Tanshinone IIA attenuates renal injury during hypothermic preservation via the MEK/ERK1/2/GSK-3ß pathway.

BACKGROUND: Oxidative stress-induced injury during hypothermic preservation is a universal problem that delays graft function and decrease the success of organ transplantation. Tanshinone IIA (Tan IIA) was reported to exhibit a variety of biochemical activities, including protection against oxidative stress. Therefore, the specific molecular pathway by which Tan IIA protects renal tissues during preservation was investigated in this study. METHODS: In vivo study, Sprague-Dawley (SD) rats were divided into twelve groups and the kidneys were isolated and preserved in different solutions for 0, 24 or 48 h, respectively: control group (Celsior solution) and Tan II groups (Celsior solution containing 10, 50,100 µM). In vitro study, primary renal cell from SD rats was cultured which was treated H2O2 (800 µM) for 6 h to mimic oxidative stress injury. Four groups were finally divided: control group; H2O2 group; H2O2 + Tan IIA group; H2O2 + Tan IIA + G15 group. RESULTS: In present study, we demonstrate data indicating that a significant increase in the superoxide dismutase (SOD) activity and a decrease in the reactive oxygen species (ROS) content were observed in the kidneys and renal cells preserved with Tan IIA compared with those preserved with the Celsior solution alone after 24 h and 48 h of hypothermic preservation (P < 0.01). The expression of phosphorylated mitogen-activated protein kinase kinase (MEK), phosphorylated extracellular signal-regulated protein kinases 1/2 (ERK1/2), phosphorylated glycogen synthase kinase-3ß (GSK-3ß) and cleaved caspase-3 was lower in the kidneys and renal cells preserved with Tan IIA than in those preserved with the Celsior solution alone after 24 h and 48 h of hypothermic preservation (P < 0.01). The mitochondrial morphology was rescued and adenosine triphophate (ATP) production and mitochondrial membrane potential were increased in the Tan IIA groups. Finally, Tan IIA also decreased cell apoptosis. CONCLUSION: It suggests that the supplementation of the standard Celsior solution with Tan IIA may significantly improve long-term kidney preservation. Tan IIA attenuated oxidative stress injury and decreased apoptosis levels via activation of the MEK/ERK1/2/GSK-3ß signaling pathway during kidney hypothermic preservation.

Effects of Dendrobium officinale flowers on testivular tissue and sperm quality in parent and offspring rats / 预防医学

Objective@#To learn the effects of Dendrobium officinale flowers on testivular tissue morphology and sperm quality in parent and offspring rats,so as to provide reference for safety evaluation of Dendrobium officinale flowers.@*Methods@#The 40 SD rats was randomly divided into the low-,middle-,high-dose and the control group,given 2.0,4.0,6.4 and 0 g/kgbw Dendrobium officinale flowers,respectively. After three months,the body weight,mass and organ/body coefficients of testis and epididymis of parent （P） and offspring （F1,F2） rats were measured;the number,activity and deformity of sperms were observed under microscope;the changes of testis and epididymis were observed by hematoxylin eosin staining. @* Results@#There were no significantly statistical differences in the body weight,mass and organ/body coefficients of testis and epididymis,sperm quantity,sperm motility rate among four groups of P、F1、F2 male rats （P>0.05）. There were no significantly statistical differences in sperm malformation rate between the high-dose group and the control group （P>0.05）. There was no significant change in testis and epididymis of P,F1 and F2 male rats. @*Conclusion@#Dendrobium officinale flowers did not show obviously adverse effects on testivular tissue morphology and sperm quality in parent and offsping rats.

Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila.

Alpha-synuclein aggregation is the central hallmark of both sporadic and familial Parkinson's disease (PD). Patients with different PD-causing genetic defects of alpha-synuclein usually show distinctive clinical features that are atypical to sporadic PD. Iron accumulation is invariably found in PD. Recent studies showed that mutant and wild-type alpha-synuclein may have differential interaction with iron and mutant alpha-synuclein toxicity could be preferentially exacerbated by iron. We hence hypothesized that iron overload could selectively influence mutant alpha-synuclein toxicity and disease phenotypes. To test the hypothesis, we investigated if Drosophila melanogaster over-expressing A53T, A30P, and wild-type (WT) alpha-synuclein have different responses to iron treatment. We showed that iron treatment induced similar reduction of survival rate in all flies but induced a more severe motor decline in A53T and A30P mutant alpha-synuclein expressing flies, suggesting interaction between mutant alpha-synuclein and iron. Although no significant difference in total head iron content was found among these flies, we demonstrated that iron treatment induced selective DA neuron loss in motor-related PPM3 cluster only in the flies that express A53T and A30P mutant alpha-synuclein. We provided the first in vivo evidence that iron overload could induce distinctive neuropathology and disease phenotypes in mutant but not WT alpha-synuclein expressing flies, providing insights to the cause of clinical features selectively exhibited by mutant alpha-synuclein carriers.

Drosophila models for studying iron-related neurodegenerative diseases.

In recent years, iron has been regarded as a common pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Friedreich's ataxia (FRDA). A number of genes involved in iron transport, storage and regulation have been found associated with initiation and progression of neurodegeneration. However, whether iron abnormalities represent a primary or secondary event still remains unknown. Due to the limitation in transgenic rodent model construction and transfection systems, the progress in unraveling the pathogenic role of different iron-related proteins in neurodegenerative diseases has been slow. Drosophila melanogaster, a simple organism which has a shorter lifespan and smaller genome with many conserved genes, and captures many features of human nervous system and neurodegeneration, may help speed up the progress. The characteristics that spatial- and temporal-specific transgenic Drosophila can be easily constructed and raised in large quantity with phenotype easily determined turn Drosophila into an excellent in vivo genetic system for screening iron-related modifiers in different neurodegenerative conditions and hence provide a better picture about the pathogenic contribution of different iron-related protein abnormalities. It is believed that identification of important iron-related genes that can largely stop or even reverse degenerative process in Drosophila models may lead to development of novel therapeutic strategies against neurodegenerative diseases.

Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease.

Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease.

Effects of hypoxic preconditioning on the expression of iron influx and efflux proteins in primary neuron culture.

The mechanisms of neuroprotection induced by hypoxic preconditioning (HP) and the effects of HP on iron metabolism proteins in the brain have not been fully elucidated. Based on the accumulated information, we hypothesized that HP would be able to affect the expression of iron metabolism proteins in the brain and that the changes in the expression of these proteins induced by HP might be partly associated with the HP-induced neuroprotection. Here, we demonstrated for the first time that HP could induce a significant increase in the expression of HIF-1alpha as well as iron uptake (TfR1 and DMT1) and release (Fpn1) proteins and thus increase transferrin-bound iron (Tf-Fe) and non-transferrin-bound iron (NTBI) uptake and iron release, and also a progressive increase in cellular iron content in the cultured neurons. We concluded that HP has the ability to speed iron transport rate and proposed that the increase in iron transport rate and cellular iron in neurons might be one of the mechanisms involved in neuroprotection in the HP neurons. We also demonstrated that Fpn1 expression was significantly affected by HIF-1alpha, implying that the gene encoding this iron efflux protein is hypoxia-inducible.