Jianfei Chao

Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity

Oxyresveratrol (OXY) is a polyhydroxylated stilbene existing in mulberry. Increasing lines of evidence have shown its neuroprotective effects against Alzheimer disease and stroke. However, little is known about its neuroprotective effect in Parkinson disease (PD). Owing to its antioxidant activity, blood-brain barrier permeativity, and water solubility, we hypothesized that OXY may exert neuroprotective effects against parkinsonian mimetic 6-hydroxydopamine (6-OHDA) neurotoxicity. Neuroblastoma SH-SY5Y cells have long been used as dopaminergic neurons in PD research. We found that both pretreatment and posttreatment with OXY on SH-SY5Y cells significantly reduced the release of lactate dehydrogenase, the activity of caspase-3, and the generation of intracellular reactive oxygen species triggered by 6-OHDA. Compared to resveratrol, OXY exhibited a wider effective dosage range. We proved that OXY could penetrate the cell membrane by HPLC analysis of cell extracts. These results suggest that OXY may act as an intracellular antioxidant to reduce oxidative stress induced by 6-OHDA. Western blot analysis demonstrated that OXY markedly attenuated 6-OHDA-induced phosphorylation of JNK and c-Jun. Furthermore, we proved that OXY increased the basal levels of SIRT1, which may disclose new pathways accounting for the neuroprotective effects of OXY. Taken together, our results suggest OXY, a dietary phenolic compound, as a potential nutritional candidate for protection against neurodegeneration in PD.

Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells.

Resveratrol (3,4,5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinsons disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field.

Beneficial Effects of Cinnamon Proanthocyanidins on the Formation of Specific Advanced Glycation Endproducts and Methylglyoxal-Induced Impairment on Glucose Consumption

Advanced glycation endproducts (AGEs) are a group of complex and heterogeneous compounds formed from nonenzymatic reactions. The accumulation of AGEs in vivo has been implicated as a major pathogenic process in diabetic complications and other health disorders, such as atherosclerosis and Alzheimers disease, and normal aging. In this study, we investigate the inhibitory effects of cinnamon bark proanthocyanidins, catechin, epicatechin, and procyanidin B2 on the formation of specific AGE representatives including pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), and methylglyoxal (MGO) derived AGEs. These compounds displayed obvious inhibitory effects on these specific AGEs, which are largely attributed to both their antioxidant activities and carbonyl scavenging capacities. Meanwhile, in terms of their potent MGO scavenging capacities, effects of these proanthocyanidins on insulin signaling pathways interfered by MGO were evaluated in 3T3-L1 adipocytes. According to the results, proanthocyanidins exerted protective effects on glucose consumption impaired by MGO in 3T3-L1 fat cells.

Nutraceuticals and their preventive or potential therapeutic value in Parkinson's disease

Parkinsons disease (PD) is the second most common aging-related disorder in the world, after Alzheimers disease. It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and other parts of the brain, leading to motor impairment, cognitive impairment, and dementia. Current treatment methods, such as L-dopa therapy, are focused only on relieving symptoms and delaying progression of the disease. To date, there is no known cure for PD, making prevention of PD as important as ever. More than a decade of research has revealed a number of major risk factors, including oxidative stress and mitochondrial dysfunction. Moreover, numerous nutraceuticals have been found to target and attenuate these risk factors, thereby preventing or delaying the progression of PD. These nutraceuticals include vitamins C, D, E, coenzyme Q10, creatine, unsaturated fatty acids, sulfur-containing compounds, polyphenols, stilbenes, and phytoestrogens. This review examines the role of nutraceuticals in the prevention or delay of PD as well as the mechanisms of action of nutraceuticals and their potential applications as therapeutic agents, either alone or in combination with current treatment methods.

A pro-drug of the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine

Regular consumption of green tea benefits people in prevention from cardiovascular disorders, obesity as well as neurodegenerative diseases. (-)-Epigallocatechin-3-gallate (EGCG) is regarded as the most biologically active catechin in green tea. However, the stability and bioavailability of EGCG are restricted. The purpose of the present study was to investigate whether a pro-drug, a fully acetylated EGCG (pEGCG), could be more effective in neuroprotection in Parkinsonism mimic cellular model. Retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cells were pre-treated with different concentrations of EGCG and pEGCG for 30 min and followed by incubation of 25 microM 6-hydroxydopamine (6-OHDA) for 24h. We found that a broad dosage range of pEGCG (from 0.1 to 10 microM) could significantly reduce lactate dehydrogenase release. Likewise, 10 microM of pEGCG was effective in reducing caspase-3 activity, while EGCG at all concentrations tested in the model failed to attenuate caspase-3 activity induced by 6-OHDA. Furthermore, Western-blot analysis showed that Akt could be one of the specific signaling pathways stimulated by pEGCG in neuroprotection. It was demonstrated that 25 microM of 6-OHDA significantly suppressed the phosphorylation level of Akt. Only pEGCG at 10 microM markedly increased its phosphorylation level compared to 6-OHDA alone. Taken together, as pEGCG has higher stability and bioavailability for further investigation, it could be a potential neuroprotective agent and our current findings may offer certain clues for optimizing its application in future.

Inhibition of mutagenic PhIP formation by epigallocatechin gallate via scavenging of phenylacetaldehyde.

Chemical model investigation showed that both epigallocatechin gallate (EGCG) and its peracetate, which has all the hydroxyl groups acetylated, effectively reduced the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine found in foods. Mechanistic study was subsequently carried out to characterize the probable inhibitory mechanism involved. GC-MS analysis showed that EGCG in only one-fourth molar quantity of phenylalanine reduced formation of phenylacetaldehyde, a key PhIP intermediate by nearly 90%. Its peracetate also showed similar inhibitory activity. This further supported the existence of an antioxidant-independent mechanism contributing to the inhibition of PhIP formation by EGCG. Subsequent LC-MS analyses of samples from a wide range of model systems consisting of PhIP precursors showed the generation of characteristic analytes with molecular weight corresponding to the sum of EGCG and phenylalanine fragment(s) only in models where phenylalanine and EGCG were simultaneously present. An isotope-labeling study revealed that these analytes all contained fragment(s) of phenylalanine origin. Direct reaction employing phenylacetaldehyde and EGCG further confirmed the capability of EGCG to form adducts with phenylacetaldehyde, thus reducing its availability for PhIP formation. Finally, an investigation of the time course of the generation of postulated adduction products supported EGCG as an effective inhibitor of PhIP formation in prolonged heating processes.

Small-Molecule-Based Lineage Reprogramming Creates Functional Astrocytes

Growing evidence indicates important roles for astrocytes in neurodevelopment and diseases. However, astrocytes and their roles in these processes remain poorly understood. Despite recent progress in reprogramming somatic cells into different types of neural cells, reprogramming to astrocytes has lagged. Here, we show that functional astrocytes can be generated from mammalian fibroblasts usingxa0only small molecules. Induced mouse astrocytesxa0resemble primary astrocytes in astrocytic gene expression and epigenomic status and exhibit functional properties in promoting neuronal maturation, glutamate uptake, and calcium signaling. Moreover, these cells can recapitulate the Alexander disease phenotype of protein aggregation when expressing Gfap with a disease-causing mutation. The same compounds can also reprogram human fibroblasts into astroglial progenitor cells that can further mature into functional astrocytes. These chemically induced astrocytes may provide cellular models to uncover roles of astrocytes in normal neurodevelopment and pathogenesis of neurological diseases.

Sulfur-containing constituents and one 1H-pyrrole-2-carboxylic acid derivative from pineapple [Ananas comosus (L.) Merr.] fruit.

Two sulfur-containing compounds, (S)-2-amino-5-((R)-1-carboxy-2-((E)-3-(4-hydroxy-3-methoxyphenyl)allylthio)ethyl-amino)-5-oxopentanoic acid (1) and (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-((E)-3-(4-hydroxyphenyl)allylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (2), and one 1H-pyrrole-2-carboxylic acid derivative, 6-(3-(1H-pyrrole-2-carbonyloxy)-2-hydroxypropoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid (3), together with eighteen known phenolic compounds, were isolated from the fruits of pineapple. Their structures were elucidated by a combination of spectroscopic analyses. Some of these compounds showed inhibitory activities against tyrosinase. The half maximal inhibitory concentration values of compounds 1, 4, 5, 6, 7 are lower than 1 mM. These compounds may contribute to the well-known anti-browning effect of pineapple juice and be potential skin whitening agents in cosmetic applications.

In vitro attenuation of acrolein-induced toxicity by phloretin, a phenolic compound from apple

In the current study, the protective effects of phloretin were investigated in acrolein-challenged amino acid, protein, and cell models. It was found that the formation of FDP-lysine (a typical acrolein-lysine adduct) was strongly inhibited in the presence of phloretin and the remaining electrophilic site in FDP-lysine was also blocked by phloretin. Moreover, direct trapping of acrolein by phloretin was found to be responsible for inhibiting the incorporation of carbonyl groups into BSA and oligomerisation in RNase A. Subsequently, the reduction of LDH release in human neuroblastoma SH-SY5Y cells under acrolein challenge suggested the cytoprotective effects of phloretin. Such protection might be mediated through inhibiting the increased cellular protein carbonyl level as revealed by Western blotting analysis. The present study highlighted an apple phenolic compound, phloretin as a promising candidate in prevention or treatment of acrolein-associated human diseases.

Modeling neurological diseases using iPSC-derived neural cells

Developing efficient models for neurological diseases enables us to uncover disease mechanisms and develop therapeutic strategies to treat them. Discovery of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human diseases, especially neurological diseases. Currently almost all types of neural cells, including but not limited to neural stem cells, neurons, astrocytes, oligodendrocytes and microglia, can be derived from iPSCs following developmental principles. These iPSC-derived neural cells provide valuable tools for studying neurological disease mechanisms, developing potential therapies, and deepening our understanding of the nervous system.