Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.
although research of proton conductive materials has
been extended from traditional sulfonated polymers to novel crystalline
solid materials such as MOFs, COFs, and HOFs, research on crystalline
ferrocene-based carboxylate materials is very limited. Herein, we
selected two hydrogen-bonded and π–π interactions-supported
ferrocenyl carboxylate frameworks (FCFs), [FcCO(CH2)2COOH] (FCF 1) and [FcCOOH] (FCF 2) (Fc = (η5-C5H5)Fe(η5-C5H4)) to fully investigate their water-mediated
proton conduction. Their excellent thermal, water, and chemical stabilities
were confirmed by the means of thermogravimetric analyses, PXRD, and
SEM determinations. The two FCFs indicate temperature- and humidity-dependent
proton conductive features. Intriguingly, their ultrahigh proton conductivities
are 1.17 × 10–1 and 1.01 × 10–2 S/cm, respectively, under 100 °C and 98% RH, which not only
are comparable to the commercial Nafion membranes but also rank among
the highest performing MOFs, HOFs, and COFs ever described. On the
basis of the structural analysis, calculated E
a value, H2O vapor adsorption, PXRD, and SEM measurements,
reasonable conduction mechanisms are highlighted. Our research provides
a novel inspiration for finding new high proton conducting crystalline
solid materials. Importantly, the outstanding conducting performance
of 1 and 2 suggests their, hopefully, potential
in fuel cells and related electrochemical fields.
Aging is a multifactorial phenotype characterized by physiological changes with multifaceted effects or alterations causing gradual functional decline in a living organism (López-Otín et al., 2013). These age-associated alterations are also risk factors for various complex diseases such as cancer, diabetes, cardiovascular, and neurodegenerative diseases (López-Otín et al., 2013). Given its complex nature, the biology of aging has not been completely elucidated yet (Partridge, 2010). A number of genes and proteins in diverse biologic pathways have been implicated in influencing aging and longevity (Johnson et al., 1999). Some of the mechanisms that have
Psychological and behavioural interventions may be effective in reducing menopause-related symptoms. This randomized controlled trial aimed to evaluate the effectiveness of Mindfulness-based Stress Reduction (MBSR) in reducing menopause-related symptoms by comparing with an active control group, the menopause education control (MEC). Symptomatic peri-menopausal and post-menopausal women with mild to moderate symptoms were recruited. The primary outcome was overall menopausal symptoms measured by modified Greene Climacteric Scale (GCS). Secondary outcomes include subscales of the GCS perceived stress, mindfulness and health related Quality of Life. All outcome measures were collected at baseline, 2 months (immediately post intervention), 5 and 8 months (3 and 6 months post intervention respectively). Both MBSR (n = 98) and MEC (n = 99) groups reported a reduction in total GCS score at 8 months. Between group analysis show significant symptom score reduction in MBSR group on Anxiety and Depression subscales of GCS. No differences were found between groups on other GCS subscales and majority of the secondary outcome measures. The findings show that menopausal symptoms in both MBSR and MEC significantly reduced over the study period. MBSR show a greater reduction of psychological symptoms of depression and anxiety above active controls but do not reduce other somatic, urogenital and vasomotor symptoms.
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