Palioura Dimitra, Feidantsis Konstantinos, Lazou Antigone
Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
Department of Fisheries and Aquaculture, University of Patras, 26504, Mesolonghi, Greece.
Mol Cell Biochem. 2025 Jun 3. doi: 10.1007/s11010-025-05320-0.
Diabetes mellitus (DM) is a metabolic disorder closely associated with cardiac dysfunction. Natural products are considered potential candidates for the management of DM. Crocin, a natural carotenoid derived from saffron, has been reported to possess several pharmacological properties, including cardioprotective effects. The aim of the present study was to investigate the beneficial effects of crocin on the metabolic derangement of the diabetic myocardium. Streptozotocin (STZ)-induced diabetic rats were treated with 10 mg/kg of crocin daily for two weeks. Oral administration of crocin normalized blood glucose, HbA1c, triglycerides, total cholesterol, LDL, and HDL levels. Notably, crocin reduced the elevated protein levels of cardiac PPARα and PPARδ-major transcriptional regulators of cardiac metabolism-back to normal. Consequently, the expression of the fatty acid (FA) transporter CD36 was downregulated, the activity of the FA oxidation enzyme 3-hydroxyacyl-CoA dehydrogenase (HOAD) was decreased, and intramyocardial triglyceride accumulation returned to physiological levels. Furthermore, crocin improved glucose uptake and metabolism in the diabetic myocardium, as evidenced by increased Akt phosphorylation, translocation of GLUT4 to the plasma membrane, enhanced activity of pyruvate kinase, and downregulation of pyruvate dehydrogenase kinase 4 (PDK4). Importantly, the stimulatory effect of crocin on Akt phosphorylation was also confirmed in isolated cardiac myocytes exposed to high glucose, further supporting its direct role in modulating glucose signaling pathways. Crocin treatment also reduced STZ-induced elevations in the levels of inflammatory cytokines-interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-as well as the phosphorylation of IκBα, bringing them close to basal levels. Overall, these findings suggest that crocin activates Akt signaling and thereby alleviates diabetes-induced metabolic disturbances by restoring the balance between glucose and fatty acid utilization in the hearts of STZ-induced diabetic rats. Therefore, crocin supplementation may represent a promising approach for the development of natural compound-based adjunct therapies for diabetic cardiomyopathy.
糖尿病（DM）是一种与心脏功能障碍密切相关的代谢紊乱疾病。天然产物被认为是治疗糖尿病的潜在候选物。藏红花素是一种从藏红花中提取的天然类胡萝卜素，据报道具有多种药理特性，包括心脏保护作用。本研究的目的是探讨藏红花素对糖尿病心肌代谢紊乱的有益作用。用链脲佐菌素（STZ）诱导糖尿病大鼠，每天给予10mg/kg藏红花素，持续两周。口服藏红花素可使血糖、糖化血红蛋白、甘油三酯、总胆固醇、低密度脂蛋白和高密度脂蛋白水平恢复正常。值得注意的是，藏红花素将心脏代谢的主要转录调节因子心脏过氧化物酶体增殖物激活受体α（PPARα）和心脏过氧化物酶体增殖物激活受体δ（PPARδ）升高的蛋白水平恢复到正常。因此，脂肪酸（FA）转运蛋白CD36的表达下调，FA氧化酶3-羟基酰基辅酶A脱氢酶（HOAD）的活性降低，心肌内甘油三酯积累恢复到生理水平。此外，藏红花素改善了糖尿病心肌中的葡萄糖摄取和代谢，这表现为Akt磷酸化增加、葡萄糖转运蛋白4（GLUT4）转位到质膜、丙酮酸激酶活性增强以及丙酮酸脱氢酶激酶4（PDK4）下调。重要的是，在暴露于高葡萄糖的离体心肌细胞中也证实了藏红花素对Akt磷酸化的刺激作用，进一步支持了其在调节葡萄糖信号通路中的直接作用。藏红花素治疗还降低了STZ诱导的炎症细胞因子白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）水平的升高以及IκBα的磷酸化，使其接近基础水平。总体而言，这些发现表明藏红花素激活Akt信号通路，从而通过恢复STZ诱导的糖尿病大鼠心脏中葡萄糖和脂肪酸利用之间的平衡来减轻糖尿病诱导的代谢紊乱。因此，补充藏红花素可能是开发基于天然化合物的糖尿病心肌病辅助治疗方法的一种有前途的途径。
