RESUMO
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1G93A mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1G93A mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1G93A mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.
Assuntos
Esclerose Lateral Amiotrófica , Córtex Motor , Doenças Neurodegenerativas , Camundongos , Animais , Astrócitos/metabolismo , Esclerose Lateral Amiotrófica/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Camundongos Transgênicos , Doenças Neurodegenerativas/metabolismo , Proteômica , Modelos Animais de Doenças , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
Recently, the diarylpentanoid BP-M345 (5) has been identified as a potent in vitro growth inhibitor of cancer cells, with a GI50 value between 0.17 and 0.45 µM, showing low toxicity in non-tumor cells. BP-M345 (5) promotes mitotic arrest by interfering with mitotic spindle assembly, leading to apoptotic cell death. Following on from our previous work, we designed and synthesized a library of BP-M345 (5) analogs and evaluated the cell growth inhibitory activity of three human cancer cell lines within this library in order to perform structure-activity relationship (SAR) studies and to obtain compounds with improved antimitotic effects. Four compounds (7, 9, 13, and 16) were active, and the growth inhibition effects of compounds 7, 13, and 16 were associated with a pronounced arrest in mitosis. These compounds exhibited a similar or even higher mitotic index than BP-M345 (5), with compound 13 displaying the highest antimitotic activity, associated with the interference with mitotic spindle dynamics, inducing spindle collapse and, consequently, prolonged mitotic arrest, culminating in massive cancer cell death by apoptosis.
Assuntos
Antimitóticos , Antineoplásicos , Neoplasias , Humanos , Antimitóticos/farmacologia , Mitose , Proliferação de Células , Ciclo Celular , Fuso Acromático/metabolismo , Neoplasias/metabolismo , Apoptose , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/metabolismoRESUMO
The use of dental ceramics on anterior teeth is associated with predictable and long-lasting esthetic results. However, treatment on darkened substrates is challenging. Various conservative options, including ceramic veneers, are available to change the shape and color of anterior teeth. The aim of this case report is to describe the esthetic rehabilitation of a darkened central incisor in a maxillary anterior region that had irregular gingival contours, multiple composite resin restorations, and unsatisfactory tooth shapes. Harmony was restored through periodontal recontouring surgery, placement of a lithium disilicate crown (consisting of a veneer cemented to a coping) on the darkened central incisor, and placement of lithium disilicate veneers on the other maxillary anterior teeth.
Assuntos
Porcelana Dentária , Estética Dentária , Humanos , Cerâmica , Coroas , Resinas Compostas , Coroa do Dente , Facetas DentáriasRESUMO
BACKGROUND: Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. OBJECTIVES: To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. METHODS: A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. RESULTS: Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P < 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. CONCLUSIONS: Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Levodopa , Doença de Parkinson , Humanos , Antiparkinsonianos/efeitos adversos , Carbidopa/uso terapêutico , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Estudos Cross-OverRESUMO
Antimicrobial resistance arises due to several adaptation mechanisms, being the overexpression of efflux pumps (EPs) one of the most worrisome. In bacteria, EPs can also play important roles in virulence, quorum-sensing (QS) and biofilm formation. To identify new potential antimicrobial adjuvants, a library of diarylpentanoids and chalcones was synthesized and tested. These compounds presented encouraging results in potentiating the activity of antimicrobials, being diarylpentanoid 13 the most promising. Compounds 9, 13, 16, 19, 22, and 23 displayed EP inhibitory effect, mainly in Staphylococcus aureus 272123. Compounds 13, 19, 22, and 23 exhibited inhibitory effect on biofilm formation in S. aureus 272,123 while 13 and 22 inhibited QS in the pair Sphingomonas paucimobilis Ezf 10-17 and Chromobacterium violaceum CV026. The overall results, demonstrated that diarylpentanoid 13 and chalcone 22 were active against all the resistance mechanisms tested, suggesting their potential as antimicrobial adjuvants.
Assuntos
Chalcona , Chalconas , Antibacterianos/farmacologia , Biofilmes , Chalcona/farmacologia , Chalconas/farmacologia , Chromobacterium , Percepção de Quorum , Staphylococcus aureusRESUMO
OBJECTIVE: In Europe, eslicarbazepine acetate (ESL) is approved as adjunctive therapy for the treatment of focal seizures (FS) in children aged >6â¯years. In the US, ESL is approved as both monotherapy and adjunctive therapy for the treatment of FS in patients aged ≥4â¯years. In a phase II study of children aged 6-16â¯years with FS, ESL had no significant effects on attention or behavioral functioning and decreased seizure frequency during double-blind therapy and a 1-year open-label extension (OLE). This report presents data from an additional 2-year OLE of the phase II study. METHODS: Previous recipients of ESL or placebo were treated with open-label ESL (10-30â¯mg/kg/day, adjusted for clinical response and/or adverse events [AEs]). Safety was assessed by incidence of treatment-emergent AEs (TEAEs). Efficacy endpoints were treatment retention time and change from baseline in Clinical Global Impression-Severity (CGI-S) scale scores. RESULTS: Forty-two patients entered and 31 (73.8%) completed the 2-year OLE. Median treatment retention time was 735 (95% confidence interval 728-741) days. Seven patients (17% of total, 23% of completed) experienced ≥1 TEAE during the 2-year OLE, mostly of mild or moderate intensity. The incidence of serious TEAEs was low (nâ¯=â¯2; 5% of total, 6% of completed) and none were related to ESL. One child was withdrawn because of splenomegaly that was considered possibly related to ESL. The only change from baseline in CGI-S was a 0.5-point reduction in the severity of illness score. All findings were consistent across patient subgroups based on previous double-blind treatment (placebo or ESL) and patient age (6-11 or 12-16â¯years). CONCLUSIONS: The majority of patients remained on ESL during the 2-year OLE, and treatment efficacy was maintained. Adverse events were consistent with the known safety profile of ESL, and no new safety signals were identified.
Assuntos
Anticonvulsivantes , Dibenzazepinas , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Cognição , Dibenzazepinas/efeitos adversos , Método Duplo-Cego , Humanos , Convulsões/tratamento farmacológico , Resultado do TratamentoRESUMO
Diarylpentanoids, a class of natural products and their synthetic analogs which are structurally related to chalcones, have gained increasing attention due to their wide array of biological activities, including antitumor, anti-infective, antioxidant, anti-inflammatory, antidiabetic, anti-hyperuricemic, and neuroprotective properties. Previously, we reviewed diarylpentanoids with promising antitumor activity. However, in view of the wide range of biological activities described for this class of compounds, the purpose of this review is to provide a more detailed overview of the synthetic bioactive diarylpentanoids that have been described over the last two decades, beyond simply their antitumor effects. A total of 745 compounds were found, highlighting the main synthetic methodologies used in their synthesis as well as the structure-activity relationship studies and structural features for all activities reported. Collectively, this review highlights the diarylpentanoid scaffold as a promising starting point for the development of new therapeutic agents.
Assuntos
Produtos Biológicos , Chalconas , Antioxidantes/química , Chalconas/química , Hipoglicemiantes , Relação Estrutura-AtividadeRESUMO
Tyrosinase is the central enzyme involved in the highly complex process of melanin formation, catalyzing the rate-limiting steps of this biosynthetic pathway. Due to such a preponderant role, it has become a major target in the treatment of undesired skin pigmentation conditions and also in the prevention of enzymatic food browning. Numerous phenolic-based structures from natural sources have been pointed out as potential tyrosinase inhibitors, including anthocyanins. The aim of the present study was to individually assess the tyrosinase inhibitory activity of eight purified compounds with a variable degree of structural complexity: native anthocyanins, deoxyanthocyanins, and pyranoanthocyanins. The latter two, the groups of anthocyanin-related compounds with enhanced stability, were tested for the first time. Compounds 1 to 4 (luteolinidin, deoxymalvidin, cyanidin-, and malvidin-3-O-glucoside) revealed to be the most effective inhibitors, and further kinetic studies suggested their inhibition mechanism to be of a competitive nature. Structure-activity relationships were proposed based on molecular docking studies conducted with mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (hTYRP1) crystal structures, providing information about the binding affinity and the different types of interactions established with the enzyme's active center which corroborated the findings of the inhibition and kinetic studies. Overall, these results support the applicability of these compounds as pigmentation modulators.
Assuntos
Antocianinas/química , Antocianinas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Monofenol Mono-Oxigenase/antagonistas & inibidores , Agaricales/enzimologia , Catálise , Simulação por Computador , Humanos , Técnicas In Vitro , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredução , Relação Estrutura-AtividadeRESUMO
The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53-MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53-MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Chalconas/farmacologia , Chalconas/uso terapêutico , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Humanos , Neoplasias/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismoRESUMO
Glioblastoma (GBM) is the most common and most deadly primary malignant brain tumor. Current therapies are not effective, the average survival of GBM patients after diagnosis being limited to few months. Therefore, the discovery of new treatments for this highly aggressive brain cancer is urgently needed. Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, three chalcone derivatives were tested regarding their inhibitory activity and selectivity towards GBM cell lines (human and mouse) and a non-cancerous mouse brain cell line. The chalcone 1 showed the most potent and selective cytotoxic effects in the GBM cell lines, being further investigated regarding its ability to reduce critical hallmark features of GBM and to induce apoptosis and cell cycle arrest. This derivative showed to successfully reduce the invasion and proliferation capacity of tumor cells, both key targets for cancer treatment. Moreover, to overcome potential systemic side effects and its poor water solubility, this compound was encapsulated into liposomes. Therapeutic concentrations were incorporated retaining the potent in vitro growth inhibitory effect of the selected compound. In conclusion, our results demonstrated that this new formulation can be a promising starting point for the discovery of new and more effective drug treatments for GBM.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Chalconas/farmacologia , Glioblastoma/metabolismo , Animais , Antineoplásicos/química , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Humanos , Lipossomos , Camundongos , Estrutura Molecular , Invasividade NeoplásicaRESUMO
Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.
Assuntos
Antineoplásicos/química , Produtos Biológicos/química , Mitose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Segregação de Cromossomos , Células HCT116 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Microtúbulos/química , Microtúbulos/efeitos dos fármacos , Mitose/genética , Neoplasias/genéticaRESUMO
OBJECTIVE: To assess the efficacy, safety, and tolerability of eslicarbazepine acetate (ESL) monotherapy during long-term treatment. METHODS: An open-label extension (OLE) study was conducted in adults completing a phase 3, randomized, double-blind, noninferiority trial, during which they had received monotherapy with either once-daily ESL or twice-daily controlled-release carbamazepine (CBZ-CR) for newly diagnosed focal epilepsy. In the OLE study, all patients received ESL (800-1600 mg/d) for 2 years. Primary efficacy outcome was retention time (from baseline of the OLE study). Secondary efficacy assessments included seizure freedom rate (no seizures during the OLE study) and responder rate (≥50% seizure frequency reduction from baseline of double-blind trial). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs). RESULTS: Of 206 randomized patients, 96 who received ESL in the double-blind trial (ESL/ESL) and 88 who received CBZ-CR in the double-blind trial (CBZ-CR/ESL) were treated with ESL monotherapy (89.3% overall). Treatment retention time was similar between groups, with low probability of ESL withdrawal overall (<0.07 at any time). After 24 months, the probability of ESL withdrawal was 0.0638 (95% confidence interval [CI] = 0.0292-0.1366) in the ESL/ESL group and 0.0472 (95% CI = 0.0180-0.1210) in the CBZ-CR/ESL group. Seizure freedom rates were 90.6% (ESL/ESL) and 80.7% (CBZ-CR/ESL; P = .0531). Responder rates remained >80% in both groups throughout the study. Incidence of serious TEAEs was similar between groups (7.3% vs 5.7%; 0% vs 1.1% possibly related), as were the incidences of TEAEs considered at least possibly related to treatment (17.7% vs 18.2%) and TEAEs leading to discontinuation (3.1% vs 4.5%). The types of TEAEs were generally consistent with the known safety profile of ESL. SIGNIFICANCE: ESL monotherapy was efficacious and generally well tolerated over the long term, including in patients who transitioned from CBZ-CR monotherapy. No new safety concerns emerged.
Assuntos
Anticonvulsivantes/uso terapêutico , Dibenzazepinas/uso terapêutico , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: This was a phase-III, randomized, double-blind, placebo-controlled study aimed to evaluate efficacy and tolerability of eslicarbazepine acetate (ESL) as adjunctive therapy in pediatric patients with refractory focal-onset seizures (FOS). METHODS: Children (2-18â¯years old) with FOS, receiving 1-2 antiepileptic drugs, were randomized to ESL or placebo. Treatment was started at 10â¯mg/kg/day, up-titrated up to 20-30â¯mg/kg/day, and maintained for 12â¯weeks, followed by one-year open-label follow-up. Primary efficacy endpoints were relative reduction in standardized seizure frequency (SSF) and proportion of responders (≥50% SSF reduction) from baseline. Safety was evaluated by the incidence of treatment-emergent adverse events (TEAEs). RESULTS: The intention-to-treat (ITT) set included 134 patients randomized to ESL and 129 to placebo; 89.6% and 91.5%, respectively, completed the trial. An unbalanced number of seizures at baseline were observed between groups. Least square (LS) mean relative change in SSF from baseline was higher in the ESL group (-18.1%) than in placebo (-8.6%). Proportion of responders between ESL and placebo groups was not statistically different. A post hoc analysis showed greater relative reduction in SSF in patients above 6â¯years old treated with ESL 20 or 30â¯mg/kg/day compared with placebo; this was significant in patients above 6â¯years old treated with ESL 30â¯mg/kg/day (LS mean difference: 31.9%; pâ¯=â¯0.0478). The observed safety profile in children was consistent with that established in adult studies. CONCLUSIONS: Adjunctive ESL treatment was well-tolerated, but this trial failed to demonstrate that ESL was more effective than placebo in the predefined efficacy endpoints; factors that may have contributed to this outcome, affecting particularly the young age group, include etiological heterogeneity, difficulty in recognizing simple partial seizures, high seizure frequency with risk of imbalance, and underestimation of the efficacious dose range.
Assuntos
Anticonvulsivantes/administração & dosagem , Dibenzazepinas/administração & dosagem , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
OBJECTIVE: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. METHODS: Safety data from patients aged 4-17â¯years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5â¯years total duration). The OLEs evaluated the safety and tolerability of ESL (10-30â¯mg/kg/day; maximum 1200â¯mg/day). RESULTS: The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. CONCLUSIONS: Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4-17â¯years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.
Assuntos
Anticonvulsivantes , Dibenzazepinas , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Dibenzazepinas/efeitos adversos , Método Duplo-Cego , Humanos , Convulsões/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Symptomatic popliteal artery aneurysms (PAAs) can be managed by open surgery or endovascular exclusion. METHODS: The authors describe a case of a 68-mm PAA causing compressive symptoms and managed by endovascular exclusion combined with percutaneous sac decompression. RESULTS: Endovascular exclusion allows sac pressure reduction. Additional percutaneous sac aspiration and thrombin injection promote sac shrinking and avoid persistent collateral flow. CONCLUSIONS: In challenging cases, matching different techniques can be helpful.
Assuntos
Aneurisma/terapia , Implante de Prótese Vascular , Procedimentos Endovasculares , Artéria Poplítea/cirurgia , Trombina/administração & dosagem , Idoso , Aneurisma/diagnóstico por imagem , Prótese Vascular , Implante de Prótese Vascular/instrumentação , Terapia Combinada , Procedimentos Endovasculares/instrumentação , Feminino , Humanos , Injeções Intra-Arteriais , Artéria Poplítea/diagnóstico por imagem , Stents , Sucção , Resultado do TratamentoRESUMO
Freestanding films based on catechol functionalized chitosan (CHI), hyaluronic acid (HA), and bioglass nanoparticles (BGNPs) were developed by spin-coating layer-by-layer assembly (SA-LbL). The catechol groups of 3,4-dihydroxy-l-phenylalanine (DOPA) present in the marine mussels adhesive proteins (MAPs) are the main factors responsible for their characteristic strong wet adhesion. Then, the produced films were cross-linked with genipin to improve their stability in wet state. Overall, the incorporation of BGNPs resulted in thicker and bioactive films, hydrophilic and rougher surfaces, reduced swelling, higher weight loss, and lower stiffness. The incorporation of catechol groups onto the films showed a significant increase in the films' adhesion and stiffness, lower swelling, and weight loss. Interestingly, a synergetic effect on the stiffness increase was observed upon the combined incorporation of BGNPs with catechol-modified polymers, given that such films were the stiffest. Regarding the biological assays, the films exhibited no negative effects on cellular viability, adhesion, and proliferation, and the BGNPs seemed to promote higher cellular metabolic activity. These bioactive LbL freestanding films combine enhanced adhesion with improved mechanical properties and could find applications in the biomedical field, such as guided hard tissue regeneration membranes.
Assuntos
Materiais Biomiméticos/química , Materiais Revestidos Biocompatíveis/química , Nanopartículas/química , Polissacarídeos/farmacologia , Adesivos/química , Adesivos/farmacologia , Catecóis/química , Adesão Celular/efeitos dos fármacos , Cerâmica/química , Quitosana/química , Materiais Revestidos Biocompatíveis/farmacologia , Ácido Hialurônico/química , Teste de Materiais , Membranas Artificiais , Polímeros/química , Polissacarídeos/química , Proteínas/químicaRESUMO
The authors wish to make changes to the published paper [...].
RESUMO
Hierridin B (6), a methylated hydroquinone isolated from the marine picocyanobacterium Cyanobium sp. LEGE 06113, moderately inhibited the growth of colon adenocarcinoma HT-29 cells. Aiming to improve the potential antitumor activity of this natural product, the demethylated analogue, norhierridin B (10), as well as its structurally-related quinone (9), were synthesized and evaluated for their growth inhibitory effect on a panel of human tumor cell lines, including the triple-negative breast cancer (TNBC) cells MDA-MB-231, SKBR3, and MDA-MB-468. Norhierridin B (10) showed a potent growth inhibitory effect on all cancer cell lines. Moreover, the growth inhibitory effect of compound 10 on MDA-MB-231 cells was associated with cell cycle arrest and apoptosis. Norhierridin B (10) interfered with several p53 transcriptional targets, increasing p21, Bax, and MDM2, while decreasing Bcl-2 protein levels, which suggested the potential activation of a p53 pathway. Altogether, these results evidenced a great improvement of the antitumor activity of hydroquinone 10 when compared to 6 and its structurally-related quinone (9). Notably, hydroquinone 10 displayed a prominent growth inhibitory activity against TNBC cells, which are characterized by high therapeutic resistance.
Assuntos
Anisóis , Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Hidroquinonas , Neoplasias/tratamento farmacológico , Anisóis/química , Anisóis/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Células HT29 , Humanos , Hidroquinonas/química , Hidroquinonas/farmacologia , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
A series of thirteen xanthones 3-15 was prepared based on substitutional (appendage) diversity reactions. The series was structurally characterized based on their spectral data and HRMS, and the structures of xanthone derivatives 1, 7, and 8 were determined by single-crystal X-ray diffraction. This series, along with an in-house series of aminated xanthones 16-33, was tested for in-vitro antimicrobial activity against seven bacterial (including two multidrug-resistant) strains and five fungal strains. 1-(Dibromomethyl)-3,4-dimethoxy-9H-xanthen-9-one (7) and 1-(dibromomethyl)-3,4,6-trimethoxy-9H-xanthen-9-one (8) exhibited antibacterial activity against all tested strains. In addition, 3,4-dihydroxy-1-methyl-9H-xanthen-9-one (3) revealed a potent inhibitory effect on the growth of dermatophyte clinical strains (T. rubrum FF5, M. canis FF1 and E. floccosum FF9), with a MIC of 16 µg/mL for all the tested strains. Compounds 3 and 26 showed a potent inhibitory effect on two C. albicans virulence factors: germ tube and biofilm formation.
Assuntos
Antibacterianos/química , Biofilmes/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Xantonas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Biofilmes/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Cristalografia por Raios X , Humanos , Testes de Sensibilidade Microbiana , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Difração de Raios X , Xantonas/síntese química , Xantonas/farmacologiaRESUMO
An 87 year-old male presented with a 71mm proximal anastomotic aneurysm causing left renal artery displacement (Figures 1 and 2), 19 years after infra-renal aorto-aortic grafting for an infra-renal abdominal aortic aneurysm. Dilatation of visceral aorta was also observed. Management would be challenging but patient denied further intervention.