MicroRNA‐494 Promotes Cyclosporine‐Induced Nephrotoxicity and Epithelial to Mesenchymal Transition by Inhibiting PTEN

A major complication associated with cyclosporine (CsA) treatment is nephrotoxicity. In this study, we examined whether microRNAs play a role in cyclosporine‐induced nephrotoxicity. Treatment of mice with CsA resulted in nephrotoxicity that was associated with an early increase in expression of microRNA mmu‐miR‐494 (miR‐494). Similarly, tubular epithelial cell epithelial‐mesenchymal transition (EMT) induced by CsA toxicity resulted in the upregulation of microRNA‐494 and a decrease in PTEN levels in vitro. miR‐494 directly targeted Pten and negatively regulated its expression. Preventing Pten targeting by miR‐494 was sufficient to prevent CsA induced EMT. Knockdown of miR‐494 prevented the downregulation of PTEN in tubular epithelial cells following CsA treatment and also prevented CsA induced EMT. Thus, miR‐494 plays a major role in promoting CsA induced nephrotoxicity through its ability to target Pten thereby contributing to EMT. We suggest that manipulating miR‐494 expression may represent a novel approach to preventing EMT associated with CsA induced nephrotoxicity.     

Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation

Annually, about 8000 heart and lung transplantations are successfully performed worldwide. However, morbidity and mortality still pose a major concern. Renal failure in heart and lung transplant recipients is an essential adverse cause of morbidity and mortality, often originating in the early postoperative phase. At this time of clinical instability, the kidneys are exposed to numerous nephrotoxic stimuli. Among these, tacrolimus toxicity plays an important role, and its pharmacokinetics may be significantly altered in this critical phase by fluctuating drug absorption, changed protein metabolism, anemia and (multi‐) organ failure. Limited understanding of tacrolimus pharmacokinetics in these circumstances is hampering daily practice. Tacrolimus dose adjustments are generally based on whole blood trough levels, which widely vary early after transplantation. Moreover, whole blood trough levels are difficult to predict and are poorly related to the area under the concentration‐time curve. Even within the therapeutic range, toxicity may occur. These shortcomings of tacrolimus monitoring may not hold for the unbound tacrolimus plasma concentrations, which may better reflect tacrolimus toxicity. This review focuses on posttransplant tacrolimus pharmacokinetics, discusses relevant factors influencing the unbound tacrolimus concentrations and tacrolimus (nephro‐) toxicity in heart and lung transplantation patients.     

Reducing the Human Burden of Breast Cancer: Advanced Radiation Therapy Yields Improved Treatment Outcomes

Radiation therapy is an important modality in the treatment of patients with breast cancer. While its efficacy in the treatment of breast cancer was known shortly after the discovery of x‐rays, significant advances in radiation delivery over the past 20 years have resulted in improved patient outcomes. With the development of improved systemic therapy, optimizing local control has become increasingly important and has been shown to improve survival. Better understanding of the magnitude of treatment benefit, as well as patient and biological factors that confer an increased recurrence risk, have allowed radiation oncologists to better tailor treatment decisions to individual patients. Furthermore, significant technological advances have occurred that have reduced the acute and long‐term toxicity of radiation treatment. These advances continue to reduce the human burden of breast cancer. It is important for radiation oncologists and nonradiation oncologists to understand these advances, so that patients are appropriately educated about the risks and benefits of this important treatment modality.     

Simple in vitro migration assay for neural crest cells and the opposite effects of all‐trans‐retinoic acid on cephalic‐ and trunk‐derived cells

Here, we describe a simple in vitro neural crest cell (NCC) migration assay and the effects of all‐trans‐retinoic acid (RA) on NCCs. Neural tubes excised from the rhombencephalic or trunk region of day 10.5 rat embryos were cultured for 48 h to allow emigration and migration of NCCs. Migration of NCCs was measured as the change in the radius (radius ratio) calculated from the circular spread of NCCs between 24 and 48 h of culture. RA was added to the culture medium after 24 h at embryotoxic concentrations determined by rat whole embryo culture. RA (10 μM) reduced the migration of cephalic NCCs, whereas it enhanced the migration of trunk NCCs, indicating that RA has opposite effects on these two types of NCCs.     

潜在毒性中药探讨

伴随着我国医药卫生事业的蓬勃发展和医药科技水平的快速提升,传统中医药的现代应用吸引了全球范围内的瞩目,其良好的治疗效果获得了国内外的广泛认可。然而,在实际临床应用中,中药不良反应报道却也在逐渐增多,特别是一些传统意义上被认为无毒的中药,在使用过程中出现了新的不良反应或毒性反应,致使中药的安全性问题更加备受关注。目前,在中医药临床用药安全研究方面,医务人员及医药研究工作者将大部分的注意力集中在具有已知毒性的药物上,基本能够做到准确、有效地把控,而对那些已经出现不良反应报道,但尚未引起重视的潜在毒性中药却关注甚少,导致因忽视潜在毒性药物而形成的用药安全漏洞,长此下去势必造成用药安全的重大隐患。因此,本文针对近年来发现的具有潜在毒性的中药及其毒性主要表现进行了系统总结,并从个体体质差异、药材基原、药用部位、药材产地、炮制方法、制剂工艺、药物用量、用药疗程的角度,对这类中药潜在毒性产生的原因进行全面分析,从而引起对潜在毒性药物应用安全的普遍重视,为进行药物毒性深入的科学研究提供有力依据,为指导临床安全、合理地使用中药提供可靠借鉴,有助于在充分发挥中药临床应用有效性的基础上,进一步提高中药使用的安全性保障水平。     

四妙勇安汤活性部位灌胃给药的急性毒性实验研究

目的观察四妙勇安汤活性部位(SMAF)灌胃给药的急性毒性。方法通过预实验,未获得动物的半数致死量,进行最大耐受量试验。选取昆明小鼠及Wistar大鼠各40只,雌雄各半,均分为给药组(20只)及对照组(20只),雌雄各半,给药组采用一次最大浓度和最大容积灌胃给药,小鼠灌胃剂量为6.0 g/kg,大鼠灌胃剂量为3.0 g/kg,对照组灌胃等容积0.5%羧甲基纤维素。观察给药14 d内,大、小鼠的行为、体质量、进食量、死亡率及毒性反应,计算药物的最大耐受量。结果给药后14 d内,与对照组相比,给药组雌雄小鼠、大鼠活动、行为、眼睑、分泌物、呼吸、腹形、排便等均无异常,未见因药物引起的死亡。给药组雌雄小鼠、大鼠给药后7、14 d体质量与对照组同期比较差异无统计学意义(P0.05)。给药组雌雄小鼠、大鼠药后7、14 d进食量与对照组同期比较差异无统计学意义(P0.05)。给药14 d后,处死各组小、大鼠,与对照组比较,给药组均未见脏器明显的肿大、萎缩、坏死、充血、出血、水肿等异常现象。四妙勇安汤活性部位一次性灌胃给药对小鼠最大耐受量6.0 g/kg(相当于人日推荐量的360倍);对大鼠最大耐受量3.0 g/kg(相当于人日推荐量的180倍)。结论 SMAF灌胃给药没有明显毒性。     

Chemotaxis and degranulation of polymorphonuclear leukocytes in the presence of sulfide

In polymicrobial infections such as periodontal disease, the polymorphonuclear leukocytes (PMN) may have to work in the absence of oxygen and in the presence of significant levels of hydrogen sulfide. There are conflicting results reported on the chemotactic capacity of PMN under anaerobic conditions. It is not known whether PMN are able to migrate and release the contents of their granules in the presence of sulfide. PMN were exposed to various levels of sulfide and their chemotaxis and degranulation were studied when they were stimulated with N-formyl-inethionyl-leucyl-phenylalanine or zymosan-activated serum. Chemotaxis was evaluated with the agarose method. The release of granule markers, lactoferrin and myeloperoxidase, was evaluated with enzyme-linked immunosorbent assay. PMN had similar capacity for chemotaxis under aerobic and anaerobic conditions. The migration of PMN was only to a minor extent inhibited by 1–2 mM sulfide. The release of lactoferrin and myeloperoxidase was the same under aerobic and anaerobic conditions and was not significantly influenced by sulfide. PMN seem to be very well suited to defend the tissue against bacteria under the harsh conditions prevailing in the periodontal pocket.     

Effects of surface finishing conditions on the biocompatibility of a nickel-chromium dental casting alloy

Objectives

To assess the effects of surface finishing condition (polished or alumina particle air abraded) on the biocompatibility of direct and indirect exposure to a nickel-chromium (Ni-Cr) d.Sign^®10 dental casting alloy on oral keratinocytes. Biocompatibility was performed by assessing cellular viability and morphology, metabolic activity, cellular toxicity and presence of inflammatory cytokine markers.

Methods

Discs of d.Sign^®10 were cast, alumina particle air abraded and half were polished before surface roughness was determined by profilometry. Biocompatibility was assessed by placing the discs directly or indirectly (with immersion solutions) into contact with TR146 monolayers. Metal ion release was determined by ICP-MS. Cell viability was assessed by trypan blue dye exclusion, metabolic activity by XTT and cellular toxicity by LDH. Inflammatory cytokine analysis was performed using sandwich ELISAs.

Results

The mean polished Ra value was significantly reduced (P < 0.001) compared with the alumina particle air abraded discs but metal ion release was significantly increased for the polished discs. Significant reductions in cell density of polished compared with alumina particle air abraded discs was observed following direct or indirect exposure. A significant reduction in metabolic activity, increase in cellular toxicity and an increase in the presence of inflammatory cytokine markers was highlighted for the polished relative to the alumina particle air abraded discs at 24 h.

Significance

Finishing condition of the Ni-Cr dental alloy investigated has important clinical implications. The approach of employing cell density and morphology, metabolic activity, cellular toxicity levels and inflammatory marker responses to TR146 epithelial cells combined with ICP-MS afforded the authors an increased insight into the complex processes dental alloys undergo in the oral environment.