China
Africa
Explore chapters and articles related to this topic
Generalized and Metabolic Disease
Published in Wilmer W Nichols, Michael F O'Rourke, Elazer R Edelman, Charalambos Vlachopoulos, McDonald's Blood Flow in Arteries, 2022
The latest breakthrough in cardiovascular prevention is considered by many to be the development of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for the treatment of hypercholesterolemia. Their impressive reductions in lipids (about 60 percent) seems to be accompanied by a 15 percent reduction in cardiovascular events over a period of 2 to 3 years (Evolocumab, FOURIER: Sabatine et al., 2017; alirocumab, ODYSSEY outcomes: Schwartz et al., 2018). We, among others, have shown a strong, positive association of PCSK9 levels with vascular function indices identifying a new pathophysiological link for the associations of dyslipidemia and vascular dysfunction (Vlachopoulos et al., 2018; Ruscica et al., 2017). Whether these monoclonal antibodies will show an effect on arterial function and structure indices is awaited with anticipation.
Dyslipidemia
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
PCSK9 monoclonal antibodies are formulated for subcutaneous injection, once to twice per month. They stop proprotein convertase subtilisin/kexin type 9 from attaching to LDL receptors, improving their function. The LDL is lowered by 40%–70%. Trials with alirocumab and evolocumab revealed less cardiovascular events when previous atherosclerotic cardiovascular disease was present. The cholesterol absorption inhibitors, including ezetimibe, inhibit absorption of cholesterol and phytosterol in the intestines. The LDL is usually lowered by ezetimibe by 15%–20%, with small increases in HDL and a slight decrease in total triglycerides. Ezetimibe can be used alone if the patient cannot tolerate statins, or it can be added to statins if the patient is on maximum statin dosage, with LDL remaining chronically elevated. Adverse effects of cholesterol absorption inhibitors are rare.
Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
SARS-CoV and SARS-CoV-2 S proteins share 76.2% amino acid sequence homology and both use ACE-2 as a receptor [79]. Because of four amino acids (PRRA) insertion at the S1/S2 junction, a furin cleavage site (681PRRAR|SV687) has evolved for SARS-CoV-2 that is not present in SARS-CoV or its closest bat ancestor viruses [80]. Furin is a type-I transmembrane, trypsin-type, serine protease that belongs to the proprotein convertase (PC: gene PCSK) family, which cleaves precursor proteins within the motif (R/K)−(X−X)n−(R/K)| (n = 0, 1, 2, or 3) [81]. PCs activate a wide variety of host secretory proteins and viral surface glycoproteins. PCs are abundant in multiple tissues including the respiratory tract and acquisition of a furin site has led to generation of highly pathogenic avian H5 and H7 influenza viruses [82]. In fact, the furin cleavage site exists in a number of human coronaviruses (CoVs) including MERS-CoV, HKU1-CoV, and OC43-CoV [82], suggesting that the existence of a furin site does not necessarily correlate with hyper-transmissibility and pathogenesis. However, the furin site greatly enhances SARS-CoV-2 transmission and pathogenesis in animal models [83]. Thus, it is highly likely that a gain of furin cleavage site has enabled SARS-CoV-2 to jump into humans and begin its current pandemic spread [84].
Advances in the available pharmacotherapy for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation
Published in Expert Opinion on Pharmacotherapy, 2023
Antonio Greco, Simone Finocchiaro, Dominick J. Angiolillo, Davide Capodanno
Evolocumab and alirocumab are subcutaneous monoclonal antibodies inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). In the FOURIER trial, 27,564 patients with atherosclerotic cardiovascular disease already on statin were randomized to evolocumab or placebo; at 48 weeks, compared to placebo, evolocumab reduced the incidence of MACE (9.8% vs. 11.3%; HR 0.85; 95% CI 0.79 to 0.92; p < 0.001) [114]. These results were also confirmed in a prespecified subgroup analysis of patients with a recent MI (within 12 months) of the FOURIER trial [115]. Similarly, the ODYSSEY-OUTCOMES trial randomized 18,924 patients with previous ACS to alirocumab or placebo; at a median follow-up of 2.8 years, MACE were reduced with compared to placebo (9.5% vs. 11.1%; HR 0.85; 95% CI 0.78 to 0.93; p < 0.001), driven by a reduction in mortality (3.5% vs. 4.1%; HR 0.85; 95% CI 0.73 to 0.98) [116]. Alirocumab was also recently tested on top of statin in the randomized PACMAN-AMI trial: the two non-infarct-related arteries of 300 patients undergoing PCI for MI were serially studied with intravascular ultrasound, near-infrared spectroscopy, and optical coherence tomography; at 52 weeks, alirocumab was associated with significantly greater coronary plaque regression compared with placebo [117].
Antibodies against phosphorylcholine and protection against atherosclerosis, cardiovascular disease and chronic inflammation
Published in Expert Review of Clinical Immunology, 2022
Even though the role of inflammation in atherosclerosis, and thus CVD, has been known for long time, the focus of research in this field was for rather long time on other aspects, albeit important, such as dyslipidemia. This has led to development of improved prevention and/ treatment of the major established risk factors: hypertension, smoking, diabetes and hypercholesterolemia. Treatment of hypertension with different medications, is arguably one of the real successes of medicine today. Also treatment of diabetes has improved, and hypercholesterolemia can now be controlled by both statins and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)-inhibition. The role of smoking has been highlighted, and incidence of smoking has decreased in many countries. Still, there is no medication available which was developed to decrease the inflammation in atherosclerosis. In line with this, the proinflammatory immune response occurring in atherosclerosis in general remains to be treated. Even though it is likely that both statins and PCSK9-inhibition not only exert their atheroprotective and CVD-decreasing effects due to lipid lowering, but also because of anti-inflammatory and immune modulatory properties, this is difficult to demonstrate in scientific studies. Still, several lines of evidence argue that such pleiotropic effects play a role. In spite of this progress, atherosclerosis and CVD still represent the leading cause of death, not only as previously, in the ‘developed world’ but increasingly in the whole world.
DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination
Published in Journal of Extracellular Vesicles, 2020
Chu-An Wang, I-Heng Chang, Pei-Chi Hou, Yu-Jing Tai, Wan-Ning Li, Pei-Ling Hsu, Shang-Rung Wu, Wen-Tai Chiu, Chien-Feng Li, Yan-Shen Shan, Shaw-Jenq Tsai
Expression of VEGF-C in cancer cells can be controlled at different levels [32–38], but few studies focus on its post-translational regulation [39–41]. As a secreted growth factor, the function and receptor specificity of VEGF-C are determined by proteolytic cleavage via different modes [29,41]. The 30 kD VEGF-C promotes mainly lymphangiogenesis while the fully processed 21 kD VEGF-C stimulates both lymphangiogenesis and angiogenesis [4]. Therefore, it is critical to determine the level of secreted VEGF-C in conditioned medium of cancer cells. In our study, we found that DUSP2-KD not only affects the mRNA level of VEGF-C but most importantly, significantly enhances the level of secreted and functional forms of VEGF-C. The 30 kD form of VEGF-C was markedly elevated in the conditioned media and EVs of DUSP2-KD cells, which is consistent with the known function of VEGF-C and the observation that lymphangiogenesis is elevated in murine and human pancreatic cancers. Although the expression level of proprotein convertases such as furin, PC5/6, and PCSK7, is similar, overall proprotein convertase activity is increased in DUSP2-KD cell lysates. On the topic of regulation of proprotein convertase activity, little is known besides that autocleavage and correct subcellular location are required [42,43]. Thus, a detailed mechanism of how DUSP2 regulates proprotein convertase activity remains to be investigated.