MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses ...pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.
•ERK phosphorylation followed by Pin1-mediated isomerization impairs XPO5 activity•Downregulation of miR-122 leads to taxol resistance through septin-9 and MARK4•XPO5 phosphorylation correlates with poor prognosis in HCC patients•Pin1 and MARK4 are potential targets for clinical intervention in liver cancer
Sun et al. find that ERK phosphorylates XPO5, which induces a Pin1-mediated conformational change that inhibits the ability of XPO5 to load and export pre-miRNA from the nucleus. Phosphorylation of XPO5 is associated with global miRNA downregulation and correlates with poor survival in hepatocellular carcinoma.
In this study, a marine brown alga
-derived fungal strain,
SC29, was isolated and identified. Column chromatography of the extracts from liquid fermented products of the fungal strain was carried out ...and led to the isolation of six compounds. Their structures were elucidated by spectroscopic analysis and supported by single-crystal X-ray diffraction as four previously undescribed (
)-3-hydroxybutyric acid and glycolic acid derivatives, namely penisterines A (
) and C-E (
-
) and penisterine A methyl ether (
), isolated for the first time from natural resources, along with (
)-3-hydroxybutyric acid (
). Of these compounds identified, penisterine E (
) was a unique 6/6/6-tricyclic ether with an acetal and two hemiketal functionalities. All the isolates were subjected to in vitro anti-angiogenic assays using a human endothelial progenitor cell (EPCs) platform. Among these, penisterine D (
) inhibited EPC growth, migration, and tube formation without any cytotoxic effect. Further, in in vivo bioassays, the percentages of angiogenesis of compound
on
(
:EGFP) transgenic zebrafish were 54% and 37% as the treated concentration increased from 10.2 to 20.4 µg/mL, respectively, and the percentages of angiogenesis of compound
were 52% and 41% as the treated concentration increased from 8.6 to 17.2 µg/mL, respectively. The anti-angiogenic activity of penisterine D (
) makes it an attractive candidate for further preclinical investigation.
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•Plumbagin does not affect the cell viability of human EPCs.•Plumbagin suppresses VEGF-promoted EPC migration and tube formation.•Plumbagin reduces VEGF-induced promotion of PLC, Akt ...and ERK activation.•Plumbagin inhibits VEGF-induced promotion of NF-κB and HIF-1 activation in EPCs.•Plumbagin suppress EPC expression and angiogenesis in vivo.
Plumbagin, a naturally occurring naphthoquinone component isolated from the root of Plumbago zeylanica, reduces angiogenesis in human umbilical vein endothelial cells; whether plumbagin also has anti-angiogenic activity in human endothelial progenitor cells (EPCs) has remained unclear. Importantly, the recruitment of bone marrow-derived EPCs promotes physiological and pathological neovascularization. In this study, plumbagin inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human EPCs, without cytotoxic effects. We also found that plumbagin inhibited angiogenesis via the phospholipase C (PLC), Akt, extracellular-signal-regulated kinase (ERK), nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)-1 signaling pathways. In an EPC Matrigel plug assay, plumbagin significantly diminished microvessel formation and EPC-specific marker expression. Our report is the first to reveal that plumbagin reduces EPC-related angiogenesis both in vitro and in vivo. Further evaluations of plumbagin are warranted, to determine its antitumor activity and other angiogenesis-related disorders.
This paper proposes a new quadratic stabilization condition for Takagi-Sugeno (T-S) fuzzy control systems. The condition is represented in the form of linear matrix inequalities (LMIs) and is shown ...to be less conservative than some relaxed quadratic stabilization conditions published recently in the literature. A rigorous theoretic proof is given to show that the proposed condition can include previous results as special cases. In comparison with conventional conditions, the proposed condition is not only suitable for designing fuzzy state feedback controllers but also convenient for fuzzy static output feedback controller design. The latter design work is quite hard for T-S fuzzy control systems. Based on the LMI-based conditions derived, one can easily synthesize controllers for stabilizing T-S fuzzy control systems. Since only a set of LMIs is involved, the controller design is quite simple and numerically tractable. Finally, the validity and applicability of the proposed approach are successfully demonstrated in the control of a continuous-time nonlinear system.
Agar-based disc diffusion antimicrobial assay has shown that the ethyl acetate extract of the fermented broth of
NTU967 isolated from
exhibited significant antimicrobial activity in our preliminary ...screening of bioactive fungal strains. Therefore, column chromatography of the active principles from liquid- and solid-state fermented products of the fungal strain was carried out, and which had led to isolation of eleven compounds. Their structures were determined by spectral analysis to be seven new highly oxygenated polyketides, namely aspergilsmins A-G (
-
), along with previously reported patulin, deoxytryptoquivaline, tryptoquivaline and quinadoline B. Among these, aspergilsmin C (
) and patulin displayed promising anticancer activities against human hepatocellular carcinoma SK-Hep-1 cells and prostate cancer PC-3 cells with IC
values between 2.7-7.3 μM. Furthermore, aspergilsmin C (
) and patulin exhibited significant anti-angiogenic functions by impeding cell growth and tube formation of human endothelial progenitor cells without any cytotoxicity.
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•Sorghum distilled residue (SDR) is a potential low-cost feedstock for astaxanthin fermentation.•Aurantiochytrium sp. CJ6 can grow on SDR alone to produce astaxanthin via ...fermentation.•Illumination strategy significantly affects astaxanthin production with CJ6 strain.•Salinity (2.5%) and pH 7 were optimal for cell growth and astaxanthin production.•Using CF-FB fermentation gives max. astaxanthin content (93.9 μg/g) and concentration (0.565 mg/L).
In this study, Aurantiochytrium sp. CJ6 was cultivated heterotrophically on a waste resource, sorghum distillery residue (SDR) hydrolysate without adding any nitrogen sources. Mild sulfuric acid treatment released sugars that supported the growth of CJ6. Optimal operating parameters (salinity, 2.5%; pH, 7.5; with light exposure) determined using batch cultivation attained biomass concentration and astaxanthin content of 3.72 g/L and 69.32 µg/g dry cell weight (DCW), respectively. Using continuous-feeding fed-batch (CF-FB) fermentation, the biomass concentration of CJ6 increased to 6.3 g/L with biomass productivity and sugar utilization rate of 0.286 mg/L/d and 1.26 g/L/d, respectively. Meanwhile, CJ6 obtained maximum astaxanthin content (93.9 µg/g DCW) and astaxanthin concentration (0.565 mg/L) after 20-day cultivation. Thus, the CF-FB fermentation strategy seems to have a high potential for the cultivation of thraustochytrids to produce the high-value product (astaxanthin) using SDR as the feedstock to achieve circular economy.
Abstract
Pulmonary tuberculosis (TB) caused by
Mycobacterium tuberculosis
(
Mtb
) is a global public health concern. Although inflammasome and the toll-like receptor 2 (
TLR2
) genes play an ...important role in host defense against
Mtb
, the associations of polymorphisms in these genes with TB risk are incompletely understood. A total of 230 TB patients and 213 individuals without TB were enrolled in this study. A significant difference in the frequencies of different
AIM2
rs2276405 genotypes between the non-TB and TB groups was detected. When the patients were stratified by gender or age, significant differences in genotype frequencies at
NLRP3
rs34298354 in men and in non-aged (≤65-year-old) subjects and at
IFI16
rs1772408 in women were found. OR analysis showed that the TC rs34298354 genotype in
NLRP3
was associated with reduced risk of TB. In women, the AG rs1772408 genotype in
IFI16
was associated with decreased TB risk. Haplotype analysis showed that, in comparison with the most common haplotype (T-T) of rs3804099-rs3804100 in the
TLR2
gene, the C-T haplotype was associated with an increased risk for TB. Our study indicates that rs34298354 in
NLRP3
and rs1772408 in
IFI16
protect individuals from TB, and that the less common
TLR2
haplotype is associated with increased TB susceptibility.
The recruitment of bone marrow-derived endothelial progenitor cells (EPCs) facilitates physiological and pathological processes involved in new blood vessel synthesis. Glucocerebroside, an extract of ...Cordyceps militaris, inhibits inflammatory cytokine production and monocyte migration, although its anti-angiogenic properties in human EPCs has remained largely unknown up until now. We describe how glucocerebroside reduces migration as well as tube formation induced by vascular endothelial growth factor (VEGF) stimulation in human EPCs, without affecting cell viability. This inhibitory effect was achieved through the focal adhesion kinase (FAK)/c-Src pathways. We also found that glucocerebroside reduced VEGF-promoted upregulation of the transcription factor Runx2 in the EPCs. The in vivo chick embryo chorioallantoic membrane model demonstrated that glucocerebroside reduces new vessel formation. Our investigation is the first to show that glucocerebroside reduces angiogenesis in human EPCs and to describe the underlying mechanisms. Further investigations are needed to examine the effects of glucocerebroside in other angiogenesis-related disorders.
Introduction
Osteoporosis has been demonstrated to be a risk factor for rotator cuff retears after surgery; however, no studies have directly investigated the association between osteoporosis and the ...development of rotator cuff tears. To investigate whether osteoporosis is associated with an increased risk of rotator cuff tears.
Materials and methods
We conducted a population-based, matched-cohort study with a 7-year follow-uTwo matched cohorts (
n
= 3511 with osteoporosis and 17,555 without osteoporosis) were recruited from Taiwan’s Longitudinal Health Insurance Dataset. Person-year data and incidence rates were evaluated. A multivariable Cox model was used to derive an adjusted hazard ratio (aHR) after controlling for age, sex, and various prespecified comorbidities. Age and sex were added in the model to test for interaction with osteoporosis.
Results
Women constituted 88.5% of the cohorts. During follow-up of 17,067 and 100,501 person-years for the osteoporosis and nonosteoporosis cohorts, 166 and 89 rotator cuff tears occurred, respectively. The cumulative incidence of rotator cuff tears was significantly higher in the osteoporosis cohort than in the nonosteoporosis cohort (
p
< 0.001, log-rank). The Cox model revealed a 1.79-fold increase in rotator cuff tears in the osteoporosis cohort, with an aHR of 1.79 (95% confidence interval, 1.55–2.05). Effect modification of sex and age on rotator cuff tears was not found in patients with osteoporosis.
Conclusion
This population-based study supports the hypothesis that compared with individuals without osteoporosis, those with osteoporosis have a higher risk of developing rotator cuff tears.
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