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1.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

3.
Cell Metab ; 31(5): 892-908.e11, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32375062

RESUMO

Nonalcoholic steatohepatitis (NASH) is becoming one of the leading causes of hepatocellular carcinoma (HCC). Sorafenib is the only first-line therapy for advanced HCC despite its serious adverse effects. Here, we report that at an equivalent of approximately one-tenth the clinical dose for HCC, sorafenib treatment effectively prevents the progression of NASH in both mice and monkeys without any observed significant adverse events. Mechanistically, sorafenib's benefit in NASH is independent of its canonical kinase targets in HCC, but involves the induction of mild mitochondrial uncoupling and subsequent activation of AMP-activated protein kinase (AMPK). Collectively, our findings demonstrate a previously unappreciated therapeutic effect and signaling mechanism of low-dose sorafenib treatment in NASH. We envision that this new therapeutic strategy for NASH has the potential to translate into a beneficial anti-NASH therapy with fewer adverse events than is observed in the drug's current use in HCC.

4.
Cell Metab ; 31(4): 726-740.e8, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32268115

RESUMO

Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.

5.
Comput Struct Biotechnol J ; 17: 619-627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31193098

RESUMO

Single-component nanomaterials such as bismuth (Bi) based on nanoparticles (NPs) intrinsically having both diagnostic and therapeutic capabilities are widely needed in biomedical fields. However, their design and fabrication still face enormous challenges. Here, a kind of pure Bi NPs with ultrahigh X-ray attenuation coeffcient was developed and evaluated as a simple but powerful theranostic nanomaterals and potent light-to-heat conversion efficiency for photoacuostic imaging (PAI)/photothermal therapy (PTT) in this study. The prepared pure Bi NPs showed excellent photothermal performance and the temperature of NPs solution (1 mg/mL) increased to 70 °C under near-infrared light irradiation within 4 min. The pure Bi NPs showed obvious enhancement effect both in X-ray computed tomography (CT) and PA imaging modalities in vivo. In addition, the glioma growth was efficiently suppressed by the pure Bi NPs after 808 nm laser irradiation, while maintained the biosafety and low toxicity. Thus, it is notable that this type of Bi nanomaterial has great potential in multi-imaging guided cancer treatment.

6.
Biomaterials ; 159: 37-47, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29309992

RESUMO

Multifunctional nanomaterials with simple structure and good biosafety, integrating multimodal imaging and therapeutic functions, can facilitate the development of clinical cancer treatments. Here, a simple but powerful pure bismuth based nanoparticle (Gd-PEG-Bi NPs) was developed from pure Bi NPs and gadolinium-diethylenetriaminepentaacetic acid-bis-tetradecylamide, which not only shows high quality MRI/CT/PAI triple-modal imaging, but can also be a potent photothermal therapy agent under the guidance of the triple-modal imaging. The Gd-PEG-Bi NPs showed good stability and excellent biocompatibility. In vitro and in vivo study demonstrated that Gd-PEG-Bi NPs have ultrahigh X-ray attenuation coefficient, short T1 relaxation time in MRI, and strong PAI signal. Following the imaging diagnosis, the excellent light-to-heat conversion efficiency of Gd-PEG-Bi NPs was capable of suppressing the tumor growth effectively under near-infrared laser radiation in vivo. Such multifunctional nanoparticles were ideal candidates for cancer diagnosis and treatment.


Assuntos
Bismuto/química , Meios de Contraste/química , Gadolínio/química , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Animais , Feminino , Hemólise , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pentético/análogos & derivados , Ácido Pentético/química
7.
Nat Med ; 24(1): 73-83, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29227475

RESUMO

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.


Assuntos
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Fígado/irrigação sanguínea , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biossíntese , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metabolismo dos Lipídeos , Camundongos , Traumatismo por Reperfusão/parasitologia , Suínos
8.
Int J Nanomedicine ; 12: 4467-4478, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28670120

RESUMO

The major challenge in current clinic contrast agents (CAs) and chemotherapy is the poor tumor selectivity and response. Based on the self-quench property of IR820 at high concentrations, and different contrast effect ability of Gd-DOTA between inner and outer of liposome, we developed "bomb-like" light-triggered CAs (LTCAs) for enhanced CT/MRI/FI multimodal imaging, which can improve the signal-to-noise ratio of tumor tissue specifically. IR820, Iohexol and Gd-chelates were firstly encapsulated into the thermal-sensitive nanocarrier with a high concentration. This will result in protection and fluorescence quenching. Then, the release of CAs was triggered by near-infrared (NIR) light laser irradiation, which will lead to fluorescence and MRI activation and enable imaging of inflammation. In vitro and in vivo experiments demonstrated that LTCAs with 808 nm laser irradiation have shorter T1 relaxation time in MRI and stronger intensity in FI compared to those without irradiation. Additionally, due to the high photothermal conversion efficiency of IR820, the injection of LTCAs was demonstrated to completely inhibit C6 tumor growth in nude mice up to 17 days after NIR laser irradiation. The results indicate that the LTCAs can serve as a promising platform for NIR-activated multimodal imaging and photothermal therapy.


Assuntos
Meios de Contraste/química , Imagem Multimodal/métodos , Neoplasias Experimentais/diagnóstico por imagem , Animais , Feminino , Compostos Heterocíclicos/química , Humanos , Verde de Indocianina/análogos & derivados , Verde de Indocianina/química , Raios Infravermelhos , Lipossomos/química , Imageamento por Ressonância Magnética/métodos , Camundongos Endogâmicos BALB C , Camundongos Nus , Imagem Multimodal/instrumentação , Neoplasias/patologia , Neoplasias Experimentais/terapia , Compostos Organometálicos/química , Fototerapia/métodos , Razão Sinal-Ruído , Nanomedicina Teranóstica/instrumentação , Nanomedicina Teranóstica/métodos
9.
Biomater Sci ; 5(9): 1746-1750, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28657073

RESUMO

Porphyrin derivatives have been widely applied in MR imaging and photodynamic cancer therapy. We here report a novel Gd/Pt bifunctionalized porphyrin derivative (Gd/Pt-P1) for MRI-guided chemo-photodynamic cancer therapy. Gd/Pt-P1 was prepared from tetra(4-pyridyl) porphyrin (P1) via step by step coordination to cisplatin and gadolinium (Gd(iii)). Gd/Pt-P1 showed a particularly high synergetic chemo-photodynamic antitumor effect in vivo with a tumor inhibition rate (TIR) of 96.6% and excellent MR imaging performance.


Assuntos
Gadolínio/química , Imageamento por Ressonância Magnética , Fotoquimioterapia/métodos , Platina/química , Porfirinas/química , Porfirinas/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Porfirinas/uso terapêutico
10.
Acta Biomater ; 55: 194-203, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28363789

RESUMO

Superparamagnetic iron oxide nanoparticles (SPION) are contrast agents used for noninvasive tumor magnetic resonance imaging (MRI). SPION with active targeting by tumor-specific ligands can effectively enhance the MRI sensitivity and specificity of tumors. However, the challenge remains when the tumor specific markers are yet to be determined, especially in the case of early tumor detection. In this study, the effectiveness of pH-responsive SPION via a pH low insertion peptide (pHLIP) to target tumor acidic microenvironments was investigated. Polylysine polymers were first successfully modified with pHLIP to have the pH-responsive capability. SPION pHLIP nanoclusters of 64, 82, 103, and 121nm size were then assembled by the pH-responsive polymers in a size-controlled manner. The pH-responsive SPION nanoclusters of the 64nm size exhibited the most effective pH-responsive retention in cells and tumor selective imaging in MRI. More importantly, the unique contrast enhancement of tumor inner core by the pH-responsive SPION in three different tumor models demonstrated the clinical potential to target tumor acidic microenvironment through pHLIP for tumor early detection and diagnosis by MRI. STATEMENT OF SIGNIFICANCE: Detection and diagnosis of tumors at early stage are critical for the improvement of the survival rate of cancer patients. However, the challenge remains when the tumor specific markers are yet to be determined, especially in early tumor detection. pH low insertion peptide (pHLIP) has been used as a specific ligand to target the tumor acidic microenvironment for tumors at early and metastatic stages. Superparamagnetic iron nanoparticles (SPION) are contrast enhancing agents used in the noninvasive magnetic resonance imaging for tumors. This research has demonstrated that pH-responsive pHLIP nanoclusters of SPION were able to target different tumors and facilitate the noninvasive diagnosis of tumors by MRI.


Assuntos
Meios de Contraste , Sistemas de Liberação de Medicamentos , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita , Proteínas de Membrana , Neoplasias Experimentais/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Meios de Contraste/química , Meios de Contraste/farmacologia , Humanos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia
11.
J Biomed Nanotechnol ; 11(5): 854-64, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26349397

RESUMO

Although superparamagnetic iron oxide (SPIO) nanoparticles have been developed as a contrast agent for magnetic resonance imaging (MRI), acute iron overload due to the persistently high retention of SPIOs in the liver and spleen that are slowly converted to ferroproteins is a serious safety concern. Here, we report that the addition of poly-L-lysine polymers to an SPIO hydroxyethyl starch solution produced tightly controlled, monodispersed nanoparticles in a size-dependent manner as effective contrast agents for the MRI of liver tumors. High MRI contrast was demonstrated with an orthotopic liver tumor model at a low injection dose. Simultaneously, rapid bioclearance of excess iron in the lung and spleen and in blood serum was observed within 24 h post-injection. The full excretion of excess iron was confirmed in urine post-intravenous injection, suggesting that the effective clearance of SPIOs could be achieved with our SPIO nanoclusters as a liver imaging contrast agent to resolve acute iron overload in the clinical usage of SPIOs as a contrast agent.


Assuntos
Materiais Biocompatíveis , Meios de Contraste , Neoplasias Hepáticas/diagnóstico , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Animais , Materiais Biocompatíveis/farmacocinética , Células Cultivadas , Meios de Contraste/química , Meios de Contraste/farmacocinética , Compostos Férricos/química , Compostos Férricos/farmacocinética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Nanopartículas de Magnetita/química , Masculino , Teste de Materiais , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Polilisina/química , Polilisina/farmacologia
12.
Acta Biomater ; 15: 117-26, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25595473

RESUMO

Polymeric micelles functionalized with folate conjugated bovine serum albumin (FA-BSA) and loaded with superparamagnetic iron oxide nanoparticles (SPIONs) are investigated as a specific contrast agent for tumor targeting and magnetic resonance imaging (MRI) in vitro and in vivo. The SPIONs-loaded polymeric micelles are produced by self-assembly of amphiphilic poly(HFMA-co-MOTAC)-g-PEGMA copolymers and oleic acid modified Fe3O4 nanoparticles and functionalized with FA-BSA by electrostatic interaction. The FA-BSA modified magnetic micelles have a hydrodynamic diameter of 196.1 nm, saturation magnetization of 5.5 emu/g, and transverse relaxivity of 167.0 mM(-1) S(-1). In vitro MR imaging, Prussian blue staining, and intracellular iron determination studies demonstrate that the folate-functionalized magnetic micelles have larger cellular uptake against the folate-receptor positive hepatoma cells Bel-7402 than the unmodified magnetic micelles. In vivo MR imaging conducted on nude mice bearing the Bel-7402 xenografts after bolus intravenous administration reveals excellent tumor targeting and MR imaging capabilities, especially at 24h post-injection. These findings suggest the potential of FA-BSA modified magnetic micelles as targeting MRI probe in tumor detection.


Assuntos
Dextranos , Ácido Fólico , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita , Micelas , Neoplasias/diagnóstico , Polímeros , Soroalbumina Bovina , Animais , Bovinos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dextranos/ultraestrutura , Humanos , Nanopartículas de Magnetita/ultraestrutura , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia , Espectroscopia de Prótons por Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Ensaios Antitumorais Modelo de Xenoenxerto
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