Synthesis and biological evaluation of 21-arylidenepregnenolone derivatives as neuroprotective agents.

A series of 21-arylidenepregnenolone derivatives and their corresponding epoxides were synthesized. The neuroprotective effects of these steroidal compounds against amyloid-ß(25-35) (Aß(25-35))- and hydrogen peroxide (H(2)O(2))-induced neurotoxicity in PC12 cells, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells were evaluated. The bioassay results indicated that several 3ß-pregn-21-benzylidene-20-one derivatives displayed potent in vitro neuroprotective effects in different screening models, for example, compounds 2b, 3a, 3b, and 3s showing significant activities against Aß(25-35)-induced neurotoxicity in PC12 cells, 2b showing significant activities against H(2)O(2)-induced neurotoxicity in PC12 cells, and 2g, 3b, and 3e showing potent protection against OGD insult. The results suggested that introduction of an arylidene group into steroidal nucleus played an important role in neuroprotective activity, while the formation of epoxy group at C-5,6 could be also important for the neuroprotective activity in some degree. The pharmacological data reported here are helpful for the design of novel steroidal neuroprotective candidates.

Constitutive expression of GmF6'H1 from soybean improves salt tolerance in transgenic Arabidopsis.

Coumarin plays a pivotal role in plant response to biotic stress, as well as in the mediation of nutrient acquisition. However, its functions in response to abiotic stresses are largely unknown. In this work, a homologous gene, GmF6'H1, of AtF6'H1, which encodes the enzyme catalyzing the final rate-limiting step in the biosynthesis pathway of coumarin, was isolated from soybean. GmF6'H1 protein shares very high amino acid identity with AtF6'H1, and expression of GmF6'H1 in atf6'h1 can successfully restore the decreased coumarin production in the T-DNA insertion mutant. Further study revealed that the expression of GmF6'H1 in soybean was remarkably induced by salt stress. Constitutive expression of GmF6'H1 in Arabidopsis, driven by 35S promoter, significantly enhanced the resistance to salt of transgenic Arabidopsis. All these results suggest that GmF6'H1 can be used as a potential candidate gene for the engineering of plants with improved resistance to both biotic and abiotic stresses.

Ac-cel, a novel antioxidant, protects against hydrogen peroxide-induced injury in PC12 cells via attenuation of mitochondrial dysfunction.

Oxidative stress has been implicated in pathophysiology of many neurodegenerative diseases (ND) and increased oxidative stress is closely associated with mitochondrial dysfunction. As a result, looking for potent antioxidants, especially those targeting mitochondria, has become an attractive strategy in ND therapy. In this study, we explored protective effects and potential mechanism of Ac-cel, a novel compound, against hydrogen peroxide (H(2)O(2))-induced injury in PC12 cells. Pretreatment of PC12 cells with Ac-cel prior to 24 h of H(2)O(2) exposure markedly attenuated cytotoxicity induced by H(2)O(2) as evidenced by morphological changes and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Ac-cel also exhibited potent antiapoptotic effect demonstrated by results of annexin V and PI staining. The above beneficial effects of Ac-cel were accompanied by improved mitochondrial function, reduced caspase-3 cleavage as well as upregulated ratio of Bcl-2/Bax protein expression. Moreover, Ac-cel pretreatment markedly reversed intracellular reactive oxygen species (ROS) accumulation following 30 min of H(2)O(2) exposure in PC12 cells. Further, subcellular investigation indicated that Ac-cel significantly reduced production of mitochondrial ROS in isolated rat cortical mitochondria. Taken together, the present study, for the first time, reports that Ac-cel pretreatment inhibits H(2)O(2)-stimulated early accumulation of intracellular ROS possibly via reducing mitochondrial ROS production directly and leads to subsequent preservation of mitochondrial function. These results indicate that Ac-cel is a potential drug candidate for treatment of oxidative stress-associated ND.