低分子量肝素通过保护紧密连接蛋白改善老年雄性大鼠的肠屏障功能障碍

IF 4.4 4区医学 Q1 GERIATRICS & GERONTOLOGY

Biogerontology Pub Date : 2024-11-01 Epub Date: 2024-07-06 DOI:10.1007/s10522-024-10118-6

Shaojun Wang, Hong Yang

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引用次数: 0

摘要

人到老年，肠道屏障功能减弱，出现慢性肠道炎症，引发老年性疾病。最新研究表明，低分子量肝素（LMWH）除具有抗凝作用外，还具有抗炎和抗细胞凋亡作用，可保护肠道屏障。本研究旨在分析 LMWH 对老年雄性啮齿动物肠道屏障的影响。本研究将 Sprague-Dawley 雄性大鼠分为四组：幼年组（3 个月）、幼年 + LMWH 组、老年组（20 个月）和老年 + LMWH 组。LMWH 组大鼠皮下注射 1 毫克/千克 LMWH，连续注射 7 天。使用光学显微镜和透射电子显微镜（TEM）检查肠粘膜因衰老而发生的形态学变化。使用异硫氰酸荧光素（FITC）-葡聚糖测量肠道通透性。ELISA 试剂盒用于检测血清中 IL-6 和 IL-1β 的水平，定量 RT-PCR 检测肠组织中这两种物质的 mRNA 水平。免疫印迹和免疫组织化学（IHC）评估了紧密连接（TJ）蛋白水平，如闭塞素、闭塞带-1（ZO-1）和Claudin-2。Western 印迹法评估了凋亡标记物裂解的 caspase 3 的表达，而 IHC 则用于检测 LGR5+ 肠干细胞。老龄大鼠的肠道通透性明显高于年轻大鼠，表明两者存在显著差异。随着年龄的增长，occludin 和 ZO-1 蛋白水平明显下降，而 claudin-2 水平明显上升。同时，我们的研究发现，随着年龄的增长，IL-1β和IL-6的水平明显升高。LMWH干预可有效缓解与年龄相关的肠屏障功能障碍。在接受 LMWH 治疗的老年大鼠中，肠道中的 occludin 和 ZO-1 蛋白表达量增加，而 claudin-2 的表达量减少。此外，老年大鼠服用 LMWH 后，IL-1β 和 IL-6 水平下降。LMWH还降低了与年龄相关的裂解caspase3表达，但IHC显示不同组间的LGR5+肠干细胞没有差异。研究表明，通过保护TJ蛋白、减少炎症和细胞凋亡，LMWH有可能成为与肠屏障功能障碍相关的老年疾病的有利治疗选择。

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Low-molecular-weight heparin ameliorates intestinal barrier dysfunction in aged male rats via protection of tight junction proteins.

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Low-molecular-weight heparin ameliorates intestinal barrier dysfunction in aged male rats via protection of tight junction proteins.

The intestinal barrier weakens and chronic gut inflammation occurs in old age, causing age-related illnesses. Recent research shows that low-molecular-weight heparin (LMWH), besides anticoagulation, also has anti-inflammatory and anti-apoptotic effects, protecting the intestinal barrier. This study aims to analyze the effect of LMWH on the intestinal barrier of old male rodents. This study assigned Sprague-Dawley male rats to four groups: young (3 months), young + LMWH, old (20 months), and old + LMWH. The LMWH groups received 1 mg/kg LMWH via subcutaneous injection for 7 days. Optical and transmission electron microscopy (TEM) were used to examine morphological changes in intestinal mucosa due to aging. Intestinal permeability was measured using fluorescein isothiocyanate (FITC)-dextran. ELISA kits were used to measure serum levels of IL-6 and IL-1β, while Quantitative RT-PCR detected their mRNA levels in intestinal tissues. Western blotting and immunohistochemistry (IHC) evaluated the tight junction (TJ) protein levels such as occludin, zonula occludens-1 (ZO-1), and claudin-2. Western blotting assessed the expression of the apoptosis marker cleaved caspase 3, while IHC was used to detect LGR5+ intestinal stem cells. The intestinal permeability of aged rats was significantly higher than that of young rats, indicating significant differences. With age, the protein levels of occludin and ZO-1 decreased significantly, while the level of claudin-2 increased significantly. Meanwhile, our study found that the levels of IL-1β and IL-6 increased significantly with age. LMWH intervention effectively alleviated age-related intestinal barrier dysfunction. In aged rats treated with LMWH, the expression of occludin and ZO-1 proteins in the intestine increased, while the expression of claudin-2 decreased. Furthermore, LMWH administration in aged rats resulted in a decrease in IL-1β and IL-6 levels. LMWH also reduced age-related cleaved caspase3 expression, but IHC showed no difference in LGR5+ intestinal stem cells between groups. Research suggests that LMWH could potentially be a favorable therapeutic choice for age-related diseases associated with intestinal barrier dysfunction, by protecting TJ proteins, reducing inflammation, and apoptosis.

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来源期刊

Biogerontology 医学-老年医学

CiteScore

8.00

自引率

4.40%

发文量

审稿时长

>12 weeks

期刊介绍： The journal Biogerontology offers a platform for research which aims primarily at achieving healthy old age accompanied by improved longevity. The focus is on efforts to understand, prevent, cure or minimize age-related impairments. Biogerontology provides a peer-reviewed forum for publishing original research data, new ideas and discussions on modulating the aging process by physical, chemical and biological means, including transgenic and knockout organisms; cell culture systems to develop new approaches and health care products for maintaining or recovering the lost biochemical functions; immunology, autoimmunity and infection in aging; vertebrates, invertebrates, micro-organisms and plants for experimental studies on genetic determinants of aging and longevity; biodemography and theoretical models linking aging and survival kinetics.