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<p>Type 2 diabetes mellitus (T2DM) is a multi-faceted metabolic disease marked by the malfunctioning of fat tissue, improper lipid metabolism, and the failure of insulin-related signaling pathways. Through the secretion of adipokines and the activity of lipid-modulating enzymes, adipose tissue establishes itself as the central endocrine regulator of metabolic homeostasis and thus becomes a potential therapeutic target. The current study took advantage of a combined approach using phytochemistry, biochemistry, and systems biology to shed light on the mechanistic contribution of <i>Hygrophila auriculata</i> and its bioactive constituent in the regulation of T2DM-associated pathways. Gas chromatography was used for profiling of the ethanolic extract, and it successfully identified seventy-three phytoconstituents, among which 13-docosenamide was found to be the most abundant. The compound was obtained at a high purity level through preparative HPLC (RT 3.801&#xa0;min, 99.997%) and was structurally confirmed as (Z)-13-docosenamide through GC–MS, FTIR, and UV–Vis analyses. The functional validation showed strong α -glucosidase inhibition (81.34% at 500&#xa0;µg/mL; IC₅₀ = 71.41&#xa0;µg/mL) and moderate α-amylase inhibition which pointed out the suppressive effect of postprandial hyperglycemia. The low toxicity (IC₅₀ = 445.3&#xa0;µg/mL) revealed by cytotoxicity evaluation in 3T3-L1 adipocytes reinforced the biological safety of the compound. Network pharmacology analysis pointed out 14 common targets that connect 13-docosenamide with lipid metabolism genes related to T2DM. Through topological analysis, it was found that PPAR-γ, AKT-1, EGFR, PIK3CA, and CYP19A1 are the main hub regulators and α-amylase, α –glucosidase which was the key enzymes involved in insulin signaling, PPAR, AMPK, and fatty acid metabolic pathways. Additionally, molecular docking confirmed that 13-docosenamide formed strong and stable interactions with these targets, similar to metformin, due to the presence of favourable hydrogen bonds and hydrophobic interactions. The overall results of the study show that the first mechanistic evidence of 13-docosenamide derived from <i>H. auriculata</i> as a multitasking phytomodulator able to target the connected PPAR, AMPK and insulin signaling networks was obtained. The integration of the herb–compound–target–pathway framework created at this point backstops the possibility of 13-docosenamide being the natural leading compound for metabolic regulation and T2DM prevention through the system-wide modulation of lipid and glucose homeostasis.</p>

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Systems-Level Analysis of 13-Docosenamide Reveals its Regulatory Role on PPAR, AMPK, and Insulin Pathways in T2DM: In vitro and In silico Approaches

  • 期刊论文

  • 发表日期：

    2026年2月27日

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  • Snega Saravanan,
  • Edward Arockiasamy

摘要

Type 2 diabetes mellitus (T2DM) is a multi-faceted metabolic disease marked by the malfunctioning of fat tissue, improper lipid metabolism, and the failure of insulin-related signaling pathways. Through the secretion of adipokines and the activity of lipid-modulating enzymes, adipose tissue establishes itself as the central endocrine regulator of metabolic homeostasis and thus becomes a potential therapeutic target. The current study took advantage of a combined approach using phytochemistry, biochemistry, and systems biology to shed light on the mechanistic contribution of Hygrophila auriculata and its bioactive constituent in the regulation of T2DM-associated pathways. Gas chromatography was used for profiling of the ethanolic extract, and it successfully identified seventy-three phytoconstituents, among which 13-docosenamide was found to be the most abundant. The compound was obtained at a high purity level through preparative HPLC (RT 3.801 min, 99.997%) and was structurally confirmed as (Z)-13-docosenamide through GC–MS, FTIR, and UV–Vis analyses. The functional validation showed strong α -glucosidase inhibition (81.34% at 500 µg/mL; IC₅₀ = 71.41 µg/mL) and moderate α-amylase inhibition which pointed out the suppressive effect of postprandial hyperglycemia. The low toxicity (IC₅₀ = 445.3 µg/mL) revealed by cytotoxicity evaluation in 3T3-L1 adipocytes reinforced the biological safety of the compound. Network pharmacology analysis pointed out 14 common targets that connect 13-docosenamide with lipid metabolism genes related to T2DM. Through topological analysis, it was found that PPAR-γ, AKT-1, EGFR, PIK3CA, and CYP19A1 are the main hub regulators and α-amylase, α –glucosidase which was the key enzymes involved in insulin signaling, PPAR, AMPK, and fatty acid metabolic pathways. Additionally, molecular docking confirmed that 13-docosenamide formed strong and stable interactions with these targets, similar to metformin, due to the presence of favourable hydrogen bonds and hydrophobic interactions. The overall results of the study show that the first mechanistic evidence of 13-docosenamide derived from H. auriculata as a multitasking phytomodulator able to target the connected PPAR, AMPK and insulin signaling networks was obtained. The integration of the herb–compound–target–pathway framework created at this point backstops the possibility of 13-docosenamide being the natural leading compound for metabolic regulation and T2DM prevention through the system-wide modulation of lipid and glucose homeostasis.