Background
Metastatic castration‐resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet ...need for this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti‐CRPC strategy.
Methods
Cell proliferation was examined in CRPC PC‐3 and DU‐145 cells using sulforhodamine B assay and anchorage‐dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell‐cycle progression. Cell‐based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis.
Results
A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC50, 3.5 nM in enzyme assay; IC50, 1.0 μM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC50, 5.4 μM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α‐tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl‐2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin‐induced cell death through impairment of cisplatin‐evoked DNA damage response and DNA repair in both ATR–Chk1 and ATM–Chk2 pathways.
Conclusion
The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin‐induced cell apoptosis through impeding DNA damage repair pathways.
Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. However, transmembrane ionic channels perturbed by this ...compound remain largely unclear, although the agent is thought to alter the gating characteristics of voltage-gated Na
(Na
) channel current. In this study, we reappraised whether and how it and other related compounds can make any further modifications on voltage-gated Na
current (
) in pituitary tumor (GH
) cells. Cell exposure to DLT produced a differential and dose-dependent stimulation of peak (transient,
) or sustained (late,
)
; consequently, the EC
value required for DLT-stimulated
or
was determined to be 11.2 or 2.5 μM, respectively. However, neither the fast nor slow component in the inactivation time constant of
activated by short depolarizing pulse was changed with the DLT presence; conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, can accentuate
with a slowing in inactivation time course of the current. The
augmented by DLT was attenuated by further application of either dapagliflozin (Dapa) or amiloride, but not by chlorotoxin. During pulse train (PT) stimulation, with the Tef or DLT presence, the cumulative inhibition of
became slowed; moreover, following PT stimuli, a large tail current with a slowly recovering process was observed. Alternatively, during rapid depolarizing pulse, the amplitude of
and tail
(
) for each depolarizing pulse became progressively increased by adding DLT, not by Tef. The recovery time constant following PT stimulation with continued presence of Tef or DLT was shortened by further addition of Dapa. The voltage-dependent hysteresis (Hys
) of persistent
was differentially augmented by Tef or DLT. Taken together, the magnitude, gating, frequency dependence, as well as Hys
behavior of
exerted by the presence of DLT or Tef might exert a synergistic impact on varying functional activities of excitable cells in culture or in vivo.
MiR-17-92 cluster and immunity Kuo, George; Wu, Chao-Yi; Yang, Huang-Yu
Journal of the Formosan Medical Association,
January 2019, 2019-Jan, 2019-01-00, 20190101, 2019-01-01, Volume:
118, Issue:
1
Journal Article
Peer reviewed
Open access
MicroRNAs (MiR, MiRNA) are small single-stranded non-coding RNAs that play an important role in the regulation of gene expression. MircoRNAs exert their effect by binding to complementary nucleotide ...sequences of the targeted messenger RNA, thus forming an RNA-induced silencing complex. The mircoRNA-17-92 cluster encoded by the miR-17-92 host gene is first found in malignant B-cell lymphoma. Recent research identifies the miR-17-92 cluster as a crucial player in the development of the immune system, the heart, the lung, and oncogenic events. In light of the miR-17-92 cluster's increasing role in regulating the immune system, our review will discuss the latest knowledge regarding its involvement in cells of both innate and adaptive immunity, including B cells, subsets of T cells such as Th1, Th2, T follicular helper cells, regulatory T cells, monocytes/macrophages, NK cells, and dendritic cells, and the possible targets that are regulated by its members.
Emulsion gels with low oil contents have been continuously developed in recent decades. In this study, the use of high-intensity ultrasound for the preparation of low oil emulsion gel (oil fraction ...of 0.25) was investigated. Specifically, defatted Antarctic krill protein (dAKP) was used to stabilize the interface of soybean oil and water. Then, the microstructure and the stabilization mechanism of the formed emulsion gel were evaluated by cryo-SEM, CLSM, zeta potential, rheological measurements, and FTIR. Besides, the particle diameter was measured to be around 5 μm. The results of CLSM indicated that the emulsion gel was the oil-in-water type. The emulsion gel exhibited gel-like viscoelastic behavior even at a low concentration of dAKP due to the formation of a rigid particle network while the rheological behavior of the emulsion gel was significantly affected by the concentration of dAKP. The stabilization of the emulsion gel can be maintained by space steric hindrance and hydrophobic interactions between particles in the emulsion gel system.
Cancer is associated with a profound perturbation in myelopoiesis that results in the accumulation of myeloid-derived suppressor cells (MDSCs) to promote disease progression. Recent studies in mice ...suggest that tumor-derived factors could regulate the differentiation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and subsequently contribute to dysregulation of hematopoiesis. However, the nature and role of HPSCs in patients with cancer remain unknown. Here we show, in detailed studies of the peripheral blood from 133 untreated patients with seven different types of tumors, that the composition of circulating HSPCs was significantly altered in patients with solid tumors. The frequencies of circulating granulocyte—monocyte progenitors (GMPs) were increased four to seven fold in all types of tumors examined, and the circulating hematopoietic precursors exhibited myeloid bias with a skew toward granulocytic differentiation in patients with solid tumors. These myeloid precursors are selectively enriched in tumor tissues, and the high levels of circulating GMPs were positively correlated with disease progression. By using cord blood-derived CD34+ cells, we developed an in vitro short-term culture model to effectively induce the rapid generation of MDSCs. We found that, among the factors produced by various tumors, GM-CSF, granulocyte colony-stimulating factor, and IL-6 could not only promote the myeloid-biased differentiation, but also induce the differentiation of myeloid precursors into functional MDSCs. These findings suggest that the altered circulating HSPCs may serve as an important link between dysregulated bone marrow hematopoiesis and accumulated MDSCs in patients with cancer.
Background
Observational studies and meta‐analyses have indicated associations between blood lipid profiles and asthma. However, the causal association is unknown. Therefore, this study investigated ...the causal relationship between blood lipid profiles and asthma using bidirectional Mendelian randomization analysis.
Methods and materials
Our analyses were performed using individual data from the Taiwan Biobank and summary statistics from the Asian Genetic Epidemiology Network (AGEN). The causal estimates between all genetic variants, exposures of interest and asthma were calculated using an inverse‐variance weighted method based on Taiwan Biobank data from 24,853 participants (mean age, 48.8 years; 49.8% women). Sensitivity analyses, including the weighted median, MR Egger regression, MR‐PRESSO, mode‐based estimate, contamination mixture methods, and leave‐one‐out analysis, were applied to validate the results and detect pleiotropy.
Results
In the inverse‐variance weighted (IVW) analyses, we found evidence of a significant causal effect of an increased level of low‐density lipoprotein cholesterol on asthma risk (βIVW = 1.338, p = 0.001). A genetically decreased level of high‐density lipoprotein cholesterol was also associated with asthma risk (βIVW = −0.338, p = 0.01). We also found that an increased level of total cholesterol was associated with an increased risk of asthma (βIVW = 1.343, p = 0.001). Several sensitivity analyses generated consistent findings. We did not find evidence to support the causality between asthma and blood lipid profiles in either direction.
Conclusion
Our results supported the causal relationship between higher levels of LDL cholesterol and total cholesterol and lower levels of HDL cholesterol with an increased risk of asthma.
Highlights • TLR4 expression was associated with the ability of invasion and migration in HCC. • TLR4 expression contributes to the stem-like properties of HCC cells. • The high expression of TLR4 is ...associated with clinicopathological characteristics and prognosis of HCC.
Aims/hypothesis
Type 2 diabetes is highly correlated with nonalcoholic fatty liver disease (NAFLD). Hepatocyte-derived fibrinogen-related protein 1 (HFREP1) is a hepatokine that mediates NAFLD ...development; however, the role of HFREP1 in the development of insulin resistance and diabetes remains obscure.
Methods
A total of 193 age- and sex-matched participants with normal glucose tolerance, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and newly diagnosed diabetes (NDD) were recruited for a cross-sectional study. Plasma HFREP1 levels were measured and multivariate linear regression analysis was used to evaluate the relationship between HFREP1, IFG, IGT and NDD. The causal relationship between HFREP1 and insulin resistance was then investigated in animal and cell models. Glucose and insulin tolerance tests, and euglycaemic–hyperinsulinaemic clamp, were used to evaluate insulin sensitivity in animals with
Hfrep1
overexpression or knockdown in liver by lentiviral vectors. HepG2 cells were used to clarify the possible mechanism of HFREP1-induced insulin resistance.
Results
Plasma HFREP1 concentrations were significantly increased in participants with IFG, IGT and NDD. HFREP1 concentrations were independently associated with fasting plasma glucose levels, insulin resistance, IFG, IGT and NDD. Injection of recombinant HFREP1 or
Hfrep1
overexpression induced insulin resistance in mice, and HFREP1 disrupted insulin signalling to induce insulin resistance through an extracellular signal-regulated kinase (ERK)1/2-dependent pathway. Moreover, hepatic knockdown of HFREP1 improved insulin resistance in both mice fed a high-fat diet and
ob
/
ob
mice.
Conclusions/interpretation
These findings highlight the crucial role of HFREP1 in insulin resistance and diabetes, and provide a potential strategy and biomarker for developing therapeutic approaches to combat these diseases.
Hyperuricemia has been associated with chronic kidney disease (CKD) progression. The antihyperuricemic febuxostat's potential renoprotective effect has been demonstrated in stage 1–3 CKD. Large‐scale ...studies comparing the renoprotective potential of febuxostat and allopurinol in advanced CKD are lacking. We exclusively selected 6,057 eligible patients with predialysis stage 5 CKD prescribed either febuxostat or allopurinol using the National Health Insurance Research Database in Taiwan during 2012–2015. There were 69.57% of allopurinol users and 42.01% febuxostat users who required long‐term dialysis (P < 0.0001). The adjusted hazard ratio (HR) of 0.65 (95% confidence interval (CI) 0.60–0.70) indicated near 35% lower hazards of long‐term dialysis with febuxostat use. The renal benefit of febuxostat was consistent across most patient subgroups and/or using the propensity score‐matched cohort. The adjusted HR was 0.66 (95% CI, 0.61–0.70) for long‐term dialysis or death. In conclusion, lower risk of progression to dialysis was observed in predialysis stage 5 CKD febuxostat users without compromising survival.
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