PCSK9 and cancer: Rethinking the link Mahboobnia, Khadijeh; Pirro, Matteo; Marini, Ettore ...
Biomedicine & pharmacotherapy,
August 2021, 2021-08-00, 2021-08-01, Letnik:
140
Journal Article
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Cancer is emerging as a major problem globally, as it accounts for the second cause of death despite medical advances. According to epidemiological and basic studies, cholesterol is involved in ...cancer progression and there are abnormalities in cholesterol metabolism of cancer cells including prostate, breast, and colorectal carcinomas. However, the importance of cholesterol in carcinogenesis and thereby the role of cholesterol homeostasis as a therapeutic target is still a debated area in cancer therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9), a serine protease, modulates cholesterol metabolism by attachment to the LDL receptor (LDLR) and reducing its recycling by targeting the receptor for lysosomal destruction. Published research has shown that PCSK9 is also involved in degradation of other LDLR family members namely very-low-density-lipoprotein receptor (VLDLR), lipoprotein receptor-related protein 1 (LRP-1), and apolipoprotein E receptor 2 (ApoER2). As a result, this protein represents an interesting therapeutic target for the treatment of hypercholesterolemia. Interestingly, clinical trials on PCSK9-specific monoclonal antibodies have reported promising results with high efficacy in lowering LDL-C and in turn reducing cardiovascular complications. It is important to note that PCSK9 mediates several other pathways apart from its role in lipid homeostasis, including antiviral activity, hepatic regeneration, neuronal apoptosis, and modulation of various signaling pathways. Furthermore, recent literature has illustrated that PCSK9 is closely associated with incidence and progression of several cancers. In a number of studies, PCSK9 siRNA was shown to effectively suppress the proliferation and invasion of the several studied tumor cells. Hence, a novel application of PCSK9 inhibitors/silencers in cancer/metastasis could be considered. However, due to poor data on effectiveness and safety of PCSK9 inhibitors in cancer, the impact of PCSK9 inhibition in these pathological conditions is still unknown.
A vast literature search was conducted to find intended studies from 1956 up to 2020, and inclusion criteria were original peer-reviewed publications.
To date, PCSK9 has been scantly investigated in cancer. The question that needs to be discussed is “How does PCSK9 act in cancer pathophysiology and what are the risks or benefits associated to its inhibition?”. We reviewed the available publications highlighting the contribution of this proprotein convertase in pathways related to cancer, with focus on the potential implications of its long-term pharmacological inhibition in cancer therapy.
•PCSK9 is a serine protease modulating cholesterol metabolism by attachment to the LDL receptor.•Recent literature suggests that PCSK9 is associated with incidence and progression of several cancers.•Herein, we reviewed how PCSK9 acts in cancer pathophysiology.•We also explored potential risks or benefits associated to PCSK9 inhibition in cancer.
Spin waves, and their quanta magnons, are prospective data carriers in future signal processing systems because Gilbert damping associated with the spin-wave propagation can be made substantially ...lower than the Joule heat losses in electronic devices. Although individual spin-wave signal processing devices have been successfully developed, the challenging contemporary problem is the formation of two-dimensional planar integrated spin-wave circuits. Using both micromagnetic modeling and analytical theory, we present an effective solution of this problem based on the dipolar interaction between two laterally adjacent nanoscale spin-wave waveguides. The developed device based on this principle can work as a multifunctional and dynamically reconfigurable signal directional coupler performing the functions of a waveguide crossing element, tunable power splitter, frequency separator, or multiplexer. The proposed design of a spin-wave directional coupler can be used both in digital logic circuits intended for spin-wave computing and in analog microwave signal processing devices.
Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease. NAFLD is considered a multifactorial disease and a clinically relevant hepatic manifestation of metabolic syndrome. ...NAFLD is often accompanied by a constellation of metabolic and non-metabolic alterations, like dyslipidemia, insulin resistance in the liver and peripheral tissues, inflammation and oxidative stress; therefore, treatment of NAFLD should be directed at correcting all of these disturbances. The natural polyphenol curcumin has been the subject of increasing research for the treatment of NAFLD due to its lipid-modifying, antioxidant, anti-inflammatory, insulinsensitizing, anti-steatotic, and anti-fibrotic properties. The therapeutic efficacy of curcumin has been demonstrated in several experimental models of NAFLD, however, clinical evidence is still scarce. The present review summarizes the current knowledge on the impact of curcumin supplementation on different biochemical and histopathological features of NAFLD.
In recent years, several disease-modifying therapies have been developed for the treatment of multiple sclerosis (MS). Cladribine transiently depletes B and T lymphocytes, with subsequent gradual ...cell recovery. No cases are reported in literature describing Cladribine drug-induced liver injury (DILI). We describe the case of a 19-year-old woman who developed acute idiosyncratic liver injury 12 days after treatment with Cladribine. Post-marketing adverse event reporting is of paramount importance to allow an early recognition and treatment. Moreover, evaluation of the physiopathological mechanism underlying drug-induced hepatic toxicity can provide clinicians with valuable instruments for prevention and treatment.
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to ...fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943.
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•LY3437943 has triple agonist activity at the glucagon, GIP, and GLP-1 receptors•LY3437943 caused greater body weight loss in obese mice than tirzepatide•LY3437943 increased energy expenditure through glucagon receptor activation•Safety and tolerability of LY3437943 were similar to other incretin-based drugs
Coskun et al. demonstrate that LY3437943, a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes, can reduce body weight through increased energy expenditure and reduced calorie intake in obese mice. Its safety and tolerability in healthy participants were similar to other incretin-based therapies.
The miniaturization of complementary metal–oxide–semiconductor (CMOS) devices becomes increasingly difficult due to fundamental limitations and the increase of leakage currents. Large research ...efforts are devoted to find alternative concepts that allow for a larger data-density and lower power consumption than conventional semiconductor approaches. Spin waves have been identified as a potential technology that can complement and outperform CMOS in complex logic applications, profiting from the fact that these waves enable wave computing on the nanoscale. The practical application of spin waves, however, requires the demonstration of scalable, CMOS compatible spin-wave detection schemes in material systems compatible with standard spintronics as well as semiconductor circuitry. Here, we report on the wave-vector independent detection of short-waved spin waves with wavelengths down to 150 nm by the inverse spin Hall effect in spin-wave waveguides made from ultrathin Ta/Co8Fe72B20/MgO. These findings open up the path for miniaturized scalable interconnects between spin waves and CMOS and the use of ultrathin films made from standard spintronic materials in magnonics.
Effects of statins on mitochondrial pathways Mollazadeh, Hamid; Tavana, Erfan; Fanni, Giovanni ...
Journal of cachexia, sarcopenia and muscle,
April 2021, Letnik:
12, Številka:
2
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Statins are a family of drugs that are used for treating hyperlipidaemia with a recognized capacity to prevent cardiovascular disease events. They inhibit β‐hydroxy β‐methylglutaryl‐coenzyme A ...reductase, i.e. the rate‐limiting enzyme in mevalonate pathway, reduce endogenous cholesterol synthesis, and increase low‐density lipoprotein clearance by promoting low‐density lipoprotein receptor expression mainly in the hepatocytes. Statins have pleiotropic effects including stabilization of atherosclerotic plaques, immunomodulation, anti‐inflammatory properties, improvement of endothelial function, antioxidant, and anti‐thrombotic action. Despite all beneficial effects, statins may elicit adverse reactions such as myopathy. Studies have shown that mitochondria play an important role in statin‐induced myopathies. In this review, we aim to report the mechanisms of action of statins on mitochondrial function. Results have shown that statins have several effects on mitochondria including reduction of coenzyme Q10 level, inhibition of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation of Ca2+ metabolism, and carnitine palmitoyltransferase‐2 expression. The use of statins has been associated with the onset of additional pathological conditions like diabetes and dementia as a result of interference with mitochondrial pathways by various mechanisms, such as reduction in mitochondrial oxidative phosphorylation, increase in oxidative stress, decrease in uncoupling protein 3 concentration, and interference in amyloid‐β metabolism.
Overall, data reported in this review suggest that statins may have major effects on mitochondrial function, and some of their adverse effects might be mediated through mitochondrial pathways.
Cytokine members of the IL‐12 family have attracted enormous attention in the last few years, with IL‐35 being the one of the most attractive‐suppressive cytokine. IL‐35 is an important mediator of ...regulatory T cell function. Regulatory T cells play key roles in restoring immune homeostasis after facing challenges such as infection by specific pathogens. Moreover, a crucial role for regulatory T cell populations has been demonstrated in several physiological processes, including establishment of fetal–maternal tolerance, maintenance of self‐tolerance and prevention of autoimmune diseases. However, a deleterious involvement of immune regulatory T cells has been documented in specific inhibition of immune responses against tumor cells, promotion of chronic infections and establishment of chronic inflammatory disorders. In this review, we attempt to shed light on the concept of immune‐homoeostasis on the aforementioned issues, taking IL‐35 as the hallmark of regulatory responses. The dilemma between immune‐mediated cancer treatment and inflammation is discussed. Histopathological indications of chronic vs. acute infections are elaborated. Moreover, the evidence that IL‐35 requires additional immune‐regulatory cytokines, such as IL‐10 and TGF‐β, to induce effective and maximal anti‐inflammatory effects suggest that immune‐regulation requires multi‐factorial analysis of many immune playmakers rather than a specific immune target.
IMPORTANCE: Refractive error (RE) is the most common form of visual impairment, and myopic RE is associated with an increased risk of primary open-angle glaucoma (POAG). Whether this association ...represents a causal role of RE in the etiology of POAG remains unknown. OBJECTIVE: To evaluate shared genetic influences and investigate the association of myopic RE with the risk for POAG. DESIGN, SETTING, AND PARTICIPANTS: Observational analyses were used to evaluate the association between mean spherical equivalent (MSE) RE (continuous trait) or myopia (binary trait) and POAG risk in individuals from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. To quantify genetic overlap, genome-wide genetic correlation analyses were performed using genome-wide association studies (GWAS) of MSE RE or myopia and POAG from GERA. Potential causal effects were assessed between MSE RE and POAG using 2-sample Mendelian randomization. Genetic variants associated with MSE RE were derived using GWAS summary statistics from a GWAS of RE conducted in 102 117 UK Biobank participants. For POAG, we used GWAS summary statistics from our previous GWAS (3836 POAG cases and 48 065 controls from GERA). Data analyses occurred between July 2020 and October 2021. MAIN OUTCOMES AND MEASURE: Our main outcome was POAG risk as odds ratio (OR) caused by per-unit difference in MSE RE (in diopters). RESULTS: Our observational analyses included data for 54 755 non-Hispanic White individuals (31 926 58% females and 22 829 42% males). Among 4047 individuals with POAG, mean (SD) age was 73.64 (9.20) years; mean (SD) age of the 50 708 controls was 65.38 (12.24) years. Individuals with POAG had a lower refractive MSE and were more likely to have myopia or high myopia compared with the control participants (40.2% vs 34.1%, P = 1.31 × 10−11 for myopia; 8.5% vs 6.8%, P = .004 for high myopia). Our genetic correlation analyses demonstrated that POAG was genetically correlated with MSE RE (rg, −0.24; SE, 0.06; P = 3.90 × 10−5), myopia (rg, 0.21; SE, 0.07; P = .004), and high myopia (rg, 0.23; SE, 0.09; P = .01). Genetically assessed refractive MSE was negatively associated with POAG risk (inverse-variance weighted model: OR per diopter more hyperopic MSE = 0.94; 95% CI, 0.89-0.99; P = .01). CONCLUSIONS AND RELEVANCE: These findings demonstrate a shared genetic basis and an association between myopic RE and POAG risk. This may support population POAG risk stratification and screening strategies, based on RE information.
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