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Nutrition and Nutraceutical Supplements for the Treatment of Hypertension
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2015
Increased sodium intake has a direct adverse effect on endothelial cells.57–61 Sodium promotes cutaneous lymphangiogenesis; increases endothelial cell stiffness; reduces size, surface area, volume, cytoskeleton, deformability, and pliability; reduces eNOS and NO production; and increases asymmetric dimethyl arginine (ADMA), oxidative stress, and TGF-β. All of these abnormal vascular responses are increased in the presence of aldosterone.57–61 These changes occur independent of BP and may be partially counteract by dietary potassium.57–61 The endothelial cells act as vascular salt sensors.62 Endothelial cells are targets for aldosterone, which activate epithelial sodium channels and have a negative effect on the release of NO and on endothelial function. The mechanical stiffness of the cell plasma membrane and the submembranous actin network (endothelial glycocalyx) (“shell”) serve as a “firewall” to protect the endothelial cells and are regulated by serum sodium, potassium, and aldosterone within the physiological range.62 Changes in shear stress–dependent activity of the endothelial NO synthase located in the caveolae regulate the viscosity in this shell.62 High plasma sodium gelates the shell of the endothelial cell, whereas the shell is fluidized by high potassium. These communications between extracellular ions and intracellular enzymes occur at the plasma membrane barrier, whereas 90% of the total cell mass remains uninvolved in these changes. Blockade of the epithelial sodium channel (ENaC) with spironolactone (100%) or amiloride (84%) minimizes or stops many of these vascular endothelial responses and increases NO.60,63 Nitric oxide release follows endothelial nanomechanics and not vice versa and membrane depolarization decreases vascular endothelial cell stiffness, which improves flow-mediated nitric oxide–dependent vasodilation.64,65 In the presence of vascular inflammation and increased HS-CRP, the effects of aldosterone on ENaC is enhanced further increasing vascular stiffness and BP.66 High sodium intake also abolishes the AT2R-mediated vasodilation immediately, with complete abolition of endothelial vasodilation within 30 days.67 Thus, it is clear that increased dietary sodium has adverse effects on the vascular system, BP, and CVD by altering the endothelial glycocalyx, which is a negatively charged biopolymer that lines the blood vessels and serves as a protective barrier against sodium overload, increased sodium permeability, and sodium-induced TOD.68 Certain SNPs of salt-inducible kinase I (SIK1) that alter Na+/K+ ATPase determine sodium-induced hypertension and LVH.69
Desmoplastic small round cell tumor: from state of the art to future clinical prospects
Published in Expert Review of Anticancer Therapy, 2023
Shushan Hovsepyan, Claudia Giani, Sandro Pasquali, Angela Di Giannatale, Stefano Chiaravalli, Chiara Colombo, Daniel Orbach, Luca Bergamaschi, Sabina Vennarini, Susanne Andrea Gatz, Patrizia Gasparini, Pablo Berlanga, Michela Casanova, Andrea Ferrari
Other hypotheses paving the way to clinical trials were formulated following the development of new cell lines and PDX models. One example concerns the Salt-Inducible Kinase 1 (SIK1), a member of the AMPK-related kinase family involved in a broad spectrum of biological processes, which is a direct target of the EWSR1:WT1 fusion protein[112]. Interestingly, a reduction in SIK1 causes a tumor cell growth inhibition comparable with what happens when EWSR1:WT1 expression is abolished, and SIK1 silencing leads to the cessation of DNA replication and tumor growth inhibition. Targeting SIK1 with the YKL-05-099 small-molecule inhibitors resulted in significant cytotoxicity. Another relevant example concerns the activation of the ERBB pathway in DSRCT, which occurred through the fusion protein EWSR1:WT1 and resulted in the upregulation of EGFR, ERBB2, ERK1/2, and AKT, and the stimulation of cell growth. DSRCT cell line proliferation could be blocked by antagonizing EGFR function with shRNAs, the small-molecule inhibitors afatinib and neratinib, or the anti-EGFR antibody cetuximab [113]. Remarkably, a combination of cetuximab and afatinib inhibited tumor growth in PDX of DSRCT, giving rise to a preclinical hypothesis promoting the clinical testing of agents that target EGFR in DSRCT.
Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake
Published in Clinical and Experimental Hypertension, 2021
Nuno M. Pires, Bruno Igreja, Patrício Soares-da-Silva
Salt-inducible kinases (SIKs) represent a subfamily of AMP-activated protein kinase (AMPK) family kinases (1). Within the AMPK family, the subfamily of SIKs contains three kinases (SIK1, SIK2, and SIK3). SIK1, the founding member of this subfamily, was identified and named as a kinase whose expression is induced in the adrenal gland of rats fed a high-salt (HS) diet (2). Subsequent homology searches led to the identification of SIK2 and SIK3 and all three SIK family kinases are expressed broadly (3–5). As an isoform of the SIK family, SIK2 modulates various biological functions and acts as a signal transmitter in various pathways (3,6). Compared with that in adjacent normal tissues, the expression of SIK2 is significantly higher in multiple types of tumors, which indicates its pivotal effect in oncogenesis (7).
Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors
Published in Drug Delivery, 2021
Xianhu Zeng, Zhipeng Li, Chunrong Zhu, Lisa Xu, Yong Sun, Shangcong Han
The recombinant adenovirus was constructed by cloning the 2,337 base-pair PCR product into linearized adenovirus plasmid GV314 using T4 DNA ligase and transfecting into competent Escherichia coli cells. Positive clones were screened by ampicillin resistance and then underwent ABI 3730 sequencing analysis. SIK1-overexpressing adenovirus (Ad-SIK1) was packaged in human embryonic kidney 293 T cells and purified with the Adenovirus X purification kit. The virus titer was determined by an end-point dilution method (Zhou et al. 2019). The results showed that SIK1 plays an important role in the regulation of liver glucose and lipid metabolism, and it inhibits liver gluconeogenesis and lipogenesis. SIK1 also plays a role in the regulation of metabolic diseases and is found in tumor diseases. In cervical squamous cell carcinoma cells, SIK1 inhibits the invasion and metastasis of cancer cells (Peng et al. 2020). In colorectal cancer, the upregulated targeting of SIK1 by miR-17 has been found to promote the process of colorectal cancer, and thus, this mechanism has also become a potential therapeutic target (Huang et al. 2019).