Brinkpearson4323

Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.Skeletal muscle, a significant contributor to resting energy expenditure and reactive oxygen species, may play a critical role in body-weight regulation and aging processes. Methionine restriction (MR) is a dietary intervention which extends lifespan, lowers body-weight and enhances energy expenditure in rodents, all of which have been linked to mitochondrial function in various tissues including liver, kidney, heart and brown adipose tissue; however, mitochondrial responses to MR in skeletal muscle is largely unknown. Given the importance of skeletal muscle on energy metabolism and aging-related processes, we investigated if there are changes in skeletal muscle mitochondrial energetics in response to MR. selleck Although MR lowers body-weight in rats, neither respiration, proton leak nor hydrogen peroxide metabolism were altered in isolated skeletal muscle mitochondria. This suggests that mitochondrial function in skeletal muscle remains conserved while MR alters metabolism in other tissues.Concussion has become a growing concern among sport and healthcare practitioners. Experts continue to investigate ways to advance the quality of concussion evaluation, diagnosis and management. Psychological conditions have been reported to influence concussion assessment outcomes at baseline and post-concussion; however, little evidence has examined psychological conditions and their effect on multifaceted measures of concussion. A retrospective cohort design was employed to examine differences between those with and without a premorbid psychological condition for high school and collegiate athletes who completed a preseason baseline battery, consisting of symptom reporting, computerized neurocognitive assessment, Vestibular-Ocular Motor Screening (VOMS), and the King-Devick (KD) test. Forty athletes within the sample self-reported a diagnosed psychological risk factor, consisting of depression and/or anxiety, and each were matched with a discordant control. Controls were matched on sex, age, sport, concussion history and ocular history. Athletes with psychological conditions reported higher symptom severity and had worse visual motor speed than controls. There were no differences between groups on other neurocognitive domains, VOMS, or KD. These results suggest that vestibular-ocular tools may be more consistent or less likely to vary between those with and without a premorbid psychological diagnosis, adding value to tools such as the KD and VOMS.Amyotrophic Lateral Sclerosis (ALS) is a fast-progressive neurodegenerative disease leading to progressive physical immobility with usually normal or mild cognitive and/or behavioural involvement. Many patients are relatively young, instructed, sensitive to new technologies, and professionally active when developing the first symptoms. Older patients usually require more time, encouragement, reinforcement and a closer support but, nevertheless, selecting user-friendly devices, provided earlier in the course of the disease, and engaging motivated carers may overcome many technological barriers. ALS may be considered a model for neurodegenerative diseases to further develop and test new technologies. From multidisciplinary teleconsults to telemonitoring of the respiratory function, telemedicine has the potentiality to embrace other fields, including nutrition, physical mobility, and the interaction with the environment. Brain-computer interfaces and eye tracking expanded the field of augmentative and alternative communication in ALS but their potentialities go beyond communication, to cognition and robotics. Virtual reality and different forms of artificial intelligence present further interesting possibilities that deserve to be investigated. COVID-19 pandemic is an unprecedented opportunity to speed up the development and implementation of new technologies in clinical practice, improving the daily living of both ALS patients and carers. The present work reviews the current technologies for ALS patients already in place or being under evaluation with published publications, prompted by the COVID-19 pandemic.Strict quality control for mitochondrial proteins is necessary to ensure cell homeostasis. Two cellular pathways-Ubiquitin Proteasome System (UPS) and autophagy-contribute to mitochondrial homeostasis under stressful conditions. Here, we investigate changes to the mitochondria proteome and to the ubiquitin landscape at mitochondria in response to proteasome inhibition. Treatment of HeLa cells devoid of Parkin, the primary E3 ligase responsible for mitophagy, with proteasome inhibitor MG132 for a few hours caused mitochondrial oxidative stress and fragmentation, reduced energy output, and increased mitochondrial ubiquitination without inducing mitophagy. Overexpression of Parkin did not show any induction of mitophagy in response to MG132 treatment. Analysis of ubiquitin chains on isolated mitochondria revealed predominance of K48, K29 and K63-linked polyubiquitin. Interestingly, of all ubiquitinated mitochondrial proteins detected in response to MG132 treatment, a majority (≥90%) were intramitochondrial irrespective of Parkin expression.