Images under the category Signalling
Figure 3Pro-inflammatory hypertensive signalling in the hypothalamus In response to overnutrition states, pro-inflammatory signalling including IKKβ/NF-κB is activated in certain hypothalamic neurons such as POMC neurons in the ARC. NF-κB activation triggers a variety of molecular reactions, such as increased levels of SOCS3 and of PTP1B, contributing to SNS activation and subsequent increased blood pressure. In addition, POMC neurons bind TNF-α, which further stimulates SNS activation. Also, TNF-α and IL-1β activate perivascular macrophages that produce prostaglandin E2 (PGE2), which signals through the PVN to activate the SNS and subsequent hypertension. Central RAS activation and Ang II production stimulate IKKβ/NF-κB activation and ROS production in PVN neurons. Subsequent release of pro-inflammatory cytokines further contributes to ROS production, mitochondrial dysfunction, neuroinflammation and sustained increase in blood pressure leading to pathological hypertension.
Figure 2Hypothalamic mechanisms of hypertension The hypothalamus activates the SNS and other pathways contributing to the pathogenesis of hypertension. Dysregulated AVP neurons in the SON and PVN produce excess AVP, which activates hypothalamic V1a, brain V2 and peripheral V1a receptors, thus activating the SNS, RAS or endothelial cells respectively. Circulating cortisol activates MRs in the hypothalamus to simultaneously stimulate the SNS and RAS. Leptin binds to the LepR to activate AMPK and the SNS. The ARC produces α-MSH, which binds to the MC4 in the hypothalamus to increase SNS outflow. Dysregulated clock gene expression promotes aldosterone production leading to salt-sensitive hypertension.
Figure 1Pathways of synthesis and breakdown of purines Uric acid is the endpoint of purine catabolism. Major inhibitors (allopurinol and febuxostat) of XOR lead to a build-up of purine bases (adenine, hypoxanthine and guanine) which are salvaged, returned to ribonucleoside monophosphate forms (AMP, IMP, GMP) and inhibit the de novo synthesis of purines from ribose-5 phosphate (ribose-5-P). APRT: adenine phosphoribosyltransferase; HGPRT: hypoxanthine-guanine phosphoribosyltransferase; PNP: purine nucleoside phosphorylase; PRPP: phosphoribosyl pyrophosphate.
Figure 1Summary of known interactions of major cell death pathways Many factors and stimuli can lead to cellular demise. Necrosis occurs only as ACD, due to severe cellular damage. RCD modes occur after ligation of specific extracellular signals to receptors or intracellular stimuli. Apoptosis is probably the main outcome, when RCD is activated. Necroptosis and pyroptosis are only executed, when apoptosis is inhibited, i.e. by inhibition of executioner caspases. Autophagy is usually a process to recycle resources or degrade damaged proteins or organelles within cells. Autophagy can either promote cell survival by blocking apoptosis or lead to cell death, depending on extent of damage and status of the cell. Remains of dying cells, either as apoptotic bodies or as debris, can elicit an immune response, which may facilitate release of pro-inflammatory or pro-apoptotic signals by immune cells.
Figure 6HGF/Met drives cardiac repair and regeneration Different pools of progenitor cells contribute to cardiac regeneration: resident CPCs and circulating progenitor cells of various origins. HGF is secreted by MSCs, multipotent BM-derived cells, EPCs and adipose stem cells. HGF stimulates mobilization, expansion and differentiation of CPCs into the three main cardiac populations: cardiomyocytes, endothelial cells and VSMCs. HGF/Met co-operates with Notch1 receptor, which regulates the cell fate of CPCs. Another source of progenitor cells is the epicardium. Epicardial cells secrete HGF and undergo the process of EMT, producing epicardial progenitor cells, which differentiate into cardiomyocytes, endothelial cells and VSMCs. HGF–IgG protein complexes and the subsequent Wnt receptor activation are probably the molecular mechanism involved in EMT induction after injury. Finally, HGF mobilizes various different sources of circulating progenitor cells, such as MSCs, haemopoietic progenitor cells, multipotent BM-derived cells, EPCs and adipose stem cells. The mechanism of circulating multipotent BM-derived cells homing to the site of injury involves HGF/Met and SDF-1/CXCR4 chemotaxis.
Figure 4HGF/Met has anti-fibrotic activity Representation of major molecular mechanisms involved in HGF/Met-mediated anti-fibrotic activity. HGF neutralizes the pro-fibrotic action of TGFβ1 by multiple mechanisms in fibroblasts: inhibition of TGFβ1 secretion (1), up-regulation of decorin which binds active TGFβ1 and sequesters its action (2), promotion of myofibroblast apoptosis (3), down-regulation of TGFβ1 synthesis (4), interference with TGFβ1-initiated Smad signalling (5), and protection from oxidative stress (6). In endothelial cells, HGF blocks their transformation into myofibroblasts (7) and induces up-regulation of iNOS followed by increased production of NO (8).
Figure 3HGF/Met promotes formation of new vessels through stimulation of endothelial and vascular smooth muscle cells HGF is a powerful stimulator of proliferation and migration of endothelial cells and is released, together with VEGF-A, by endothelial cells and SMCs. The link between HGF/Met and VEGF receptors may be represented by neuropilin co-receptors. HGF enhances the endothelial barrier function through Rac1-mediated regulation of actin cytoskeleton and microtubules. HGF is up-regulated by angiopoietin 1 (Ang1) in endothelial cells and stimulates migration and recruitment of SMCs. HGF counteracts AngII-dependent oxidative stress in SMCs.
Figure 1Structure and conformation of mTOR Structures of mTOR kinases ∆Nter–mLST8 and FKBP12–rapamycin complex interacting with the binding domain of human FRAP, adapted from Yang et al. [19] and Choi et al. [117] respectively. Molecular graphics were created using the UCSF Chimera package [216,217] and ePMV [218].
Figure 2mTOR complexes: mTORC1 and mTORC2 mTOR forms two large structurally and functionally distinct complexes: mTORC1 and mTORC2. (a) Both structures contain the catalytic subunit deptor, mLST8 and the Tti1–Tel2 complex. mTORC1 specifically contains raptor and PRAS40 subunits, whereas mTORC2 contains rictor, mSin1 and protor-1/2. (b) mTORC1 assembly is essential for its subcellular localization, recruitment of 4E-BP1 and sensing amino acids. mTORC2 assembly is essential for its catalytic activity and substrate binding.
Figure 3mTOR signalling pathway The mTOR signalling pathway serves as the central regulator of cell metabolism and proliferation. In response to stimulus from growth factors, amino acids and energy, mTORC1 positively regulates major processes such as cell growth, proliferation, protein synthesis, lipid synthesis and autophagy. Other factors such as low energy, low oxygen levels and DNA damage inhibit mTORC1 activity through p53-, PTEN-, AMPK- and REDD1-dependent mechanisms. Growth-factor-stimulated PI3K signalling also activates mTORC2, which regulates actin cytoskeletal organization, ion transport and growth. However, the effectors and inhibitors of mTORC2 signalling remain to be elucidated.
