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1.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443608

RESUMO

In order to develop novel bioactive substances with potent activities, some new valine-derived compounds incorporating a 4-(phenylsulfonyl)phenyl fragment, namely, acyclic precursors from N-acyl-α-amino acids and N-acyl-α-amino ketones classes, and heterocycles from the large family of 1,3-oxazole-based compounds, were synthesized. The structures of the new compounds were established using elemental analysis and spectral (UV-Vis, FT-IR, MS, NMR) data, and their purity was checked by reversed-phase HPLC. The newly synthesized compounds were evaluated for their antimicrobial and antibiofilm activities, for toxicity on D. magna, and by in silico studies regarding their potential mechanism of action and toxicity. The 2-aza-3-isopropyl-1-[4-(phenylsulfonyl)phenyl]-1,4-butanedione 4b bearing a p-tolyl group in 4-position exhibited the best antibacterial activity against the planktonic growth of both Gram-positive and Gram-negative strains, while the N-acyl-α-amino acid 2 and 1,3-oxazol-5(4H)-one 3 inhibited the Enterococcus faecium biofilms. Despite not all newly synthesized compounds showing significant biological activity, the general scaffold allows several future optimizations for obtaining better novel antimicrobial agents by the introduction of various substituents on the phenyl moiety at position 5 of the 1,3-oxazole nucleus.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Cetonas/síntese química , Cetonas/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Anti-Infecciosos/química , Biofilmes/efeitos dos fármacos , Técnicas de Química Sintética , Cetonas/química , Oxazóis/química , Relação Estrutura-Atividade
2.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198585

RESUMO

The present investigation informs a descriptive study of 1-(4-Hydroxyphenyl) -3-phenylprop-2-en-1-one compound, by using density functional theory at B3LYP method with 6-311G** basis set. The oxygen atoms and π-system revealed a high chemical reactivity for the title compound as electron donor spots and active sites for an electrophilic attack. Quantum chemical parameters such as hardness (η), softness (S), electronegativity (χ), and electrophilicity (ω) were yielded as descriptors for the molecule's chemical behavior. The optimized molecular structure was obtained, and the experimental data were matched with geometrical analysis values describing the molecule's stable structure. The computed FT-IR and Raman vibrational frequencies were in good agreement with those observed experimentally. In a molecular docking study, the inhibitory potential of the studied molecule was evaluated against the penicillin-binding proteins of Staphylococcus aureus bacteria. The carbonyl group in the molecule was shown to play a significant role in antibacterial activity, four bonds were formed by the carbonyl group with the key protein of the bacteria (three favorable hydrogen bonds plus one van der Waals bond) out of six interactions. The strong antibacterial activity was also indicated by the calculated high binding energy (-7.40 kcal/mol).


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cetonas/química , Cetonas/farmacologia , Alcenos/química , Alcenos/farmacologia , Domínio Catalítico , Teoria da Densidade Funcional , Modelos Moleculares , Simulação de Acoplamento Molecular , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Análise Espectral Raman/métodos , Eletricidade Estática
3.
Eur J Med Chem ; 221: 113556, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087498

RESUMO

A series of epoxyketone analogues with varying N-caps and P3-configurations were designed, synthesized and evaluated. We found that D-Ala in P3 was crucial for ß5i selectivity over ß5c. Notably, compounds 20j (ß5i IC50 = 26.0 nM, 25-fold selectivity) and 20l (ß5i IC50 = 25.1 nM, 24-fold selectivity) with the D-configuration at P3 were the most selective inhibitors. Although 20j and 20l showed only moderate anti-proliferative activity against RPMI-8226 and MM.1S cell lines, based on our experiments, it indicates that the inhibition of ß5i alone is not sufficient to exert anticancer effects and may rely on the complementary inhibition of ß1i, ß5c and ß5i. These data further increase our understanding of immunoproteasome inhibitors in hematologic malignancies.


Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Compostos de Epóxi/farmacologia , Cetonas/farmacologia , Peptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Humanos , Cetonas/síntese química , Cetonas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
4.
Colloids Surf B Biointerfaces ; 205: 111920, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34144324

RESUMO

Poly-ether-ether-ketone (PEEK) is a promising material in oral repair and orthopedic implantation field due to its stability and proper elastic modulus. However, the lack of simple but effective strategy to functionalize PEEK and improve its antibacterial function hinders its further biomedical application. In this study, a sulfonated 3D porous PEEK is fabricated via sulfonation treatment, and then decorated with the in situ synthesized zeolitic imidazolate framework-8 (ZIF-8), in which Ag+ ions were loaded with high loading capacity. Surface morphology, roughness, chemical composition and hydrophilicity of all the substrates were evaluated in details, suggesting Ag+ ions loaded ZIF-8 on sulfonated PEEK (SPZA) was successfully prepared. The antibacterial activity of pristine and functionalized PEEK was evaluated by inhibition zone test, spread plate assay, growth curve, and morphology of bacteria. Experimental results demonstrate that the SPZA has effectively bacteriostatic performance against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The excellent antimicrobial activity is attributed to the synergistic effect of Ag+ and Zn2+ ions released continuously from SPZA. This work provides a promising route for surface modification of PEEK and offer a potential candidate for biomedical implants.


Assuntos
Anti-Infecciosos , Estruturas Metalorgânicas , Zeolitas , Antibacterianos/farmacologia , Escherichia coli , Éter , Éteres/farmacologia , Cetonas/farmacologia , Estruturas Metalorgânicas/farmacologia , Polietilenoglicóis , Porosidade , Prata , Staphylococcus aureus , Zeolitas/farmacologia
5.
Mater Sci Eng C Mater Biol Appl ; 126: 112109, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34082931

RESUMO

OBJECTIVE: This study aimed to construct a tightly binding antibiotic sustained release system on the polyetheretherketone (PEEK) surface and investigate the cellular activity and antibacterial properties of the new oral implant materials. METHODS: Low-temperature argon plasma under certain parameters was used to prepare P-PEEK with nano-topology, and chemical deposition technology was adopted to form a polydopamine (PDA) coating on the PEEK surface to build a biological binding platform, PDA/P-PEEK. Subsequently, vancomycin gelatin nanoparticles (Van-GNPs) were prepared by two-step desolvation method. Finally, Van-GNPs were combined with PEEK implant material surface to form a new composite material, Van-GNPs/PEEK. scanning electron microscope (SEM), atomic force microscope (AFM), energy dispersive spectrometer (EDS), and contact angle tester were used to comprehensively characterize the materials. The in vitro release test of Van was performed by dynamic dialysis with ultraviolet spectrophotometer. The cell cytotoxicity and adhesion tests were studied by mouse embryonic osteoblasts. The antibacterial properties were evaluated by bacterial adhesion test, plate colony counting, and antimicrobial ring test with Staphylococcus aureus and Streptococcus mutans. RESULTS: PEEK was treated with low-temperature argon plasma and attached to PDA to form a biological binding platform. The synthesized Van-GNPs were smooth, round, with uniform particle size distribution, and bound to PEEK to form a new composite material, which can release Van constantly. Cell experiments showed that Van-GNPs/PEEK had no cytotoxicity and had good interaction with osteoblasts. Bacterial experiments showed that surface conjugation with Van-GNPs could significantly improve the antibacterial performance of PEEK against S. aureus and S. mutans. SIGNIFICANCE: This study demonstrated that Van-GNPs/PEEK have good cellular compatibility and autonomous antibacterial properties, which provide a theoretical basis for the wide application of PEEK in the field of stomatology.


Assuntos
Anti-Infecciosos , Staphylococcus aureus , Animais , Antibacterianos/farmacologia , Preparações de Ação Retardada/farmacologia , Cetonas/farmacologia , Camundongos , Polietilenoglicóis , Propriedades de Superfície
6.
Am J Physiol Regul Integr Comp Physiol ; 321(2): R100-R111, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132115

RESUMO

Hyperbaric oxygen (HBO2) is breathing >1 atmosphere absolute (ATA; 101.3 kPa) O2 and is used in HBO2 therapy and undersea medicine. What limits the use of HBO2 is the risk of developing central nervous system (CNS) oxygen toxicity (CNS-OT). A promising therapy for delaying CNS-OT is ketone metabolic therapy either through diet or exogenous ketone ester (KE) supplement. Previous studies indicate that KE induces ketosis and delays the onset of CNS-OT; however, the effects of exogeneous KE on cognition and performance are understudied. Accordingly, we tested the hypothesis that oral gavage with 7.5 g/kg induces ketosis and increases the latency time to seizure (LSz) without impairing cognition and performance. A single oral dose of 7.5 g/kg KE increases systemic ß-hydroxybutyrate (BHB) levels within 0.5 h and remains elevated for 4 h. Male rats were separated into three groups: control (no gavage), water-gavage, or KE-gavage, and were subjected to behavioral testing while breathing 1 ATA (101.3 kPa) of air. Testing included the following: DigiGait (DG), light/dark (LD), open field (OF), and novel object recognition (NOR). There were no adverse effects of KE on gait or motor performance (DG), cognition (NOR), and anxiety (LD, OF). In fact, KE had an anxiolytic effect (OF, LD). The LSz during exposure to 5 ATA (506.6 kPa) O2 (≤90 min) increased 307% in KE-treated rats compared with control rats. In addition, KE prevented seizures in some animals. We conclude that 7.5 g/kg is an optimal dose of KE in the male Sprague-Dawley rat model of CNS-OT.


Assuntos
Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ésteres/farmacologia , Cetonas/farmacologia , Atividade Motora/efeitos dos fármacos , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidade , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Ésteres/farmacocinética , Ésteres/toxicidade , Oxigenação Hiperbárica/efeitos adversos , Cetonas/farmacocinética , Cetonas/toxicidade , Masculino , Ratos Sprague-Dawley , Tempo de Reação , Convulsões/etiologia , Convulsões/fisiopatologia , Convulsões/psicologia
7.
Mol Pharmacol ; 100(2): 144-154, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34031188

RESUMO

The nontaxane microtubule inhibitor eribulin is an approved therapeutic for metastatic breast cancer and liposarcoma. Eribulin was previously tested in unselected patients with lung cancer and yielded a modest objective response rate of ∼5%-12%. Because lung cancers represent diverse histologies and driving oncogenic mutations, we postulated that eribulin may exhibit properties of a precision oncology agent with a previously undefined specificity for a molecularly distinct subset of lung cancers. Herein, we screened a panel of 44 non-small cell and small-cell lung cancer cell lines for in vitro growth sensitivity to eribulin. The results revealed a greater than 15,000-fold range in eribulin sensitivity (IC50 = 0.005-89 nM) among the cell lines that was not correlated with their sensitivity to the taxane-based inhibitor paclitaxel. The quartile of cell lines exhibiting the lowest eribulin IC50 values was not enriched for specific histologies, epithelial-mesenchymal differentiation, or specific oncogene drivers but was significantly enriched for nonsense/frameshift TP53 mutations and low-TP53 mRNA but not missense TP53 mutations. By comparison, the mutation status of cyclin-dependent kinase inhibitor 2A, STK11, and KEAP1 was not associated with eribulin sensitivity. Finally, the highest eribulin IC50 quartile (>1 nM) exhibited significantly elevated mRNA expression of the drug pump, ATP binding cassette B1, defined resistance mechanism to eribulin, and paclitaxel. The findings support further investigations into basic mechanisms by which complete lack of TP53 function regulates anticancer activity of eribulin and the potential utility of TP53 null phenotypes distinct from TP53 missense mutations as a biomarker of response in patients with lung cancer. SIGNIFICANCE STATEMENT: Distinct from precision oncology agents that are matched to cancers bearing oncogenically activated versions of their targets, microtubule inhibitors, such as eribulin, are deployed in an unselected manner. The results in this study demonstrate that lung cancer cell lines exhibiting the highest sensitivity to eribulin bear TP53 null phenotypes, supporting a rationale to consider the status of this tumor suppressor in the clinical setting.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Pequenas/genética , Furanos/farmacologia , Cetonas/farmacologia , Neoplasias Pulmonares/genética , Proteína Supressora de Tumor p53/genética , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Mutação com Perda de Função , Neoplasias Pulmonares/tratamento farmacológico , Medicina de Precisão
8.
Aging (Albany NY) ; 13(9): 12526-12536, 2021 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-33934091

RESUMO

To investigate the suppressive function of RO4929097, a potent -secretase inhibitor, on RANKL-induced osteoclastogenesis. The cytotoxicity of RO4929097 was evaluated. The suppressive effect and possible molecular mechanism of RO4929097 on RANKL-induced osteoclastogenesis was evaluated both in vitro and in vivo. The IC50 of RO4929097 was 2.93 µM. Treatment with different doses of RO4929097 (100 nM, 200 nM, and 400 nM) effectively reduced osteoclast formation (number and resorption area) in a dose-dependent manner. The qPCR results revealed that RO4929097 attenuates RANKL-induced osteoclast formation and NFATc1 protein expression. The in vivo experiments demonstrated that RO4929097 had an inhibitory effect on LPS-induced bone resorption. Our in vitro experiments showed that RO4929097 can potently inhibit osteoclastogenesis and bone resorption by down-regulating the Notch/MAPK/JNK/Akt-mediated reduction of NFATc1. In accordance with these in vitro observations, RO4929097 attenuated LPS-induced osteolysis in mice. In conclusion, our findings indicate that Notch may represent a potential therapeutic target for the treatment of osteolytic diseases.


Assuntos
Benzazepinas/farmacologia , Fluorenos/farmacologia , Cetonas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteólise/tratamento farmacológico , Animais , Diferenciação Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Osteogênese/fisiologia , Osteólise/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos
9.
Anticancer Res ; 41(4): 1779-1784, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813382

RESUMO

BACKGROUND/AIM: Osteosarcoma is a rare type of bone cancer that affects mostly children and adolescents. First-line chemotherapy for osteosarcoma has not been improved for many decades. Eribulin has been used to treat breast cancer and liposarcoma in the clinic. MATERIALS AND METHODS: A patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma was established by tumor insertion within the tibia. This model more closely mimics osteosarcoma in clinical settings and was used to test the efficacy of eribulin. Tibia-insertion osteosarcoma PDOX mouse models were randomized into two groups: a control group (n=4) and an eribulin-treatment group (n=5). Mice were treated for fourteen days, four weeks after initial implantation. Tumor size and body weight were measured, and tumor histology was examined. RESULTS: Significant tumor growth inhibition (p=0.044) was observed in mice treated with eribulin compared to the control group. Histology demonstrated necrosis in the eribulin-treated tumors. There was no body-weight loss in the treated mice. CONCLUSION: Eribulin may be a clinically-effective, off-label chemotherapy for recalcitrant osteosarcoma that has failed first- and second-line therapy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Furanos/farmacologia , Cetonas/farmacologia , Osteossarcoma/tratamento farmacológico , Tíbia/efeitos dos fármacos , Adolescente , Animais , Neoplasias Ósseas/patologia , Humanos , Masculino , Camundongos Nus , Necrose , Osteossarcoma/patologia , Tíbia/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Int J Mol Sci ; 22(8)2021 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-33921647

RESUMO

Platyphyllenone is a type of diarylheptanoid that exhibits anti-inflammatory and chemoprotective effects. However, its effect on oral cancer remains unclear. In this study, we investigated whether platyphyllenone can promote apoptosis and autophagy in SCC-9 and SCC-47 cells. We found that it dose-dependently promoted the cleavage of PARP; caspase-3, -8, and -9 protein expression; and also led to cell cycle arrest at the G2/M phase. Platyphyllenone up-regulated LC3-II and p62 protein expression in both SCC-9 and SCC-47 cell lines, implying that it can induce autophagy. Furthermore, the results demonstrated that platyphyllenone significantly decreased p-AKT and increased p-JNK1/2 mitogen-activated protein kinase (MAPK) signaling pathway in a dose-dependent manner. The specific inhibitors of p-JNK1/2 also reduced platyphyllenone-induced cleavage of PARP, caspase-3, and caspase -8, LC3-II and p62 protein expression. These findings are the first to demonstrate that platyphyllenone can induce both autophagy and apoptosis in oral cancers, and it is expected to provide a therapeutic option as a chemopreventive agent against oral cancer proliferation.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Cetonas/farmacologia , Neoplasias Bucais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Western Blotting , Caspase 3 , Caspase 8/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
J Mater Chem B ; 9(14): 3153-3160, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33885619

RESUMO

Photothermal therapy is promising for augmenting cancer therapeutic outcomes in cancer treatment. Diketopyrrolopyrrole (DPP)-conjugated polymer nanoparticles are in focus due to their dual photoacoustic imaging and photothermal therapy functions. Herein, the design and synthesis of three near-infrared absorbing conjugated polymers, named DPP-SO, DPP-SS and DPP-SSe, with heteroatom substitution of the thiophene moiety were developed for a photoacoustic imaging guided photothermal therapy. It was demonstrated that systematically changing only the heteroatom from O to S or Se could apparently adjust the absorption spectrum and energy gap of DPP-conjugated polymers to obtain the most suitable photothermal transduction agents (PTAs) for use in biomedicine. The characterization of photophysical properties proved that the photothermal conversion efficiency and absorption coefficient of DPP-SO nanoparticles under 808 nm irradiation was up to 79.3% and 66.51 L g-1 cm-1, respectively, which were much higher than those of DPP-SS and DPP-SSe nanoparticles. Remarkably, the IC50 value of DPP-SO for killing A549 cells was half that of DPP-SS and DPP-SSe nanoparticles. Further in vivo works demonstrated efficient photothermal therapeutic effects of DPP-SO nanoparticles with the guidance of photoacoustic imaging. Thus, this is an efficient method to regulate the photothermal performance of DPP-conjugated polymers by changing the heteroatom in the molecular skeleton.


Assuntos
Antineoplásicos/farmacologia , Calcogênios/farmacologia , Cetonas/farmacologia , Nanopartículas/química , Técnicas Fotoacústicas , Terapia Fototérmica , Polímeros/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Calcogênios/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/química , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Polímeros/química , Pirróis/química
12.
J Med Chem ; 64(7): 3508-3545, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33764065

RESUMO

Over the years, researchers in drug discovery have taken advantage of the use of privileged structures to design innovative hit/lead molecules. The α-ketoamide motif is found in many natural products, and it has been widely exploited by medicinal chemists to develop compounds tailored to a vast range of biological targets, thus presenting clinical potential for a plethora of pathological conditions. The purpose of this perspective is to provide insights into the versatility of this chemical moiety as a privileged structure in drug discovery. After a brief analysis of its physical-chemical features and synthetic procedures to obtain it, α-ketoamide-based classes of compounds are reported according to the application of this motif as either a nonreactive or reactive moiety. The goal is to highlight those aspects that may be useful to understanding the perspectives of employing the α-ketoamide moiety in the rational design of compounds able to interact with a specific target.


Assuntos
Amidas/farmacologia , Química Farmacêutica/métodos , Cetonas/farmacologia , Amidas/química , Animais , Linhagem Celular Tumoral , Humanos , Cetonas/química
13.
Br J Cancer ; 124(9): 1581-1591, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33723394

RESUMO

BACKGROUND: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance. METHODS: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway. RESULTS: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment. CONCLUSIONS: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Furanos/farmacologia , Cetonas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Sci Rep ; 11(1): 6341, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737707

RESUMO

Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA2 and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA2 activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro, we utilized bone marrow-derived macrophages to determine myelin's effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS + INF-γ; M1) macrophage activation, whereas myelin did not induce pro-inflammatory responses in unstimulated or anti-inflammatory (IL-4; M2) macrophages. Specifically, myelin increased levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide production in M1 macrophages as well as M1-mediated neurotoxicity. PACOCF3 (cPLA2 inhibitor) blocked myelin's detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA2 play an important role in the pathophysiology of SCI inflammation and the phenotype-specific response to myelin implicate diverse roles of myelin in neuroinflammatory conditions.


Assuntos
Inflamação/genética , Bainha de Mielina/genética , Fosfolipases A2 Citosólicas/genética , Traumatismos da Medula Espinal/genética , Animais , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Interleucina-4/biossíntese , Cetonas/farmacologia , Lipídeos/biossíntese , Lipídeos/genética , Ativação de Macrófagos/genética , Camundongos , Microglia/metabolismo , Microglia/patologia , Óxido Nítrico/biossíntese , Fagocitose/genética , Fenótipo , Fosfolipases A2 Citosólicas/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Traumatismos da Medula Espinal/patologia
15.
Biomolecules ; 11(2)2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671577

RESUMO

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 µM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.


Assuntos
Morte Celular , Ácido Glutâmico/toxicidade , Cetonas/farmacologia , Neurônios/metabolismo , Oxigênio/metabolismo , Extratos Vegetais/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose , Compostos de Bifenilo/farmacologia , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular , Cromatina/metabolismo , Embriófitas/genética , Sequestradores de Radicais Livres , Ácido Glutâmico/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/metabolismo , Hipocampo/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Camundongos , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Fosforilação , Picratos/farmacologia , Plantas Medicinais , Espécies Reativas de Oxigênio
16.
Eur J Med Chem ; 215: 113267, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33639344

RESUMO

Inhibitors of the proteasome have been extensively studied for their applications in the treatment of human diseases such as hematologic malignancies, autoimmune disorders, and viral infections. Many of the proteasome inhibitors reported in the literature target the non-primed site of proteasome's substrate binding pocket. In this study, we designed, synthesized and characterized a series of novel α-keto phenylamide derivatives aimed at both the primed and non-primed sites of the proteasome. In these derivatives, different substituted phenyl groups at the head group targeting the primed site were incorporated in order to investigate their structure-activity relationship and optimize the potency of α-keto phenylamides. In addition, the biological effects of modifications at the cap moiety, P1, P2 and P3 side chain positions were explored. Many derivatives displayed highly potent biological activities in proteasome inhibition and anticancer activity against a panel of six cancer cell lines, which were further rationalized by molecular modeling analyses. Furthermore, a representative α-ketoamide derivative was tested and found to be active in inhibiting the cellular infection of SARS-CoV-2 which causes the COVID-19 pandemic. These results demonstrate that this new class of α-ketoamide derivatives are potent anticancer agents and provide experimental evidence of the anti-SARS-CoV-2 effect by one of them, thus suggesting a possible new lead to develop antiviral therapeutics for COVID-19.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Cetonas/farmacologia , Inibidores de Proteassoma/farmacologia , SARS-CoV-2/efeitos dos fármacos , Amidas/síntese química , Amidas/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Calpaína/química , Calpaína/metabolismo , Linhagem Celular Tumoral , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cetonas/síntese química , Cetonas/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
17.
Molecules ; 26(4)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578831

RESUMO

Currently, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has infected people among all countries and is a pandemic as declared by the World Health Organization (WHO). SARS-CoVID-2 main protease is one of the therapeutic drug targets that has been shown to reduce virus replication, and its high-resolution 3D structures in complex with inhibitors have been solved. Previously, we had demonstrated the potential of natural compounds such as serine protease inhibitors eventually leading us to hypothesize that FDA-approved marine drugs have the potential to inhibit the biological activity of SARS-CoV-2 main protease. Initially, field-template and structure-activity atlas models were constructed to understand and explain the molecular features responsible for SARS-CoVID-2 main protease inhibitors, which revealed that Eribulin Mesylate, Plitidepsin, and Trabectedin possess similar characteristics related to SARS-CoVID-2 main protease inhibitors. Later, protein-ligand interactions are studied using ensemble molecular-docking simulations that revealed that marine drugs bind at the active site of the main protease. The three-dimensional reference interaction site model (3D-RISM) studies show that marine drugs displace water molecules at the active site, and interactions observed are favorable. These computational studies eventually paved an interest in further in vitro studies. Finally, these findings are new and indeed provide insights into the role of FDA-approved marine drugs, which are already in clinical use for cancer treatment as a potential alternative to prevent and treat infected people with SARS-CoV-2.


Assuntos
Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , SARS-CoV-2/fisiologia , Inibidores de Serino Proteinase/farmacologia , Domínio Catalítico , Depsipeptídeos/química , Depsipeptídeos/farmacologia , Reposicionamento de Medicamentos , Furanos/química , Furanos/farmacologia , Humanos , Cetonas/química , Cetonas/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , SARS-CoV-2/efeitos dos fármacos , Inibidores de Serino Proteinase/química , Trabectedina/química , Trabectedina/farmacologia , Proteínas Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos
18.
Mol Biol Rep ; 48(2): 1299-1310, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33590414

RESUMO

Antimicrobial compounds from the safest source have gained greater relevance because of their wide spectrum of possible applications, especially in aquaculture industry, where pathogenic threat and antibacterial resistance are serious concerns. Bacillus stercoris MBTDCMFRI Ba37 isolated from mangrove environment of tropical estuarine habitats of Cochin exhibited a wide spectrum of antibacterial activity against major aquaculture pathogens belonging to genus Vibrio and Aeromonas. The structural characterization of the antibacterial compound from this strain may help in identifying their role as a biocontrol agent in aquaculture and allied sectors. The highest antibacterial activity was detected in 3rd day culture, grown in a modified Bacillus medium containing 1% of glycerol and 0.5% of glutamic acid at 30 °C, pH 8.0 and 15 ppt saline conditions. The inhibitory activity of the cell free supernatant was evident even at 20% v/v dilution. Preliminary studies on the nature of antibacterial action indicated that the bioactive principle is stable at temperatures up to 70 °C, between pH 6-9 and instable to lyzozyme and proteolytic enzymes. Bioassay guided purification followed by spectroscopic characterization of active fractions of B. stercoris MBTDCMFRI Ba37 revealed that the compound 1-(1-Hydroxyethyl)-1,7,10,12,13,15,17 heptamethyl-16-oxatetracyclo[8.7.0.02,3.012,13]heptadecan-5-one, is responsible for its major antibacterial activity. This is the first report on isolation and characterization of an antibacterial compound from the species B. stercoris. The results of this study indicated that B. stercoris MBTDCMFRI Ba37 has beneficial antibacterial properties which could be useful in developing novel antimicrobial therapeutics against a variety of aquaculture and other pathogens.


Assuntos
Anti-Infecciosos/isolamento & purificação , Bacillus/química , Cetonas/isolamento & purificação , Vibrio/efeitos dos fármacos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Aquicultura , Meios de Cultura/química , Meios de Cultura/farmacologia , Ecossistema , Cetonas/química , Cetonas/farmacologia , Testes de Sensibilidade Microbiana , Probióticos/química , Probióticos/farmacologia , Vibrio/patogenicidade
19.
Int J Nanomedicine ; 16: 725-740, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33542627

RESUMO

Purpose: As a dental material, polyetheretherketone (PEEK) is bioinert that does not induce cellular response and bone/gingival tissues regeneration. This study was to develop bioactive coating on PEEK and investigate the effects of coating on cellular response. Materials and Methods: Tantalum pentoxide (TP) coating was fabricated on PEEK surface by vacuum evaporation and responses of rat bone marrow mesenchymal stem (RBMS) cells/human gingival epithelial (HGE) were studied. Results: A dense coating (around 400 nm in thickness) of TP was closely combined with PEEK (PKTP). Moreover, the coating was non-crystalline TP, which contained many small humps (around 10 nm in size), exhibiting a nanostructured surface. In addition, the roughness, hydrophilicity, surface energy, and protein adsorption of PKTP were remarkably higher than that of PEEK. Furthermore, the responses (adhesion, proliferation, and osteogenic gene expression) of RBMS cells, and responses (adhesion and proliferation) of HGE cells to PKTP were remarkably improved in comparison with PEEK. It could be suggested that the nanostructured coating of TP on PEEK played crucial roles in inducing the responses of RBMS/HGE cells. Conclusion: PKTP with elevated surface performances and outstanding cytocompatibility might have enormous potential for dental implant application.


Assuntos
Células Epiteliais/citologia , Gengiva/citologia , Cetonas/farmacologia , Células-Tronco Mesenquimais/citologia , Nanoestruturas/química , Óxidos/farmacologia , Polietilenoglicóis/farmacologia , Tantálio/farmacologia , Adsorção , Fosfatase Alcalina/metabolismo , Animais , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/ultraestrutura , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/enzimologia , Nanoestruturas/ultraestrutura , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície , Difração de Raios X
20.
BMC Complement Med Ther ; 21(1): 28, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441125

RESUMO

BACKGROUND: Ulcerative colitis is a gut inflammatory disorder due to altered immune response to gut microbiome, with interplay of environmental and genetic factors. TNF-α activates inflammatory response through a cascade of immune responses, augmenting pro-inflammatory mediators and proteases, activating chemotaxis, and infiltration of inflammatory cells, leading to ulceration and haemorrhage through cytotoxic reactive oxygen species. 6-Paradol, a dietary component in several plants belonging to the Zingiberaceae family, has shown anti-inflammatory and antioxidant activities. Current study evaluates the effect of 6-paradol in amelioration of ulcerative colitis in rats for the first time. METHODS: 6-Paradol (95% purity) was obtained from seeds of Aframomum melegueta. Rats were divided randomly into six groups (n = 8). Group one was administered normal saline; group two was treated with the vehicle only; group three, sulfasalazine 500 mg/kg; and groups four, five, and six, were given 6-paradol (50, 100, 200, respectively) mg/kg orally through gastric gavage for 7 days. Colitis was induced on 4th day by intrarectal administration of 2 ml acetic acid (3%), approximately 3 cm from anal verge. On 8th day, rats were sacrificed, and distal one-third of the colon extending proximally up to 4 cm from anal orifice was taken for biochemical and gross examination. Two centimetres of injured mucosal portion was taken for histopathological investigations. SPSS (ver.26) was used for statistical analysis. RESULTS: Colonic and serum glutathione (GSH) levels decreased, while colonic and serum malondialdehyde (MDA), colonic myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6), serum tumour necrosis factor-α (TNF-α) levels, and colon weight to length ratio were increased significantly in the colitis untreated group compared to normal control. Treatment with 6-paradol considerably improved all these parameters, especially at a dose of 200 mg/kg (p < 0.001), revealing non-significant differences with sulfasalazine 500 mg/kg and normal control (p = 0.998). Sulfasalazine and 6-paradol in a dose dependent manner also markedly reversed mucosal oedema, atrophy and inflammation, cryptic damage, haemorrhage, and ulceration. There were non-significant differences between low and medium doses and between medium and high doses of 6-paradol for IL-6 and serum MDA levels. CONCLUSION: 6-Paradol demonstrated protection against acetic acid-induced ulcerative colitis, probably by anti-inflammatory and antioxidant actions.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Colite Ulcerativa , Guaiacol/análogos & derivados , Cetonas/farmacologia , Ácido Acético/toxicidade , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Glutationa/metabolismo , Guaiacol/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Sementes/química , Zingiberaceae/química
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