The GLUT4 and PI3K/AKT signaling pathways are the key sensors of energy status and they regulate glucose and lipid metabolism. Phloretin activates the PI3K/AKT pathway by promoting GLUT4 translocation and expression, thereby improving glucose consumption and tolerance. As metformin can regulate glucose metabolism, we hypothesized that phloretin can amplify its gluco-regulatory effects. Male Sprague Dawley rats were fed with a high-fat and high-sugar diet for 8 weeks and injected with a low dose of streptozotocin to induce type 2 diabetes. The diabetic rats were randomized to receive phloretin (100 mg kg⁻¹ d⁻¹), metformin (250 mg kg⁻¹ d⁻¹), or phloretin + metformin via oral gavage for another 4 weeks. Random blood glucose, serum insulin, free fatty acid, total cholesterol, triglyceride, and low-density lipoprotein levels were detected in type 2 diabetic rats. Hematoxylin–eosin and Oil Red O staining were used to observe the pathological changes in the liver, pancreas, and adipose tissues of type 2 diabetic rats. The expression levels of IRS-1, PI3K, P-AKT, and GLUT4 in skeletal muscle were detected using western blotting. Phloretin plus metformin improved fasting blood glucose levels, glucose tolerance, and insulin sensitivity in type 2 diabetic rats. In addition, this combination reduced lipid accumulation, improved the pathological changes in the liver, pancreas, and adipose tissue, and increased IRS-1, PI3K, P-AKT, and GLUT4 expression in skeletal muscle and the liver of type 2 diabetic rats. Thus, phloretin can be used in a potential combination therapy with metformin for the prevention and rescue of type 2 diabetes.

This study aimed to evaluate the pharmacokinetics of acipimox in rats under simulated high altitude hypoxia conditions. A sensitive and reliable LC–MS/MS method has been established for the quantitation of acipimox in rat plasma and tissue homogenate and validated according to the guidelines of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Western blotting and enzyme linked immunosorbent assay (ELISA) were used to investigate the expression of lipid metabolism-related proteins and free fatty acid (FFA) levels, respectively. Cell viability was detected using a Cell Counting kit-8 assay (CCK-8). The method was then successfully applied in a pharmacokinetic comparison between normoxic and hypoxic rats. The results indicated that there were significant differences in the main pharmacokinetics parameters of acipimox between normoxic and hypoxic rats. HCAR2 expression in the hypoxia group was upregulated compared to that in the normoxia group and the levels of FFA decreased more in the hypoxia group. Under the hypoxia condition, the proliferation of HK2 cells was inhibited with increasing concentrations of acipimox. The results provide important and valuable information for the safety and efficacy of acipimox, which indicated that the dosage of acipimox might be adjusted appropriately during clinical medication in hypoxia.

Post-traumatic stress disorder (PTSD) is a persistent psychiatric condition that arises following exposure to traumatic events such as warfare, natural disasters, or other catastrophic incidents, typically characterized by heightened anxiety, depressive symptoms, and cognitive dysfunction. In this study, animals subjected to single prolonged stress (SPS) were administered evodiamine (EVO) and compared to a positive control group receiving sertraline. The animals were then assessed for alterations in anxiety, depression, and cognitive function. Histological analysis was conducted to examine neuronal changes in the hippocampus. In order to predict the core targets and related mechanisms of evodiamine intervention in PTSD, network pharmacology was used. The metabolic markers pre- and post-drug administration were identified using nontargeted serum metabolomics techniques, and the intersecting Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were screened. Finally, the core targets were validated through molecular docking, enzyme-linked immunosorbent assays, and immunofluorescence staining to confirm the anti-PTSD effects and mechanisms of these targets. As well as improving cognitive impairment, evodiamine reversed anxiety- and depression-like behaviors. It also inhibited the reduction in the number of hippocampal neuronal cells and Nissl bodies in SPS mice inhibited angiotensin converting enzyme (ACE) levels in the hippocampus of SPS mice, and modulated the renin angiotensin pathway and its associated serum metabolites in brain tissue. Evodiamine shows promise as a potential candidate for alleviating the symptoms of post-traumatic stress disorder.

This study aims to establish a hypobaric hypoxia-induced immune injury model and investigate the intervention and therapeutic effects of Astragaloside IV (AS-IV). This study simulated hypobaric hypoxia stimulation in mice at an altitude of 7000 m on a plateau for 1, 3, 5, and 7 days. HE staining and transcriptomic analysis were performed on mouse spleens. In addition, AS-IV was selected for intervention in prevention and treatment, and validated by flow cytometry, ELISA, and Q-PCR. The results showed that under simulated hypoxic conditions at an altitude of 7000 m for 5 days, the peripheral blood lymphocytes of mice decreased, and the CD45⁺ cells, CD3⁺ T cells, and CD3⁺CD4⁺ T cells, and CD4⁺/CD8⁺ cell ratio in the spleen all decreased. AS-IV can significantly alleviate pathological damage to the spleen, decrease serum levels of IL-2 and IL-6, increase IL-4 and IL-10, and raise CD3⁺CD4⁺ T cells and the CD4⁺/CD8⁺ cell ratio in peripheral blood and the spleen, while increasing CD4⁺IFN-γ⁺cells in spleen, reducing ROS and apoptosis levels in spleen, and increasing the content of relevant mRNA in the Th1/Th2 cell pathway. In summary, simulating hypoxia at an altitude of 7000 m for 5 days can establish a stable hypobaric hypoxic immune injury model, and AS-IV can effectively alleviate hypobaric hypoxic immune injury.

Purpose: This study aimed to develop quercetin-loaded nanoliposomes (QUL) to improve the oral bioavailability of quercetin (QU). Furthermore, we comprehensively evaluated the potential of QU for preventing high-altitude pulmonary edema (HAPE) and explored its underlying molecular mechanisms. Methods: Quercetin nanoliposome was created using thin-film hydration method, which was analyzed for morphology, zeta potential, drug loading, encapsulation efficiency, and release in vitro. A simple, sensitive and accurate LC MS/MS method was developed and validated for the simultaneous quantification of QU and QUL in rat plasma using Carbamazepine as internal standard (IS). The efficacy of QU and QUL in preventing HAPE was demonstrated in vitro and in vivo. Various techniques such as Western blotting, and immunofluorescence were employed to elucidate the associated mechanism. Results: Transmission electron microscopy proved that the nanoparticles were evenly distributed. The mean particle size (DLS) was determined to be 157.08± 1.215 nm, with a polydispersity index (PDI) of 0.204± 0.012. After oral administration of QU and QUL, Tmax values were 2.677± 1.033h and 1.167± 0.408h, respectively. Additionally, the Cmax values were 0.37± 0.049ug/mL and 0.585± 0.032ug/mL, respectively, suggesting a faster absorption rate and greater absorption content for QUL. QU and QUL improved lung permeability, reduced mortality, and decreased lung water content in a mouse model. Moreover, they significantly inhibited hypoxia-induced hyperproliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Mechanistic studies indicated that these effects were mediated through the PI3K/AKT/VEGF and ROCK/HIF/TRPC signaling pathways. Conclusion: QU reduces lung water content by modulating the PI3K/AKT/VEGF and ROCK/HIF/TRPC signaling pathways, suggesting its potential for preventing and treating HAPE. Furthermore, quercetin-loaded lipid nanoparticles improve oral bioavailability, thereby enhancing the therapeutic efficacy of quercetin in HAPE management.