The Akt family of serine/threonine protein kinases are key regulators of multiple aspects of cell behaviour, including proliferation, survival, metabolism, and tumorigenesis. Growth-factor-activated Akt signalling promotes progression through normal, unperturbed cell cycles by acting on diverse downstream factors involved in controlling the G1/S and G2/M transitions. Remarkably, several recent studies have also implicated Akt in modulating DNA damage responses and genome stability. High Akt activity can suppress ATR/Chk1 signalling and homologous recombination repair (HRR) via direct phosphorylation of Chk1 or TopBP1 or, indirectly, by inhibiting recruitment of double-strand break (DSB) resection factors, such as RPA, Brca1, and Rad51, to sites of damage. Loss of checkpoint and/or HRR proficiency is therefore a potential cause of genomic instability in tumor cells with high Akt. Conversely, Akt is activated by DNA double-strand breaks (DSBs) in a DNA-PK- or ATM/ATR-dependent manner and in some circumstances can contribute to radioresistance by stimulating DNA repair by nonhomologous end joining (NHEJ). Akt therefore modifies both the response to and repair of genotoxic damage in complex ways that are likely to have important consequences for the therapy of tumors with deregulation of the PI3K-Akt-PTEN pathway.

Hypoxia activates autophagy, an evolutionarily conserved cellular catabolic process. Dysfunction in the autophagy pathway has been implicated in an increasing number of human diseases, including ca...

Metabolic stress induces autophagy as an alternative source of energy and metabolites. Insufficient autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. Here, we performed a functional screen in search of novel autophagy regulators from natural products. We showed that oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes and impaired degradation of SQSTM1/p62. Costaining of GFP-LC3B with LysoTracker Red or LAMP1 antibody demonstrates that autophagosome-lysosome fusion is blocked by OC treatment. Furthermore, OC inhibits lysosomal proteolytic activity by altering lysosomal acidification and downregulating the expression of lysosomal cathepsins. Importantly, OC can eliminate the tolerance of cancer cells to nutrient starvation. Starvation dramatically increases the susceptibility of cancer cells to OC-induced CASP3-dependent apoptosis...

The rationale for using traditional Chinese medicine (TCM) is based on the experience that has been gained from its wide use over thousands of years. However, the mechanisms of action of many TCM are still unclear. Proteomics, which mainly characterizes protein functions, protein-protein interactions, and protein modification in tissues or animals, can be used to investigate signaling pathway perturbations in cells or the whole body. Proteomics has improved the discovery process of effective TCM compounds, and has helped to elucidate their possible mechanisms of action. Therefore, a systematic review of the application of proteomics on TCM research is of great importance and necessity. This review strives to describe the literature on the application of proteomics to elucidate the mechanism of action of TCM on various diseases, and provide the essential discussion on the further utilization of proteomics data to accelerate TCM research. Literature survey was performed via electronic search on Pubmed with keywords 'Proteomics' and 'Traditional Chinese Medicine'. The papers written in English were acquired and analyzed in this review. This review mainly summarizes the application of proteomics to investigate TCM remedies for neuronal disease, cancer, cardiovascular disease, diabetes, and immunology-related disease. Researchers have applied proteomics to study the mechanism of action of TCM and made substantial progresses. Further studies are required to determine the protein targets of the active compounds, analyze the mechanism of actions in patients, compare the clinical effects with western medicine.

β Amyloid protein (Aβ) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)‐tacrine, a novel dimeric AChE inhibitor, on Aβ‐induced neurotoxicity in primary cortical neurons. Bis(7)‐tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Aβ‐induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation. Both nicotinic and muscarinic receptor antagonists failed to block the effects of bis(7)‐tacrine. Instead, nimodipine, a blocker of L‐type voltage‐dependent Ca²⁺ channels (VDCCs), attenuated Aβ neurotoxicity, whereas N‐, P/Q‐ or R‐type VDCCs blockers and ionotropic glutamate receptor antagonists did not. Fluorescence Ca²⁺ imaging assay revealed that, similar to nimodipine, bis(7)‐tacrine reversed Aβ‐triggered intracellular Ca²⁺ increase, which was mainly contributed by the extracellular Ca²⁺ instead of endoplasmic reticulum and mitochondria Ca²⁺. Concurrently, using whole cell patch‐clamping technique, it was found that bis(7)‐tacrine significantly reduced the augmentation of high voltage‐activated inward calcium currents induced by Aβ. These results suggest that bis(7)‐tacrine attenuates Aβ‐induced neuronal apoptosis by regulating L‐type VDCCs, offers a novel modality as to how the agent exerts neuroprotective effects.