Reduction of specific enterocytes from loss of intestinal LGR4 improves lipid metabolism in mice.

Whether intestinal Leucine-rich repeat containing G-protein-coupled receptor 4 (LGR4) impacts nutrition absorption and energy homeostasis remains unknown. Here, we report that deficiency of Lgr4 (Lgr4iKO) in intestinal epithelium decreased the proportion of enterocytes selective for long-chain fatty acid absorption, leading to reduction in lipid absorption and subsequent improvement in lipid and glucose metabolism. Single-cell RNA sequencing demonstrates the heterogeneity of absorptive enterocytes, with a decrease in enterocytes selective for long-chain fatty acid-absorption and an increase in enterocytes selective for carbohydrate absorption in Lgr4iKO mice. Activation of Notch signaling and concurrent inhibition of Wnt signaling are observed in the transgenes. Associated with these alterations is the substantial reduction in lipid absorption. Decrement in lipid absorption renders Lgr4iKO mice resistant to high fat diet-induced obesity relevant to wild type littermates. Our study thus suggests that targeting intestinal LGR4 is a potential strategy for the intervention of obesity and liver steatosis.

Applications of Artificial Intelligence to Diagnosis of Neurodegenerative Diseases.

Artificial Intelligence (AI) is an umbrella term that represents a new technology for simulating and expanding human intelligence by using machines and computer systems. It consists of methods such as machine learning (ML), deep learning (DL), and natural language processing (NLP). In the era of big data, AI has emerged as an essential tool for improving the detection of neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases, amyotrophic lateral sclerosis, etc. AI with its ability to extract critical information from the mass of data has enabled scientists to deal with various types of large-volume data, including genetic data, imaging data, and clinical data, rapidly generated in the course of neurodegenerative disease research. This review provides a comprehensive overview of the literature on current AI applications in the diagnosis of neurodegenerative diseases. Firstly, bioinformatics and AI approaches to identify potential biomarkers for neurodegenerative diseases such as AD are reviewed. Secondly, the use of ML and DL methods to analyze Magnetic Resonance Imaging (MRI) data for a better understanding of disease progression and predicting patient outcomes is discussed. Finally, the use of AI methods including NLP for Electronic Health Record (EHR) data analysis to extract meaningful information and identify patterns that may contribute to early diagnosis and treatment planning are reviewed. The potential benefits of AI-based approaches in improving patient outcomes and the challenges associated with their implementations are also discussed. Overall, this paper highlights the promise of AI in transforming the diagnosis and management of neurodegenerative diseases.

Maternal intermittent fasting deteriorates offspring metabolism via suppression of hepatic mTORC1 signaling.

The metabolic benefits of intermittent fasting (IF) have been well recognized. However, limited studies have examined the relationship between long-term maternal IF before pregnancy and offspring health. In this study, a C57BL/6J mouse model of long-term IF before pregnancy was established: 4-week-old female mice were subjected to alternate-day fasting for 12 weeks and resumed normal diet after mating. Female mice in the control group were fed ad libitum. Offspring mice were weaned at 6 weeks of age and fed a normal chow diet or a 60% high-fat diet. The effects of long-term pre-pregnancy IF on offspring metabolism and its underlying mechanism were examined. We found that neonatal IF offspring weighted significantly less relevant to control mice. This difference gradually disappeared as a result of catch-up growth. In the IF offspring, adipose tissue mass was significantly increased. This alteration was associated with a considerable deterioration in glucose tolerance. No significant difference in food intake was observed. Further, lipid deposition as well as triglyceride contents in the liver were greatly increased. Maternal IF significantly decreased levels of DNA methyltransferase in the liver of offspring. DNA methylation modifications of molecules associated with the mTORC1 signaling pathway were significantly altered, leading to the significant inhibition of mTORC1 signaling. Overexpression of S6K1 activated hepatic mTORC1 signaling and reversed the metabolic dysfunction in IF offspring. In conclusion, long-term pre-pregnancy IF increases hepatic steatosis and adiposity, as well as impairs glucose metabolism in adult offspring. This occurs through DNA methylation-dependent suppression of hepatic mTORC1 signaling activity.

Maternal intermittent fasting in mice disrupts the intestinal barrier leading to metabolic disorder in adult offspring.

Maternal nutrition plays a critical role in energy metabolism of offspring. We aim to elucidate the effect of long-term intermittent fasting (IF) before pregnancy on health outcomes of offspring. Here we show long-term IF before pregnancy disrupts intestinal homeostasis of offspring with subsequent disorder of glucose and lipid metabolism. This occurs through the reduction in beneficial microbiota such as Lactobacillus_intestinalis. Our observations further support the concept that intestinal microbiota in offspring is vulnerable to maternal nutrition, and its homeostasis is critical for the integrity of intestinal barrier and metabolic homeostasis.

Potential Mechanisms of Gut-Derived Extracellular Vesicle Participation in Glucose and Lipid Homeostasis.

The intestine participates in the regulation of glucose and lipid metabolism in multiple facets. It is the major site of nutrient digestion and absorption, provides the interface as well as docking locus for gut microbiota, and harbors hormone-producing cells scattered throughout the gut epithelium. Intestinal extracellular vesicles are known to influence the local immune response, whereas their roles in glucose and lipid homeostasis have barely been explored. Hence, this current review summarizes the latest knowledge of cargo substances detected in intestinal extracellular vesicles, and connects these molecules with the fine-tuning regulation of glucose and lipid metabolism in liver, muscle, pancreas, and adipose tissue.

Oral insulin delivery by epithelium microenvironment-adaptive nanoparticles.

Oral protein drug delivery using nano-based systems remains challenging, as contradictory surface properties are required for efficient navigation through the intestinal mucus and epithelium barriers. Therefore, new nanoplatforms with tunable surface properties in vivo are urgently needed. Inspired by the slightly acidic microclimate of the jejunal epithelial surface, we report a novel epithelium microenvironment-adaptive nanoplatform that undergoes a hydrophilicity-hydrophobicity transition at the epithelial surface. First, we synthesized and characterized a biodegradable copolymer consisting of PEG and PLGA building blocks linked by a hydrazone bond (PLGA-Hyd-PEG) to fabricate the pH-sensitive core-shell architecture of an oral insulin system. Then we loaded the system as a freeze-dried powder into enteric-coated capsules. PLGA-Hyd-PEG nanoparticles showed excellent drug protection and rapid mucus penetration owing to the high stability of the PEG coating in jejunal fluid. In the acidic microenvironment of the jejunal epithelial surface (pH ~5.5), PEG was rapidly cleaved and the hydrazone bond was hydrolyzed, converting the nanoparticle surface from hydrophilic to hydrophobic, thereby facilitating internalization into cells. Pharmacodynamic studies showed that PLGA-Hyd-PEG nanoparticles resulted in significant decrease in blood glucose level after intrajejunal administration in both normal and diabetic rats relative to control nanoparticles. In addition, enteric-coated capsules containing PLGA-Hyd-PEG nanoparticles reduced blood glucose by 35% for up to 10 h after oral administration to diabetic rats. Our findings provide a new strategy for regulating the surface properties of nanoparticles for efficient oral drug delivery.

Hydrophobic ion-pairing assembled liposomal Rhein with efficient loading for acute pancreatitis treatment.

AIM: The present study aimed to develop liposomal Rhein by employing a hydrophobic ion-pairing technique (HIP) for improved pancreatitis therapy. METHODS: F127 modified liposomal Rhein (F127-RPC-Lip) was prepared using a two-step process consisting of complexation first, followed by a film-ultrasonic dispersion step. The drug-phospholipid interaction was characterised by FT-IR and P-XRD. Particle size and morphology were investigated using DLS and TEM, respectively. Biodistribution and therapeutic efficacy of F127-RPC-Lip were evaluated in a rat model of acute pancreatitis. RESULTS: F127-RPC-Lip achieved efficient drug encapsulation after complexation with lipids through non-covalent interactions and had an average hydrodynamic diameter of about 141 nm. F127-RPC-Lip demonstrated slower drug release (55.90 ± 3.60%, w/w) than Rhein solution (90.27 ± 5.11%) within 24 h. Compared with Rhein, F127-RPC-Lip exhibited prolonged systemic circulation time, superior drug distribution, and attenuated injury in the pancreas of rats post-injection. CONCLUSIONS: HIP-assembled liposomes are a promising strategy for Rhein in treating pancreatitis.

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-ß-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy.

Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 µg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8-12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving 1H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-ß-cyclodextrin (G2-ß-CD-Frax). Notably, G2-ß-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G2-ß-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G2-ß-CD-Frax (5 mg/kg) efficiently inhibited CCl4-induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.

Distribution of systemically administered nanoparticles during acute pancreatitis: effects of particle size and disease severity.

Nanoparticles (NPs) promise to address current limitations for treating acute pancreatitis (AP) via inflammatory cell-mediated sequestration. However, very few studies have explored the influence of NP size on their behavior in different stages of AP. The present work investigated the biodistribution of IR780 loaded mesoporous silica nanoparticles (MSNs) with sizes of 60, 150 or 300 nm after intravenous administration to rats of mild AP (MAP) or severe AP (SAP). Four hours after administration, MSN150 was present to a much greater extent in the pancreas than MSN60 or MSN300, irrespective of disease severity. MSN150 was present to a lower extent in pancreas, intestine and ascites in SAP than MAP rats, indicating weaker passive targeting in SAP rats. This may reflect greater blood loss and slower blood flow in SAP. These findings may guide the rational engineering of NPs with respect to particle size and disease severity for AP therapy.