Atherosclerosis is one of the main complications of diabetes mellitus, involving a variety of pathogenic factors. Endothelial dysfunction, inflammation, and oxidative stress are hallmarks of diabetes mellitus and atherosclerosis. Although the ability of diabetes to promote atherosclerosis has been demonstrated, a deeper understanding of the underlying biological mechanisms is critical to identifying new targets. NLRP3 plays an important role in both diabetes and atherosclerosis. While the diversity of its activation modes is one of the underlying causes of complex effects in the progression of diabetes and atherosclerosis, it also provides many new insights for targeted interventions in metabolic diseases.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is a common metabolic liver disease worldwide. Currently, satisfactory drugs for NAFLD treatment remain lacking. Obesity and diabetes are the leading causes of NAFLD, and compounds with anti-obesity and anti-diabetic activities are considered suitable candidates for treating NAFLD. In this study, biochemical and histological assays revealed that a natural lignan schisanhenol (SAL) effectively decreased lipid accumulation and improved hepatic steatosis in free fatty acid (FFA)-treated HepG2 cells and high-fat diet (HFD)-induced NAFLD mice. Further, molecular analyses, microRNA (miRNA)-seq, and bioinformatics analyses revealed that SAL may improve NAFLD by targeting the miR-802/adenosine monophosphate-activated protein kinase (AMPK) pathway. Liver-specific overexpression of miR-802 in NAFLD mice significantly impaired SAL-mediated liver protection and decreased the protein levels of phosphorylated (p)-AMPK and PRKAB1. Dual-luciferase assay analysis further confirmed that miR-802 inhibits hepatic AMPK expression by binding to the 3' untranslated region of mouse Prkab1 or human PRKAA1. Additionally, genetic silencing of PRKAA1 blocked SAL-induced AMPK pathway activation in FFA-treated HepG2 cells. The results demonstrate that SAL is an effective drug candidate for treating NAFLD through regulating miR-802/AMPK-mediated lipid metabolism.

Berberine is an effective antimicrobial and antidiabetic alkaloid, primarily extracted from divergent botanical lineages, specifically Coptis (Ranunculales, early-diverging eudicot) and Phellodendron (Sapindales, core eudicot). In comparison with its known pathway in Coptis species, its biosynthesis in Phellodendron species remains elusive. Using chromosome-level genome assembly, coexpression matrix, and biochemical assays, we identified six key steps in berberine biosynthesis from Phellodendron amurense , including methylation, hydroxylation, and berberine bridge formation. Notably, we discovered a specific class of O -methyltransferases (NOMT) responsible for N -methylation. Structural analysis and mutagenesis of PaNOMT9 revealed its unique substrate-binding conformation. In addition, unlike the classical FAD-dependent berberine bridge formation in Ranunculales, Phellodendron uses a NAD(P)H-dependent monooxygenase (PaCYP71BG29) for berberine bridge formation, originating from the neofunctionalization of tryptamine 5-hydroxylase. Together, these findings reveal the convergence of berberine biosynthesis between Coptis and Phellodendron and signify the role of the convergent evolution in plant specialized metabolisms.

Pestalafuranones A–E (compounds 1–5), five new 2(5H)-furanones, have been isolated from cultures of an isolate of Pestalotiopsis besseyi. The structures of these compounds were elucidated mainly by analysis of their NMR spectroscopic data and HRESIMS experiments. Pestalafuranones A–C (compounds 1–3) displayed weak inhibitory effects against HIV-1 replication in C8166 cells, whereas pestalafuranones D (4) and E (5) showed moderate antifungal activity against the plant pathogens Verticillium dahiae and Alternaria longipes.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide and has become a recognized global health problem. Therefore, the search for new anti-CRC agents or the exploration of new effective drug targets for CRC therapy is urgent. Chloroquine (CQ) is a widely-used antimalarial drug and has shown anti-proliferative effects in CRC. However, the underlying mechanisms are not well understood, particularly as the direct targets of CQ have not been identified. In this study, choline kinase alpha (CHKA) and ATP-dependent 6-phosphofructokinase, muscle type (PFKM) were identified and verified as the binding targets of CQ. CQ specifically binds to CHKA, inhibits its expression and enzymatic activity, and downregulates the downstream phosphorylation of PI3K and AKT, thereby suppressing tumor cell proliferation and inducing apoptosis. CQ also binds to PFKM and inhibits its expression and activity, thereby blocking the Warburg effect. In addition, the downregulation of CHKA can decrease the expression of PFKM and inhibit its activity, thereby blocking the Warburg effect. These observations shed new light on the antitumor mechanisms of CQ and provide new evidence for the close relationship between the PI3K/AKT signaling pathway and the Warburg effect, providing new therapeutic targets for treating CRC.

The polyamidoamine (PAMAM) dendrimer is a highly efficient absorption promoter. In the present study, we studied the absorption-enhancing effects and the mechanism of PAMAM dendrimers with generation 0 to generation 3 (G0–G3) and concentrations (0.1–1.0%) on the pulmonary absorption of macromolecules. The absorption-enhancing mechanisms were elucidated by microarray, western blotting analysis, and PCR. Fluorescein isothiocyanate-labeled dextrans (FDs) with various molecular weights were used as model drugs of poorly absorbable drugs. The absorption-enhancing effects of PAMAM dendrimers on the pulmonary absorption of FDs were in a generation- and concentration-dependent manner. The G3 PAMAM dendrimer with high effectiveness was considered to the best absorption enhancer for improving the pulmonary absorption of FDs. G3 PAMAM dendrimers at three different concentrations were non-toxic to Calu-3 cells. Based on the consideration between efficacy and cost, the 0.1% G3 PAMAM dendrimer was selected for subsequent studies. The results showed that treatment with a 0.1% G3 PAMAM dendrimer could increase the secretion of organic cation transporters (OCTs), OCT1, OCT2, and OCT3, which might be related to the absorption-enhancing mechanisms of the pulmonary absorption of FDs. These findings suggested that PAMAM dendrimers might be potentially safe absorption enhancers for improving absorption of FDs by increasing the secretion of OCT1, OCT2, and OCT3.