Dillonholden7400

Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs.

Steady state blood samples were collected from 97 APL patients. H

O

and HClO

were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAs

), arsenate (iAs

), monomethylarsonic acid (MMA

) and dimethylarsinic acid (DMA

) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species.

The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DM. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients.Trimethyltin chloride (TMT) is a by-product in the synthesis of organotin, a plastic stabilizer. With the rapid development of industry, the occupational hazards caused by TMT cannot be ignored. TMT is a typical neurotoxicant, which mainly damages the limbic system and brainstem of the nervous system. Previous studies have demonstrated that the neurotoxicity induced by TMT is linked to the inhibition of energy metabolism, but the underlying mechanism remains elusive. In order to investigate the mechanism of TMT-induced inhibition of energy metabolism, C57BL/6 male mice were administered by IP injection in different TMT doses (0 mg/kg, 1.00 mg/kg, 2.15 mg/kg and 4.64 mg/kg) and times (1d, 3d and 6d), and then the changes of superoxide dismutase (SOD) activity, malondialdehyde (MDA) level and Na+-K+-ATPase activity in cerebral cortex, cerebellum, hippocampus, pons, medulla oblongata of mice, the expressions of Na+-K+-ATPase protein, AMP-activated protein kinase (AMPK), phosphorylated AMP-activated protein kinaslism may be related to p-AMPK and down-regulation of PGC-1α in the hippocampus and medulla oblongata.Ricin toxin (RT) is one of the most lethal toxins derived from the seed of castor beans. In addition to its main toxic mechanism of inhibiting the synthesis of cellular proteins, RT can induce the production of inflammatory cytokines. MicroRNAs (miRNAs) play a key role in regulating both innate and adaptive immunity. To elucidate the regulation of miRNAs in RT-induced inflammation injury, the RNA high-throughput sequencing (RNA-Seq) technology was used to analyze the expression profile of miRNAs and mRNAs in RT-treated RAW264.7 cells. Results showed that a total of 323 mRNAs and 19 miRNAs differentially expressed after RT treated. Meanwhile, 713 miRNA-mRNA interaction pairs were identified by bioinformatics analysis. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis showed that those interaction pairs were mainly involved in JAK-STAT, T cell receptor, and MAPK signaling pathways. Moreover, we further predicted and determined the targeting relationship between miR-155-3p and GAB2 through TargetScan and dual-luciferase reporter assay. Mechanically, overexpression of miR-155-3p can reduce the secretion of TNF-α in RAW264.7 cells, revealing a possible mechanism of miR-155-3p regulating RT-induced inflammatory injury. This study provides a new perspective for clarifying the mechanism of RT-induced inflammatory injury and reveals the potential role of miRNAs in innate immune regulation.HepG2 cells continue to be a valuable tool in early drug discovery and pharmaceutical development. In the current study we develop a 3D in vitro liver model, using HepG2/C3A cells that is predictive of human genotoxic exposure. HepG2/C3A cells cultured for 7-days in agarose-coated microplates formed spheroids which were uniform in shape and had well defined outer perimeters and no evidence of a hypoxic core. Quantitative real-time-PCR analysis showed statistically significant transcriptional upregulation of xenobiotic metabolising genes (CYP1A1, CYP1A2, UG1A1, UGT1A3, UGT1A6, EPHX, NAT2) and genes linked to liver function (ALB, CAR) in 3D cultures. In response to three model pro-genotoxicants benzo[a]pyrene, amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-aminoanthracene (2-AA), we observed further transcriptional upregulation of xenobiotic metabolising genes (CYP1A1, CYP1A2, NAT1/2, SULT1A2, UGT1A1, UGT1A3) compared to untreated spheroids. Consistent with this, spheroids were more sensitive than 2D monolayers to compound induced single- and double- stranded DNA-damage as assessed by the comet assay and γH2AX phosphorylation respectively. In contrast, levels of DNA-damage induced by the direct acting mutagen 4-nitroquinoline N-oxide (4NQO) was the same in spheroids and monolayers. In support of the enhanced genotoxic response in spheroids we also observed transcriptional upregulation of genes relating to DNA-damage and cellular stress response (e.g. GADD45A and CDKN1A) in spheroids. In conclusion, HepG2/C3A 3D spheroids are a sensitive model for in vitro genotoxicity assessment with potential applications in early stage drug development.In 2021 we are celebrating the 100th anniversary of the discovery of insulin, which 1923 was awarded with a Nobel Prize in Physiology or Medicine to Banting and MacLeod. The development of insulin was foregone by an interesting piece of medical history starting with the first known mentioning of a disease resembling diabetes about 1550 BCE in Eberś papyrus. The Indian physician Charaka made the first reference to the sweetness of the urine about 280 BCE while the connection of the sweet taste of urine with an excess of sugar in the blood remained undescribed until 1776 when Dobson published his first experience on this subject. Langerhans description of "islands of clear cells" in the pancreatic gland was of great importance when published 1869. The first connection of pancreas to diabetes was made by Lancereaux 1877. The experiments 1890 by Minkowski and von Mering, depriving dogs of pancreas, noting that they died with symptoms of diabetes was another step forward. A first attempt to isolate pancreatic extrrevealed via the archives of the Nobel Assembly of the Karolinska Institutet, Stockholm, Sweden.Insulin regimens have been evolving for a century. The schemes used for type 1 (T1D) and type 2 (T2D) diabetes differ due to differences in pathophysiology but share important features. Insulin is required for both types of diabetes when other means of controlling glucose are insufficient. For T1D this requires multiple daily injections or continuous subcutaneous infusion assisted by CGM, whereas in early T2D basal insulin together with oral agents or GLP-1RA is usually effective. In both cases current schemes typically maintain HbA1c levels between 7 and 8%, a range that limits but does not eliminate the long-term complications of diabetes, but do not restore glycemic control to a fully protective level. Inability to control postprandial hyperglycemia without problematic weight gain and hypoglycemia is a leading obstacle in both T1D and long-duration T2D. A greater share of prandial dosing decisions will have to be provided by smart electronic systems. Further changes in the structure or formulation of insulin are of uncertain potential, but schemes including delivery of amylin, GLP-1, and glucagon show promise. More reliable access to insulins, delivery devices, and capable medical advisors will be needed to optimize replacement of this essential hormone.Although insulin therapy was already introduced one-hundred years ago, insulin formulations are still being refined to reduce the risk of hypoglycaemia and of other insulin side effects such as weight gain. This review summarises the available clinical data for some ongoing developments of new insulins and evaluates their potential for future insulin therapy. Once-weekly insulins will most likely be the next addition to the insulin armamentarium. see more First clinical studies indicate low peak-to-trough fluctuations with these insulins indicating the potential to achieve better glycaemic control or reduce hypoglycaemic events versus available basal insulins. Proof-of-concept has also been established for hepato-preferential and oral insulins; however, adverse effects and low bioavailability still need to be overcome. It will take much longer, before glucose-responsive "smart" insulins will be available. A first clinical study and numerous pre-clinical data show the potential, but also the challenges of designing an insulin that quickly reacts to blood glucose changes and prevents hypoglycaemia and pronounced hyperglycaemia. Nevertheless, it is reassuring that the search for better insulins has never stopped since its first use one-hundred years ago and is still ongoing. New developments have a high potential of further improving the safety and efficacy of insulin therapy in the future.Human tauopathies represent a group of neurodegenerative disorders, characterized by abnormal hyperphosphorylation and aggregation of tau protein, which ultimately cause neurodegeneration. The aberrant tau hyperphosphorylation is mostly attributed to the kinases/phosphatases imbalance, which is majorly contributed by the generation of reactive oxygen species (ROS). Globin(s) represent a well-conserved group of proteins which are involved in O2 management, regulation of cellular ROS in different cell types. Similarly, Drosophila globin1 (a homologue of human globin) with its known roles in oxygen management and development of nervous system exhibits striking similarities with the mammalian neuroglobin. Several recent evidences support the hypothesis that neuroglobins are associated with Alzheimer's disease pathogenesis. We herein noted that targeted expression of human-tau induces the cellular level of Glob1 protein in Drosophila tauopathy models. Subsequently, RNAi mediated restored level of Glob1 restricts the pathogenic effect of human-tau by minimizing its hyperphosphorylation via GSK-3β/p-Akt and p-JNK pathways. In addition, it also activates the Nrf2-keap1-ARE cascade to stabilize the tau-mediated increased level of ROS. These two parallel cellular events provide a significant rescue against human tau-mediated neurotoxicity in the fly models. For the first time we report a direct involvement of an oxygen sensing globin gene in tau etiology. In view of the fact that human genome encodes for the multiple Globin proteins including a nervous system specific neuroglobin; and therefore, our findings may pave the way to investigate if the conserved oxygen sensing globin gene(s) can be exploited in devising novel therapeutic strategies against tauopathies.Ecosystems on earth are strongly affected by human life. We pay attention to pest control in a patchy environment. To date, many authors have reported the indeterminacy in pest control. Most of these works have been studied in single-habitat systems. In the present article, however, we consider a food chain model (prey, predator and top predator) on five networks of patches, where node and link denote habitable patch and migration path, respectively. Each network includes three layers which represent the activity ranges of respective species. Reaction-migration equations are solved analytically and numerically. It is found the dynamics largely change depending on the geometry of networks. When removal rate of top predator is increased, the so-called "top-down effect" is commonly observed. In this case, the pest control will be successful, but extinction point of top predator largely differs on different networks. When removal rate of intermediate predator is increased, the responses of system become complicated.