Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.

Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties.

Poor survival of mesenchymal stem cells (MSCs) compromised the efficacy of stem cell therapy for myocardial infarction. The increase of exogenous reactive oxygen species (ROS) in infracted heart is one of the important factors that challenged the survival of donor MSCs. In the study we aimed to evaluate the effect of oxidative stress on the cell death of MSCs and investigate its mechanisms in order to help with the identification of new biological compounds to reduce donor cells damage. Apoptosis of MSCs were evaluated with Hoechst 33342 staining and flow cytometry analysis. The mitochondrial membrane potential of MSCs was analyzed with JC-1 staining. Signaling pathways involved in H(2)O(2) induced apoptosis were analyzed with Western blot. H(2)O(2) induced apoptosis of MSCs in a dose- and time-dependent manner. H(2)O(2) induced apoptosis of MSCs via both endoplasmic reticulum (ER) and mitochondrial pathways rather than extrinsic apoptosis pathway. H(2)O(2) caused transient rather than sustained activation of p38 and JNK with no effect on ERK1/2 pathway. P38 was involved in the regulation of early apoptosis of MSCs while JNK was involved in the late apoptosis. P38 directed both ER stress and mitochondria death pathway in the early apoptosis. In conclusion, exogenous ROS was a major factor to induce apoptosis of MSCs. Both ER stress and mitochondria death pathway were involved in the apoptosis of MSCs. H(2)O(2) activated p38 that directed the above two pathways in the regulation of early apoptosis of MSCs while JNK was involved in the late apoptosis of MSCs.

Apoptosis of mesenchymal stem cells induced by hydrogen peroxide concerns both endoplasmic reticulum stress and mitochondrial death pathway through regulation of caspases, p38 and JNK

Although physiological levels of reactive oxygen species (ROS) are required to maintain the self-renewal capacity of stem cells, elevated ROS levels can induce chromosomal aberrations, mitochondrial DNA damage, and defective stem cell differentiation. Over the past decade, several studies have shown that antioxidants can not only mitigate oxidative stress and improve stem cell survival but also affect the potency and differentiation of these cells. Further beneficial effects of antioxidants include increasing genomic stability, improving the adhesion of stem cells to culture media, and enabling researchers to manipulate stem cell proliferation by using different doses of antioxidants. These findings can have several clinical implications, such as improving neurogenesis in patients with stroke and neurodegenerative diseases, as well as improving the regeneration of infarcted myocardial tissue and the banking of spermatogonial stem cells. This article reviews the cellular and molecular effects of antioxidant supplementation to cultured or transplanted stem cells and draws up recommendations for further research in this area.

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Effects of Antioxidant Supplements on the Survival and Differentiation of Stem Cells

Mesenchymal stem cells (MSCs), which can be isolated from umbilical cords and induced to differentiate into multiple cell types in vitro, represent an ideal source for cell and gene therapy. MSCs are typically expanded in culture prior to their therapeutic application. However, similar to other types of stem cell, MSCs undergo senescence following a certain number of cell expansion passages in vitro, and eventually stop proliferating. The objective of the present study was to measure the changes that occur over successive passages of MSCs during long‑term in vitro culture, and to detect the effect of aging on MSC morphology, phenotype, proliferation, cell cycle, differentiation, intracellular reactive oxygen species (ROS) levels and gene expression. To understand the importance of oxidative stress in the aging of adult stem cells, the current study established a cell model of H2O2‑induced MSC premature senescence. Analysis of the biological characteristics of human umbilical cord MSCs during replicative and premature senescence revealed the importance of extrinsic factors in the aging of stem cells, particularly ROS. The findings of the present study suggest that cellular senescence, a state of irreversible growth arrest, can be triggered by ROS. Thus, it is important to improve the extrinsic culture environment of MSCs to retain the phenotype of expanded cells and delay the process of senescence prior to their clinical application.

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Changes in mesenchymal stem cells following long-term culture in vitro

Zinc complexes in OLEDs: An overview

Novel 2-vinyl-8-hydroxyquinoline derivatives as potential antioxidants and regulators of H2O2-induced oxidative stress in rat bone marrow mesenchymal stem cells (MSCs) are first reported. The antiradical properties and the reducing power of these compounds were assessed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and auto-oxidation of pyrogallol method, respectively. The activity against lipid peroxidation was determined using ammonium thiocyanate method. The results revealed that introduction of electron-donating groups at 2nd position decreased the antioxidant activities of 8-hydroxyquinoline derivatives. In addition, compound 4, the structure of which is similar to melatonin, exhibited superior antioxidant activities in scavenging DPPH free radical, ˙O2 free radical, and anti-LPO activities. Except for compounds 7, 12, and 15, the other compounds exhibited a stimulatory effect on MSCs growth. Using hydrogen peroxide (H2O2), we also investigated the protective efficacy of 2-vinyl-8-hydroxyquinoline derivatives against oxidative stress-induced cell death of MSCs. Cell viability assayed by MTT method indicated that exposure of MSCs cultures to hydrogen peroxide resulted in a concentration-dependent decrease in cell viability, and compounds 4 and 5 at given concentration (2.62 × 10−3 m) could protect MSCs against H2O2-induced oxidative stress in bone mesenchymal stem cell (BMSCs).

In vitro studies on the antioxidant and protective effect of 2-substituted -8-hydroxyquinoline derivatives against H(2)O(2)-induced oxidative stress in BMSCs.

Synthesis of light-emmting materials bis-[2′-2″-(9H-fluoren-2-yl)-vinyl-8-hydroxyquinoline] zinc(II) and bis-[2′-4″-(4,5-diphenyl-1H-imidazol-2-yl)styryl-8-hydroxyquinoline] zinc(II)

Gong-Chang Zeng

Papers

In vitro studies on the antioxidant and protective effect of 2-substituted -8-hydroxyquinoline derivatives against H(2)O(2)-induced oxidative stress in BMSCs.

Synthesis of light-emmting materials bis-[2′-2″-(9H-fluoren-2-yl)-vinyl-8-hydroxyquinoline] zinc(II) and bis-[2′-4″-(4,5-diphenyl-1H-imidazol-2-yl)styryl-8-hydroxyquinoline] zinc(II)