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Title: [Berberine protects myocardial injury and cardiac dysfunction in a septic rat model].
Author: Jin JL, Zhang H, Liu Q, Jiang HH, Liu XX, Tang XZ.
Journal: Zhonghua Yi Xue Za Zhi; 2020 Sep 22; 100(35):2779-2784. PubMed ID: 32972060.
Abstract:
Objectives: To investigated whether berberine could ameliorate septic cardiomyopathy in a rat model of sepsis and it's mechanisms. Methods: SD rats were divided into 3 groups: sepsis group (LPS group), rats were intraperitoneal injected of LPS (10 mg/kg); Berberine intervention group (Ber group), Ber (50 mg/kg, one time per day) was gavage fed 3 days before intraperitoneally injection of lipopolysaccharides (LPS); control group (Con group), rats were gavage fed with double distilled water (2 ml/100 g, one time per day) 3 days before intraperitoneal injection of normal saline (1 ml/100 g). LPS group and the Ber group was further divided into 3 subgroups (n=6), and the follow-up experiments were conducted at 6 h, 24 h and 48 h after LPS injection (of which 48 h subgroup rats were gavage fed with Ber/saline at 24 h). Left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and the maximum rate of change of left ventricular pressure (±dp/dtmax) were monitored, the level of cardiac troponin T (cTnT), tumor necrosis factor (TNF)-α and interleukin (IL)-1β was detected by ELISA method, HE staining of myocardial tissues was done to observe myocardial injury; Western blotting method was used to detect the expression of toll-like receptor 4(TLR4) protein in rat myocardial tissue, the level of myocardial cell nucleus protein p65 was detected to reflects the degree of NF-κB activation. The correlation of factors was analyzed with Pearson correlation analysis. Results: Pre-treatment with berberine stabilized cardiac hemodynamics and improved the systolic function and diastolic function in the heart of LPS-induced rats, as evidenced by the partial recovery of the reduced±dp/dtmax and LVSP, as well as the decreased LVEDP. Compared with the LPS group, the Ber group showed improved myocardial injury, as demonstrated by decreased cTnT at each time point. HE staining results showed that berberine decreased inflammatory cell infiltration and LPS-induced cell swelling. These effects were observed early at 6 hours, severe at 24 hours, and become more serious at 48 hours after LPS injection. Further, TLR4 and NF-κB p65 subunits, which were the two key factors of the TLR4/NF-κB signaling, were upregulated in the LPS group and attenuated in the Ber group. Consistently, the expression levels of the downstream cytokines TNF-α and IL-1β were lower in the Ber group than those in the LPS group (all P<0.05). Myocardial injury markers were positively correlated with the markers of TLR4/NF-κB signals and the downstream host inflammatory factors (all P<0.05). Conclusions: Berberine can improve myocardial injury and cardiac function in sepsis rats, the mechanism is considered to be related to that it can inhibit the activation of TLR4/NF-κB signaling pathway induced by LPS and further reducing the production of TNF-α and IL-1β. 目的： 研究黄连素对脓毒症大鼠心肌损伤和心功能障碍的影响及其作用机制。 方法： 将实验SD大鼠采用随机数字表法分为3组：脓毒症组（LPS组）、黄连素干预组（Ber组）、对照组。LPS组给予腹腔注射LPS（10 mg/kg）；Ber组实验前3 d开始灌胃Ber（50 mg/kg，每日1次），第3天灌胃1 h后腹腔注射LPS；对照组（Con组），分别给予双蒸水（2 ml/100 g）灌胃和生理盐水（1 ml/100 g）腹腔注射。LPS组和Ber组每组又分为3个亚组（n=6），分别于LPS注射后6、24和48 h进行后续实验（其中48 h亚组大鼠在24 h时给予灌胃Ber/生理盐水1次）。监测大鼠左心室收缩压（LVSP）、左心室舒张末期压（LVEDP）、左心室压力最大变化速率（±dp/dtmax）；ELISA法检测大鼠血浆中心肌损伤标志物心肌肌钙蛋白T（cTnT）水平以及心肌组织肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β水平；取心肌组织行HE染色，观察心肌损伤情况；Western印迹法检测大鼠心肌组织Toll样受体4（TLR4）蛋白表达情况；检测大鼠心肌细胞核内p65蛋白水平反映核因子（NF）-κB活化程度。用Pearson相关系数法分析各因素间的相关性。 结果： LPS 6、24和48 h组大鼠的LVSP、+dp/dtmax和-dp/dtmax均明显低于对照组（均P<0.05），LVEDP均高于对照组（均P<0.05），Ber 48 h组大鼠LVSP高于LPS 48 h组（均P<0.05），Ber 6、24和48 h组大鼠的±dp/dtmax均高于相应LPS组（均P<0.05），Ber 6、24和48 h组大鼠的LVEDP均低于相应LPS组（均P<0.05）。LPS 6、24和48 h组大鼠cTnT浓度明显高于对照组（均P<0.05），Ber 6、24和48 h组大鼠cTnT浓度均低于相应LPS组（均P<0.05）。与对照组相比，LPS 6 h组大鼠心肌细胞肿胀肥大，心肌细胞纤维部分断裂，可见淋巴细胞和中性粒细胞浸润，LPS 24 h组最为严重。Ber 6、24和48 h组大鼠心肌细胞的损伤表现及炎症细胞浸润情况较相应LPS组轻。LPS 6 h、LPS 24 h和LPS 48 h组大鼠心肌组织上TLR4蛋白表达、心肌细胞核内p65蛋白浓度、心肌组织TNF-α、IL-1β含量均较对照组升高（均P<0.05），Ber 6 h、Ber 24 h、Ber 48 h组大鼠上述指标较相应LPS组低（均P<0.05）。 结论： Ber可改善脓毒症大鼠心肌损伤和心功能，机制考虑与其抑制LPS诱导的TLR4/NF-κB信号通路激活，降低TNF-α、IL-1β等炎症因子表达有关。.

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