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1.
J Mol Recognit ; 35(12): e2988, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36054561

RESUMO

Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6. Through the analysis of binding-free energies and conformational rearrangements after 1 µs molecular dynamics simulation, it could be learned that although the residues in the binding site remained highly consistent, the binding mechanisms of BRD9757 and compound 8 in HDAC1&6 were different, which will provide valuable hints for the discovery of novel selective HDAC6 inhibitors.


Assuntos
Inibidores de Histona Desacetilases , Simulação de Dinâmica Molecular , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Sítios de Ligação
2.
Bioorg Chem ; 125: 105874, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35636097

RESUMO

The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC1&6 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.


Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
3.
Cancer Cell Int ; 20(1): 563, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33292278

RESUMO

BACKGROUND: CD44 is highly expressed in most cancer cells and its cross-linking pattern is closely related to tumor migration and invasion. However, the underlying molecular mechanism regarding CD44 cross-linking during cancer cell metastasis is poorly understood. Therefore, the purpose of this study was to explore whether disruption of CD44 cross-linking in breast cancer cells could prevent the cells migration and invasion and determine the effects of CD44 cross-linking on the malignancy of the cancer cells. METHODS: The expression of CD44, CD44 cross-linking and Moesin phosphorylation in breast cancer cells was assessed by Western Blot assays. Effects of CD44 cross-linking on tumor metastasis were evaluated by Transwell assay. The effects of CD44 cross-linking disruption on cell viability were assessed using CCK-8 assays. The expression of p-Moesin between normal and breast cancer tissues was examined by immunohistochemical staining. RESULTS: High expression of CD44 cross-linking was found in invasive breast cancer cells (BT-549 and MDA-MB-231), which is associated with the malignancy of breast cancer. The expressions of ERM complex in a panel of breast cancer cell lines indicate that Moesin and its phosphorylation may play a significant role in cell metastasis. Moesin phosphorylation was inhibited by CD44 de-crosslinking in breast cancer cells and Moesin shRNA knockdown attenuated the promotion of CD44 cross-linking on cell migration and invasion. Finally, immunohistochemistry results demonstrated that p-Moesin was overexpressed in primary and metastatic cancers. CONCLUSIONS: Our study suggested that CD44 cross-linking could elevate p-Moesin expression and further affect migration and invasion of breast cancer cells. These results also indicate that p-Moesin may be useful in future targeted cancer therapy.

4.
Cell Commun Signal ; 18(1): 89, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517712

RESUMO

BACKGROUND: Hyaluronan (HA) is an abundant component of the bone marrow (BM) extracellular matrix. Here, we investigated the abnormal deposition of HA in the BM microenvironment and its remodelling in mediating the malignancy of breast cancer cells (BCCs). METHODS: BCCs were transplanted into nude mice by intracardiac injection. The BCCs were cocultured with BM-derived stromal HS5 cells. Then, the abnormal metabolism of HA and its correlation with the malignant growth and the intracellular signalling pathways of the BCCs were investigated. After knockdown/out of the HA receptor CD44 in cancer cells by shRNA and CRISPR/Cas9, the mechanism was investigated in vivo through intratibial inoculation and in vitro by coculture with HS5 cells. RESULTS: The malignancy of cancer cells was highly related to the degree of accumulation of HA in the BM. Further, stromal cell-derived HA, especially the mixed complex, significantly promoted the growth of BCCs and osteolysis by binding to the CD44 receptor. Additionally, the investigation of the underlying mechanism revealed that the PI3K, Cyclin D1, and CDK4 pathways were involved in the effect of bone stromal cell-derived HA on the BCC activities. CONCLUSION: These data suggested that HA in abnormal BM stroma might be a therapeutic candidate for bone metastasis of breast cancer. Video Abstract.


Assuntos
Medula Óssea , Neoplasias da Mama/metabolismo , Ácido Hialurônico/metabolismo , Células-Tronco Mesenquimais , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Nus , Microambiente Tumoral
5.
J Cell Biochem ; 114(7): 1695-703, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23386430

RESUMO

The F1F0 ATP synthase has recently become the focus of anti-cancer research. It was once thought that ATP synthases were located strictly on the inner mitochondrial membrane; however, in 1994, it was found that some ATP synthases localized to the cell surface. The cell surface ATP synthases are involved in angiogenesis, lipoprotein metabolism, innate immunity, hypertension, the regulation of food intake, and other processes. Inhibitors of this synthase have been reported to be cytotoxic and to induce intracellular acidification. However, the mechanisms by which these effects are mediated and the molecular pathways that are involved remain unclear. In this study, we aimed to determine whether the inhibition of cell proliferation and the induction of cell apoptosis that are induced by inhibitors of the cell surface ATP synthase are associated with intracellular acidification and to investigate the mechanism that underlines the effects of this inhibition, particularly in an acidic tumor environment. We demonstrated that intracellular acidification contributes to the cell proliferation inhibition that is mediated by cell surface ATP synthase inhibitors, but not to the induction of apoptosis. Intracellular acidification is only one of the mechanisms of ecto-ATP synthase-targeted antitumor drugs. We propose that intracellular acidification in combination with the inhibition of cell surface ATP generation induce cell apoptosis after cell surface ATP synthase blocked by its inhibitors. A better understanding of the mechanisms activated by ecto-ATP synthase-targeted cancer therapies may facilitate the development of potent anti-tumor therapies, which target this enzyme and do not exhibit clinical limitations.


Assuntos
Adenosina Trifosfatases/metabolismo , Acidose/enzimologia , Acidose/metabolismo , Animais , Apoptose/fisiologia , Western Blotting , Células CHO , Linhagem Celular , Proliferação de Células , Cricetinae , Cricetulus , Imunofluorescência , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal , Células PC12 , Ratos
6.
Front Microbiol ; 12: 724935, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34690966

RESUMO

There is a growing global concern regarding the rise of antimicrobial resistance among Ureaplasma spp. isolates. However, studies on the antimicrobial susceptibility profiles, resistance mechanisms, and clonality of Ureaplasma spp. clinical isolates are still limited and cover only some geographic regions. Firstly, Ureaplasma species from the urogenital tracts of patients in Shanghai, China, were isolated by using the culture medium (A8 and 10B broth), and identified the genotype by polymerase chain reaction (PCR). Secondly, the antimicrobial susceptibility tests were determined by using broth microdilution assay. Then, the resistance genetic determinants to fluoroquinolones (FQs), macrolides, and tetracyclines were investigated through PCR/DNA sequencing. Finally, the molecular epidemiology of Ureaplasma species was studied by multilocus sequence typing (MLST). Among 258 isolates, Ureaplasma parvum (UPA) and Ureaplasma urealyticum (UUR) were found in 226 (87.60%) and 32 (12.40%) isolates, respectively. The minimum inhibitory concentrations (MICs) of 258 Ureaplasma spp. strains ranged from 0.015 to 64µg/ml for all 11 kinds of antimicrobials. Regardless of species, the isolates were most sensitive to AZI (1.94%), JOS (3.49%), and CLA (4.23%). Among them, there were 39 (15.12%) multidrug-resistant (MDR) strains, including 32 UPA isolates. The resistance rates of UPA to CIP (91.59%), and ROX (36.28%) were significantly higher than those of UUR. Twenty six FQ-resistant isolates had amino acid substitutions in gyrA and in parC (Ser83Leu). Mutations were detected in genes encoding ribosomal proteins L4 (Thr84Ile) and L22 (Ser81Pro) in macrolide-resistant isolates. Tet(M) was found in four UPA isolates. These mutations were mainly found in UPA isolates. Sequence type 1 (ST1) was the predominant ST, which contained 18 isolates. In conclusion, this study showed a higher resistance rate (especially to ROX and CIP), higher substitution rate, and higher MDR rate among UPA strains. The most active antimicrobial agents were AZI, JOS, and CLA. Identifying UPA or UUR in clinical isolates could help clinicians to choose appropriate drugs for treatment. The main resistance mechanisms may involve gene substitution of Ser83Leu in parC and Ser81Pro in L22. ST1 was the predominant ST of Ureaplasma isolates with MDR to FQs and macrolides in Shanghai, China.

7.
Cell Death Dis ; 11(10): 831, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024087

RESUMO

Most luminal breast carcinomas (BrCas) bearing PIK3CA mutations initially respond to phosphoinositide-3-kinase (PI3K)-α inhibitors, but many eventually become resistant. The underlying mechanisms of this resistance remain obscure. In this work, we showed that a CD44high state due to aberrant isoform splicing was acquired from adaptive resistance to a PI3Kα inhibitor (BLY719) in luminal BrCas. Notably, the expression of CD44 was positively correlated with estrogen receptor (ER) activity in PIK3CA-mutant breast cancers, and ER-dependent transcription upon PI3Kα pathway inhibition was in turn mediated by CD44. Furthermore, the interaction of CD44 with the ligand hyaluronan (HA) initiated the Src-ERK signaling cascade, which subsequently maintained AKT and mTOR activity in the presence of a PI3Kα inhibitor. Activation of this pathway was prevented by disruption of the CD44/HA interaction, which in turn restored sensitivity to BLY719. Our results revealed that an ER-CD44-HA signaling circuit that mediates robust compensatory activation of the Src-ERK signaling cascade may contribute to the development of acquired resistance to PI3Kα inhibitors. This study provides new insight into the mechanism of adaptive resistance to PI3Kα inhibition therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores de Hialuronatos/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/efeitos dos fármacos
9.
Zhonghua Nan Ke Xue ; 9(2): 136-9, 2003 Apr.
Artigo em Zh | MEDLINE | ID: mdl-12749137

RESUMO

Neutrophil Elastase(NE) is a kind of neutral proteinase. Its value in the diagnosis of male genital tract infection has attracted increasing attention in recent years. NE has special diagnostic value in screening the typical genital tract infection caused by Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticum and Trichomonas, as well as other kinds of genital infection, such as leukocytospermia and periorchitis. NE has been considered as a specific marker of the male genital tract infection.


Assuntos
Doenças dos Genitais Masculinos/diagnóstico , Elastase de Leucócito/sangue , Doenças Bacterianas Sexualmente Transmissíveis/diagnóstico , Chlamydia trachomatis , Doenças dos Genitais Masculinos/sangue , Doenças dos Genitais Masculinos/microbiologia , Humanos , Masculino , Neisseria gonorrhoeae , Prognóstico , Doenças Bacterianas Sexualmente Transmissíveis/sangue , Doenças Bacterianas Sexualmente Transmissíveis/microbiologia , Ureaplasma urealyticum
10.
Biomaterials ; 34(28): 6829-38, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23764114

RESUMO

Breast cancer is characterized by a stromal microenvironment consisting of highly abundant hyaluronan (HA). The role of the HA-coat as a 'fortress' fencing off tumor cells from drugs applied in the circulation has been largely neglected by previous research efforts. In this study we demonstrated that an unusually abundant secreted HA contributed to drug resistance in breast cancer. However, oligosaccharides of HA (oHA) treatment disrupted the cell-associated HA-coat and rendered breast cancer cells profoundly vulnerable to paclitaxel. Next the anti-tumor activity of self-assembled oHA-loaded nanoparticles was evaluated. Results showed that the nanoparticles induced an anti-tumor response both in vitro and in vivo. Systemic application of the nanoparticles dramatically increased the activity of chemotherapies and reduced tumor growth in breast tumor-bearing mouse model, possibly as a result of reduced accumulation of HA in the extracellular matrix surrounding xenografts tumor. We provided direct evidence suggesting that oHA possesses the advantages of ideal drug carrier and drug targeting, and oHA-loaded nanoparticles have great potential to overcome HA associated chemoresistance and improve cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Oligossacarídeos/química , Oligossacarídeos/uso terapêutico , Animais , Linhagem Celular Tumoral , Glicocálix/química , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus
11.
Matrix Biol ; 29(2): 107-16, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19913615

RESUMO

The biological roles of hyaluronan (HA) fragments in angiogenesis acceleration have been investigated recently. Studies have confirmed that oligosaccharides of HA (o-HA) are capable of stimulating neovascularization in vitro and promoting blood flow or angiogenesis in animal models. However, few laboratories have studied the function of o-HA as an exogenous treatment in injured tissue repair in vivo. It is thought that o-HA may lose its activities when used topically in vivo due to its small size, which may be absorbed quickly by the surrounding tissues. In this study, we prepared a special slow-releasing gel that contains a mixture of defined size of o-HA and studied the healing effects of o-HA by topical application to an acute wound model. We report that o-HA complex promotes the repair of tissue injury of a murine excisional dermal wound. The therapy by o-HA was compared with high molecular weight HA (HMW-HA) and the known angiogenesis stimulator, VEGF. At days 6 to 8 after treatment, significant differences were seen in wound closure rates between o-HA and control or HMW-HA groups, in which o-HA showed an increased wound recovery. Histological analysis revealed that increased neo-blood and lymph vessels were formed in wounded tissues treated by o-HA. In addition, treatments of wounds with o-HA resulted in more granulation production, collagen deposition, and fibroblast proliferation. Analysis of gene expression by real-time RT-PCR demonstrated a significant up-regulation of some cytokines or adhesion molecules in o-HA-treated wounds, which corresponds with the increased granulation tissue in these wounds. Our findings suggested that o-HA therapy may be useful in acute wound repair.


Assuntos
Ácido Hialurônico/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Matriz Extracelular/fisiologia , Humanos , Ácido Hialurônico/química , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pele/metabolismo , Pele/patologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Cicatrização/fisiologia
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