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1.
Biomed Pharmacother ; 139: 111386, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243594

RESUMO

Renal interstitial fibrosis (RIF) is a common pathological response in a broad range of prevalent chronic kidney diseases and ultimately leads to renal failure and death. Although RIF causes a high morbi-mortality worldwide, effective therapeutic drugs are urgently needed. Myofibroblasts are identified as the main effector during the process of RIF. Multiple types of cells, including fibroblasts, epithelial cells, endothelial cells, macrophages and pericytes, contribute to renal myofibroblasts origin, and lots of mediators, including signaling pathways (Transforming growth factor-ß1, mammalian target of rapamycin and reactive oxygen species) and epigenetic modifications (Histone acetylation, microRNA and long non-coding RNA) are participated in renal myofibroblasts activation during renal fibrogenesis, suggesting that these mediators may be the promising targets for treating RIF. In addition, many small molecules show profound therapeutic effects on RIF by suppressing the origin and activation of renal myofibroblasts. Taken together, the review focuses on the mechanisms of the origin and activation of renal myofibroblasts in RIF and the small molecules against them improving RIF, which will provide a new insight for RIF therapy.


Assuntos
Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Fibroblastos/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos
2.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199865

RESUMO

In obese patients, enhanced serum levels of free fatty acids (FFA), such as palmitate (PA) or oleate (OA), are associated with an increase in systemic inflammatory markers. Bacterial infection during periodontal disease also promotes local and systemic low-grade inflammation. How both conditions concomitantly impact tooth movement is largely unknown. Thus, the aim of this study was to address the changes in cytokine expression and the secretion of human periodontal ligament fibroblasts (HPdLF) due to hyperlipidemic conditions, when additionally stressed by bacterial and mechanical stimuli. To investigate the impact of obesity-related hyperlipidemic FFA levels on HPdLF, cells were treated with 200 µM PA or OA prior to the application of 2 g/cm2 compressive force. To further determine the additive impact of bacterial infection, HPdLF were stimulated with lipopolysaccharides (LPS) obtained from Porphyromonas gingivalis. In mechanically compressed HPdLF, PA enhanced COX2 expression and PGE2 secretion. When mechanically stressed HPdLF were additionally stimulated with LPS, the PGE2 and IL6 secretion, as well as monocyte adhesion, were further increased in PA-treated cultures. Our data emphasize that a hyperlipidemic condition enhances the susceptibility of HPdLF to an excessive inflammatory response to compressive forces, when cells are concomitantly exposed to bacterial components.


Assuntos
Fibroblastos/imunologia , Hiperlipidemias/fisiopatologia , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Ligamento Periodontal/imunologia , Porphyromonas gingivalis/química , Estresse Mecânico , Força Compressiva , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/patologia , Pressão
3.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200169

RESUMO

BACKGROUND: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory responses are of particular importance. METHODS: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 h. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. RESULTS & CONCLUSION: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in reactive oxygen species (ROS) homeostasis. Low and high concentrations of aqueous fullerene dispersions (AFD) have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both "prooxidant" and "antioxidant" effects but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced "prooxidant" properties.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fibroblastos/metabolismo , Fulerenos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Cultivadas , Feto/efeitos dos fármacos , Feto/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Nanopartículas , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Água/química
4.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200896

RESUMO

The goals of this study are to develop a high purity patented silk fibroin (SF) film and test its suitability to be used as a slow-release delivery for insulin-like growth factor-1 (IGF-1). The release rate of the SF film delivering IGF-1 followed zero-order kinetics as determined via the Ritger and Peppas equation. The release rate constant was identified as 0.11, 0.23, and 0.09% h-1 at 37 °C for SF films loaded with 0.65, 6.5, and 65 pmol IGF-1, respectively. More importantly, the IGF-1 activity was preserved for more than 30 days when complexed with the SF film. We show that the IGF-1-loaded SF films significantly accelerated wound healing in vitro (BALB/3T3) and in vivo (diabetic mice), compared with wounds treated with free IGF-1 and an IGF-1-loaded hydrocolloid dressing. This was evidenced by a six-fold increase in the granulation tissue area in the IGF-1-loaded SF film treatment group compared to that of the PBS control group. Western blotting analysis also demonstrated that IGF-1 receptor (IGF1R) phosphorylation in diabetic wounds increased more significantly in the IGF-1-loaded SF films group than in other experimental groups. Our results suggest that IGF-1 sustained release from SF films promotes wound healing through continuously activating the IGF1R pathway, leading to the enhancement of both wound re-epithelialization and granulation tissue formation in diabetic mice. Collectively, these data indicate that SF films have considerable potential to be used as a wound dressing material for long-term IGF-1 delivery for diabetic wound therapy.


Assuntos
Bombyx/química , Diabetes Mellitus Experimental/fisiopatologia , Sistemas de Liberação de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroínas/química , Fator de Crescimento Insulin-Like I/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Bandagens , Preparações de Ação Retardada , Feminino , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Reepitelização , Receptores para Leptina/fisiologia
5.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200927

RESUMO

Bacterial cellulose membranes (BCs) are becoming useful as a drug delivery system to the skin. However, there are very few reports on their application of plant substances to the skin. Komagataeibacter xylinus was used for the production of bacterial cellulose (BC). The BC containing 5% and 10% ethanolic extract of Epilobium angustifolium (FEE) (BC-5%FEE and BC-10%FEE, respectively) were prepared. Their mechanical, structural, and antioxidant properties, as well as phenolic acid content, were evaluated. The bioavailability of BC-FESs using mouse L929 fibroblasts as model cells was tested. Moreover, In Vitro penetration through the pigskin of the selected phenolic acids contained in FEE and their accumulation in the skin after topical application of BC-FEEs was examined. The BC-FEEs were characterized by antioxidant activity. The BC-5% FEE showed relatively low toxicity to healthy mouse fibroblasts. Gallic acid (GA), chlorogenic acid (ChA), 3,4-dihydroxybenzoic acid (3,4-DHB), 4-hydroxybenzoic acid (4-HB), 3-hydroxybenzoic acid (3-HB), and caffeic acid (CA) found in FEE were also identified in the membranes. After topical application of the membranes to the pigskin penetration of some phenolic acid and other antioxidants through the skin as well as their accumulation in the skin was observed. The bacterial cellulose membrane loaded by plant extract may be an interesting solution for topical antioxidant delivery to the skin.


Assuntos
Antioxidantes/administração & dosagem , Celulose/química , Epilobium/química , Fibroblastos/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Pele/efeitos dos fármacos , Administração Tópica , Animais , Bactérias/química , Fibroblastos/metabolismo , Camundongos , Pele/metabolismo , Suínos
6.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199374

RESUMO

BACKGROUND: Skinboosters represent the latest category of hyaluronan (HA) hydrogels released for aesthetic purposes. Different from originally developed gels, they are intended for more superficial injections, claiming a skin rejuvenation effect through hydration and possibly prompting biochemical effects in place of the conventional volumetric action. Here, three commercial skinboosters were characterized to unravel the scientific basis for such indication and to compare their performances. METHODS: Gels were evaluated for water-soluble/insoluble-HA composition, rheology, hydration, cohesivity, stability and effect, in vitro, on human dermal fibroblasts towards the production of extracellular matrix components. RESULTS: Marked differences in the insoluble-hydrogel amount and in the hydrodynamic parameters for water-soluble-HA chains were evidenced among the gels. Hydration, rigidity and cohesivity also varied over a wide range. Sensitivity to hyaluronidases and Reactive Oxygen Species was demonstrated allowing a stability ranking. Slight differences were found in gels' ability to prompt elastin expression and in ColIV/ColI ratio. CONCLUSIONS: A wide panel of biophysical and biochemical parameters for skinboosters was provided, supporting clinicians in the conscious tuning of their use. Data revealed great variability in gels' behavior notwithstanding the same clinical indication and unexpected similarities to the volumetric formulations. Data may be useful to improve customization of gel design toward specific uses.


Assuntos
Ácido Hialurônico/química , Hialuronoglucosaminidase/genética , Hidrogéis/química , Pele/efeitos dos fármacos , Elastina/química , Fibroblastos/efeitos dos fármacos , Humanos , Hialuronoglucosaminidase/química , Injeções , Espécies Reativas de Oxigênio/química , Rejuvenescimento/fisiologia , Reologia , Pele/crescimento & desenvolvimento , Pele/patologia , Envelhecimento da Pele/genética , Viscosidade
7.
Int J Mol Sci ; 22(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198681

RESUMO

Lack of adult cells' ability to produce sufficient amounts of elastin and assemble functional elastic fibers is an issue for creating skin substitutes that closely match native skin properties. The effects of female sex hormones, primarily estrogen, have been studied due to the known effects on elastin post-menopause, thus have primarily included older mostly female populations. In this study, we examined the effects of female sex hormones on the synthesis of elastin by female and male human dermal fibroblasts in engineered dermal substitutes. Differences between the sexes were observed with 17ß-estradiol treatment alone stimulating elastin synthesis in female substitutes but not male. TGF-ß levels were significantly higher in male dermal substitutes than female dermal substitutes and the levels did not change with 17ß-estradiol treatment. The male dermal substitutes had a 1.5-fold increase in cAMP concentration in the presence of 17ß-estradiol compared to no hormone controls, while cAMP concentrations remained constant in the female substitutes. When cAMP was added in addition to 17ß-estradiol and progesterone in the culture medium, the sex differences were eliminated, and elastin synthesis was upregulated by 2-fold in both male and female dermal substitutes. These conditions alone did not result in functionally significant amounts of elastin or complete elastic fibers. The findings presented provide insights into differences between male and female cells in response to female sex steroid hormones and the involvement of the cAMP pathway in elastin synthesis. Further explorations into the signaling pathways may identify better targets to promote elastic fiber synthesis in skin substitutes.


Assuntos
Monofosfato de Adenosina/farmacologia , Derme/fisiologia , Elastina/biossíntese , Estradiol/farmacologia , Caracteres Sexuais , Pele Artificial , Engenharia Tecidual , Adulto , Meios de Cultura , AMP Cíclico/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Receptores de Superfície Celular/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto Jovem
8.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201111

RESUMO

Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA5m.SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [68Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA5.SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of the complexes were characterized and compared with those of DOTA.SA.FAPi. AAZTA5.SA.FAPi and its derivatives labelled with non-radioactive isotopes demonstrated similar excellent inhibitory potencies compared to the previously published SA.FAPi ligands, i.e., sub-nanomolar IC50 values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA5.SA.FAPi compared to the corresponding DOTA analogue at ambient temperature. Especially, scandium-44 labeling with the AAZTA derivative resulted in higher specific activities. Both DOTA.SA.FAPi and AAZTA5.SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP.


Assuntos
Acetatos/farmacologia , Azepinas/farmacologia , Fibroblastos/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Quinina/análogos & derivados , Endopeptidases , Fibroblastos/metabolismo , Radioisótopos de Gálio/farmacologia , Humanos , Ligantes , Lutécio/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Quinina/farmacologia , Radioisótopos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Escândio/farmacologia , Serina Endopeptidases/metabolismo
9.
Anticancer Res ; 41(7): 3293-3298, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230124

RESUMO

BACKGROUND/AIM: Plexiform neurofibromas (PNFs) are benign tumors composed mainly of tumorous Schwann cells and non-tumorous fibroblasts. This study examined the possible enhancing effect of vitamin D on the efficacy of drugs used for the treatment of PNF in vitro. MATERIALS AND METHODS: Paired Schwann cells and fibroblasts were cultured from 10 PNFs and treated with imatinib and nilotinib in the absence and presence of calcipotriol, an analogue of the active metabolite of vitamin D. IC50 values for cell proliferation were calculated. RESULTS: Calcipotriol reduced the IC50 of the two drugs in both tumorous Schwann cells and non-tumorous fibroblasts by 40 to 45%. CONCLUSION: Calcipotriol enhanced the efficacy of imatinib and nilotinib on PNF-derived cells in vitro, though rather non-specifically. Nevertheless, sustaining vitamin D at 100-200 nM, the physiological range, may be beneficial for reducing the dose of drugs without scarifying efficacy.


Assuntos
Calcitriol/análogos & derivados , Mesilato de Imatinib/farmacologia , Neurofibroma Plexiforme/tratamento farmacológico , Pirimidinas/farmacologia , Calcitriol/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Células de Schwann/efeitos dos fármacos , Vitamina D/farmacologia
10.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208590

RESUMO

Osteoarthritis (OA) is the most common musculoskeletal disorder causing a great disability and a reduction in the quality of life. In OA, articular chondrocytes (AC) and synovial fibroblasts (SF) release innate-derived immune mediators that initiate and perpetuate inflammation, inducing cartilage extracellular matrix (ECM) degradation. Given the lack of therapies for the treatment of OA, in this study, we explore biomarkers that enable the development of new therapeutical approaches. We analyze the set of secreted proteins in AC and SF co-cultures by stable isotope labeling with amino acids (SILAC). We describe, for the first time, 115 proteins detected in SF-AC co-cultures stimulated by fibronectin fragments (Fn-fs). We also study the role of the vasoactive intestinal peptide (VIP) in this secretome, providing new proteins involved in the main events of OA, confirmed by ELISA and multiplex analyses. VIP decreases proteins involved in the inflammatory process (CHI3L1, PTX3), complement activation (C1r, C3), and cartilage ECM degradation (DCN, CTSB and MMP2), key events in the initiation and progression of OA. Our results support the anti-inflammatory and anti-catabolic properties of VIP in rheumatic diseases and provide potential new targets for OA treatment.


Assuntos
Condrócitos/metabolismo , Fibroblastos/metabolismo , Osteoartrite/metabolismo , Proteoma , Proteômica , Membrana Sinovial/citologia , Peptídeo Intestinal Vasoativo/metabolismo , Biomarcadores , Condrócitos/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/metabolismo , Suscetibilidade a Doenças , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Osteoartrite/etiologia , Osteoartrite/patologia , Proteômica/métodos , Peptídeo Intestinal Vasoativo/farmacologia
11.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208633

RESUMO

The clinical application of human platelet lysate (HPL) holds promise for tissue regeneration, and the development of an efficient vehicle for its delivery is desired. Chitosan-based hydrogels are potential candidates, but they often exhibit weak mechanical properties. In this study, a chitosan/gelatin (CS-GE) hydrogel crosslinked by glyoxal was fabricated for sustained release of HPL. The influence of HPL on Hs68 fibroblast and human umbilical vein endothelial cell (HUVEC) culture was evaluated, and we found that supplementing 5% HPL in the medium could significantly improve cell proliferation relative to supplementing 10% fetal bovine serum (FBS). Moreover, HPL accelerated the in vitro wound closure of Hs68 cells and facilitated the tube formation of HUVECs. Subsequently, we fabricated CS-GE hydrogels crosslinked with different concentrations of glyoxal, and the release pattern of FITC-dextrans (4, 40 and 500 kDa) from the hydrogels was assessed. After an ideal glyoxal concentration was determined, we further characterized the crosslinked CS-GE hydrogels encapsulated with different amounts of HPL. The HPL-incorporated hydrogel was shown to significantly promote the proliferation of Hs68 cells and the migration of HUVECs. Moreover, the release pattern of transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor-BB (PDGF-BB) from hydrogel was examined in vitro, demonstrating a sustained release profile of the growth factors. Finally, the chick chorioallantoic membrane assay revealed that HPL encapsulation in the hydrogel significantly stimulated angiogenesis in ovo. These results demonstrate the great potential of the crosslinked CS-GE hydrogel to serve as an effective delivery system for HPL to promote tissue regeneration.


Assuntos
Produtos Biológicos/farmacologia , Plaquetas/metabolismo , Quitosana , Gelatina , Glioxal , Hidrogéis , Regeneração/efeitos dos fármacos , Proliferação de Células , Quitosana/química , Dextranos/química , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Gelatina/química , Glioxal/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrogéis/química , Neovascularização Fisiológica , Porosidade , Cicatrização/efeitos dos fármacos
12.
Int J Mol Sci ; 22(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199748

RESUMO

BACKGROUND: Psoriasis, a chronic inflammatory disease affecting 2-3% of the population, is characterised by epidermal hyperplasia, a sustained pro-inflammatory immune response and is primarily a T-cell driven disease. Previous work determined that Connexin26 is upregulated in psoriatic tissue. This study extends these findings. METHODS: Biopsies spanning psoriatic plaque (PP) and non-involved tissue (PN) were compared to normal controls (NN). RNA was isolated and subject to real-time PCR to determine gene expression profiles, including GJB2/CX26, GJB6/CX30 and GJA1/CX43. Protein expression was assessed by immunohistochemistry. Keratinocytes and fibroblasts were isolated and used in 3D organotypic models. The pro-inflammatory status of fibroblasts and 3D cultures was assessed via ELISA and RnD cytokine arrays in the presence or absence of the connexin channel blocker Gap27. RESULTS: Connexin26 expression is dramatically enhanced at both transcriptional and translational level in PP and PN tissue compared to NN (>100x). In contrast, CX43 gene expression is not affected, but the protein is post-translationally modified and accumulates in psoriatic tissue. Fibroblasts isolated from psoriatic patients had a higher inflammatory index than normal fibroblasts and drove normal keratinocytes to adopt a "psoriatic phenotype" in a 3D-organotypic model. Exposure of normal fibroblasts to the pro-inflammatory mediator peptidoglycan, isolated from Staphylococcus aureus enhanced cytokine release, an event protected by Gap27. CONCLUSION: dysregulation of the connexin26:43 expression profile in psoriatic tissue contributes to an imbalance of cellular events. Inhibition of connexin signalling reduces pro-inflammatory events and may hold therapeutic benefit.


Assuntos
Conexinas/genética , Regulação da Expressão Gênica , Psoríase/genética , Adulto , Idoso , Biópsia , Conexinas/metabolismo , Conexinas/farmacologia , Epiderme/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Células HaCaT , Humanos , Mediadores da Inflamação , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/patologia , Pessoa de Meia-Idade , Modelos Biológicos , Oligopeptídeos/farmacologia , Peptidoglicano/isolamento & purificação , Fosforilação , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Psoríase/patologia , Staphylococcus aureus/fisiologia , Adulto Jovem
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071450

RESUMO

Receptor-interacting protein kinase 1 (RIPK1) is a key component of the tumor necrosis factor (TNF) receptor signaling complex that regulates both pro- and anti-apoptotic signaling. The reciprocal functions of RIPK1 in TNF signaling are determined by the state of the posttranslational modifications (PTMs) of RIPK1. However, the underlying mechanisms associated with the PTMs of RIPK1 are unclear. In this study, we found that RING finger protein 4 (RNF4), a RING finger E3 ubiquitin ligase, is required for the RIPK1 autophosphorylation and subsequent cell death. It has been reported that RNF4 negatively regulates TNF-α-induced activation of the nuclear factor-κB (NF-κB) through downregulation of transforming growth factor ß-activated kinase 1 (TAK1) activity, indicating the possibility that RNF4-mediated TAK1 suppression results in enhanced sensitivity to cell death. However, interestingly, RNF4 was needed to induce RIPK1-mediated cell death even in the absence of TAK1, suggesting that RNF4 can promote RIPK1-mediated cell death without suppressing the TAK1 activity. Thus, these observations reveal the existence of a novel mechanism whereby RNF4 promotes the autophosphorylation of RIPK1, which provides a novel insight into the molecular basis for the PTMs of RIPK1.


Assuntos
Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Adolescente , Animais , Apoptose/efeitos dos fármacos , Caspase 8/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Cultivadas , Embrião de Mamíferos/citologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Immunoblotting , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos Knockout , Fosforilação , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética
14.
Molecules ; 26(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069021

RESUMO

The present work investigated the effect of Polylactic acid (PLA) fibers produced by centrifugal spinning with incorporated BaTiO3 particles to improve their bacteriostatic behavior. The PLA matrix and three composites, presenting three different amounts of fillers, were subjected to UV/O3 treatment monitoring the possible modifications that occurred over time. The morphological and physical properties of the surfaces were characterized by different microscopic techniques, contact angle, and surface potential measurements. Subsequently, the samples were tested in vitro with human dermal fibroblasts (HDF) to verify the cytotoxicity of the substrates. No significant differences between the PLA matrix and composites emerged; the high hydrophobicity of the fibers, derived by the polymer structure, represented an obstacle limiting the fibroblast attachment. Samples underwent bacterial exposure (Staphylococcus epidermidis) for 12 and 24 h. Increasing the concentration of BT, the number of living bacteria and their distribution decreased in comparison with the PLA matrix suggesting an effect of the inorganic filler, which generates a neutralization effect leading to reactive oxygen species (ROS) generation and subsequently to bacterial damages. These results suggest that the barium titanate (BT) fillers clearly improve the antibacterial properties of PLA fibers after aging tests made before bacterial exposure, representing a potential candidate in the creation of composites for medical applications.


Assuntos
Antibacterianos/farmacologia , Compostos de Bário/farmacologia , Poliésteres/farmacologia , Titânio/farmacologia , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Centrifugação , Derme/citologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Espectrometria por Raios X , Staphylococcus epidermidis/efeitos dos fármacos , Água/química
15.
ACS Appl Mater Interfaces ; 13(23): 27430-27444, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34060800

RESUMO

Life-threatening invasive fungal infections represent an urgent threat to human health worldwide. The limited set of antifungal drugs has critical constraints such as resistance development and/or adverse side effects. One approach to overcome these limitations is to mimic naturally occurring antifungal peptides called defensins. Inspired by their advantageous amphiphilic properties, a library of 35 synthetic, linear, ternary polyacrylamides was prepared by controlled/living radical polymerization. The effect of the degree of polymerization (20, 40, and 100) and varying hydrophobic functionalities (branched, linear, cyclic, or aromatic differing in their number of carbons) on their antifungal activity was investigated. Short copolymers with a calculated log P of ∼1.5 revealed optimal activity against the major human fungal pathogen Candida albicans and other pathogenic fungal species with limited toxicity to mammalian host cells (red blood cells and fibroblasts). Remarkably, selected copolymers outperformed the commercial antifungal drug amphotericin B, with respect to the therapeutic index, highlighting their potential as novel antifungal compounds.


Assuntos
Resinas Acrílicas/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Desenho de Fármacos , Eritrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Biblioteca de Peptídeos , Resinas Acrílicas/química , Animais , Humanos , Camundongos , Testes de Sensibilidade Microbiana
16.
Molecules ; 26(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064528

RESUMO

Ultraviolet (UV) irradiation is a serious problem for skin health thus the interest in the research to develop sunscreen agent has been increasing. Chalcone is a promising compound to be developed as its chromophore absorbs in the UV region. Therefore, in the present work, we synthesized eight chalcone derivatives through Claisen-Schmidt condensation at room temperature. The evaluation of the optical properties of each chalcone derivatives in the UV region was conducted through spectroscopic and computational studies. The synthesized chalcones were obtained in good yields and they were active in the UV region. The results revealed that more methoxy substituents to chalcone leads toward red shift. All chalcone derivatives have high molar absorptivity value (21,000-56,000) demonstrating that they have the potential to be used as the sunscreen agent. The cytotoxicity assay showed that chalcone derivatives were demonstrating low toxicity toward normal human fibroblast cell, which is remarkable. Therefore, we concluded that the synthesized chalcones in this work were potential to be developed as novel sunscreen agents in real application.


Assuntos
Chalconas/síntese química , Chalconas/farmacologia , Protetores Solares/farmacologia , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Fibroblastos/efeitos dos fármacos , Humanos , Espectrofotometria Ultravioleta
17.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064656

RESUMO

Although the major components of various organs of sea buckthorn have been identified (particularly phenolic compounds), biological properties of many of these phytochemicals still remain poorly characterized. In this study, we focused on the chemical composition and biological activity of preparations that were obtained from sea buckthorn twigs and leaves. The objective was to investigate cytotoxicity of these preparations against human fibroblast line HFF-1, using MTT reduction assay, their anti- or pro-oxidant activities against the effects of a biological oxidant -H2O2/Fe-on human plasma lipids and proteins in vitro (using TBARS and carbonyl groups as the markers of oxidative stress). Antimicrobial activity of the tested preparations against Gram-positive (Staphylococcus aureus, S. epidermidis, Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), as well as against fungi (Candida albicans, C. glabrata) by the EUCAST-approved broth microdilution method, followed by growth on solid media, were also assessed. Our analysis showed significant differences in chemical composition and biological properties of the tested preparations (A-F). All tested preparations from sea buckthorn twigs (D-F) and one preparation from sea buckthorn leaves (preparation C) may be a new source of phenolic antioxidants for pharmacological and cosmetic applications.


Assuntos
Anti-Infecciosos/farmacologia , Antioxidantes/farmacologia , Elaeagnaceae/química , Fenóis/química , Folhas de Planta/química , Biomarcadores/sangue , Morte Celular/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Estresse Oxidativo/efeitos dos fármacos
18.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069278

RESUMO

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic® F127 hybrid dendritic-linear-dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2'-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2'-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Portadores de Fármacos/química , Micelas , Polímeros/química , Células A549 , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cloroquina/administração & dosagem , Cloroquina/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/farmacocinética , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Poloxâmero/química , Polímeros/síntese química
19.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069489

RESUMO

In this pilot study, ethosomes and transethosomes were investigated as potential delivery systems for cholecalciferol (vitamin D3), whose deficiency has been correlated to many disorders such as dermatological diseases, systemic infections, cancer and sarcopenia. A formulative study on the influence of pharmaceutically acceptable ionic and non-ionic surfactants allowed the preparation of different transethosomes. In vitro cytotoxicity was evaluated in different cell types representative of epithelial, connective and muscle tissue. Then, the selected nanocarriers were further investigated at light and transmission electron microscopy to evaluate their uptake and intracellular fate. Both ethosomes and transethosomes proven to have physicochemical properties optimal for transdermal penetration and efficient vitamin D3 loading; moreover, nanocarriers were easily internalized by all cell types, although they followed distinct intracellular fates: ethosomes persisted for long times inside the cytoplasm, without inducing subcellular alteration, while transethosomes underwent rapid degradation giving rise to an intracellular accumulation of lipids. These basic results provide a solid scientific background to in vivo investigations aimed at exploring the efficacy of vitamin D3 transdermal administration in different experimental and pathological conditions.


Assuntos
Colecalciferol/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanocápsulas/química , Linhagem Celular , Química Farmacêutica/métodos , Colecalciferol/metabolismo , Colecalciferol/farmacologia , Portadores de Fármacos/química , Fibroblastos/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Lipídeos/química , Lipossomos/química , Mioblastos/efeitos dos fármacos , Projetos Piloto , Pele/metabolismo , Absorção Cutânea , Tensoativos/metabolismo
20.
Molecules ; 26(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072474

RESUMO

Ficus deltoidea var. deltoidea is used as traditional medicine for diabetes, inflammation, and nociception. However, the antimutagenic potential and cytoprotective effects of this plant remain unknown. In this study, the mutagenic and antimutagenic activities of F. deltoidea aqueous extract (FDD) on both Salmonella typhimurium TA 98 and TA 100 strains were assessed using Salmonella mutagenicity assay (Ames test). Then, the cytoprotective potential of FDD on menadione-induced oxidative stress was determined in a V79 mouse lung fibroblast cell line. The ferric-reducing antioxidant power (FRAP) assay was conducted to evaluate FDD antioxidant capacity. Results showed that FDD (up to 50 mg/mL) did not exhibit a mutagenic effect on either TA 98 or TA 100 strains. Notably, FDD decreased the revertant colony count induced by 2-aminoanthracene in both strains in the presence of metabolic activation (p < 0.05). Additionally, pretreatment of FDD (50 and 100 µg/mL) demonstrated remarkable protection against menadione-induced oxidative stress in V79 cells significantly by decreasing superoxide anion level (p < 0.05). FDD at all concentrations tested (12.5-100 µg/mL) exhibited antioxidant power, suggesting the cytoprotective effect of FDD could be partly attributed to its antioxidant properties. This report highlights that F. deltoidea may provide a chemopreventive effect on mutagenic and oxidative stress inducers.


Assuntos
Antimutagênicos/química , Antioxidantes/química , Ficus/metabolismo , Extratos Vegetais/química , Animais , Ânions , Linhagem Celular , Cricetulus , Diabetes Mellitus , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glutationa , Camundongos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade , Mutagênicos , Estresse Oxidativo , Salmonella typhimurium/efeitos dos fármacos , Sais de Tetrazólio/química , Tiazóis/química , Vitamina K 3/química , Água
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