Panduratin A Derivative Protects against Cisplatin-Induced Apoptosis of Renal Proximal Tubular Cells and Kidney Injury in Mice

Background: Panduratin A is a bioactive cyclohexanyl chalcone exhibiting several pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-cancer activities. Recently, the nephroprotective effect of panduratin A in cisplatin (CDDP) treatment was revealed. The present study examined the potential of certain compounds derived from panduratin A to protect against CDDP-induced nephrotoxicity. Methods: Three derivatives of panduratin A (DD-217, DD-218, and DD-219) were semi-synthesized from panduratin A. We investigated the effects and corresponding mechanisms of the derivatives of panduratin A for preventing nephrotoxicity of CDDP in both immortalized human renal proximal tubular cells (RPTEC/TERT1 cells) and mice. Results: Treating the cell with 10 µM panduratin A significantly reduced the viability of RPTEC/TERT1 cells compared to control (panduratin A: 72% ± 4.85%). Interestingly, DD-217, DD-218, and DD-219 at the same concentration did not significantly affect cell viability (92% ± 8.44%, 90% ± 7.50%, and 87 ± 5.2%, respectively). Among those derivatives, DD-218 exhibited the most protective effect against CDDP-induced renal proximal tubular cell apoptosis (control: 57% ± 1.23%; DD-218: 19% ± 10.14%; DD-219: 33% ± 14.06%). The cytoprotective effect of DD-218 was mediated via decreases in CDDP-induced mitochondria dysfunction, intracellular reactive oxygen species (ROS) generation, activation of ERK1/2, and cleaved-caspase 3 and 7. In addition, DD-218 attenuated CDDP-induced nephrotoxicity by a decrease in renal injury and improved in renal dysfunction in C57BL/6 mice. Importantly, DD-218 did not attenuate the anti-cancer efficacy of CDDP in non-small-cell lung cancer cells or colon cancer cells. Conclusions: This finding suggests that DD-218, a derivative of panduratin A, holds promise as an adjuvant therapy in patients receiving CDDP.     

重金属暴露与肾功能的关联性研究：基于代谢综合征人群的横断面研究证据

探索代谢综合征人群中重金属暴露与肾功能的相关性,为特定人群中慢性肾脏病的诊治提供新思路。基于2011—2018年美国健康与营养调查数据,纳入2 474名代谢综合征患者作为研究对象;探讨四种血液金属元素(包括镉、铅、硒、锰)对肾功能的影响。肾功能主要通过慢性肾病(CKD)、估计的肾小球滤过率(eGFR),尿微量白蛋白肌酐比(UACR)和尿酸(UA)评估。通过加权多因素Logistic回归模型及线性回归模型分析血液中金属元素水平与肾功能的关系。进一步按照年龄、性别、体质量指数(BMI)、是否患高血压、糖尿病及血脂异常进行亚组分析。研究发现血液中镉、铅水平与CKD的发生呈正相关,与eGFR呈现负相关。血硒与CKD的发生存在负向关联,而血锰与eGFR水平存在正相关(P<0.05)。而亚组分析结果显示,女性及老年代谢综合征患者对于金属暴露的效应更为敏感。代谢综合征人群中重金属暴露与肾功能存在关联,铅、镉暴露可能会导致肾功能受损,而硒、锰暴露则可能会起到一定的保护作用。     

Flavonoids in Treatment of Chronic Kidney Disease

Chronic kidney disease (CKD) is a progressive systemic disease, which changes the function and structure of the kidneys irreversibly over months or years. The final common pathological manifestation of chronic kidney disease is renal fibrosis and is characterized by glomerulosclerosis, tubular atrophy, and interstitial fibrosis. In recent years, numerous studies have reported the therapeutic benefits of natural products against modern diseases. Substantial attention has been focused on the biological role of polyphenols, in particular flavonoids, presenting broadly in plants and diets, referring to thousands of plant compounds with a common basic structure. Evidence-based pharmacological data have shown that flavonoids play an important role in preventing and managing CKD and renal fibrosis. These compounds can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress and inflammation. In this review, we summarize the function and beneficial properties of common flavonoids for the treatment of CKD and the relative risk factors of CKD.     

不同草酸/钙摩尔比条件下草酸钙晶体的生长及对HK-2细胞的毒性

研究了不同草酸/钙(Ox/Ca)摩尔比对Ca Ox晶体在损伤前后的人肾近曲小管上皮细胞(HK-2)表面的生长差异及形成的晶体对细胞的毒性差异.实验结果表明,Ca Ox过饱和溶液对正常细胞和损伤细胞均会产生进一步的损伤,导致细胞活力、溶酶体的完整性和线粒体膜电位降低,而细胞内活性氧(ROS)、细胞骨架的紊乱程度、磷酯酰丝氨酸(PS)外翻比例和骨桥蛋白(OPN)表达量均增加;且随着过饱和溶液中Ox/Ca摩尔比的增加而损伤加重.正常细胞主要诱导二水草酸钙(COD)晶体形成,且COD的含量与Ox/Ca摩尔比成正相关.损伤细胞表面主要生成一水草酸钙(COM),且晶体的数量和聚集程度与Ox/Ca摩尔比成正相关.相比于正常细胞,损伤细胞诱导的晶体棱角更加尖锐,其对细胞的损伤大于棱角圆钝的晶体.实验结果还表明,降低Ca Ox的过饱和度、减小Ox/Ca摩尔比和修复受损伤的肾上皮细胞均有利于抑制Ca Ox结石形成.     

原发肾病综合征患儿超声颈动脉参数、血清sTREM-1、suPAR水平变化及与急性肾损伤的相关性

选取原发性肾病综合征(PNS)患儿96例作为研究组,选取同期96例健康体检儿童作为对照组,开展前瞻性队列研究,均行超声颈动脉参数、血清可溶性髓系细胞表达的触发受体-1(sTREM-1)、可溶性尿激酶型纤溶酶原激活物受体(suPAR)水平检测,并进行对比分析.本研究发现,研究组患儿颈动脉内中膜厚度(cIMT)、平均管壁横...     

基于同步辐射显微CT的肾结石微观结构特征研究

肾结石是全球的泌尿系统常见病、多发病,且复发率高居不下。一般认为,尿中结石晶体的盐类呈超饱和状态,以及尿中抑制晶体形成物质不足是肾结石产生的主要因素。肾结石病因较复杂,目前提出了多种有关肾结石病因的学说,主要是从人体种族遗传、疾病、代谢和饮食习惯等方面研究结石病因,来推测其导致不同的种类的产生,再针对性制定治疗方案,但临床上肾结石内科治疗效果仍欠佳。积极探索肾结石形成和生长机制,无疑能对科学治疗肾结石有积极的意义。直观观察到结石的内部结构,并根据这些结构特征推测出结石的形成和成长轨迹,是研究肾结石形成和生长机制的重要一环。传统的研究手段难以无损获得结石的内部结构,目前未见肾结石微观结构相关报道。高分辨率显微CT特别是同步辐射X射线显微CT的出现,无疑能为这一研究提供先进的检测手段。上海同步辐射光源作为第三代优质同步辐射光源,具有高光子通量、高准直性、高极化性、高相干性及宽频谱范围等特点,其配合高分辨的X射线探测器可实现精确、灵敏的组织结构信息的快速、无损检测,在保持标本完整性的前提下,清晰再现样品内部的三维显微结构,从而克服了传统的二维切片技术存在破坏组织结构的完整性、无法准确获得组织...     

Highly sensitive simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry

Indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid are uremic toxins that accumulate in renal failure and have been reported to decrease the activities of the drug-metabolizing enzyme cytochrome P450 3A and the drug transporter organic anion transporting polypeptides 1B, respectively. In this study, we established and validated an assay for simultaneous quantification of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid in human plasma. The samples were pretreated by solid-phase extraction, and measured by ultra-high-performance liquid chromatography–tandem mass spectrometry. The validation results for this assay were within the acceptable limits recommended by the US Food and Drug Administration, with a lower limit of quantitation of 0.05 μg/mL for both indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. Recovery rates of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 100.7–101.9 and 100.2–101.3%, respectively. Matrix effects of indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid corrected by internal standard were 101.1–105.5 and 97.0–103.8%, respectively. The validated assay was used to analyze indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations in the plasma samples of healthy volunteers and patients with chronic kidney disease. All the measured plasma indoxyl sulfate and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid concentrations were within the calibration ranges. This novel method may contribute to predicting the activities of drug-metabolizing enzymes and drug transporters in individual patients.     

Growth of calcium oxalate monohydrate on uric acid crystals at sustained supersaturation

The effect of uric acid seeds on calcium oxalate formation was studied at pH 4.50 and 37 °C using a system providing constant supersaturation with respect to calcium oxalate and saturated in uric acid. In all cases the only solid‐phase forming was identified as calcium oxalate monohydrate (COM). Kinetic analysis of the initial rates showed that they were proportional with the relative supersaturation with respect to calcium oxalate monohydrate. The linear dependence of the rate of precipitation of COM on uric acid suggested that growth is mediated through a surface diffusion controlled mechanism. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

The determination of β-agonist residues in bovine tissues using liquid chromatography–tandem mass spectrometry

We aimed to develop a rapid, simple and reproducible method based on LC–tandem mass spectrometry (LC–MS/MS) to analyze β-agonist residues (clenbuterol, zilpaterol, ractopamine and isoxsuprine) in bovine tissues. The method was validated in accordance with the European Council Decision 2002/657/EC. The samples were homogenized, and then 10 mL of an acetate buffer was added to a 5-g sample. The sample was then centrifuged at 12,000 rpm and filtered. Sodium hydroxide (2 m ) was added to adjust pH of the sample that was centrifuged again. The extract was filtered through a solid-phase extraction column. The residue was re-dissolved in 250 μL acetonitrile and then subjected to LC–MS/MS. The separation was done on a C₁₈ column. The mobile phase consisted of 0.1% formic acid in deionized water and 0.1% formic acid in methanol. The mean recoveries of β-agonists were in the range of 84.3%–119.1% with relative standard deviations (%RSDs) of 0.683%–4.05%. Decision limits and detection capabilities of the analytes ranged from 0.0960 to 4.9349 μg/kg and from 0.0983 to 5.0715, respectively. This method was used to detect four β-agonists in 100 bovine muscle, 100 liver and 100 kidney tissues from a slaughterhouse. No residue was found above the maximum residue limit level.     

Protective Effects of Traditional Polyherbs on Cisplatin-Induced Acute Kidney Injury Cell Model by Inhibiting Oxidative Stress and MAPK Signaling Pathway

Acute kidney injury (AKI) is a disease caused by sudden renal dysfunction, which is an important risk factor for chronic renal failure. However, there is no effective treatment for renal impairment. Although some traditional polyherbs are commercially available for renal diseases, their effectiveness has not been reported. Therefore, we examined the nephroprotective effects of polyherbs and their relevant mechanisms in a cisplatin-induced cell injury model. Rat NRK-52E and human HK-2 subjected to cisplatin-induced AKI were treated with four polyherbs, Injinhotang (IJ), Ucha-Shinki-Hwan (US), Yukmijihwang-tang (YJ), and Urofen^TM (Uro) similar with Yondansagan-tang, for three days. All polyherbs showed strong free radical scavenging activities, and the treatments prevented cisplatin-induced cell death in both models, especially at 1.2 mg/mL. The protective effects involved antioxidant effects by reducing reactive oxygen species and increasing the activities of superoxide dismutase and catalase. The polyherbs also reduced the number of annexin V-positive apoptotic cells and the expression of cleaved caspase-3, along with inhibited expression of mitogen-activated protein kinase-related proteins. These findings provide evidence for promoting the development of herbal formulas as an alternative therapy for treating AKI.