Gene/Protein Disease Symptom Drug Enzyme Compound
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 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer), has demonstrated activity against a variety of solid tumors. Sunitinib is "multi-targeted," inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However cardiac dysfunction has been associated with its use. Identification of the target of sunitinib associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anti-cancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib-induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, AMPK activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib-treated mice and cardiomyocytes in culture and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus-mediated gene transfer of an actived mutant of AMPK reduces sunitinib-induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off-target effects of TKIs contributing to cardiotoxicity. While multi-targeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction.
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PMID:Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. 2037 35

Since the discovery of antibiotics in the first quarter of the twentieth century, their use has been the principal approach to treat bacterial infection. Modernized medicine such as cancer therapy, organ transplantation or advanced major surgeries require effective antibiotics to manage bacterial infections. However, the irresponsible use of antibiotics along with the lack of development has led to the emergence of antimicrobial resistance which is considered a serious global threat due to the rise of multidrug-resistant bacteria (Wang et al. in Antibiotic resistance: a rundown of a global crisis, pp. 1645-1658, 2018). Currently employed diagnostics techniques are microscopy, colony counting, ELISA, PCR, RT-PCR, surface-enhanced Raman scattering and others. These techniques provide satisfactory selectivity and sensitivity (Joung et al. in Sens Actuators B Chem 161:824-831, 2012). Nevertheless, they demand specialized personnel and expensive and sophisticated machinery which can be labour-intensive and time-consuming, (Malvano et al. in Sensors (Switzerland) 18:1-11, 2018; Mantzila et al. in Anal Chem 80:1169-1175, 2008). To get around these problems, new technologies such as biosensing and lab-on-a-chip devices have emerged in the last two decades. Impedimetric immunosensors function by applying electrochemical impedance spectroscopy to a biosensor platform using antibodies or other affinity proteins such as Affimers (Tiede et al. in Elife 6(c):1-35, 2017) or other binding proteins (Weiss et al. in Electrochim Acta 50:4248-4256, 2005) as bioreceptors, which provide excellent sensitivity and selectivity. Pre-enrichment steps are not required and this allows miniaturization and low-cost. In this review different types of impedimetric immunosensors are reported according to the type of electrode and their base layer materials, either self-assembled monolayers or polymeric layers, composition and functionalization for different types of bacteria, viruses, fungi and disease biomarkers. Additionally, novel protein scaffolds, both antibody derived and non-antibody derived, used to specifically target the analyte are considered.
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PMID:A review on impedimetric immunosensors for pathogen and biomarker detection. 3224 98