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1.
Nat Commun ; 10(1): 3733, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427575

RESUMO

Hearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.

2.
PLoS One ; 14(3): e0212670, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913212

RESUMO

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of-function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.


Assuntos
Imunidade Celular , Vigilância Imunológica , Linfócitos/imunologia , Neoplasias Experimentais/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Linfócitos/patologia , Camundongos , Camundongos Mutantes , Neoplasias Experimentais/genética , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Microambiente Tumoral/genética
3.
Chem Commun (Camb) ; 54(89): 12618-12621, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30349928

RESUMO

Polyelectrolyte-protein complexes are widely used to deliver therapeutic proteins. Here, we present a method for imaging the release of drugs from polyion complex (PIC) micelles in 3D tumour spheroids using light-sheet microscopy. A negatively charged block copolymer was condensed with a positively charged model drug, hen egg white lysozyme (HEWL) by electrostatic interaction. We were able to observe the distribution of polymer and protein within the entire tumour spheroid, showing that the protein was released from the polyelectrolyte complex upon cell internalization at the peripheral cell layer of the spheroid.


Assuntos
Sistemas de Liberação de Medicamentos , Micelas , Muramidase/química , Polímeros/química , Esferoides Celulares/química , Portadores de Fármacos/química , Humanos , Íons/química , Células MCF-7 , Microscopia de Fluorescência , Estrutura Molecular , Muramidase/metabolismo , Esferoides Celulares/metabolismo , Eletricidade Estática
4.
Artigo em Inglês | MEDLINE | ID: mdl-30112880

RESUMO

Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-ß superfamily, and they play important roles in the development of numerous organs, including the inner ear. The inner ear is a relatively small organ but has a highly complex structure and is involved in both hearing and balance. Here, we discuss BMPs and BMP signaling pathways and then focus on the role of BMP signal pathway regulation in the development of the inner ear and the implications this has for the treatment of human hearing loss and balance dysfunction.

5.
Neural Plast ; 2018: 7691473, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30008743

RESUMO

Sudden sensorineural hearing loss (SSHL) is a clinically common acute symptom in otolaryngology. Although the incidence of SSHL has increased around the world in recent years, the etiology of the disease is still unclear. It has been reported that infections, ototoxic drugs, membrane labyrinth rupture, carcinomas, circulatory system diseases, autoimmune diseases, brain lesions, mental diseases, congenital or inherited diseases, and so on, are all risk factors for SSHL. Here, we discuss the autoimmune mechanisms behind SSHL, which might be induced by type II-IV allergic reactions. We also introduce the main immunosuppressive medications that have been used to treat SSHL, which will help us to identify potential targets for immune therapy.

6.
Front Mol Neurosci ; 11: 137, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760650

RESUMO

Dysfunctions in hearing and balance are largely connected with hair cell (HC) loss. Although regeneration of HCs in the adult cochlea does not occur, there is still limited capacity for HC regeneration in the mammalian utricle from a distinct population of supporting cells (SCs). In response to HC damage, these Lgr5+ SCs, especially those in the striolar region, can regenerate HCs. In this study, we isolated Lgr5+ SCs and Plp1+ SCs (which originate from the striolar and extrastriolar regions, respectively) from transgenic mice by flow cytometry so as to compare the properties of these two subsets of SCs. We found that the Lgr5+ progenitors had greater proliferation and HC regeneration ability than the Plp1+ SCs and that the Lgr5+ progenitors responded more strongly to Wnt and Notch signaling than Plp1+ SCs. We then compared the gene expression profiles of the two populations by RNA-Seq and identified several genes that were significantly differentially expressed between the two populations, including genes involved in the cell cycle, transcription and cell signaling pathways. Targeting these genes and pathways might be a potential way to activate HC regeneration.

7.
Drug Deliv ; 25(1): 1033-1043, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30799660

RESUMO

Aminoglycoside-induced hair cell (HC) loss is a major cause of hearing impairment, and the effective prevention of HC loss remains an unmet medical need. Epigenetic mechanisms have been reported to be involved in protecting cochlear cells against ototoxic drug injury, and in this study we developed new bioactive compounds that have similar chemical structures as the epigenetics-related lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors have been reported to protect cochlear cells by preventing demethylation of dimethylated histone H3K4 (H3K4me2). To determine whether these new compounds exert similar protective effects on HCs, we treated mouse cochlear explant cultures with the new compounds together with gentamycin. There was a severe loss of HCs in the organ of Corti after gentamycin exposure, while co-treatment with the new compounds significantly protected against gentamycin-induced HC loss. H3K4me2 levels in the nuclei of HCs decreased after exposure to gentamycin, but H3K4me2 levels were maintained in the presence of the new compounds. Apoptosis is also involved in the injury process, and the new compounds protected the inner ear HCs against apoptosis by reducing caspase-3 activation. Together, our findings demonstrate that our new compounds prevent gentamycin-induced HC loss by preventing the demethylation of H3K4me2 and by inhibiting apoptosis, and these results might provide the theoretical basis for novel drug development for hearing protection.


Assuntos
Antibacterianos/toxicidade , Apoptose/efeitos dos fármacos , Gentamicinas/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Histonas/efeitos dos fármacos , Animais , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Cóclea/efeitos dos fármacos , Ciclopropanos/farmacologia , Histonas/metabolismo , Camundongos , Órgão Espiral/efeitos dos fármacos , Éteres Fenílicos/farmacologia
8.
Front Med ; 10(2): 143-51, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27189205

RESUMO

Hair cells regenerate throughout the lifetime of non-mammalian vertebrates, allowing these animals to recover from hearing and balance deficits. Such regeneration does not occur efficiently in humans and other mammals. Thus, balance deficits become permanent and is a common sensory disorder all over the world. Since Forge and Warchol discovered the limited spontaneous regeneration of vestibular hair cells after gentamicininduced damage in mature mammals, significant efforts have been exerted to trace the origin of the limited vestibular regeneration in mammals after hair cell loss. Moreover, recently many strategies have been developed to promote the hair cell regeneration and subsequent functional recovery of the vestibular system, including manipulating the Wnt, Notch and Atoh1. This article provides an overview of the recent advances in hair cell regeneration in mammalian vestibular epithelia. Furthermore, this review highlights the current limitations of hair cell regeneration and provides the possible solutions to regenerate functional hair cells and to partially restore vestibular function.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Ciliadas Vestibulares/fisiologia , Receptor Notch1/genética , Regeneração , Via de Sinalização Wnt , Animais , Proliferação de Células , Humanos , Camundongos , Equilíbrio Postural
9.
J Am Chem Soc ; 138(21): 6739-45, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27167770

RESUMO

The energy difference between a singlet exciton and twice of a triplet exciton, ΔESF, provides the thermodynamic driving force for singlet exciton fission (SF). This work reports a systematic investigation on the effect of ΔESF on SF efficiency of five heteroacenes in their solutions. The low-temperature, near-infrared phosphorescence spectra gave the energy levels of the triplet excitons, allowing us to identify the values of ΔESF, which are -0.58, -0.34, -0.31, -0.32, and -0.34 eV for the thiophene, benzene, pyridine, and two tetrafluorobenzene terminated molecules, respectively. Corresponding SF efficiencies of the five heteroacenes in 0.02 M solutions were determined via femtosecond transient absorption spectroscopy to be 117%, 124%, 140%, 132%, and 135%, respectively. This result reveals that higher ΔESF is not, as commonly expected, always beneficial for higher SF efficiency in solution phase. On the contrary, excessive exoergicity results in reduction of SF efficiency in the heteroacenes due to the promotion of other competitive exciton relaxation pathways. Therefore, it is important to optimize thermodynamic driving force when designing organic materials for high SF efficiency.

10.
ACS Appl Mater Interfaces ; 7(36): 19914-22, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26261995

RESUMO

Two molecules containing a central diketopyrrolopyrrole and two oligothiophene units have been designed and synthesized. Comparisons between the molecules containing terminal F (FDPP) and Cl (CDPP) atoms allowed us to evaluate the effects of halogenation on the photovoltaic properties of the small molecule organic solar cells (OSCs). The OSCs devices employing FDPP:PC71BM films showed power conversion efficiencies up to 4.32%, suggesting that fluorination is an efficient method for constructing small molecules for OSCs.

11.
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288682

RESUMO

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

12.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683

RESUMO

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

13.
Bioorg Med Chem Lett ; 25(14): 2809-12, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25987372
14.
Neurosci Lett ; 571: 61-5, 2014 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24810885

RESUMO

Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of opiate addiction. Both increased and decreased serum BDNF levels have been reported in heroin addicts. Moreover, the role of BDNF in heroin-dependent patients during withdrawal has not been studied. This study aimed to explore the differences in serum BDNF levels of heroin addicts and healthy controls, and investigate the changes of serum BDNF levels in heroin addicts at baseline and at one month after heroin cessation. Seventy-two heroin-dependent patients and ninety age- and gender-matched healthy controls were enrolled in this study. We measured serum BDNF levels at baseline (both heroin addicts and healthy controls) and one month after heroin cessation (heroin addicts only). A total of 37 (51.4%) heroin addicts completed the one-month study. We found that baseline serum BDNF levels were significantly higher in heroin addicts compared to controls (F=36.5, p=0.001). There was no difference in serum BDNF levels among heroin addicts at baseline and one month after heroin cessation (F=1.101, p=0.301). These results indicate that BDNF may play a critical role in the course of opiate addiction and withdrawal.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Dependência de Heroína/sangue , Heroína/efeitos adversos , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Síndrome de Abstinência a Substâncias/sangue
15.
Ann Nutr Metab ; 60(4): 293-7, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22678104

RESUMO

BACKGROUND/AIMS: Supplementation with antioxidants is of special interest in preventing or delaying the development and progression of age-related macular degeneration (AMD). This investigation aimed to assess the effect of α- lipoic acid (LA) on serum lipids, serum malondialdehyde (MDA) and superoxide dismutase (SOD) in patients with AMD. METHODS: A total of 62 patients (50-75 years old) with early and intermediate dry form of AMD were randomly assigned to two groups, i.e. LA administration (n = 32) and placebo (n = 30). The levels of serum lipids and MDA and SOD activity were measured before and after LA and placebo intervention. RESULTS: Compared with the parameters at baseline, serum total cholesterol (CHO), triglyceride and high- and low-density lipoprotein CHO (HDL and LDL) levels were not significantly different after LA and placebo intervention. There was a slight but statistically nonsignificant decrease in serum MDA levels and a statistically significant increase in serum SOD activity after LA intervention. There were no statistically significant differences in serum MDA levels or SOD activity after placebo intervention. CONCLUSION: The apparent increase in SOD activity caused by LA supplementation indicates that LA may have a possible preventive effect in the development of AMD through an antioxidant mechanism.


Assuntos
Antioxidantes/metabolismo , Suplementos Nutricionais , Lipoproteínas LDL/sangue , Degeneração Macular/fisiopatologia , Ácido Tióctico/administração & dosagem , Administração Oral , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Degeneração Macular/sangue , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco , Superóxido Dismutase/sangue , Triglicerídeos/sangue
16.
Cell Biochem Funct ; 30(2): 129-38, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22125055

RESUMO

The possibility of differentiating bone marrow-derived mesenchymal stem cells (BMSCs) into tubular epithelial-like cells is explored in vitro. Purified BMSCs from Sprague-Dawley rats were obtained by density gradient centrifugation. Third generation BMSCs were divided into six groups and were cultured under different conditions. The expression of alkaline phosphatase and cytokeratin (CK)-18 protein was detected through staining and immunocytochemistry, respectively, and the expression of E-cadherin proteins was recorded through immunofluorescence. Some cells in ischemia/reperfusion (I/R), all-trans retinoic acid (ATRA), epidermal growth factor (EGF) and bone morphogenetic protein-7 (BMP-7) groups turned positive, whereas the positive cells in the combined group significantly increased compared with the other groups. Compared with the control group, the positive expression rates of CK-18 in the I/R, ATRA, EGF, BMP-7 and the combined group were 11·50% ± 3·84%, 27·40% ± 2·70%, 29·60% ± 4·51%, 26·80% ± 5·00% and 44·00% ± 3·16%, respectively, and CK-18 mRNA expression in the combined group was obviously higher than that in the other groups (P < 0·01). Immunofluorescence detection showed that E-cadherin expression was not detectable in the control group, whereas the positive expression rates of E-cadherin in the I/R, ATRA, EGF, BMP-7 and the combined group were 6·75% ± 2·13%, 16·40% ± 2·69%, 18·25% ± 3·50%, 16·06% ± 2·00% and 30·26% ± 5·16%, respectively. The addition of ATRA, EGF and BMP-7 induces BMSCs differentiation into tubular epithelial-like cells in stimulated acute renal failure microenvironment in vitro.


Assuntos
Células da Medula Óssea/citologia , Diferenciação Celular , Células Epiteliais/citologia , Células-Tronco Mesenquimais/citologia , Animais , Células da Medula Óssea/metabolismo , Proteína Morfogenética Óssea 7/metabolismo , Caderinas/genética , Caderinas/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Células Epiteliais/metabolismo , Queratina-18/genética , Queratina-18/metabolismo , Células-Tronco Mesenquimais/metabolismo , Ratos , Ratos Sprague-Dawley , Tretinoína/metabolismo
18.
Bioorg Med Chem Lett ; 18(2): 634-9, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18055203

RESUMO

2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC(50)=0.6 nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations.


Assuntos
Receptor trkA/antagonistas & inibidores , Tiazóis/farmacologia , Fosforilação , Receptor trkA/metabolismo , Relação Estrutura-Atividade , Tiazóis/química
19.
Acta Crystallogr C ; 63(Pt 11): m481-3, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17989457

RESUMO

The title compound, [Zn(2)(C(16)H(12)O(6))(2)(C(12)H(8)N(2))(2)(H(2)O)(2)](n), consists of linear chains formed through 5-[4-(hydroxymethyl)benzyloxy]isophthalate (mabobdc) ligands linking five- and six-coordinated Zn(II) ions. The linear chains are linked into a bilayer network via O-H...O hydrogen bonds. Adjacent bilayer structures are further linked with each other via C-H...O hydrogen bonds and pi-pi and C-H...pi interactions to give a three-dimensional supramolecular framework. The results demonstrate the coordination and supramolecular chemistry of the mabobdc ligand.

20.
Mol Cancer Ther ; 5(6): 1571-6, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16818516

RESUMO

Receptor tyrosine kinases (RTK) remain an area of therapeutic interest because of their role in epithelial tumors, and experimental models specific to these targets are highly desirable. Chimeric receptors were prepared by in-frame fusion of the CD8 extracellular sequence with the cytoplasmic sequences of RTKs. A CD8HER2 fusion protein was shown to form disulfide-mediated homodimers and to transform fibroblasts and epithelial cells. CD8RTK fusion proteins transform rat kidney epithelial cells and impart phenotypes that may reflect signaling specificity inherent in the native receptors. Transgenic expression of CD8HER2 and CD8Met in mice resulted in the formation of salivary and mammary gland tumors. The transgenic tumors allow the derivation of allograft tumors and cell lines that are sensitive to inhibition by small molecule kinase inhibitors. This approach provides excellent cell and tumor models for the characterization of signaling properties of diverse RTKs and for the evaluation of rationally designed antagonists targeting these kinases.


Assuntos
Antígenos CD8/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Mamárias Animais/genética , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão/genética , Neoplasias das Glândulas Salivares/genética , Animais , Western Blotting , Transformação Celular Neoplásica/genética , Dimerização , Modelos Animais de Doenças , Dissulfetos/farmacologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Fragmentos de Peptídeos/imunologia , Plasmídeos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/etiologia , Transfecção
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