DataSheet1_Zn(II)–curcumin prevents cadmium-aggravated diabetic nephropathy by regulating gut microbiota and zinc homeostasis.doc

Background: Diabetic nephropathy (DN) is known as the most common complication of diabetes, resulting from a complex inheritance-environment interaction without effective clinical treatments. Herein, we revealed the protective effects and mechanisms of Zn(II)-curcumin, a curcumin derivative, against streptozotocin-induced DN in rats in the presence or absence of cadmium exposure.
Methods: The present study focused on investigating the therapy of Zn(II)-curcumin against cadmium-aggravated DN by regulating gut microbiota, metabolism, inflammation and zinc homeostasis based on pathological changes, TLR4/NF-κB signaling pathway, inductively coupled plasma-mass spectrometry (ICP-MS), 16S rRNA gene sequencing and gas chromatography-mass spectrometer (GC-MS).
Results: We found Zn(II)-curcumin significantly mitigated the cadmium-aggravated phenotypes of diabetic nephropathy, as indicated by the remission of renal dysfunction, pathological changes, inflammation and zinc dyshomeostasis in streptozotocin-treated rats exposed to cadmium. Administration of Zn(II)-curcumin significantly alleviated the dysbiosis of gut microbiota and the changes of serum metabolite profiles in rats treated with streptozotocin in combination with cadmium. Notably, fecal microbial transplantation identified the ability of Zn(II)-curcumin to regulate renal function, inflammation and zinc homeostasis was partly dependent on the gut microbiota.
Conclusion: These findings revealed that Zn(II)-curcumin alleviated cadmium-aggravated diabetic nephropathy by reshaping the gut microbiota and zinc homeostasis, which provided unique insights into the mechanisms of the treatment and prevention of diabetic nephropathy.

背景：糖尿病肾病（Diabetic nephropathy, DN）是公认的糖尿病最常见并发症，由复杂的遗传-环境交互作用引发，目前尚无有效的临床治疗手段。本研究揭示了姜黄素衍生物Zn(II)-姜黄素（Zn(II)-curcumin）在暴露或未暴露于镉的情况下，对链脲佐菌素诱导的大鼠糖尿病肾病的保护作用及其机制。
方法：本研究聚焦于探究Zn(II)-姜黄素通过调控肠道菌群、代谢、炎症反应及锌稳态，以治疗镉加重型糖尿病肾病的效果，研究基于病理组织学改变、Toll样受体4/核因子κB（TLR4/NF-κB）信号通路、电感耦合等离子体质谱法（inductively coupled plasma-mass spectrometry, ICP-MS）、16S rRNA基因测序（16S rRNA gene sequencing）技术以及气相色谱-质谱联用仪（gas chromatography-mass spectrometer, GC-MS）展开。
结果：研究发现，在暴露于镉的链脲佐菌素处理大鼠中，Zn(II)-姜黄素可显著缓解镉加重的糖尿病肾病表型，具体体现为肾功能障碍、病理组织学改变、炎症反应及锌稳态失衡得到改善。对于联合给予链脲佐菌素与镉的大鼠，Zn(II)-姜黄素给药可显著减轻肠道菌群失调及血清代谢物谱的异常改变。值得注意的是，粪便微生物移植实验证实，Zn(II)-姜黄素对肾功能、炎症反应及锌稳态的调控作用，部分依赖于肠道菌群。
结论：本研究结果表明，Zn(II)-姜黄素可通过重塑肠道菌群及锌稳态，缓解镉加重型糖尿病肾病，这为糖尿病肾病的治疗与预防机制研究提供了独特的见解。