The binding effects and mechanisms of dissolved organic matter (DOM) on the fate of mercury in sludge anaerobic digestion combined with thermal hydrolysis.

Dissolved organic matter (DOM) plays an important role in regulating the fate of mercury (Hg), e.g., mobility, bioavailability, and toxicity. Clarifying the role of DOM in binding Hg in the treatment processes of sewage sludge is important for relieving Hg contamination risks in land applications. However, the impacts of DOM on Hg binding in sewage sludge are still unclear. In this study, we investigated the evolution of Hg and its speciation in full-scale sludge anaerobic digestion (AD) with thermal hydrolysis. The role of DOM in binding Hg(II) was further analyzed. The results showed that AD with thermal hydrolysis led to an increase in the Hg content in the sludge (from 3.72 ± 0.47 mg/kg to 10.75 ± 0.16 mg/kg) but a decrease in Hg mobility (the mercury sulfide fraction increased from 60.56 % to 79.78 %). Further adsorption experiments revealed that at equivalent DOM concentrations, DOM with a low molecular weight (MW<1 kDa) in activated sludge, DOM with a medium molecular weight (1 kDa 5 kDa) in both anaerobically digested sludge and conditioned sludge showed high binding amounts of Hg(II), with 1372.54, 535.28, 942.09 and 801.51 mg Hg/g DOM, respectively. Parallel factor analysis (PARAFAC) and fluorescence quotient (FQ) results showed that tryptophan-like and tyrosine-like substances had high binding affinities for Hg(II). Furthermore, X-ray photoelectron spectroscopy (XPS) indicated that the reduced organic sulfur contained in the DOM was potentially bound to Hg through the interactions of Hg-S and Hg-O. These results indicated that DOM may play special roles in regulating Hg speciation. The association between DOM and Hg(II), such as the significant positive correlation (p < 0.05) between the dissolution rate of Hg(II) and release of tryptophan-like substances during thermal hydrolysis, suggested the potential way for removing Hg from sludge.

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot-Marie-Tooth Disease Type 4B1.

Background: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders involving peripheral nervous system. Charcot-Marie-Tooth disease 4B1 (CMT4B1) is a rare subtype of CMT. CMT4B1 is an axonal demyelinating polyneuropathy with an autosomal recessive mode of inheritance. Patients with CMT4B1 usually manifested with dysfunction of the motor and sensory systems which leads to gradual and progressive muscular weakness and atrophy, starting from the peroneal muscles and finally affecting the distal muscles. Germline mutations in MTMR2 gene causes CMT4B1. Material and Methods: In this study, we investigated a 4-year-old Chinese boy with gradual and progressive weakness and atrophy of both proximal and distal muscles. The proband's parents did not show any abnormalities. Whole-exome sequencing and Sanger sequencing were performed. Results: Whole-exome sequencing identified a novel homozygous nonsense mutation (c.118A>T; p.Lys40*) in exon 2 of MTMR2 gene in the proband. This novel mutation leads to the formation of a truncated MTMR2 protein of 39 amino acids instead of the wild- type MTMR2 protein of 643 amino acids. This mutation is predicted to cause the complete loss of the PH-GRAM domain, phosphatase domain, coiled-coil domain, and PDZ-binding motif of the MTMR2 protein. Sanger sequencing revealed that the proband's parents carried the mutation in a heterozygous state. This mutation was absent in 100 healthy control individuals. Conclusion: This study reports the first mutation in MTMR2 associated with CMT4B1 in a Chinese population. Our study also showed the importance of whole-exome sequencing in identifying candidate genes and disease-causing variants in patients with CMT4B1.

Efficacy and safety of total glucosides of paeony in the treatment of recurrent aphthous ulcers: a systematic review and meta-analysis.

Background: Recurrent aphthous ulcer (RAU) had high prevalence and lacked widely recognized treatment. Total glucosides of paeony (TGP) was used in the treatment of RAU in recent years. This study was to summarize the efficacy and safety of TGP in the treatment of RAU. Methods: We searched eight commonly used databases for relevant studies that published before 1 November 2023. Primary outcome was visual analogue scale (VAS). Secondary outcomes included overall response rate, significant response rate, ulcer healing time, interval, number of ulcers, and serum inflammatory factors. We conducted the meta-analysis, assessed risk of bias and the confidence of the evidence, by using Stata 15.0, Review Manager 5.4, and Gradepro. Results: Nine randomized controlled trials (RCTs) encompassing 883 patients with RAU were included in the final analysis. The VAS in the TGP group was lower than that in the control group (MD = -1.18, 95% CI = -1.58 to -0.78, p < 0.001, moderate-certainty evidence), subgroup analysis suggested longer (>8 weeks) medication and observation led to a more significant reduction in pain (p = 0.02). Moreover, TGP had higher overall response rate (RR = 1.18, 95% CI = 1.04 to 1.33, p = 0.008, very low-certainty evidence) and significant response rate (RR = 1.72, 95% CI = 1.38 to 2.14, p < 0.001, very low-certainty evidence), accelerated ulcer healing (MD = -1.79, 95% CI = -2.67 to -0.91, p < 0.001, low-certainty evidence), and extended intervals (MD = 23.60, 95% CI = 14.17 to 33.03, p < 0.001, very low-certainty evidence). The efficacy of TGP in reducing the number of ulcers showed no significant difference compared to the control group (MD = -1.66, 95% CI = -3.60 to 0.28, p = 0.09, low-certainty evidence). Moreover, TGP treatment was associated with a higher incidence of abdominal symptoms (RR = 3.27, 95% CI = 1.62 to 6.60, p < 0.001). Conclusion: TGP appears to hold promise as a widely-used clinical therapeutic option for treating RAU. Nevertheless, further rigorous studies of high quality are required to validate its effectiveness. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=471154, Identifier CRD42023471154.

Portable hydroxyl-functionalized coal gangue-based cordierite porous ceramics sheets for effective adsorption of fluorine-containing wastewater.

Monolithic adsorbent removal of fluoride from water is considered an effective and non-secondary pollution method. Here, a portable hydroxyl-functionalized coal gangue-based cordierite porous ceramic sheet (ACGC-Fe) is prepared by using coal gangue solid waste with a specific silicon-aluminum-rich composition ratio and a small amount of magnesium oxide as a raw material through powder compression molding and mild chemical modification. The prepared ACGC-Fe can be used to treat fluorine-containing wastewater and the maximum adsorption of fluorine can reach 18.69 mg g-1. The Langmuir (Freundlich) adsorption isotherm model and pseudo-second-order kinetic model here provided a satisfactory description of the fluoride removal operating mechanism, and it is confirmed that the adsorption mechanism of ACGC-Fe is mainly attributed to the chemisorption of hydrogen bonds (with hydroxyl group) and ionic bonds (with metal), and physical adsorption based on cordierite porous ceramic pores. This research will provide a new idea for designing high-performance materials by mining and analyzing the composition and structure characteristics of coal gangue solid waste itself and broaden the application range of high-value-added coal gangue solid waste.

Association of genetic variants related to combined lipid-lowering and antihypertensive therapies with risk of cardiovascular disease: 2 × 2 factorial Mendelian randomization analyses.

BACKGROUND: Lipid-lowering drugs and antihypertensive drugs are commonly combined for cardiovascular disease (CVD). However, the relationship of combined medications with CVD remains controversial. We aimed to explore the associations of genetically proxied medications of lipid-lowering and antihypertensive drugs, either alone or both, with risk of CVD, other clinical and safety outcomes. METHODS: We divided 423,821 individuals in the UK Biobank into 4 groups via median genetic scores for targets of lipid-lowering drugs and antihypertensive drugs: lower low-density lipoprotein cholesterol (LDL-C) mediated by targets of statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, lower systolic blood pressure (SBP) mediated by targets of ß-blockers (BBs) or calcium channel blockers (CCBs), combined genetically lower LDL-C and SBP, and reference (genetically both higher LDL-C and SBP). Associations with risk of CVD and other clinical outcomes were explored among each group in factorial Mendelian randomization. RESULTS: Independent and additive effects were observed between genetically proxied medications of lipid-lowering and antihypertensive drugs with CVD (including coronary artery disease, stroke, and peripheral artery diseases) and other clinical outcomes (ischemic stroke, hemorrhagic stroke, heart failure, diabetes mellitus, chronic kidney disease, and dementia) (P > 0.05 for interaction in all outcomes). Take the effect of PCSK9 inhibitors and BBs on CVD for instance: compared with the reference, PCSK9 group had a 4% lower risk of CVD (odds ratio [OR], 0.96; 95%CI, 0.94-0.99), and a 3% lower risk was observed in BBs group (OR, 0.97; 95%CI, 0.94-0.99), while combined both were associated with a 6% additively lower risk (OR, 0.94; 95%CI, 0.92-0.97; P = 0.87 for interaction). CONCLUSIONS: Genetically proxied medications of combined lipid-lowering and antihypertensive drugs have an independent and additive effects on CVD, other clinical and safety outcomes, with implications for CVD clinical practice, subsequent trials as well as drug development of polypills.

Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial.

OBJECTIVE: To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors. METHODS: In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1. RESULTS: 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%). CONCLUSIONS: The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety. TRIAL REGISTRATION NUMBER: NCT05180851.

Mesoporous silica nanoparticles as a drug delivery mechanism.

Research in intelligent drug delivery systems within the field of biomedicine promises to enhance drug efficacy at disease sites and reduce associated side effects. Mesoporous silica nanoparticles (MSNs), characterized by their large specific surface area, appropriate pore size, and excellent biocompatibility, have garnered significant attention as one of the most effective carriers for drug delivery. The hydroxyl groups on their surface are active functional groups, facilitating easy functionalization. The installation of controllable molecular machines on the surface of mesoporous silica to construct nanovalves represents a crucial advancement in developing intelligent drug delivery systems (DDSs) and addressing the issue of premature drug release. In this review, we compile several notable and illustrative examples of MSNs and discuss their varied applications in DDSs. These applications span regulated and progressive drug release mechanisms. MSNs hold the potential to enhance drug solubility, improve drug stability, and mitigate drug toxicity, attributable to their ease of functionalization. Furthermore, intelligent hybrid nanomaterials are being developed, featuring programmable properties that react to a broad spectrum of stimuli, including light, pH, enzymes, and redox triggers, through the use of molecular and supramolecular switches.

Impact of ozonation on disinfection byproducts formation from phenylalanine during chlorination.

As a strong oxidizing agent, ozone is used in some water treatment facilities for disinfection, taste and odor control, and removal of organic micropollutants. Phenylalanine (Phe) was used as the target amino acid to comprehensively investigate variability of disinfection byproducts (DBPs) formation during chlorine disinfection and residual chlorine conditions subsequent to ozonation. The results showed that subsequent to ozonation, the typical regulated and unregulated DBPs formation potential (DBPsFP), including trichloromethane (TCM), dichloroacetonitrile (DCAN), chloral hydrate (CH), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), and trichloroacetamide (TCAcAm) increased substantially, by 2.4, 3.3, 5.6, 1.2, 2.5, and 6.0 times, respectively, compared with only chlorination. Ozonation also significantly increased the DBPs yield under a 2 day simulated residual chlorine condition that mimicked the water distribution system. DBPs formations followed pseudo first order kinetics. The formation rates of DBPs in the first 6 hr were higher for TCM (0.214 hr-1), DCAN (0.244 hr-1), CH (0.105 hr-1), TCAcAm (0.234 hr-1), DCAA (0.375 hr-1) and TCAA (0.190 hr-1) than thereafter. The peak DBPsFP of TCM, DCAN, CH, TCAcAm, DCAA, and TCAA were obtained when that ozonation time was set at 5-15 min. Ozonation times > 30 min increased the mineralization of Phe and decreased the formation of DBPs upon chlorination. Increasing bromine ion (Br-) concentration increased production of bromine- DBPs and decreased chlorine-DBPs formation by 59.3%-92.2% . Higher ozone dosages and slight alkaline favored to reduce DBP formation and cytotoxicity. The ozonation conditions should be optimized for all application purposes including DBPs reduction.

Preliminary study on the ability of the machine learning models based on 18F-FDG PET/CT to differentiate between mass-forming pancreatic lymphoma and pancreatic carcinoma.

PURPOSE: The objective of this study was to preliminarily assess the ability of metabolic parameters and radiomics derived from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to distinguish mass-forming pancreatic lymphoma from pancreatic carcinoma using machine learning. METHODS: A total of 88 lesions from 86 patients diagnosed as mass-forming pancreatic lymphoma or pancreatic carcinoma were included and randomly divided into a training set and a validation set at a 4-to-1 ratio. The segmentation of regions of interest was performed using ITK-SNAP software, PET metabolic parameters and radiomics features were extracted using 3Dslicer and PYTHON. Following the selection of optimal metabolic parameters and radiomics features, Logistic regression (LR), support vector machine (SVM), and random forest (RF) models were constructed for PET metabolic parameters, CT radiomics, PET radiomics, and PET/CT radiomics. Model performance was assessed in terms of area under the curve (AUC), accuracy, sensitivity, and specificity in both the training and validation sets. RESULTS: Strong discriminative ability observed in all models, with AUC values ranging from 0.727 to 0.978. The highest performance exhibited by the combined PET and CT radiomics features. AUC values for PET/CT radiomics models in the training set were LR 0.994, SVM 0.994, RF 0.989. In the validation set, AUC values were LR 0.909, SVM 0.883, RF 0.844. CONCLUSION: Machine learning models utilizing the metabolic parameters and radiomics of 18F-FDG PET/CT show promise in distinguishing between pancreatic carcinoma and mass-forming pancreatic lymphoma. Further validation on a larger cohort is necessary before practical implementation in clinical settings.

Structurally Diverse Phenylpropanamides from Cannabis Fructus and Their Potential Neuroprotective Effects.

This study aimed to investigate the chemical components and potential health benefits of the fruits of Cannabis sativa L. Fourteen new phenylpropanamides designated as cannabisin I-XIV (1-14) and 40 known analogs were isolated and characterized via nuclear magnetic resonance spectroscopy, high-resolution electrospray ionization mass spectrometry, and electronic circular dichroism. In vitro bioassay using H2O2-induced PC12 cell damage models demonstrated that hempseeds extract and compounds 1, 3, 15, 26, 30, 36, 41, and 48 exhibited neuroprotective properties. 3,3'-Demethylgrossamide (30) displayed encouraging protection activity, which was further investigated to relieve the oxidative stress and apoptosis of PC12 cells treated with H2O2. The isolation and characterization of these neuroprotective phenylpropanamides from the fruits of C. sativa provide insights into its health-promoting properties as a healthy food and herbal medicine for preventing and treating neurodegenerative diseases, especially Alzheimer's disease.

Bioreactor Expansion Affects Microbial Succession of Mixotrophic Acidophiles and Bioremediation of Cadmium-Contaminated Soils.

Microbial scale-up cultivation is the first step to bioremediating cadmium (Cd)-contaminated soils at the industrial scale. However, the changes in the microbial community as the bioreactor volume expands and their associations with soil Cd removal remain unclear. Herein, a six-stage scale-up cultivation process of mixotrophic acidophiles was conducted, scaling from 0.1 L to 10 m3, to remediate Cd-contaminated soils. The findings showed that bioreactor expansion led to a delay in sulfur and glucose oxidations, resulting in a reduced decline in solution pH and cell density. There were minimal differences observed in bacterial alpha-diversity and community structure as the bioreactor volume increased, except for the 10 m3 scale. However, bioreactor expansion decreased fungal alpha-diversity, changed the community structure, and simplified fungal community compositions. At the family level, Acidithiobacillaceae and Debaryomycetaceae dominated the bacterial and fungal communities throughout the scale-up process, respectively. Correlation analysis indicated that the indirect effect of mixotrophic acidophiles played a significant role in soil Cd removal. Bacterial community shifts, driven by changes in bioreactor volume, decreased the pH value through sulfur oxidation, thereby indirectly enhancing Cd removal efficiency. This study will contribute to the potential industrial application of mixotrophic acidophiles in bioremediating Cd-contaminated soils.

Alleles on locus chromosome 4B from different parents confer tiller number and the yield-associated traits in wheat.

Pleiotropy is frequently detected in agronomic traits of wheat (Triticum aestivum). A locus on chromosome 4B, QTn/Ptn/Sl/Sns/Al/Tgw/Gl/Gw.caas-4B, proved to show pleiotropic effects on tiller, spike, and grain traits using a recombinant inbred line (RIL) population of Qingxinmai × 041133. The allele from Qingxinmai increased tiller numbers, and the allele from line 041133 produced better performances of spike traits and grain traits. Another 52 QTL for the eight traits investigated were detected on 18 chromosomes, except for chromosomes 5D, 6D, and 7B. Several genes in the genomic interval of the locus on chromosome 4B were differentially expressed in crown and inflorescence samples between Qingxinmai and line 041133. The development of the KASP marker specific for the locus on chromosome 4B is useful for molecular marker-assisted selection in wheat breeding.

Microenvironmental dynamics of diabetic wounds and insights for hydrogel-based therapeutics.

The rising prevalence of diabetes has underscored concerns surrounding diabetic wounds and their potential to induce disability. The intricate healing mechanisms of diabetic wounds are multifaceted, influenced by ambient microenvironment, including prolonged hyperglycemia, severe infection, inflammation, elevated levels of reactive oxygen species (ROS), ischemia, impaired vascularization, and altered wound physicochemical properties. In recent years, hydrogels have emerged as promising candidates for diabetic wound treatment owing to their exceptional biocompatibility and resemblance to the extracellular matrix (ECM) through a three-dimensional (3D) porous network. This review will first summarize the microenvironment alterations occurring in the diabetic wounds, aiming to provide a comprehensive understanding of its pathogenesis, then a comprehensive classification of recently developed hydrogels will be presented, encompassing properties such as hypoglycemic effects, anti-inflammatory capabilities, antibacterial attributes, ROS scavenging abilities, promotion of angiogenesis, pH responsiveness, and more. The primary objective is to offer a valuable reference for repairing diabetic wounds based on their unique microenvironment. Moreover, this paper outlines potential avenues for future advancements in hydrogel dressings to facilitate and expedite the healing process of diabetic wounds.

The association between hematologic traits and aneurysm-related subarachnoid hemorrhage: a two-sample mendelian randomization study.

Several hematologic traits have been suggested to potentially contribute to the formation and rupture of intracranial aneurysms (IA). The purpose of this study is to explore the causal association between hematologic traits and the risk of IA. To explore the causal association between hematologic traits and the risk of IA, we employed two-sample Mendelian randomization (MR) analysis. Two independent summary-level GWAS data were used for preliminary and replicated MR analyses. The inverse variance weighted (IVW) method was employed as the primary method in the MR analyses. The stabilities of the results were further confirmed by a meta-analysis. In the preliminary MR analysis, hematocrit, hemoglobin concentration (p = 0.0047), basophil count (p = 0.0219) had a suggestive inverse causal relationship with the risk of aneurysm-associated subarachnoid hemorrhage (aSAH). The monocyte percentage of white cells (p = 0.00956) was suggestively positively causally correlated with the risk of aSAH. In the replicated MR analysis, only the monocyte percentage of white cells (p = 0.00297) remained consistent with the MR results in the preliminary analysis. The hematocrit, hemoglobin concentration, and basophil count no longer showed significant causal relationship (p > 0.05). Meta-analysis results further confirmed that only the MR result of monocyte percentage of white cells reached significance in the random effect model and fixed effect model. None of the 25 hematologic traits was causally associated with the risk of unruptured intracranial aneurysms (uIA). This study revealed a suggestive positive association between the monocyte percentage of white cells and the risk of aSAH. This finding contributes to a better understanding that monocytes/macrophages could participate in the risk of aSAH.

Virtual draw of microstructured optical fiber based on physics-informed neural networks.

The implementation of microstructured optical fibers (MOFs) with novel micro-structures and perfect performance is challenging due to the complex fabrication processes. Physics-informed neural networks (PINNs) offer what we believe to be a new approach to solving complex partial differential equations within the virtual fabrication model of MOFs. This study, for what appears to be the first time, integrates the complex partial differential equations and boundary conditions describing the fiber drawing process into the loss function of a neural network. To more accurately solve the free boundary of the fiber's inner and outer diameters, we additionally construct a neural network to describe the free boundary conditions. This model not only captures the evolution of the fiber's inner and outer diameters but also provides the velocity distribution and pressure distribution within the molten glass, thus laying the foundation for a quantitative analysis of capillary collapse. Furthermore, results indicate that the trends in the effects of temperature, feed speed, and draw speed on the fiber drawing process align with actual fabrication conditions, validating the feasibility of the model. The methodology proposed in this study offers what we believe to be a novel approach to simulating the fiber drawing process and holds promise for advancing the practical applications of MOFs.

Comparative characteristics of early-onset vs. late-onset advanced colorectal cancer: a nationwide study in China.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC, diagnosed in patients under the age of 50 years) has been increasing around the world. Here, we aimed to systematically identify distinctive features of EOCRC. METHODS: From 2020 to 2021, we conducted a nationwide survey in 19 hospitals, collecting data on advanced CRC patients' demographics, clinical features, disease knowledge, medical experiences, expenditures, and health-related quality of life (HRQOL). We compared these features between EOCRC and late-onset colorectal cancer (LOCRC, ≥ 50 years old) groups and analyzed the association between EOCRC and HRQOL using multivariate linear regression. FINDINGS: In total, 991 patients with EOCRC and 3581 patients with LOCRC were included. Compared to the LOCRC group, the EOCRC group had higher levels of education, were more informed about the risk factors for CRC, were more likely to have widespread metastases throughout the body, were more inclined to undergo gene testing, and were more likely to opt for targeted therapy, radiotherapy, and chemotherapy. However, HRQOL in the EOCRC group was similar to that of the LOCRC group, and no significant association was observed between EOCRC and HRQOL (beta: -0.753, P value: 0.307). INTERPRETATION: In Chinese patients, EOCRC patients had more aggressive features. Despite undergoing more intensified treatments and gene testing, they had similar HRQOL compared with LOCRC. These findings advocate for a more tailored approach to treatment, especially for young CRC patients with advanced TNM stages and metastasis.

Differences in the response of normal oral mucosa, oral leukoplakia, oral squamous cell carcinoma-derived mesenchymal stem cells, and epithelial cells to photodynamic therapy.

OBJECTIVE: The objective of this study is to investigate the variances in transcriptome gene expression of normal oral mucosa-derived mesenchymal stem cell (OM-MSC), oral leukoplakia-derived MSC (OLK-MSC) and oral squamous cell carcinoma-derived MSC(OSCC-MSC). as Additionally, the study aims to compare the in vitro proliferation, migration, invasion ability, and response to photodynamic therapy (PDT) of these three MSC, HOK, DOK, leuk1, and Cal27 cell lines. METHODS: HOK, DOK, leuk1, Cal27 cells were cultured in vitro. 3 MSC cells were obtained from OM, OLK, OSCC tissue (n = 3) and identified through flow cytometry. They were also cultured in vitro for osteogenic and lipogenic-induced differentiation. Based on the Illumina HiSeq high-throughput sequencing platform, OM-MSC, OLK-MSC, OSCC-MSC (n = 3) were subjected to transcriptome sequencing, functional annotation, and enrichment analysis of differentially expressed genes and related genes. CCK8 assay, wound healing assay, and transwell assay were performed to compare the proliferation, migration, and invasion of the seven types of cells. The 7 cells were incubated with 0, 0.125 mM, 0.25 mM, 0.5 mM, 1 mM, and 2 mM of the photosensitizer (5-aminolevulinic acid, 5-ALA) in vitro. Subsequently, they were irradiated with a 150 mM, 635 nm laser for 1 min, and the cell activity was detected using the CCK8 assay after 24 h. The mitochondrial changes in the 7 cells before and after the treatment of PDT were detected using the JC-10 probe, and the changes in ATP content were measured before and after the PDT treatment. RESULTS: OM-MSC, OLK-MSC, and OSCC-MSC expressed positive MSC surface markers. After osteogenic and lipogenic-induced differentiation culture, stained calcium nodules and lipid droplets were visible, meeting the identification criteria of MSC. Pathway enrichment analysis revealed that the differentially expressed genes (DEGs) of OSCC-MSC compared to OLK-MSC were primarily associated with the PI3K-Akt signaling pathway and tumor-related pathways. OSCC-MSC exhibited stronger migratory and invasive abilities compared to Cal27. The IC50 values required for OM, OLK, and OSCC-derived MSC were lower than those required for epithelial cells treated with PDT, which were 1.396 mM, 0.9063 mM, and 2.924 mM, respectively. Cell membrane and mitochondrial disruption were observed in seven types of cells after 24 h of PDT treatment. However, HOK, DOK, leuk1, and Cal27 cells had an ATP content increased. CONCLUSIONS: OLK, OSCC epithelial cells require higher concentrations of 5-ALA for PDT treatment than MSC of the same tissue origin. The concentration of 5-ALA required increases with increasing cell malignancy. Differences in the response of epithelial cells and MSC to PDT treatment may have varying impacts on OLK recurrence and malignancy.

A potassium-chloride co-transporter with altered genome architecture functions as a suppressor in glioma.

Gliomas, the most lethal tumours in brain, have a poor prognosis despite accepting standard treatment. Limited benefits from current therapies can be attributed to genetic, epigenetic and microenvironmental cues that affect cell programming and drive tumour heterogeneity. Through the analysis of Hi-C data, we identified a potassium-chloride co-transporter SLC12A5 associated with disrupted topologically associating domain which was downregulated in tumour tissues. Multiple independent glioma cohorts were included to analyse the characterization of SLC12A5 and found it was significantly associated with pathological features, prognostic value, genomic alterations, transcriptional landscape and drug response. We constructed two SLC12A5 overexpression cell lines to verify the function of SLC12A5 that suppressed tumour cell proliferation and migration in vitro. In addition, SLC12A5 was also positively associated with GABAA receptor activity and negatively associated with pro-tumour immune signatures and immunotherapy response. Collectively, our study provides a comprehensive characterization of SLC12A5 in glioma and supports SLC12A5 as a potential suppressor of disease progression.

Antidiabetic action of the Chinese formula Shouhuitongbian and the underlying mechanism associated with alteration of gut microbiota.

BACKGROUND: The prevalence and incidence of type 2 diabetes mellitus (T2DM) have dramatically increased. The intestinal flora and its derived metabolites are demonstrated to play vital roles in the etiology and onset of T2DM. Shouhuitongbian (SHTB) is a traditional Chinese formula to treat constipation. SHTB is composed of seven herbs and components of Colla corii asini (CCA) that are obtained from the hide of Equus asinus L.. Some of herbs in SHTB such as Aloe vera (L.) Burm.f., Cassia obtusifolia L., fruits of Lycium barbarum L., and Citrus aurantium L. have shown to improve insulin resistance (IR) and T2DM in early reports. We hypothesized that SHTB composed of these herbs has antidiabetic effects. The antidiabetic efficacy and mechanism of action of SHTB have not been previously reported. HYPOTHESIS/PURPOSE: To demonstrate the antidiabetic effect and elucidate the underlying mechanisms of SHTB from the perspective of gut microbiota. STUDY DESIGN: The main compounds were identified and quantified by high-performance liquid chromatography (HPLC)-mass spectrometry analysis. High fat diet (HFD)-fed mice and db/db mice were used to assess the antidiabetic effects and the mechanism of SHTB. The underlying mechanisms were evaluated by enzyme-linked immunosorbent assay (ELISA), western blot analysis, quantitative real time polymerase chain reaction (qPCR) analysis, 16S rRNA high-throughput sequencing, and targeted metabolome analysis. METHODS: HFD-fed mice and db/db mice were orally treated with the standard positive drug metformin (100 mg/kg/d) and with SHTB (200 and 100 mg/kg/d), which was chemically characterized according to the European Medicine Agency (EMA) guidelines. The beneficial effects of SHTB were studied by homeostasis model assessment of insulin resistance (HOMA-IR) index, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), total cholesterol (T-CHO), triglyceride (TG), and inflammation. Subsequently, 16S rDNA-based high-throughput pyrosequencing and GC-MS-based targeted metabolomics profiling were performed to analyze the gut microbiota composition and metabolites profile in the gut, respectively. Moreover, the mammalian target of rapamycin complex 1 (mTORC1) / insulin receptor substrate 1 (IRS-1) / phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) pathway was evaluated via qPCR and western blot. RESULTS: Chemically characterized SHTB, in which six markers were quantified, effectively alleviated glucose intolerance and IR, ameliorated lipid metabolism dysfunction, and reduced inflammation. In addition, 16S rDNA sequencing found that SHTB reshaped the composition of intestinal flora, as indicated by the enrichment of Akkermansia and Parabacteroides in both HFD-fed and db/db mice. Moreover, SHTB enhanced the intestinal production of short-chain fatty acids (SCFAs) and branched short-chain fatty acids (BSCFAs), and reduced the levels of the fecal and circulating branched-chain amino acids (BCAAs). The IRS-1/PI3K/AKT signaling pathway was upregulated after treatment with SHTB. CONCLUSION: Orally administration of SHTB effectively improved IR and reduced hyperglycemia in mice. Treatment with SHTB regulated the gut BCAAs-mTORC1/IRS-1/PI3K/AKT axis by enhancing the BCAAs catabolism in the gut, which attenuated the deleterious effect of BCAAs on the IRS-1 signaling pathway.

[Non-targeted metabolomics of spleen and liver metabolism in mice treated with Pruni Semen processed with different methods].

Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to investigate the impacts of Pruni Semen processed with different methods(raw and fried) on the liver and spleen metabolism in mice. A total of 24 male mice were randomly assigned to three groups: raw Pruni Semen group, fried Pruni Semen group, and control(deionized water) group. Mice in the three groups were orally administrated with 0.01 g·mL~(-1) Pruni Semen decoction or deionized water for one week. After that, the liver and spleen tissues were collected, and liquid chromatography-mass spectrometry(LC-MS)-based metabolomic analysis was carried out to investigate the impact of Pruni Semen on the liver and spleen metabolism in mice. Compared with thte control group, the raw Pruni Semen group showed up-regulation of 11 metabolites and down-regulation of 57 metabolites in the spleen(P<0.05), as well as up-regulation of 15 metabolites and down-regulation of 58 metabolites in the liver(P<0.05). The fried Pruni Semen group showed up-regulation of 31 metabolites and down-regulation of 10 metabolites in the spleen(P<0.05), along with up-regulation of 26 metabolites and down-regulation of 61 metabolites in the liver(P<0.05). The differential metabolites identified in the raw Pruni Semen group were primarily associated with alanine, aspartate, and glutamate metabolism, purine metabolism, amino sugar and nucleotide sugar metabolism, and D-glutamine and D-glutamate metabolism. The differential metabolites identified in the fried Pruni Semen group predominantly involved riboflavin metabolism, amino sugar and nucleotide sugar metabolism, purine metabolism, alanine, aspartate, and glutamate metabolism, D-glutamine and D-glutamate metabolism, and glutathione metabolism. The findings suggest that both raw and fried Pruni Semen have the potential to modulate the metabolism of the liver and spleen in mice by influencing the glutamine and glutamate metabolism.