RESUMO
In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, 6e demonstrated the highest activity in the enzymatic assay with an IC50 value of 8.52 ± 0.44 µM. The IC50 value for Nirmatrelvir (PF-07321332, used as a reference) was 0.84 ± 0.37 µM. The cytotoxic properties were determined in the MTT assay using MRC-5 and HEK-293 cell lines. In the course of the investigation, we found that the newly obtained maleimide derivatives are not substantially cytotoxic (IC50 values for most compounds were above 200 µM).
Assuntos
COVID-19 , Humanos , Células HEK293 , SARS-CoV-2 , Maleimidas/farmacologia , Lactamas , Leucina , Nitrilas , Inibidores de Proteases/farmacologia , Simulação de Acoplamento Molecular , Antivirais/farmacologiaRESUMO
Pancreatic cancer, notorious for its grim 10% five-year survival rate, poses significant clinical challenges, largely due to late-stage diagnosis and limited therapeutic options. This review delves into the generation of organoids, including those derived from resected tissues, biopsies, pluripotent stem cells, and adult stem cells, as well as the advancements in 3D printing. It explores the complexities of the tumor microenvironment, emphasizing culture media, the integration of non-neoplastic cells, and angiogenesis. Additionally, the review examines the multifaceted properties of graphene oxide (GO), such as its mechanical, thermal, electrical, chemical, and optical attributes, and their implications in cancer diagnostics and therapeutics. GO's unique properties facilitate its interaction with tumors, allowing targeted drug delivery and enhanced imaging for early detection and treatment. The integration of GO with 3D cultured organoid systems, particularly in pancreatic cancer research, is critically analyzed, highlighting current limitations and future potential. This innovative approach has the promise to transform personalized medicine, improve drug screening efficiency, and aid biomarker discovery in this aggressive disease. Through this review, we offer a balanced perspective on the advancements and future prospects in pancreatic cancer research, harnessing the potential of organoids and GO.
Assuntos
Pesquisa Biomédica , Grafite , Neoplasias Pancreáticas , Adulto , Humanos , Estudos Prospectivos , Pâncreas , Neoplasias Pancreáticas/tratamento farmacológico , Hormônios Pancreáticos , Microambiente TumoralRESUMO
Oxidovanadium(V) complexes, [(+)VOL1-5] and [(-)VOL1-5], with chiral tetradentate Schiff bases, which are products of monocondensation of S(â)-3-amino-1,2-propanediol or R(+)-3-amino-1,2-propanediol with salicylaldehyde derivatives, have been synthesized. Different spectroscopic methods, viz. 1H and 51V NMR, IR, UV-Vis, and circular dichroism, as well as elemental analysis, have been used for their detailed characterization. Furthermore, the epoxidation of styrene, cyclohexene, and two monoterpenes, S(â)-limonene and (â)-α-pinene, using two oxidants, aqueous 30% H2O2 or tert-butyl hydroperoxide (TBHP) in decane, has been studied with catalytic amounts of all complexes. Finally, biological cytotoxicity studies have also been performed with these oxidovanadium(V) compounds for comparison with cis-dioxidomolybdenum(VI) Schiff base complexes with the same chiral ligands, as well as to determine the cytoprotection against the oxidative damage caused by 30% H2O2 in the HT-22 hippocampal neuronal cells in the range of their 10-100 µM concentration.
Assuntos
Bases de Schiff , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Catálise , Estereoisomerismo , Animais , Vanádio/química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Estresse Oxidativo/efeitos dos fármacos , Camundongos , HumanosRESUMO
New oxidovanadium(V) complexes, VOL1-VOL10, with chiral tetradentate Schiff bases obtained by monocondensation reaction of salicylaldehyde derivatives with 1S,2S-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. All complexes have been characterized using different spectroscopic methods, viz. IR, UV-Vis, circular dichroism, one- (1H, 51V) and two-dimensional (COSY, NOESY) NMR spectroscopy, and elemental analysis. Furthermore, the catalytic ability of all compounds in the epoxidation of styrene, cyclohexene, and its naturally occurring monoterpene derivatives, i.e., S(-)-limonene and (-)-α-pinene has also been studied, using two different oxidants, i.e., aqueous 30% H2O2 or tert-butyl hydroperoxide (TBHP). In addition, the biological properties of these chiral oxidovanadium(V) compounds, but also cis-dioxidomolybdenum(VI) complexes with the same chiral Schiff bases, were studied. Their cytotoxic and cytoprotective activity studies with the HT-22 hippocampal neuronal cells revealed a concentration-dependent effect in the range of 10-100 µM. Moreover, vanadium(V) complexes, in contrast to cis-dioxidomolybdenum(VI) compounds, demonstrated higher cytotoxicity and lack of cytoprotective ability against H2O2-induced cytotoxicity.
Assuntos
Complexos de Coordenação , Compostos Organometálicos , Compostos Organometálicos/química , Bases de Schiff/farmacologia , Bases de Schiff/química , Peróxido de Hidrogênio , Espectroscopia de Ressonância Magnética , Vanádio/química , Complexos de Coordenação/química , LigantesRESUMO
In this work, we designed, synthesised and biologically investigated a novel series of 14 N- and O-phosphorylated tacrine derivatives as potential anti-Alzheimer's disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products 6-13 and 16-21 that were characterised by 1H, 13 C, 31 P NMR and MS. The results of the docking studies revealed that the designed phosphorus hybrids, in theory can bind to AChE and BChE. All compounds exhibited significantly lower AutoDock Vina scores compared to tacrine. The inhibitory potency evaluation was performed using the Ellman's method. The most inhibitory activity against AChE exhibited compound 8 with an IC50 value of 6.11 nM and against BChE 13 with an IC50 value of 1.97 nM and they were 6- and 12-fold potent than tacrine. Compound 19 showed the lack of hepatocytotoxicity in MTT assay.
Assuntos
Doença de Alzheimer , Tacrina , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/química , Humanos , Relação Estrutura-Atividade , Tacrina/químicaRESUMO
Despite significant progress in the pathogenesis, diagnosis, treatment, and prevention of cancer and neurodegenerative diseases, their occurrence and mortality are still high around the world. The resistance of cancer cells to the drugs remains a significant problem in oncology today, while in the case of neuro-degenerative diseases, therapies reversing the process are still yet to be found. Furthermore, it is important to seek new chemotherapeutics reversing side effects of currently used drugs or helping them perform their function to inhibit progression of the disease. Carnosine, a dipeptide constisting of ß-alanine and l-histidine, has a variety of functions to mention: antioxidant, antiglycation, and reducing the toxicity of metal ions. It has therefore been proposed to act as a therapeutic agent for many pathological states. The aim of this paper was to find if carnosine and its derivatives can be helpful in treating various diseases. Literature search presented in this review includes review and original papers found in SciFinder, PubMed, and Google Scholar. Searches were based on substantial keywords concerning therapeutic usage of carnosine and its derivatives in several diseases including neurodegenerative disorders and cancer. In this paper, we review articles and find that carnosine and its derivatives are potential therapeutic agents in many diseases including cancer, neurodegenerative diseases, diabetes, and schizophrenia. Carnosine and its derivatives can be used in treating neurodegenerative diseases, cancer, diabetes, or schizophrenia, although their usage is limited. Therefore, there's an urge to synthesize and analyze new substances, overcoming the limitation of carnosine itself.
Assuntos
Carnosina/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Carnosina/análogos & derivados , Carnosina/química , Carnosina/metabolismo , Humanos , Conformação Molecular , Neoplasias/patologiaRESUMO
Due to the high toxicity of currently used chemotherapeutics, novel methods of cancer treatment are needed. Gold nanoparticles (AuNPs) seem to be an interesting alternative due to penetration through biological membranes and systemic barriers. AuNPs as carriers of chemotherapeutics allow for reduced concentrations whilst maintaining the expected effect, and thus reducing the costs of therapy and adverse effects. We synthesized AuNPs stabilized with reduced glutathione (GSH) and conjugated with doxorubicin (DOX), gemcitabine (GEM) or cytarabine (CTA). This is the first study in which cytarabine-AuNPs were synthesized and characterized. Transmission electron microscopy (TEM), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR) and high-performance liquid chromatography (HPLC) were used to chemically characterize obtained nanoparticles. Antitumor activity and safety of application were assessed by MTT assay in in vitro model (human osteosarcoma cells -143B, human osteoblast- hFOB1.19, breast cancer cells - MCF7, breast epithelial cells - MCF10A, pancreatic cancer cells - PANC-1, and pancreatic cells - hTERT-HPNE cells). We have shown that cellular response varies according to the type and concentration of AuNPs. At some concentrations, we were able to show selective cytotoxicity of our AuNPs conjugates only to cancer cell lines. Synthesized nanoparticles were more cytotoxic to tumor cell lines than chemotherapeutics alone.
Assuntos
Glutationa/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Cromatografia Líquida de Alta Pressão , Citarabina/química , Citarabina/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Glutationa/química , Ouro/efeitos adversos , Humanos , Células MCF-7 , Nanopartículas Metálicas/efeitos adversos , Microscopia Eletrônica de Transmissão , Neoplasias/genética , Neoplasias/patologia , Osteoblastos/efeitos dos fármacos , Telomerase/química , GencitabinaRESUMO
Discovering that metals are essential for the structure and function of biomolecules has given a completely new perspective on the role of metal ions in living organisms. Nowadays, the design and synthesis of new metal-based compounds, as well as metal ion binding components, for the treatment of human diseases is one of the main aims of bioinorganic chemistry. One of the areas in vanadium-based compound research is their potential anticancer activity. In this review, we summarize recent molecular and cellular mechanisms in the cytotoxic activity of many different synthetic vanadium complexes as well as inorganic salts. Such mechanisms shall include DNA binding, oxidative stress, cell cycle regulation and programed cell death. We focus mainly on cellular studies involving many type of cancer cell lines trying to highlight some new significant advances.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos de Vanádio/química , Compostos de Vanádio/farmacologia , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Due to development of nanotechnology and gold nanoparticles (AuNPs) increasing use in different areas of medicine, especially in oncology, better understanding of their potential cytotoxicity is necessary to protect patients safety. Shape and size of AuNPs is an important modulator of their cytotoxicity. Therefore, we investigated the cytotoxicity of AuNPs rods (≈39 nm length, 18 nm width), AuNPs stars (≈ 215 nm) and AuNPs spheres (≈ 6.3 nm) against human fetal osteoblast (hFOB 1.19), osteosarcoma (143B, MG63) and pancreatic duct cell (hTERT-HPNE) lines by MTT and neutral-red uptake assay. Moreover, influence of AuNPs on level of proapoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) was measured by western blot. Cellular uptake of nanoparticles and ultrastructure changes were examined by transmission electron microscopy (TEM). In the present study we have proven that AuNPs stars are the most cytotoxic against human cells. We observed that cancer cells are more susceptible to AuNPs cytotoxic effect. Furthermore, AuNPs rods and AuNPs stars caused increased expression of Bax and decreased expression of Bcl-2 protein in osteosarcoma cells. We found that AuNPs penetrated through the cell membrane and caused ultrastructural changes. Our results clearly demonstrated that the cytotoxicity of AuNPs was shape-dependent. AuNPs stars with the highest anti-cancer potential were also the most cytotoxic type of tested NPs, whereas AuNPs spheres which appears to be the safest one had small anti-cancer potential.
Assuntos
Antineoplásicos/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Osteoblastos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Células A549 , Materiais Biocompatíveis , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Células Hep G2 , Humanos , Nanosferas , Osteoblastos/metabolismo , Osteossarcoma/metabolismo , Ductos Pancreáticos , Tamanho da Partícula , Segurança do Paciente , Proteína X Associada a bcl-2/metabolismoRESUMO
Pancreatic cancer is characterized by one of the lowest five-year survival rates. In search for new treatments, some studies explored several metal complexes as potential anticancer drugs. Therefore, we investigated three newly synthesized oxidovanadium(IV) complexes with 2-methylnitrilotriacetate (bcma3-), N-(2-carbamoylethyl)iminodiacetate (ceida3-) and N-(phosphonomethyl)-iminodiacetate (pmida4-) ligands as potential anticancer compounds using pancreatic cancer cell lines. We measured: Cytotoxicity using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) assay; antiproliferative activity by bromodeoxyuridine BrdU assay; reactive oxygen species (ROS) generation and cell cycle analysis by flow cytometry; protein level by Western blot and cellular morphology by confocal laser scanning microscopy. The results showed that these oxidovanadium(IV) complexes were cytotoxic on pancreatic cancer cells (PANC-1 and MIA PaCa2), but not on non-tumor human immortalized pancreas duct epithelial cells (hTERT-HPNE) over the concentration range of 10â»25 µM, following 48 h incubation. Furthermore, molecular mechanisms of cytotoxicity of [4-NH2-2-Me(Q)H][VO(bcma)(H2O)]2H2O (T1) were dependent on antiproliterative activity, increased ROS generation, cell cycle arrest in G2/M phase with simultaneous triggering of the p53/p21 pathway, binucleation, and induction of autophagy. Our study indicates that oxidovanadium(IV) coordination complexes containing 2-methylnitrilotriacetate ligand are good candidates for preclinical development of novel anticancer drugs targeting pancreatic cancer.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Ductal Pancreático/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Neoplasias Pancreáticas/metabolismo , Compostos de Vanádio/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Compostos de Vanádio/química , Neoplasias PancreáticasRESUMO
The use of protonated N-heterocyclic compound, i.e. 2,2'-bipyridinium cation, [bpyH+], enabled to obtain the new nitrilotriacetate oxidovanadium(IV) salt of the stoichiometry [bpyH][VO(nta)(H2O)]H2O. The X-ray measurements have revealed that the compound comprises the discrete mononuclear [VO(nta)(H2O)]- coordination ion that can be rarely found among other known compounds containing nitrilotriacetate oxidovanadium(IV) moieties. The antitumor activity of [bpyH][VO(nta)(H2O)]H2O and its phenanthroline analogue, [phenH][VO(nta)(H2O)](H2O)0.5, towards human osteosarcoma cell lines (MG-63 and HOS) has been assessed (the LDH and BrdU tests) and referred to cis-Pt(NH3)2Cl2 (used as a positive control). The compounds exert a stronger cytotoxic effect on MG-63 and HOS cells than in untransformed human osteoblast cell line. Thus, the [VO(nta)(H2O)]- containing coordination compounds can be considered as possible antitumor agents in the osteosarcoma model of bone-related cells in culture.
Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Ácido Nitrilotriacético/farmacologia , Osteoblastos/efeitos dos fármacos , Compostos de Vanádio/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Humanos , Ácido Nitrilotriacético/análogos & derivados , Osteoblastos/patologia , Potenciometria , Compostos de Vanádio/químicaRESUMO
Objectives: In dentistry, silver nanoparticles (AgNPs) have drawn particular attention because of their wide antimicrobial activity spectrum. However, controversial information on AgNPs toxicity limited their use in oral infections. Therefore, the aim of the present study was to evaluate the antibacterial activities against a panel of oral pathogenic bacteria and bacterial biofilms together with potential cytotoxic effects on human gingival fibroblasts of 10 nm AgNPs: non-functionalized - uncapped (AgNPs-UC) as well as surface-functionalized with capping agent: lipoic acid (AgNPs-LA), polyethylene glycol (AgNPs-PEG) or tannic acid (AgNPs-TA) using silver nitrate (AgNO3) as control. Methods: The interaction of AgNPs with human gingival fibroblast cells (HGF-1) was evaluated using the mitochondrial metabolic potential assay (MTT). Antimicrobial activity of AgNPs was tested against anaerobic Gram-positive and Gram-negative bacteria isolated from patients with oral cavity and respiratory tract infections, and selected aerobic Staphylococci strains. Minimal inhibitory concentration (MIC) values were determined by the agar dilution method for anaerobic bacteria or broth microdilution method for reference Staphylococci strains and Streptococcus mutans. These strains were also used for antibiofilm activity of AgNPs. Results: The highest antimicrobial activities at nontoxic concentrations were observed for the uncapped AgNPs and the AgNPs capped with LA. It was found that AgNPs-LA and AgNPs-PEG demonstrated lower cytotoxicity as compared with the AgNPs-TA or AgNPs-UC in the gingival fibroblast model. All of the tested nanoparticles proved less toxic and demonstrated wider spectrum of antimicrobial activities than AgNO3 solution. Additionally, AgNPs-LA eradicated Staphylococcus epidermidis and Streptococcus mutans 1-day biofilm at concentration nontoxic to oral cells. Conclusions: Our results proved that a capping agent had significant influence on the antibacterial, antibiofilm activity and cytotoxicity of AgNPs. Clinical significance: This study highlighted potential usefulness of AgNPs against oral anaerobic Gram-positive and Gram-negative bacterial infections and aerobic Staphylococci strains provided that pharmacological activity and risk assessment are carefully performed.
Assuntos
Antibacterianos/farmacologia , Bactérias Anaeróbias/efeitos dos fármacos , Materiais Dentários/farmacologia , Materiais Dentários/toxicidade , Gengiva/efeitos dos fármacos , Nanopartículas Metálicas , Prata/farmacologia , Prata/toxicidade , Antibacterianos/toxicidade , Biofilmes/efeitos dos fármacos , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Gengiva/citologia , Humanos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Polietilenoglicóis/química , Staphylococcus epidermidis/efeitos dos fármacos , Streptococcus mutans/efeitos dos fármacos , Taninos/química , Ácido Tióctico/químicaRESUMO
The aim of this work was to find a relationship between physicochemical properties of the oxovanadium(IV) complexes, namely [VO(ODA)(H2O)2], [VO(ODA)(phen)]·1.5H2O and [VO(ODA)(bipy)]·2H2O (ODA = oxydiacetate) as well as [VO(H2O)5](2+), and their biological activity. A potentiometric titration method has been used to characterize the stability of the complexes in aqueous solutions. Furthermore, the reactivity of the complexes towards superoxide free radicals was assessed by employing the NBT assay as well as a cyclic voltammetry (CV) technique. Additionally, the investigations of the antioxidant properties of the complexes were complemented by studying their reactivity towards organic radicals (the ABTS and DPPH tests). Finally, the biological properties of the complexes were investigated in relation to their cytoprotective activity against the oxidative damage generated exogenously by using hydrogen peroxide in the Hippocampal neuronal cell line HT22 (the MTT and LDH tests). The obtained results showed that all the compounds under study display antioxidant properties but a concentration-depended protective effect against the oxidative damage was found for [VO(ODA)(bipy)]·2H2O only.
Assuntos
Sequestradores de Radicais Livres/farmacologia , Fármacos Neuroprotetores/farmacologia , Vanadatos/química , 2,2'-Dipiridil/química , Acetatos/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Sequestradores de Radicais Livres/química , Hipocampo/citologia , Concentração de Íons de Hidrogênio , Camundongos , Fármacos Neuroprotetores/química , Fenantrolinas/química , Soluções , Superóxidos/químicaRESUMO
Carnosine, an endogenous dipeptide, has been found to have a plethora of medicinal properties, such as antioxidant, antiageing, and chelating effects, but with one downside: a short half-life. Carnosinases and two hydrolytic enzymes, which remain enigmatic, are responsible for these features. Hence, here we emphasize why research is valuable for better understanding crucial concepts like ageing, neurodegradation, and cancerogenesis, given that inhibition of carnosinases might significantly prolong carnosine bioavailability and allow its further use in medicine. Herein, we explore the literature regarding carnosinases and present a short in silico analysis aimed at elucidating the possible recognition pattern between CN1 and its ligands.
Assuntos
Carnosina , Dipeptidases , Humanos , Carnosina/química , Carnosina/metabolismo , Antioxidantes , Dipeptidases/química , Dipeptidases/metabolismo , EnvelhecimentoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) presents a formidable challenge with high lethality and limited effective drug treatments. Its heightened metastatic potential further complicates the prognosis. Owing to the significant toxicity of current chemotherapeutics, compounds like [Met5]-enkephalin, known as opioid growth factor (OGF), have emerged in oncology clinical trials. OGF, an endogenous peptide interacting with the OGF receptor (OGFr), plays a crucial role in inhibiting cell proliferation across various cancer types. This in vitro study explores the potential anticancer efficacy of a newly synthesized OGF bioconjugate in synergy with the classic chemotherapeutic agent, gemcitabine (OGF-Gem). The study delves into assessing the impact of the OGF-Gem conjugate on cell proliferation inhibition, cell cycle regulation, the induction of cellular senescence, and apoptosis. Furthermore, the antimetastatic potential of the OGF-Gem conjugate was demonstrated through evaluations using blood platelets and AsPC-1 cells with a light aggregometer. In summary, this article demonstrates the cytotoxic impact of the innovative OGF-Gem conjugate on pancreatic cancer cells in both 2D and 3D models. We highlight the potential of both the OGF-Gem conjugate and OGF alone in effectively inhibiting the ex vivo pancreatic tumor cell-induced platelet aggregation (TCIPA) process, a phenomenon not observed with Gem alone. Furthermore, the confirmed hemocompatibility of OGF-Gem with platelets reinforces its promising potential. We anticipate that this conjugation strategy will open avenues for the development of potent anticancer agents.
RESUMO
There is growing evidence that amorphous silica nanoparticles (SiO2-NP) can cause an inflammatory response in the lung. We studied in vitro the effects of exposing human lung submucosal cells to SiO2-NP of various sizes (10, 150, and 500 nm) for 2-24 h. Cell survival, reactive oxygen species (ROS), malondialdehyde (MDA) levels, cytokine production, inflammatory gene expression, and genotoxicity were measured after exposure of Calu-3 cells to 10SiO2-NP in the presence or absence of the flavanoid fisetin and an antioxidant enzyme catalase. The exposure of Calu-3 cells to 10SiO2-NP resulted in (1) increased cytotoxicity and cell death in a time- and concentration-dependent manner, with a lethal concentration (LC50) of 9.7 µg/mL after 24 h; (2) enhanced gene expression of interleukin (IL)-6, IL-8, and matrix metalloproteinase-9; (3) a significant correlation between increases in MDA and cytotoxicity at 18 h; (4) ROS production; (5) IL-6 and IL-8 release; and (6) up-regulation of the pro-apoptotic genes, p53 and caspase-3. Cell death and inflammatory reactions were attenuated by fisetin and catalase. We observed that 150- and 500SiO2-NP exerted no toxic effects on Calu-3 cells. In conclusion, the nanotoxicity of amorphous 10SiO2-NP on submucosal cells is associated with inflammation, the release of ROS leading to apoptosis, and decreased cell survival. The nanotoxic effects of 10SiO2-NP can be decreased by fisetin and catalase treatment, implicating oxidative stress in this injury.
Assuntos
Citotoxinas/toxicidade , Flavonoides/farmacologia , Pulmão/efeitos dos fármacos , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Caspase 3/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular , Flavonóis , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/prevenção & controle , Interleucina-6/genética , Interleucina-8/genética , Pulmão/citologia , Pulmão/metabolismo , Malondialdeído/metabolismo , Metaloproteinase 9 da Matriz/genética , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
According to the WHO, cancer is the second leading cause of death in the world. This is an important global problem and a major challenge for researchers who have been trying to find an effective anticancer therapy. A large number of newly discovered compounds do not exert selective cytotoxic activity against tumorigenic cells and have too many side effects. Therefore, research on muramyl dipeptide (MDP) analogs has attracted interest due to the urgency for finding more efficient and safe treatments for oncological patients. MDP is a ligand of the cytosolic nucleotide-binding oligomerization domain 2 receptor (NOD2). This molecule is basic structural unit that is responsible for the immune activity of peptidoglycans and exhibits many features that are important for modern medicine. NOD2 is a component of the innate immune system and represents a promising target for enhancing the innate immune response as well as the immune response against cancer cells. For this reason, MDP and its analogs have been widely used for many years not only in the treatment of immunodeficiency diseases but also as adjuvants to support improved vaccine delivery, including for cancer treatment. Unfortunately, in most cases, both the MDP molecule and its synthesized analogs prove to be too pyrogenic and cause serious side effects during their use, which consequently exclude them from direct clinical application. Therefore, intensive research is underway to find analogs of the MDP molecule that will have better biocompatibility and greater effectiveness as anticancer agents and for adjuvant therapy. In this paper, we review the MDP analogs discovered in the last 10 years that show promise for antitumor therapy. The first part of the paper compiles the achievements in the field of anticancer vaccine adjuvant research, which is followed by a description of MDP analogs that exhibit promising anticancer and antiproliferative activity and their structural changes compared to the original MDP molecule.
RESUMO
Human gastrointestinal cells can be exposed to different xenobiotics present in food or drinking water. In this work, we assessed the cytotoxicity of polystyrene nanoparticles (PS-NPs) and how it is impacted by fluoride (F-) presence. We decided to examine PS-NPs and F- which can be easily found in drinking water and food. Commercially available amine-modified 100 nm PS-NPs were used in the study. Scanning Electron Microscopy with Electron Dispersive Spectroscopy (SEM-EDS) and Dynamic Light Scattering (DLS) were used to characterize PS-NPs. The colon cell lines (HT-29, Caco-2, CCD 841 CoN) were used. Cytotoxicity of PS-NPs and F- alone or in co-exposition were assessed with MTT assay in a time- and concentration-dependent manner. Flow cytometry was used to measure reactive oxygen species (ROS) production, cell cycle distribution, and apoptosis analysis. Transmission electron microscopy (TEM) was used to determine whether PS-NPs and/or F- can cause ultrastructure changes in the cells. We have shown that PS-NPs are cytotoxic to human colon cells in a time- and concentration-dependent manner. PS-NPs did not impact neither intracellular ROS production nor the cells cell cycle distribution. However, if HT-29 cells were co-exposed to PS-NPs and F-, an increased number of cells in G0/G1 phase and decreased number of cells in G2/M were observed. PS-NPs can cause apoptosis in HT-29 cells, this effect was enhanced if cells were co-exposed to PS-NP and F-. PS-NPs were internalised by the cells and caused ultrastructure changes. Fluoride itself (1 mM) was not cytotoxic to the cells and did not cause any changes in the ultrastructure of the cells. We have proven that polystyrene nanoparticles can be cytotoxic to human gastrointestinal cells and this effect is enhanced by fluoride.
Assuntos
Água Potável , Nanopartículas , Aminas , Células CACO-2 , Fluoretos , Humanos , Nanopartículas/química , Poliestirenos/química , Poliestirenos/toxicidade , Espécies Reativas de Oxigênio/metabolismoRESUMO
Purpose: In the search for new drug delivery platforms for cardiovascular diseases and coating of medical devices, we synthesized eptifibatide-functionalized silver nanoparticles (AgNPs-EPI) and examined the pharmacological activity of AgNPs-EPI on platelets and endothelial cells in vitro and ex vivo. Methods: Spherical AgNPs linked to eptifibatide were synthesized and characterized. Cytotoxicity was measured in microvascular endothelial cells (HMEC-1), platelets and red blood cells. Platelet mitochondrial respiration was measured using the Oxygraph-2k, a high-resolution modular respirometry system. The effect of AgNPs-EPI on the aggregation of washed platelets was measured by light aggregometry and the ex vivo occlusion time was determined using a reference laboratory method. The surface amount of platelet receptors such as P-selectin and GPIIb/IIIa was measured. The influence of AgNPS-EPI on blood coagulation science was assessed. Finally, the effect of AgNPs-EPI on endothelial cells was measured by the levels of 6-keto-PGF1alpha, tPa, cGMP and vWF. Results: We describe the synthesis of AgNPs using eptifibatide as the stabilizing ligand. The molecules of this drug are directly bonded to the surface of the nanoparticles. The synthesized AgNPs-EPI did not affect the viability of platelets, endothelial cells and erythrocytes. Preincubation of platelets with AgNPs-EPI protected by mitochondrial oxidative phosphorylation capacity. AgNPs-EPI inhibited aggregation-induced P-selectin expression and GPIIb/IIIa conformational changes in platelets. AgNPs-EPI caused prolongation of the occlusion time in the presence of collagen/ADP and collagen/adrenaline. AgNPs-EPI regulated levels of 6-keto-PGF1alpha, tPa, vWf and cGMP produced in thrombin stimulated HMEC-1 cells. Conclusion: AgNPs-EPI show anti-aggregatory activity at concentrations lower than those required by the free drug acting via regulation of platelet aggregation, blood coagulation, and endothelial cell activity. Our results provide proof-of-principle evidence that AgNPs may be used as an effective delivery platform for antiplatelet drugs.
Assuntos
Nanopartículas Metálicas , Selectina-P , Difosfato de Adenosina/metabolismo , Difosfato de Adenosina/farmacologia , Plaquetas , Colágeno/metabolismo , Células Endoteliais/metabolismo , Epinefrina/metabolismo , Epinefrina/farmacologia , Eptifibatida/farmacologia , Ligantes , Selectina-P/metabolismo , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Prata/metabolismo , Prata/farmacologia , Trombina/metabolismo , Fator de von Willebrand/metabolismoRESUMO
PURPOSE: Periodontal disease (PD), defined as oral inflammation caused by dental plaque, is an emerging problem. PD may lead to tooth loss, and treatment options are limited. In this study, we designed, synthesized, and characterized silver nanoparticles (AgNPs) conjugated with chlorhexidine (AgNPs-CHL) or metronidazole (AgNPs-PEG-MET) to determine whether they can be used to treat PDs. MATERIALS AND METHODS: AgNPs were synthesized and characterized by transmission electron microscopy, UV-vis spectrometry, thermogravimetric analyses, and dynamic light scattering. We determined the safety and the antimicrobial and anti-inflammatory properties of synthesized AgNPs in an in vitro model of periodontitis. Antimicrobial properties were determined by measuring the minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC) on reference strains of bacteria and fungi. Human gingival fibroblast (HGF-1), murine macrophage (RAW264.7) and human foetal osteoblast (hFOB1.19) cells were used in the study. Lipopolysaccharide (LPS) was used to induce inflammation. Cytokine levels were measured using an enzyme-linked immunosorbent assay; metalloproteinase expression was measured using Western blotting. RESULTS: The synthesized AgNPs were spherical and narrow-dispersed with an average diameter of 13.4 nm ± 3.0 nm in the case of AgNPs-CHL and 3.72 nm ± 0.72 nm in the case of AgNPs-PEG-MET. Both types of AgNPs were active against bacteria and fungi. AgNPs-CHL proved to be a more potent antimicrobial agent, although they were more cytotoxic than AgNPs-PEG-MET; however, both demonstrated beneficial properties in nontoxic concentrations. AgNPs-CHL and AgNPs-PEG-MET decreased the production of proinflammatory cytokines IL-1ß, IL-6, IL-8 and TNFα. Both agents also decreased the levels of metalloproteinases MMP3 and MMP8, which may indicate that they will inhibit tissue degradation. CONCLUSION: AgNPs-CHL and AgNPs-PEG-MET may be possible therapeutic options for PD, as they have antibacterial and anti-inflammatory properties. However, to fully understand the potential of AgNPs, our in vitro findings must be evaluated in an in vivo model.