China
Africa
Explore chapters and articles related to this topic
Milroy Disease
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Expressed mainly in lymphatic endothelia, FLT4 interacts with VEGFC (which is a key regulator of blood vessel development in embryos and angiogenesis in adult tissues), enhances VEGFC production, promotes growth, survival, and migration of endothelial cells, and contributes to adult lymphangiogenesis and the buildup of the vascular network and the cardiovascular system during embryogenesis. In addition, FLT4 mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, the MAPK8 and the JUN signaling pathway, and the AKT1 signaling pathway, and promotes phosphorylation of PIK3R1 (regulatory subunit of phosphatidylinositol 3-kinase) and MAPK8 at “Thr-183” and “Tyr-185”, and of AKT1 at “Ser-473” [8,9].
Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
IRS proteins contain an N-terminal pleckstrin homology (PH) domain adjacent to a phosphotyrosine-binding (PTB) domain, which is followed by several regulatory tyrosine and serine/threonine phosphorylation sites. Here, the PTB domain represents the binding site of IRS proteins to phosphotyrosine residues on the insulin receptor after insulin activation. The PH domain can bind phosphatidylinositol lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) as a substrate of PI3K. Furthermore, the tyrosine phosphorylation sites coordinate downstream signaling cascades by also binding effector proteins like the above-mentioned PI3K or growth factor receptor-bound protein 2 (GRB2). By contrast, the specific serine phosphorylation sites, phosphorylated by the c-Jun N-terminal kinase (JNK1, also known as MAPK8) and other protein kinases, inhibit insulin-stimulated tyrosine phosphorylation. First, this is a negative feedback loop to limit over-stimulation of downstream pathways by insulin (33); second, it also represents one mechanism of insulin resistance if it persists. Upon recruitment of IRS-1 to the insulin receptor by binding of the PTB domain to phosphorylated IR tyrosine residue Tyr999 (note: original publications refer to this tyrosine residue as Tyr960 which shifted due to subsequent sequence updates), the kinase domain of the IR can then phosphorylate tyrosine residues on IRS-1 (34, 35). While the human and murine IRS-1 amino acid sequences are well conserved, the exact position of the tyrosine (Y) residues differ slightly, denoted by either hY or mY for the human or mouse residue, respectively. Thus, the phosphorylated tyrosine residues on IRS-1 are hY465/mY460, hY612/mY608, hY632/mY628, hY662/mY658, hY896/mY891, hY941/mY935, hY989/mY983, hY1179/mY1173, and hY1229/mY1220 (36–39). From here the downstream signaling branches out to either engage the PI3K-AKT or the MAPK pathways.
Identification of dysregulated genes and pathways of different brain regions in Alzheimer’s disease
Published in International Journal of Neuroscience, 2020
In PPI network, YAP1, MAPK9 and GJA1 had the high connectivity with DEGs in HIP, TG and FG, respectively. Moreover, YAP1 and GJA1 were significantly up-regulated; MAPK9 was significantly down-regulated in HIP, TG and FG. YAP1 is a downstream nuclear effector of the Hippo signaling pathway, which is involved in development, growth, repair and homeostasis. Xu et al. demonstrate that knockdown of YAP1 expression leads to increased Aβ production and tau phosphorylation in U251-APP cells, whereas overexpression of YAP1 had opposite effects [30]. GJA1 is a component of gap junctions. Kajiwara et al. report that GJA1 is strongly associated with AD amyloid and tau pathologies. Astrocytes lacking Gja1 show reduced Apoe protein levels as well as impaired Aβ phagocytosis. Wild-type neurons co-cultured with Gja1−/− astrocytes contain higher levels of Aβ species than those with wild-type astrocytes [31]. MAPK9 (also named as JNK2) and MAPK8 (also named as JNK1) belong to MAP kinase family. MAPK8 is significantly down-regulated in both HIP and TG. It is reported that JNKs are activated in degenerating neurons in AD [32]. Nicotinamide treatment significantly decreases β-amyloid production, amyloid plaque burden, synaptic loss and inflammatory responses in AD transgenic animals by the inhibition of JNK activation [33]. Wnt signaling pathway and MAPK signaling pathway were significantly enriched in AD. The canonical and non-canonical Wnt signaling pathways play neuroprotective roles in AD through modulation of mitochondrial processes [34]. Tapia-Rojas et al. report that Wnt signaling inhibitors induced severe changes in the hippocampus, including severe cognitive deficits, increased tau phosphorylation and Aβ1-42 peptide levels, decreased Aβ42/Aβ40 ratio and Aβ1-42 concentration in the cerebral spinal fluid, and high levels of soluble Aβ species and synaptotoxic oligomers in the hippocampus of AD mouse model [35,36]. Bhaskar’s group report that p38αMAPK inhibitor (MW108) suppresses p38α MAPK activation, leading to reduced tau phosphorylation and preventing cognitive impairment in aged hTau mice [37,38]. Moreover, miR-330 plays a protective role in reducing amyloid β-protein production, alleviating oxidative stress and mitochondrial dysfunction in AD by targeting VAV1 via the MAPK signaling pathway [39].
Mechanism of action of Tripterygium wilfordii for treatment of idiopathic membranous nephropathy based on network pharmacology
Published in Renal Failure, 2022
Honghong Shi, Yanjuan Hou, Xiaole Su, Jun Qiao, Qian Wang, Xiaojiao Guo, Zhihong Gao, Lihua Wang
Using STRING, MCODE, and combined the results of KEGG, we found the MAPK8, STAT3, IFNG, ICAM1, IL4, TGFB1, MMP1 may be important targets of T. wilfordii in the treatment of IMN. MAPK8, also known as JNK1, belong to the family of MAPKs. Activation of MAPK8 correlates with a variety of cellular responses, including inflammation, oxidative stress and apoptosis [29]. Moreover, complement membranous attack complex could activate nicotinamide adenine dinucleotide phosphate hydrogen oxidase and JNK in podocytes, which could induce production of ROS in these cells, and a high amount of ROS has been documented to be associated with proteinuria in patients with MN [30]. STAT3, a member of the STAT family, is known to be activated by some upstream cytokines, such as TNF-α, IL-6 [31]. The biological functions of the STAT3 included cell proliferation, differentiation, survival and angiogenesis. Activation of STAT3 contributes to proliferation of extra-capillary glomerular epithelial cells and extent of injury in glomerulonephritis [31,32]. And STAT3 signaling was activated in the kidneys of mice [33] and human [33] with glomerulonephritis. Sublytic C5b-9, also called membrane attack complex, can attack podocytes to cause injuries which promoted the occurrence and development of MN and finally led to ESKD [34]. In C5b-9-induced podocyte injury model, STAT3 inhibitor had a protective effect on CXCL12-treated podocytes [34]. IFNG, one of the most important regulatory cytokines produced in response to viruses and microbe, stimulates Th-1 clonal expansion and inhibits Th-2 expansion, and the balance between Th-1 and Th-2 CD4 cells is relevant to autoimmunity [35]. The data from single-cell RNA sequencing showed that IFNG is up-regulated in MN patients [36]. MN is generally considered as an immune complex-mediated disease with predominant Th-2 nephritogenic immune, and correlated significantly with urinary protein excretion [37]. In addition, in patients with MN, Th2 subclass IgG production is stimulated by IL-4 at the microenvironment level, and other mechanisms of proteinuria in MN could be the direct effect of IL-4 on podocytes [38]. These proteins are related to inflammation, immunity, oxidative stress and apoptosis. Based on STRING, MCODE results, and combined with the GO analysis results, the potential mechanism of treating IMN of T. wilfordii is probably associated with its participance in BPs of response to lipopolysaccharide, response to molecule of bacterial origin, and positive regulation of cytokine production. These BPs are related to immune response, and inflammation [39]. IMN is a pathological pattern of glomerular damage caused by an autoimmune response. Immune complex deposition, thickness of glomerular basement membrane, and changes in the podocyte morphology are responsible for the development of proteinuria, which is caused by the targeted binding of auto-antibodies to podocytes [40]. In addition, there are close associations between IMN and inflammation, and chronic inflammation is one of important characteristic of MN [41]. Through regulation of immune-related cell and inflammatory mediators, T. wilfordii show potent immunosuppressive activity, thus it has the great potential for the treatment of immune diseases [42].