Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Exosome Carrying MiRNA-312 Inhibits Sevoflurane-Induced Cardiomyocyte Apoptosis Through Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway

This study was to explore the mechanism by how exosomes (exo) derived from BMSCs affects cardiomyocyte apoptosis. BMSCs were isolated and incubated with cardiomyocytes while the cardiomyocytes were exposed to sevoflurane or DMSO treatment. Apoptotic cells were calculated and level of apoptosis related proteins was detected by Western blot. Through transfection with microRNA-(miRNA)-312 inhibitor, we evaluated the effect of BMSC-exo on the sevoflurane-induced apoptosis. Sevoflurane significantly inhibited the viability of cardiomyocytes and induced cardiomyocyte apoptosis. Besides, sevoflurane decreased the expression of miR-312 and enhanced Bax expression in cardiomyocytes through restraining the phosphorylation of MAPK/ERK. Treatment with BMSC-exo, however, activated MAPK/ERK signaling by up-regulating miR-312, thereby inhibiting cardiomyocyte apoptosis, promoting cardiomyocyte proliferation, and elevating the level of Bcl-2. In conclusion, BMSC-exo-derived miR-312 inhibits sevoflurane-induced cardiomyocyte apoptosis by activating PI3K/AKT signaling pathway.

Hantaan virus replication is promoted via AKT activated mitochondria OXPHOS

Oxidative phosphorylation (OXPHOS) is a vital pathway provides ATP for intracellular activities. Here, we found that Hantaan virus (HTNV) exploited mitochondria OXPHOS to assist its replication in host cells and Protein Kinase B/AKT played a major function in this process. Inhibiting AKT activation by BEZ treatment can inhibit HTNV replication and prevent the increase of OXPHOS level caused by HTNV infection. We also found that HTNV infection can promote AKT translocation to mitochondria, where AKT phosphorylates Polynucleotide phosphorylase (PNPT). Taken together, our research demonstrates that HTNV replication exploits OXPHOS in host cells and it increases OXPHOS function by AKT-PNPT interaction in mitochondria.

Fucoidans from Cucumaria frondosa ameliorates renal interstitial fibrosis via inhibition of PI3K/Akt/NF-κB signaling pathway

The effects of Cucumaria frondosa polysaccharides (CFP) on renal interstitial fibrosis via regulating phosphatidylinositol-3-hydroxykinase/protein kinase-B/Nuclear factor-κB (PI3K/AKT/NF-κB) signaling pathway were investigated in vivo and in vitro in this research. A...

Molecular Mechanism of Extractum Liquidum Drug Loading Materials on Promoting Chronic Wound Tissue Repair Through Phosphatidylinositol 3 Kinase/Protein Kinase B/Hypoxia Induction Factor 1α Signal Pathway

To solve the shortcomings of traditional Zeji extractum liquidum (traditional Chinese medicine used for wound healing), and to explore the effect of Zeji Etractum Lquidum (ZLE) Nano Materials (ZLENM) on chronic wound (CW) healing and its molecular mechanism. 30 SD rats were divided into 3 groups in random: control group (Ctrl group), model group (CW group), and treatment group (ZLENM group). The results of wound healing rate showed that, in contrast with the CW, the healing rate of back wounds in the ZLENM group was greatly increased on the 7th and 14th days (P < 0.05). In contrast with the Ctrl, the rats in the CW and the ZLENM groups had greatly increased CD31 positive staining on the 7th and 14th days (P < 0.05), and the CW was lower than the ZLENM group (P < 0.05). In contrast with the 7th day, the MVD in the CW and the ZLENM groups was greatly reduced on the 14th day (P < 0.05). Western blot analysis of the expression of related signal molecules showed that the expressions of P-Akt, P-PI3K, HIF-1α, and VEGFR2 protein in the wounds in the CW and ZLENM groups were greatly increased in contrast with the Ctrl (P < 0.05), and CW was lower than ZLENM group (P < 0.05). In conclusion, ZLENM can promote wound healing and increase the number of wound angiogenesis in CW rats. The mechanism is related to the activation of phosphatidylinositol 3 kinase/protein kinase B/hypoxia induction factor 1α (PI3K/AKT/HIF-1α) signaling pathway.

Targeting Phosphoinositide 3-Kinase – Five Decades of Chemical Space Exploration

Phosphoinositide 3-kinase (PI3K) plays a key role in a plethora of physiologic processes and controls cell growth, metabolism, immunity, cardiovascular and neurological function, and more. The discovery of wort-mannin as the first potent PI3K inhibitor (PI3Ki) in the 1990s provided rapid identification of PI3K-dependent processes, which drove the discovery of the PI3K/protein kinase B (PKB/Akt)/target of rapamycin (mTOR) pathway. Genetic mouse models and first PI3K isoform-specific inhibitors pinpointed putative therapeutic applications. The recognition of PI3K as target for cancer therapy drove subsequently drug development. Here we provide a brief journey through the emerging roles of PI3K to the development of preclinical and clinical PI3Ki candidates.

In Silico Studies of Piperidine Derivatives as Protein Kinase B Inhibitors through 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation

Background: Protein kinase B (Akt) is a serine/threonine-protein kinase that drives the diverse physiological process. Akt is a promising therapeutic target, which involves cancer cell growth, survival, proliferation and metabolism. Objective: The study aims to design highly active Akt inhibitors and to elucidate the structural requirements for their biological activity, we analyzed the key binding features and summarized the structural determinants for their bioactivities. Methods: A series of piperidine derivatives have been investigated employing three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulation. Results: The statistics of the comparative molecular field analysis (CoMFA) model (Q2=0.631, R2=0.951) and the comparative molecular similarity index analysis (CoMSIA) model (Q2=0.663, R2=0.966) indicated that our 3D-QSAR model was accurate and reliable. Besides, the stability of receptor-ligand interactions under physiological conditions was then evaluated by molecular dynamics simulation, in agreement with the molecular docking results. Conclusion: Our study provided valuable insights for the discovery of potent Akt inhibitors.