Toxic effects of Fusarium mycotoxin butenolide on rat myocardium and primary culture of cardiac myocytes.

Mycotoxin toxicosis has been implicated in the etiopathogenesis of Keshan disease (KD), an endemic cardiomyopathy prevailing in some regions of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone, CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species such as Fusarium tricinctum and Fusarium graminearum, is frequently detected from the cereals in the endemic areas of KD. The present study is undertaken to investigate whether this mycotoxin can induce myocardial damage. Exposure of primary culture of cardiac myocytes to butenolide resulted in significant cytotoxicity, manifested by changes in cell morphology and decreases in cell viability. Consistent with the in vitro findings, distinct myocardial toxicity in vivo was observed after administration of rats by gavage with butenolide (10 and 20 mg/kg/day) for 2 months, and the myocardial injuries were characterized by focal necrosis of myocardium and fragmentation of myofiber. Butenolide also induced significant oxidative damage to the myocardium in vitro evidenced by a concentration-dependent lipid peroxidation in the myocardial homogenates, whereas antioxidants superoxide dismutase (SOD), N-acetylcysteine (NAC) and glutathione (GSH) provided significant protections against this oxidative effect. Taken together, these results clearly reveal that butenolide possesses the potential to induce myocardial toxicity. The present findings may reinforce the hypothesis that toxicosis by mycotoxins is one of the etiological factors for KD.     

脾气虚、肝郁脾虚及胃实热证患者阿魏酸药代动力学特征比较

目的:应用药代动力学(pharmacokinetics,PK)方法研究中医证本质,探讨脾气虚、肝郁脾虚及胃实热证患者体内阿魏酸(ferulicacid,FA)的PK特征。方法:选择21例健康自愿者、20例肝郁脾虚证患者、22例脾气虚证患者和19例胃实热证患者,予以口服自拟加味逍遥散后,采用高效液相色谱法观察血清FA的PK参数。结果:与健康自愿者比较,脾虚证患者的吸收速度常数和消除速度常数均下降,表观一级吸收速率常数升高;肝郁脾虚证患者的吸收速度常数、消除速度常数和表观一级吸收速率常数均下降;胃实热证患者的消除速度常数和表观一级吸收速率常数均升高;差异有统计学意义。结论:脾气虚证患者PK特征表现为吸收速度加快,分布和排泄减慢;肝郁脾虚证患者PK特征表现为吸收、分布和排泄均减慢;胃实热证患者PK特征表现为吸收和排泄加快。提示三种中医证型患者的PK特征存在差异。     

Correction to: Effect of JAK inhibitors on high- and low-density lipoprotein in patients with rheumatoid arthritis: a systematic review and network meta-analysis

Clinical Rheumatology -     

高度近视薄角膜患者LASIK术后3a疗效观察

目的:通过研究角膜相对较薄的高度近视患者LASIK术后的远期效果,进一步探讨LASIK术中保留角膜基质床厚度与术后疗效的关系,以及可能影响术后屈光回退的因素.方法:选2001-01/2002-10在我院行LASIK手术的高度近视相对薄角膜患者21例39眼,查术后3a的视力、眼压、屈光状态、角膜曲率及中央角膜厚度,并与术前及术后早期数据进行统计学比较分析.结果:术后3a无1例出现继发圆锥角膜改变,术后视力0.8以上25眼,占64%,术后视力与术前最佳矫正视力间呈低度正相关.术后3a与早期视力无显著性差异,但屈光与角膜曲率有明显增加.术后3a屈光回退量≥1.00D30眼,占77%,屈光回退量与术前屈光度呈负相关,与患者年龄、术后角膜曲率的改变和实际角膜厚度与预留角膜厚度的差值呈正相关.结论:高度近视薄角膜患者LASIK术后的远期稳定性较低,可预测性较差,术后屈光回退可能与术前屈光、年龄、角膜厚度和曲率的改变有关.本组患者今后是否会继发圆锥角膜的改变仍需进一步观察研究.     

线粒体在丁烯酸内酯致细胞氧化损伤中的作用

目的研究线粒体呼吸链是否是丁烯酸内酯(But)致细胞内活性氧过量产生的来源,及其在But致细胞毒性中的作用。方法线粒体呼吸链复合物特异性抑制剂及线粒体氧化磷酸化解偶联剂预处理HepG2细胞后,染毒But。采用MTT法测定细胞存活率,二氯荧光素荧光法测定细胞内活性氧的产生。结果呼吸链复合物Ⅰ,Ⅱ,Ⅲ和Ⅳ抑制剂鱼藤酮、噻吩甲酰三氟丙酮(TTFA)、抗霉素A、氰化钾及氧化磷酸化解偶联剂羰氰氯苯腙(CCCP)能够明显改变But所致细胞内活性氧的产生。鱼藤酮和抗霉素A能够增强But引起的细胞毒性,而CCCP则能明显减轻But引起的细胞毒性。结论线粒体呼吸链是But致细胞内活性氧过量产生的重要来源,且活性氧的过量产生在But的细胞毒性中发挥着重要的作用。     

Circulating ghrelin in patients with chronic obstructive pulmonary disease

OBJECTIVE: Unexplained weight loss is common in patients with chronic obstructive pulmonary disease (COPD). Because ghrelin plays an important role in energy homeostasis, this study investigated the plasma level of ghrelin in COPD. METHODS: Plasma ghrelin levels and levels of leptin, tumor necrosis factor-alpha, and C-reactive protein were measured in 29 patients with COPD and 17 healthy controls. Body composition was assessed with bioelectrical impedance analysis. RESULTS: Body mass index and percentage of body fat were lower in patients who had COPD than in healthy controls. Plasma ghrelin and leptin concentrations were significantly lower in patients who had COPD than in healthy controls (ghrelin: 0.25+/-0.22 ng/mL versus 0.43+/-0.24 ng/mL, P=0.013; leptin: 1.77+/-0.70 ng/mL versus 2.85+/-0.96 ng/mL, P=0.000). In contrast, tumor necrosis factor-alpha and C-reactive protein were significantly higher in those with COPD than in controls. Plasma ghrelin (log transformed) was positively correlated with body mass index and percentage of body fat in patients with COPD but negatively correlated in control subjects. Plasma ghrelin was negatively correlated with tumor necrosis factor-alpha and C-reactive protein in COPD. CONCLUSION: Plasma ghrelin level was decreased in COPD and this is different from other weight-loss diseases. These data suggest that decreased ghrelin and other factors may contribute to alterations in metabolic status during inflammatory stress in this disease.     

Fluid flow-induced increase in inward Ba2+ current expressed in HEK293 cells transiently transfected with human neuronal L-type Ca2+ channels

Mechanical forces can alter the gating of several kinds of ion channels in many types of cells, but the mechanisms underlying the mechanosensitivity are not clearly understood. To date, there are very few reports on mechanosensitivity of Ca2+ channels, particularly neuronal Ca2+ channels. We examined the mechanical sensitivity of human recombinant L-type Ca2+ channels in response to fluid flow. Neuronal L-type Ca2+ channels (Ca(v) 1.2) were expressed transiently in HEK293 cells using expression cDNA clones of human alpha1C, alpha2delta, and beta subunits along with green fluorescent protein (GFP) as a reporter protein. Current (I(Ba)) through these heterologously-expressed channels was measured using whole cell recording technique with 20 mM Ba2+ as charge carrier. Transfected cells were exposed to a constant, increased fluid flow from a separate pipette during current recording. The L-type I(Ba) was found to be very sensitive to the flow-induced shear forces. Peak current amplitude increased by as much as approximately 50% during fluid flow as compared to that in the absence of fluid pressure. However, no change was observed in the amplitude of the average current during the final 5 ms of the 150-ms voltage step. Current amplitude promptly returned to normal control levels upon stopping fluid flow. The current-voltage relationship was not altered by fluid flow. The flow-induced increase in current amplitude exhibited an apparent shift in steady-state inactivation toward more negative potentials; inactivation was faster but was not voltage dependent. Activation was slightly faster under flow. Thus, increased mechanical tension associated with fluid flow can alter the fundamental properties of voltage-gated Ca2+ channels, even for channels which might not normally be exposed to fluid flow shear forces in their native environment.     

Comparative effects of methylmercury and Hg(2+) on human neuronal N- and R-type high-voltage activated calcium channels transiently expressed in human embryonic kidney 293 cells

Expression cDNA clones of alpha1B-1 or alpha1E-3 subunits coding for human neuronal N-(Cav2.2) or R-subtype (Cav2.3) Ca2+ channels, respectively, was combined with alpha2-bdelta and beta3-a Ca2+ channel subunits, and transfected into human embryonic kidney cells for transient expression to determine whether specific types of neuronal voltage-sensitive Ca2+ channels are affected differentially by methylmercury (MeHg) and Hg2+. For both Ca2+ channel subtypes, MeHg (0.125-5.0 microM) or Hg2+ (0.1-5 microM) caused a time- and concentration-dependent reduction of current. MeHg caused an initial, rapid component and a subsequent more gradual component of inhibition. The rapid component of block was completed between 100 and 150 s after beginning treatment. At 0.125 to 1.25 microM, MeHg caused a more gradual decline in current. Apparent IC50 values were 1.3 and 1.1 microM for MeHg, and 2.2 and 0.7 microM for Hg2+ on N- and R-types, respectively. For N-type current, effects of Hg2+ were initially greater on the peak current than on the sustained current remaining at the end of a test pulse; subsequently, Hg2+ blocked both components of current. For R-type current, Hg2+ affected peak and sustained current approximately equally. Kinetics of inactivation also seemed to be affected by Hg2+ in cells expressing N-type but not R-type current. Washing with MeHg-free solution could not reverse effects of MeHg on either type of current. The effect of Hg2+ on N- but not R-type current was partially reversed by Hg2+-free wash solution. Therefore, different types of Ca2+ channels have differential susceptibility to neurotoxic mercurials even when expressed in the same cell type.     

Repeated administration of a Fusarium mycotoxin butenolide to rats induces hepatic lipid peroxidation and antioxidant defense impairment

Butenolide, a mycotoxin elaborated by several toxigenic Fusarium species, frequently contaminates important agricultural products, and has been considered a potential health risk to humans and animals. However, many toxicology issues including toxicity targets and mechanisms of butenolide remain unclear. Previous study indicated that acute butenolide exposure produced hepatic oxidative toxicity, but its chronic toxicity is still unknown. The present study therefore attempted to reveal the adverse effects of repeated butenolide exposure from a viewpoint of oxidative damage focusing on the liver. Intragastic administration of rats with butenolide for seven consecutive weeks resulted in hepatic injury as shown by obvious changes of serum biochemistry parameters indicating liver function. Repeated butenolide exposure also induced oxidative stress as manifested by impairment of antioxidant defenses including depletion of sulfhydryl groups and reduction of glutathione peroxidase activity, and enhancement of lipid peroxidation both in serum and liver. In conclusion, the present study indicated that repeated butenolide exposure induced a significant liver injury, and oxidative damage may serve as a mediator in the toxicity of butenolide. The current findings contribute to the understanding of the toxic profile of butenolide.