Structure of the Human TELO2-TTI1-TTI2 Complex.

Phosphatidylinositol 3-kinase-related protein kinases (PIKKs) play critical roles in various metabolic pathways related to cell proliferation and survival. The TELO2-TTI1-TTI2 (TTT) complex has been proposed to recognize newly synthesized PIKKs and to deliver them to the R2TP complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) and the heat shock protein 90 chaperone, thereby supporting their folding and assembly. Here, we determined the cryo-EM structure of the TTT complex at an average resolution of 4.2 Å. We describe the full-length structures of TTI1 and TELO2, and a partial structure of TTI2. All three proteins form elongated helical repeat structures. TTI1 provides a platform on which TELO2 and TTI2 bind to its central region and C-terminal end, respectively. The TELO2 C-terminal domain (CTD) is required for the interaction with TTI1 and recruitment of Ataxia-telangiectasia mutated (ATM). The N- and C-terminal segments of TTI1 recognize the FRAP-ATM-TRRAP (FAT) domain and the N-terminal HEAT repeats of ATM, respectively. The TELO2 CTD and TTI1 N- and C-terminal segments are required for cell survival in response to ionizing radiation.

An integrated virtual screening and drug repurposing strategy for the discovery of new antimalarial drugs against Plasmodium falciparum phosphatidylinositol 3-kinase.

The emergence and spread of drug resistance in Plasmodium falciparum, the parasite causing the most severe form of human malaria, is a major threat to malaria control and elimination programs around the globe. With P. falciparum having evolved widespread resistance against a number of previously widely used drugs, currently, artemisinin (ART) and its derivatives are the cornerstones of first-line treatments of uncomplicated malaria. However, growing incidences of ART failure reflect the spread of ART-resistant P. falciparum strains. Despite current efforts to understand the primary cause of ART resistance due to mutations in the Kelch 13 gene (PfK13), the mechanism underlying ART resistance is still not completely unclear and no feasible strategies to counteract the causes and thereby restoring the efficiency of ART have been developed. We use a polypharmacology approach to identify potential drugs that can be used for the novel purpose (target). Of note, we have designed a multimodal stratagem to identify approved drugs with a potential antimalarial activity using computational drug reprofiling. Our investigations suggest that oxetacaine, simvastatin, repaglinide, aclidinium, propafenone, and lovastatin could be repurposed for malaria control and prevention.

Rosmarinic Acid Induces Proliferation Suppression of Hepatoma Cells Associated with NF-κB Signaling Pathway.

BACKGROUND: Rosmarinic acid (RA) is a natural phenolic compound that acts as a Fyn inhibitor by 53 homology modeling of the human Fyn structure. Therefore, the apoptosis mechanism related to  NF-κB signaling pathway induced by RA in HepG2 was investigated. METHODS: The cell growth, apoptosis, and proliferation of HepG2 regulated by various concentrations of RA were studied. The proteins expression of MMP-2, MMP-9, PI3K, AKT, NF-κB, and apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 were detected. RESULTS: RA significantly reduced proliferation rates, inhibited migration and invasion, and decreased the expressions of invasion-related factors, such as matrix metalloproteinase (MMP)-2 and MMP-9. TUNEL staining revealed that RA resulted in a dose-dependent increase of HepG2 cell apoptosis. In line with this finding, the expression of apoptosis suppressor protein Bcl-2 was downregulated and that of the pro-apoptotic proteins Bax and cleaved caspase-3 was increased. In addition, we found that the phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor kappa B (NF-κB) signaling pathway was involved in RA-mediated inhibition of HepG2 cell metastasis. CONCLUSION: Our study identified that  RA as a drug candidate for the treatment of HCC.

Dynamic remodeling of host membranes by self-organizing bacterial effectors.

During infection, intracellular bacterial pathogens translocate a variety of effectors into host cells that modify host membrane trafficking for their benefit. We found a self-organizing system consisting of a bacterial phosphoinositide kinase and its opposing phosphatase that formed spatiotemporal patterns, including traveling waves, to remodel host cellular membranes. The Legionella effector MavQ, a phosphatidylinositol (PI) 3-kinase, was targeted to the endoplasmic reticulum (ER). MavQ and the Legionella PI 3-phosphatase SidP, even in the absence of other bacterial components, drove rapid PI 3-phosphate turnover on the ER and spontaneously formed traveling waves that spread along ER subdomains inducing vesicle and tubule budding. Thus, bacteria can exploit a self-organizing membrane-targeting mechanism to hijack host cellular structures for survival.

Attenuating PI3K/Akt- mTOR pathway reduces dihydrosphingosine 1 phosphate mediated collagen synthesis and hypertrophy in primary cardiac cells.

Cardiac fibrosis and myocyte hypertrophy play contributory roles in the progression of diseases such as heart Failure (HF) through what is collectively termed cardiac remodelling. The phosphoinositide 3- kinase (PI3K), protein kinase B (Akt) and mammalian target for rapamycin (mTOR) signalling pathway (PI3K/Akt- mTOR) is an important pathway in protein synthesis, cell growth, cell proliferation, and lipid metabolism. The sphingolipid, dihydrosphingosine 1 phosphate (dhS1P) has been shown to bind to high density lipids in plasma. Unlike its analog, spingosine 1 phosphate (S1P), the role of dhS1P in cardiac fibrosis is still being deciphered. This study was conducted to investigate the effect of dhS1P on PI3K/Akt signalling in primary cardiac fibroblasts and myocytes. Our findings demonstrate that inhibiting PI3K reduced collagen synthesis in neonatal cardiac fibroblasts (NCFs), and hypertrophy in neonatal cardiac myocytes (NCMs) induced by dhS1P, in vitro. Reduced activation of the PI3K/Akt- mTOR signalling pathway led to impaired translation of fibrotic proteins such as collagen 1 (Coll1) and transforming growth factor ß (TGFß) and inhibited the transcription and translation of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). PI3K inhibition also affected the gene expression of S1P receptors and enzymes such as the dihydroceramide delta 4 desaturase (DEGS1) and sphingosine kinase 1 (SK1) in the de novo sphingolipid pathway. While in myocytes, PI3K inhibition reduced myocyte hypertrophy induced by dhS1P by reducing skeletal muscle α- actin (αSKA) mRNA expression, and protein translation due to increased glycogen synthase kinase 3ß (GSK3ß) mRNA expression. Our findings show a relationship between the PI3K/Akt- mTOR signalling cascade and exogenous dhS1P induced collagen synthesis and myocyte hypertrophy in primary neonatal cardiac cells.

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects.

Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20-30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.

The dual HDAC-PI3K inhibitor CUDC-907 displays single-agent activity and synergizes with PARP inhibitor olaparib in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a deadly neuroendocrine tumor with limited therapeutic options. Recent data suggest that histone deacetylases (HDACs) and the phosphatidylinositol 3-kinase (PI3K) pathway play essential roles in SCLC cell proliferation and survival. METHODS: The inhibition of the PI3K signaling and HDAC activity by CUDC-907 was analyzed by western blotting. The effect of CUDC-907 on olaparib-induced DNA damage response was assessed by western blotting and Immunofluorescence staining. The cytotoxicity of CUDC-907 alone or in combination with olaparib in a panel of SCLC cell lines were evaluated by the CellTiter-Glo Luminescent Cell Viability Assay and flow cytometry. The in vivo effects of CUDC-907 and olaparib alone or in combination were examined using a patient-derived xenografts (PDX) model of SCLC. RESULTS: CUDC-907 treatment downregulated MYC paralogs and FoxM1, induced G1 cell-cycle arrest, and impaired DNA double-strand break (DSB) repair capacity in SCLC cells, which produced a potent antiproliferative effect. Furthermore, we showed that CUDC-907 treatment enhanced the therapeutic efficacy of PARP inhibitor olaparib in SCLC cellular models and a PDX model. Mechanistic investigations demonstrated that CUDC-907 synergized with olaparib through the blockade of DSB repair pathways and downregulation of MYC paralogs and FoxM1. CONCLUSIONS: Our study uncovers that dual PI3K and HDAC inhibition by CUDC-907 exerts significant single-agent activity and strong synergistic effects with PARP inhibitor olaparib in SCLC, which thus provides a rational combination treatment strategy for SCLC clinical investigation.

Structural Features that Distinguish Inactive and Active PI3K Lipid Kinases.

PI3K lipid kinases signal through the PI3K/Akt pathway, regulating cell growth and proliferation. While the structural features that distinguish between the active and inactive states of protein kinases are well established, that has not been the case for lipid kinases, and neither was the structural mechanism controlling the switch between the two states. Class I PI3Ks are obligate heterodimers with catalytic and regulatory subunits. Here, we analyze PI3K crystal structures. Structures with the nSH2 (inactive state) are featured by collapsed activation loop (a-loop) and an IN kinase domain helix 11 (kα11). In the active state, the a-loop is extended and kα11 in the OUT conformation. Our analysis suggests that the nSH2 domain in the regulatory subunit regulates activation, catalysis and autoinhibition through the a-loop. Inhibition, activation and catalytic scenarios are shared by class IA PI3Ks; the activation is mimicked by oncogenic mutations and the inhibition offers an allosteric inhibitor strategy.

Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer.

BACKGROUND: Despite increases in diagnostics and effective treatments, over 300,000 men die from prostate cancer highlighting the need for specific and differentiating biomarkers. AR phosphorylation associates with castrate-resistance, with pARser213 promoting transcriptional activity. We hypothesise that combined pARser81 and pARser213 reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease. METHODS: Immunohistochemistry and immunofluorescence were performed on matched hormone-naive and castrate-resistant prostate cancer samples. TempO-Seq gene profiling was analysed using DESeq2 package. LNCaP-AI cells were stimulated with DHT or EGF. WST-1 assays were performed to determine effects of Enzalutamide and BKM120 on cell viability. RESULTS: Following the development of castrate-resistance, pARser81 expression reduced and pARser213 expression increased. Castrate-resistance pARser81 expression was not associated with survival but high pARser213 expression was associated with reduced survival from relapse. Combined high pARser81 and pARser213 was associated with reduced survival from relapse. pARser81 expression was induced by 10 nM DHT or 10 nM EGF and pARser213 expression was induced by treatment with 10 nM EGF in LNCaP-AI cells. Cell viability was reduced following treatment with 10 nM Enzalutamide and 10 nM BKM120. Eight genes were differentially expressed between hormone-naive and castrate-resistant tumours and twenty-five genes were differentially expressed between castrate-resistant tumours with high and low pARser213 expression. CONCLUSION: Combined pARser81 and pARser213 provides a novel prognostic biomarker for castrate-resistant disease and a potential predictive and therapeutic target for prostate cancer. Further studies will be required to investigate the combined effects of targeting AR and PI3K/AKT signalling.

Geraniin inhibits proliferation and induces apoptosis through inhibition of phosphatidylinositol 3-kinase/Akt pathway in human colorectal cancer in vitro and in vivo.

Geraniin, a polyphenolic component isolated from Phyllanthus amarus, has been reported to possess diverse biological activities, including antitumor, antiinflammatory, antihyperglycemic, antihypertensive, and antioxidant. However, the role and underlying mechanisms of geraniin in colorectal cancer still remain unclear. In the present study, we found that geraniin notably inhibited cell proliferation and clonogenic formation of colorectal cancer cell SW480 and HT-29 in a dose-dependent manner by Cell Counting Kit 8, EdU, and colony formation assays, respectively. Additionally, geraniin remarkably induced apoptosis of SW480 and HT-29 cells in a dose-dependent way by Hoechst 33342 staining, flow cytometric analysis, and TdT-mediated dUTP nick-end labeling assays and increased the expressions of Bax, caspase-3, and caspase-9, while decreased the level of Bcl-2. Besides, wound healing, transwell migration, and invasion assays demonstrated that geraniin obviously inhibited the migration and invasion of SW480 and HT-29 cells. Moreover, it also inhibited the levels of phospho (p)-phosphatidylinositol 3-kinase and p-Akt. Furthermore, in-vivo animal study revealed that geraniin had the significant inhibitory effects on tumor growth and promoted cancer cell apoptosis remarkably, which further confirmed the antitumor effect of geraniin. Taken together, the present study exhibited the positive role of geraniin in inhibiting proliferation and inducing apoptosis through suppression of phosphatidylinositol 3-kinase/Akt pathway in colorectal cancer cells in vitro and in vivo, which might provide new insights in searching for new drug candidates of anticolorectal cancer.

VS-5584 Inhibits Human Osteosarcoma Cells Growth by Induction of G1- phase Arrest through Regulating PI3K/mTOR and MAPK Pathways.

BACKGROUND: Activation of the PI3K/mTOR signaling pathway plays a key role in the progression of human osteosarcoma. Studies have confirmed that VS-5584 was a novel inhibitor of the PI3K/mTOR pathway, and displayed potential anticancer activity. OBJECTIVE: To explore the anticancer effect and underlying mechanism of VS-5584 against the growth of human osteosarcoma cells. METHODS: U2OS and MG-63 human osteosarcoma cells were cultured and the cytotoxicity, cell apoptosis in VS-5584-treated cells were explored by the CCK8 assay, flow cytometric analysis and western blot. Cell migration and tube formation were also employed to examine the anticancer potential. RESULTS: The results showed that VS-5584 treatment dose-dependently inhibited the growth of U2OS and MG-63 cells by induction of G1-phase arrest through regulating p21, p27, Cyclin B1 and Cdc2. Further investigation revealed that VS-5584 treatment effectively inhibited the PI3K/mTOR signaling pathway and triggered MAPK phosphorylation. Moreover, VS-5584 treatment dramatically suppressed cell migration and tube formation of HUVECs, followed by the down-regulation of HIF-1α and VEGF. CONCLUSION: Our findings validated that VS-5584 may be a promising anticancer agent with potential application in the chemotherapy and chemoprevention of human osteosarcoma.

Structural and functional characterization of Solanum lycopersicum phosphatidylinositol 3-kinase C2 domain.

Phosphatidylinositol 3-kinases (PI3Ks) are characterized by the presence of a C2 domain at the N-terminal end (class I, III); or at both the N-terminal and C-terminal ends (class II), sometimes including a Plextrin homology domain and/or a Ras domain. Plant PI3Ks are analogous to the class III mammalian PI3K. An N-terminal fragment (~170 aa) of the tomato PI3K regulatory domain including the C2 domain, was cloned and expressed in a bacterial system. This protein was purified to homogeneity and its physicochemical properties analyzed. The purified protein showed strong binding with monophosphorylated phosphatidylinositols, and the binding was dependent on calcium ion concentration and pH. In the overall tertiary structure of PI3K, C2 domain showed unique characteristics, having three antiparallel beta-sheets, hydrophobic regions, acidic as well as alkaline motifs, that can enable its membrane binding upon activation. To elucidate the functional significance of C2 domain, transgenic tobacco plants expressing the C2 domain of PI3K were generated. Transgenic plants showed defective pollen development and disrupted seed set. Flowers from the PI3K-C2 transgenic plants showed delayed wilting, and a decrease in ethylene production. It is likely that introduction of the PI3K-C2 segment may have interfered with the normal binding of PI3K to the membrane, delaying the onset of membrane lipid catabolism that lead to senescence.

The Preparation of Ginsenoside Rg5, Its Antitumor Activity against Breast Cancer Cells and Its Targeting of PI3K.

Ginsenosides have been reported to possess various pharmacological effects, including anticancer effects. Nevertheless, there are few reports about the antitumor activity and mechanisms of ginsenoside Rg5 against breast cancer cells. In the present study, the major ginsenoside Rb1 was transformed into the rare ginsenoside Rg5 through enzymatic bioconversion and successive acid-assisted high temperature and pressure processing. Ginsenosides Rb1, Rg3, and Rg5 were investigated for their antitumor effects against five human cancer cell lines via the MTT assay. Among them, Rg5 exhibited the greatest cytotoxicity against breast cancer. Moreover, Rg5 remarkably suppressed breast cancer cell proliferation through mitochondria-mediated apoptosis and autophagic cell death. LC3B-GFP/Lysotracker and mRFP-EGFP-LC3B were utilized to show that Rg5 induced autophagosome-lysosome fusion. Western blot assays further illustrated that Rg5 decreased the phosphorylation levels of PI3K, Akt, mTOR, and Bad and suppressed the PI3K/Akt signaling pathway in breast cancer. Moreover, Rg5-induced apoptosis and autophagy could be dramatically strengthened by the PI3K/Akt inhibitor LY294002. Finally, a molecular docking study demonstrated that Rg5 could bind to the active pocket of PI3K. Collectively, our results revealed that Rg5 could be a potential therapeutic agent for breast cancer treatment.

Rational discovery of a highly novel and selective mTOR inhibitor.

Aided by Structure Based Drug Discovery (SBDD), we rapidly designed a highly novel and selective series of mTOR inhibitors. This chemotype conveys exquisite kinase selectivity, excellent in vitro and in vivo potencies and ADME safety profiles. These compounds could serve as good tools to explore the potential of TORC inhibition in various human diseases.

Atomic structure of PI3-kinase SH3 amyloid fibrils by cryo-electron microscopy.

High resolution structural information on amyloid fibrils is crucial for the understanding of their formation mechanisms and for the rational design of amyloid inhibitors in the context of protein misfolding diseases. The Src-homology 3 domain of phosphatidyl-inositol-3-kinase (PI3K-SH3) is a model amyloid system that plays a pivotal role in our basic understanding of protein misfolding and aggregation. Here, we present the atomic model of the PI3K-SH3 amyloid fibril with a resolution determined to 3.4 Å by cryo-electron microscopy (cryo-EM). The fibril is composed of two intertwined protofilaments that create an interface spanning 13 residues from each monomer. The model comprises residues 1-77 out of 86 amino acids in total, with the missing residues located in the highly flexible C-terminus. The fibril structure allows us to rationalise the effects of chemically conservative point mutations as well as of the previously reported sequence perturbations on PI3K-SH3 fibril formation and growth.

Functional differentiation of three phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) in response to Vibrio anguillarum infection in turbot (Scophthalmus maximus).

PIK3CA has been extensively investigated from its molecular mechanism perspective and association with its mutations in different types of cancers. However, little has been reported regarding the pathological significance of PIK3CA expression in teleost. Here, in our present study, three PIK3CA genes termed SmPIK3CAa, SmPIK3CAb and SmPIK3CA-like were firstly identified in the genome of turbot S. maximus. Although these three genes located in different chromosomes, all of them share the same five domains. Phylogenetic and synteny analysis indicated that SmPIK3CAa, SmPIK3CAb and SmPIK3CA-like were three paralogs that may originate from duplication of the same ancestral PIK3CA gene. Subcellular localization analysis confirmed the cytoplasm distribution of these three paralogs. All three SmPIK3CA were ubiquitously expressed in examined tissues in turbot, with the higher expression levels in immune-related tissues such as blood, spleen, kidney, gills and intestines. Upon Vibrio anguillarum challenge, SmPIK3CAa and SmPIK3CA-like transcripts were significantly induced in spleen, intestine and blood despite of differential expression levels and responsive time points. Additionally, individuals in resistant group showed significantly higher expression level of both two genes than in the susceptible group. Moreover, four SNPs (102, 2530, 3027 and 3060) and one haplotype (Hap2) located in exon region of SmPIK3CA-like were identified and confirmed to be associated with V. anguillarum resistance in turbot by association analysis in different populations. Taken together, these results suggested that functional differentiation occurred in three SmPIK3CA paralogs with Vibrio anguillarum resistance and SmPIK3CAa and SmPIK3CA-like probable play potential roles in innate immune response to pathogenic invasions in turbot.

A Peptide Derived from Phosphoinositide 3-kinase Inhibits Endocytosis and Influenza Virus Infection.

Endocytosis mediates the internalization and ingestion of a variety of endogenous or exogenous substances, including virus particles, under the control of intracellular signaling pathways. We have previously reported that the complex formed between the small GTPase Ras and phosphoinositide 3-kinase (PI3K) translocates from the plasma membrane to endosomes, signaling from which thereby regulates clathrin-independent endocytosis, endosome maturation, influenza virus internalization, and infection. However, the molecular mechanism by which the Ras-PI3K complex is recruited to endosomes remains unclear. Here, we have identified the amino acid sequence responsible for endosomal localization of the Ras-PI3K complex. PI3K lacking this sequence failed to translocate to endosomes, and expression of the peptide comprising this PI3K-derived sequence inhibited clathrin-independent endocytosis, influenza virus internalization, and infection. Moreover, treatment of cells with this peptide in an arginine-rich, cell-penetrating form successfully suppressed influenza virus infection in vitro and ex vivo, making this peptide a potential therapeutic agent against influenza virus infection.Key words: signal transduction, endocytosis, endosome, imaging, influenza virus.

pik3r3b, a novel immune-related gene in Nile tilapia (Oreochromis niloticus): Identification, expression and analysis of antibacterial activity.

A full-length cDNA encoding phosphatidylinositol 3-kinase regulatory subunit gamma b gene in Nile tilapia (Oreochromis niloticus), termed as On-pik3r3b, was identified and characterized in this study. The sequence analysis demonstrated that the full-length cDNA of On-pik3r3b was 2018 bp, containing a 5' untranslated region (UTR) of 171 bp, an open reading frame (ORF) of 1422 bp and a 3' UTR of 425 bp. Its protein sequence displayed a high degree of identity with other fish. Using qPCR, the expression patterns of On-pik3r3b were investigated. In healthy Nile tilapia, the transcripts of On-pik3r3b were detected in all examined tissues, except the skin. Upon the stimulation with Streptococcus agalactiae, the On-pik3r3b expression level in liver, spleen, kidney and gill were significantly increased at 12 h after infection. The recombinant On-pik3r3b showed in vitro antibacterial activity, against S. agalactiae and E. coli. Our observation strongly indicates that On-pik3r3b is involved in the innate immune response in Nile tilapia.

New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity.

A series of quinoline-chalcone hybrids was designed as potential anti-cancer agents, synthesized and evaluated. Different cytotoxic assays revealed that compounds experienced promising activity. Compounds 9i and 9j were the most potent against all the cell lines tested with IC50 = 1.91-5.29 µM against A549 and K-562 cells. Mechanistically, 9i and 9j induced G2/M cell cycle arrest and apoptosis in both A549 and K562 cells. Moreover, all PI3K isoforms were inhibited non selectively with IC50s of 52-473 nM when tested against the two mentioned compounds with 9i being most potent against PI3K-γ (IC50 = 52 nM). Docking of 9i and 9j showed a possible formation of H-bonding with essential valine residues in the active site of PI3K-γ isoform. Meanwhile, Western blotting analysis revealed that 9i and 9j inhibited the phosphorylation of PI3K, Akt, mTOR, as well as GSK-3ß in both A549 and K562 cells, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings support the antitumor potential of quinoline-chalcone derivatives for NSCLC and CML by inhibiting the PI3K/Akt/mTOR pathway.

Downregulating PI3K/Akt/NF-κB signaling with allicin for ameliorating the progression of osteoarthritis: in vitro and vivo studies.

Osteoarthritis (OA) is characterized by the degeneration and destruction of articular cartilage. Allicin, a dietary garlic active constituent, exerts anti-inflammatory effects on several diseases. However, its effects on OA have not been clearly elucidated. In this study, we explored the effects of allicin on OA in both in vitro and in vivo models. Allicin inhibited interleukin-1ß (IL-1ß) induced overproduction of nitric oxide, inducible nitric oxide synthase, prostaglandin E2, and cyclooxygenase-2, as well as pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 in chondrocytes in a dose-dependent manner. Meanwhile, allicin reversed the overproduction of metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motifs-5 and the decrease of aggrecan and type II collagen. Furthermore, allicin dramatically suppressed IL-1ß-stimulated PI3K/Akt/NF-κB activation in chondrocytes. In vivo, treatment with allicin prevented the destruction of cartilage and inhibited PI3K/Akt/NF-κB activation in the cartilage of mice OA models. Taken together, these results indicate that allicin may be a potential therapeutic agent for OA.