Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease,Investigation of the Interactions with Uremic Toxins,Inflammation and Oxidative Stress

Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m², not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.     

The Role of Oxidative Stress, Metabolic Compromise, and Inflammation in Neuronal Injury Produced by Amphetamine-Related Drugs of Abuse

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are amphetamine derivatives with high abuse liability. These amphetamine-related drugs of abuse mediate their effects through the acute activation of both dopaminergic and serotonergic neurons. Long-term abuse of these amphetamine derivatives, however, results in damage to both dopaminergic and serotonergic terminals throughout the brain. This toxicity is mediated in part by oxidative stress, metabolic compromise, and inflammation. The overall objective of this review is to highlight experimental evidence that METH and MDMA increase oxidative stress, produce mitochondrial dysfunction, and increase inflammation that converge and culminate in the long-term toxicity to dopaminergic and serotonergic neurons.     

MC-LR Exposure Leads to Subfertility of Female Mice and Induces Oxidative Stress in Granulosa Cells

Health risk of human exposure to microcystin-leucine arginine (MC-LR) has aroused more and more attention over the past few decades. In the present study, MC-LR was orally administered to female mice at 0, 1, 10 and 40 μg/L for three and six months. We found that chronic exposure to MC-LR at environmental levels could stimulate follicle atresia and lead to decreased developmental follicles, accompanied by a reduction of gonadosomatic index (GSI). In line with the irregular gonadal hormone level and estrus cycles, subfertility of female mice was also confirmed by analyzing numbers of litters and pups. The in vitro study suggested that granulosa cells could uptake MC-LR and should be the target of the toxicant. Oxidative stress in granulose cells induced by MC-LR promoted follicle atresia and eventually leads to female subfertility.     

The Role of Dietary Fiber and Gut Microbiome Modulation in Progression of Chronic Kidney Disease

Nutrition is one of the fundamental approaches to promoting and preventing all kinds of diseases, especially kidney diseases. Dietary fiber forms a significant aspect of renal nutrition in treating chronic kidney disease (CKD). Dietary fiber intake influences the composition and metabolism of the gut microbiome with proven roles in reducing uremic toxin production, preserving kidney function, and retarding the progression of CKD through mechanisms of regulating metabolic, immunological, and inflammatory processes. Understanding dietary fiber’s pathogenesis and mechanistic action in modulating host and microbiome interactions provides a potential adjunct therapeutic target for preventing, controlling, and treating CKD patients. In this regard, a recommendation of adequate and appropriate dietary fiber intake to restore beneficial gut microbiota composition would reduce the risks and complications associated with CKD. This mini review summarizes current evidence of the role of dietary fiber intake in modulating the gut microbiome to improve kidney health.     

甜橙黄酮体外抑制氧化应激减轻肾小球微血管内皮细胞焦亡的机制研究

目的 糖尿病肾脏疾病(diabetic kidney disease,DKD)的发病率逐年升高,氧化应激诱发的肾小球微血管内皮损伤与其发生发展具有重大关联,但其潜在机制尚不完全清楚,且治疗策略有限。甜橙黄酮是一种广泛用于治疗心血管疾病的多甲氧基化黄酮类化合物,有研究显示其抗氧化的作用较为显著。然而,甜橙黄酮是否抑制肾小球微血管内皮细胞的氧化应激来延缓DKD的进展尚不清楚。因此,本研究旨在从一个全新的角度探讨DKD发生发展的机制,并证实甜橙黄酮的作用和机理,为DKD的治疗提供新思路。方法 采用Px-12孵育人肾小球微血管内皮细胞(human renal glomerular microvascular endothelial cells, HRGEC)在体外建立细胞氧化损伤模型。根据光镜观察细胞形态、细胞活性检测试剂盒-8明确细胞活性、并使用(reactive oxygen species ,SROS)/O_^2?荧光探针测定各组HRGEC细胞氧化应激水平的差异。通过透射电镜观察各组细胞膜形态的变化以及western blot检测膜穿孔蛋白(gasdermin D,GSDMD)蛋白表达的变化来明确细胞焦亡的情况。最后通过增加氧化应激抑制剂和细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1/2)抑制剂,采用western blot探讨间隙连接、丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPK)信号通路在HRGEC细胞焦亡中的调控关系以及甜橙黄酮的作用机理。结果 Px-12可诱导HRGEC细胞细胞膜完整性破坏,并可使 GSDMD蛋白剪切暴露其NT端,出现细胞焦亡的发生；Px-12可明显上调ROS/O_^2-的表达,激活氧化应激水平；甜橙黄酮可明显的抑制Px-12诱导的ROS/O_^2-增加,同时能够减少Px-12诱导的GSDMD-NT的形成和ERK的磷酸化；Px-12可诱导间隙连接蛋白43(Connexin 43,Cx43)的表达明显的增加,ERK信号通路抑制剂PD98059则可以明显的抑制Cx43的表达,而甜橙黄酮与其作用相似。结论 甜橙黄酮可减轻Px-12诱导的HRGEC细胞焦亡,可能与调控ERK-MAPK/Cx43信号通路相关。     

Ochratoxin A Induces Oxidative Stress in HepG2 Cells by Impairing the Gene Expression of Antioxidant Enzymes

Ochratoxin A (OTA) is a mycotoxin frequently found in raw and processed foods. While it is considered a possible human carcinogen, the mechanism of action remains unclear. OTA has been shown to be hepatotoxic in both in vitro and in vivo models and oxidative stress may be one of the factors contributing to its toxicity. Hence, the effect of OTA on human hepatocellular carcinoma, HepG2 cells, was investigated on oxidative stress parameters. The cytotoxicity of OTA on HepG2 was time- and dose-dependent within a range between 0.1 and 10 µM; while 100 μM of OTA increased the intracellular reactive oxygen species (ROS) in a time-dependent manner. Additionally, the levels of glutathione (GSH) were increased by 9.7% and 11.3% at 10 and 100 nM of OTA, respectively; while OTA at 100 μM depleted GSH by 40.5% after 24 h exposure compared with the control. Finally, the mRNA level of catalase (CAT) was downregulated by 2.33-, 1.92-, and 1.82-fold after cells were treated with 1, 10, and 10 μM OTA for 24 h, respectively; which was linked to a decrease in CAT enzymatic activity. These results suggest that oxidative stress is involved in OTA-mediated toxicity in HepG2 cells.     

Curcumin Alleviates LPS-Induced Oxidative Stress,Inflammation and Apoptosis in Bovine Mammary Epithelial Cells via the NFE2L2 Signaling Pathway

Lipopolysaccharide (LPS) is an endotoxin, which may cause immune response and inflammation of bovine mammary glands. Mastitis impairs animal health and results in economic loss. Curcumin (CUR) is a naturally occurring diketone compound, which has attracted widespread attention as a potential anti-inflammatory antioxidant. The purpose of this study is to investigate whether CUR can reduce the damage of bovine mammary epithelial cells (MAC-T) induced by LPS and its underlying molecular mechanism. The MAC-T cell line was treated with different concentrations of LPS and CUR for 24 h. The results showed that CUR rescued the decrease of MAC-T cell viability and cell damage induced by LPS. At the same time, 10 µM CUR and 100 µg/mL LPS were used to treat the cells in the follow-up study. The results showed CUR treatment reduced the accumulation of reactive oxygen species (ROS), the expression of inflammatory cytokines (tumor necrosis factor-a (TNF-α), interleukin-8 (IL-8), IL-6 and IL-1β) and the rate of apoptosis induced by LPS. These effects were associated with the activation of the nuclear factor E2-related factor 2 (NFE2L2)-antioxidant response element (ARE) pathway coupled with inactivation of the nuclear factor-κB (NF-κB) inflammatory and caspase/Bcl2 apoptotic pathways.     

氧化应激在乙醇诱导内皮细胞凋亡中的作用

目的 观察乙醇诱导的内皮细胞凋亡及氧化应激所起的作用.方法 体外培养人内皮细胞株EA.hy926,实验分对照组、实验组（ 0.6% 乙醇）、N-乙酰半胱氨酸（NAC）组（0.6% 乙醇＋ 10 mmol&#8226;L^-1 NAC）,各组以相应药物孵育12 h,采用四甲基偶氮唑蓝法检测细胞抑制率,流式细胞仪检测细胞活性氧（ROS）和凋亡率,相应试剂盒测定超氧化物歧化酶（SOD）活力及丙二醛（MDA）水平.结果与对照组相比,实验组内皮细胞增殖受到明显抑制,SOD活力从(40.8±2.9 )U&#8226;mg^-1蛋白降至（29.2±4.0） U&#8226;mg^-1蛋白、MDA水平由（46.5±3.8） nmol&#8226;mg^-1蛋白升至（89.5±5.6） nmol&#8226;mg^-1蛋白、ROS荧光强度从（93.69±7.58）升高到（162.30±18.85）,凋亡率由（0.49± 0.16）% 增至（5.31±0.54）% (均P＜0.01);而NAC组凋亡率、ROS和MDA水平较实验组均降低（P＜0.01),SOD活力显著恢复.结论 乙醇引起的氧化应激在其诱导的内皮细胞凋亡中起重要作用.     

Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells

Aristolochic acids (AAs) are powerful nephrotoxins that cause severe tubulointerstitial fibrosis. The biopsy-proven peritubular capillary rarefaction may worsen the progression of renal lesions via tissue hypoxia. As we previously observed the overproduction of reactive oxygen species (ROS) by cultured endothelial cells exposed to AA, we here investigated in vitro AA-induced metabolic changes by ¹H-NMR spectroscopy on intracellular medium and cell extracts. We also tested the effects of nebivolol (NEB), a β-blocker agent exhibiting antioxidant properties. After 24 h of AA exposure, significantly reduced cell viability and intracellular ROS overproduction were observed in EAhy926 cells; both effects were counteracted by NEB pretreatment. After 48 h of exposure to AA, the most prominent metabolite changes were significant decreases in arginine, glutamate, glutamine and glutathione levels, along with a significant increase in the aspartate, glycerophosphocholine and UDP-N-acetylglucosamine contents. NEB pretreatment slightly inhibited the changes in glutathione and glycerophosphocholine. In the supernatants from exposed cells, a decrease in lactate and glutamate levels, together with an increase in glucose concentration, was found. The AA-induced reduction in glutamate was significantly inhibited by NEB. These findings confirm the involvement of oxidative stress in AA toxicity for endothelial cells and the potential benefit of NEB in preventing endothelial injury.     

Human Proximal Tubule Epithelial Cells (HK-2) as a Sensitive In Vitro System for Ochratoxin A Induced Oxidative Stress

Ochratoxin A (OTA) is a mycotoxin that is potentially carcinogenic to humans. Although its mechanism remains unclear, oxidative stress has been recognized as a plausible cause for the potent renal carcinogenicity observed in experimental animals. The effect of OTA on oxidative stress parameters in two cell lines of LLC-PK1 and HK-2 derived from the kidneys of pig and human, respectively, were investigated and compared. We found that the cytotoxicity of OTA on LLC-PK1 and HK-2 cells was dose- and time-dependent in both cell lines. Furthermore, increased intracellular reactive oxygen species (ROS) induced by OTA in both cell lines were observed in a time-dependent manner. Glutathione (GSH) was depleted by OTA at >48 h in HK-2 but not in LLC-PK1 cells. While the mRNA levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione peroxidase 1 (GPX1) in LLC-PK1 were down-regulated by 0.67- and 0.66-fold, respectively, those of catalase (CAT), glutathione reductase (GSR), and superoxide dismutase 1 (SOD) in HK-2 were up-regulated by 2.20-, 2.24-, and 2.75-fold, respectively, after 72 h exposure to OTA. Based on these results, we conclude that HK-2 cells are more sensitive to OTA-mediated toxicity than LLC-PK1, and OTA can cause a significant oxidative stress in HK-2 as indicated by changes in the parameter evaluated.     

乌苯美司对慢性阻塞性肺疾病小鼠免疫失衡及氧化应激的影响

目的 研究乌苯美司对慢性阻塞性肺疾病（chronic obstructive pulmonary disease,COPD）小鼠免疫失衡及氧化应激的影响。方法 50只小鼠随机分为空白组、模型组、乌苯美司组、氨茶碱+吸氧组、氨茶碱+吸氧+乌苯美司组,共5组。空白组不做处理,其余4组均诱导建立COPD小鼠模型,造模第8天开始,乌苯美司组以20 mg·kg^-1乌苯美司灌胃治疗;氨茶碱+吸氧组采用吸氧、氨茶碱溶液（10 mL·kg^-1）灌胃常规治疗;氨茶碱+吸氧+乌苯美司组在氨茶碱+吸氧组基础上加以20 mg·kg^-1灌胃乌苯美司治疗;空白组、模型组予以同等剂量的生理盐水,连续给药4周,采用Buxco系统检测小鼠肺功能吸气峰流量（peak inspiratory flow,PIF）、呼气峰流量（peak expiratory flow,PEF）、每分钟通气量（minute volume,MV）后处死小鼠,采血样及肺组织样本。HE染色考察肺组织病理学变化;流式细胞测定全血CD3⁺、CD4⁺、CD8⁺水平,并计算CD4⁺/CD8⁺;ELISA检测血清MDA、SOD、IL-8、TNF-α、CRP水平。结果 与模型组相比,乌苯美司组、氨茶碱+吸氧组、氨茶碱+吸氧+乌苯美司组病理损伤明显减轻;氨茶碱+吸氧+乌苯美司组PIF、PEF、MV及CD3⁺、CD4⁺、CD4⁺/CD8⁺水平明显升高（P<0.01）,CD8⁺水平明显降低（P<0.05）;仅氨茶碱+吸氧+乌苯美司组较模型组MDA、SOD、TNF-α、IL-8、CRP含量均明显改善（P<0.01）。结论 乌苯美司辅助常规治疗能有效改善COPD小鼠肺功能及免疫水平,减轻炎症反应和调节氧化应激,促进肺组织明显恢复。     

辛伐他汀对肥胖伴高脂血症患者炎症状态及氧化应激水平的影响

目的:观察辛伐他汀对肥胖伴高脂血症患者炎症状态及氧化应激水平的影响。方法:选择我院39例肥胖伴高脂血症的患者为试验组,服用辛伐他汀8周;并选择20例健康志愿者设为健康对照组,不作任何干预。所有研究对象在对照组服药前后检测血脂、血清C反应蛋白(CRP)、丙二醛(MDA)、过氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)。结果:治疗前与健康对照组比较,试验组患者血浆中炎症指标血浆CRP水平明显升高,氧化应激指标中MDA明显升高,SOD水平、GSH-Px活性明显降低,差异均有统计学意义(P<0.05)。服用辛伐他汀8周后,试验组患者较治疗前血清CRP、MDA明显降低,SOD水平、GSH-Px活性明显回升,差异亦有统计学意义(P<0.05)。结论:辛伐他汀可通过抗炎和抗氧化应激机制对肥胖伴高脂血症患者起到保护作用。     

Intestinal Chelators,Sorbants, and Gut-Derived Uremic Toxins

Chronic kidney disease (CKD) is a highly prevalent condition and is associated with a high comorbidity burden, polymedication, and a high mortality rate. A number of conventional and nonconventional risk factors for comorbidities and mortality in CKD have been identified. Among the nonconventional risk factors, uremic toxins are valuable therapeutic targets. The fact that some uremic toxins are gut-derived suggests that intestinal chelators might have a therapeutic effect. The phosphate binders used to prevent hyperphosphatemia in hemodialysis patients act by complexing inorganic phosphate in the gastrointestinal tract but might conceivably have a nonspecific action on gut-derived uremic toxins. Since phosphorous is a major nutrient for the survival and reproduction of bacteria, changes in its intestinal concentration may impact the gut microbiota’s activity and composition. Furthermore, AST-120 is an orally administered activated charcoal adsorbent that is widely used in Asian countries to specifically decrease uremic toxin levels. In this narrative review, we examine the latest data on the use of oral nonspecific and specific intestinal chelators to reduce levels of gut-derived uremic toxins.     

阿托伐他汀联合乌司他丁对慢性阻塞性肺病急性加重期的疗效及对氧化应激、肺功能的影响

目的:探讨阿托伐他汀联合乌司他丁对慢性阻塞性肺病急性加重期(AECOPD)的疗效及对氧化应激、肺功能的影响.方法:将某院88例AECOPD患者作为研究对象,随机分为观察组和对照组各44例.对照组采用常规治疗,观察组在对照组基础上给予阿托伐他汀联合乌司他丁进行治疗,对比两组临床疗效.结果:观察组总有效率高于对照组(P<0...     

槟榔碱对细胞增殖、凋亡和炎症反应影响的研究进展

目的与方法综合整理并介绍槟榔碱及其衍生物对细胞增殖和凋亡影响的研究历程及新进展。结果与结论槟榔碱及其衍生物通过产生亚硝胺类和活性氧族的广泛作用,对细胞多个靶点的进攻最终产生系统毒性作用,进一步抑制细胞增殖、阻断细胞周期、诱导细胞的凋亡。通过调节多种具有重要作用的细胞因子的表达,影响机体免疫功能并导致炎症反应的发生。对其结构中的某些基团进行修饰可能导致其生物学效应发生改变,为抗肿瘤新药的开发提供新的思路和途径。     

Cyclophilin D Promotes Acute,but Not Chronic,Kidney Injury in a Mouse Model of Aristolochic Acid Toxicity

The plant-derived toxin, aristolochic acid (AA), is the cause of Chinese Herb Nephropathy and Balkan Nephropathy. Ingestion of high dose AA induces acute kidney injury, while chronic low dose ingestion leads to progressive kidney disease. Ingested AA is taken up by tubular epithelial cells of the kidney, leading to DNA damage and cell death. Cyclophilin D (CypD) participates in mitochondrial-dependent cell death, but whether this mechanism operates in acute or chronic AA-induced kidney injury is unknown. We addressed this question by exposing CypD-/- and wild type (WT) mice to acute high dose, or chronic low dose, AA. Administration of 5 mg/kg AA to WT mice induced acute kidney injury 3 days later, characterised by loss of kidney function, tubular cell damage and death, and neutrophil infiltration. All of these parameters were significantly reduced in CypD-/- mice. Chronic low dose (2 mg/kg AA) administration in WT mice resulted in chronic kidney disease with impaired renal function and renal fibrosis by day 28. However, CypD-/- mice were not protected from AA-induced chronic kidney disease. In conclusion, CypD facilitates AA-induced acute kidney damage, but CypD does not contribute to the transition of acute kidney injury to chronic kidney disease during ongoing AA exposure.