Previous studies have shown that berberine, an isoquinoline alkaloid isolated from several traditional Chinese herbal medicines, suppresses growth and induces apoptosis in some tumor cell lines. It has also been shown that berberine possesses anti-atherosclerosis and antioxidant activities in hyperlipidemic model rats. Our previous study in mice found that berberine causes harmful effects on preimplantation and postimplantation embryonic development, both in vitro and in vivo, by triggering reactive oxygen species (ROS)-mediated apoptotic cascades in mouse blastocysts. In the current investigation, we further showed that berberine treatment has distinct dose-dependent effects on oocyte maturation and subsequent development. Preincubation of oocytes with 2.5 μM berberine significantly enhanced maturation and in vitro fertilization (IVF) rates, with subsequent beneficial effects on embryonic development. In contrast, preincubation with 10 μM berberine negatively impacted mouse oocyte maturation, decreased IVF rates and impaired subsequent embryonic development. Similar dose-dependent effects were also demonstrated in vivo. Specifically, intravenous injection of berberine significantly enhanced mouse oocyte maturation, IVF rate and early-stage embryo development after fertilization at a dose of 1 mg/kg body weight but significantly impaired oocyte maturation and IVF rates and caused harmful effects on early embryonic development at a dose of 5 mg/kg. Mechanistically, we found that berberine enhanced intracellular ROS production and apoptosis of oocytes at a concentration of 10 μM but actually significantly decreased total intracellular ROS content and had no apoptotic effect at a concentration of 2.5 μM. Moreover, pretreatment of oocytes with Ac-DEVD-cho, a caspase-3–specific inhibitor, effectively blocked berberine-induced negative impacts on oocyte maturation, fertilization and subsequent development. Collectively, these findings establish the dose-dependent beneficial versus deleterious effects of berberine and suggest that the mechanism underlying the deleterious effects of berberine involves a caspase-3–dependent apoptotic process acting downstream of an increase in intracellular ROS levels.

中文翻译：

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小ber碱对小鼠卵母细胞成熟，受精和胎儿发育的剂量依赖性有益和有害作用。

先前的研究表明，小ber碱是一种从几种传统中草药中分离出来的异喹啉碱，可抑制某些肿瘤细胞系的生长并诱导其凋亡。还已经证明，小ber碱在高脂血症模型大鼠中具有抗动脉粥样硬化和抗氧化活性。我们先前在小鼠中的研究发现，小ber碱在体外和体内均会对植入前和植入后的胚胎发育产生有害影响通过触发小鼠胚泡中的活性氧（ROS）介导的凋亡级联反应。在当前的研究中，我们进一步表明，小ber碱治疗对卵母细胞成熟和随后的发育具有明显的剂量依赖性作用。将卵母细胞与2.5μM的小碱预孵育可显着提高成熟度和体外受精（IVF）速率，并对胚胎发育产生有益的影响。相反，与10μM小ber碱的预温育对小鼠卵母细胞成熟有负面影响，降低了IVF率并损害了随后的胚胎发育。在体内也证明了类似的剂量依赖性作用。具体而言，以1 mg / kg体重的剂量静脉注射小ber碱能显着增强小鼠卵母细胞的成熟度，IVF率和受精后早期胚胎的发育，但会显着损害卵母细胞的成熟度和IVF率，并在一定程度上对早期胚胎发育产生有害影响。剂量为5 mg / kg。从机理上讲，我们发现小ine碱在10μM的浓度下会增强卵母细胞的细胞内ROS生成和凋亡，但实际上显着降低了总细胞内ROS的含量，在2.5μM的浓度下没有凋亡作用。此外，用caspase-3特异性抑制剂Ac-DEVD-cho预处理卵母细胞可有效阻断小ber碱诱导的对卵母细胞成熟，受精和后续发育的负面影响。总的来说，