Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview

Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.

Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.

Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes.     

Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition

Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).Objectives: The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models.Methods: To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.Results: A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.Conclusions: Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993     

Running on water: Three-dimensional force generation by basilisk lizards

Water provides a unique challenge for legged locomotion because it readily yields to any applied force. Previous studies have shown that static stability during locomotion is possible only when the center of mass remains within a theoretical region of stability. Running across a highly yielding surface could move the center of mass beyond the edges of the region of stability, potentially leading to tripping or falling. Yet basilisk lizards are proficient water runners, regularly dashing across bodies of water to evade predators. We present here direct measurements of time-averaged force produced by juvenile plumed basilisk lizards (Basiliscus plumifrons) while running across water. By using digital particle image velocimetry to visualize fluid flow induced by foot movement, we show that sufficient support force is generated for a lizard to run across water and that novel strategies are also required to run across a highly yielding surface. Juvenile basilisk lizards produce greatest support and propulsive forces during the first half of the step, when the foot moves primarily vertically downwards into the water; they also produce large transverse reaction forces that change from medial (79% body weight) to lateral (37% body weight) throughout the step. These forces may act to dynamically stabilize the lizards during water running. Our results give insight into the mechanics of how basilisk lizards run across water and, on a broader scale, provide a conceptual basis for how locomotor surface properties can challenge established rules for the mechanics of legged locomotion.     

Encephalopathy and acute axonal sensorimotor polyneuropathy following acute pancreatitis: a case report and review of the literature

A case of a 22-year-old woman with rare neurologic complications including encephalopathy and acute axonal sensorimotor polyneuropathy in the course of acute pancreatitis is reported. The encephalopathy emerged 3 weeks after the onset of the illness with complete remission being noted 1 week later. The polyneuropathy presented as quadriplegia and respiratory failure that required intubation and partially remitted gradually. There was no pancreatic lesion, no major pancreatic surgery, no sepsis, and no multiple organ failure, all of which had been proposed as the predisposing factors. Severe inflammatory response syndrome (SIRS) that developed during the clinical course of this patient might have induced these neurologic complications.     

Nonmyeloablative allogeneic bone marrow transplantation for orbital granulocytic sarcoma associated with t(8;21)(q22;q22) in acute myeloid leukemia

We report a nonmyeloablative allogeneic bone marrow transplant (allo-BMT) from an HLA-matched unrelated donor in a case of acute myeloid leukemia (AML), M2 with t(8;21)(q22;q22) and the presence of orbital granulocytic sarcoma (GS), who had residual tumor after conventional chemotherapy. The course of BMT was well tolerated, with no major procedure-related toxicity. The residual orbital GS regressed completely 4 months after BMT. She is currently 19 months post BMT, disease-free. To our knowledge, this is the first reported pediatric patient with AML, GS and t(8;21)(q22;q22) who received a nonmyeloablative allo-BMT.     

Significant elevation of antiviral activity of strictinin from Pu’er tea after thermal degradation to ellagic acid and gallic acid

Compared with abundant catechins, strictinin is a minor constituent in teas and has been demonstrated to possess inhibitory potency on influenza virus. In this study, strictinin was found as the major phenolic compound in Pu’er teas produced from leaves and buds of wild trees. Due to its thermal instability, strictinin, in tea infusion or in an isolated form, was completely decomposed to ellagic acid and gallic acid after being autoclaved for 7 minutes. A plaque reduction assay was employed to compare the relative inhibitory potency between strictinin and its thermally degraded products against human influenza virus A/ Puerto Rico/8/34. The results showed that the antiviral activity of ellagic acid regardless of the presence or absence of gallic acid was significantly higher than that of strictinin. Thermal degradation of strictinin to ellagic acid and gallic acid seems to be beneficial for the preparation of Pu’er teas in terms of enhancing antiviral activity.     

Effects of extracts from Gynura bicolor (Roxb. & Willd.) DC. on iron bioavailability in rats

Gynura bicolor (Roxb. & Willd.) DC. is widely distributed in certain areas of Asia and is very popular in vegetarian cuisine in Taiwan. This study investigates the effects of G. bicolor extracts with different polarities of 80 mg/kg body weight (BW) G. bicolor alcohol extract, 80 mg/kg BW G. bicolor water extract, and 80 mg/kg BW G. bicolor ether extract on Fe bioavailability using the hemoglobin repletion efficiency assay. Wistar rats were assigned to five groups: a group receiving an iron-deficient (ID) diet; a group receiving an ID diet supplemented with ferrous sulfate (20 mg Fe/kg BW); and three groups receiving ID diets supplemented with ferrous sulfate and one of G. bicolor alcohol extract, G. bicolor water extract, or G. bicolor water extract. The results indicated that the levels of hemoglobin, serum iron, serum ferritin, liver ferritin, hemoglobin regeneration efficiency, relative biological value, and hepcidin all were significantly higher than those of the ID diet group. Besides, the iron transporter divalent metal transporter-1 was significantly reduced, but iron release protein expression of ferroportin was significantly increased. It was concluded that G. bicolor extracts may promote iron bioavailability and regulate the expressions of divalent metal transporter-1 and ferroportin.