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Protein Sources, CVD, Type 2 Diabetes, and Total Mortality
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Peter Clifton, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Fish/seafood or DHA and EPA consumption had no overall effect on the risk of type 2 diabetes in 18 separate cohorts (Wu et al. 2012). However, in Asian cohorts, there was an 11% reduced risk in the highest intake, while there was a significant 20% increase (p < 0.02 for interaction) risk in diabetes in Western populations (North America and Europe). Asian subjects with type 2 diabetes also had significantly lower tissue levels of 22:6 N3 compared with those without diabetes (Zheng et al. 2012). Another meta-analysis found a significant protective effect of oily fish only, with a 20% reduced risk of type 2 diabetes per 80 g of fish/day. Ethnicity was not assessed in this study (Zhang et al. 2013). In Japan, fish intake was associated with a significant 27%–32% reduced risk of type 2 diabetes in men, but there was no significant effect in women. The fat content of fish was unrelated to risk (Nanri et al. 2011). In the Women’s Health Study, both fish and N3 intake were associated with increased risk of type 2 diabetes, but adjustment of fish for DHA content removed the risk, suggesting it was not fish per se but fish oil fatty acids that increased the risk (Djoussé et al. 2011). This may be due to N3 fats modulating the insulin receptor lipid microdomain.
Freeze-Fracture (-Etching) Analysis of Exo-Endocytosis
Published in Sek Wen Hui, Freeze-Fracture Studies of Membranes, 1989
The presence of regular IMP arrays in motor end plates and, less evidently though, in some spinal cord and brain cells (Table 1) might suggest that this precise ultrastructural setup could account for a rapid reaction to a stimulus. For example, Figure 18, from the work of Heuser et al.12 clearly shows that, in motor end plates of frogs, the exocytotic release of transmitter takes place in close association with perl-strings of IMP. As mentioned, ultrathin sections of this region had shown the occurrence of “connecting materials”45 of so far unidentified nature (see Section VII). In paramecia the release of trichocysts is also very rapid (though we do not yet know why). Why IMP arrays are needed in other systems listed in Table 1 is also poorly understood since not all these cells are known to have to release materials by exocytosis very rapidly. The implication of “rhoptries” (their fusion sites being endowed with rosettes) in host cell invasion also has become questioned.66-68 But clearly in heterothermic organisms, particularly in protozoa, IMP arrays are much more frequent than in higher organisms (Table 1). Unfortunately, no heterothermic organism has so far been thoroughly analyzed by freeze-fracturing with regard to IMP arrays in different secretory cells. So far we can only stress the possible importance (1) of the occurrence of some IMP and (2) of some kind of “connecting material” as general features relevant for exo-endocytotic membrane fusion. These may occur in a less concentrated form or as regular arrays at the exocytotically active regions of most organisms except for those listed in Table 1. Since regular IMP arrays are more evident in heterothermic organisms (Table 1), the question arises whether they might help there to provide a specific lipid microdomain which would be sufficiently susceptible to fusion triggering even at unfavorable temperatures. We do not know the answer to this question, however.
Structure, Function, and Regulation of Pulmonary Surfactant Proteins
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Jeffrey A. Whitsett, Timothy E. Weaver
Knowledge of the functions of SP-B in surfactant homeostasis are derived primarily from in vitro studies in which the SP-B peptide was reconstituted with phospholipids (Table 4). SP-B enhanced the adsorption and surface tension-lowering properties of synthetic phospholipids at low concentrations of peptide (0.1 to 1% by weight).133–136 Native SP-B and synthetic SP-B peptides improved the surface properties of lipids and lung function in premature rabbits in an excised rat lung model.135,136 Phospholipid mixtures containing SP-B achieve extremely low surface tension, as assessed by Wilhelmy balance or by pulsating bubble experiments, suggesting a role for SP-B in the purification of the lipids from the monolayer. SP-B interacts with SP-A in a cooperative manner to further enhance surface properties of surfactant lipid extracts91 and contributes to the structural organization of tubular myelin structures in vitro.84 The structural basis for the activity of the SP-B peptide has not been established with certainty. Theoretical modeling predicts that the SP-B peptide may be amphipathic in structure, with hydrophilic amino acid residues on one face and hydrophobic residues on the other. Such a model predicts that SP-B interacts primarily with the surfaces of the phospholipids (see Figure 5).137 Analysis of fluorescence anisotropy and fluorescence polarization, utilizing distinct fluorescent probes which localize near the polar head groups of the lipids (NBD-phosphatidylcholine) or more deeply in the interior of the acyl chain (trans-paranaric acid), support the concept that SP-B interacts primarily with the polar head groups of the phospholipids, organizing the surface of the lipids, and does not primarily alter the packing of acyl chains more deeply within the phospholipid bilayer.137 Fluorescence studies with NBD-PG support the concept that SP-B interacts selectively with phosphatidylglycerol. SP-B may therefore provide a protein-lipid microdomain in which phosphatidylglycerol clusters. Such clustering might then facilitate purification of the lipid monolayer during compression and relaxation associated with the respiratory cycle. Removal of PG would provide a more stable monolayer composed primarily of dipalmitoylphosphatidylcholine. While the precise molecular mechanisms underlying the effects of SP-B on surface activity remain to be clarified, the critical role of SP-B in lung function is supported by the observation that mice bearing monoclonal antibodies to SP-B develop severe lung injury and respiratory failure.138
Inhibitors of immuno-oncology target HPK1 – a patent review (2016 to 2020)
Published in Expert Opinion on Therapeutic Patents, 2021
HPK1, also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a member of the STE20-like serine/threonine kinase family whose expression is restricted to hematopoietic cells [8]. Other members of the MAP4K family include Germinal Center Kinase (GCK, MAP4K2), GCK-like kinase (GLK, MAP4K3), HPK1/GCK-like kinase (HGK, MAP4K4), Kinase homologous to SPS1/STE20 (KHS, MAP4K5) and Misshapen/Nck-related kinase (MINK MAP4K6) [9]. HPK1 is involved in the modulation of various downstream signaling pathways, such as extracellular signal–regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) [10,11] which are all associated with the regulation of cellular proliferation and immune cell activation. Upon T-cell antigen receptor (TCR) activation HPK1 migrates to the cholesterol-rich lipid microdomain where if forms a complex with the linker for activation of T-cells (LAT) and Gads [12]. Upon complexation with LAT/Gads HPK1 is phosphorylated at Tyr381 by Zeta Chain Of T Cell Receptor Associated Protein Kinase 70 (ZAP-70) generating the optimal-binding site for SH2-domain-containing leukocyte protein of 76 kDa (SLP-76). The binding of SLP76 alongside autophosphorylation at Thr165 and PKD1-mediated phosphorylation at Ser171 generate the fully active HPK1 [13,14]. Upon becoming catalytically active, HPK1 phosphorylates SLP-76 at Ser376 and Gads at Thr262 resulting in the disruption of the SLP-76/LAT complex and subsequent limitation of the strength and duration of the TCR signal [15,16]. Therefore, HPK1 can be considered as a negative regulator of T-cell function with possible inhibition of HPK1 leading to increased T-cell proliferation and cytokine production and thus an attractive approach for the immunotherapy of cancer.
CD133: beyond a cancer stem cell biomarker
Published in Journal of Drug Targeting, 2019
Amir Barzegar Behrooz, Amir Syahir, Syahida Ahmad
In summary, as shown in Figure 1, prominin-1, a plasma membrane cholesterol-binding pentaspan glycoprotein (lipid microdomain), is specifically located to plasma membrane protrusions and accumulates in membrane lipid microdomains [4,13] (Figure 1).
Amelioration of Cholesterol Rich diet-induced Impaired Cognition in AD Transgenic Mice by an LXR Agonist TO901317 Is Associated with the Activation of the LXR-β-RXR-α-ABCA1 Transmembrane Transport System and Improving the Composition of Lipid Raft
Published in Experimental Aging Research, 2023
Yang Na, Lin Ke, Zhang Jie, Wang Jinping, Meng Tao, Zhu Jie, Yang Liu, Zhou Yueqin
Lipid raft is a dynamic microstructure with abundant cholesterol and sphingolipids on the plasma membrane, and with a large number of membrane protein receptors. Lipid rafts are closely related to signal transduction Meran, Jeong, Yen, & Somi, (2020) substance transport (Huaming, Yuan, Dongsheng, & Zhenqiang, 2019) and neural protrusion plasticity (Wei, Qianyi, Liuwang, Zhiping, & Xiangqi, 2019). There is an increasing evidence that lipid rafts are associated with Aβ. It mainly shows as the following 3 respects: firstly, the lipid raft contains β secretase and γ secretase for Aβ degradation (Yoon, Oh-Hoon, & Sungkwon, 2020); secondly, ABCA1 and ApoE exist on the lipid raft, which can bind to Aβ (Hyun et al., 2016; Se-In et al., 2021) (Sup Figure S2); last, the content of lipid rafts in neurons in typical areas of AD, such as cerebral cortex and hippocampus, was significantly higher than that in other brain areas (Fiorella et al., 2010). Caveolae, flask-shaped, invaginated structures of the plasma membrane with a diameter of approximately 50–100 nm are involved in a number of important cellular processes including vesicular transport, cholesterol homeostasis, signal transduction and tumor suppression (Cristina et al., 2021; Yao et al., 2021). Caveolin-1, a multifunctional and scaffolding membrane protein, is a key biomarker of membranal caveolae of lipid rafts, which involves cholesterol trafficking to plasma lipid microdomain. In CAV-1-overexpressing animal models, plasma total cholesterol levels and hepatic free cholesterol levels were elevated; while, Frank et al., found that caveolin-1-deficient (CAV-1−/−) mice exhibited enhanced plasma triglyceride (TG) levels, increased high-density lipoprotein (HDL) levels, and reduced hepatic very low-density lipoprotein (VLDL) secretion (Philippe, Stephanos, Michelle, Kristin, & Michael, 2008). In CNS, Caveolin-1 organizes and targets synaptic parts of the neurotransmitter and neurotrophic receptor signaling pathways. Studies have shown that Caveolin-1 was closely related to AD. On one hand, Caveolin-1 was related to the cholesterol imbalance of AD; on the other hand, Caveolin-1 participated in the cleavage of APP and the formation of Aβ (Messiha, Ali, Khattab, & Abo-Youssef, 2020; Wenxin, Yan, Yan, & Qiang, 2021). Therefore, lipid raft is a key place of neurons for Aβ generation. Reducing the content of cholesterol will not only change the composition of lipid raft, but also affect the Aβ generation process. The results showed that TO901317 decreased the expression of caveolin-1, APP, BACE1 on the lipid raft in the brain of AD mice fed with cholesterol rich diet, and GSK2033 also partially antagonized the effect of TO901317.