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1.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065900

RESUMO

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.


Assuntos
Antineoplásicos/farmacologia , Di-Hidropiridinas/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias Pancreáticas/genética , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Neoplasias Pancreáticas/tratamento farmacológico , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
2.
Viruses ; 13(6)2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070524

RESUMO

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl2 (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.


Assuntos
Antivirais/farmacologia , Compostos Organometálicos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/química , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organometálicos/química , SARS-CoV-2/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos
3.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067452

RESUMO

A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the "tail approach" and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.


Assuntos
Carboidratos/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Humanos , Simulação de Acoplamento Molecular , Microambiente Tumoral/efeitos dos fármacos
4.
Eur Rev Med Pharmacol Sci ; 25(10): 3908-3913, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34109605

RESUMO

OBJECTIVE: Coronavirus 2019 (COVID-19) has now been declared as a worldwide pandemic. Currently, no drugs have been endorsed for its treatment; in this manner, a pressing need has been developed for any antiviral drugs that will treat COVID-19. Coronaviruses require the SARS-CoV-2 3CL-Protease (3CL-protease) for cleavage of its polyprotein to yield a single useful protein and assume a basic role in the disease progression. In this study, we demonstrated that punicalagin, the fundamental active element of pomegranate in addition to the combination of punicalagin with zinc (Zn) II, appear to show powerful inhibitory activity against SARS-CoV-2. MATERIALS AND METHODS: The 3CL protease assay kit was used to quantify 3CL protease action. The tetrazolium dye, MTS, was used to evaluate cytotoxicity. RESULTS: Punicalagin showed inhibitory action against the 3CL-protease in a dose-dependent manner, and IC50 was found to be 6.192 µg/ml for punicalagin. Punicalagin (10 µg/mL) demonstrated a significant inhibitory activity toward 3CL-protease activity (p < 0.001), yet when punicalagin is combined with zinc sulfate monohydrate (punicalagin/Zn-II) extremely strong 3CL-protease activity (p < 0.001) was obtained. The action of 3CL-protease with punicalagin/Zn-II was decreased by approximately 4.4-fold in contrast to only punicalagin (10 µg/mL). Likewise, we did not notice any significant cytotoxicity caused by punicalagin, Zn-II, or punicalagin/Zn-II. CONCLUSIONS: We suggest that these compounds could be used as potential antiviral drugs against COVID-19.


Assuntos
Proteases 3C de Coronavírus/metabolismo , Taninos Hidrolisáveis/química , SARS-CoV-2/enzimologia , Sulfato de Zinco/química , Animais , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , COVID-19/patologia , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Proteases 3C de Coronavírus/antagonistas & inibidores , Sinergismo Farmacológico , Humanos , Taninos Hidrolisáveis/metabolismo , Taninos Hidrolisáveis/farmacologia , SARS-CoV-2/isolamento & purificação , Células Vero , Sulfato de Zinco/metabolismo , Sulfato de Zinco/farmacologia
5.
Int J Nanomedicine ; 16: 3789-3802, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34103915

RESUMO

Introduction: It has been reported that low-molecular-weight hyaluronic acid (LMWHA) exhibits a potentially beneficial effect on cancer therapy through targeting of CD44 receptors on tumor cell surfaces. However, its applicability towards tumor detection is still unclear. In this regard, LMWHA-conjugated iron (Fe3O4) nanoparticles (LMWHA-IONPs) were prepared in order to evaluate its application for enhancing the T2* weighted MRI imaging sensitivity for tumor detection. Methods: LMWHA and Fe3O4 NPs were produced using γ-ray irradiation and chemical co-precipitation methods, respectively. First, LMWHA-conjugated FITC was prepared to confirm the ability of LMWHA to target U87MG cells using fluorescence microscopy. The hydrodynamic size distribution and dispersion of the IONPs and prepared LMWHA-IONPs were analyzed using dynamic light scattering (DLS). In addition, cell viability assays were performed to examine the biocompatibility of LMWHA and LMWHA-IONPs toward U87MG human glioblastoma and NIH3T3 fibroblast cell lines. The ability of LMWHA-IONPs to target tumor cells was confirmed by detecting iron (Fe) ion content using the thiocyanate method. Finally, time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging and in vitro magnetic resonance imaging (MRI) were performed to confirm the contrast enhancement effect of LMWHA-IONPs. Results: Florescence analysis results showed that LMWHA-FITC successfully targeted the surfaces of both tested cell types. The ability of LMWHA to target U87MG cells was higher than for NIH3T3 cells. Cell viability experiments showed that the fabricated LMWHA-IONPs possessed good biocompatibility for both cell lines. After co-culturing test cells with the LMWHA-IONPs, detected Fe ion content in the U87MG cells was much higher than that of the NIH3T3 cells in both thiocyanate assays and TOF-SIMs images. Finally, the addition of LMWHA-IONPs to the U87MG cells resulted in an obvious improvement in T2* weighted MR image contrast compared to control NIH3T3 cells. Discussion: Overall, the present results suggest that LMWHA-IONPs fabricated in this study provide an effective MRI contrast agent for improving the diagnosis of early stage glioblastoma in MRI examinations.


Assuntos
Raios gama , Glioblastoma/diagnóstico por imagem , Ácido Hialurônico/química , Ferro/química , Imageamento por Ressonância Magnética , Nanopartículas Metálicas/química , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Ácido Hialurônico/ultraestrutura , Nanopartículas Metálicas/ultraestrutura , Camundongos , Peso Molecular , Células NIH 3T3 , Ácido Oleico/química , Tamanho da Partícula
6.
Biomolecules ; 11(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067685

RESUMO

Cm-p5 is a snail-derived antimicrobial peptide, which demonstrated antifungal activity against the pathogenic strains of Candida albicans. Previously we synthetized a cyclic monomer as well as a parallel and an antiparallel dimer of Cm-p5 with improved antifungal activity. Considering the alarming increase of microbial resistance to conventional antibiotics, here we evaluated the antimicrobial activity of these derivatives against multiresistant and problematic bacteria and against important viral agents. The three peptides showed a moderate activity against Pseudomonas aeruginosa, Klebsiella pneumoniae Extended Spectrum ß-Lactamase (ESBL), and Streptococcus agalactiae, with MIC values > 100 µg/mL. They exerted a considerable activity with MIC values between 25-50 µg/mL against Acinetobacter baumanii and Enterococcus faecium. In addition, the two dimers showed a moderate activity against Pseudomonas aeruginosa PA14. The three Cm-p5 derivatives inhibited a virulent extracellular strain of Mycobacterium tuberculosis, in a dose-dependent manner. Moreover, they inhibited Herpes Simplex Virus 2 (HSV-2) infection in a concentration-dependent manner, but had no effect on infection by the Zika Virus (ZIKV) or pseudoparticles of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). At concentrations of >100 µg/mL, the three new Cm-p5 derivatives showed toxicity on different eukaryotic cells tested. Considering a certain cell toxicity but a potential interesting activity against the multiresistant strains of bacteria and HSV-2, our compounds require future structural optimization.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Antivirais/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Antivirais/química , Candida albicans/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Dimerização , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , SARS-CoV-2/efeitos dos fármacos
7.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069441

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here, we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans, facilitate the cellular entry of SARS-CoV-2. Among syndecans, the lung abundant syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus's interactions with syndecans. Besides the polyanionic heparan sulfate chains, other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing the cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offer molecularly precise yet simple strategies to overcome the complex nature of SARS-CoV-2 infection.


Assuntos
COVID-19/metabolismo , Receptores de Coronavírus/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Sindecanas/metabolismo , Internalização do Vírus , Amilorida/farmacologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , COVID-19/virologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Humanos , Peptídeos/farmacologia , Domínios Proteicos , SARS-CoV-2/metabolismo , Sindecana-4/antagonistas & inibidores , Sindecana-4/metabolismo , Sindecanas/antagonistas & inibidores
8.
AAPS PharmSciTech ; 22(5): 171, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34100170

RESUMO

Macrophages act as a cellular reservoir in HIV infection. Elimination of HIV from macrophages has been an unfulfilled dream due to the failure of drugs to reach them. To address this, we developed CD44 receptor-targeted, novel hyaluronic acid (HA)-coated nanostructured lipid carriers (NLCs) of efavirenz via washless layer-by-layer (LbL) assembly of HA and polyallylamine hydrochloride (PAH). NLCs were subjected to TEM analysis, size and zeta potential, in vitro release and encapsulation efficiency studies. The uptake of NLCs in THP-1 cells was studied using fluorescence microscopy and flow cytometry. The anti-HIV efficacy was evaluated using p24 antigen inhibition assay. NLCs were found to be spherical in shape with anionic zeta potential (-23.66 ± 0.87 mV) and 241.83 ± 5.38 nm particle size. NLCs exhibited prolonged release of efavirenz during in vitro drug release studies. Flow cytometry revealed 1.73-fold higher uptake of HA-coated NLCs in THP-1 cells. Cytotoxicity studies showed no significant change in cell viability in presence of NLCs as compared with the control. HA-coated NLCs distributed throughout the cell including cytoplasm, plasma membrane and nucleus, as observed during fluorescence microscopy. HA-coated NLCs demonstrated consistent and significantly higher inhibition (81.26 ± 1.70%) of p24 antigen which was 2.08-fold higher than plain NLCs. The obtained results suggested preferential uptake of HA-coated NLCs via CD44-mediated uptake. The present finding demonstrates that HA-based CD44 receptor targeting in HIV infection is an attractive strategy for maximising the drug delivery to macrophages and achieve effective viral inhibition.


Assuntos
Portadores de Fármacos/administração & dosagem , HIV-1/efeitos dos fármacos , Receptores de Hialuronatos , Macrófagos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Alcinos/administração & dosagem , Alcinos/síntese química , Alcinos/metabolismo , Benzoxazinas/administração & dosagem , Benzoxazinas/síntese química , Benzoxazinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ciclopropanos/administração & dosagem , Ciclopropanos/síntese química , Ciclopropanos/metabolismo , Relação Dose-Resposta a Droga , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/fisiologia , Humanos , Receptores de Hialuronatos/metabolismo , Lipídeos/administração & dosagem , Lipídeos/síntese química , Macrófagos/metabolismo , Nanoestruturas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Células THP-1
9.
Int J Nanomedicine ; 16: 3599-3612, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079252

RESUMO

Purpose: Vernonia amygdalina (VA) is a traditional African herbal medicine that has been reported to possess anticancer properties. However, the anticancer properties of VA silver nanoparticles have not been studied. The aim of the study was to examine and evaluate the anticancer activities of VA leaf extracts and VA silver nanoparticles on the human breast cancer cell line, MCF-7. Methods: VA leaves were extracted using sequential extraction assisted with ultrasound using three different solvents: ethanol, 50% ethanol, and deionized water. The silver nanoparticles were synthesised with VA aqueous extract. Results: The ethanol extract and VA silver nanoparticles inhibit MCF-7 cell proliferation with an average half-maximal inhibitory concentration (IC50) value of 67µg/mL and 6.11µg/mL, respectively, after 72 hours of treatment. The ethanol extract and VA silver nanoparticles also caused G1 phase cell cycle arrest, induced apoptosis and nuclear fragmentation in MCF-7 cells. Conclusion: VA ethanol extracts and VA silver nanoparticles decreased the cell viability in MCF-7 cells in a time and dose-dependent manner by inducing apoptosis and causing DNA damage. Further research is needed to elucidate the mechanism of action of VA leaf extracts and VA silver nanoparticles. This study is the first to report on the anticancer activity of VA silver nanoparticles in MCF-7 cells.


Assuntos
Nanopartículas Metálicas , Extratos Vegetais/química , Folhas de Planta/química , Prata/química , Prata/farmacologia , Vernonia/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Dano ao DNA , Química Verde , Humanos , Células MCF-7 , Solventes/química
10.
Molecules ; 26(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063349

RESUMO

Sweet cherries (Prunus avium L.) are among the most appreciated fruits worldwide because of their organoleptic properties and nutritional value. The accurate phytochemical composition and nutritional value of sweet cherries depends on the climatic region, cultivar, and bioaccessibility and bioavailability of specific compounds. Nevertheless, sweet cherry extracts are highly enriched in several phenolic compounds with relevant bioactivity. Over the years, technological advances in chemical analysis and fields as varied as proteomics, genomics and bioinformatics, have allowed the detailed characterization of the sweet cherry bioactive phytonutrients and their biological function. In this context, the effect of sweet cherries on suppressing important events in the carcinogenic process, such as oxidative stress and inflammation, was widely documented. Interestingly, results from our research group and others have widened the action of sweet cherries to many hallmarks of cancer, namely metabolic reprogramming. The present review discusses the anticarcinogenic potential of sweet cherries by addressing their phytochemical composition, the bioaccessibility and bioavailability of specific bioactive compounds, and the existing knowledge concerning the effects against oxidative stress, chronic inflammation, deregulated cell proliferation and apoptosis, invasion and metastization, and metabolic alterations. Globally, this review highlights the prospective use of sweet cherries as a dietary supplement or in cancer treatment.


Assuntos
Antineoplásicos Fitogênicos/química , Compostos Fitoquímicos/química , Prunus avium/química , Antineoplásicos Fitogênicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Suplementos Nutricionais , Humanos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia
11.
Molecules ; 26(10)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065773

RESUMO

The present study reports the synthesis of new purine bioisosteres comprising a pyrazolo[3,4-d]pyrimidine scaffold linked to mono-, di-, and trimethoxy benzylidene moieties through hydrazine linkages. First, in silico docking experiments of the synthesized compounds against Bax, Bcl-2, Caspase-3, Ki67, p21, and p53 were performed in a trial to rationalize the observed cytotoxic activity for the tested compounds. The anticancer activity of these compounds was evaluated in vitro against Caco-2, A549, HT1080, and Hela cell lines. Results revealed that two (5 and 7) of the three synthesized compounds (5, 6, and 7) showed high cytotoxic activity against all tested cell lines with IC50 values in the micro molar concentration. Our in vitro results show that there is no significant apoptotic effect for the treatment with the experimental compounds on the viability of cells against A549 cells. Ki67 expression was found to decrease significantly following the treatment of cells with the most promising candidate: drug 7. The overall results indicate that these pyrazolopyrimidine derivatives possess anticancer activity at varying doses. The suggested mechanism of action involves the inhibition of the proliferation of cancer cells.


Assuntos
Antineoplásicos/síntese química , Compostos de Benzilideno/síntese química , Biomarcadores Tumorais/metabolismo , Neoplasias/metabolismo , Pirazóis/química , Pirimidinas/química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Biomarcadores Tumorais/química , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Concentração Inibidora 50 , Antígeno Ki-67/química , Antígeno Ki-67/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/tratamento farmacológico
12.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067147

RESUMO

Stress resistance mechanisms include upregulation of heat shock proteins (HSPs) and formation of granules. Stress-induced granules are classified into stress granules and nuclear stress bodies (nSBs). The present study examined the involvement of nSB formation in thermal resistance. We used chemical compounds that inhibit heat shock transcription factor 1 (HSF1) and scaffold attachment factor B (SAFB) granule formation and determined their effect on granule formation and HSP expression in HeLa cells. We found that formation of HSF1 and SAFB granules was inhibited by 2,5-hexanediol. We also found that suppression of HSF1 and SAFB granule formation enhanced heat stress-induced apoptosis. In addition, the upregulation of HSP27 and HSP70 during heat stress recovery was suppressed by 2,5-hexanediol. Our results suggested that the formation of HSF1 and SAFB granules was likely to be involved in the upregulation of HSP27 and HSP70 during heat stress recovery. Thus, the formation of HSF1 and SAFB granules was involved in thermal resistance.


Assuntos
Apoptose , Fatores de Transcrição de Choque Térmico/antagonistas & inibidores , Resposta ao Choque Térmico , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Proteínas Associadas à Matriz Nuclear/metabolismo , Receptores de Estrogênio/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Grânulos Citoplasmáticos/efeitos dos fármacos , Grânulos Citoplasmáticos/metabolismo , Técnicas de Silenciamento de Genes , Glicóis/farmacologia , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Células HeLa , Fatores de Transcrição de Choque Térmico/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Humanos , Modelos Biológicos , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Temperatura , Regulação para Cima/efeitos dos fármacos
13.
Food Chem ; 358: 129910, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33957602

RESUMO

Sodium metabisulfite (SMB), an antioxidant agent, is extensively used as a preservative in food industry. The current study was aimed to clarify its potential toxic effects on human fetal foreskin fibroblasts (HFFF2) cells, in vitro. Subsequently, MTT results illustrated that exposure to SMB significantly (p < 0.0001) decreased HFFF2 cell viability in a dose-dependent manner, and the concentration of 25 µM reduced cell survival rates to 50% as the half-maximal inhibitory concentration of SMB. It was further shown that SMB exerted this cytotoxic effect on HFFF2 cells through apoptosis induction. qRT-PCR and western blotting results showed that treatment of HFFF2 cells with this food additive led to significant upregulation of Bax, caspase 8, and caspase 9 pro-apoptotic genes and downregulation of Bcl-2 expression as a pro-survival agent. Furthermore, SMB remarkably increased caspase 3 levels and promoted its activation through cleavage in treated cells. Besides, exposure to SMB increased ROS levels and activated autophagy in treated cells, which are considered as the other indicators for cell damage. Taken together, our findings suggested that SMB could exert remarkable toxic effects on human normal cells through multiple mechanisms, including apoptosis activation, and its widespread usage in food safety should be reconsidered.


Assuntos
Apoptose/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Aditivos Alimentares/toxicidade , Sulfitos/toxicidade , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Caspase 3/genética , Caspase 8/genética , Caspase 9/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Fibroblastos/fisiologia , Aditivos Alimentares/administração & dosagem , Prepúcio do Pênis/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Espécies Reativas de Oxigênio/metabolismo , Sulfitos/administração & dosagem , Proteína X Associada a bcl-2/genética
14.
Food Funct ; 12(9): 3939-3953, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977959

RESUMO

Nowadays, it is very important to identify the traditional uses of different plants and to create the context in which new cultural or economic value is given to local resources. In this study, two wild fruits traditionally harvested in autumn in Romania were selected to investigate the effects of drying conditions on the chemical compositions and bioactivities exerted by the extracts and to select the best conditions in terms of air temperature and time of drying. The extracts obtained were assessed in terms of antioxidant capacity and enzyme inhibitory activity, and their main bioactive compounds were identified and quantified. The data presented in this article represent a step forward in applying this process on an industrial-scale.


Assuntos
Dessecação , Flavonoides/análise , Conservação de Alimentos , Hippophae/química , Extratos Vegetais , Rosa/química , Animais , Anti-Inflamatórios não Esteroides/análise , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/análise , Antioxidantes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Flavonoides/farmacologia , Frutas/química , Inibidores de Glicosídeo Hidrolases/análise , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos
15.
Biochem Biophys Res Commun ; 561: 14-18, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34000512

RESUMO

In spite of numerous studies, many details of SARS-Cov-2 interaction with human cells are still poorly understood. The 674-685 fragment of SARS-Cov-2 spike protein is homologous to the fragment of α-cobratoxin underlying its interaction with α7 nicotinic acetylcholine receptors (nAChRs). The interaction of 674-685 peptide with α7 nAChR has been predicted in silico. In the present paper we confirm this prediction experimentally and investigate the effect of SARS-Cov-2 spike protein peptide on mitochondria, which express α7 nAChRs to regulate apoptosis-related events. We demonstrate that SARS-Cov-2 spike protein peptide 674-685 competes with the antibody against 179-190 fragment of α7 nAChR subunit for the binding to α7-expressing cells and mitochondria and prevents the release of cytochrome c from isolated mitochondria in response to 0.5 mM H2O2 but does not protect intact U373 cells against apoptogenic effect of H2O2. Our data suggest that the α7 nAChR-binding portion of SARS-Cov-2 spike protein prevents mitochondria-driven apoptosis when the virus is uncoated inside the cell and, therefore, supports the infected cell viability before the virus replication cycle is complete.


Assuntos
Apoptose , Citocromos c/metabolismo , Mitocôndrias/metabolismo , Fragmentos de Peptídeos/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Feminino , Peróxido de Hidrogênio/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/crescimento & desenvolvimento , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
16.
Nat Commun ; 12(1): 2877, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001881

RESUMO

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Linfoma de Célula do Manto/genética , Análise de Célula Única/métodos , Microambiente Tumoral/genética , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Humanos , Imidazóis/farmacologia , Linfoma de Célula do Manto/diagnóstico por imagem , Linfoma de Célula do Manto/tratamento farmacológico , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Naftoquinonas/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Análise de Sequência de RNA/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Medicine (Baltimore) ; 100(21): e25808, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032694

RESUMO

ABSTRACT: MicroRNAs play important roles in gestational diabetes mellitus (GDM), and this study aimed to elucidate the clinical significance of miR-96-5p in diagnosing GDM.There are 123 pregnant women diagnosed with GDM and 123 healthy pregnant women were enrolled as control participants. Placenta and plasma samples from the patients and control participants were collected, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine miR-96-5p expression levels. Moreover, a receiver operating characteristic (ROC) curve was established to evaluate the significance of miR-96-5p in diagnosing GDM. HRT-8/SVneo trophoblasts were cultured under high glucose conditions and treated with miR-96-5p mimics, and cell viability was examined.miR-96-5p levels were significantly decreased in both the placenta and plasma samples of patients with GDM. The ROC curve indicated that miR-96-5p can serve as a diagnostic biomarker for GDM with high sensitivity and specificity. Moreover, miR-96-5p levels were markedly low under high glucose conditions, and the overexpression of miR-96-5p increased the viability, respectively, of trophoblasts in vitro.miR-96-5p may participate in the pathogenesis of GDM by exerting effects on the viability of trophoblasts.


Assuntos
Diabetes Gestacional/diagnóstico , MicroRNAs/análise , Adulto , Biomarcadores/análise , Biomarcadores/metabolismo , Glicemia/análise , Estudos de Casos e Controles , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura/metabolismo , Diabetes Gestacional/sangue , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , MicroRNAs/agonistas , MicroRNAs/metabolismo , Placenta/patologia , Gravidez , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trofoblastos
18.
J Med Chem ; 64(9): 5551-5576, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33934604

RESUMO

N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.


Assuntos
Antidepressivos/química , Transtorno Depressivo Maior/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/metabolismo , Potenciais de Ação/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Furanos/química , Furanos/metabolismo , Furanos/farmacologia , Furanos/uso terapêutico , Meia-Vida , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/genética , Relação Estrutura-Atividade
19.
J Med Chem ; 64(9): 5874-5885, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33945286

RESUMO

Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.


Assuntos
Meios de Contraste/química , Imageamento por Ressonância Magnética , Peroxidase/metabolismo , Animais , Aterosclerose/diagnóstico por imagem , Sítios de Ligação , Cálcio/química , Cálcio/metabolismo , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/metabolismo , Meios de Contraste/farmacologia , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Gadolínio DTPA/química , Gadolínio DTPA/metabolismo , Meia-Vida , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/química , Células RAW 264.7 , Razão Sinal-Ruído , Distribuição Tecidual , Zinco/química , Zinco/metabolismo
20.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946271

RESUMO

Mitochondria are key regulators of cell survival and are involved in a plethora of mechanisms, such as metabolism, Ca2+ signaling, reactive oxygen species (ROS) production, mitophagy and mitochondrial transfer, fusion, and fission (known as mitochondrial dynamics). The tuning of these processes in pathophysiological conditions is fundamental to the balance between cell death and survival. Indeed, ROS overproduction and mitochondrial Ca2+ overload are linked to the induction of apoptosis, while the impairment of mitochondrial dynamics and metabolism can have a double-faceted role in the decision between cell survival and death. Tumorigenesis involves an intricate series of cellular impairments not yet completely clarified, and a further level of complexity is added by the onset of apoptosis resistance mechanisms in cancer cells. In the majority of cases, cancer relapse or lack of responsiveness is related to the emergence of chemoresistance, which may be due to the cooperation of several cellular protection mechanisms, often mitochondria-related. With this review, we aim to critically report the current evidence on the relationship between mitochondria and cancer chemoresistance with a particular focus on the involvement of mitochondrial dynamics, mitochondrial Ca2+ signaling, oxidative stress, and metabolism to possibly identify new approaches or targets for overcoming cancer resistance.


Assuntos
Antineoplásicos/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Mitofagia/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo/efeitos dos fármacos
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