Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10⁹ blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.     

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone’s (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.     

Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?

Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing’s syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease.     

超高效液相色谱-串联质谱法测定化妆品中同分异构体构型糖皮质激素

目的 建立超高效液相色谱-串联质谱法(ultra performance liquid chromatography-tandem mass spectrometry, UPLC-MS/MS)测定化妆品中同分异构体构型糖皮质激素(glucocorticoids, GCs)的分析方法。方法样品经饱和氯化钠分散、乙腈提取,亚铁氰化钾-醋酸锌沉淀大分子基质后,通过分散固相萃取技术(QuEChERS)净化。以0.1%甲酸水溶液和乙腈作为流动相迚行梯度洗脱,采用多反应监测模式(multiple reaction monitoring, MRM)对美白祛斑类化妆品中同分异构体构型糖皮质激素迚行定量和定性检测。结果 本方法完成了对糖皮质激素中最难以分离的差向同分异构体倍他米松、地塞米松以及它们的衍生物倍他米松醋酸酯、地塞米松醋酸酯的分离检测。在5.0、10和20μg/kg添加水平时的回收率为78.6%～102.7%,相对标准偏差小于10.60%(n=6),方法定量限为6.0μg/kg。结论 该方法快速、稳定、灵敏度高、选择性好,适合分析检测化妆品中非法添加的GCs类化合物。     

Glucocorticoid-Dependent Mechanisms of Brain Tolerance to Hypoxia

Adaptation of organisms to stressors is coordinated by the hypothalamic-pituitary-adrenal axis (HPA), which involves glucocorticoids (GCs) and glucocorticoid receptors (GRs). Although the effects of GCs are well characterized, their impact on brain adaptation to hypoxia/ischemia is still understudied. The brain is not only the most susceptible to hypoxic injury, but also vulnerable to GC-induced damage, which makes studying the mechanisms of brain hypoxic tolerance and resistance to stress-related elevation of GCs of great importance. Cross-talk between the molecular mechanisms activated in neuronal cells by hypoxia and GCs provides a platform for developing the most effective and safe means for prevention and treatment of hypoxia-induced brain damage, including hypoxic pre- and post-conditioning. Taking into account that hypoxia- and GC-induced reprogramming significantly affects the development of organisms during embryogenesis, studies of the effects of prenatal and neonatal hypoxia on health in later life are of particular interest. This mini review discusses the accumulated data on the dynamics of the HPA activation in injurious and non-injurious hypoxia, the role of the brain GRs in these processes, interaction of GCs and hypoxia-inducible factor HIF-1, as well as cross-talk between GC and hypoxic signaling. It also identifies underdeveloped areas and suggests directions for further prospective studies.     

Naturalistic Stress Hormone Levels Drive Cumulative Epigenomic Changes along the Cellular Lifespan

Environmental stress is ubiquitous in modern societies and can exert a profound and cumulative impact on cell function and health phenotypes. This impact is thought to be in large part mediated by the action of glucocorticoid stress hormones, primarily cortisol in humans. While the underlying molecular mechanisms are unclear, epigenetics—the chemical changes that regulate genomic function without altering the genetic code—has emerged as a key link between environmental exposures and phenotypic outcomes. The present study assessed genome-wide DNA (CpG) methylation, one of the key epigenetic mechanisms, at three timepoints during prolonged (51-day) exposure of cultured human fibroblasts to naturalistic cortisol levels, which can be reached in human tissues during in vivo stress. The findings support a spatiotemporal model of profound and widespread stress hormone-driven methylomic changes that emerge at selected CpG sites, are more likely to spread to nearby located CpGs, and quantitatively accrue at open sea, glucocorticoid receptor binding, and chromatin-accessible sites. Taken together, these findings provide novel insights into how prolonged stress may impact the epigenome, with potentially important implications for stress-related phenotypes.     

Transient Receptor Potential Ankyrin 1 (TRPA1)—An Inflammation-Induced Factor in Human HaCaT Keratinocytes

Transient receptor potential ankyrin 1 (TRPA1) is an ion channel mainly studied in sensory neurons where it mediates itch, pain and neurogenic inflammation. Recently, some nonneuronal cells have also been shown to express TRPA1 to support inflammatory responses. To address the role of TRPA1 in skin inflammation, we aimed to investigate TRPA1 expression in keratinocytes. HaCaT cells (a model of human keratinocytes) and skin biopses from wild-type and TRPA1 deficient mice were used in the studies. TRPA1 expression in nonstimulated keratinocytes was very low but significantly inducible by the proinflammatory cytokine tumor necrosis factor (TNF) in an nuclear factor kappa B (NF-κB), and mitogen-activated protein (MAP) kinase (p38 and c-Jun N-terminal kinase, JNK)-dependent manner. Interestingly, drugs widely used to treat skin inflammation, the calcineurin inhibitors tacrolimus and cyclosporine and the glucocorticoid dexamethasone, significantly decreased TRPA1 expression. Furthermore, pharmacological inhibition and genetic deletion of TRPA1 reduced the synthesis of TNF-induced monocyte chemoattractant protein 1 (MCP-1) in keratinocytes and mouse skin biopsies. In conclusion, these findings point to an inflammatory role for TRPA1 in keratinocytes and present TRPA1 as a potential drug target in inflammatory skin diseases.     

血栓性血小板减少性紫癜的临床特点及预后

目的探讨血栓性血小板减少性紫癜(thrombotic thrombocytopenic purpura,TTP)的临床特点及预后因素。方法回顾性分析北京协和医院2012至2017年60例TTP患者的临床表现、实验室检查、诊断、治疗及转归,采用Logistic单因素及多因素回归分析危险因素对预后的影响,采用K多个独立样本检验及Mann-Whitney U检验分析不同治疗方案对预后的影响。结果 60例患者中,男性17例(28.3%,17/60),女性43例(71.7%,43/60),平均年龄(41±15)岁。28例患者(46.7%,28/60)表现为发热、微血管病性溶血性贫血、血小板降低三联征,23例(38.3%,23/60)表现为发热、微血管病性溶血性贫血、血小板降低、肾功能不全、神经系统异常五联征,其余9例(15.0%,9/60)无典型三联征/五联征表现。28例患者接受血管性血友病因子裂解蛋白酶13(a disintegrin and metalloproteinase with a thrombospondin type 1motif,member 13,ADAMTS13)活性检测,其中23例ADAMTS13活性<10%,阳性率为82.1%(23/28);20例患者检测了ADAMTS13抑制物,阳性率为90.0%(18/20);20例同时行ADAMTS13活性及其抑制物检测,二者均为阳性者占90.0%(18/20)。根据是否有血源、患者经济条件等不同情况,采用血浆置换、糖皮质激素、利妥昔单抗、免疫抑制剂、注射用免疫球蛋白等不同治疗方案,42例患者(70.0%,42/60)病情缓解,18例(30.0%,18/60)死亡。在血浆置换及激素治疗的基础上加用免疫抑制治疗,可将缓解率由57.1%提高至85.2%(P=0.032)。未发现导致患者死亡率增高的危险因素。结论 TTP多表现为三联征或五联征,ADAMTS13活性降低及抑制物检测阳性率高,免疫抑制治疗可改善预后。