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1.
Eur J Med Chem ; 210: 112981, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33160761

RESUMO

Proteolysis targeting chimera (PROTAC), hijacking protein of interest (POI) and recruiting E3 ligase for target degradation via the ubiquitin-proteasome pathway, is a novel drug discovery paradigm which has been widely used as biological tools and medicinal molecules with the potential of clinical application value. Currently, ARV-110, an orally small molecule PROTAC was designed to specifically target Androgen receptor (AR), firstly enters clinical phase I trials for the treatment of metastatic castration-resistant prostate cancer, which turns a new avenue for the development of PROTAC. We herein provide a detail summary on the latest one year progress of PROTAC target various proteins and elucidate the advantages of PROTAC technology. Finally, the potential challenges of this vibrant field are also discussed.

2.
Cancer Control ; 27(1): 1073274820969703, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33167712

RESUMO

OBJECTIVES: Lung cancer (LC) is often accompanied by significant methylation abnormalities. This study aimed to develop a decision tree (DT) accompanied the stature homeobox 2 gene (SHOX2) / prostaglandin E receptor 4 (PTGER4) gene DNA methylation with traditional tumor marker in the differential diagnosis of benign and malignant lung nodule. METHODS: We performed a study with 104 patients enrolled in the LC group and 36 patients in the benign lung diseases group. All the clinical data of these patients were collected through electronic medical record. Total Methylation (TM) status of both SHOX2 and PTGER4 was defined as methylation levels of SHOX2 plus methylation levels of PTGER4. One-way analysis was used to compare the concentrations of serum samples and t-test was used to compare pairwise mean values between groups. Receiver operating curve (ROC) was used to evaluate the diagnostic value. Furthermore, the strategy was validated in 19 LC patients and 11 patients with benign lung diseases. RESULTS: There were significant differences between the concentration of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21 -1) and the methylation levels of SHOX2, PTGER4 and TM in lung benign diseases and cancer group. The AUCs of NSE, CEA, CYFRA21 -1, Methylation SHOX2, Methylation PTGER4 and TM were 0.721 (95% CI: 0.627-0.816), 0.753 (95% CI: 0.673-0.833) and 0.778(95% CI: 0.700-0.856), 0.851(0.786-0.916), 0.847(0.780-0.913) and 0.861(0.800-0.922) respectively. We developed a DT model with TM and CYFRA21 -1 used in this study, and the area under the curve (AUC) of DT was 0.921 and the sensitivity up to 0.856. In the validation cohort, the AUC of SHOX2, PTGER4 and TM was also much higher than traditional serum markers. CONCLUSIONS: Our results indicated that the DT model calculated from the TM and CYFRA21 -1 can accurately classify LC and benign diseases, which showed better diagnostic performance than traditional serum parameter.

3.
Bioorg Chem ; 105: 104377, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33091668

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec kinases family and is essential for B cell receptor (BCR) mediated signaling. BTK inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. Here we disclose a potent, selective, and covalent BTK inhibitor, HZ-A-005, currently in preclinical development. HZ-A-005 demonstrated dose-dependent activity in two xenograft models of lymphoma in vivo. It showed highly favourable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical studies. On the basis of its potency, selectivity, and covalent mode of inhibition, HZ-A-005 reveals the potential to be a promising BTK inhibitor for a wide range of cancer indications.

4.
Chem Biol Drug Des ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32946197

RESUMO

Andrographolide is a traditional Chinese medicine monomer with many pharmacological activities, but has potential nephrotoxicity. Here, we aim to investigate the relationship between modification of andrographolide structure and its nephrotoxicity. Twenty-three andrographolide derivatives were synthesized, and their structures were confirmed by 1 H-NMR and HRMS. Nephrotoxicity of these compounds against human renal tubular epithelial (HK-2) cells was evaluated using the MTT assay. The results indicated that most of them had significantly reduced nephrotoxicity, especially compounds III, V, and IXc , with IC50 values of 1,985, 1,300, and 806.9 µmol/L, respectively, which were obviously superior to andrographolide (IC50 30.60 µmol/L). However, compounds Ia -If (IC50 values < 30 µmol/L), the 14-OH derivatives of andrographolide, showed higher nephrotoxicity than that of andrographolide. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models of COMFA and COMSIA were established (COMFA: q2  = 0.639, r2  = 0.951; COMSIA: q2  = 0.569, r2  = 0.857). This model allowed proposing five new compounds with lower theoretical nephrotoxicity, which would be worthwhile to synthesize and evaluate. We believe that predicted models will help us to understand the structural modification requirements of andrographolide to reduce the nephrotoxicity, and further investigations will be needed to determine the mechanism involved in the effect of less nephrotoxic compounds.

5.
J Enzyme Inhib Med Chem ; 35(1): 1606-1615, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32779949

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

6.
Cancer Lett ; 482: 56-71, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32289442

RESUMO

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death due to its early recurrence and widespread metastatic potential. Accumulating studies have reported that dysregulation of circadian rhythms-associated regulators is implicated in the recurrence and metastasis of NSCLC. Therefore, identification of metastasis-associated circadian rhythm genes is clinically necessary. Here we report that the circadian gene hepatic leukemia factor (HLF), which was dramatically reduced in early-relapsed NSCLC tissues, was significantly correlated with early progression and distant metastasis in NSCLC patients. Upregulating HLF inhibited, while silencing HLF promoted lung colonization, as well as metastasis of NSCLC cells to bone, liver and brain in vivo. Importantly, downexpression of HLF promoted anaerobic metabolism to support anchorage-independent growth of NSCLC cells under low nutritional condition by activating NF-κB/p65 signaling through disrupting translocation of PPARα and PPARγ. Further investigations revealed that both genetic deletion and methylation contribute to downexpression of HLF in NSCLC tissues. In conclusion, our results shed light on a plausible mechanism by which HLF inhibits distant metastasis in NSCLC, suggesting that HLF may serve as a novel target for clinical intervention in NSCLC.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Regulação para Baixo , Neoplasias Pulmonares/patologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Ritmo Circadiano , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , NF-kappa B/metabolismo , Metástase Neoplásica , Transplante de Neoplasias , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais
7.
Bioact Mater ; 5(2): 334-347, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32206735

RESUMO

There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery. Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capacity in vivo. However, the amount of Sr in the cement to provide an optimal combination of physicochemical properties and capacity to stimulate bone regeneration and the underlying molecular mechanism of this stimulation is yet to be determined. In this study, bone cements composed of bioactive borosilicate glass particles substituted with varying amounts of Sr (0 mol% to 12 mol% SrO) were created and evaluated in vitro and in vivo. The setting time of the cement increased with Sr substitution of the glass. Upon immersion in PBS, the cement degraded and converted more slowly to HA (hydroxyapatite) with increasing Sr substitution. The released Sr2+ modulated the proliferation, differentiation, and mineralization of hBMSCs (human bone marrow mesenchymal stem cells) in vitro. Osteogenic characteristics were optimally enhanced with cement (designated BG6Sr) composed of particles substituted with 6mol% SrO. When implanted in rabbit femoral condyle defects, BG6Sr cement supported better peri-implant bone formation and bone-implant contact, comparing to cements substituted with 0mol% or 9mol% SrO. The underlying mechanism is involved in the activation of Wnt/ß-catenin signaling pathway in osteogenic differentiation of hBMSCs. These results indicate that BG6Sr cement has a promising combination of physicochemical properties and biological performance for minimally invasive healing of bone defects.

8.
Mol Pharm ; 16(12): 5076-5084, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31670968

RESUMO

Progesterone (PG) is an essential sex hormone with a variety of important biological functions, but its insolubility leads to low bioavailability of most water-based formulations. What is more, the commercial oil-based formulations often cause severe side effects after long-term injection due to poor tissue absorption of oil. Herein, we report an aseptic bottom-up method utilizing emulsion freeze-drying technology that produces size-controllable, highly bioavailable, and water-based PG nanocrystal injection. The key factors that can determine the features of nanocrystals were investigated, including solvents, water-to-oil ratio, drug concentrations, type of surfactants, temperature in freeze-drying process, and lyoprotectants. Mechanisms of crystal growth formation process for PG nanocrystals were also analyzed theoretically. The prepared water-based PG nanocrystal suspension injection (PG/NSI) not only showed quick dissolution behaviors but also had significantly improved bioavailability in vivo. Therefore, this method can effectively control the size of nanocrystals, enhance bioavailability of insoluble drugs, and produce aseptic water-based nanocrystals that can be directly used for injection. Moreover, this method can also be used to prepare nanocrystals with the desired size under aseptic conditions for other poorly water-soluble drugs.

9.
Future Med Chem ; 11(20): 2715-2734, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571504

RESUMO

Proteolysis-targeting chimeras (PROTACs) have received much attention for their promising therapeutic intervention in recent years. These molecules, with the mechanism of simultaneous recruitment of target protein and an E3 ligase, can trigger the cellular ubiquitin-proteasome system to degrade the target proteins. This article systematically introduces the mechanism of small-molecule PROTACs, and summarized the research progress of small-molecule PROTACs. The prospect for further application and the problems to be solved are also discussed.

10.
Onco Targets Ther ; 12: 7573-7580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571908

RESUMO

Purpose: Colorectal cancer (CRC) is the most common malignancy in the gastrointestinal tract. The liver is the most common location of CRC metastases, which are the main causes of CRC-related death. However, the mechanisms underlying metastasis of CRC to the liver have not been characterized, resulting in therapeutic challenges. Methods: The effects of hepatic stellate cells (HSCs) on T cells were evaluated using in vitro mixed lymphocyte reactions (MLRs) and cytokine production assays. HSC-induced CT26 cell migration and proliferation were evaluated in vitro and in vivo. Results: HSCs induced T cell hypo-responsiveness, promoted T cell apoptosis, and induced regulatory T cell expansion in vitro. IL-2 and IL-4 were significantly lower in MLRs incubated with HSCs. Supernatants of MLRs with HSCs promoted CT26 cell proliferation and migration. Furthermore, the presence of HSCs increased the number of liver metastases and promoted proliferation of liver metastatic tumor cells in vivo. Conclusion: HSCs may contribute to an immunosuppressive liver microenvironment, resulting in a favorable environment for the colonization of CRC cells in the liver. These findings highlight a potential strategy for treatment of CRC liver metastases.

11.
Mater Sci Eng C Mater Biol Appl ; 105: 110076, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31546443

RESUMO

The composite scaffolds of bioactive glasses and polymers are often used in bone regeneration which could improve the stiffness, compressive strength and bioactivity of polymers while maintaining the osteoconductivity and osteoinductivity of bioactive glasses. But due to complicated situations and limitations of compositing process, the prepared composite materials have low uniformity and obvious phase separation, leading to problems such as poor mechanical properties and inferior new bone formation capacity. In this paper, a modified sol-gel processing technique was used to realize the homogeneous inorganic-organic composites. After hydrolysis of the metal alkoxide, the sol was mixed with the aqueous solution of polyvinyl alcohol (PVA), and through gelation and chemical reaction, the mixture was solidified into the inorganic-organic composite hydrogel. The composites showed as a uniform single phase with interpenetrating networks of PVA gel and borosilicate gel (BG) that chemically and physically interacted at the scale of molecular or nanometer, therefore PVA-BG hybrids were obtained. When immersed in phosphate-buffered saline, the PVA-BG hybrid-derived scaffolds released beneficial ions into the medium and converted to hydroxyapatite. The scaffolds were not toxic to the rat bone marrow-derived mesenchymal stem cells (rBMSCs), and supported rBMSCs proliferation. Furthermore, the alkaline phosphatase activity of the rBMSCs and the expression levels of osteogenic-related genes (alkaline phosphatase, osteocalcin and runt-related transcription factor 2) increased significantly with increasing amount of BG in the hybrid scaffolds. Finally, the bone defect repair results of critical-sized femoral condyle defect rat model demonstrated that PVA-BG hybrid scaffolds could enhance bone regeneration compared with PVA scaffolds. The results suggested that PVA-BG hybrid scaffolds may be a promising biomaterial for bone regeneration.


Assuntos
Células da Medula Óssea/metabolismo , Regeneração Óssea , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Álcool de Polivinil/química , Silicatos/química , Tecidos Suporte/química , Animais , Células da Medula Óssea/citologia , Células-Tronco Mesenquimais/citologia , Ratos , Ratos Sprague-Dawley
12.
Eur J Med Chem ; 179: 502-514, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276895

RESUMO

Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 µM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Proteínas Nucleares/antagonistas & inibidores , Fenantridinas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Feminino , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Proteínas Nucleares/metabolismo , Fenantridinas/administração & dosagem , Fenantridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo
13.
Int J Biol Sci ; 15(6): 1113-1124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223273

RESUMO

The osteogenic capacity of synthetic bone substitutes is will be highly stimulated by a well-established functional vascularized network. Cobalt (Co) ions are known that can generate a hypoxia-like response and stimulates the production of kinds of angiogenic factors. Herein, we investigated the mechanism of cobalt-doped bioactive borosilicate (36B2O3, 22CaO, 18SiO2, 8MgO, 8K2O, 6Na2O, 2P2O5; mol%) glass scaffolds for bone tissues repairing and blood vessel formation in the critical-sized cranial defect site of rats and their effects on the hBMSCs in vitro were researched. The scaffolds can control release Co2+ ions and convert into hydroxyapatite soaking in simulative body fluids (SBF). The fabircated scaffolds without cytotoxic strongly improves HIF-1α generation, VEGF protein secretion, ALP activity and upregulates the expression of osteoblast and angiogenic relative genes in hBMSCs. Eight weeks after implantation, the bioactive glass scaffolds with 3wt % CoO remarkablely enhance bone regeneration and blood vascularized network at the defective site. In conclusion, as a graft material for bone defects, low-oxygen simulated cobalt-doped bioactive glass scaffold is promising.


Assuntos
Regeneração Óssea , Cobalto/farmacologia , Osteogênese/genética , Engenharia Tecidual/métodos , Tecidos Suporte , Animais , Osso e Ossos , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Hipóxia Celular , Proliferação de Células , Células Cultivadas , Células-Tronco Mesenquimais , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Eur J Med Chem ; 177: 247-258, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158742

RESUMO

Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-ß (Aß) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Aß aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.


Assuntos
Quelantes/farmacologia , Inibidores da Colinesterase/farmacologia , Nootrópicos/farmacologia , Quinolinas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/química , Animais , Barreira Hematoencefálica/metabolismo , Quelantes/síntese química , Quelantes/farmacocinética , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/toxicidade , Desenho de Fármacos , Canal de Potássio ERG1/antagonistas & inibidores , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Nootrópicos/síntese química , Nootrópicos/farmacocinética , Nootrópicos/toxicidade , Fragmentos de Peptídeos/química , Multimerização Proteica/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/farmacocinética , Quinolinas/toxicidade , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Peixe-Zebra
15.
J Enzyme Inhib Med Chem ; 34(1): 808-817, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30879350

RESUMO

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.


Assuntos
Cumarínicos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Administração Oral , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cumarínicos/administração & dosagem , Cumarínicos/farmacocinética , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Concentração Inibidora 50 , Quinazolinonas/química , Relação Estrutura-Atividade
16.
Drug Deliv ; 26(1): 63-69, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30744429

RESUMO

The influence of chiral excipient D-chitosan (CS) on the stereoselective release of racemic ketoprofen (rac-KET) microspheres has been investigated in comparison to those microspheres containing individual enantiomers in vitro and in vivo. Stereoselectivity was observed in vitro release test, with R-KET release slightly higher than that of S-KET, especially in 3% rac-KET loading microspheres. Stereoselectivity is dependent on the content of chiral excipient and pH of release medium. A molecular docking study between CS and KET enantiomers further revealed that S-KET has a stronger interaction with CS compared to R-KET. Moreover, the plasma concentration of KET enantiomers in rats shows substantial differences, as the plasma levels of S-KET were higher than those of R-KET. Plasma levels of enantiomers from the R-KET microspheres had similar stereoselectivity as rac-KET microspheres. The S/R ratio of rac-KET microspheres was significantly lower than that of rac-KET suspension (regular-release formulation) (p<.05), and the differences is 3-5 fold. Besides, rates of R-KET converted to S-KET exhibited differences between rac-KET microspheres and suspension. Similar results were also found between R-KET microspheres and suspension. All investigations suggest that the chitosan interacting preferentially with S-KET to R-KET significantly affect the stereoselective pharmacokinetics of rac-KET from chitosan microspheres in rats.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Quitosana/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Cetoprofeno/administração & dosagem , Microesferas , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Quitosana/química , Quitosana/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Cetoprofeno/química , Cetoprofeno/metabolismo , Masculino , Simulação de Acoplamento Molecular/métodos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo
17.
ACS Appl Mater Interfaces ; 11(9): 9557-9572, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30720276

RESUMO

It is generally accepted that biodegradable materials greatly influence the nearby microenvironment where cells reside; however, the range of interfacial properties has seldom been discussed due to technical bottlenecks. This study aims to depict biomaterial microenvironment boundaries by correlating interfacial H+ distribution with surrounding cell behaviors. Using a disuse-related osteoporotic mouse model, we confirmed that the abnormal activated osteoclasts could be suppressed under relatively alkaline conditions. The differentiation and apatite-resorption capability of osteoclasts were "switched off" when cultured in titrated material extracts with pH values higher than 7.8. To generate a localized alkaline microenvironment, a series of borosilicates were fabricated and their interfacial H+ distributions were monitored spatiotemporally by employing noninvasive microtest technology. By correlating interfacial H+ distribution with osteoclast "switch on/off" behavior, the microenvironment boundary of the tested material was found to be 400 ± 50 µm, which is broader than the generally accepted value, 300 µm. Furthermore, osteoporotic mice implanted with materials with higher interfacial pH values and boarder effective ranges had lower osteoclast activities and a thicker new bone. To conclude, effective proton microenvironment boundaries of degradable biomaterials were depicted and a weak alkaline microenvironment was shown to promote regeneration of osteoporotic bones possibly by suppressing abnormal activated osteoclasts.


Assuntos
Materiais Biocompatíveis/química , Regeneração Óssea , Meios de Cultura/química , Animais , Materiais Biocompatíveis/farmacologia , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Durapatita/química , Feminino , Concentração de Íons de Hidrogênio , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley
18.
J Biomed Mater Res B Appl Biomater ; 107(3): 818-824, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30195262

RESUMO

The repair and regeneration of loaded segmental bone defects is a challenge for both materials and biomedical science communities. Our recent work demonstrated the capability of bioactive glass in supporting bone healing and defect bridging using a rabbit femur segmental defect model without growth factors or bone marrow stromal cells (BMSCs). Here in the current work, a comprehensive in vitro evaluation of bioactive silicate (13-93) and borosilicate (2B6Sr) glass scaffolds was conducted to provide further understanding of their biological performances and to establish a correlation between in vitro and in vivo behaviors. Our in vitro evaluation using a murine MC3T3-E1 cell line confirmed the capability of both scaffolds to support cell attachment, vascular endothelial growth factor (VEGF) formation, and to stimulate mineral deposition and osteoblast marker gene expression. In particular, borosilicate (2B6Sr) glass showed a better capability in supporting the mineralization and gene expression than silicate (13-93) glass, consistent with a faster bone healing ability in vivo. The current in vitro results, combined with our previous in vivo findings, provide a strong basis for the further translational evaluation of bioactive glass scaffolds and for potential preclinical practice. © 2018 Wiley Periodicals, Inc. J. Biomed. Mater. Res. Part B, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 818-824, 2019.

19.
Pulm Pharmacol Ther ; 53: 100-106, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30394340

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis is a lethal fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with poor prognosis. Since pirfenidone was approved for IPF treatment, the search for more effective candidates has been greatly intensified. METHODS: In this study, the antifibrotic effects and mechanisms of compound PBD-617, the ideal candidate discovered in our previous work, were investigated on transforming growth factor-ß1 (TGF-ß1)-induced human embryonic lung fibroblasts (HELF) and on bleomycin (BLM)-induced pulmonary fibrotic rats. RESULTS: Oral administration with PBD-617 decreased the levels of collagen I, collagen III and matrix metalloproteinase 7, and inhibited the protein expression of α-smooth muscle actin in BLM-induced pulmonary fibrosis rats. Furthermore, PBD-617 suppressed the expression of TGF-ß1, phosphorylated Smad3, phosphorylated p38 and activator protein 1 on TGF-ß1-induced HELF, while the regulation could be rescued by using p38 agonist p79350. CONCLUSION: PBD-617 not only inhibited TGF-ß1-induced HELF proliferation, but also attenuated BLM-induced pulmonary fibrosis in rats, with efficacy to some extent higher than that of pirfenidone at the same effective dosage. PBD-617 attenuated pulmonary fibrosis effectively by suppressing activation of TGF-ß1/Smad3 and p38 signaling pathways.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/farmacologia , Animais , Bleomicina/administração & dosagem , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Masculino , Ratos , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/administração & dosagem , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Cell Biosci ; 8: 60, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30479742

RESUMO

Background: Microglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear. Results: In the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1ß-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling. Conclusions: Thus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.

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