Endocrine therapy is one of the main treatments for estrogen receptor–positive breast cancers. Tamoxifen is the most commonly used drug for endocrine therapy. However, primary or acquired tamoxifen ...resistance occurs in a large proportion of breast cancer patients, leading to therapeutic failure. We found that the combination of tamoxifen and ACT001, a nuclear factor‐κB (NF‐κB) signaling pathway inhibitor, effectively inhibited the proliferation of both tamoxifen‐sensitive and tamoxifen‐resistant cells. The tamoxifen‐resistant cell line MCF7R/LCC9 showed active NF‐κB signaling and high apoptosis‐related gene transcription, especially for antiapoptotic genes, which could be diminished by treatment with ACT001. These results demonstrate that ACT001 can prevent and reverse tamoxifen resistance by inhibiting NF‐κB activation.
Tamoxifen simultaneously promotes apoptosis and activates the nuclear factor‐κB (NF‐κB)–mediated antiapoptotic pathway, as a stress response, and that NF‐κB signaling and antiapoptotic gene expression are associated with tamoxifen resistance.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims
Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has ...potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia‐induced cognitive decline in mice.
Methods
Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia and HNK or SIRT3 inhibitor (3‐TYP) treatment. Cognitive function and locomotor activity of mice were evaluated using fear conditioning test and open field test on postoperative 1 and 3 days. Neuronal apoptosis in CA1 and CA3 area of hippocampus was examined using TUNEL assay. And Western blot was applied to measure the expression of pro‐inflammatory cytokines and SIRT3/SOD2 signaling‐associated proteins in hippocampus. Meanwhile, SIRT3 positive cells were calculated by immunohistochemistry. The mitochondrial membrane potential, malondialdehyde (MDA), and mitochondrial radical oxygen species (mtROS) were detected using standard methods.
Results
Honokiol attenuated surgery‐induced memory loss and neuronal apoptosis, decreased neuroinflammatory response, and ameliorated oxidative damage in hippocampus. Notably, surgery/anesthesia induced an obviously decrease in hippocampal SIRT3 expression, whereas the HNK increased SIRT3 expression and thus decreased the acetylation of superoxide dismutase 2 (SOD2). However, 3‐TYP treatment inhibited the HNK's rescuing effects.
Conclusions
These results suggested that activation of SIRT3 by honokiol may attenuate surgery/anesthesia‐induced cognitive impairment in mice through regulation of oxidative stress and neuroinflammatory in hippocampus.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The human ether-a-go-go-related gene (hERG) K
channel conducts a rapidly activating delayed rectifier K
current (I
), which is essential for normal electrical activity of the heart. Precise ...regulation of hERG channel biogenesis is critical for serving its physiological functions, and deviations from the regulation result in human diseases. However, the mechanism underlying the precise regulation of hERG channel biogenesis remains elusive. Here, by using forward genetic screen, we found that PATR-1, the
homolog of the yeast DNA topoisomerase 2-associated protein PAT1, is a critical regulator for the biogenesis of UNC-103, the ERG K
channel in
. A loss-of-function mutation in
down-regulates the expression level of UNC-103 proteins and suppresses the phenotypic defects resulted from a gain-of-function mutation in the
gene. Furthermore, downregulation of PATL1 and PATL2, the human homologs of PAT1, decreases protein levels and the current density of native hERG channels in SH-SY5Y cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Knockdown of PATL1 and PATL2 elongates the duration of action potentials in hiPSC-CMs, suggesting that PATL1 and PATL2 affect the function of hERG channels and hence electrophysiological characteristics in the human heart. Further studies found that PATL1 and PATL2 interact with TFIIE, a general transcription factor required for forming the RNA polymerase II preinitiation complex, and dual-luciferase reporter assays indicated that PATL1 and PATL2 facilitate the transcription of hERG mRNAs. Together, our study discovers that evolutionarily conserved DNA topoisomerase 2-associated proteins regulate the biogenesis of hERG channels via a transcriptional mechanism.
Background. The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative ...diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia. Methods. In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy. Results. The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated. Conclusion. These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Parallel test assembly has long been an important yet challenging topic in educational assessment. Cognitive diagnosis models (CDMs) are a new class of assessment models and have drawn increasing ...attention for being able to measure examinees' ability in detail. However, few studies have been devoted to the parallel test assembly problem in CDMs (CDM-PTA). To fill the gap, this paper models CDM-PTA as a subset-based bi-objective combinatorial optimization problem. Given an item bank, it aims to find a required number of tests that achieve optimal but balanced diagnostic performance, while satisfying important practical requests in the aspects of test length, item type distribution, and overlapping proportion. A set-based multiobjective particle swarm optimizer based on decomposition (S-MOPSO/D) is proposed to solve the problem. To coordinate with the property of CDM-PTA, S-MOPSO/D utilizes an assignment-based representation scheme and a constructive learning strategy. Through this, promising solutions can be built efficiently based on useful assignment patterns learned from personal and collective search experience on neighboring scalar problems. A heuristic constraint handling strategy is also developed to further enhance the search efficiency. Experimental results in comparison with three representative approaches validate that the proposed algorithm is effective and efficient.
Purpose
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease with synovitis as pathological changes. The immune microenvironment of RA promotes metabolic reprogramming of immune cells ...and stromal cells, which leads to dysfunction and imbalance of immune homeostasis. Cell metabolism undergoes the switch from a static regulatory state to a highly metabolic active state, which changes the redox-sensitive signaling pathway and also leads to the accumulation of metabolic intermediates, which in turn can act as signaling molecules and further aggravate the inflammatory response. The reprogramming of immunometabolism affects the function of immune cells and is crucial to the pathogenesis of RA. In addition, mitochondrial dysfunction plays a key role in glycolytic reprogramming in RA. These metabolic changes may be potential therapeutic targets for RA. Therefore, we reviewed the metabolic reprogramming of RA immune cells and fibroblast-like synovium cells (FLS) and its relationship with mitochondrial dysfunction.
Methods
A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning immunometabolic reprogramming, mitochondrial dysfunction, and rheumatoid arthritis.
Results
This article reviews the metabolic reprogramming of immune cells and fibroblast-like synoviocytes in RA and their relationship to mitochondrial disfunction, as well as the key pro-inflammatory pathways associated with metabolic reprogramming and chemotherapy as a potential future therapeutic strategy for RA.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This study develops a tunable 3D nanostructured conductive gel framework as both binder and conductive framework for lithium ion batteries. A 3D nanostructured gel framework with continuous electron ...pathways can provide hierarchical pores for ion transport and form uniform coatings on each active particle against aggregation. The hybrid gel electrodes based on a polypyrrole gel framework and Fe3O4 nanoparticles as a model system in this study demonstrate the best rate performance, the highest achieved mass ratio of active materials, and the highest achieved specific capacities when considering total electrode mass, compared to current literature. This 3D nanostructured gel‐based framework represents a powerful platform for various electrochemically active materials to enable the next‐generation high‐energy batteries.
A tunable 3D nanostructured gel framework with continuous electron pathways can provide hierarchical pores for ion transport and form uniform coatings on each active particle against aggregation. The hybrid gel electrodes based on a polypyrrole gel framework and Fe3O4 nanoparticles demonstrate one of the best rate performances and the highest achieved specific capacities when considering total electrode mass.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Palladium-catalyzed regioselective α-amino C–H functionalization via the isomerization of α,β-unsaturated carbonyls including esters, ketones, and amides has been established, providing an easy ...access to a wide array of tricyclic 1,2,3,4-tetrahydro-b-carbolines, azepinoindoles, 2,3,4,5-tetrahydro-1H-pyrido4,3-bindoles, 4,5,6,7-tetrahydro-1H-pyrrolo2,3-cpyridines, 1,2,3,4-tetrahydropyrazino-1,2-aindoles, pyran-fused indoles, and tetrahydroisoquinolines in good to excellent yields. This transformation showed high regioselectivity, excellent functional group tolerance, and scalability. Moreover, this methodology was also employed as the key step for the total synthesis of desbromoarborescidines A, B, and C. Preliminary mechanistic studies revealed that the palladium catalyst not only formed Pd–H to promote the isomerization of α,β-unsaturated carbonyls but also played a role as a Lewis acid for the final protonation/cyclization.
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IJS, KILJ, NUK, PNG, UL, UM
Reining in the outliers: An efficient approach for enantioselective hydrogenation of 3,4‐disubstituted isoquinolines was successfully developed. When isoquinolines are treated with ...Ir(cod)Cl2/(R)‐synphos in the presence of 1‐bromo‐3‐chloro‐5,5‐dimethyl‐hydantoin (BCDMH), the chiral 3,4‐disubstituted tetrahydroisoquinoline derivatives are obtained with ee values as high as 96 % (see scheme; cod=1,5‐cyclooctadiene).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated
. Although there has been a global increase in human life expectancy, increasing ...longevity is rarely accompanied by an extended healthspan
. Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases
shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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