The epigenetic reader BRD4 is involved in chromatin remodelling and transcriptional regulation, making it a promising therapeutic target. However, over the past decades, many BRD4 inhibitors that ...entered clinical trials were, in the main, unsatisfactory, due to some therapeutic limitations such as off‐target effects and drug resistance. Combining a BRD4 inhibitor with another drug was expected to be an ideal option to overcome these hurdles and to improve therapeutic outcomes. However, such combination therapy could trigger toxicity caused by drug‐drug interactions, complex pharmacokinetics, and additive effects. Recently, the application of dual‐target drugs targeting BRD4 and other kinases has become an attractive approach to remedy the defects of a single BRD4 inhibitor. This review focuses on recent advances in the discovery of dual BRD4‐kinase inhibitors, with an emphasis on their co‐crystal structures and structure‐activity relationships (SARs), as well as future perspectives in this field.
This review covers recent research progress in the discovery and development of dual BRD4‐kinase inhibitors, summarizing currently available co‐crystal structures to aid in subsequent design efforts. It also discusses the current challenges and future development direction in this new field. The development of dual BRD4‐kinase inhibitors provides more therapeutic options for future cancer treatment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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This review summarized recent research progresses on the in-situ synthesis of molecular magnetorefrigerant materials derived from organic ligands, metal ions and templates generated ...in-situ.
•In-situ synthetic strategy for the construction of molecular magnetorefrigerant materials has been reviewed.•Molecular magnetorefrigerant materials with ligands, metal ions and templates formed in-situ have been illustrated.•The influencing factors toward magnetocaloric effect of the molecular magnetorefrigerants are detail discussed.
Zero-dimensional cluster complexes and coordination polymers for magnetic refrigeration have attracted great interest in the last decade. In-situ synthesis is a widely-used method to assemble various molecular magnetorefrigerant materials derived from different types of ligands. This review focuses mainly on the synthesis, structure and magnetochemistry of molecular magnetorefrigerant materials via in-situ synthesis, with an emphasis on in-situ generation of ligands, metal ions and templates. The first section gives a brief discussion on molecular magnetorefrigerants and some important principles obtained from magneto–structural correlation. The in-situ synthetic strategy will also be referred to and elucidated in this part. The next three sections give overviews of the main results obtained by our group and other groups in recent years, which are, in-situ generated ligands, metal ions and templates in the synthesis of molecular magnetorefrigerant materials. Finally, the conclusions and perspectives of molecular magnetorefrigerant materials will be presented. Some of the trends could provide new insights for the further development of this promising area.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Strongly acidic condition (pH 2.0) significantly increased the leachable Pb and Ca.•Leachable Pb and Ca changed only marginally for the cases of pH 4.0 and 7.0.•Amount of Pb leached directly ...correlated to the amount of Ca leached.•Leachable Pb depended on stability of Ca(OH)2/CSH and soil buffering capacity.
Cement stabilization is a practical approach to remediate soils contaminated with high levels of lead. However, the potential for leaching of lead out of these stabilized soils under variable acid rain pH conditions is a major environmental concern. This study investigates the effects of acid rain on the leaching characteristics of cement stabilized lead contaminated soil under different pH conditions. Clean kaolin clay and the same soil spiked with 2% lead contamination are stabilized with cement contents of 12 and 18% and then cured for 28 days. The soil samples are then subjected to a series of accelerated leaching tests (or semi-dynamic leaching tests) using a simulated acid rain leachant prepared at pH 2.0, 4.0 or 7.0. The results show that the strongly acidic leachant (pH ∼2.0) significantly altered the leaching behavior of lead as well as calcium present in the soil. However, the differences in the leaching behavior of the soil when the leachant was mildly acidic (pH ∼4.0) and neutral (pH ∼7.0) prove to be minor. In addition, it is observed that the lead contamination and cement content levels can have a considerable impact on the leaching behavior of the soils. Overall, the leachability of lead and calcium is attributed to the stability of the hydration products and their consequent influence on the soil buffering capacity and structure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the ...modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.
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•Recent advances in the development of selective HDAC6 inhibitors were summarized.•Hydroxamic acid-based selective HDAC6 inhibitors.•A sulfur containing ZBG based selective HDAC6 inhibitors.•Other ZBG-derived selective HDAC6 inhibitors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Glioblastoma is the most common primary brain tumor in adults and still remains incurable, due to the limited accumulation of drugs in the tumor area. Herein, iRGD‐modified nanoparticles, ...DOX@MSN‐SS‐iRGD&1MT, are developed for simultaneous delivery of chemotherapeutic agents (doxorubicin, DOX) and immune checkpoint inhibitor (1‐methyltryptophan, 1MT) into orthotopic glioma. The nanoparticles are comprised of mesoporous silica nanoparticles loaded with DOX, combined with Asp‐Glu‐Val‐Asp (DEVD) connected 1MT, and finally modified by iRGD. These nanoparticles show the capability of penetrating through blood brain barrier into the tumor area, and significantly improve accumulation of drugs in orthotopic brain tumors with minimal side effects. The nanoparticles also activate cytotoxic CD8+ T lymphocytes and inhibit CD4+ T cells in both GL261 cells cocultured with splenocytes in vitro and GL261‐luc orthotopic tumors in vivo. Moreover, the expression of antitumor cytokines IFNα/β, IFN‐γ, TNF, IL‐17, STING, and GrzB is upregulated while protumor proteins p‐STAT3 and IL‐10 are downregulated in the brain tumor area. This study demonstrates the advantages of chemo‐immunotherapeutic nanoparticles accumulated in the brain tumor area and their effectively inhibiting tumor proliferation, which establishes a delivery platform to promote antitumor immunity against glioblastoma.
Anti‐glioblastoma immunotherapy triggered by chemo‐immunotherapeutic nanoparticles:iRGD modified nanoparticles delivers immune checkpoint inhibitor and chemotherapeutic drugs into orthotopic glioma area. With the release of loaded drugs, tumor infiltrating lymphocytes are recruited and activated. The combinational chemo‐immunotherapeutic nanoparticles elicit significant antitumor immunity against glioblastoma.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Tumor vasculature is an important target in cancer treatment. Two distinct vasculartargeting therapeutic strategies are applied to attack cancer cells indirectly. The antiangiogenic approach ...intervenes in the neovascularization processes and blocks the formation of new blood vessels, while th e antivascular approach targets the established tumor blood vessels, making vascular shutdown and resulting in rapid haemorrhagic necrosis and tumor cell death. A number of compounds with diverse structural scaffolds have been designed to target tumor vasculature and they are called vascular disrupting agents (VDAs). The biological or ligand-directed VDAs utilize antibodies, peptides or growth factors to deliver toxins or pro-coagulants or proapoptotic affectors to tumor-related blood vessels, while the small-molecule VDAs selectively target tumor blood vessels and have little effects on the normal endothelium. Among the small-molecule VDAs, the tubulin colchicine binding site inhibitors have been extensively studied and many of them have entered the clinical trials, including CA-4P, CA-1P, AVE8062, OXi4503, CKD-516, BNC105P, ABT-751, CYT- 997, ZD6126, NPI-2358, MN-029 and EPC2407. This review makes a summary of the small-molecule VDAs in clinical developments and highlights some potential VDA leads or candidates for the treatment of tumors.
This work is aimed to study in situ upgrading of Shengli lignite pyrolysis vapors over different metal-loaded HZSM-5 in a drop tube reactor. Co/HZSM-5, Mo/HZSM-5 and Ni/HZSM-5 (5.0wt%) were prepared ...by wet impregnation and characterized by N2 adsorption-desorption analyzer, X-ray diffraction, transmission electron microscope, Fourier transform infrared spectrometer and temperature programmed desorption of ammonia. The effects of temperature and catalyst on product yields and tar properties were investigated. The results show that the optimal temperature for liquid product was 600°C and aromatics can be directly produced from solid lignite by catalytic fast pyrolysis over metal-loaded HZSM-5 under such mild condition. Due to the participation of metal and acid sites, the bifunctional metal-loaded HZSM-5 showed comparable catalytic activity for deoxygenation reaction in the valorization of oxygen content below 7.1%. The introduction of metal causes the increase of aromatics and the decrease of organic oxygen species in upgraded tar remarkably. Among the catalysts, Ni/HZSM-5 exhibited the best performance for production of high quality tars with highest aromatics content of 94.2% (area%), which can be used as a potential candidate for catalytic upgrading of pyrolysis oil.
•Metal-loaded HZSM-5 was prepared for conversion of lignite to light aromatics.•The BTEXN formation was enhanced by metal-loaded HZSM-5.•Oxygen content in pyrolysis tar is remarkably decreased by metal-loaded HZSM-5.•Ni-loaded HZSM-5 is a potential candidate in catalytic upgrading of pyrolysis oil.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Heteroatom-doped carbon dots (CDs), due to their excellent photoluminescence (PL) properties, attracted widespread attention recently and demonstrated immense promise for diverse applications, ...particularly for biological applications. The objective of this feature article is to provide a comprehensive overview of the recent progress in the research and development of heteroatom-doped CDs and a detailed description of the influence of single or co-doping heteroatoms on their PL behavior. The most recent understanding and critical insights into the PL mechanism of heteroatom-doped CDs are also highlighted. Moreover, potential bio-related applications of heteroatom-doped CDs in biosensing, bioimaging, and theranostics are also reviewed. This state-of-the-art review will provide a platform for understanding the intricate details of heteroatom-doped CDs, a summary of the latest progress in the field, and related applications in biology and is expected to inspire further developments in this exciting class of materials.
This review summarized the recent progress in the synthesis, characterization, properties, photoluminescence mechanism and biological applications of carbon dots.
Three dimensional multicellular aggregate, also referred to as cell spheroid or microtissue, is an indispensable tool for in vitro evaluating antitumor activity and drug efficacy. Compared with ...classical cellular monolayer, multicellular tumor spheroid (MCTS) offers a more rational platform to predict in vivo drug efficacy and toxicity. Nevertheless, traditional processing methods such as plastic dish culture with nonadhesive surfaces are regularly time-consuming, laborious and difficult to provide uniform-sized spheroids, thus causing poor reproducibility of experimental data and impeding high-throughput drug screening. In order to provide a robust and effective platform for in vitro drug evaluation, we present an agarose scaffold prepared with the template containing uniform-sized micro-wells in commercially available cell culture plates. The agarose scaffold allows for good adjustment of MCTS size and large-scale production of MCTS. Transparent agarose scaffold also allows for monitoring of spheroid formation under an optical microscopy. The formation of MCTS from MCF-7 cells was prepared using different-size-well templates and systematically investigated in terms of spheroid growth curve, circularity, and cell viability. The doxorubicin cytotoxicity against MCF-7 spheroid and MCF-7 monolayer cells was compared. The drug penetration behavior, cell cycle distribution, cell apoptosis, and gene expression were also evaluated in MCF-7 spheroid. The findings of this study indicate that, compared with cellular monolayer, MCTS provides a valuable platform for the assessment of therapeutic candidates in an in vivo-mimic microenvironment, and thus has great potential for use in drug discovery and tumor biology research.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The low structural stability of hydrogen‐bonded organic frameworks (HOFs) is a thorny issue retarding the development of HOFs. A rational design approach is now proposed for construction of a stable ...HOF. The resultant HOF (PFC‐1) exhibits high surface area of 2122 m2 g−1 and excellent chemical stability (intact in concentrated HCl for at least 117 days). A new method of acid‐assisted crystalline redemption is used to readily cure the thermal damage to PFC‐1. With periodic integration of photoactive pyrene in the robust framework, PFC‐1 can efficiently encapsulate Doxorubicin (Doxo) for synergistic chemo‐photodynamic therapy, showing comparable therapeutic efficacy with the commercial Doxo yet considerably lower cytotoxicity. This work demonstrates the notorious stability issue of HOFs can be properly addressed through rational design, paving a way to develop robust HOFs and offering promising application perspectives.
An ultra‐robust hydrogen‐bonded organic framework with high BET surface area and acid‐assisted crystalline recovery was developed through several rational design strategies. With periodic integration of photoactive pyrene in the framework, this material can efficiently encapsulate the drug doxorubicin for synergistic chemo‐photodynamic therapy, showing low cytotoxicity and prominent therapeutic efficacy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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