Cross-sectional and Mendelian randomization study of fibroblast growth factor 19 reveals causal associations with metabolic diseases.

BACKGROUND AND AIM: Fibroblast growth factor 19 (FGF19) is an intestinal-derived factor that plays a role in metabolic diseases. We performed a differential study of circulating FGF19 levels and investigated the causal effects of FGF19 on metabolic diseases using Mendelian randomization (MR). METHODS: Firstly, 958 subjects were included in the physical examination center of affiliated hospital from January 2019 to January 2021. Dividing the subjects into different subgroups to compare FGF19 levels. We conducted a two-sample MR analysis of genetically predicted circulating FGF19 in relation to alcohol, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available genome-wide association study summary statistics data. RESULTS: The circulating FGF19 levels in nonalcoholic fatty liver disease (NAFLD) patients were lower than those without NAFLD (P < 0.001). The FGF19 levels in participants with obese were lower than those without obese (P < 0.001). In two-sample MR analyses, genetically predicted higher circulating FGF19 levels was significantly associated with lower aspartate aminotransferase, γ-glutamyltransferase, triglycerides, total cholesterol, low-density lipoprotein, and C-reactive protein concentrations (P < 0.05) and a negative correlation with cardiovascular disease and cirrhosis whereas a positive association with type 2 diabetes mellitus (P < 0.05). CONCLUSIONS: Our study found that circulating FGF19 levels were lower in NAFLD and obese populations. Additionally, our MR research results support the causal effects of FGF19 on improved liver function, lipids, and reduced the occurrence of inflammation, cardiovascular disease, and cirrhosis. We found a positive correlation with diabetes, which may indicate a compensatory increase in regulating above FGF19 resistance states in humans.

Nano-Fe3O4: Enhancing the tolerance of Elymus nutans to Cd stress through regulating programmed cell death.

Cadmium (Cd) poses a significant threat to plant growth and the environment. Nano-Fe3O4 is effective in alleviating Cd stress in plants. Elymus nutans Griseb. is an important fodder crop on the Qinghai-Tibetan Plateau (QTP). However, the potential mechanism by which nano-Fe3O4 alleviates Cd stress in E. nutans is not well understood. E. nutans were subjected to single Cd, single nano-Fe3O4, and co-treatment with nano-Fe3O4 and Cd, and the effects on morphology, Cd uptake, antioxidant enzyme activity, reactive oxygen species (ROS) levels and programmed cell death (PCD) were studied to clarify the regulatory mechanism of nano-Fe3O4. The results showed that Cd stress significantly decreased the germination percentage and biomass of E. nutans. The photosynthetic pigment content decreased significantly under Cd stress. Cd stress also caused oxidative stress and lipid peroxidation, accumulation of excessive ROS, resulting in PCD, but the effect of nano-Fe3O4 was different. Seed germination, seedling growth, and physiological processes were analyzed to elucidate the regulatory role of nano-Fe3O4 nanoparticles in promoting photosynthesis, reducing Cd accumulation, scavenging ROS, and regulating PCD, to promote seed germination and seedling growth in E. nutans. This report provides a scientific basis for improving the tolerance of Elymus to Cd stress by using nano-Fe3O4.

Prognostic impact of metformin in solid cancer patients receiving immune checkpoint inhibitors: novel evidences from a multicenter retrospective study.

Objective: Metformin as a common antidiabetic drug, has recently found to exert its anti-cancer and immunomodulatory effect in numerous preclinical studies. This study aims to clarify the prognostic impact of metformin use in solid cancer patients receiving immune checkpoint inhibitors (ICIs). Methods: A retrospective cohort enrolling 516 solid cancer patients who received ICI-based therapy between 2018 and 2023 at three hospitals was analyzed. The primary endpoints included overall survival (OS) and progression-free survival (PFS). In addition, a bioinformatics analysis based on TCGA and GSE cohort was performed to investigate the prognostic significance of metformin target genes (MTGs) and their correlation with immune infiltration in non-small cell lung cancer (NSCLC) patients. Results: In the entire cohort, a total of 76 patients received metformin before and/or during ICI therapy. The global analysis demonstrated that metformin use was unrelated with the OS (p = 0.064) and PFS (p = 0.059) of ICI-treated cancer patients, which was confirmed in the subgroups of esophagus, hepatobiliary or pancreatic cancer (all p > 0.05). However, metformin use was significantly correlated with better OS (p = 0.012) and PFS (p = 0.005) in ICI-treated lung cancer patients. Metformin use was also identified as an independent favorable prognostic factor for these patients. The bioinformatics analysis identified five favorable prognostic MTGs (RPS6KA5, RORA, SH3BP5, NUPR1, and CD40LG) for NSCLC patients, all of which was downregulated in lung cancer tissues as compared with normal tissues. The expressions of five MTGs not only could effectively stratify the OS of NSCLC patients, but also was correlated with infiltration of immune cells such as CD4+ and CD8+ T cells. Conclusion: Metformin use was significantly correlated with better OS and PFS in ICI-treated lung cancer patients. MTGs has the potential to serve as novel clinical biomarkers or druggable targets for cancer immunotherapy. Considering study limitations, the actual impact of metformin use on ICI therapy needs to be clarified by more clinical trials.

Evaluation of different bermudagrass germplasm at physiological and molecular level under shade along longitudinal and latitudinal gradients.

Responses of turfgrass to shade vary in individual species, and the degree and quality of low light; therefore, the selection of low light tolerant cultivars of turfgrass is important and beneficial for turf management rather than other practices. The stolons of thirteen bermudagrass genotypes were planted with two treatments and three replications of each treatment to establish for one month in the Yangzhou University Jiangsu China greenhouse. The established plants were transferred outside of the greenhouse, and 50% shading was applied to them with a black net. After 30 days of stress treatment, the morpho-physiological and biochemical analyses were performed. The expression of genes such as HEMA, HY5, PIF4, and Cu/ZnSOD was assessed. Cynodon dactylon is a C4, and perennial that grows as lawn grass and is used as forage. Based on different indicator measurements, the most shade-tolerant germplasm was L01 and L06 along the longitudes and L09 and L10 along the latitudes. At the same time, L02 and L08 were more susceptible, respectively. However, germplasm showed greater tolerance in higher latitudes while longitudinal plants showed less stress response. The current study aimed (1) to screen out the most shade-tolerant Cynodon dactylon genotype among 13 along longitudinal and latitudinal gradients in China. (2) to examine morpho-physiological indicators of different bermudagrassgenotypes; (3) to evaluate if and how differences in various indicators of bermudagrass correlated with geographic region. This study will significantly advance the use of Cynodon germplasm in breeding, genomics, management, nomenclature, and phylogeographical study. It will decisively define whether natural selection and migration can drive evolutionary responses for populations to adapt to their new environments effectively.

Effect of smoking cessation on the likelihood of pancreatitis and pancreatic cancer.

INTRODUCTION: Tobacco smoking is a major risk factor for various diseases worldwide, including pancreatic exocrine diseases such as pancreatitis and pancreatic cancer (PC). Currently, few studies have examined the impact of smoking cessation on the likelihood of common pancreatic exocrine diseases. This study sought to determine whether smoking cessation would reduce pancreatitis and PC morbidity. METHODS: This cohort study used data from the UK Biobank (UKB) to examine the association between smoking status and the likelihood of pancreatitis and PC among 492855 participants. The subjects were divided into never smokers, ex-smokers, and current smokers. Using a multivariate-adjusted binary logistic regression model, we analyzed the relationship between different smoking conditions and the likelihood of pancreatitis and PC. Further, we studied the impact of smoking cessation on pancreatitis and PC compared with current smoking. RESULTS: After adjusting for potential confounders, current smokers had higher odds for acute pancreatitis (AP) (AOR=1.38; 95% CI: 1.18-1.61), chronic pancreatitis (CP) (AOR=3.29; 95% CI: 2.35-4.62) and PC (AOR=1.72; 95% CI: 1.42-2.09). People who quit smoking had comparable odds for the diseases as those who never smoked. Compared with current smokers, ex-smokers had reduced odds for AP (AOR=0.76; 95% CI: 0.64-0.89), CP (AOR=0.31; 95% CI: 0.21-0.46), and PC (AOR=0.62; 95% CI: 0.50-0.76). Subgroup analysis revealed reduced odds for these pancreatic diseases in males and females. CONCLUSIONS: Smokers have an increased odds for pancreatitis and pancreatic cancer. Moreover, smoking cessation can significantly reduce the odds for acute pancreatitis, chronic pancreatitis and pancreatic cancer.

Physiochemically and Genetically Engineered Bacteria: Instructive Design Principles and Diverse Applications.

With the comprehensive understanding of microorganisms and the rapid advances of physiochemical engineering and bioengineering technologies, scientists are advancing rationally-engineered bacteria as emerging drugs for treating various diseases in clinical disease management. Engineered bacteria specifically refer to advanced physiochemical or genetic technologies in combination with cutting edge nanotechnology or physical technologies, which have been validated to play significant roles in lysing tumors, regulating immunity, influencing the metabolic pathways, etc. However, there has no specific reviews that concurrently cover physiochemically- and genetically-engineered bacteria and their derivatives yet, let alone their distinctive design principles and various functions and applications. Herein, the applications of physiochemically and genetically-engineered bacteria, and classify and discuss significant breakthroughs with an emphasis on their specific design principles and engineering methods objective to different specific uses and diseases beyond cancer is described. The combined strategies for developing in vivo biotherapeutic agents based on these physiochemically- and genetically-engineered bacteria or bacterial derivatives, and elucidated how they repress cancer and other diseases is also underlined. Additionally, the challenges faced by clinical translation and the future development directions are discussed. This review is expected to provide an overall impression on physiochemically- and genetically-engineered bacteria and enlighten more researchers.

An integration of physiology, transcriptomics, and proteomics reveals carbon and nitrogen metabolism responses in alfalfa (Medicago sativa L.) exposed to titanium dioxide nanoparticles.

Nanoparticle (NP) pollution has negative impacts and is a major global environmental problem. However, the molecular response of alfalfa (Medicago sativa L.) to titanium dioxide nanoparticles (TiO2 NPs) is limited. Herein, the dual effects of TiO2 NPs (0-1000 mg L-1) on carbon (C) and nitrogen (N) metabolisms in alfalfa were investigated. The results showed that 500 mg L-1 TiO2 NPs (Ti-500) had the highest phytotoxicity in the C/N metabolizing enzymes; and it significantly increased total soluble sugar, starch, sucrose, and sucrose-phosphate synthase. Furthermore, obvious photosynthesis responses were found in alfalfa exposed to Ti-500. By contrast, 100 mg L-1 TiO2 NPs (Ti-100) enhanced N metabolizing enzymes. RNA-seq analyses showed 4265 and 2121 differentially expressed genes (DEGs) in Ti-100 and Ti-500, respectively. A total of 904 and 844 differentially expressed proteins (DEPs) were identified in Ti-100 and Ti-500, respectively. Through the physiological, transcriptional, and proteomic analyses, the DEGs and DEPs related to C/N metabolism, photosynthesis, chlorophyll synthesis, starch and sucrose metabolism, and C fixation in photosynthetic organisms were observed. Overall, TiO2 NPs at low doses improve photosynthesis and C/N regulation, but high doses can cause toxicity. It is valuable for the safe application of NPs in agriculture.

Transcriptomic and metabolomic insights into the antimony stress response of tall fescue (Festuca arundinacea).

Antimony (Sb) is a toxic heavy metal that severely inhibits plant growth and development and threatens human health. Tall fescue, one of the most widely used grasses, has been reported to tolerate heavy metal stress. However, the adaptive mechanisms of Sb stress in tall fescue remain largely unknown. In this study, transcriptomic and metabolomic techniques were applied to elucidate the molecular mechanism of the Sb stress response in tall fescue. These results showed that the defense process in tall fescue was rapidly triggered during the early stages of Sb stress. Sb stress had toxic effects on tall fescue, and the cell wall and voltage-gated channels are crucial for regulating Sb permeation into the cells. In addition, the pathway of glycine, serine and threonine metabolism may play key roles in the Sb stress response of tall fescue. Genes such as ALDH7A1 and AGXT2 and metabolites such as aspartic acid, pyruvic acid, and biuret, which are related to biological processes and pathways, were key genes and compounds in the Sb stress response of tall fescue. Therefore, the regulatory mechanisms of specific genes and pathways should be investigated further to improve Sb stress tolerance.

Naringenin Alleviates Radiation-Induced Intestinal Injury by Inhibiting TRPV6 in Mice.

SCOPE: Naringenin (NAR) possesses unique anti-inflammatory, antiapoptosis effects and various bioactivities; however, its role against radiation-induced intestinal injury (RIII) remains unclear. This study aims to investigate whether NAR has protective effects against radiation-induced intestinal injury and the underlying mechanisms. METHODS AND RESULTS: C57BL/6J mice are exposed to a single dose of 13 Gy X-ray total abdominal irradiation (TAI), then gavaged with NAR for 7 days. NAR treatment prolongs the survival rate, protects crypts and villi from damage, alleviates the level of radiation-induced inflammation, and mitigates intestinal barrier damage in the irradiated mice. Additionally, NAR reduces immune cell infiltration and intestinal epithelial cell apoptosis. NAR also shows radioprotective effects in human colon cancer cells (HCT116) and human intestinal epithelial cells (NCM460). It reduces cell damage by reducing intracellular calcium ion levels and reactive oxygen species (ROS) levels. NAR-mediated radioprotection is associated with the downregulation of transient receptor potential vanilloid 6 (TRPV6), and inhibition of apoptosis pathway. Notably, treatment with NAR fails to further increase the protective effects of the TRPV6 inhibitor 2-APB, indicating that TRPV6 inhibition is essential for NAR activity. CONCLUSION: NAR inhibits the apoptosis pathway by downregulating TRPV6 and reducing calcium ion level, thereby alleviating RIII. Therefore, NAR is a promising therapeutic drug for RIII.

Assessment of the changes in growth, photosynthetic traits and gene expression in Cynodon dactylon against drought stress.

Drought stress considered a key restrictive factor for a warm-season bermudagrass growth during summers in China. Genotypic variation against drought stress exists among bermudagrass (Cynodon sp.), but the selection of highly drought-tolerant germplasm is important for its growth in limited water regions and for future breeding. Our study aimed to investigate the most tolerant bermudagrass germplasm among thirteen, along latitude and longitudinal gradient under a well-watered and drought stress condition. Current study included high drought-resistant germplasm, "Tianshui" and "Linxiang", and drought-sensitive cultivars; "Zhengzhou" and "Cixian" under drought treatments along longitude and latitudinal gradients, respectively. Under water deficit conditions, the tolerant genotypes showed over-expression of a dehydrin gene cdDHN4, antioxidant genes Cu/ZnSOD and APX which leads to higher antioxidant activities to scavenge the excessive reactive oxygen species and minimizing the membrane damage. It helps in maintenance of cell membrane permeability and osmotic adjustment by producing organic osmolytes. Proline an osmolyte has the ability to keep osmotic water potential and water use efficiency high via stomatal conductance and maintain transpiration rate. It leads to optimum CO2 assimilation rate, high chlorophyll contents for photosynthesis and elongation of leaf mesophyll, palisade and thick spongy cells. Consequently, it results in elongation of leaf length, stolon and internode length; plant height and deep rooting system. The CdDHN4 gene highly expressed in "Tianshui" and "Youxian", Cu/ZnSOD gene in "Tianshui" and "Linxiang" and APX gene in "Shanxian" and "Linxiang". The genotypes "Zhongshan" and "Xiaochang" showed no gene expression under water deficit conditions. Our results indicate that turfgrass show morphological modifications firstly when subjected to drought stress; however the gene expression is directly associated and crucial for drought tolerance in bermudagrass. Hence, current research has provided excellent germplasm of drought tolerant bermudagrass for physiological and molecular study and future breeding.

Efficacy and safety of consolidation chemotherapy after adjuvant therapy in stage IB-IIA cervical cancer patients with risk factors: a retrospective single-center study.

Objective: Accumulated evidence has suggested a relatively high recurrence rate in early-stage cervical cancer (CC) patients with risk factors. This study aimed to assess the efficacy and safety of consolidation chemotherapy following adjuvant therapy (concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone) in stage IB-IIA CC patients with risk factors. Methods: A total of 237 stage IB-IIA CC patients who received radical surgery between January 2014 and December 2021 were included in the retrospective study. According to the types of adjuvant therapies, the patients were classified into the control group (CCRT or RT alone) and the study group (consolidation chemotherapy following CCRT or RT alone). The propensity score matching (PSM) was used to balance baseline characteristics between the two groups. The primary end points of the study were disease-free survival (DFS) and overall survival (OS). Results: For the entire cohort, no significant difference was observed in the DFS or OS between the study and control group, which was also confirmed in the PSM cohort (n=124). The multivariate analysis identified the high-risk factor type was an independent adverse prognostic factor for the patients. In patients with high risk factors, consolidation chemotherapy following adjuvant therapy was significantly associated with better clinical outcomes and identified as an independent prognostic favorable factor. Moreover, this association remained statistically significant in high-risk patients with ≥2 metastatic lymph nodes. In patients with intermediate risk factors, consolidation chemotherapy following adjuvant therapy was unrelated to DFS or OS. The safe assessment demonstrated consolidation chemotherapy following adjuvant therapy was significantly correlated with higher rates of ≥ grade 3 hematologic toxicities in both the global and subgroup analysis stratified by risk factor type. Conclusion: Consolidation chemotherapy after adjuvant therapy provided survival benefits in stage IB-IIA CC patients with high risk factors, particularly those with ≥2 metastatic lymph nodes. However, related hematologic toxicities should be alerted in patient management. The actual efficacy and safety of consolidation chemotherapy still need to be investigated in more well-designed clinical trials.

Zinc oxide nanoparticles alleviate cadmium toxicity and promote tolerance by modulating programmed cell death in alfalfa (Medicago sativa L.).

Cadmium (Cd) can induce programmed cell death (PCD) and zinc oxide nanoparticles (ZnO NPs) effectively alleviate Cd stress. However, the mechanisms of ZnO NPs-mediated Cd detoxification in alfalfa (Medicago sativa L.) are limited. The pot experiment was conducted with Cd soil (19.2 mg kg-1) and foliar ZnO NPs (100 mg L-1) on alfalfa. The results showed that Cd reduced shoot height and biomass, and accumulated reactive oxygen species (ROS), resulting in oxidative stress and further PCD (plasmolysis, cytosolic and nuclear condensation, subcellular organelle swelling, and cell death). ZnO NPs positively regulated the antioxidant system, cell membrane stability, ultrastructure, osmotic homeostasis, and reduced PCD, indicating a multi-level coordination for the increased Cd tolerance. ZnO NPs up-regulated the activity and expression of antioxidant enzymes and regulated PCD-related genes to scavenge ROS and mitigate PCD caused by Cd. The genes related to ZnO NPs-mediated Cd detoxification were significantly enriched in cell death and porphyrin and chlorophyll metabolism. Overall, it elucidates the molecular basis of ZnO NPs-mediated Cd-tolerance by promoting redox and osmotic homeostasis, maintaining cellular ultrastructure, reducing Cd content, and attenuating Cd-induced PCD. it provides a promising application of ZnO NPs to mitigate Cd phytotoxicity and the related cellular and biochemical mechanisms. ENVIRONMENTAL IMPLICATION: Cd, one of the most toxic heavy metals, has caused serious environmental pollution. ZnO NPs can effectively alleviate Cd stress on plants and the environment. This study revealed that foliar-applied ZnO NPs alleviate Cd toxicity by mitigating the oxidative damage and regulating Cd-induced PCD via morphological, physiological, and transcriptomic levels. The findings elucidated the molecular basis of ZnO NPs-mediated Cd tolerance by promoting osmotic and redox homeostasis, reducing Cd content and lipid peroxidation, attenuating Cd-induced PCD features, and altering PCD-related genes in alfalfa. The study laid a theoretical foundation for the safe production of alfalfa under Cd pollution.

A novel investigation into the negative impact of opioid use on the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have effectively improved the clinical outcome of advanced non-small cell lung cancer (NSCLC). Opioids are commonly used for pain relief in cancer patients. This study aims to clarify the prognostic impact of opioid use in advanced NSCLC patients receiving ICI therapy. METHODS: A systematic literature review was carried out using online databases before July 2023. The meta-analysis was used to clarify the correlation of opioid use with the overall survival (OS) or progression-free survival (PFS) of ICI-treated NSCLC patients, both of which were determined using hazard ratios (HRs) coupled with 95 % confidence intervals (CIs). Then, an independent cohort enrolling 181 NSCLC patients was utilized for validation. Finally, a comprehensive bioinformatics analysis based on TCGA cohort was performed to investigate the prognostic significance of opioid target genes (OTGs) and their correlation with immune infiltration in NSCLC patients. RESULTS: A total of 8 studies enrolling 1174 patients were included in the meta-analysis. Opioid use was negatively associated with worse PFS (HR = 2.16, 95 %CI: 1.26-3.71) and OS (HR = 2.02, 95 %CI: 1.54-2.63) in ICI-treated NSCLC patients. The retrospective validation confirmed the above result and identified opioid use as an independent unfavorable predictor for PFS and OS in both the entire cohort and ICI subgroup. The bioinformatic analysis identified 14 prognostic OTGs (CYP17A1, PDYN, PYCARD, FGA, NTSR1, FABP1, HPCA, PENK, PDGFB, LIN7A, FKBP5, TYMS, CACNA1H and LDHA), most of which were correlated with immune infiltration in NSCLC. A risk model was constructed based on 14 OTGs and found to effectively stratify the clinical outcome in both the training and validation set, independent of age, gender and TNM staging system. The model was also significantly correlated with infiltration of activated dendritic cells, neutrophils and tumor infiltrating lymphocytes. Finally, a nomogram was constructed based on the model, age, gender and TNM stage, which could predict well the 1-, 3- and 5-year survival of NSCLC patients. CONCLUSION: Opioid use is correlated with the poor clinical outcome in ICI-treated NSCLC patients. Precise pain management is highly advocated and opioids are recommended to be cautiously used in these patients. OTGs have the potential to be prognostic biomarkers for NSCLC patients and their role in tumor immunity needs to be further investigated.

Identification of C-PLAN index as a novel prognostic predictor for advanced lung cancer patients receiving immune checkpoint inhibitors.

Objective: Increasing studies have highlighted the potential utility of non-invasive prognostic biomarkers in advanced lung cancer patients receiving immune checkpoint inhibitor (ICI) based anti-cancer therapies. Here, a novel prognostic predictor named as C-PLAN integrating C-reactive protein (CRP), Performance status (PS), Lactate dehydrogenase (LDH), Albumin (ALB), and derived Neutrophil-to-lymphocyte ratio (dNLR) was identified and validated in a single-center retrospective cohort. Methods: The clinical data of 192 ICI-treated lung cancer patients was retrospectively analyzed. The pretreatment levels of CRP, PS, LDH, ALB and dNLR were scored respectively and then their scores were added up to form C-PLAN index. The correlation of C-PLAN index with the progression-free survival (PFS) or overall survival (OS) was analyzed by a Kaplan-Meier model. The multivariate analysis was used to identify whether C-PLAN index was an independent prognostic predictor. Results: A total of 88 and 104 patients were included in the low and high C-PLAN index group respectively. High C-PLAN index was significantly correlated with worse PFS and OS in ICI-treated lung cancer patients (both p<0.001). The multivariate analysis revealed high C-PLAN index was an independent unfavorable factor affecting PFS (hazard ratio (HR)=1.821; 95%confidence interval (CI)=1.291-2.568) and OS (HR=2.058, 95%CI=1.431-2.959). The high C-PLAN index group had a significantly lower disease control rate than the low C-PLAN index group (p=0.024), while no significant difference was found for objective response rate (p=0.172). The subgroup analysis based on clinical features (pathological type, therapy strategy, TNM stage and age) confirmed the prognostic value of C-PLAN index, except for patients receiving ICI monotherapy or with age ranging from 18 to 65 years old. Finally, a nomogram was constructed based on C-PLAN index, age, gender, TNM stage and smoking status, which could predict well the 1-, 2- and 3-year survival of ICI-treated lung cancer patients. Conclusion: The C-PLAN index has great potential to be utilized as a non-invasive, inexpensive and reliable prognostic predictor for advanced lung cancer patients receiving ICI-based anti-cancer therapies.

Microbiological and metabolic pathways analysing the mechanisms of alfalfa polysaccharide and sulfated alfalfa polysaccharide in alleviating obesity.

Alfalfa polysaccharide (AP) and sulfated alfalfa polysaccharide (SAP) exhibit potential for alleviating obesity. This study aimed to analyze the mechanism of action of AP and SAP in alleviating obesity through combined microbiomics and metabolomics. The research selected validated optimal AP and SAP concentration for experiment. The results showed that AP and SAP down-regulated colonic inflammatory gene expression, regulated intestinal pH to normal, and restored intestinal growth. Microbial sequencing showed that AP and SAP altered the microbial composition ratio. AP increased the relative abundance of Muribaculaceae and Romboutsia. SAP increased the relative abundance of Dubosiella, Fecalibaculum and Desulfovibrionaceae. Metabolomic analysis showed that AP regulated steroid hormone biosynthesis, neuroactive ligand-receptor interactions and bile secretion pathways. SAP focuses more on pathways related to amino acid metabolism. Meanwhile, AP and SAP down-regulated the mRNA expression of colonic COX-2, PepT-1 and HK2 and up-regulated the mRNA expression of TPH1. Correlation analysis showed a strong correlation between metabolites and gut bacteria. Dubosiella, Faecalibaculum may be the critical marker flora for polysaccharides to alleviate obesity. This study indicates that AP and SAP alleviate obesity through different pathways and that specific polysaccharide modifications affect characteristic microbial and metabolic pathways, providing new insights into polysaccharide modifications.

Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15.

Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.

Nanopore sequencing of infectious fluid is a promising supplement for gold-standard culture in real-world clinical scenario.

Introduction: Infectious diseases are major causes of morbidity and mortality worldwide, necessitating the rapid identification and accurate diagnosis of pathogens. While unbiased metagenomic next-generation sequencing (mNGS) has been extensively utilized in clinical pathogen identification and scientific microbiome detection, there is limited research about the application of nanopore platform-based mNGS in the diagnostic performance of various infectious fluid samples. Methods: In this study, we collected 297 suspected infectious fluids from 10 clinical centers and detected them with conventional microbiology culture and nanopore platform-based mNGS. The objective was to assess detective and diagnostic performance of nanopore-sequencing technology (NST) in real-world scenarios. Results: Combined with gold-standard culture and clinical adjudication, nanopore sequencing demonstrated nearly 100% positive predictive agreements in microbial-colonized sites, such as the respiratory and urinary tracts. For samples collected from initially sterile body sites, the detected microorganisms were highly suspected pathogens, and the negative predictive agreements were relatively higher than those in the microbial-colonized sites, particularly with 100% in abscess and 95.7% in cerebrospinal fluid. Furthermore, consistent performance was also observed in the identification of antimicrobial resistance genes and drug susceptibility testing of pathogenic strains of Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii. Discussion: Rapid NST is a promising clinical tool to supplement gold-standard culture, and it has the potential improve patient prognosis and facilitate clinical treatment of infectious diseases.

[Three-dimensional radiographic features of calcifying odontogenic cyst and calcifying epithelial odontogenic tumor].

OBJECTIVE: To analyze the three-dimensional radiographic characteristics of calcifying odontogenic cyst and calcifying epithelial odontogenic tumor using spiral computed tomography (CT) and cone-beam computed tomography (CBCT). METHODS: Clinical records, histopathological reports, and CBCT or non-enhanced spiral CT images of 19 consecutive patients with calcifying odontogenic cyst (COC) and 16 consecutive patients with calcifying epithelial odontogenic tumor (CEOT) were retrospectively acquired, and radiographic features, including location, size, expansion, internal structure and calcification, were analyzed. RESULTS: Among the 19 COC cases (12 males and 7 females, with an average age of 27 years), 89.5% (17/19) of the lesions originated from the anterior and premolar areas, 100.0% of them exhibited cortex expansion, and 78.9% had discontinued cortex. Among the 16 CEOT cases (3 males and 13 females, with an average age of 36 years), 81.3% (13/16) of the lesions were in the premolar and molar areas, 56.3% of them exhibited cortex expansion, and 96.8% had discontinued cortex. According to the distribution of internal calcifications, these lesions were divided into: Ⅰ (non-calcification type): absence of calcification; Ⅱ (eccentric marginal type): multiple calcifications scattered along one side of the lesion; Ⅲ (diffused type): numerous calcifications diffusely distributed into the lesion; Ⅳ (plaque type): with a ≥ 5 mm calcified patch; Ⅴ (peri-coronal type): multiple calcifications clustered around impacted teeth. Calcifications were present in 73.7% of COC lesions, including 9 type Ⅱ, 3 type Ⅲ and 2 type Ⅳ lesions, and 42.8% of CEOT lesions had calcification images, including 2 type Ⅲ and 5 type Ⅴ lesions. Six COC lesions had odontoma-like images. Moreover, 8 of 9 type Ⅰ CEOTs were histologically Langerhans cell-rich subtype, which had a smaller size (with an average mesiodistal diameter of 17.8 mm) and were not associated with impacted teeth. CONCLUSION: COC lesions tended to originate from the anterior part of the jaw and exhibit cortex expansion, and were sometimes associated with odontoma. CEOT commonly occurred in the posterior jaw and had discontinued cortex. Two lesions had significantly different calcification map. Over 70% of COC lesions had calcification images, which were mostly scattered along one side of the cysts, far from the impacted teeth. Approximately 60% of CEOT lesions exhibited smaller size and non-calcification, and the remaining CEOT cases often had calcification images clustered around the impacted teeth.

Metabolic dysfunction-associated fatty liver disease and nonalcoholic fatty liver disease from clinical to pathological characteristics: a multi-center cross-sectional study in real world.

BACKGROUND: The evaluation of patients with fatty liver as defined by metabolic dysfunction-associated fatty liver disease (MAFLD) in the real world remains poorly researched. This study aimed to analyse the clinical and histological features of patients with MAFLD and nonalcoholic fatty liver disease (NAFLD) and to characterize each metabolic subgroup of MAFLD. METHODS: A total of 2563 patients with fatty liver confirmed by ultrasonography and/or magnetic resonance tomography and/or liver biopsy-proven from three hospitals in China were included in the study. Patients were divided into different groups according to diagnostic criteria for MAFLD and NAFLD, and MAFLD into different subgroups. RESULTS: There were 2337 (91.2%) patients fitting the MAFLD criteria, and 2095 (81.7%) fitting the NAFLD criteria. Compared to patients with NAFLD, those with MAFLD were more likely to be male, had more metabolic traits, higher liver enzyme levels, and noninvasive fibrosis scores. Among the patients with liver biopsy, the extent of advanced fibrosis in cases with MAFLD was significantly higher than those with NAFLD, 31.8% versus 5.2% (P < .001); there was no significant difference in advanced fibrosis between obese cases and lean individuals in MAFLD (P > .05); MAFLD complicated with diabetes had significantly higher advanced fibrosis than those without diabetes (43.3% and 17.2%, respectively; P < .001). CONCLUSIONS: Patients with MAFLD have a higher degree of liver fibrosis than NAFLD patients. In addition, diabetic patients should be screened for fatty liver and liver fibrosis degree.

Lima bean (Phaseolus lunatus Linn.) protein isolate as a promising plant protein mixed with xanthan gum for stabilizing oil-in-water emulsions.

BACKGROUND: Lima bean protein isolate (LPI) is an underutilized plant protein. Similar to other plant proteins, it may display poor emulsification properties. In order to improve its emulsifying properties, one effective approach is using protein and polysaccharide mixtures. This work investigated the structural and emulsifying properties of LPI as well as the development of an LPI/xanthan gum (XG)-stabilized oil-in-water emulsion. RESULTS: The highest protein solubility (84.14%) of LPI was observed and the molecular weights (Mw ) of most LPI subunits were less than 35 kDa. The enhanced emulsifying activity index (15.97 m2 g-1 ) of LPI might be associated with its relatively high protein solubility and more low-Mw subunits (Mw < 35 kDa). The effects of oil volume fraction (ϕ) on droplet size, microstructure, rheological behavior and stability of emulsions were investigated. As ϕ increased from 0.2 to 0.8, the emulsion was arranged from spherical and dispersed oil droplets to polyhedral packing of oil droplets adjacent to each other, while the LPI/XG mixtures changed from particles (in the uncrowded interfacial layer) to lamellae (in the crowded interfacial layer). When ϕ was 0.6, the emulsion was in a transitional state with the coexistence of particles and lamellar structures on the oil droplet surface. The LPI/XG-stabilized emulsions with ϕ values of 0.6-0.8 showed the highest stability during a 14-day storage period. CONCLUSION: This study developed a promising plant-based protein resource, LPI, and demonstrates potential application of LPI/XG as an emulsifying stabilizer in foods. © 2023 Society of Chemical Industry.