Peroxisome proliferator-activated receptor gamma (PPARγ) is a key target for metabolic disorders that contribute to obesity and type 2 diabetes mellitus (T2DM). However, full agonists such as thiazolidinediones (TZDs) have limitations in terms of side effects. Selective PPARγ modulators (SPPARγMs) that target alternative binding pockets offer the potential for safer partial agonists. Here, we employed six computational algorithms (Fpocket, DeepSite, CavityPlus, DoGSiteScorer, CASTpFold, POCASA) to identify a novel allosteric pocket (pocket 6–5) in the PPARγ ligand-binding domain (LBD), localized at the helix 3 (H3), helix 2 (H2), helix 2'(H2′), and β-sheet interface. A virtual screening of 4,097 natural compounds from traditional Chinese medicine (TCM) libraries was conducted, which led to the identification of ginsenoside Rg5 (TWSZ-5) as a top hit. Molecular docking and molecular dynamics (MD) dynamics revealed TWSZ-5 stabilizes pocket 6–5 through hydrogen bonds with Ser342, Gln345, Lys261, and Lys263. TWSZ-5 promoted beige adipocyte differentiation in adipose-derived stem cells (ADSCs) in vitro, upregulating Ucp1, Prdm16, Cpt1α, and Pgc1α. The present study identifies TWSZ-5 as a novel SPPARγM that utilizes an allosteric binding pocket to enhance thermogenesis while mitigating adverse effects. These findings emphasize the potential of TCM derivatives and structure-based screening strategies to develop safer antidiabetic therapies with precision pharmacology.

Precise neoepitope discovery is crucial for effective cancer therapeutic vaccines. Conventional approaches struggle to build a repertoire with sufficient immunogenic epitopes. We developed a workflow leveraging full-length ribosome–nascent chain complex–bound mRNA sequencing (FL-RNC seq) and artificial intelligence–based predictive models to accurately identify the neoepitope landscape, especially large-scale transcript variants (LSTVs) missed by short-read sequencing. In the MC38 mouse model, we identified 22 LSTV-derived neoepitopes encoded by a synthesized mRNA lipid nanoparticle vaccine. As a standalone therapy and combined with anti–PD-1 immunotherapy, the vaccine curbed tumor progression, induced robust T cell–specific immunity, and modulated the tumor microenvironment. This underscores the multifaceted potentials of LSTV-derived vaccines. Our approach expands the neoepitope source repertoire, offering a method for discovering personalized cancer vaccines applicable to a broader tumor range. The results highlight the importance of comprehensive neoepitope identification and the promise of LSTV-based vaccines for cancer immunotherapy.

Background: Sleep deprivation (SD) is a common condition affecting many people in modern life. Edaravone (Eda) is a neuroprotective drug, but whether it can improve cognitive impairment caused by SD remains unclear. Methods: Animals received oral gavage doses of Eda (10, 20, and 40 mg/kg) for 8 and 5 days before and during SD. Starting from the 6th day, a modified multiple platform model was used to produce SD in mice for 72 h. The Lashley III maze was used for evaluating spatial learning and memory. Malondialdehyde (MDA) in the hippocampus and serum corticosterone were assessed. Total antioxidant capacity (TAC) and the activity of the enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. Growth-associated protein 43 (GAP-43), synapsin 1 (SYN-1), post-synaptic density-95 (PSD-95), synaptophysin (SYP), and signs of inflammation were detected using Western blotting. Results: SD caused cognitive impairment, whereas Eda pretreatment warded off such an effect. While serum corticosterone levels rose with SD as well, they decreased in SD mice that received Eda (p < 0.05). Moreover, Eda normalized the SD-induced decline in hippocampal activity of SOD and GPx, lowered MDA levels, and elevated TAC (p < 0.01). Additionally, the hippocampal levels of GAP-34, SYP, SYN-I, and PSD-95 were elevated, while IL-1β and tumor necrosis factor α (TNF-α) were lowered following Eda pretreatment (p < 0.05). Conclusions: SD caused memory impairment; however, pretreatment with Eda improved memory by upregulating synaptic proteins in the hippocampus and having anti-inflammatory and antioxidant effects.

Introduction: Alzheimer’s disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown. Methods: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways. Results: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid β, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice. Conclusion: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Background/Objectives: Colorectal cancer (CRC) frequently co-occurs with intestinal system diseases (ISDs), yet their molecular interplay remains poorly understood. We employed a comprehensive bioinformatics approach to elucidate shared genetic signatures and pathways between CRC and ISDs. Methods: We systematically analyzed 12 microarray and RNA-seq datasets encompassing 989 samples across seven ISDs and CRC. Differentially expressed genes (DEGs) were identified using Limma and DESeq2. Functional enrichment analysis was performed using clusterProfiler. Protein–protein interaction networks were constructed via STRING and visualized with Cytoscape to identify hub genes. Clinical significance of shared genes was further assessed through survival analysis and validated by immunohistochemistry staining of 30 paired CRC–normal tissue samples. Results: Integrating bioinformatics and machine learning approaches, we uncovered 160 shared DEGs (87 upregulated, 73 downregulated), which predominantly enriched cell metabolism, immune homeostasis, gut–brain communication, and inflammation pathways. Network analysis revealed nine key hub proteins linking CRC and ISDs, with seven upregulated (CD44, MYC, IL17A, CXCL1, FCGR3A, SPP1, and IL1A) and two downregulated (CXCL12 and CCL5). Survival analysis demonstrated the prognostic potential of these shared genes, while immunohistochemistry confirmed their differential expression in CRC tissues. Conclusions: Our findings unveil potential biomarkers and therapeutic targets, providing insights into ISD-influenced CRC progression and offering a robust foundation for improved diagnostic and treatment strategies in ISD-associated CRC.