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.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Corner‐sharing and edge‐sharing networks are the two most important material genomes. Inspired by the efficient electron transport capacity of corner‐sharing structures and the low steric hindrance ...of edge‐sharing units, an attempt is made to exert both merits by combining these two networks. Here, a unique self‐assembled hybrid SrCo0.55Fe0.5O3‐δ nanorod composed of a corner‐sharing SrCo0.5Fe0.5O3‐δ phase and edge‐sharing Co3O4 structure is synthesized through a Co‐site enrichment method, which exhibits the low overpotentials of 310 and 290 mV at 10 mA cm–2 for oxygen‐evolving reaction in 0.1 m and 1.0 m KOH, respectively. This efficiency is attributed to the high Co valence with strong CoO covalence and the short distance between CoCo/Fe metal active sites in hybrid nanorods, realizing a synergistic benefit. Combined multiple operando/ex situ characterizations and computational studies show that the edge‐sharing units in hybrid nanorods can help facilitate the deprotonation step of lattice oxygen mechanism (LOM) while the corner‐sharing motifs can accelerate the electron transport during LOM processes, triggering an unusual lattice‐oxygen activation. This methodology of combining important material structural genomes can offer meaningful insights and guidance for various catalytic applications.
Based on material structural genomes, a unique hybrid‐phase SrCo0.55Fe0.5O3‐δ nanorod composed of corner‐sharing units (SrCo0.5Fe0.5O3‐δ perovskite) with strong electron transport capacity and edge‐sharing motifs (Co3O4 spinel) with low reaction steric hindrance by a self‐assembled Co‐site enrichment method are developed. SrCo0.55Fe0.5O3‐δ nanorod exhibits efficient oxygen‐evolving performance with exceptional lattice oxygen activation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ag-doped Bi2WO6-graphene based photocatalysts were found to exhibit hydrogen production activity. The performance of Bi2WO6-graphene based photocatalysts were investigated and optimized in this ...study. The activity can be further improved by Ag-doping. The morphology, surface chemistry, and phase structure of the photocatalysts were investigated by Field emission scanning electron microscopy, Transmission electron microscopy, X-ray photoelectron spectroscopy, Raman spectra, and X-ray diffraction. UV–vis diffuse reflectance spectroscopy and zeta potential were measured to study the optical properties, bandgap and dispersion stability of the photocatalysts. The effects of forming Bi2WO6-graphene contact and Ag doping on the light absorption, band gap, dispersion stability, and photocatalytic H2 production performance of the composite photocatalysts were evaluated. The improved photocatalytic performance is mainly owing to the Ag doping and high electrical conductivity of graphene.
•Ag doped Bi2WO6–graphene photocatalysts exhibited H2 production activity.•H2 production activity was improved by Ag doping and forming Bi2WO6-graphene contact.•Ag doping leads to decreased bandgap and increased light absorption.•Dispersion stability of Ag-doped sample deteriorated due to decreased zeta potential.•80% activity can be retained when the photocatalyst was recycled after 3 cycles.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Genotype I (GI) virus has replaced genotype III (GIII) virus as the dominant Japanese encephalitis virus (JEV) in the epidemic area of Asia. The mechanism underlying the genotype replacement remains ...unclear. Therefore, we focused our current study on investigating the roles of mosquito vector and amplifying host(s) in JEV genotype replacement by comparing the replication ability of GI and GIII viruses. GI and GIII viruses had similar infection rates and replicated to similar viral titers after blood meal feedings in Culex tritaeniorhynchus. However, GI virus yielded a higher viral titer in amplifying host-derived cells, especially at an elevated temperature, and produced an earlier and higher viremia in experimentally inoculated pigs, ducklings, and young chickens. Subsequently we identified the amplification advantage of viral genetic determinants from GI viruses by utilizing chimeric and recombinant JEVs (rJEVs). Compared to the recombinant GIII virus (rGIII virus), we observed that both the recombinant GI virus and the chimeric rJEVs encoding GI virus-derived NS1-3 genes supported higher replication ability in amplifying hosts. The replication advantage of the chimeric rJEVs was lost after introduction of a single substitution from a GIII viral mutation (NS2B-L99V, NS3-S78A, or NS3-D177E). In addition, the gain-of-function assay further elucidated that rGIII virus encoding GI virus NS2B-V99L/NS3-A78S/E177E substitutions re-gained the enhanced replication ability. Thus, we conclude that the replication advantage of GI virus in pigs and poultry is the result of three critical NS2B/NS3 substitutions. This may lead to more efficient transmission of GI virus than GIII virus in the amplifying host-mosquito cycle.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite recent advances in biofabrication, recapitulating complex architectures of cell‐laden vascular constructs remains challenging. To date, biofabricated vascular models have not yet realized ...four fundamental attributes of native vasculatures simultaneously: freestanding, branching, multilayered, and perfusable. In this work, a microfluidics‐enabled molding technique combined with coaxial bioprinting to fabricate anatomically relevant, cell‐laden vascular models consisting of hydrogels is developed. By using 3D porous molds of poly(ethylene glycol) diacrylate as casting templates that gradually release calcium ions as a crosslinking agent, freestanding, and perfusable vascular constructs of complex geometries are fabricated. The bioinks can be tailored to improve the compatibility with specific vascular cells and to tune the mechanical modulus mimicking native blood vessels. Crucially, the integration of relevant vascular cells (such as smooth muscle cells and endothelial cells) in a multilayer and biomimetic configuration is highlighted. It is also demonstrated that the fabricated freestanding vessels are amenable for testing percutaneous coronary interventions (i.e., drug‐eluting balloons and stents) under physiological mechanical states such as stretching and bending. Overall, a versatile fabrication technique with multifaceted possibilities of generating biomimetic vascular models that can benefit future research in mechanistic understanding of cardiovascular diseases and the development of therapeutic interventions is introduced.
A microfluidics‐enabled molding technique combined with coaxial bioprinting to fabricate anatomically‐relevant, cell‐laden vascular models consisting of hydrogels is demonstrated. The fabricated vascular model can be branched, 3D, and laden with relevant cells comprising vasculatures.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Exposure assessment is a key component in the risk assessment of engineered nanomaterials (ENMs). While direct and quantitative measurements of ENMs in complex environmental matrices remain ...challenging, environmental fate models (EFMs) can be used alternatively for estimating ENMs' distributions in the environment. This review describes and assesses the development and capability of EFMs, focusing on surface waters. Our review finds that current engineered nanomaterial (ENM) exposure models can be largely classified into three types: material flow analysis models (MFAMs), multimedia compartmental models (MCMs), and spatial river/watershed models (SRWMs). MFAMs, which is already used to derive predicted environmental concentrations (PECs), can be used to estimate the releases of ENMs as inputs to EFMs. Both MCMs and SRWMs belong to EFMs. MCMs are spatially and/or temporally averaged models, which describe ENM fate processes as intermedia transfer of well-mixed environmental compartments. SRWMs are spatiotemporally resolved models, which consider the variability in watershed and/or stream hydrology, morphology, and sediment transport of river networks. As the foundation of EFMs, we also review the existing and emerging ENM fate processes and their inclusion in recent EFMs. We find that while ENM fate processes, such as heteroaggregation and dissolution, are commonly included in current EFMs, few models consider photoreaction and sulfidation, evaluation of the relative importance of fate processes, and the fate of weathered/transformed ENMs. We conclude the review by identifying the opportunities and challenges in using EFMs for ENMs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Results from studies investigating the association between coffee consumption and osteoporosis or bone mineral density (BMD) have been inconsistent. This longitudinal study was performed to assess ...the effect of coffee drinking on bone health of Taiwanese adults.
Data were retrieved from the Li-Shin (Landseed) Hospital in Taoyuan City. In 2006, 6152 participants completed a questionnaire on coffee drinking and other lifestyle factors. In 2014, 5077 of them were followed up. Nonetheless, a total of 2395 participants with incomplete data were excluded. The final analyses included 2682 participants comprising 1195 men and 1487 women (706 premenopausal and 781 postmenopausal). T-scores were derived from the osteo-sono assessment index (OSI) which is a surrogate of BMD. Coffee drinking was categorized as "no, medium, and high" based on the number of cups that were consumed per week in both 2006 and 2014.
In general, medium and high coffee drinking were associated with higher T-scores. However, significant results were observed only among high drinkers (β = 0.158; P = 0.0038). Nonetheless, the test for linear trend was significant (P = 0.0046). After stratification by sex, medium and high coffee drinking were associated with higher T-scores. However, significant results were prominent only among high male drinkers (β = 0.237; P = 0.0067) and the test for trend was significant (P = 0.0161). Based on menopausal status, coffee drinking was associated with higher T-scores. Nevertheless, significant results were found only among premenopausal women (β = 0.233; P = 0.0355 and β = 0.234; P = 0.0152 for medium and high coffee drinking, respectively. The test for linear trend was significant (P = 0.0108).
Coffee drinking was significantly associated with higher T-scores hence, a lower risk of osteoporosis in men and premenopausal women.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in ...Asian populations (Chinese and Thai).
METHODS:We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database.
RESULTS:We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10; odds ratio 27.90; 95% confidence interval CI 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077–0.584).
CONCLUSIONS:Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.
Abstract
The current state of the COVID-19 pandemic is a global health crisis. To fight the novel coronavirus, one of the best-known ways is to block enzymes essential for virus replication. ...Currently, we know that the SARS-CoV-2 virus encodes about 29 proteins such as spike protein, 3C-like protease (3CLpro), RNA-dependent RNA polymerase (RdRp), Papain-like protease (PLpro), and nucleocapsid (N) protein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) for viral entry and transmembrane serine protease family member II (TMPRSS2) for spike protein priming. Thus in order to speed up the discovery of potential drugs, we develop DockCoV2, a drug database for SARS-CoV-2. DockCoV2 focuses on predicting the binding affinity of FDA-approved and Taiwan National Health Insurance (NHI) drugs with the seven proteins mentioned above. This database contains a total of 3,109 drugs. DockCoV2 is easy to use and search against, is well cross-linked to external databases, and provides the state-of-the-art prediction results in one site. Users can download their drug-protein docking data of interest and examine additional drug-related information on DockCoV2. Furthermore, DockCoV2 provides experimental information to help users understand which drugs have already been reported to be effective against MERS or SARS-CoV. DockCoV2 is available at https://covirus.cc/drugs/.
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