Apolipoprotein A-I: Potential Protection Against Intestinal Injury Induced by Dietary Lipid.

The intestinal barrier system protects the human body from harmful factors, by continuously renewing the intestinal epithelium, tight junctions and enteric microbes. However, dietary fat can harm the intestinal epithelial barrier enhancing gut permeability. In recent years, Apolipoprotein A-I has attracted much attention because of its anti-inflammatory properties. Numerous studies have demonstrated that Apolipoprotein A-I can regulate mucosal immune cells, inhibit the progression of inflammation, promote epithelial proliferation and repair, and maintain physical barrier function; it can also regulate angiogenesis, thereby improving local circulation. This article is intended to elucidate the mechanism by which Apolipoprotein A-I improves intestinal barrier damage caused by dietary fat and to review the role of Apolipoprotein A-I in maintaining intestinal homeostasis.

Improving management in gastroesophageal reflux disease through leveraging WeChat platform for mobile health care: A randomized control trial.

BACKGROUND: Gastroesophageal reflux disease (GERD) refers to a clinical condition characterized by gastric content reflux into the esophagus, causing symptoms like acid regurgitation and heartburn. While patient education is essential for GERD treatment, traditional educational models often struggle to effectively improve treatment outcomes. METHODS: Between January 2021 and April 2022, we enrolled 257 patients and assessed their GERD knowledge. The patients were randomly assigned to either the WeChat group (60 participants) for health education via WeChat platform or the control group (60 participants) for conventional education only. GERD-Q scores were collected at 1, 3, and 6 months post-intervention, with compliance and satisfaction assessed at the study's conclusion. RESULTS: The overall awareness rate of GERD among patients was approximately 22.3 %. The WeChat group showed better compliance than the control group in terms of adhering to a proper diet, taking medication on time, and engaging in moderate exercise (P < 0.05 for all). Furthermore, the WeChat group demonstrated significantly higher treatment effectiveness and satisfaction than the control group (P < 0.05 for all). CONCLUSION: Patients have a relatively low level of knowledge regarding GERD. WeChat has the potential to facilitate lifestyle changes and improve compliance, treatment effectiveness, and treatment satisfaction among patients with gastroesophageal reflux disease.

Emamectin benzoate exposure induced carp kidney injury by triggering mitochondrial oxidative stress to accelerate ferroptosis and autophagy.

Emamectin benzoate (EMB), commonly used as an insecticide in fishery production, inevitably leaves residual chemicals in aquatic environments. High-level EMB exposure can cause severe damage to multiple systems of marine animals, potentially through mechanisms involving severe mitochondrial damage and oxidative stress. However, it is not clear yet how EMB exposure at a certain level can cause damage to fish kidney tissue. In this study, we exposed carps to an aquatic environment containing 2.4 µg/L of EMB and cultured carp kidney cells in vitro, established a cell model exposed to EMB. Our findings revealed that EMB exposure resulted in severe kidney tissue damage in carp and compromised the viability of grass carp kidney cells (CIK cells). By RNA-seq analysis, EMB exposure led to significant differences in mitochondrial homeostasis, response to ROS, ferroptosis, and autophagy signals in carp kidney tissue. Mechanistically, EMB exposure induced mitochondrial oxidative stress by promoting the generation of mitochondrial superoxide and reducing the activity of antioxidant enzymes. Additionally, EMB exposure triggered loss of mitochondrial membrane potential, an imbalance in mitochondrial fusion/division homeostasis, and dysfunction in oxidative phosphorylation, ultimately impairing ATP synthesis. Notably, EMB exposure also accelerated excessive autophagy and ferroptosis of cells by contributing to the formation of lipid peroxides and autophagosomes, and the deposition of Fe2+. However, N-acetyl-L-cysteine (NAC) treatment alleviated the damage and death of CIK cells by inhibiting oxidative stress. Overall, our study demonstrated that EMB exposure induced mitochondrial oxidative stress, impaired mitochondrial homeostasis, and function, promoted autophagy and ferroptosis of kidney cells, and ultimately led to kidney tissue damage in carp. Our research enhanced the toxicological understanding on EMB exposure and provides a model reference for comparative medicine.

TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.

Comparative gene regulatory networks modulating APOE expression in microglia and astrocytes.

Background: Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse expression states. Apolipoprotein E (APOE), a pivotal risk-modifying gene in Alzheimer's disease (AD), is expressed in specific glial transcriptional states associated with AD. However, it is still unknown whether the upstream regulatory programs that modulate its expression are shared across brain cell types or specific to microglia and astrocytes. Methods: We used pySCENIC to construct state-specific gene regulatory networks (GRNs) for resting and activated cell states within microglia and astrocytes based on single-nucleus RNA sequencing data from AD patients' cortices from the Knight ADRC-DIAN cohort. We then identified replicating TF using data from the ROSMAP cohort. We identified sets of genes co-regulated with APOE by clustering the GRN target genes and identifying genes differentially expressed after the virtual knockout of TFs regulating APOE. We performed enrichment analyses on these gene sets and evaluated their overlap with genes found in AD GWAS loci. Results: We identified an average of 96 replicating regulators for each microglial and astrocyte cell state. Our analysis identified the CEBP, JUN, FOS, and FOXO TF families as key regulators of microglial APOE expression. The steroid/thyroid hormone receptor families, including the THR TF family, consistently regulated APOE across astrocyte states, while CEBP and JUN TF families were also involved in resting astrocytes. AD GWAS-associated genes (PGRN, FCGR3A, CTSH, ABCA1, MARCKS, CTSB, SQSTM1, TSC22D4, FCER1G, and HLA genes) are co-regulated with APOE. We also uncovered that APOE-regulating TFs were linked to circadian rhythm (BHLHE40, DBP, XBP1, CREM, SREBF1, FOXO3, and NR2F1). Conclusions: Our findings reveal a novel perspective on the transcriptional regulation of APOE in the human brain. We found a comprehensive and cell-type-specific regulatory landscape for APOE, revealing distinct and shared regulatory mechanisms across microglia and astrocytes, underscoring the complexity of APOE regulation. APOE-co-regulated genes might also affect AD risk. Furthermore, our study uncovers a potential link between circadian rhythm disruption and APOE regulation, shedding new light on the pathogenesis of AD.

Metabolite Study and Structural Authentication for the First-in-Human Use Sphingosine-1-phosphate Receptor 1 Radiotracer.

The sphingosine-1-phosphate receptor 1 (S1PR1) radiotracer [11C]CS1P1 has shown promise in proof-of-concept PET imaging of neuroinflammation in multiple sclerosis (MS). Our HPLC radiometabolite analysis of human plasma samples collected during PET scans with [11C]CS1P1 detected a radiometabolite peak that is more lipophilic than [11C]CS1P1. Radiolabeled metabolites that cross the blood-brain barrier complicate quantitative modeling of neuroimaging tracers; thus, characterizing such radiometabolites is important. Here, we report our detailed investigation of the metabolite profile of [11C]CS1P1 in rats, nonhuman primates, and humans. CS1P1 is a fluorine-containing ligand that we labeled with C-11 or F-18 for preclinical studies; the brain uptake was similar for both radiotracers. The same lipophilic radiometabolite found in human studies also was observed in plasma samples of rats and NHPs for CS1P1 labeled with either C-11 or F-18. We characterized the metabolite in detail using rats after injection of the nonradioactive CS1P1. To authenticate the molecular structure of this radiometabolite, we injected rats with 8 mg/kg of CS1P1 to collect plasma for solvent extraction and HPLC injection, followed by LC/MS analysis of the same metabolite. The LC/MS data indicated in vivo mono-oxidation of CS1P1 produces the metabolite. Subsequently, we synthesized three different mono-oxidized derivatives of CS1P1 for further investigation. Comparing the retention times of the mono-oxidized derivatives with the metabolite observed in rats injected with CS1P1 identified the metabolite as N-oxide 1, also named TZ82121. The MS fragmentation pattern of N-oxide 1 also matched that of the major metabolite in rat plasma. To confirm that metabolite TZ82121 does not enter the brain, we radiosynthesized [18F]TZ82121 by the oxidation of [18F]FS1P1. Radio-HPLC analysis confirmed that [18F]TZ82121 matched the radiometabolite observed in rat plasma post injection of [18F]FS1P1. Furthermore, the acute biodistribution study in SD rats and PET brain imaging in a nonhuman primate showed that [18F]TZ82121 does not enter the rat or nonhuman primate brain. Consequently, we concluded that the major lipophilic radiometabolite N-oxide [11C]TZ82121, detected in human plasma post injection of [11C]CS1P1, does not enter the brain to confound quantitative PET data analysis. [11C]CS1P1 is a promising S1PR1 radiotracer for detecting S1PR1 expression in the CNS.

Risk factors for lymph node metastasis in superficial esophageal squamous cell carcinoma.

In this editorial, we comment on the article by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. We focused on identifying risk factors for lymph node metastasis (LNM) in superficial esophageal squamous cell carcinoma (SESCC) patients and how to construct a simple and reliable clinical prediction model to assess the risk of LNM in SESCC patients, thereby helping to guide the selection of an appropriate treatment plan. The current standard treatment for SESCC is radical esophagectomy with lymph node dissection. However, esophagectomy is associated with considerable morbidity and mortality. Endoscopic resection (ER) offers a safer and less invasive alternative to surgical resection and can enable the patient's quality of life to be maintained while providing a satisfactory outcome. However, since ER is a localized treatment that does not allow for lymph node dissection, the risk of LNM in SESCC limits the effectiveness of ER. Understanding LNM status can aid in determining whether patients with SESCC can be cured by ER without the need for additional esophagectomy. Previous studies have shown that tumor size, macroscopic type of tumor, degree of differentiation, depth of tumor invasion, and lymphovascular invasion are factors associated with LNM in patients with SESCC. In addition, tumor budding is commonly associated with LNM, recurrence, and distant metastasis, but this topic has been less covered in previous studies. By comprehensively evaluating the above risk factors for LNM, useful evidence can be obtained for doctors to select appropriate treatments for SESCC patients.

Altered mucosal bacteria and metabolomics in patients with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterized by the development of pigmented spots, gastrointestinal polyps and increased susceptibility to cancers. Currently, most studies have investigated intestinal microbiota through fecal microbiota, and there are few reports about mucosa-associated microbiota. It remains valuable to search for the key intestinal microbiota or abnormal metabolic pathways linked to PJS. AIM: This study aimed to assess the structure and composition of mucosa-associated microbiota in patients with PJS and to explore the potential influence of intestinal microbiota disorders and metabolite changes on PJS. METHODS: The bacterial composition was analyzed in 13 PJS patients and 12 controls using 16S rRNA gene sequencing (Illumina MiSeq) for bacteria. Differential analyses of the intestinal microbiota were performed from the phylum to species level. Liquid chromatography-tandem mass spectrometry (LC‒MS) was used to detect the differentially abundant metabolites of PJS patients and controls to identify different metabolites and metabolic biomarkers of small intestinal mucosa samples. RESULTS: High-throughput sequencing confirmed the special characteristics and biodiversity of the mucosa microflora in patients with PJS. They had lower bacterial biodiversity than controls. The abundance of intestinal mucosal microflora was significantly lower than that of fecal microflora. In addition, lipid metabolism, amino acid metabolism, carbohydrate metabolism, nucleotide metabolism and other pathways were significantly different from those of controls, which were associated with the development of the enteric nervous system, intestinal inflammation and development of tumors. CONCLUSION: This is the first report on the mucosa-associated microbiota and metabolite profile of subjects with PJS, which may be meaningful to provide a structural basis for further research on intestinal microecology in PJS.