Integrating network pharmacology, molecular docking, and experimental validation to elucidate the functional mechanism of Betulin in treating diabetic neuropathy

IF 6.7 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Current Research in Biotechnology Pub Date : 2026-01-01 Epub Date: 2026-06-06 DOI:10.1016/j.crbiot.2026.100397

Bikas Kishan, Supriti Mohanty, Atish Kumar Sahoo

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引用次数: 0

Abstract

Betulin (BET) is a naturally occurring triterpenoid, primarily found in the bark of the Betula species. Although it has demonstrated antidiabetic and neuroprotective properties, the underlying mechanism by which it alleviates diabetic neuropathy (DN) remains unclear. The present study investigates the therapeutic efficacy of BET (40 mg/kg) in a high-fat diet-fed, streptozotocin (HFD/STZ)-induced rat model of DN through an integrated strategy combining network pharmacology, molecular docking, and experimental validation. Antioxidant capacity was assessed using ORAC (AUC, BET: 15.54; better than Trolox: 12.06) and CAP-e tests (IC₅₀: 17.22 ± 0.39 µg/mL). BET exhibited mixed-competitive inhibition of α-amylase (IC₅₀ 44.64 ± 1.25 µg/mL) and competitive inhibition of α-glucosidase (9.52 ± 0.70 µg/mL). BET demonstrated potent inhibition of acetylcholinesterase (0.93 ± 0.12 µg/mL) and butyrylcholinesterase activities (5.02 ± 0.52 µg/mL). BET improved markers of hyperglycemia, hepatic, and dyslipidemia. It improved oxidative and inflammatory markers, increased cholinesterase and BDNF levels, decreased Aβ₄₂-aggregation, inhibited abnormal MAP-τ phosphorylation, lowered BACE1-expression, and raised ATP1A3 in DN rats. Histological examination showed improved pancreatic tissue integrity and neuronal cell morphology in DN rats. Network pharmacology revealed 67 potential targets between BET and DN, such as EGFR, STAT3, ESR1, MTOR, GSK3B, NFKB1, HSP90AA1, JAK2, PTGS2, ACHE, BCHE, INSR, NTRK1, and VEGF in the PPI network. KEGG analysis revealed IR, AGE-RAGE, PI3K-Akt, and insulin signalling pathways. Strong binding affinities between BET and pathogenic targets (AChE: −7.1, BChE: −10.4, TNF-α: −8.6, IL-6: −7.0, hs-CRP: −7.3, BACE1: −8.2, Atp1a3: −7.3 kcal/mol). BET combated hyperglycemia-induced oxidative stress, improved neurotransmitters, alleviated neuropeptides, and inflammation in DN rats due to the antioxidant capacity offered by the triterpenoid skeleton possessing OH-groups at C-3 and C-28 positions.

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结合网络药理学、分子对接、实验验证，阐明白桦素治疗糖尿病神经病变的作用机制

桦木素（Betulin， BET）是一种天然存在的三萜，主要存在于桦树的树皮中。虽然它已被证明具有抗糖尿病和神经保护作用，但其减轻糖尿病性神经病变（DN）的潜在机制尚不清楚。本研究通过网络药理学、分子对接、实验验证相结合的综合策略，探讨BET （40 mg/kg）对高脂饮食喂养链脲佐菌素（HFD/STZ）诱导的DN大鼠模型的治疗效果。采用ORAC法（AUC, BET: 15.54，优于Trolox: 12.06）和CAP-e法（IC50: 17.22±0.39µg/mL）测定抗氧化能力。BET对α-淀粉酶的IC50为44.64±1.25µg/mL，对α-葡萄糖苷酶的IC50为9.52±0.70µg/mL。BET对乙酰胆碱酯酶活性（0.93±0.12µg/mL）和丁基胆碱酯酶活性（5.02±0.52µg/mL）有明显的抑制作用。BET改善了高血糖、肝脏和血脂异常的标志物。改善DN大鼠氧化和炎症标志物，增加胆碱酯酶和BDNF水平，降低a - β42聚集，抑制MAP-τ异常磷酸化，降低bace1表达，升高ATP1A3。组织学检查显示DN大鼠胰腺组织完整性和神经元细胞形态改善。网络药理学揭示了BET和DN之间的67个潜在靶点，如PPI网络中的EGFR、STAT3、ESR1、MTOR、GSK3B、NFKB1、HSP90AA1、JAK2、PTGS2、ACHE、BCHE、INSR、NTRK1和VEGF。KEGG分析显示IR、AGE-RAGE、PI3K-Akt和胰岛素信号通路。BET与致病靶点的结合亲和力强（AChE:−7.1,BChE:−10.4,TNF-α:−8.6,IL-6:−7.0,hs-CRP:−7.3,BACE1:−8.2,Atp1a3:−7.3 kcal/mol）。BET对抗高血糖诱导的氧化应激，改善神经递质，减轻神经肽和DN大鼠的炎症，这是由于在C-3和C-28位置具有oh基团的三萜骨架提供的抗氧化能力。

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来源期刊

Current Research in Biotechnology Biochemistry, Genetics and Molecular Biology-Biotechnology

CiteScore

6.70

自引率

3.60%

发文量

审稿时长

38 days

期刊介绍： Current Research in Biotechnology (CRBIOT) is a new primary research, gold open access journal from Elsevier. CRBIOT publishes original papers, reviews, and short communications (including viewpoints and perspectives) resulting from research in biotechnology and biotech-associated disciplines. Current Research in Biotechnology is a peer-reviewed gold open access (OA) journal and upon acceptance all articles are permanently and freely available. It is a companion to the highly regarded review journal Current Opinion in Biotechnology (2018 CiteScore 8.450) and is part of the Current Opinion and Research (CO+RE) suite of journals. All CO+RE journals leverage the Current Opinion legacy-of editorial excellence, high-impact, and global reach-to ensure they are a widely read resource that is integral to scientists' workflow.