of DG and PF. Our results confirmed the prevention capacity of DG and PF on AmB-induced liver and kidney injury through the alleviation of pathological changes and enzyme reducing action. Furthermore, DG and PF suppressed ROS-mediated mitochondrial apoptosis in AmB-treated mice and cells through Caspase pathway and Caspase-independent AIF pathway. In summary, DG and PF could protect AmB-induced hepatotoxicity and nephrotoxicity by disrupting oxidative stress and apoptosis.

Prediction of blood-brain barrier permeability using machine learning approaches based on various molecular representation.

The assessment of compound blood-brain barrier (BBB) permeability poses a significant challenge in the discovery of drugs targeting the central nervous system. Conventional experimental approaches to measure BBB permeability are labor-intensive, cost-ineffective, and time-consuming. In this study, we constructed six machine learning classification models by combining various machine learning algorithms and molecular representations. The model based on ExtraTree algorithm and random partitioning strategy obtains the best prediction result, with AUC value of 0.932±0.004 and balanced accuracy (BA) of 0.837±0.010 for the test set. We employed the SHAP method to identify important features associated with BBB permeability. In addition, matched molecular pair (MMP) analysis and representative substructure derivation method were utilized to uncover the transformation rules and distinctive structural features of BBB permeable compounds. The machine learning models proposed in this work can serve as an effective tool for assessing BBB permeability in the drug discovery for central nervous system disease.

Nanoplastics exposure simplifies the network structure of sea cucumber (Apostichopus japonicus) gut microbiota and improves cluster randomness.

Nanoplastics (NPs) are abundant in ocean environments, leading to environmental pollution and notable disruptions to the physiological functions of marine animals. To investigate the toxic effects of NPs on echinoderms, specifically sea cucumbers (Apostichopus japonicus), they were exposed to varying concentrations of NPs (0, 102, 104 particles/L) for 14 d. Subsequently, the 102 particles/L exposure group was purified for 35 d to elucidate the impact of both NPs exposure and purification on the intestinal bacteria structure and function. The results showed that the richness and variety of intestinal bacteria in sea cucumbers significantly reduced under NPs exposure, and then they could be restored to the pre-exposure treatment state after 35 d of purification. With the increase of NPs exposure concentration in the environment, the intestinal core bacteria gradually changed from Firmicutes and Proteobacteria to Pseudoalteromonas and Vibrio. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database annotated that the gut microbiota of sea cucumbers was significantly downregulated in the glycosylation, carbohydratic and amino acid metabolic pathways (P < 0. 05), exogenous substance biodegradation and metabolism, DNA replication and repair pathways were significantly up-regulated (P < 0.05) under the exposure of NPs. In addition, nanoplastics exposure simplified the symbiotic network relationships of the gut bacteria, reduced the selective effect of host on the intestinal bacteria, and increased stochasticity. In conclusion, waterborne NPs can adversely affect the structure and function of sea cucumber intestinal bacteria, with these effects persisting for a duration. However, as the purification time lengthens, these adverse effects gradually diminish. This study aims to provide some theoretical basis for the biotoxic effects of NPs.

Cell cycle associated protein 1 associates with immune infiltration and ferroptosis in gastrointestinal cancer.

Background: Cell Cycle-Associated Protein 1 (CAPRIN1) play an important role in cell proliferation, oxidative stress, and inflammatory response. Nonetheless, its role in tumor immunity and ferroptosis is largely unknown in gastrointestinal cancer patients. Methods: Through comprehensive bioinformatics, we investigate CAPRIN1 expression patterns and its role in diagnosis, functional signaling pathways, tumor immune infiltration and ferroptosis of different gastrointestinal cancer subtypes. Besides, immunohistochemistry (IHC) and immune blot were used to validate our esophagus cancer clinical data. The ferroptotic features of CAPRIN1 in vitro were assessed through knockdown assays in esophagus cancer cells. Results: CAPRIN1 expression was significantly upregulated, correlated with poor prognosis, and served as an independent risk factor for most gastrointestinal cancer. Moreover, CAPRIN1 overexpression positively correlated with gene markers of most infiltrating immune cells, and immune checkpoints. CAPRIN1 knockdown significantly decreased the protein level of major histocompatibility complex class I molecules. We also identified a link between CAPRIN1 and ferroptosis-related genes in gastrointestinal cancer. Knockdown of CAPRIN1 significantly increased the production of lipid reactive oxygen species and malondialdehyde. Inhibition of CAPRIN1 expression promoted ferroptotic cell death induced by RAS-selective lethal 3 and erastin in human esophagus cancer cells. Conclusion: Collectively, our results demonstrate that CAPRIN1 is aberrantly expressed in gastrointestinal cancer, is associated with poor prognosis, and could potentially influence immune infiltration and ferroptosis.