Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. ...Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.
Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic ...cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N¹-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9–mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.
Abstract
Objective
To observe the effect of niacinamide‐containing body emollients combined with a cleansing gel on the clinical symptoms of mild atopic dermatitis (AD) in adults.
Methods
From July ...2022 to January 2023, adults with mild AD were enrolled at Huashan Hospital Affiliated to Fudan University using single‐center, randomized and placebo‐controlled methods. They were divided into three groups: the control group, treatment group 1 (T1) receiving niacinamide‐containing body emollients alone, and treatment group 2 (T2) receiving emollients plus niacinamide‐containing cleansing gel. All patients were orally administered 10 mg of ebastine tablets daily. AD severity (SCORAD score), peak pruritus numeric rating scale (PP‐NRS), patient‐oriented measure of eczema (POEM), dermatological quality of life index (DLQI) score, transepidermal water loss (TEWL), and stratum corneum water content (SCWC) were measured by the same dermatologist at days 0, 7, 14, and 28.
Results
A total of 122 patients were enrolled, including 38 in the control group, 42 in the T1 group and 42 in the T2 group. There were no obvious adverse reactions at the end of the study and the clinical scores and stratum corneum barrier of all the groups improved significantly relative to baseline. The SCORAD, PP‐NRS, DLQI, TEWL and SCWC scores in T1 group (12.43 ± 3, 3.3 ± 0.9, 7.1 ± 2.33, 17.1 ± 9.12, 67.2 ± 21.46, seperately) and T2 group (11.17 ± 3.26, 3 ± 1.3, 6.5 ± 2.11, 16.3 ± 9.12, 69.4 ± 24.52, seperately) were significantly improved than the control group(15.1 ± 3.64, 4.3 ± 1.7, 9.5 ± 2.46, 21.2 ± 9.47, 52.7 ± 22.43, seperately) at the endpoint of the study, while compared the POEM scores, only T2 group showed the difference with control group (5.2 ± 1.4 vs. 6 ± 1.6). The epidermal barrier parameters of TEWL and SCWC in the T2 group (17.57 ± 5.24, 66.46 ± 21.38, seperately) were significantly better than that of the T1 (19.96 ± 4.45, 56.45 ± 20.48, seperately) and control group(21.89 ± 7.03, 51.56 ± 16.58, seperately) on the 14th day of follow‐up.
Conclusion
The use of niacinamide‐containing body emollients can significantly improve the clinical symptoms, quality of life, and skin barrier function in patients with mild AD. The addition of niacinamide‐containing cleansing gel can also affect the clinical efficacy at certain time points.
Targeting mitochondrial quality control with melatonin has been found promising for attenuating diabetic cardiomyopathy (DCM), although the underlying mechanisms remain largely undefined. Activation ...of SIRT6 and melatonin membrane receptors exerts cardioprotective effects while little is known about their roles during DCM. Using high‐fat diet‐streptozotocin‐induced diabetic rat model, we found that prolonged diabetes significantly decreased nocturnal circulatory melatonin and heart melatonin levels, reduced the expressions of cardiac melatonin membrane receptors, and decreased myocardial SIRT6 and AMPK‐PGC‐1α‐AKT signaling. 16 weeks of melatonin treatment inhibited the progression of DCM and the following myocardial ischemia‐reperfusion (MI/R) injury by reducing mitochondrial fission, enhancing mitochondrial biogenesis and mitophagy via re‐activating SIRT6 and AMPK‐PGC‐1α‐AKT signaling. After the induction of diabetes, adeno‐associated virus carrying SIRT6‐specific small hairpin RNA or luzindole was delivered to the animals. We showed that SIRT6 knockdown or antagonizing melatonin receptors abolished the protective effects of melatonin against mitochondrial dysfunction as evidenced by aggravated mitochondrial fission and reduced mitochondrial biogenesis and mitophagy. Additionally, SIRT6 shRNA or luzindole inhibited melatonin‐induced AMPK‐PGC‐1α‐AKT activation as well as its cardioprotective actions. Collectively, we demonstrated that long‐term melatonin treatment attenuated the progression of DCM and reduced myocardial vulnerability to MI/R injury through preserving mitochondrial quality control. Melatonin membrane receptor‐mediated SIRT6‐AMPK‐PGC‐1α‐AKT axis played a key role in this process. Targeting SIRT6 with melatonin treatment may be a promising strategy for attenuating DCM and reducing myocardial vulnerability to ischemia‐reperfusion injury in diabetic patients.
Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining ...activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53K98R) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KRK117R+K161R+K162R) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity.
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•CBP acetylates human p53 at K101 and mouse p53 at K98•K98 acetylation of mouse p53 contributes to regulation of certain metabolic genes•p534KR98 is defective in suppressing tumor growth•Ferroptosis and repression of SLC7A11 are defective in p534KR98-expressing cells
Wang et al. show that K98 acetylation of mouse p53 by CBP further contributes to the regulation of p53 transcriptional function by other known p53 acetylations (K117/161/162). Simultaneous absence of acetylation at K98 and at other positions in the DNA-binding domain results in the loss of tumor suppression in xenografts and ferroptosis.
Dark matter detectors with directional sensitivity have the capability to distinguish dark matter induced nuclear recoils from isotropic backgrounds, thus providing a smoking gun signature for dark ...matter in the Galactic halo. Motivated by recent progress in graphene and two-dimensional materials research, we propose a novel class of directional dark matter detectors utilizing graphene-based van der Waals heterostructures. A conceptual design of the detector based on graphene/hexagonal boron nitride and graphene/molybdenum disulfide heterostructures is developed and analyzed. The proposed detector has modular scalability, keV-scale detection threshold, nanometer position resolution, sensitivity down to 10
GeV
/
c
2
dark matter mass, and intrinsic head-tail discrimination and background rejection capabilities.
The p53 tumor suppressor is a multifaceted polypeptide that impedes tumorigenesis by regulating a diverse array of cellular processes. Triggered by a wide variety of stress stimuli, p53 ...transcriptionally regulates genes involved in the canonical tumor suppression pathways of apoptosis, cell-cycle arrest, and senescence. We recently discovered a novel mechanism whereby p53 inhibits cystine uptake through repression of the SLC7A11 gene to mediate ferroptosis. Importantly, this p53-SLC7A11 axis is preserved in the p53
3KR
mutant, and contributes to its ability to suppress tumorigenesis in the absence of the classical tumor suppression mechanisms. Here, we report that wild type p53 can induce both apoptosis and ferroptosis upon reactive oxygen species (ROS)-induced stress. Furthermore, we demonstrate that p53's functional N-terminal domain is required for its capacity to regulate oxidative stress responses and ferroptosis. Notably, activated p53 dynamically modulates intracellular ROS, causing an initial reduction and a subsequent increase of ROS levels. Taken together, these data implicate ferroptosis as an additional component of the cell death program induced by wild type p53 in human cancer cells, and reveal a complex and dynamic role of p53 in oxidative stress responses.
Full-waveform inversion (FWI) utilizes optimization methods to recover an optimal Earth model to best fit the observed seismic record in a sense of a predefined norm. Since FWI combines mathematic ...inversion and full-wave equations, it has been recognized as one of the key methods for seismic data imaging and Earth model building in the fields of global/regional and exploration seismology. Unfortunately, conventional FWI fixes background velocity mainly relying on refraction and turning waves that are commonly rich in large offsets. By contrast, reflections in the short offsets mainly contribute to the reconstruction of the high-resolution interfaces. Restricted by acquisition geometries, refractions and turning waves in the record usually have limited penetration depth, which may not reach oil/gas reservoirs. Thus, reflections in the record are the only source that carries the information of these reservoirs. Consequently, it is meaningful to develop reflection-waveform inversion (RWI) that utilizes reflections to recover background velocity including the deep part of the model. This review paper includes: analyzing the weaknesses of FWI when inverting reflections; overviewing the principles of RWI, including separation of the tomography and migration components, the objective functions, constraints; summarizing the current status of the technique of RWI; outlooking the future of RWI.
Optical coherence elastography (OCE) represents the frontier of optical elasticity imaging techniques and focuses on the micro‐scale assessment of tissue biomechanics in 3D that is hard to achieve ...with traditional elastographic methods. Benefit from the advancement of optical coherence tomography, and driven by the increasing requirements in nondestructive biomechanical characterization, this emerging technique recently has experienced a rapid development. In this paper, we start with the description of the mechanical contrast that has been employed by OCE and review the state‐of‐the‐art techniques based on the reported applications and discuss the current technical challenges, emphasizing the unique role of OCE in tissue mechanical characterization.
The position of OCE among other elastography techniques.
Optical coherence elastography (OCE) is an emerging 3D nondestructive biomechanical imaging technique that has recently experienced a rapid development. In this paper, the mechanical contrast employed by OCE is described, the state‐of‐the‐art OCE techniques are reviewed from the application point of view, and the current challenges and potential solutions are discussed. Throughout this review, the unique role of OCE for the mechanical characterization of tissue are emphasized and highlighted.
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