Attenuation of oxidative stress-induced neuronal cell death by Hydnophytum formicar-um Jack.

Objective: To investigate protective effects of Hydnophytum formicarum Jack.(H. formicarum) extracts via regulation of SIRT1-FOXO3a-ADAM10 signaling and antioxidant activity against H_2O_2-induced neurotoxicity in neuroblastoma SH-SY5Y cells. Methods: Cell viability and apoptosis of neuronal cells pretreated with H. formicarum Jack. extracts under oxidative stress were determined by MTT assay and flow cytometry. The intracellular reactive oxygen species(ROS) was performed using Carboxy-DCFDA assay. Additionally, a profile of protein expressions related to neuroprotection was detected by western blot analysis. Results: The plant extracts(methanol and ethyl acetate) elicited protective effects on the neuronal cell death as performed by the MTT assay and by apoptosis analysis via the activation of BCL-2. Both ethyl acetate and methanol extracts exerted inhibitory effects against H_2O_2-induced ROS generation in the SH-SY5Y cells. Furthermore, the possible mechanism of neuroprotection of H. formicarum Jack. was observed through its antioxidant properties by maintaining the levels of catalase and SOD2 proteins as well as activating SIRT1-FOXO3a pathway. Importantly, pretreatment of neuronal cells with H. formicarum Jack. significantly recovered the levels of ADAM10 protein compared with the H_2O_2 treatment alone. Conclusions: The recent findings suggest the protective effects of H. formicarum Jack. plant extracts on attenuating H_2O_2-induced neurotoxicity in human SH-SY5Y cells.     

Butein,isoliquiritigenin, and scopoletin attenuate neurodegeneration via antioxidant enzymes and SIRT1/ADAM10 signaling pathway

Neuronal cell death is a key feature of neurodegenerative disorders such as Parkinson''s and Alzheimer''s diseases. Plant polyphenols, namely butein, isoliquiritigenin, and scopoletin, have been shown to exhibit various biological activities including anti-inflammatory, antimicrobial, and antioxidant activities. Herein, butein, isoliquiritigenin, and scopoletin were explored for their neuroprotective properties against oxidative stress-induced human dopaminergic SH-SY5Y cell death. The cells exposed to hydrogen peroxide (H₂O₂) revealed a reduction in cell viability and increases in apoptosis and levels of reactive oxygen species (ROS). Interestingly, pretreatment of SH-SY5Y cells with 5 μM of butein, isoliquiritigenin, or scopoletin protected against the cell death induced by H₂O₂, and decreased the levels of apoptotic cells and ROS. In addition, the levels of SIRT1, FoxO3a, ADAM10, BCL-2, and antioxidant enzymes (catalase and SOD2) were maintained in the cells pretreated with butein, isoliquiritigenin, or scopoletin before H₂O₂ treatment compared to cells without pretreatment and the reference (resveratrol). Molecular docking analysis revealed that the interactions between the activator-binding sites of SIRT1 and the phenolic compounds were similar to those of resveratrol. Taken together, the data suggest that these polyphenolic compounds could be potential candidates for prevention and/or treatment of neurodegeneration.

Neuronal cells exposed to H₂O₂ may undergo increase ROS, reduction in cell viability and cell death. Butein, isoliquiritigenin, and scopoletin ameliorated H₂O₂-induced neurotoxicity by reducing ROS, balancing antioxidants and activating SIRT1-FoxO3a-ADAM10 pathway.     

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on- andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease-modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β-amyloid precursor protein (βAPP) and β-amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.