A small population of cancer stem cells named the "side population" (SP) has been demonstrated to be responsible for the persistence of many solid tumors. However, the role of the SP in leukemic ...pathogenesis remains controversial. The resistance of leukemic stem cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ATP-binding cassette sub-family G member 2 (ABCG2), is well known as a specific marker of the SP and could be controlled by several pathways, including the PI3K/Akt pathway. Our data demonstrated that compared with wild-type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated phosphatase and tensin homologue deleted on chromosome -10 (PTEN) and activated phosphorylated-Akt (p-Akt). PTEN and p-Akt downregulation could be abrogated by both the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin. Moreover, in CML patients in the accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression was accompanied by the loss of PTEN protein and the up-regulation of p-Akt expression. These results suggested that the expression of ABCG2 and the SP may be regulated by PTEN through the PI3K/Akt pathway, which would be a potentially effective strategy for targeting CML stem cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by ...targeting specific cellular proteins remains largely unknown. In the present work, self‐assembling nanomicelles are constructed using small‐molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N‐terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor‐bearing mouse models and stimulate immune cell infiltration. Collectively, this proof‐of‐concept study advances the mechanical understanding of nanostructure‐guided biological effects via their inherent capacity to activate proteasome.
Self‐assembling nanomicelles constructed by small‐molecule oleanolic acid (OA) significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanistically, OA nanomicelles interact with PSMA6 to dynamically modulate its N‐terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome, thus accelerating the degradation of several crucial proteins and driving cancer cell pyroptosis.
Protopanaxadiol (PPD), a main ginseng metabolite, exerts powerful anticancer effects against multiple types of cancer; however, its cellular targets remain elusive. Here, we synthesized a ...cell‐permeable PPD probe via introducing a bifunctional alkyne‐containing diazirine photo‐crosslinker and performed a photoaffinity labeling‐based chemoproteomic study. We identified retinoblastoma binding protein 4 (RBBP4), a chromatin remodeling factor, as an essential cellular target of PPD in HCT116 colorectal cancer cells. PPD significantly decreased RBBP4‐dependent trimethylation at lysine 27 of histone H3 (H3K27me3), a crucial epigenetic marker that correlates with histologic signs of colorectal cancer aggressiveness, and PPD inhibition of proliferation and migration of HCT116 cells was antagonized by RBBP4 RNA silencing. Collectively, our study highlights a previously undisclosed anti‐colorectal cancer cellular target of the ginseng metabolite and advances the fundamental understanding of RBBP4 functions via a chemical biology strategy.
HCT116 cells were treated with the cell permeable probe AD‐PPD, and irradiated with UV in situ. Labelled proteomes were further conjugated to biotin‐PEG3‐azide via click chemistry, and the target of protopanaxadiol (PPD) was identified as RBBP4 by LC‐MS/MS analysis.
The swim bladder of the croceine croaker (
) was believed to have good curative effects in various diseases, including amnesia, insomnia, dizziness, anepithymia, and weakness after giving birth, in ...traditional Chinese medicine. However, there is no research focusing on the antioxidant and anti-fatigue peptides from croceine croaker swim bladders at present. Therefore, the purpose of this study was to investigate the bioactivities of peptide fractions from the protein hydrolysate of croceine croaker related to antioxidant and anti-fatigue effects. In the study, swim bladder peptide fraction (SBP-III-3) was isolated from the protein hydrolysate of the croceine croaker, and its antioxidant and anti-fatigue activities were measured using in vitro and in vivo methods. The results indicated that SBP-III-3 exhibited good scavenging activities on hydroxyl radicals (HO•) (EC
(the concentration where a sample caused a 50% decrease of the initial concentration of HO•) = 0.867 mg/mL), 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH•) (EC
= 0.895 mg/mL), superoxide anion radical ( O 2 - •) (EC
= 0.871 mg/mL), and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid radical (ABTS⁺•) (EC
= 0.346 mg/mL). SBP-III-3 also showed protective effects on DNA damage in a concentration-effect manner and prolonged the swimming time to exhaustion of Institute of Cancer Research (ICR) mice by 57.9%-107.5% greater than that of the control. SBP-III-3 could increase the levels of muscle glucose (9.4%-115.2% increase) and liver glycogen (35.7%-157.3%), and decrease the levels of blood urea nitrogen (BUN), lactic acid (LA), and malondialdehyde (MDA) by 16.4%-22.4%, 13.9%-20.1%, and 28.0%-53.6%, respectively. SBP-III-3 also enhanced the activity of lactic dehydrogenase to scavenge excessive LA for slowing the development of fatigue. In addition, SBP-III-3 increased the activities superoxide dismutase, catalase, and glutathione peroxidase to reduce the reactive oxygen species (ROS) damage in mice. In conclusion, SBP-III-3 possessed good anti-fatigue capacities on mice by inhibiting the oxidative reactions and provided an important basis for developing the swim bladder peptide functional food.
The aim of the study was to testify the association of dietary resveratrol (RSV) intakes with hip fracture risk in Chinese elderly. This was a 1:1 age‐ and gender‐ matched case–control study. ...Eligible cases were newly diagnosed patients of hip fracture. Dietary assessment was made by a 79‐item validated food frequency questionnaire. Habitual RSV intakes were estimated as the sum of trans‐ and cis‐ isomers of resveratrol and piceid according to the available database. Multivariable conditional logistic regression was applied to examine the relationship of dietary RSV and RSV‐rich foods with hip fracture risk. A total of 1,070 pairs of hip fracture incident cases and controls were recruited and 1,065 were included for analysis. Compared with the lowest group, total RSV in the highest quartile group had significantly reduced hip fracture risk by 66.3% (OR: 0.337, 0.222 ~ 0.571, ptrend < 0.001). Similar findings were observed for cis‐ and trans‐RSV, cis‐ and trans‐Piceid, as well as RSV‐rich foods (grapes, apples and nuts) respectively. Subgroup analysis suggested more evident findings among female and less obese participants. Our findings demonstrated that higher habitual RSV intakes and RSV‐rich foods, even in a relatively low amount, were associated with reduced risk of hip fracture in Chinese elderly.
Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that ...iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.
Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy ...represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate–cysteine ligase GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH). Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.
Wedge‐shaped molecules, such as dendrons, are among the most important building blocks for directed supramolecular self‐assembly. Here we present a new approach aimed at widening the range and ...complexity of potential mesophases by introducing double‐tapered mesogens. Two series of compounds are presented, both alkali metal salts (Li, Na, Cs) of 3,4,5‐tris‐alkoxybenzoic acid with a second tapered tris‐alkoxyaryl group attached at the end of an alkoxy chain. The double‐tapered compounds all display an unusual hexagonal columnar phase consisting of one ionic and three non‐ionic columns per unit cell. The cation size has an unexpectedly drastic effect on unit cell size. Unlike most columnar phases, the current phases show unusually high dimensional stability on heating, and high stiffness in spite of being 80–85 % aliphatic, attributed to their molecular topology. The described approach may lead to co‐assemblies of multifunctional materials, for example, parallel p‐ and n‐semiconducting nanowires or parallel ionic and electronic conductors.
The introduction of double‐taper shaped molecules using a series of simple model carboxylate salt mini‐dendrons opens a route to complex self‐assembly of mixed columns, mixed spheres, or mixed columns and spheres, leading potentially to new self‐organized multifunctional materials.
Pulse wave velocity (PWV) is a measure of arterial stiffness and predicts cardiovascular events and mortality in the general population and various patient populations. In the present study, we ...investigated the predictive value of brachial-ankle PWV for mortality in an elderly Chinese population. Our study subjects were older (≥60 years) persons living in a suburban town of Shanghai. We measured brachial-ankle PWV using an automated cuff device at baseline and collected vital information till June 30, 2013, during follow-up. The 3876 participants (1713 44.2% men; mean ±SD age, 68.1±7.3 years) included 2292 (59.1%) hypertensive patients. PWV was on average 17.8 (±4.0) m/s and was significantly (P<0.0001) associated with age (r=0.48) and in unadjusted analysis with all-cause (n=316), cardiovascular (n=148), stroke (n=46), and noncardiovascular mortality (n=168) during a median follow-up of 5.9 years. In further adjusted analysis, we studied the risk of mortality according to the decile distributions of PWV. Only the subjects in the top decile (23.3-39.3 m/s) had a significantly (P≤0.003) higher risk of all-cause mortality (hazard ratio relative to the whole study population, 1.56; 95% confidence interval, 1.16-2.08), especially in hypertensive patients (hazard ratio, 1.86; 95% confidence interval, 1.31-2.64; P=0.02 for the interaction between PWV and hypertension). Similar trends were observed for cardiovascular, stroke, and noncardiovascular mortality, although statistical significance was not reached (P≥0.08). In conclusion, brachial-ankle PWV predicts mortality in elderly Chinese on the conditions of markedly increased PWV and hypertension.
To better understand the olfactory mechanisms in the rice leaf folder, Cnaphalocrocis medinalis (Guenée), a serious pest of rice in Asia, we established six partial transcriptomes from antennae, ...protarsus, and reproductive organs of male and female adults. A total of 102 transcripts were identified, including 29 odorant receptors (ORs), 15 ionotropic receptors (IRs), 30 odorant-binding proteins (OBPs), 26 chemosensory proteins (CSPs), and 2 sensory neuron membrane proteins (SNMPs). The expression patterns of these genes were calculated by fragments per kilobase of exon per million fragments mapped (FPKM) and validated by real-time quantitative PCR (RT-qPCR). Some transcripts were exclusively expressed in specific organs, such as female protarsus, whereas others were universally expressed, this varied expression profile may provide insights into the specific functions mediated by chemoreception proteins in insects. To the best of our knowledge, among the 102 identified transcripts, 81 are novel and have never been reported before. In addition, it also is the first time that ORs and IRs are identified in C. medinalis. Our findings significantly enhance the currently limited understanding olfactory mechanisms of the olfactory mechanisms underlying the chemoreception system in C. medinalis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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