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1.
J Hematol Oncol ; 14(1): 30, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33596982

RESUMO

Histone methylation is a key posttranslational modification of chromatin, and its dysregulation affects a wide array of nuclear activities including the maintenance of genome integrity, transcriptional regulation, and epigenetic inheritance. Variations in the pattern of histone methylation influence both physiological and pathological events. Lysine-specific demethylase 5A (KDM5A, also known as JARID1A or RBP2) is a KDM5 Jumonji histone demethylase subfamily member that erases di- and tri-methyl groups from lysine 4 of histone H3. Emerging studies indicate that KDM5A is responsible for driving multiple human diseases, particularly cancers. In this review, we summarize the roles of KDM5A in human cancers, survey the field of KDM5A inhibitors including their anticancer activity and modes of action, and the current challenges and potential opportunities of this field.

2.
ACS Sens ; 6(1): 166-174, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33356166

RESUMO

Lysosomes are membrane-bound organelles that regulate protein degradation and cellular organelle recycling. Homeostatic alteration by lysosomotropic compounds has been suggested as a potential approach for the treatment of cancer. However, because of the high false-negative rate resulting from strong fluorescent background noise, few luminescent high-throughput screening methods for lysosomotropic compounds have been developed for cancer therapy. Imidazole is a five-membered heterocycle that can act within the acidic interior of lysosomes. To develop an efficient lysosomotropic compound screening system, we introduced an imidazole group to iridium-based complexes and designed a long-lifetime lysosomal probe to monitor lysosomal activity in living cells. By integrating time-resolved emission spectroscopy (TRES) with the novel iridium-based lysosomal probe, a high-throughput screening platform capable of overcoming background fluorescent interference in living cells was developed for discovering lysosomotropic drugs. As a proof-of-concept, 400 FDA/EMA-approved drugs were screened using the TRES system, revealing five compounds as potential lysosomotropic agents. Significantly, the most promising potent lysosomotropic compound (mitoxantrone) identified in this work would have showed less activity if screened using a commercial lysosomal probe because of interference from the intrinsic fluorescence of mitoxantrone. We anticipate that this TRES-based high-throughput screening system could facilitate the development of more lysosomotropic drugs by avoiding false results arising from the intrinsic fluorescence of both bioactive compounds and/or the cell background.

3.
J Cell Mol Med ; 25(4): 1972-1981, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33377602

RESUMO

Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five-year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF-selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan-RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan-RAF and S100B pathways.

4.
Front Chem ; 8: 767, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33088800

RESUMO

Ochratoxin A (OTA) is a mycotoxin that is widespread throughout the world. It contaminates foods such as vegetables, fruits, and rice. It harms human health and has potential carcinogenic effects. The G-quadruplex (G4) is a tetraplexed DNA structure generated from guanine-rich DNA that has found emerging use in aptamer-based sensing systems. This review outlines the status of OTA contamination and conventional detection methods for OTA. Various G4-based methods to detect OTA developed in recent years are summarized along with their advantages and disadvantages compared to existing approaches.

5.
Oxid Med Cell Longev ; 2020: 4946902, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832000

RESUMO

Intracellular reactive apoptosis and reactive oxygen species (ROS) play a crucial role in ultraviolet- (UV-) induced inflammation and aging reaction in human dermal tissues. This study determines the mechanism by which Haematococcus pluvialis extracts (HPE) and purified astaxanthin (HPA) to promote skin regeneration in the injured tissue in vitro and in vivo. The results show that HPE and HPA decrease the DNA damage and promote the secretion of collagen from the human normal fibroblast cell line (Hs68) in a dose-dependent manner. UV irradiation and HPA reduce oxidative stress damage due to phorbol-12-myristate-13-acetate (PMA). When skin cells are injured by free radicals, cells undergo a programmed cellular death. Cellular apoptotic death is determined using annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining to verify that there is no cell membrane asymmetry and that the nuclear membrane is broken. Inflammatory symptoms and apoptotic injuries to experimental rats in a group that is treated with HPA treated are decreased in a dose-dependent manner after UVB exposure (300 mJ/cm2) for 15 min in vivo, compared to the vehicle control group. These positive results show that HPA repairs UVB-triggered skin tissue injury and aging by conducting electrons out of cells to maintain a low level of oxidative stress so that collagen is synthesized in vitro and in vivo.

6.
Int J Biol Macromol ; 164: 3204-3220, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860796

RESUMO

Melanoma is the most dangerous type of skin cancer because of its high invasion and metastasis ability. Bromodomain-containing protein 4 (BRD4), an acetylation-recognizing reader, mediates the proliferation, metastasis, and invasion of melanoma, and is thus a potential therapeutic target. Mounting evidence suggests that inhibition of single bromodomain of BRD4 would improve specificity and reduce cytotoxicity to non-tumor tissues or cells. In this study, a hierarchical virtual screening campaign was performed against BRD4 BD2 from a chemical database including over 90,000 natural/natural-like compounds. Using various biochemical assays, the 7-methoxycoumarin derivative N13 was identified as a potent inhibitor of BRD4 BD2. Compared with the well-known BRD4 inhibitor JQ1, N13 exhibited higher potency against BRD4 BD2 and much higher specificity for BRD4 BD2 over BRD4 BD1. Additionally, N13 inhibited the proliferation of two kinds of BRD4-overexpressing melanoma cell lines. Mechanistically, N13 impaired the protein-protein interaction (PPI) between BRD4 BD2 and its acetylated ligand proteins (Twist1 K73/K76Ac and FOXO3a K242/245Ac), leading to reducing levels of Wnt5A and CDK6 expression, inducing cell senescence of melanoma cancer cells, and ultimately weakening the adhesion, metastasis, and invasion ability of melanoma cancer cells. To our knowledge, N13 is the first 7-methoxybicoumarin-based BRD4 BD2 inhibitor described to date and may function as a new scaffold for developing more specific and potent therapeutic agents against BRD4 BD2. In addition, our research highlights the druggability of BRD4 BD2 as a target for BRD4-overexpressing melanoma and provides a potential mechanism for the anti-melanoma activity of BRD4 BD2 inhibitor.

7.
Angew Chem Int Ed Engl ; 59(41): 17897-17902, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32649787

RESUMO

Gastrin-releasing peptide receptor (GRPr) plays proliferative and inflammatory roles in living systems. Here, we report a highly selective GRPr antagonist (JMV594)-tethered iridium(III) complex for probing GRPr in living cancer cells and immune cells. This probe exhibited desirable photophysical properties and also displayed negligible cytotoxicity, overcoming the inherent toxicity of the iridium(III) complex. Its long emission lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using a time-resolved technique. This probe selectively visualized living cancer cells via specific binding to GRPr, while it also modulated the function of GRPr on TNF-α secretion in immune cells. To our knowledge, this is the first peptide-conjugated iridium(III) complex developed as a GRPr bioimaging probe and modulator of GRPr activity. This theranostic agent shows great potential at unmasking the diverse roles of GRPr in living systems.

8.
Drug Discov Today ; 25(9): 1754-1761, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679172

RESUMO

S100 calcium-binding protein B (S100B) is overexpressed in various malignant tumors, where it regulates cancer cell proliferation and metabolism by physical interactions with other molecules. Interfering with S100B-effector protein interactions is a potential strategy to treat malignant tumors. Although some S100B inhibitors have been discovered by virtual screening (VS), most target the S100B-p53 interaction. Hence, there is scope for the discovery of other S100B-effector protein interaction modulators for malignant tumors. In this review, we provide an overview of S100B-effector protein interaction inhibitor discovery using VS and discuss promising S100B-effector protein interaction targets that permit in silico analysis for drug discovery.

9.
J Hematol Oncol ; 13(1): 102, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709244

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

10.
J Hematol Oncol ; 13(1): 26, 2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-32228680

RESUMO

Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis of a range of human diseases, including cancer. Hence, the inhibition of PPIs has attracted significant attention in drug discovery. Covalent inhibitors have been reported to achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues in the target protein. Evidence suggests that there is a reduced risk for the development of drug resistance against covalent drugs, which is a major challenge in areas such as oncology and infectious diseases. Recent improvements in structural biology and chemical reactivity have enabled the design and development of potent and selective covalent PPI inhibitors. In this review, we will highlight the design and development of therapeutic agents targeting PPIs for cancer therapy.

11.
J Pharm Biomed Anal ; 185: 113235, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32182447

RESUMO

Polysaccharides have broad bioactivities and are major components of water decoction of herb formulae. However, the quality control of polysaccharides remains a challenge. Oligosaccharide-fragment approach has been considered in elucidating chemical structures of polysaccharides, but never been used for quantitation. Using reference chemicals and a real sample Danggui Buxue Tang (DBT) in this study, an oligosaccharide-marker approach was established to quantify specific polysaccharides. Firstly, linear relationships between parent polysaccharides and hydrolysis-produced daughter oligosaccharides were verified using reference polysaccharides. Then in case of DBT, two fluorescence-labeled oligosaccharides with high specificity to individual parent polysaccharides were selected as markers. They were easily isolated and identified. Their potential in quantification of parent polysaccharides were satisfactorily validated in terms of linearity (r≥0.99), repeatability (RSD ≤ 8.4 %), and spike recovery (≥80 %). This method could be a promising approach for quality assessment of polysaccharides in herbal formulae.

12.
J Mater Chem B ; 8(22): 4715-4725, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32100789

RESUMO

Neurodegenerative diseases are the result of neurodegeneration, which is the process of losing neuronal functions gradually due to the irreversible damage and death of neurons. Metal complexes have attracted intense interest over recent decades as probes or inhibitors of biomolecules. In this review, we discuss the application of transition metal complexes in the diagnosis and therapy of different neurodegenerative diseases. We first briefly introduce conventional approaches for the diagnosis and treatment of neurodegenerative diseases. Then, the characteristics and mechanisms of transition metal complexes as luminescent probes and drug candidates are discussed. Representative examples of the use of metal complexes in targeted detection and treatment of neurodegenerative diseases are highlighted. Finally, the challenges and future perspectives of this field are presented.

13.
J Nat Prod ; 83(1): 45-54, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31891260

RESUMO

Antrodia camphorata is a rare and valuable medicinal mushroom. In this work, 11 new triterpenoids, namely, antcamphorols A-K (1-11), together with 10 known triterpenoids, 12-21, were isolated from dish-cultured A. camphorata. Compound 1 is an unprecedented C31 lanostane-type triterpenoid featuring a methyl group at C-15 and a C-21-O-C-24 tetrahydropyran ring at C-17. Compounds 2-11 are ergostane-type triterpenoids, and they include two pairs of norergostanes 2-5. The structures of the new compounds were identified by NMR, 2D NMR, and HRESIMS data analyses. The absolute configurations of 1 and 6 were defined by X-ray diffraction data, and the absolute configuration at C-25 of 4 was determined by the modified Mosher's method. Compounds 7, 9, 10, 16, and 19 showed significant ROS scavenging activities (63.9-70.5% at 20 µM) in high-glucose-induced HUVECs. Compounds 3 and 8 exhibited moderate cytotoxic activities against U251 (IC50, 9.2 µM) and MCF-7 (IC50, 8.1 µM) human cancer cell lines, respectively.

14.
J Mater Chem B ; 8(16): 3249-3260, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31647090

RESUMO

Protein biomarkers, particularly abnormally expressed receptor proteins, have been proved to be one of the crucial biomarkers for the rapid assessment, diagnosis, prognosis and prediction of specific human diseases. Transition metal based strategies in particular possess delightful strengths in the in-field and real-time visualization of receptor proteins owing to their unique photophysical properties. In this review, we highlight recent advances in the development of detection methods for receptor protein biomarkers using transition metal based approaches, particularly those employing transition metal complexes. We first discuss the strengths and weaknesses of various strategies used for protein biomarker monitoring in live cells. We then describe the principles of the various sensing platforms and their application for receptor protein detection. Finally, we discuss the challenges and future inspirations in this specific field.

15.
Molecules ; 24(24)2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817099

RESUMO

As protein-protein interactions (PPIs) are highly involved in most cellular processes, the discovery of PPI inhibitors that mimic the structure of the natural protein partners is a promising strategy toward the discovery of PPI inhibitors. In this review, we discuss recent advances in the application of virtual screening for identifying mimics of protein partners. The classification and function of the mimicking protein partner inhibitor discovery by virtual screening are described. We anticipate that this review would be of interest to medicinal chemists and chemical biologists working in the field of protein-protein interaction inhibitors or probes.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Interface Usuário-Computador , Desenho de Fármacos , Descoberta de Drogas , Humanos , Ligação Proteica , Mapeamento de Interação de Proteínas
16.
Aging (Albany NY) ; 11(23): 11084-11110, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31806859

RESUMO

Low-grade chronic adipose tissue inflammation contributes to the onset and development of aging-related insulin resistance and type 2 diabetes. In the current study, α-mangostin, a xanthone isolated from mangosteen (Garcinia mangostana), was identified to ameliorate lipopolysaccharides-induced acute adipose tissue inflammation in mice, by reducing the expression of pro-inflammatory cytokines and chemokines. In a cohort of young (3 months) and old (18-20 months) mice, α-mangostin mitigated aging-associated adiposity, hyperlipidemia, and insulin resistance. Further study showed that α-mangostin alleviated aging-related adipose tissue inflammation by reducing macrophage content and shifting pro-inflammatory macrophage polarization. Moreover, α-mangostin protected the old mice against liver injury through suppressing the secretion of microRNA-155-5p from macrophages. The above results demonstrated that α-mangostin represents a new scaffold to alleviate adipose tissue inflammation, which might be a novel candidate to treat aging-related metabolic disorders.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Envelhecimento , Inflamação/tratamento farmacológico , Doenças Metabólicas/prevenção & controle , Xantonas/farmacologia , Tecido Adiposo/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B , Inibidores de Proteínas Quinases/farmacologia , Sirtuína 3/genética , Sirtuína 3/metabolismo
17.
J Biol Inorg Chem ; 24(8): 1159-1170, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31486954

RESUMO

Alzheimer's disease (AD) is a type of neurodegenerative malady that is associated with the accumulation of amyloid plaques. Metal ions are critical for the development and upkeep of brain activity, but metal dyshomeostasis can contribute to the development of neurodegenerative diseases, including AD. This review highlights the association between metal dyshomeostasis and AD pathology, the feasibility of rebalancing metal homeostasis as a therapeutic strategy for AD, and a survey of current drugs that action via rebalancing metal homeostasis. Finally, we discuss the challenges that should be overcome by researchers in the future to enable the practical use of metal homeostasis rebalancing agents for clinical application.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Quelantes/uso terapêutico , Cobre/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Zinco/metabolismo , Sequência de Aminoácidos , Peptídeos beta-Amiloides/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Multimerização Proteica/efeitos dos fármacos
18.
Anal Chim Acta ; 1083: 166-171, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31493807

RESUMO

A series of iridium(III) dimers were synthesized and their ability to interact with diethyldithiocarbamate for CS2 sensing was evaluated. Upon the addition of CS2, diethylamine can capture CS2 to form diethyldithiocarbamate, which could chelate with the iridium(III) dimer to form a diethyldithiocarbamate iridium(III) complex, resulting in a yellow luminescence. Dimer 8 exhibited a maximum 18-fold of luminescence enhancement upon the addition of CS2. The luminescence signal of the detection system could be readily distinguished from the highly fluorescent media using time-resolved emission spectroscopy (TRES). The capability of the system to determine CS2 level in water samples was also demonstrated.

19.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509940

RESUMO

Due to role of the Keap1-Nrf2 protein-protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1-Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1-Nrf2 protein-protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1-Nrf2 protein-protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.


Assuntos
Descoberta de Drogas/métodos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/prevenção & controle , Humanos , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos
20.
ACS Omega ; 4(5): 9228-9234, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31460012

RESUMO

The peptidyl-prolyl isomerase Pin1 is correlated with the progression of cervical cancer via regulating numerous oncogenic and tumor suppressor pathways. p65 is a crucial regulator of tumorigenesis that is regulated by Pin1, and p65 signaling suppression can enhance the antitumor efficacy of doxorubicin (DOX). Here, we utilized a structural mimicry approach to synthesize a series of dibenzothiophene analogues and evaluated their ability to inhibit Pin1 activity. Compound 1a was identified as a potent Pin1 inhibitor that inhibited p65 signaling in vitro and in cervical cancer cells. Moreover, compound 1a enhanced the cytotoxicity of DOX in cervical cancer cells via reducing p65 nuclear accumulation and enhancing DOX uptake. These compounds are promising scaffolds for developing more potent Pin1 inhibitors against cervical cancer, either alone or in combination with anticancer drugs such as DOX.

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