Pharmacological elevation of glutathione inhibits status epilepticus-induced neuroinflammation and oxidative injury.

Glutathione (GSH) is a major endogenous antioxidant, and its depletion has been observed in several brain diseases including epilepsy. Previous studies in our laboratory have shown that dimercaprol (DMP) can elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme and inhibit neuroinflammation in vitro. Here we determined 1) the role of cysteamine as a new mechanism by which DMP increases GSH biosynthesis and 2) its ability to inhibit neuroinflammation and neuronal injury in the rat kainate model of epilepsy. DMP depleted cysteamine in a time- and concentration-dependent manner in a cell free system. To guide the in vivo administration of DMP, its pharmacokinetic profile was determined in the plasma, liver, and brain. The results confirmed DMP's ability to cross the blood-brain-barrier. Treatment of rats with DMP (30 mg/kg) depleted cysteamine in the liver and hippocampus that was associated with increased GCL activity in these tissues. GSH levels were significantly increased (20 %) in the hippocampus 1 h after 30 mg/kg DMP administration. Following DMP (30 mg/kg) administration once daily, a marked attenuation of GSH depletion was seen in the SE model. SE-induced inflammatory markers including cytokine release, microglial activation, and neuronal death were significantly attenuated in the hippocampus with DMP treatment. Taken together, these results highlight the importance of restoring redox status with rescue of GSH depletion by DMP in post epileptogenic insults.

Weak magnetic field and coexisting ions accelerate phenol removal by ZVI/H2O2 system: their efficiency and mechanism.

Human activity and industrial production have led to phenol becoming a significant risk factor. The proper treatment of phenol in wastewater is essential. In this study, the utilization of weak magnetic field (WMF) and zero-valent iron (ZVI) was proposed to activate H2O2 to degrade phenol contaminant. The results show that the weak magnetic field has greatly enhanced the reaction rate of ZVI/H2O2 removal of phenol. The removal rates of phenol by ZVI/H2O2/WMF generally decreased with increasing initial pH and phenol concentrations, and firstly increase and then decrease with increasing Fe0 or H2O2 dosage. When the initial pH is 5.0, ZVI concentration of 0.2 g/L, H2O2 concentration of 6 mM, and phenol concentration of 100 mg/L were used, complete removal of phenol can be achieved within 180 min at 25 °C. The degradation process was consistent with the pseudo-first-order kinetic model when the experimental data was fitted. The ZVI/H2O2/WMF process exhibited a 1.05-2.66-fold enhancement in the removal rate of phenol under various conditions, surpassing its counterpart lacking WMF. It was noticed that the presence of 1-5 mM of Ca2+, Mg2+, Cl-, SO42- ions can significantly enhance the kinetics of phenol removal by ZVI/H2O2 system with or without WMF to 2.22-10.40-fold, but NO3- , CO32-, PO43- inhibited the reaction significantly in the following order: PO43-> CO32- >NO3-. Moreover, pre-magnetization for 3 min could enhance the ZVI/H2O2 process which was valuable in treatment of real wastewater. The hydroxyl radical has been identified as the primary radical species responsible for phenol degradation. The presence of WMF accelerates the corrosion rate of ZVI, thereby promoting the release of Fe2+ ions, which in turn induces an increased production of hydroxyl radicals and facilitates phenol degradation. The compounds hydroquinone, benzoquinone, catechol, maleic acid, and CO2 were identified using GC-MS, and degradation pathways were proposed. Employing WMF in combination with various ions like Ca2+, Mg2+, Cl-, SO42- is a novel method, which can enhance oxidation capacity of ZVI/H2O2 and may lead to economic benefit.

Harnessing Sulforaphane Potential as a Chemosensitizing Agent: A Comprehensive Review.

Recent advances in oncological research have highlighted the potential of naturally derived compounds in cancer prevention and treatment. Notably, sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables including broccoli and cabbage, has exhibited potent chemosensitizing capabilities across diverse cancer types of bone, brain, breast, lung, skin, etc. Chemosensitization refers to the enhancement of cancer cell sensitivity to chemotherapy agents, counteracting the chemoresistance often developed by tumor cells. Mechanistically, SFN orchestrates this sensitization by modulating an array of cellular signaling pathways (e.g., Akt/mTOR, NF-κB, Wnt/ß-catenin), and regulating the expression and activity of pivotal genes, proteins, and enzymes (e.g., p53, p21, survivin, Bcl-2, caspases). When combined with conventional chemotherapeutic agents, SFN synergistically inhibits cancer cell proliferation, invasion, migration, and metastasis while potentiating drug-induced apoptosis. This positions SFN as a potential adjunct in cancer therapy to augment the efficacy of standard treatments. Ongoing preclinical and clinical investigations aim to further delineate the therapeutic potential of SFN in oncology. This review illuminates the multifaceted role of this phytochemical, emphasizing its potential to enhance the therapeutic efficacy of anti-cancer agents, suggesting its prospective contributions to cancer chemosensitization and management.

Novel Catalytic Antioxidant Formulation Decreases Oxidative Stress, Neuroinflammation and Cognitive Dysfunction in a Model of Nerve Agent Intoxication.

Reactive oxygen species have an emerging role in the pathologic consequences of status epilepticus. We have previously demonstrated the efficacy of a water-for-injection formulation of the meso-porphyrin catalytic antioxidant, manganese (III) meso-tetrakis (N-N-diethylimidazole) porphyrin (AEOL10150) against oxidative stress, neuroinflammation, and neuronal death initiated by kainic acid, pilocarpine, diisopropylflurophosphate (DFP), and soman. This previous dose and dosing strategy of AEOL10150 required smaller multiple daily injections, precluding our ability to test its efficacy against delayed consequences of nerve agent exposure such as neurodegeneration and cognitive dysfunction. Therefore, we developed formulations of AEOL10150 designed to deliver a larger dose once daily with improved brain pharmacodynamics. We examined four new formulations of AEOL10150 that resulted in 8 times higher subcutaneous dose with lower acute toxicity, slower absorption, longer half-life, and higher maximal plasma concentrations compared with our previous strategy. AEOL10150 brain levels exhibited improved pharmacodynamics over 24 hours with all four formulations. We tested a subcutaneous dose of 40 mg/kg AEOL10150 in two formulations (2% carboxymethyl cellulose and 4% polyethylene glycol-4000) in the DFP rat model, and both formulations exhibited significant protection against DFP-induced oxidative stress. Additionally, and in one formulation (4% polyethylene glycol-4000), AEOL10150 significantly protected against DFP-induced neuronal death, microglial activation, delayed memory impairment, and mortality. These results suggest that reformulation of AEOL10150 can attenuate acute and delayed outcomes of organophosphate neurotoxicity. SIGNIFICANCE STATEMENT: Reformulation of manganese (III) meso-tetrakis (N-N-diethylimidazole) porphyrin allowed higher tolerated doses of the compound with improved pharmacodynamics. Specifically, one new formulation allowed fewer daily doses and improvement in acute and delayed outcomes of organophosphate toxicity.

Soluble E-cadherin participates in BLM-induced pulmonary fibrosis by promoting EMT and lung fibroblast migration.

Soluble E-cadherin (sE-cad) is an 80 kDa fragment derived from E-cadherin that is shed from the cell surface through proteolytic cleavage and is a biomarker in various cancers that promotes invasion and migration. Alveolar epithelial destruction, aberrant lung fibroblast migration and inflammation contribute to pulmonary fibrosis. Here, we hypothesized that E-cadherin plays an important role in lung fibrosis. In this study, we found that E-cadherin was markedly increased in the bronchoalveolar lavage fluid (BALF) and serum of mice with pulmonary fibrosis and that blocking sE-cad with HECD-1, a neutralizing antibody targeting the ectodomain of E-cadherin, effectively inhibited myofibroblast accumulation and collagen deposition in the lungs after bleomycin (BLM) exposure. Moreover, transforming growth factor-ß (TGF-ß1) induced the shedding of sE-cad from A549 cells, and treatment with HECD-1 inhibited epithelial-mesenchymal transition (EMT) stimulated by TGF-ß1. Fc-E-cadherin (Fc-Ecad), which is an exogenous form of sE-cad, robustly promoted lung fibroblast migration. E-cadherin participates in bleomycin (BLM)-induced lung fibrosis by promoting EMT in the alveolar epithelium and fibroblast activation. E-cadherin may be a novel therapeutic target for lung fibrosis.

Potential significance of high-mobility group protein box 1 in cerebrospinal fluid.

High-mobility group protein box 1 (HMGB1) is a cytokine with multiple functions (according to its subcellular location) that serves a marker of inflammation. CSF HMGB1 could be the part of pathological mechanisms that underlie the complications associated with CNS diseases. HMGB1 actively or passively released into the CSF is detected in the CSF in many diseases of the central nervous system (CNS) and thus may be useful as a biomarker. Pathological alterations in distant areas were observed due to lesions in a specific region, and the level of HMGB1 in the CSF was found to be elevated. Reducing the HMGB1 level via intraventricular injection of anti-HMGB1 neutralizing antibodies can improve the outcomes of CNS diseases. The results indicated that CSF HMGB1 could serve as a biomarker for predicting disease progression and may also act as a pathogenic factor contributing to pathological alterations in distant areas following focal lesions in the CNS. In this mini-review, the characteristics of HMGB1 and progress in research on CSF HMGB1 as a biomarker of CNS diseases were discussed. CSF HMGB1 is useful not only as a biomarker of CNS diseases but may also be involved in interactions between different brain regions and the spinal cord.

Increasing glutathione levels by a novel posttranslational mechanism inhibits neuronal hyperexcitability.

Glutathione (GSH) depletion, and impaired redox homeostasis have been observed in experimental animal models and patients with epilepsy. Pleiotropic strategies that elevate GSH levels via transcriptional regulation have been shown to significantly decrease oxidative stress and seizure frequency, increase seizure threshold, and rescue certain cognitive deficits. Whether elevation of GSH per se alters neuronal hyperexcitability remains unanswered. We previously showed that thiols such as dimercaprol (DMP) elevate GSH via post-translational activation of glutamate cysteine ligase (GCL), the rate limiting GSH biosynthetic enzyme. Here, we asked if elevation of cellular GSH by DMP altered neuronal hyperexcitability in-vitro and in-vivo. Treatment of primary neuronal-glial cerebrocortical cultures with DMP elevated GSH and inhibited a voltage-gated potassium channel blocker (4-aminopyridine, 4AP) induced neuronal hyperexcitability. DMP increased GSH in wildtype (WT) zebrafish larvae and significantly attenuated convulsant pentylenetetrazol (PTZ)-induced acute 'seizure-like' swim behavior. DMP treatment increased GSH and inhibited convulsive, spontaneous 'seizure-like' swim behavior in the Dravet Syndrome (DS) zebrafish larvae (scn1Lab). Furthermore, DMP treatment significantly decreased spontaneous electrographic seizures and associated seizure parameters in scn1Lab zebrafish larvae. We investigated the role of the redox-sensitive mammalian target of rapamycin (mTOR) pathway due to the presence of several cysteine-rich proteins and their involvement in regulating neuronal excitability. Treatment of primary neuronal-glial cerebrocortical cultures with 4AP or l-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of GSH biosynthesis, significantly increased mTOR complex I (mTORC1) activity which was rescued by pre-treatment with DMP. Furthermore, BSO-mediated GSH depletion oxidatively modified the tuberous sclerosis protein complex (TSC) consisting of hamartin (TSC1), tuberin (TSC2), and TBC1 domain family member 7 (TBC1D7) which are critical negative regulators of mTORC1. In summary, our results suggest that DMP-mediated GSH elevation by a novel post-translational mechanism can inhibit neuronal hyperexcitability both in-vitro and in-vivo and a plausible link is the redox sensitive mTORC1 pathway.

Evaluation of Interfraction Setup Uncertainty of Patients With Glioblastoma Wearing TTFields (Tumor Treating Fields) During Radiation Therapy.

PURPOSE: Tumor treating fields (TTFields) with concurrent radiation therapy (RT) might improve the outcome of patients with newly diagnosed glioblastoma. Several trials, including that conducted in our center, have allowed patients to wear TTFields during RT. We aimed to evaluate the setup uncertainty introduced by TTFields and calculate the planning target volume (PTV) margin for clinical reference. METHODS AND MATERIALS: We collected and analyzed 201 cone beam computed tomography images of 22 patients in our center. Patients with or without TTFields were divided into the control and TTFields groups. We evaluated the setup errors in 6 degrees of freedom and 3 degrees of freedom and the magnitudes in the 3-dimensional vectors. An estimated PTV margin for patients requiring nonimaging-guided RT was recommended. RESULTS: A significant difference was observed in the longitudinal axis between the TTFields and control groups (P < .05). These results were consistent with that of the intragroup comparison of the TTFields group. The position error of the longitudinal axis (from head to feet) was -0.51 ± 2.05 mm in the TTFields group. CONCLUSIONS: Wearing TTFields during RT increased the uncertainty, especially in the longitudinal axis, with a system error of 1.40 mm and a random error of 1.28 mm. Daily image guided RT for TTFields patients seems necessary. However, the recommended expansion margin of the PTV is 5 mm for patients requiring nonimage-guided RT to enhance the safety and efficacy of treatment.

Chitinase-Like Protein PpCTL1 Contributes to Maintaining Fruit Firmness by Affecting Cellulose Biosynthesis during Peach Development.

The firmness of the flesh fruit is a very important feature in the eating process. Peach fruit is very hard during development, but its firmness slightly decreases in the later stages of development. While there has been extensive research on changes in cell wall polysaccharides during fruit ripening, little is known about the changes that occur during growth and development. In this study, we investigated the modifications in cell wall components throughout the development and ripening of peach fruit, as well as its impact on firmness. Our findings revealed a significant positive correlation between fruit firmness and cellulose content at development stage. However, the correlation was lost during the softening process, suggesting that cellulose might be responsible for the fruit firmness during development. Members of the chitinase-like protein (CTL) group are of interest because of their possible role in plant cell wall biosynthesis. Here, two CTL homologous genes, PpCTL1 and PpCTL2, were identified in peach. Spatial and temporal expression patterns of PpCTLs revealed that PpCTL1 exhibited high expression abundance in the fruit and followed a similar trend to cellulose during fruit growth. Furthermore, silencing PpCTL1 expression resulted in reduced cellulose content at 5 DAI (days after injection), this change that would have a negative effect on fruit firmness. Our results indicate that PpCTL1 plays an important role in cellulose biosynthesis and the maintenance of peach firmness during development.

Machine learning-based solution reveals cuproptosis features in inflammatory bowel disease.

Background: Cuproptosis, a new cell death mode, is majorly modulated by mitochondrial metabolism and protein lipoylation. Nonetheless, cuproptosis-related genes (CRGs) have not yet been thoroughly studied for their clinical significance and relationship with the immune microenvironment in inflammatory bowel disease (IBD). Methods: We screened CRGs that had a significant correlation with immune status, which was determined utilizing single-sample GSEA (ssGSEA) and Gene Expression Omnibus datasets (GSE75214). Furthermore, utilizing the R package "CensusClusterPlus", these CRGs' expression was used to obtain different patient clusters. Subsequently, gene-set enrichment analysis (GSEA), gene set variation analysis (GSVA), and CIBERSORT assessed the variations in the enrichment of gene function and the abundance of immune cell infiltration and immune functions across these clusters. Additionally, weighted gene co-expression network analysis (WGCNA) and analysis of differentially expressed genes (DEGs) were executed, and for the purpose of identifying hub genes between these clusters, the construction of protein-protein interaction (PPI) network was done. Lastly, we used the GSE36807 and GSE10616 datasets as external validation cohorts to validate the immune profiles linked to the expression of CRG. ScRNA-seq profiling was then carried out using the publicly available dataset to examine the CRGs expression in various cell clusters and under various conditions. Results: Three CRGs, PDHA1, DLD, and FDX1, had a significant association with different immune profiles in IBD. Patients were subsequently classified into two clusters: low expression levels of DLD and PDHA1, and high expression levels of FDX1 were observed in Cluster 1 compared to Cluster 2. According to GSEA, Cluster 2 had a close association with the RNA processes and protein synthesis whereas Cluster 1 was substantially linked to environmental stress response and metabolism regulations. Furthermore, Cluster 2 had more immune cell types, which were characterized by abundant memory B cells, CD4+ T memory activated cells, and follicular helper T cells, and higher levels of immune-related molecules (CD44, CD276,CTLA4 and ICOS) than Cluster 1. During the analysis, the PPI network was divided into three significant MCODEs using the Molecular Complex Detection (MCODE) algorithm. The three MCODEs containing four genes respectively were linked to mitochondrial metabolism, cell development, ion and amino acid transport. Finally, external validation cohorts validated these findings, and scRNA-seq profiling demonstrated diverse intestinal cellular compositions with a wide variation in CRGs expression in the gut of IBD patients. Conclusions: Cuproptosis has been implicated in IBD, with PDHA1, DLD, and FDX1 having the potential as immune biomarkers and therapeutic targets. These results offer a better understanding of the development of precise, dependable, and cutting-edge diagnosis and treatment of IBD.

Association of serum alkaline phosphatase and depression in US adults: a population-based cross-sectional study.

Background: Depression, a serious public health disorder, is increasingly prevalent worldwide. An association between alkaline phosphatase (ALP) and neurological disorders has been reported. However, data on ALP and depression risk are scarce, which warrants attention. Methods: We assessed the association between ALP and risk of depression in adults from the 2007-2014 National Health and Nutrition Examination Survey (NHANES). Depression was assessed using the Patient Health Questionnaire-9. Univariate and multivariate logistic regression were used to assess the association between ALP and risk of depression, and subgroup analyses were also performed. Results: A total of 17,485 participants were included. The prevalence of depression was 9.3% (1,631/17,485) and ALP was significantly associated with the risk of depression when ALP was a categorical variable (quadratic or categorized by 79 U/L) in a multivariate logistic regression model after adjusting for confounding factors (≥79 U/L vs. <79 U/L, adjusted OR, 1.15; 95%CI, 1.02-1.29). Each 1-unit increase in ALP (log2) was associated with a 20% increase in depression prevalence (adjusted OR, 1.20; 95%CI, 1.06-1.36) when ALP was used as a continuous variable. Subgroup analysis showed that ALP was positively associated with the risk of depression with different characteristics. Conclusion: Our findings suggest that higher alkaline phosphatase levels, even within the normal range, are significantly associated with a higher risk of depression in US adults. Such findings require further prospective studies to provide more evidence.

Behaviors of AlGaN Strain Relaxation on a GaN Porous Structure Studied with d-Spacing Crystal Lattice Analysis.

The high porosity of a GaN porous structure (PS) makes it mechanically semi-flexible and can shield against the stress from the thick growth template on an overgrown layer to control the lattice structure or composition within the overgrown layer. To understand this stress shield effect, we investigated the lattice constant variations among different growth layers in various samples of overgrown Al0.3Ga0.7N on GaN templates under different strain-relaxation conditions based on d-spacing crystal lattice analysis. The fabrication of a strain-damping PS in a GaN template shields against the stress from the thick GaN template on the GaN interlayer, which lies between the PS and the overgrown AlGaN layer, such that the stress counteraction of the AlGaN layer against the GaN interlayer can reduce the tensile strain in AlGaN and increase its critical thickness. If the GaN interlayer is thin, such that a strong AlGaN counteraction occurs, the increased critical thickness can become larger than the overgrown AlGaN thickness. In this situation, crack-free, thick AlGaN overgrowth is feasible.

Neuronal SIRT3 Deletion Predisposes to Female-Specific Alterations in Cellular Metabolism, Memory, and Network Excitability.

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass spectrometry-based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons in the cortex and hippocampus produces altered neuronal excitability and metabolic dysfunction in female mice. Targeted deletion of SIRT3 from neuronal helix-loop-helix 1 (NEX)-expressing neurons resulted in mitochondrial hyperacetylation, female-specific superoxide dismutase-2 (SOD2) modification, increased steady-state superoxide levels, metabolic reprogramming, altered neuronal excitability, and working spatial memory deficits. Inducible neuronal deletion of SIRT3 likewise produced female-specific deficits in spatial working memory. Together, the data demonstrate that deletion of SIRT3 from forebrain neurons selectively predisposes female mice to deficits in mitochondrial and cognitive function.SIGNIFICANCE STATEMENT Mitochondrial SIRT3 is an enzyme shown to regulate energy metabolism and antioxidant function, by direct deacetylation of proteins. In this study, we show that neuronal SIRT3 deficiency renders female mice selectively vulnerable to impairment in redox and metabolic function, spatial memory, and neuronal excitability. The observed sex-specific effects on cognition and neuronal excitability in female SIRT3-deficient mice suggest that mitochondrial dysfunction may be one factor underlying comorbid neuronal diseases, such as Alzheimer's disease and epilepsy. Furthermore, the data suggest that SIRT3 dysfunction may predispose females to age-related metabolic and cognitive impairment.

A novel machine learning model based on ubiquitin-related gene pairs and clinical features to predict prognosis and treatment effect in colon adenocarcinoma.

BACKGROUND: Ubiquitin and ubiquitin-like (UB/UBL) conjugations are essential post-translational modifications that contribute to cancer onset and advancement. In colon adenocarcinoma (COAD), nonetheless, the biological role, as well as the clinical value of ubiquitin-related genes (URGs), is unclear. The current study sought to design and verify a ubiquitin-related gene pairs (URGPs)-related prognostic signature for predicting COAD prognoses. METHODS: Using univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression, URGP's predictive signature was discovered. Signatures differentiated high-risk and low-risk patients. ROC and Kaplan-Meier assessed URGPs' signature. Gene set enrichment analysis (GSEA) examined biological nomogram enrichment. Chemotherapy and tumor immune microenvironment were also studied. RESULTS: The predictive signature used six URGPs. High-risk patients had a worse prognosis than low-risk patients, according to Kaplan-Meier. After adjusting for other clinical characteristics, the URGPs signature could reliably predict COAD patients. In the low-risk group, we found higher amounts of invading CD4 memory-activated T cells, follicular helper T cells, macrophages, and resting dendritic cells. Moreover, low-risk group had higher immune checkpoint-related gene expression and chemosensitivity. CONCLUSION: Our research developed a nomogram and a URGPs prognostic signature to predict COAD prognosis, which may aid in patient risk stratification and offer an effective evaluation method of individualized treatment in clinical settings.

Changes in the Gut Microbiome Associated with Intussusception in Patients with Peutz-Jeghers Syndrome.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder characterized by intestinal polyposis, and intestinal intussusception is one of the most urgent complications. While it is known that imbalance of the gut microbiota is highly associated with intestinal disorders, the role of the gut microbiome in the pathogenesis of PJS has not been reported. In this study, we performed 16S rRNA sequencing on stools from 168 patients and 68 healthy family members who lived together to determine the gut microbiome composition of PJS patients. Metagenomics sequencing was further performed on the representative samples (61 PJS patients and 27 healthy family members) to analyze the functional changes. We found that the fecal microbiome of patients with PJS showed a greater variation in ß-diversity. An enhancement of Escherichia coli and a reduction of Faecalibacterium prausnitzii was identified in PJS patients. Further reduction of Faecalibacterium prausnitzii was the characteristic microbial change observed in patients with intussusception. Functional analysis revealed that the abundance of propanoate metabolism was enriched in PJS patients and further enriched in those with intussusception. Escherichia coli was the major contributor to the enrichment of this metabolism pathway, which was associated with the abnormal expression of methylglyoxal synthase (encoded by mgsA) and phosphate acetyltransferase (encoded by pta). Our findings showed a distinct gut microbiome signature in PJS patients and identified the connection between the gut microbiome and intussusception. Alterations in the gut microbiome might be involved in the pathogenesis of PJS and may serve as biomarkers for gastrointestinal surveillance. IMPORTANCE Recent research has established a link between the gut microbiome and polyps and neoplasia, and antibiotic use influences the microbiome and the development of colorectal polyps. Familial adenomatous polyposis (FAP), which is characterized by the early development of benign precursor lesions (polyps), is associated with enterotoxigenic Bacteroides fragilis and Escherichia coli biofilms. However, the relationship between the gut microbiome and the pathophysiology of PJS has not yet been established. In this study, we found that PJS patients had a distinct microbiome composition, with a greater variation in ß-diversity, an increase in Escherichia coli, and a decrease in Faecalibacterium prausnitzii. A further reduction of Faecalibacterium prausnitzii was observed in patients with intussusception. Moreover, PJS involved increased propanoate metabolism as well as abnormal mgsA and pta expression. These findings may contribute to a better understanding of the etiology of PJS and improve disease control strategies.

Gapless genome assembly of East Asian finless porpoise.

In recent years, conservation efforts have increased for rare and endangered aquatic wildlife, especially cetaceans. However, the East Asian finless porpoise (Neophocaena asiaeorientalis sunameri), which has a wide distribution in China, has received far less attention and protection. As an endangered small cetacean, the lack of a chromosomal-level reference for the East Asian finless porpoise limits our understanding of its population genetics and conservation biology. To address this issue, we combined PacBio HiFi long reads and Hi-C sequencing data to generate a gapless genome of the East Asian finless porpoise that is approximately 2.5 Gb in size over its 21 autosomes and two sex chromosomes (X and Y). A total of 22,814 protein-coding genes were predicted where ~97.31% were functionally annotated. This high-quality genome assembly of East Asian finless porpoise will not only provide new resources for the comparative genomics of cetaceans and conservation biology of threatened species, but also lay a foundation for more speciation, ecology, and evolutionary studies. Measurement(s) Neophocaena asiaeorientalis sunameri • Gapless genome assembly • sequence annotation Technology Type(s) MGISEQ. 2000 • PacBio HiFi Sequencing • Hi-C Sample Characteristic - Organism Neophocaena asiaeorientalis sunameri Sample Characteristic - Environment seawater Sample Characteristic - Location Yellow Sea near Lianyungang City, Jiangsu Province, China.

A novel fatty acid metabolism-related gene signature predicts the prognosis, tumor immune properties, and immunotherapy response of colon adenocarcinoma patients.

Colon adenocarcinoma (COAD) has a high incidence and death rate. Despite the fact that change in fatty acid metabolism promotes tumor growth and metastasis to the greatest degree among metabolite profiles, a thorough investigation on the involvement of fatty acid metabolism-related genes (FAMRGs) in COAD has yet not been conducted. Here, the clinical data as well as the gene expression profiles were extracted from The Cancer Genome Atlas (TCGA) database. Based on the FAMRG expression data and clinical information, a FAMRG risk signature was developed using LASSO as well as multivariate and univariate Cox regression analyses. Then, the nomogram was used to create a customized prognostic prediction model, and the calibration and receiver operating characteristic curves were used to evaluate the nomogram's prediction performance and discriminative capability. Lastly, a number of studies were conducted to assess the influence of independent FAMRGs on COAD, including unsupervised cluster analysis, functional analysis, and drug sensitivity analysis. Three hundred and sixty-seven patients were included in this study, and a 12-FAMRG risk signature was discovered in the training cohort based on a detailed examination of the FAMRGs expression data and clinical information. After that, risk scores were computed to classify patients into low or high-risk groups, and the Kaplan-Meier curve analysis revealed that patients in the low-risk group exhibited an elevated overall survival (OS) rate. The FAMRG was shown to be substantially correlated with prognosis in multivariate Cox regression analysis and was validated using the validation dataset. Then, using the clinical variables and risk signature, we developed and validated a prediction nomogram for OS. Functional characterization showed a strong correlation between this signature and immune cell infiltration and immune modulation. Additionally, by evaluating the GDSC database, it was determined that the high-risk group exhibited medication resistance to many chemotherapeutic and targeted medicines, including VX.680, gemcitabine, doxorubicin, and paclitaxel. Overall, we have revealed the significance of a FAMRG risk signature for predicting the prognosis and response to immunotherapy in COAD, and our findings might contribute to an enhanced comprehension of metabolic pathways and the future development of innovative COAD therapeutic methods.

The toxicity mechanism of glabridin in prostate cancer cells is involved in reactive oxygen species-dependent PI3K/Akt pathway: Integrated utilization of bioinformatic analysis and in vitro test validation.

Glabridin is a prenylated isoflavonoid with considerable anticancer property. Reactive oxygen species (ROS) have evolved as regulators of many cellular signaling pathways in prostate cancer (PC). However, the role of ROS signaling in the anticancer activity of glabridin has not been investigated. Here, we attempted to evaluate the effect of glabridin on PC and the involvement of ROS signaling. Intracellular ROS and mitochondrial ROS (mitoROS) production in PC cell lines, DU-145 and LNCaP, were measured by H2DCFDA and MitoSOX Red staining, respectively. MTT assay was used to analyze the cellular viability. EdU staining assay was conducted to analyze the cell proliferation. To analyze apoptotic rate, TUNEL assay was performed. Caspase-3 activity was detected to reflect cell apoptosis. Western blot was carried out to detect the expression levels of Akt and p-Akt. We found that intracellular ROS and mitoROS levels were dose-dependently upregulated after glabridin treatment in both DU-145 and LNCaP cells, which was reversed by the treatment of ROS inhibitor, N-acetyl-L-cysteine (NAC). Glabridin inhibited the cell viability and reduced the number of EdU-positive DU-145 and LNCaP cells, which were respectively proved by MTT assay and EdU staining assay. Glabridin promoted cell death with increased apoptotic rate and caspase-3 activity in DU-145 and LNCaP cells. The effects of glabridin on cell proliferation and apoptosis were reversed by NAC. Moreover, glabridin suppressed the ratio of p-Akt/Akt, while NAC mitigated the decreased p-Akt/Akt ratio. In addition, the effects of glabridin on cell proliferation and apoptosis were also attenuated by Akt activator, SC79. Collectively, our results demonstrated that glabridin suppressed proliferation and induced apoptosis in PC cells via regulating ROS-mediated PI3K/Akt pathway. These findings suggested that glabridin might hold a promising prospective as a therapeutic agent against PC.

DNA damage repair-related gene signature predicts prognosis and indicates immune cell infiltration landscape in skin cutaneous melanoma.

Background: DNA damage repair plays an important role in the onset and progression of cancers and its resistance to treatment therapy. This study aims to assess the prognostic potential of DNA damage repair markers in skin cutaneous melanoma (SKCM). Method: In this study, we have analyzed the gene expression profiles being downloaded from TCGA, GTEx, and GEO databases. We sequentially used univariate and LASSO Cox regression analyses to screen DNA repair genes associated with prognosis. Then, we have conducted a multivariate regression analysis to construct the prognostic profile of DNA repair-related genes (DRRGs). The risk coefficient is used to calculate the risk scores and divide the patients into two cohorts. Additionally, we validated our prognosis model on an external cohort as well as evaluated the link between immune response and the DRRGs prognostic profiles. The risk signature is compared to immune cell infiltration, chemotherapy, and immune checkpoint inhibitors (ICIs) treatment. Results: An analysis using LASSO-Cox stepwise regression established a prognostic signature consisting of twelve DRRGs with strong predictive ability. Disease-specific survival (DSS) is found to be lower among high-risk patients group as compared to low-risk patients. The signature may be employed as an independent prognostic predictor after controlling for clinicopathological factors, as demonstrated by validation on one external GSE65904 cohort. A strong correlation is also found between the risk score and the immune microenvironment, along with the infiltrating immune cells, and ICIs key molecules. The gene enrichment analysis results indicate a wide range of biological activities and pathways to be exhibited by high-risk groups. Furthermore, Cisplatin exhibited a considerable response sensitivity in low-risk groups as opposed to the high-risk incidents, while docetaxel exhibited a considerable response sensitivity in high-risk groups. Conclusions: Our findings provide a thorough investigation of DRRGs to develop an DSS-related prognostic indicator which may be useful in forecasting SKCM progression and enabling more enhanced clinical benefits from immunotherapy.

Commensal bacteria-derived extracellular vesicles suppress ulcerative colitis through regulating the macrophages polarization and remodeling the gut microbiota.

BACKGROUND: The extracellular vesicles (EVs) traffic constitutes an essential pathway of cellular communication. And the molecules in EVs produced by procaryotes help in maintaining homeostasis, addressing microbial imbalance and infections, and regulating the immune system. Despite the fact that Clostridium butyricum (C. butyricum) is commonly used for treating ulcerative colitis (UC), the potential role of C. butyricum-secreted EVs in commensals-host crosstalk remains unclear. RESULTS: Here, we performed flow cytometry, western blot, immunohistochemistry and 16S rRNA analysis to explore the role of C. butyricum-derived EVs on macrophage polarization and gut microbiota composition in a dextran sulfate sodium (DSS)-induced UC mouse model. The antibiotic cocktail-induced microbiome depletion and faecal transplantations were used to further investigate the mechanisms by which EVs regulate macrophage balance. Our findings showed that C. butyricum-derived EVs improved the remission of murine colitis and polarized the transformation of macrophages to the M2 type. Furthermore, C. butyricum-derived EVs restored gut dysbiosis and altered the relative abundance of Helicobacter, Escherichia-Shigella, Lactobacillus, Akkermansia and Bacteroides, which, in turn, faecal transplantations from EVs-treated mice relieved the symptoms of UC and improved the impact of EVs on the reprogramming of the M2 macrophages. CONCLUSION: C. butyricum-derived EVs could protect against DSS-induced colitis by regulating the repolarization of M2 macrophages and remodelling the composition of gut microbiota, suggesting the potential efficacy of EVs from commensal and probiotic Clostridium species against UC.