Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disorder that imposes a substantial healthcare burden globally. Recent advances highlight the potential of natural products in ameliorating T2DM. In this study, we investigated the therapeutic efficacy of nootkatone (Nok), a natural sesquiterpene ketone, in T2DM and elucidated its underlying mechanisms. In vivo experiments demonstrated that Nok administration markedly improved dysregulated glucose metabolism and ameliorated serum biochemical abnormalities in db/db mice. Leveraging a network pharmacology-based approach, we identified putative molecular targets of Nok. Subsequent in vitro analyses revealed that Nok significantly enhanced glucose consumption in cultured cells. Mechanistically, Nok robustly activated AMP-activated protein kinase (AMPK) while suppressing mitogen-activated protein kinase (MAPK) signaling. Western blot validation further indicated that Nok downregulated the phosphorylation of MAPK1/3 (ERK2/1), attenuating MAPK pathway activation and thereby alleviating metabolic dysfunction-associated fatty liver disease (MAFLD) progression in the diabetic model. Collectively, our findings suggest that Nok exerts anti-diabetic effects via dual modulation of AMPK activation and MAPK inhibition, effectively restoring metabolic homeostasis and mitigating inflammation in T2DM. This study positions Nok as a promising natural compound for therapeutic intervention in T2DM and associated metabolic disorders.

Type 2 diabetes mellitus (T2DM) is a common chronic metabolic disorder that imposes a substantial healthcare burden globally. Recent advances highlight the potential of natural products in ameliorating T2DM. In this study, we investigated the therapeutic efficacy of nootkatone (Nok), a natural sesquiterpene ketone, in T2DM and elucidated its underlying mechanisms. In vivo experiments demonstrated that Nok administration markedly improved dysregulated glucose metabolism and ameliorated serum biochemical abnormalities in db/db mice. Leveraging a network pharmacology-based approach, we identified putative molecular targets of Nok. Subsequent in vitro analyses revealed that Nok significantly enhanced glucose consumption in cultured cells. Mechanistically, Nok robustly activated AMP-activated protein kinase (AMPK) while suppressing mitogen-activated protein kinase (MAPK) signaling. Western blot validation further indicated that Nok downregulated the phosphorylation of MAPK1/3 (ERK2/1), attenuating MAPK pathway activation and thereby alleviating metabolic dysfunction-associated fatty liver disease (MAFLD) progression in the diabetic model. Collectively, our findings suggest that Nok exerts anti-diabetic effects by dual modulation of AMPK activation and MAPK inhibition, effectively restoring metabolic homeostasis and mitigating inflammation in T2DM. This study positions Nok as a promising natural compound for therapeutic intervention in T2DM and associated metabolic disorders.

The total synthesis of laurolitsine was achieved for the first time. This reaction was accomplished in 14 steps with a 2.3% yield (this was calculated using 3-hydroxy-4-methoxybenzaldehyde as the starting material) starting from two simple materials, 3-hydroxy-4-methoxybenzaldehyde and 2-(3-hydroxy-4-methoxyphenyl)acetic acid, and the longest linear sequence consisted of 11 steps. The key steps included an electrophilic addition reaction in which a nitro group was reduced to an amino group using lithium tetrahydroaluminum and a Pd-catalyzed direct biaryl coupling reaction. In this paper, many of the experimental steps were optimized, and an innovative postprocessing method in which 2-(3-(benzyloxy)-4-methoxyphenyl)ethanamine is salted with oxalic acid was proposed.

Background: Metabolic-associated fatty liver disease (MAFLD) is characterized by excessive hepatic lipid accumulation, with limited safe and effective therapeutic options currently available. Previous studies have demonstrated that mangiferin (MAN) alleviates nonalcoholic fatty liver disease via modulation of the AMPK and NLRP3 signaling pathways. However, there are no reports to date investigating whether MAN exerts anti-MAFLD effects by regulating bile acid (BAs) metabolism and its underlying molecular mechanisms. Methods: In the present study, the anti-MAFLD effects of MAN were systematically investigated using a high-fat diet (HFD)-induced MAFLD mouse model. We evaluated the therapeutic mechanisms of MAN specifically from the perspectives of BAs metabolism regulated by the farnesoid X receptor (FXR) signaling pathway and the modulation of the gut microbiota, utilizing 16S rRNA sequencing and molecular docking analyses. Results: MAN treatment (100 mg/kg) significantly ameliorated glucose and lipid metabolic disorders, as well as hepatic lipid accumulation in the HFD-induced MAFLD mice, which was accompanied by marked alterations in the BAs metabolic profile. Mechanistically, MAN activated the FXR signaling pathway, and molecular docking analysis predicted stable interactions with key FXR residues (Y365, M369, and Y373). Furthermore, 16S rRNA sequencing revealed that MAN significantly decreased the relative abundance of Lactobacillus and Limosilactobacillus , which were positively correlated with abnormal BAs (including 6,7-DKLCA, ILCA, GHDCA, and GUDCA), dyslipidemia, and liver injury markers. In contrast, MAN increased the relative abundance of Faecalibaculum , which was negatively correlated with these BAs and associated with an improved metabolic status. Conclusion: MAN exerts anti-MAFLD effects through dual mechanisms: direct activation of the FXR signaling pathway to regulate BAs homeostasis and indirect modulation of the gut microbiota to influence BAs metabolism. These findings highlight the therapeutic potential of MAN and provide new insights into natural product-based strategies for MAFLD treatment.