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1.
FASEB J ; 35(2): e21367, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33508160

RESUMO

Millions of human deaths occur annually due to chronic kidney disease, caused by diabetic kidney disease (DKD). Despite having effective drugs controlling the hyperglycemia and high blood pressure, the incidence of DKD is increasing, which indicates the need for the development of novel therapies to control DKD. In this article, we discussed the recent advancements in the basic innate immune mechanisms in renal tissues triggered under the diabetes environment, leading to the pathogenesis and progression of DKD. We also summarized the currently available innate immune molecules-targeting therapies tested against DKD in clinical and preclinical settings, and highlighted additional drug targets that could potentially be employed for the treatment of DKD. The improved understanding of the disease pathogenesis may open avenues for the development of novel therapies to rein in DKD, which consequently, can reduce morbidity and mortality in humans in the future.

2.
Bioorg Chem ; : 104561, 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33349457

RESUMO

Although targeted therapy for renal cell carcinoma (RCC) has achieved good therapeutic effects in clinic, a considerable number of patients develop drug resistance over time. So, there is still an urgent need to develop new drugs for RCC treatment. As LSD1 is considered as a promising drug target in diverse cancers, including RCC, we tried to find new LSD1 inhibitor using drug repurposing strategy from a compound library, and fenoldopam, an FDA-approved drug, was identified as a potent LSD1 inhibitor with IC50 = 0.8974 µM in a reversible manner. Molecular docking predicted that fenoldopam occupied the FAD cavity of LSD1, forming hydrogen bonds with surrounding residues. Moreover, fenoldopam inactivated LSD1 and performed antiproliferative activity against ACHN cells and promoted cells apoptosis in vitro. Taken together, fenoldopam was identified as a novel LSD1 inhibitor firstly, and may serve as a new skeleton for RCC therapy.

3.
Front Med ; 14(3): 293-304, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31884526

RESUMO

Netrin-1, an axon guidance factor, and its receptor UNC5B play important roles in axonal development and angiogenesis. This study examined netrin-1 and UNC5B expression in kidneys with diabetic kidney disease (DKD) and investigated their roles in angiogenesis. Netrin-1 and UNC5B were upregulated in streptozotocininduced DKD Wistar rats, and their expression was compared with that in healthy controls. However, exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) inhibited cell migration and tubulogenesis. This effect was likely associated with SRC pathway deactivation. Netrin-1 treatment also eliminated the pro-angiogenic effects of exogenous VEGF-165 on UNC5B-silenced HRGECs. These results indicate that UNC5B antagonizes netrin-1 and that UNC5B upregulation contributes partly to enhancing angiogenesis in DKD. Therefore, introducing exogenous netrin-1 and depleting endogenous UNC5B are potential strategies for reducing the incidence of early angiogenesis and mitigating kidney injury in DKD.

4.
Nanotechnology ; 27(8): 085104, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26808235

RESUMO

Phototherapy, which mainly includes photothermal treatment (PTT) and photodynamic treatment (PDT), is a photo-initiated, noninvasive and effective approach for cancer treatment. The high accumulation of photosensitizers (PSs) in a targeted tumor is still a major challenge for efficient light conversion, to generate reactive oxygen species (ROS) and local hyperthermia. In this study, a simple and efficient hyaluronic acid (HA)-modified nanoplatform (HA-TiO2@MWCNTs) with high tumor-targeting ability, excellent phototherapy efficiency, low light-associated side effects and good water solubility was developed. It could be an effective carrier to load hematoporphyrin monomethyl ether (HMME), owing to the tubular conjugate structure. Apart from this, the as-prepared TiO2@MWCNTs nanocomposites could also be used as PSs for tumor PTT and PDT. Those results in vitro and in vivo showed that the anti-tumor effect of this system-mediated PTT/PDT were significantly better than those of single treatment manner. In addition, this drug delivery system could realize high ratio of drug loading, sustained drug release, prolonged circulation in vivo and active targeted accumulation in tumor. These results suggest that HA-TiO2@MWCNTs/HMME has high potential for tumor synergistic phototherapy as a smart theranostic nanoplatform.


Assuntos
Hematoporfirinas/farmacologia , Nanocompostos/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Sarcoma 180/tratamento farmacológico , Titânio/farmacocinética , Animais , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Hematoporfirinas/sangue , Hematoporfirinas/farmacocinética , Humanos , Hipertermia Induzida/métodos , Injeções Subcutâneas , Lasers , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular/métodos , Nanocompostos/ultraestrutura , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestrutura , Fármacos Fotossensibilizantes/sangue , Fármacos Fotossensibilizantes/farmacocinética , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Sarcoma 180/metabolismo , Sarcoma 180/patologia , Nanomedicina Teranóstica/métodos , Titânio/sangue
5.
J Drug Target ; 23(6): 552-67, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25754587

RESUMO

Artemisinin (ART) is a kind of drug with an endoperoxide bridge which tends to react with Fe(2+) to generate radicals for killing cancer cells. However, simultaneous delivery of hydrophobic ART and Fe(2+) ions into cancer cells remains a major challenge. In this study, a multi-functional tumor-targeting drug delivery system employing hyaluronic acid-derivatized multi-walled carbon nanotubes (HA-MWCNTs) as drug carriers, transferrin (Tf) as targeting ligand and ART as a model drug for cancer treatment was constructed. This delivery system (HA-MWCNTs/Tf@ART) not only retained optical property of MWCNTs and cytotoxicity of ART but also demonstrated synergistic anti-tumor effect using ART and Tf. Compared with free ART, remarkably enhanced anti-tumor efficacy of this drug vehicle was realized both in cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of ART and co-delivery of Tf and ART analogs. HA-MWCNTs/Tf@ART with laser irradiation demonstrated the highest inhibition effect compared to the other groups. This result may provide a new way of using promising natural drugs for cancer therapy.


Assuntos
Artemisininas/administração & dosagem , Artemisininas/farmacologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/administração & dosagem , Nanotubos de Carbono/química , Transferrina/farmacocinética , Animais , Apoptose/efeitos dos fármacos , Artemisininas/química , Artemisininas/farmacocinética , Ciclo Celular/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Sinergismo Farmacológico , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Ácido Hialurônico/farmacologia , Células MCF-7 , Camundongos , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Transferrina/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Biomaterials ; 37: 353-66, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25453964

RESUMO

Artesunate (AS) is an iron-dependent drug, which has been used extensively as anti-malarial drugs worldwide with no obvious side effects. Recently, studies have shown that AS also possess profound cytotoxicity against tumor cells. However, simultaneous delivery of hydrophobic AS and Fe(2+) into tumor cells remains a major challenge. Herein, we report a new kind of active-targeting preparations which could not only specially target to tumor cells but also synchronously transfer AS and irons into tumor tissue. In this study, hyaluronic acid (HA) was grafted onto fullerene to get a water-soluble biomaterial (HA-C60) with excellent biocompatibility, and then combined with transferrin (Tf) to obtain a multi-functional drug delivery system (HA-C60-Tf) with significant tumor-targeting efficacy and powerful photodynamic therapy capacity. Finally, AS was adsorbed on HA-C60-Tf with a high loading efficacy of 162.4% (weight ratio of AS: HA-C60-Tf). Compared with free AS, remarkably enhanced antitumor efficacy of AS-loaded HA-C60-Tf nanoparticles was realized both in a cultured MCF-7 cells in vitro and in a tumor-bearing murine model in vivo, due to increased intracellular accumulation of AS in tumor and activated mechanism by co-delivery of Tf and AS analogs. Furthermore, with laser irradiation in vivo, the relative tumor volume (V/V0) of HA-C60-Tf/AS declined by half, from 1.72 ± 0.12 to 0.84 ± 0.07, suggesting a new way with multi-mechanism for tumor treatment was developed.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Fulerenos/química , Ferro/metabolismo , Nanopartículas/química , Transferrina/metabolismo , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Artemisininas/farmacocinética , Artemisininas/farmacologia , Artesunato , Sinergismo Farmacológico , Endocitose/efeitos dos fármacos , Feminino , Humanos , Ácido Hialurônico/química , Espaço Intracelular/metabolismo , Células MCF-7 , Camundongos Endogâmicos BALB C , Nanopartículas/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Transferrina/farmacocinética
7.
J Mater Chem B ; 3(30): 6310-6326, 2015 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32262750

RESUMO

As one of the most frequently used chemotherapeutic drugs, doxorubicin (DOX) is accompanied by low accumulation in tumors and severe dose-limiting side effects with systemic administration, which limits its therapeutic index. In this work, a novel and injectable in situ photo-sensitive inorganic/organic hybrid hydrogel as a localized drug-delivery system was examined. It explored poly(ethylene glycol) double acrylates (PEGDA) as a polymeric matrix, DOX as a model drug, a TiO2@MWCNT nanocomposite as the photoinitiator and photosensitizer-photothermal agent for tumor therapy possessing a multi-mechanism using a single NIR laser. Briefly, a PEGDA solution containing DOX and TiO2@MWCNTs was injected into a tumor and rapidly gelled in vivo via a photo-crosslinking action triggered by a NIR laser. DOX release from the DOX/TiO2@MWCNTs/PEGDA hydrogel was sustained and long-lasting, over 10 days, indicating that the PEGDA gel acted as a drug depot. Simultaneously, a NIR laser light was adopted which can be absorbed and converted into reactive oxygen species (ROS) or local hyperthermia by TiO2@MWCNTs, leading to tumor cell death. This DOX/TiO2@MWCNTs/PEGDA hydrogel exhibited remarkable anti-proliferative activities against MCF-7 cancer cells in vitro. Experiments in vivo showed that a single intratumoral injection of this hydrogel with 808 nm laser irradiation was the most effective among all DOX formulations in the tumor-bearing mice models. There was a relatively small DOX distribution in normal tissues and much lower systemic toxicity than the control group (DOX-only). In general, it is believed that the novel photo-sensitive hybrid hydrogel system prepared in this study can afford high drug-loading, sustained and stable drug release, as well as repeated phototherapy of the tumor with the administration of a single dose.

8.
Curr Pharm Biotechnol ; 14(13): 1105-17, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24725129

RESUMO

OBJECTIVE: A multifunctional tumor-targeting drug delivery system employing single-walled carbon nanotubes (SWCNT) as drug carriers, AS1411 as targeting ligand and doxorubicine (DOX) as a model chemotherapy drug was constructed. METHODS: Firstly, SWCNT were modified with F68 (4.0 mg/ml) by ultrasonic dispersing technology due to the action of hydrophobic force and Van der Waals force, endowing SWCNT water dispersions and biocompatibility. Meanwhile, DOX could be easily absorbed on the surface of SWCNT by the π-π stacking, electrostatic adsorption and hydrophobic interactions. Finally, AS1411 was attached to the surface of DOX-SWCNT by the π-π stacking and electrostatic adsorption to obtain a tumor-targeting delivery system. Cellular uptake, anti-tumor effect in vitro and in vivo, cell cycle and apoptosis and biodistribution of AS1411-DOX-SWCNT were investigated, compared with the DOX solution. CONCLUSION: This AS1411-mediated DOX-loaded SWCNT (AS1411-DOX-SWCNT) delivery system not only retained both optical properties of SWCNT and cytotoxicity of DOX but also could accumulate in tumors, which facilitated combination of chemotherapy and photothermal therapy. AS1411-DOX-SWCNT could effectively promote DOX cellular uptake and then increase intracellular accumulation as a targeting delivery system. AS1411-DOX-SWCNT by NIR laser excited could trigger S phase arrest and the late stage apoptotic on PC3 cancer cells. The investigation in vivo further confirmed that this system possessed higher tumor targeting capacity and antitumor efficacy than DOX, especially with NIR laser irradiation.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Aptâmeros de Peptídeos/administração & dosagem , Aptâmeros de Peptídeos/uso terapêutico , Nanotubos de Carbono , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Área Sob a Curva , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
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