Wnt Signaling pathway animation

The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.
The Wnt pathway involves a large number of proteins that can regulate the production of Wnt signaling molecules, their interactions with receptors on target cells and the physiological responses of target cells that result from the exposure of cells to the extracellular Wnt ligands. Although the presence and strength of any given effect depends on the Wnt ligand, cell type, and organism, some components of the signaling pathway are remarkably conserved in a wide variety of organisms, from Caenorhabditis elegans to humans. Protein homology suggests that several distinct Wnt ligands were present in the common ancestor of all bilaterian life, and certain aspects of Wnt signaling are present in sponges and even in slime molds.

cMET Pathway Animation

MET activation by its ligand HGF induces MET kinase catalytic activity, which triggers transphosphorylation of the tyrosines Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program.  The transducers interact with the intracellular multisubstrate docking site of MET either directly, such as GRB2, SHC,[12] SRC, and the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K),[12] or indirectly through the scaffolding protein Gab1[13] Tyr 1349 and Tyr 1356 of the multisubstrate docking site are both involved in the interaction with GAB1, SRC, and SHC, while only Tyr 1356 is involved in the recruitment of GRB2, phospholipase C γ (PLC-γ), p85, and SHP2.[14] GAB1 is a key coordinator of the cellular responses to MET and binds the MET intracellular region with high avidity, but low affinity.[15] Upon interaction with MET, GAB1 becomes phosphorylated on several tyrosine residues which, in turn, recruit a number of signalling effectors, including PI3K, SHP2, and PLC-γ. GAB1 phosphorylation by MET results in a sustained signal that mediates most of the downstream signaling pathways.

Notch signaling pathway

Notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms. Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.[2] Notch signaling promotes proliferative signaling during neurogenesis and its activity is inhibited by Numb to promote neural differentiation.
The Notch protein spans the cell membrane, with part of it inside and part outside. Ligand proteins binding to the extracellular domain induce proteolytic cleavage and release of the intracellular domain, which enters the cell nucleus to modify gene expression. Because most ligands are also transmembrane proteins, the receptor is normally triggered only from direct cell-to-cell contact. In this way, groups of cells can organise themselves, such that, if one cell expresses a given trait, this may be switched off in neighbour cells by the intercellular notch signal. In this way, groups of cells influence one another to make large structures. Thus, lateral inhibition mechanisms are key to Notch signaling. The notch cascade consists of notch and notch ligands, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. The Notch/Lin-12/Glp-1 receptor family[8] was found to be involved in the specification of cell fates during development in Drosophila and C. elegans.

Mechanism of Action of Aminosalicylates

This animation explains the mechanism of action of aminosalicylates used for the treatment of inflammatory bowel disease (IBD).Aminosalicylates include sulfasalazine and 5-aminosalicylic acid (5-ASA).Sulfasalazine, a sulfa drug, inhibits folic acid synthesis. As such, folic acid supplements should be taken with sulfasalazine to reduce the risk of neural tube defects. Sulfasalazine exhibits anti-inflammatory properties when split by gut bacterium into its metabolites: sulfapyridine and 5-ASA (mesalamine).The anti-inflammatory benefits of sulfasalazine, are chiefly derived from 5-ASA, which has fewer side effects than sulfapyridine. As such, administration of 5-ASA alone may be preferred over sulfasalazine.5-ASA is poorly absorbed by the intestines and systemic circulation, thus most remains in the terminal ileum and colon or is passed in the stool. 5-ASA within the lumen primarily exhibits a topical effect on the colonic epithelium.
Absorbed 5-ASA is extensively metabolized to N-acetyl-5-ASA by N-acetyltransferase 1 (NAT1). N-acetyl-5-ASA then binds PPAR-gamma (peroxisome proliferator-activated receptor gamma) a nuclear hormone receptor.Binding of N-acetyl-5-ASA induces the translocation of PPAR-gamma from the cytoplasm to the cell nucleus and a conformational change in PPAR-gamma.This modification permits the recruitment of the co-activator, vitamin D3 receptor-interacting protein (DRIP), which interacts directly with PPAR-gamma.Heterodimerization with the retinoid X receptor (RXR) occurs, resulting in formation of the PPAR-RXR complex, a transcriptional regulator. The PPAR-RXR heterodimer controls transcription by binding a regulatory PPAR-gamma response element (PPRE) and modulating the expression of genes involved in the inflammation process.PPAR-RXR downregulates the nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) to reduce production of pro-inflammatory cytokines. This complex also reduces COX-2 activity, leading to a reduction in prostaglandins involved in inflammation.Novel agents with similar mechanisms to 5-ASA, but which target PPAR-gamma more efficiently and report a reduction of adverse events, are currently under investigation. For example the compound, GED-0507-34, exhibits a 100- to 150-fold greater anti-inflammatory effect than 5-ASA.A new generation of 5-ASA, balsalazide, is able to bypass the small intestine and release a high concentration of 5-ASA in the colon.

Antimicrobial resistance

Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a horizontal fashion by conjugation, transduction, or transformation. Thus, a gene for antibiotic resistance that evolves via natural selection may be shared. Evolutionary stress such as exposure to antibiotics then selects for the antibiotic resistant trait. Many antibiotic resistance genes reside on plasmids, facilitating their transfer. If a bacterium carries several resistance genes, it is called multidrug resistant (MDR) or, informally, a superbug or super bacterium.

ß-Lactams: Mechanisms of Action and Resistance

Beta-lactam antibiotics are typically used to treat a broad spectrum of Gram-negative bacteria. Beta-lactamases produced by Gram-negative organisms are usually secreted.This animation starts with the explanation of bacterial cell wall synthesis, the process targeted by ß-Lactams. Structurally, most bacteria consist of a cell membrane surrounded by a cell wall and, for some bacteria, an additional outer layer. Internal to the cell membrane is the cytoplasm which contains ribosomes, a nuclear region and in some cases granules and/or vesicles. Depending on the bacterial species, a number of different external structures may be found such as a capsule, flagella and pili.
Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of E. coli, but also some strains of K. pneumoniae, Klebsiella oxytoca, P. mirabilis, and Citrobacter freundii. Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid and sulbactam, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin-clavulanate (co-amoxiclav), ticarcillin-clavulanate (co-ticarclav), and ampicillin/sulbactam, they normally remain susceptible to inhibition by tazobactam and subsequently the combination of piperacillin/tazobactam, although resistance has been described. To date, these beta-lactamases have primarily been detected in France and a few other locations within Europe.

Pelvic Inflammatory Disease

PI3K/AKT signaling pathway

Since its initial discovery as a proto-oncogene, the serine/threonine kinase Akt (also known as protein kinase B or PKB) has become a major focus of attention because of its critical regulatory role in diverse cellular processes, including cancer progression and insulin metabolism.
The Akt cascade is activated by receptor tyrosine kinases, integrins, B and T cell receptors, cytokine receptors, G protein coupled receptors and other stimuli that induce the production of phosphatidylinositol 3,4,5 triphosphates (PtdIns(3,4,5)P3) by phosphoinositide 3-kinase (PI3K). These lipids serve as plasma membrane docking sites for proteins that harbor pleckstrin-homology (PH) domains, including Akt and its upstream activator PDK1. There are three highly related isoforms of Akt (Akt1, Akt2, and Akt3) and these represent the major signaling arm of PI3K. For example, Akt is important for insulin signaling and glucose metabolism, with genetic studies in mice revealing a central role for Akt2 in these processes. Akt regulates cell growth through its effects on the mTOR and p70 S6 kinase pathways, as well as cell cycle and cell proliferation through its direct action on the CDK inhibitors p21 and p27, and its indirect effect on the levels of cyclin D1 and p53. Akt is a major mediator of cell survival through direct inhibition of pro-apoptotic signals such as Bad and the Forkhead family of transcription factors. T lymphocyte trafficking to lymphoid tissues is controlled by the expression of adhesion factors downstream of Akt. In addition, Akt has been shown to regulate proteins involved in neuronal function including GABA receptor, ataxin-1, and huntingtin proteins. Akt has been demonstrated to interact with Smad molecules to regulate TGFβ signaling. Finally, lamin A phosphorylation by Akt could play a role in the structural organization of nuclear proteins. These findings make Akt/PKB an important therapeutic target for the treatment of cancer, diabetes, laminopathies, stroke and neurodegenerative disease.