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1.
Int J Nanomedicine ; 16: 4239-4250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194227

RESUMO

Purpose: Pore-forming toxins (PFTs) perform important functions during bacterial infections. Among various virulence-targeting therapies, nanosponges (NSs) have excellent neutralization effects on multiple PFTs. To enhance treatment efficacy, NSs tend to be incorporated into other biomaterials, such as hydrogels. Methods: In the present work, red blood cell (RBC) vesicles were harvested to wrap polymer nanoparticles, leading to the formation of NSs, and the optimal Pluronic F127 hydrogel concentration was determined for gelation. Then, a novel detoxification system was constructed by incorporating NSs into an optimized Pluronic F127 hydrogel (NS-pGel). Next, the system was characterized by rheological and sustained release behavior as well as micromorphology. Then, the in vitro neutralization effect of NS-pGel on various PFTs was examined by a hemolysis protocol. Finally, therapeutic and prophylactic detoxification efficiency was evaluated in a mouse subcutaneous infection model in vivo. Results: A thermosensitive, injectable detoxification system was successfully constructed by loading NSs into a 30% Pluronic F127 hydrogel. Characterization results demonstrated that the NS-pGel hybrid system sustained an ideal fluidity and viscosity at lower temperatures but exhibited a quick sol-gel transition capacity near body temperature. In addition, this hybrid system had a sustained release behavior accompanied by good biocompatibility and biodegradability. Finally, the NS-pGel system showed neutralization effects similar to those of NSs both in vitro and in vivo, indicating a good preservation of NS functionality. Conclusion: In conclusion, we constructed a novel temperature-sensitive detoxification system with good biocompatibility and biodegradability, which may be applied to the clinical treatment of PFT-induced local lesions and infections.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Poloxâmero/química , Animais , Proteínas de Bactérias , Materiais Biocompatíveis , Eritrócitos/química , Proteínas Hemolisinas , Hemólise/efeitos dos fármacos , Masculino , Teste de Materiais , Camundongos Endogâmicos ICR , Nanopartículas/química , Testes de Neutralização , Reologia , Staphylococcus aureus/patogenicidade , Temperatura , Vibrio vulnificus/patogenicidade , Viscosidade
2.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072443

RESUMO

As an important zoonotic pathogen, Streptococcus suis (S. suis) infection has been reported to be a causative agent for variety of diseases in humans and animals, especially Streptococcal toxic shock-like syndrome (STSLS), which is commonly seen in cases of severe S. suis infection. STSLS is often accompanied by excessive production of inflammatory cytokines, which is the main cause of death. This calls for development of new strategies to avert the damage caused by STSLS. In this study, we found for the first time that Baicalein, combined with ampicillin, effectively improved severe S. suis infection. Further experiments demonstrated that baicalein significantly inhibited the hemolytic activity of SLY by directly binding to SLY and destroying its secondary structure. Cell-based assays revealed that Baicalein did not exert toxic effects and conferred protection in S. suis-infected cells. Interestingly, compared with ampicillin alone, Baicalein combined with ampicillin resulted in a higher survival rate in mice severely infected with S. suis. At the same time, we found that baicalein can be combined with meropenem against MRSA. In conclusion, these results indicate that baicalein has a good application prospect.


Assuntos
Antibacterianos/farmacologia , Flavanonas/farmacologia , Infecções Estreptocócicas/microbiologia , Streptococcus suis/efeitos dos fármacos , Animais , Antibacterianos/química , Citocinas/biossíntese , Modelos Animais de Doenças , Farmacorresistência Bacteriana/efeitos dos fármacos , Quimioterapia Combinada , Flavanonas/química , Hemólise/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/metabolismo , Infecções Estreptocócicas/patologia , Relação Estrutura-Atividade
3.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073203

RESUMO

Recently, anticancer peptides (ACPs) have emerged as unique and promising therapeutic agents for cancer treatment compared with antibody and small molecule drugs. In addition to experimental methods of ACPs discovery, it is also necessary to develop accurate machine learning models for ACP prediction. In this study, features were extracted from the three-dimensional (3D) structure of peptides to develop the model, compared to most of the previous computational models, which are based on sequence information. In order to develop ACPs with more potency, more selectivity and less toxicity, the model for predicting ACPs, hemolytic peptides and toxic peptides were established by peptides 3D structure separately. Multiple datasets were collected according to whether the peptide sequence was chemically modified. After feature extraction and screening, diverse algorithms were used to build the model. Twelve models with excellent performance (Acc > 90%) in the ACPs mixed datasets were used to form a hybrid model to predict the candidate ACPs, and then the optimal model of hemolytic peptides (Acc = 73.68%) and toxic peptides (Acc = 85.5%) was used for safety prediction. Novel ACPs were found by using those models, and five peptides were randomly selected to determine their anticancer activity and toxic side effects in vitro experiments.


Assuntos
Antineoplásicos , Bases de Dados de Proteínas , Aprendizado de Máquina , Neoplasias/tratamento farmacológico , Peptídeos , Células A549 , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Células MCF-7 , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/química , Peptídeos/genética , Peptídeos/farmacologia , Ovinos
4.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063332

RESUMO

Artificial sweeteners (AS) are synthetic sugar substitutes that are commonly consumed in the diet. Recent studies have indicated considerable health risks which links the consumption of AS with metabolic derangements and gut microbiota perturbations. Despite these studies, there is still limited data on how AS impacts the commensal microbiota to cause pathogenicity. The present study sought to investigate the role of commonly consumed AS on gut bacterial pathogenicity and gut epithelium-microbiota interactions, using models of microbiota (Escherichia coli NCTC10418 and Enterococcus faecalis ATCC19433) and the intestinal epithelium (Caco-2 cells). Model gut bacteria were exposed to different concentrations of the AS saccharin, sucralose, and aspartame, and their pathogenicity and changes in interactions with Caco-2 cells were measured using in vitro studies. Findings show that sweeteners differentially increase the ability of bacteria to form a biofilm. Co-culture with human intestinal epithelial cells shows an increase in the ability of model gut bacteria to adhere to, invade and kill the host epithelium. The pan-sweet taste inhibitor, zinc sulphate, effectively blocked these negative impacts. Since AS consumption in the diet continues to increase, understanding how this food additive affects gut microbiota and how these damaging effects can be ameliorated is vital.


Assuntos
Enterococcus faecalis/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Edulcorantes/farmacologia , Aspartame/administração & dosagem , Aspartame/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Células CACO-2 , Relação Dose-Resposta a Droga , Enterococcus faecalis/patogenicidade , Escherichia coli/patogenicidade , Microbioma Gastrointestinal/fisiologia , Hemólise/efeitos dos fármacos , Humanos , Sacarina/administração & dosagem , Sacarina/farmacologia , Sacarose/administração & dosagem , Sacarose/análogos & derivados , Sacarose/farmacologia , Edulcorantes/administração & dosagem
5.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073939

RESUMO

An amphipathic α-helical peptide, Hp1404, was isolated from the venomous gland of the scorpion Heterometrus petersii. Hp1404 exhibits antimicrobial activity against methicillin-resistant Staphylococcus aureus but is cytotoxic. In this study, we designed antimicrobial peptides by substituting amino acids at the 14 C-terminal residues of Hp1404 to reduce toxicity and improve antibacterial activity. The analog peptides, which had an amphipathic α-helical structure, were active against gram-positive and gram-negative bacteria, particularly multidrug-resistant Acinetobacter baumannii, and showed lower cytotoxicity than Hp1404. N-phenyl-1-naphthylamine uptake and DisC3-5 assays demonstrated that the peptides kill bacteria by effectively permeating the outer and cytoplasmic membranes. Additionally, the analog peptides inhibited biofilm formation largely than Hp1404 at low concentrations. These results suggest that the analog peptides of Hp1404 can be used as therapeutic agents against A. baumannii infection.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escorpiões/química , 1-Naftilamina/análogos & derivados , 1-Naftilamina/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/efeitos adversos , Peptídeos Catiônicos Antimicrobianos/química , Benzotiazóis/metabolismo , Biofilmes/efeitos dos fármacos , Carbocianinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Escherichia coli/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Listeria monocytogenes/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Proteica em alfa-Hélice , Pseudomonas aeruginosa/efeitos dos fármacos , Salmonella/efeitos dos fármacos
6.
J Med Chem ; 64(11): 7359-7370, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34032114

RESUMO

Novel antibacterial agents capable of efficiently sterilizing intracellular Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) but with low cytotoxicity and low resistance development are quite appealing. In this work, three Ru(II) complexes with photolabile ligands were explored to realize such a goal. Complex 3 (5 µM) can inhibit more than 90% growth of S. aureus/MRSA that has invaded in J774A.1 cells upon visible light irradiation, being much more efficient than vancomycin. In similar conditions, negligible dark- and phototoxicity were found toward the host cells. The bactericidal activity is highly correlated with DNA covalent binding by the Ru(II) fractions generated after ligand photodissociation. Moreover, S. aureus quickly developed resistance toward vancomycin, while negligible resistance toward complex 3 even after 700 generations was obtained. These appealing results may pave a new way for fighting against intracellular antibiotic-resistant pathogens.


Assuntos
Antibacterianos/farmacologia , Complexos de Coordenação/química , Luz , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Rutênio/química , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , DNA/química , DNA/metabolismo , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Hemólise/efeitos dos fármacos , Humanos , Ligantes , Fotólise , Coelhos
8.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916789

RESUMO

Cancer has always been one of the most common malignant diseases in the world. Therefore, there is an urgent need to find potent agents with selective antitumor activity against cancer cells. It has been reported that antimicrobial peptides (AMPs) can selectively target tumor cells. In this study, we focused on the anti-tumor activity and mechanism of Brevinin-1RL1, a cationic α-helical AMP isolated from frog Rana limnocharis skin secretions. We found that Brevinin-1RL1 preferentially inhibits tumor cells rather than non-tumor cells with slight hemolytic activity. Cell viability assay demonstrated the intermolecular disulfide bridge contributes to the inhibitory activity of the peptide as the antitumor activity was abolished when the disulfide bridge reduced. Further mechanism studies revealed that both necrosis and apoptosis are involved in Brevinin-1RL1 mediated tumor cells death. Moreover, Brevinin-1RL1 induced extrinsic and mitochondria intrinsic apoptosis is caspases dependent, as the pan-caspase inhibitor z-VAD-FMK rescued Brevinin-1RL1 induced tumor cell proliferative inhibition. Immunohistology staining showed Brevinin-1RL1 mainly aggregated on the surface of the tumor cells. These results together suggested that Brevinin-1RL1 preferentially converges on the cancer cells to trigger necrosis and caspase-dependent apoptosis and Brevinin-1RL1 could be considered as a pharmacological candidate for further development as anti-cancer agent.


Assuntos
Apoptose , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Ranidae/metabolismo , Pele/química , Sequência de Aminoácidos , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Hemólise/efeitos dos fármacos , Concentração Inibidora 50 , Peso Molecular , Necrose , Proteínas Citotóxicas Formadoras de Poros/síntese química , Proteínas Citotóxicas Formadoras de Poros/química , Proteínas Citotóxicas Formadoras de Poros/isolamento & purificação , Agregados Proteicos/efeitos dos fármacos
10.
Toxins (Basel) ; 13(4)2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916208

RESUMO

The spider family Sicariidae includes three genera, Hexophthalma, Sicarius and Loxosceles. The three genera share a common characteristic in their venoms: the presence of Sphingomyelinases D (SMase D). SMases D are considered the toxins that cause the main pathological effects of the Loxosceles venom, that is, those responsible for the development of loxoscelism. Some studies have shown that Sicarius spiders have less or undetectable SMase D activity in their venoms, when compared to Hexophthalma. In contrast, our group has shown that Sicarius ornatus, a Brazilian species, has active SMase D and toxic potential to envenomation. However, few species of Sicarius have been characterized for their toxic potential. In order to contribute to a better understanding about the toxicity of Sicarius venoms, the aim of this study was to characterize the toxic properties of male and female venoms from Sicarius tropicus and compare them with that from Loxosceles laeta, one of the most toxic Loxosceles venoms. We show here that S. tropicus venom presents active SMases D. However, regarding hemolysis development, it seems that these toxins in this species present different molecular mechanisms of action than that described for Loxosceles venoms, whereas it is similar to those present in bacteria containing SMase D. Besides, our results also suggest that, in addition to the interspecific differences, intraspecific variations in the venoms' composition may play a role in the toxic potential of venoms from Sicarius species.


Assuntos
Evolução Molecular , Hemólise/efeitos dos fármacos , Diester Fosfórico Hidrolases/toxicidade , Venenos de Aranha/toxicidade , Aranhas/enzimologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HaCaT , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Masculino , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Fatores Sexuais , Especificidade da Espécie , Venenos de Aranha/enzimologia , Venenos de Aranha/genética , Aranhas/classificação , Aranhas/genética
11.
Biochem Biophys Res Commun ; 555: 32-39, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33812056

RESUMO

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.


Assuntos
Antídotos/farmacologia , Meliteno/toxicidade , Nanopartículas Multifuncionais/química , Polietilenoglicóis/química , Animais , Antídotos/química , Antídotos/farmacocinética , Bovinos , Linhagem Celular , Hemólise/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Masculino , Meliteno/sangue , Meliteno/metabolismo , Meliteno/farmacocinética , Camundongos Endogâmicos BALB C , Nanopartículas Multifuncionais/administração & dosagem , Nanopartículas Multifuncionais/metabolismo , Distribuição Tecidual
12.
Artigo em Inglês | MEDLINE | ID: mdl-33839052

RESUMO

Snakebite is classified as a priority Neglected Tropical Disease by the World Health Organization. Understanding the pathology of individual snake venom toxins is of great importance when developing more effective snakebite therapies. Snake venoms may induce a range of pathologies, including haemolytic activity. Although snake venom-induced erythrocyte lysis is not the primary cause of mortality, haemolytic activity can greatly debilitate victims and contributes to systemic haemotoxicity. Current assays designed for studying haemolytic activity are not suitable for rapid screening of large numbers of toxic compounds. Consequently, in this study, a high-throughput haemolytic assay was developed that allows profiling of erythrocyte lysis, and was validated using venom from a number of medically important snake species (Calloselasma rhodostoma, Daboia russelii, Naja mossambica, Naja nigricollis and Naja pallida). The assay was developed in a format enabling direct integration into nanofractionation analytics, which involves liquid chromatographic separation of venom followed by high-resolution fractionation and subsequent bioassaying (and optional proteomics analysis), and parallel mass spectrometric detection. Analysis of the five snake venoms via this nanofractionation approach involving haemolytic assaying provided venom-cytotoxicity profiles and enabled identification of the toxins responsible for haemolytic activity. Our results show that the elapid snake venoms (Naja spp.) contained both direct and indirect lytic toxins, while the viperid venoms (C. rhodostoma and D. russelii) only showed indirect lytic activities, which required the addition of phospholipids to exert cytotoxicity on erythrocytes. The haemolytic venom toxins identified were mainly phospholipase A2s and cytotoxic three finger toxins. Finally, the applicability of this new analytical method was demonstrated using a conventional snakebite antivenom treatment and a small-molecule drug candidate to assess neutralisation of venom cytotoxins.


Assuntos
Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Nanotecnologia/métodos , Venenos de Serpentes , Animais , Fracionamento Químico , Cromatografia Líquida , Humanos , Espectrometria de Massas , Fosfolipases A2 , Venenos de Serpentes/química , Venenos de Serpentes/toxicidade , Serpentes
13.
J Med Chem ; 64(9): 5603-5619, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33909443

RESUMO

Infections caused by drug-resistant bacteria seriously endanger human health and global public health. Therefore, it is urgent to discover and develop novel antimicrobial agents to combat multidrug-resistant bacteria. In this study, we designed and synthesized a series of new membrane-active bakuchiol derivatives by biomimicking the structure and function of cationic antibacterial peptides. The most promising compound 28 displayed potent antibacterial activity against both Gram-positive bacteria (minimum inhibitory concentration, MIC = 1.56-3.125 µg/mL) and Gram-negative bacteria (MIC = 3.125 µg/mL), very weak hemolytic activity, and low cytotoxicity. Compound 28 had rapid bactericidal properties and avoided bacterial resistance. More importantly, compound 28 showed strong in vivo antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa in murine corneal infection models. This design strategy is expected to provide an effective solution to the antibiotic crisis.


Assuntos
Antibacterianos/síntese química , Desenho de Fármacos , Fenóis/química , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doenças da Córnea/tratamento farmacológico , Doenças da Córnea/microbiologia , Doenças da Córnea/patologia , Modelos Animais de Doenças , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Fenóis/farmacologia , Fenóis/uso terapêutico , Staphylococcus aureus/fisiologia , Relação Estrutura-Atividade
14.
Mar Drugs ; 19(4)2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33801633

RESUMO

Nine new mono-, di-, and trisulfated triterpene penta- and hexaosides, kurilosides A3 (1), D1 (2), G (3), H (4), I (5), I1 (6), J (7), K (8), and K1 (9) and two desulfated derivatives, DS-kuriloside L (10), having a trisaccharide branched chain, and DS-kuriloside M (11), having hexa-nor-lanostane aglycone with a 7(8)-double bond, have been isolated from the Far-Eastern deep-water sea cucumber Thyonidium (=Duasmodactyla) kurilensis (Levin) and their structures were elucidated based on 2D NMR spectroscopy and HR-ESI mass-spectrometry. Five earlier unknown carbohydrate chains and two aglycones (having a 16ß,(20S)-dihydroxy-fragment and a 16ß-acetoxy,(20S)-hydroxy fragment) were found in these glycosides. All the glycosides 1-9 have a sulfate group at C-6 Glc, attached to C-4 Xyl1, while the positions of the other sulfate groups vary in different groups of kurilosides. The analysis of the structural features of the aglycones and the carbohydrate chains of all the glycosides of T. kurilensis showed their biogenetic relationships. Cytotoxic activities of the compounds 1-9 against mouse neuroblastoma Neuro 2a, normal epithelial JB-6 cells, and erythrocytes were studied. The highest cytotoxicity in the series was demonstrated by trisulfated hexaoside kuriloside H (4), having acetoxy-groups at C(16) and C(20), the latter one obviously compensated the absence of a side chain, essential for the membranolytic action of the glycosides. Kuriloside I1 (6), differing from 4 in the lacking of a terminal glucose residue in the bottom semi-chain, was slightly less active. The compounds 1-3, 5, and 8 did not demonstrate cytotoxic activity due to the presence of hydroxyl groups in their aglycones.


Assuntos
Células Epiteliais/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Glicosídeos/toxicidade , Hemólise/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Pepinos-do-Mar/metabolismo , Triterpenos/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/patologia , Eritrócitos/patologia , Glicosídeos/biossíntese , Glicosídeos/isolamento & purificação , Camundongos , Estrutura Molecular , Neurônios/patologia , Relação Estrutura-Atividade , Triterpenos/isolamento & purificação , Triterpenos/metabolismo
15.
Molecules ; 26(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925223

RESUMO

Hemiscorpius lepturus scorpion stings do not induce considerable pain based on epidemiological surveys conducted in the southwest part of Iran. Accordingly, this study was aimed to identify the analgesic molecule in H. lepturus venom by analyzing a cDNA library of the scorpion venom gland looking for sequences having homology with known animal venom analgesic peptides. The analgesic molecule is a cysteine rich peptide of 55 amino acids. the synthetic peptide was deprotected and refolded. RP-HPLC, Ellman's, and DLS assays confirmed the refolding accuracy. Circular dichroism (CD) showed helix and beta sheet contents. This peptide, called leptucin, demonstrated 95% analgesic activity at the dose of 0.48 mg/kg in hot plate assay. Leptucin at the doses of 0.32, 0.48, and 0.64 mg/kg showed 100% activity in thermal tail flick test. No hemolysis or cytotoxicity was observed at 8 and 16 µg. Histopathology evaluations indicated no hepatotoxicity, nephrotoxicity, and cardiotoxicity. We thus report that leptucin is the analgesic agent of H. lepturus venom. Regarding the high in vivo efficacy of leptucin and the fact it shows no observable toxicity, it could be suggested as a drug lead in a preclinical study of acute pain as well as the study of its mechanism of action.


Assuntos
Analgésicos/farmacologia , Peptídeos/farmacologia , Escorpiões/química , Sequência de Aminoácidos , Analgésicos/química , Animais , Sequência de Bases , Cromatografia Líquida de Alta Pressão , Biologia Computacional/métodos , Hemólise/efeitos dos fármacos , Irã (Geográfico) , Dose Máxima Tolerável , Fases de Leitura Aberta , Peptídeos/química , Peptídeos/genética , Conformação Proteica , Picadas de Escorpião , Análise Espectral
16.
Biomed Res Int ; 2021: 6621264, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33834069

RESUMO

Bisphenols (BPs) are plastic components widely used worldwide and occurring in the environment. Exposure to these compounds is known to be harmful for animals and humans at different levels. The aim of this study was to evaluate and compare the oxidative effects of bisphenol A (BPA) and bisphenol S (BPS) in sheep. Reactive oxygen species (ROS) production and correlated structural alterations in sheep erythrocytes were investigated in vitro. Blood samples from four ewes were collected at fasting from the jugular vein using vacuum collection tubes containing EDTA. For ROS assay in erythrocytes, blood was properly diluted and BPA or BPS was added to obtain final bisphenol concentrations in the range between 1 and 300 µM. 2',7'-Dichlorodihydrofluorescein diacetate (H2DCF-DA) 3 µM was added to the samples, and fluorescence was read in four replicates using a microplate reader. To evaluate erythrocyte shape, blood smears of blood treated with the different concentrations of BPS and BPA were prepared. A significant increase in ROS production was observed when concentrations of BPS and BPA increased from 1 to 100 µM (p < 0.05). At the higher concentrations of the two studied BPs (300 µM of BPS and 200-300 µM of BPA), a ROS decrease was observed when compared to the control group (p < 0.01). Erythrocytes' shape alterations were observed in cells treated with BPS and BPA 200-300 µM 4 hours after the beginning of the treatment. This study confirms that BPA and BPS exhibit oxidative effects on sheep erythrocytes. At higher concentrations, BPA was able to modify erythrocytes' shape, while BPS altered their membrane as a sign of a protein clustering that could lead to eryptosis. These BPs' effects are consequent to intracellular ROS increase.


Assuntos
Compostos Benzidrílicos/farmacologia , Eritrócitos/metabolismo , Fenóis/farmacologia , Sulfonas/farmacologia , Animais , Bioensaio , Forma Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ovinos
17.
Molecules ; 26(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800774

RESUMO

Silicon dioxide, in the form of nanoparticles, possesses unique physicochemical properties (size, shape, and a large surface to volume ratio). Therefore, it is one of the most promising materials used in biomedicine. In this paper, we compare the biological effects of both mesoporous silica nanoparticles extracted from Urtica dioica L. and pyrogenic material. Both SEM and TEM investigations confirmed the size range of tested nanoparticles was between 6 and 20 nanometers and their amorphous structure. The cytotoxic activity of the compounds and intracellular ROS were determined in relation to cells HMEC-1 and erythrocytes. The cytotoxic effects of SiO2 NPs were determined after exposure to different concentrations and three periods of incubation. The same effects for endothelial cells were tested under the same range of concentrations but after 2 and 24 h of exposure to erythrocytes. The cell viability was measured using spectrophotometric and fluorimetric assays, and the impact of the nanoparticles on the level of intracellular ROS. The obtained results indicated that bioSiO2 NPs, present higher toxicity than pyrogenic NPs and have a higher influence on ROS production. Mesoporous silica nanoparticles show good hemocompatibility but after a 24 h incubation of erythrocytes with silica, the increase in hemolysis process, the decrease in osmotic resistance of red blood cells, and shape of erythrocytes changed were observed.


Assuntos
Células Endoteliais/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Nanopartículas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Dióxido de Silício/administração & dosagem , Sobrevivência Celular , Humanos , Nanopartículas/química , Porosidade , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Propriedades de Superfície
18.
Int J Nanomedicine ; 16: 2373-2388, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790555

RESUMO

Aim: The metastasis of breast cancer is an important cause of tumor recurrence. This study highlights that tyrosine kinase inhibitors dasatinib (DAS) and rosiglitazone (ROZ) inhibit tumor growth and reduce the occurrence of tumor cell metastasis. Due to the poor water solubility, short half-time in the body of DAS and ROZ, which increases the difficulty of tumor treatment, as well as the demand for nano-drug delivery systems for organ-specific therapies. Methods: Hyaluronic acid (HA) and DAS are bonded by a pH-sensitive ester bond to form an HA-DAS polymer. Then, ROZ was added as the core, D-A-tocopherol polydiethylene glycol isosuccinate (TPGS) and HA-DAS were used as carriers to form HA-DAS and TPGS mixed micelle system loaded with ROZ (THDR-NPs). The size and structure of THDR-NPs were characterized, the drug release, stability and biosafety of THDR-NPs were studied. In vitro, the cytotoxicity, targeting effect and tumor metastasis inhibition of THDR-NPs were evaluated in human breast cancer cell lines. In addition, the selective potency of designed THDR-NPs in depleting was further verified in vivo in the tumor-bearing nude mice model. Results: The designed THDR-NPs have a particle size of less than 100 nm, good stability, biological safety and sustained release, and showed strong therapeutic effects on breast cancer models in vitro and in vivo. Moreover, it has been proved that THDR-NPs have the ability to inhibit tumor metastasis. Conclusion: DAS and ROZ were designed into micelles, the efficacy of THDR-NPs was higher than that of free drugs. These results indicate that nanoparticles have a good application prospect in the treatment of tumor metastasis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Dasatinibe/administração & dosagem , Dasatinibe/farmacocinética , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Humanos , Ácido Hialurônico/química , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Rosiglitazona/farmacocinética , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Eletricidade Estática , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
19.
N Engl J Med ; 384(14): 1323-1334, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33826820

RESUMO

BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C1s/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Anemia Hemolítica Autoimune/sangue , Anemia Hemolítica Autoimune/complicações , Anemia Hemolítica Autoimune/terapia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Transfusão de Sangue , Fadiga/tratamento farmacológico , Fadiga/etiologia , Feminino , Hemoglobinas/análise , Hemólise/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
20.
AAPS PharmSciTech ; 22(4): 137, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33880681

RESUMO

A novel albumin polymer hybrid with a core-shell structure was designed to target delivery of bufalin, which is an antineoplastic monomer with serious cardiotoxicity. The sheath layer was composed of ursodeoxycholic acid (UA)-modified bovine serum albumin (UA-BSA), while the stable core consisted of poly n-butyl cyanoacrylate (PBCA) nanoparticles. The UA-BSA was synthetized, and the substitution degree was characterized. The physical properties of bufalin-loaded UA-modified protein-PBCA nanocomplexes (BF-uPPNCs), such as morphology, particle size, and encapsulation efficiency, were evaluated. FTIR and DSC revealed the bufalin to be in an amorphous state. Furthermore, the in vitro release study indicated a sustained release profile of BF-uPPNCs. The MTT and cellular uptake study demonstrated that BF-uPPNCs significantly improved the inhibitory effect of the bufalin accompanied with an enhanced cell uptake capacity on HepG2 cells. In addition, in vivo research demonstrated that BF-uPPNCs had a better antitumor effect coupled with improved therapeutic effect, and reduced hemolysis, vascular irritation, and cardiotoxicity. This work therefore presented a novel albumin polymer hybrid with favorable stability, efficient tumor-targeted delivery potential, and side effect reduction ability, which can be a potential vehicle for an anticancer drug.


Assuntos
Antineoplásicos/administração & dosagem , Bufanolídeos/administração & dosagem , Cardiotoxicidade/prevenção & controle , Portadores de Fármacos/química , Hemólise/efeitos dos fármacos , Polímeros/química , Animais , Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Morte Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Tamanho da Partícula , Soroalbumina Bovina/química
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