Bioactive plant derived compounds are important for a wide range of therapeutic applications, and some display promising anticancer properties. Further evidence suggests that phytochemicals modulate autophagy and apoptosis, the two crucial cellular pathways involved in the underlying pathobiology of cancer development and regulation. Pharmacological targeting of autophagy and apoptosis signaling using phytochemicals therefore offers a promising strategy that is complementary to conventional cancer chemotherapy. In this review, we sought to highlight the molecular basis of the autophagic-apoptotic pathway to understand its implication in the pathobiology of cancer, and explore this fundamental cellular process as a druggable anticancer target. We also aimed to present recent advances and address the limitations faced in the therapeutic development of phytochemical-based anticancer drugs.

The last two decades have shown a marked expansion in the number of publications regarding the effects ofPanax ginseng. Ginsenosides, which are unique saponins isolated fromPanax ginseng, are the pharmacologically active ingredients in ginseng, responsible for its effects on the central nervous system (CNS) and the peripheral nervous system. Recent studies have shown that ginsenosides regulate various types of ion channels, such as voltage‐dependent and ligand‐gated ion channels, in neuronal and heterologously expressed cells. Ginsenosides inhibit voltage‐dependent Ca²⁺, K⁺, and Na⁺channel activities in a stereospecific manner. Ginsenosides also inhibit ligand‐gated ion channels such as N‐methyl‐d‐aspartate, some subtypes of nicotinic acetylcholine, and 5‐hydroxytryptamine type 3 receptors. Competition and site‐directed mutagenesis experiments revealed that ginsenosides interact with ligand‐binding sites or channel pore sites and inhibit open states of ion channels. This review will introduce recent findings and advances on ginsenoside‐induced regulation of ion channel activities in the CNS, and will further expand the possibilities that ginsenosides may be useful and potentially therapeutic choices in the treatment of neurodegenerative disorders.

Alzheimer's disease (AD) is closely associated with synaptic dysfunction, and thus current treatments often aim to stimulate neurotransmission to improve cognitive impairment. Whereas the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is essential for synaptic transmission, the correlation between SNAREs and AD neuropathology is unknown. Here, we report that intracellular amyloid-β (Aβ) oligomers directly inhibit SNARE-mediated exocytosis by impairing SNARE complex formation. We observe abnormal reduction of SNARE complex levels in the brains of APP/PS1 transgenic (TG) mice compared to age-matched wild-types. We demonstrate that Aβ oligomers block SNARE complex assembly through the direct interaction with a target membrane (t)-SNARE syntaxin 1a in vitro. Furthermore, the results of the in vitro single-vesicle content-mixing assay reveal that Aβ oligomers inhibit SNARE-mediated fusion pores. Thus, our study identifies a potential molecular mechanism by which intracellular Aβ oligomers hamper SNARE-mediated exocytosis, likely leading to AD-associated synaptic dysfunctions.

Md. Ataur Rahman, and Hyewhon Rhim. BMB Reports 2017;50:345-54. https://doi.org/10.5483/BMBRep.2017.50.7.069

Neuronal L-type Ca²⁺ channels do not support synaptic transmission, but they play an essential role in synaptic activity-dependent gene expression. Ca_v1.2 and Ca_v1.3 are the two most widely expressed L-type Ca²⁺ channels in neurons and have different biophysical and subcellular distributions. The function of the Ca_v 1.3 L-type Ca²⁺ channel and its cellular mechanisms in the central nervous system are poorly understood. In this study, using a yeast two-hybrid assay, we found that the N terminus of the rat Ca_v1.3 α₁ subunit interacts with a partial N-terminal amino acid sequence of ryanodine receptor type 2 (RyR2). Reverse transcription-PCR and Western blot assays revealed high expression of both Ca_v1.3 and RyR2 in the rat hippocampus. We also demonstrate a physical association of Ca_v1.3 with RyR2 using co-immunoprecipitation assays. Moreover, immunocytochemistry revealed prominent co-localization between Ca_v1.3 and RyR2 in hippocampal neurons. Depolarizing cells by an acute treatment of a high concentration of KCl (high-K, 60 mm) showed that the activation of L-type Ca²⁺ channels induced RyR opening and led to RyR-dependent Ca²⁺ release, even in the absence of extracellular Ca²⁺. Furthermore, we found that RyR2 mRNA itself is increased by long term treatment of high-K via activation of L-type Ca²⁺ channels. These acute and long term effects of high-K on RyRs were selectively blocked by small interfering RNA-mediated silencing of Ca_v1.3. These results suggest a physical and functional interaction between Ca_v1.3 and RyR2 and important implications of Ca_v1.3/RyR2 clusters in translating synaptic activity into alterations in gene expression.