Phenethyl isothiocyanate (PEITC) is a candidate anticancer compound found in certain cruciferous vegetables. In our tumor cell xenograft model, dietary administration of PEITC (100-150 mg/kg body ...weight/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth. We found that dietary treatment with PEITC significantly inhibited tumor platelet/endothelial cell adhesion molecule (PECAM-1/CD31) expression, a marker of angiogenesis. By contrast, we did not find the inhibitory effects of PEITC on tumor growth to be associated with alteration of specific markers for apoptosis, cell proliferation or androgen receptor-mediated pathways. Consistent with in vivo results, PEITC exerted little effects on cell proliferation, cell cycle and androgen-dependent pathways. Interestingly, PEITC significantly attenuated LNCaP cell plating efficiency that correlated with inhibition of integrin family proteins integrin β1, α2 and α6 mRNA expression. Thus, PEITC may be a dietary factor that inhibits androgen-responsive prostate tumor growth indirectly by selectively targeting factors involved in the tumor microenvironment.
Aims/hypothesis
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the ...aim of identifying novel variants for type 2 diabetes in Asians.
Methods
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
Results
We identified
CDKN2A/B
and four novel type 2 diabetes association signals with
p
< 1 × 10
−5
from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (
p
meta
= 2.6 × 10
−8
; OR 95% CI 1.18 1.11, 1.25). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (
p
meta
= 2.3 × 10
−10
) and a population of European descent (
p
= 8.6 × 10
−3
). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Conclusions/interpretation
Our study identifies rs10229583 near
PAX4
as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Humidity control is an important environmental concern in storage, transport, and preservation operations in agriculture, food, medical, and other industrial fields. In the present work, we prepared ...a nanocomposite having flower shaped morphology that consists of metal (Cu) nanoparticles, a metal oxide (ZnO nanorods), and reduced graphene oxide (rGO) with a one-pot synthesis method for the AC conductivity and Humidity sensing response studies at room temperature. The morphology of the nanocomposite was characterized by using XRD, SEM, EDX, and TEM analysis. Conduction in the nanocomposite due to the hopping mechanism was confirmed by studying the power law behavior of its AC conductivity. The nanocomposite shows a maximum sensing response of 97.79% in the range of 11–97% RH, with response and recovery times of 19 s and 42 s, respectively. The nanocomposite shows a low humidity hysteresis and stable humidity sensing ability. The possible humidity sensing mechanism is discussed in detail. Our results show that the nanocomposite having flower shaped morphology is an ideal candidate for building MEMS/NEMS humidity sensors.
A genome-scale CRISPR knockout library screen of THP-1 human macrophages was performed to identify loss-of-function mutations conferring resistance to
uptake. The screen identified 183 candidate ...genes, from which 14 representative genes involved in actin dynamics (
,
,
,
,
,
, and
), glycosaminoglycan metabolism (
), receptor signaling (
and
), lipid raft formation (
), calcium transport (
and
), and cholesterol metabolism (
) were analyzed further. For some of these pathways, known chemical inhibitors could replicate the
resistance phenotype, indicating their potential as targets for host-directed therapy. The screen indicated a role for the relatively uncharacterized gene
in both
invasion and macrophage differentiation. Upon differentiation,
mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL, EIF2AK2, and KLHL13.
exploits macrophages to gain access to the lymphatic system and bloodstream to lead to local and potentially systemic infections. With an increasing number of antibiotic-resistant isolates identified in humans,
infections have become major threats to public health. Therefore, there is an urgent need to identify alternative approaches to anti-infective therapy, including host-directed therapies. In this study, we used a simple genome-wide screen to identify 183 candidate host factors in macrophages that can confer resistance to
infection. These factors may be potential therapeutic targets against
infections.
Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We ...hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells and thereby promote recruitment of monocytes. Given the inhibitory effect of broccoli-derived compounds indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) on androgen-dependent pathways, we also reasoned that I3C and DIM could modulate the effect of androgen on CCL2-mediated pathways. Dihydrotestosterone was found to induce a time-dependent (0-72 hours) and concentration-dependent (0-1 nmol/L) increase in CCL2 mRNA levels in androgen-responsive human prostate cancer cells (LNCaP). This increase in CCL2 mRNA corresponded with increased secretion of CCL2 protein. The effect of dihydrotestosterone was mediated through an androgen receptor (AR)-dependent pathway as small inhibitor RNA against AR negated the induction of CCL2. Although dihydrotestosterone also induced TWIST1 mRNA, an epithelial-mesenchymal transition-related factor, and purported inducer of CCL2, blocking its expression with small inhibitor RNA did not inhibit dihydrotestosterone induction of CCL2 mRNA. Moreover, conditioned media from androgen-treated cells promoted human monocyte THP-1 cell migration and this effect was blocked by antibody against CCL-2. Both I3C and DIM inhibited promotional effects of dihydrotestosterone on CCL2 and migration. These results show that androgen may regulate CCL2 and promote inflammatory microenvironment in prostate tumors and that this process can be blocked by broccoli-derived compounds.
Recent evidence suggests that the liver X receptor (LXR) is a potential anticancer target in prostate carcinoma. There is little characterization, however, of which of the two LXR isoforms, LXRalpha ...or LXRbeta, regulates the LXR-responsive genes ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine whether LXRalpha or LXRbeta is involved in regulating ABCA1 and ABCG1 mRNA expression in LNCaP and PC-3 cells. Treatment of both cell lines with the synthetic LXR ligand T0901317 and oxysterols: 25-hydroxycholesterol (25HC) and 24(S), 25-epoxycholesterol (24,25EC), resulted in more than a 10-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXRbeta or LXRalpha failed to inhibit T0901317 and 25HC-mediated increase of ABCA1 mRNA. siRNA silencing of LXRbeta did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXRbeta siRNA inhibited T0901317, 25HC, and 24,25EC induction of ABCA1 mRNA in PC-3 cells and ABCG1 mRNA in both LNCaP and PC-3 cells. Additional experiments revealed that T0901317 and 25HC induction of ABCA1 mRNA expression was significantly inhibited by the p38 stress kinase antagonist SB202190 and PKA inhibitor H89. Our study is the first to show that LXRbeta, but not LXRalpha, is the major regulatory isoform of ABCG1 mRNA expression in LNCaP and PC-3 cells. Our study also reveals that ABCA1 gene expression is differentially regulated by synthetic and natural LXR ligands, possibly involving kinase mediated signal transduction.
A wealth of preclinical evidence supports the antitumorigenic properties of indole-3-carbinol (I3C), which is a major bioactive food component in cruciferous vegetables. However, the underlying ...molecular mechanism(s) accounting for these effects remain unresolved. In the present study, estrogen receptor alpha (ER-α) was identified as a potential molecular target for I3C. Treating MCF-7 cells with 100 μM I3C reduced ER-α mRNA expression by approximately 60% compared to controls. This reduction in ER-α transcript levels was confirmed using real-time polymerase chain reaction. The I3C dimer, 3,3′-diindolylmethane (DIM), was considerably more effective in depressing ER-α mRNA in MCF-7 cells than the monomeric unit. The suppressive effects of 5 μM DIM on ER-α mRNA was comparable to that caused by 100 μM I3C. DIM is known to accumulate in the nucleus and is a preferred ligand for aryl hydrocarbon receptor (AhR) to I3C. The addition of other AhR ligands, α-naphthoflavone (α-NF, 10 μM) and luteolin (10 μM), to the culture media resulted in a similar suppression in ER-α mRNA levels to that caused by 5 μM DIM. Thus, it is likely that the binding of ligands to AhR inhibits nuclear ER-α transcript. The results from these experiments suggest that the antitumorigenic effects of I3C in MCF-7 human breast cancer cells may arise from its ability to reduce ER-α expression through the binding of its metabolite, DIM, to the nuclear AhR.
Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, ...metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
Select subsets of immune effector cells have the greatest propensity to mediate antitumor responses. However, procuring these subsets is challenging, and cell-based immunotherapy is hampered by ...limited effector-cell persistence and lack of on-demand availability. To address these limitations, we generated a triple-gene-edited induced pluripotent stem cell (iPSC). The clonal iPSC line was engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a and a membrane-bound interleukin (IL)-15/IL-15R fusion protein. The third edit was a knockout of the ecto-enzyme CD38, which hydrolyzes NAD+. Natural killer (NK) cells derived from these uniformly engineered iPSCs, termed iADAPT, displayed metabolic features and gene expression profiles mirroring those of cytomegalovirus-induced adaptive NK cells. iADAPT NK cells persisted in vivo in the absence of exogenous cytokine and elicited superior antitumor activity. Our findings suggest that unique subsets of the immune system can be modeled through iPSC technology for effective treatment of patients with advanced cancer.
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•iADAPT NK cells and adaptive NK cells share metabolic and transcriptional features•iADAPT NK cells are cytokine autonomous•iADAPT NK cells display enhanced innate immune function
Optimized iPSC-derived NK (iNK) cells have been developed for on-demand cancer immunotherapy. Here, Cichocki and colleagues describe a triple-gene-edited iNK cell product, termed iADAPT NK, which persists and functions in vivo in the absence of exogenous cytokines and can be combined with therapeutic antibodies for enhanced tumor targeting.
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