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Idiopathic pulmonary fibrosis (IPF) is an irreversible progressive interstitial lung disease of unknown cause. The poorly understood pathophysiology of IPF poses substantial challenges to the development of effective anti-lung fibrotic drugs. The NLRP3 inflammasome, a key component of the innate immune system, has recently been linked to the pathogenesis of lung fibrosis. However, the specific contributions of NLRP3 inflammasomes to determination of the pro-fibrotic phenotype of lung fibroblasts, which play a central role in the production of extracellular matrix protein, remain to be investigated. Therefore, the present study was performed to elucidate the involvement of NLRP3 inflammasome signalling pathways in modulation of lung fibroblast proliferation and differentiation. We found that activation of NLRP3 inflammasomes increased in lung fibroblasts derived from individuals with pulmonary fibrosis and in normal lung fibroblasts stimulated with transforming growth factor ß and platelet-derived growth factor. Importantly, blockage of NLRP3 inflammasome signalling, either by gene silencing of NLRP3 or using pharmacological inhibitors of NLRP3, caspase-1, or IL-1 receptor, inhibited the proliferation, differentiation, and extracellular matrix protein synthesis of activated lung fibroblasts. Moreover, induction of the reactive oxygen species/thioredoxin-interacting protein axis, an upstream signalling pathway of NLRP3 inflammasomes, was essential for maintenance of the pro-fibrotic phenotype of lung fibroblasts. Interestingly, treatments with pharmacological inhibitors of NLRP3 inflammasomes prevented the progression of bleomycin-induced pulmonary fibrosis in mice. Collectively, these findings suggest that aberrant activation of NLRP3 inflammasomes is a critical event in the pathogenesis of IPF and that targeting NLRP3 inflammasomes may serve as a therapeutic strategy for IPF.
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ETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing pulmonary disorder that has a poor prognosis and high mortality. Although there has been extensive effort to introduce several new anti-fibrotic agents in the past decade, IPF remains an incurable disease. Mimosa pudica L., an indigenous Vietnamese plant, has been empirically used to treat respiratory disorders. Nevertheless, the therapeutic effects of M. pudica (MP) on lung fibrosis and the mechanisms underlying those effects remain unclear. AIM OF THE STUDY: This study investigated the protective effect of a crude ethanol extract of the above-ground parts of MP against pulmonary fibrogenesis. MATERIALS AND METHODS: Inflammatory responses triggered by TNFα in structural lung cells were examined in normal human lung fibroblasts and A549 alveolar epithelial cells using Western blot analysis, reverse transcription-quantitative polymerase chain reaction assays, and immunocytochemistry. The epithelial-to-mesenchymal transition (EMT) was examined via cell morphology observations, F-actin fluorescent staining, gene and protein expression measurements, and a wound-healing assay. Anti-fibrotic assays including collagen release, differentiation, and measurements of fibrosis-related gene and protein expression levels were performed on TGFß-stimulated human lung fibroblasts and lung fibroblasts derived from mice with fibrotic lungs. Finally, in vitro anti-fibrotic activities were validated using a mouse model of bleomycin-induced pulmonary fibrosis. RESULTS: MP alleviated the inflammatory responses of A549 alveolar epithelial cells and lung fibroblasts, as revealed by inhibition of TNFα-induced chemotactic cytokine and chemokine expression, along with inactivation of the MAPK and NFκB signalling pathways. MP also partially reversed the TGFß-promoted EMT via downregulation of mesenchymal markers in A549 cells. Importantly, MP decreased the expression levels of fibrosis-related genes/proteins including collagen I, fibronectin, and αSMA; moreover, it suppressed collagen secretion and prevented myofibroblast differentiation in lung fibroblasts. These effects were mediated by FOXO3 stabilization through suppression of TGFß-induced ERK1/2 phosphorylation. MP consistently protected mice from the onset and progression of bleomycin-induced pulmonary fibrosis. CONCLUSION: This study explored the multifaceted roles of MP in counteracting the pathobiological processes of lung fibrosis. The results suggest that further evaluation of MP could yield candidate therapies for IPF.
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Transição Epitelial-Mesenquimal , Proteína Forkhead Box O3 , Sistema de Sinalização das MAP Quinases , Extratos Vegetais , Fibrose Pulmonar , Animais , Humanos , Masculino , Camundongos , Células A549 , Antifibróticos/farmacologia , Bleomicina , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Proteína Forkhead Box O3/metabolismo , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamenteRESUMO
This study isolated pure compounds from Canna edulis aerial parts and assessed their antiplatelet and anticoagulant potential. Structural elucidation resulted in the identification of two new compounds: caneduloside A (1) and caneduloside B (2), and eleven known compounds: 6'-acetyl-3,6,2'-tri-p-coumaroyl sucrose (3), 6'-acetyl-3,6,2'-triferuloyl sucrose (4), tiliroside (5), afzelin (6), quercitrin (7), 2-hydroxycinnamaldehyde (8), cinnamic acid (9), 3,4-dimethoxycinnamic acid (10), dehydrovomifoliol (11), 4-hydroxy-3,5-dimethoxybenzaldehyde (12), and (S)-(-)-rosmarinic acid (13). Compounds 3, 4, 6-9, 13 were previously reported for antithrombotic properties. Hence, antithrombotic tests were conducted for 1, 2, 5, 10-12. All tested compounds demonstrated a dose-dependent antiaggregatory effect, and 10 and 12 were the most potent for both ADP and collagen activators. Additionally, 10 and 12 showed anticoagulant effects, with prolonged prothrombin time and activated partial thromboplastin time. The new compound 1 displayed antiplatelet and anticoagulant activity, while 2 mildly inhibited platelet aggregation. C. edulis is a potential source for developing antithrombotic agents.
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Anticoagulantes , Componentes Aéreos da Planta , Inibidores da Agregação Plaquetária , Sacarose , Anticoagulantes/farmacologia , Anticoagulantes/química , Anticoagulantes/isolamento & purificação , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/isolamento & purificação , Sacarose/química , Sacarose/farmacologia , Sacarose/metabolismo , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Humanos , Ésteres/química , Ésteres/farmacologia , Ésteres/isolamento & purificação , Agregação Plaquetária/efeitos dos fármacos , Myristicaceae/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Relação Estrutura-Atividade , AnimaisRESUMO
Aim: This study aimed to assess the association between self-rated smile satisfaction and the smile dimensions among dental students. Method: An analytical cross-sectional study was conducted on 216 Vietnamese dental students. A standardized photograph was taken of each student with their frontal social smiles to assess aesthetic dimensions. A single-session self-administered questionnaire containing five questions about smile aesthetic satisfaction related to various aspects was administered to all students. Differences in smile characteristics and satisfaction scores between the two genders were evaluated. The impact of smile characteristics on satisfaction scores was assessed using multiple linear regression models. Results: Most dental students had a high smile line, parallel smile arcs, an upward upper lip curvature, a non-touching labiodental relationship, a dental midline that coincided with the midline of the face, and eight teeth displayed during smile. Most participants were satisfied with their smiles, and the self-rated satisfaction score was 67 out of 100. Self-perceived overall smile satisfaction was associated with the "smile arc", the "upper lip curvature", the "number of teeth displayed during smile", and the "dental midline". Female students had a statistically significant correlation between self-perception and smile characteristics, such as upper lip curvature, dental midline shift, and smile line. Conclusions: The smile arc, upper lip curvature, and dental midline shift affected self-perceived satisfaction among dental students. Female students showed an association between the smile parameters and self-perceived satisfaction.
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The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.
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Infecções por HIV , HIV-1 , Humanos , HIV-1/genética , Anticorpos Anti-HIV , Anticorpos Neutralizantes , Peptídeos , Sequência de Aminoácidos , Vacinas de Subunidades Antigênicas , Testes de Neutralização , Produtos do Gene env do Vírus da Imunodeficiência HumanaRESUMO
Although sediments are considered to be a major sink for microplastics (MP), there is still a relative lack of knowledge on the factors that influence the occurrence and abundance of MP in riverine sediments. The present study investigated the occurrence and distribution of MP in riverine sediments collected at twelve sites representative of different populated and urbanized rivers (To Lich, Nhue and Day Rivers) located in the Red River Delta (RRD, Vietnam, during dry and rainy seasons. MP concentrations ranged from 1600 items kg-1 dw to 94,300 items kg-1dw. Fiber shape dominated and MP were made of polypropylene (PP) and polyethylene (PE) predominantly. An absence of seasonal effect was observed for both fragments and fibers for each rivers. Decreasing MP concentrations trend was evidenced from the To Lich River, to the Nhue River and to the Day River, coupled with a decreasing fiber length and an increasing fragment area in the surface sediment from upstream to downstream. Content of organic matter was correlated to MP concentrations suggesting that, high levels of organic matter could be MP hotspots in urban rivers. Also, high population density as well as in highly residential areas are related to higher MP concentrations in sediments. Finally, a MP high ecological risk (RI: 866 to 4711) was calculated in the RDD.
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Male infertility is a growing health problem, which affects approximately 7% of the global male population. Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility caused by genetic defects, including chromosome structural abnormalities, Y chromosome microdeletions, or single-gene alterations. However, the etiology of up to 40% of NOA cases is unidentified. By whole-exome sequencing, we detected a homozygous 5-bp-deletion variant in exon 4 of the TEX12 gene (c.196-200del, p.L66fs, NM_031275.4) in two brothers with NOA of a nonconsanguineous Vietnamese family. This deletion variant of 5 nucleotides (ATTAG) results in a premature stop codon in exon 4 and truncation of the C-terminal. Segregation analysis by Sanger sequencing confirmed that the deletion variant was inherited in an autosomal recessive pattern. The 1st and 3rd infertile sons were homozygous for the deletion, whereas the 2nd fertile son and both parents were heterozygous. The new deletion mutation identified in TEX12 gene caused loss of function of TEX12 gene. The loss of TEX12 function has already caused infertility in male mice. Therefore, we concluded that the loss of TEX12 function may cause infertility in men. To our knowledge, this is the first case reported so far indicating disruption of human TEX12, which leads to infertility in men.
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Azoospermia , Infertilidade Masculina , Humanos , Masculino , Animais , Camundongos , Azoospermia/genética , Irmãos , Infertilidade Masculina/genética , HomozigotoRESUMO
One new compound, 4,7-dihydroxy-2-hydroxymethyl-5,6-dimethoxyanthraquinone (1), along with eight known compounds (2-9) were isolated from the methanol extracts of the aerial parts of Chamaecrista pumila (Lam.) K. Larsen. Their chemical structure was determined based on spectroscopic data interpretation and comparison with the reported data. The inhibitory effects of them on α-amylase and α-glucosidase were performed. The results showed that compounds 4, 6, 8, and 9 against potent α-glucosidase with the inhibition values of 98.14 ± 0.05, 98.19 ± 0.04, 97.01 ± 0.49, 84.43 ± 0.6% at 50 µM, respectively. Compounds 4 and 6 displayed significance against α-amylase at 200 µM with inhibition values of 22.35 ± 1.10 and 60.47 ± 0.91%.
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Chamaecrista , Inibidores de Glicosídeo Hidrolases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/farmacologia , alfa-Glucosidases/química , alfa-Amilases/química , Extratos Vegetais/química , Componentes Aéreos da Planta/químicaRESUMO
Despite the advances in surface-display systems for directed evolution, variants with high affinity are not always enriched due to undesirable biases that increase target-unrelated variants during biopanning. Here, our goal was to design a library containing improved variants from the information of the "weakly enriched" library where functional variants were weakly enriched. Deep sequencing for the previous biopanning result, where no functional antibody mimetics were experimentally identified, revealed that weak enrichment was partly due to undesirable biases during phage infection and amplification steps. The clustering analysis of the deep sequencing data from appropriate steps revealed no distinct sequence patterns, but a Bayesian machine learning model trained with the selected deep sequencing data supplied nine clusters with distinct sequence patterns. Phage libraries were designed on the basis of the sequence patterns identified, and four improved variants with target-specific affinity (EC50 = 80-277 nM) were identified by biopanning. The selection and use of deep sequencing data without undesirable bias enabled us to extract the information on prospective variants. In summary, the use of appropriate deep sequencing data and machine learning with the sequence data has the possibility of finding sequence space where functional variants are enriched.
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Bacteriófagos , Biblioteca de Peptídeos , Proteínas de Transporte , Teorema de Bayes , Estudos Prospectivos , Bacteriófagos/genética , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
Most polygenic risk score (PRS)models have been based on data from populations of European origins (accounting for the majority of the large genomics datasets, e.g. >78% in the UK Biobank and >85% in the GTEx project). Although several large-scale Asian biobanks were initiated (e.g. Japanese, Korean, Han Chinese biobanks), most other Asian countries have little or near-zero genomics data. To implement PRS models for under-represented populations, we explored transfer learning approaches, assuming that information from existing large datasets can compensate for the small sample size that can be feasibly obtained in developing countries, like Vietnam. Here, we benchmark 13 common PRS methods in meta-population strategy (combining individual genotype data from multiple populations) and multi-population strategy (combining summary statistics from multiple populations). Our results highlight the complementarity of different populations and the choice of methods should depend on the target population. Based on these results, we discussed a set of guidelines to help users select the best method for their datasets. We developed a robust and comprehensive software to allow for benchmarking comparisons between methods and proposed a computational framework for improving PRS performance in a dataset with a small sample size. This work is expected to inform the development of genomics applications in under-represented populations. PRSUP framework is available at: https://github.com/BiomedicalMachineLearning/VGP.
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Estudo de Associação Genômica Ampla , Herança Multifatorial , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Vietnã , Genômica/métodos , Fatores de RiscoRESUMO
The monoclonal antibody CIS43 targets the Plasmodium falciparum circumsporozoite protein (PfCSP) and prevents malaria infection in humans for up to 9 mo following a single intravenous administration. To enhance the potency and clinical utility of CIS43, we used iterative site-saturation mutagenesis and DNA shuffling to screen precise gene-variant yeast display libraries for improved PfCSP antigen recognition. We identified several mutations that improved recognition, predominately in framework regions, and combined these to produce a panel of antibody variants. The most improved antibody, CIS43_Var10, had three mutations and showed approximately sixfold enhanced protective potency in vivo compared to CIS43. Co-crystal and cryo-electron microscopy structures of CIS43_Var10 with the peptide epitope or with PfCSP, respectively, revealed functional roles for each of these mutations. The unbiased site-directed mutagenesis and screening pipeline described here represent a powerful approach to enhance protective potency and to enable broader clinical use of antimalarial antibodies.
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Antimaláricos , Vacinas Antimaláricas , Anticorpos Antiprotozoários , Antimaláricos/farmacologia , Microscopia Crioeletrônica , Humanos , Plasmodium falciparum , Proteínas de Protozoários , Saccharomyces cerevisiae/genéticaRESUMO
Balanophora laxiflora, a medicinal plant traditionally used to treat fever, pain, and inflammation in Vietnam, has been reported to possess prominent anti-inflammatory activity. This study examined the active constituents and molecular mechanisms underlying these anti-inflammatory effects using bioactivity-guided isolation in combination with cell-based assays and animal models of inflammation. Among the isolated compounds, the triterpenoid (21α)-22-hydroxyhopan-3-one (1) showed the most potent inhibitory effect on COX-2 expression in LPS-stimulated Raw 264.7 macrophages. Furthermore, 1 suppressed the expression of the inflammatory mediators iNOS, IL-1ß, INFß, and TNFα in activated Raw 264.7 macrophages and alleviated the inflammatory response in carrageenan-induced paw oedema and a cotton pellet-induced granuloma model. Mechanistically, the anti-inflammatory effects of 1 were mediated via decreasing cellular reactive oxygen species (ROS) levels by inhibiting NADPH oxidases (NOXs) and free radical scavenging activities. By downregulating ROS signalling, 1 reduced the activation of MAPK signalling pathways, leading to decreased AP-1-dependent transcription of inflammatory mediators. These findings shed light on the chemical constituents that contribute to the anti-inflammatory actions of B. laxiflora and suggest that 1 is a promising candidate for treating inflammation-related diseases.
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Berberine (BBR) is a plant-origin quaternary isoquinoline alkaloid presenting exogenous cholesterol lowering and anti-hyperlipidemia therapeutic effects. The aim of this study was to design and generate BBR-loaded proliposomes (PLs) as solid templates for high-dose liposomes and consequently, to enhance the oral bioavailability and therapeutic effect of BBR. An air-suspension coating (layering) method was used for generating BBR-loaded PLs. The size, distribution size, morphology, and entrapment efficiency (EE) of the final reconstituted liposomes were assessed. The oral bioavailability and endogenous cholesterol lowering effects of BBR loaded in liposomes were investigated in rats and mice, respectively. The BBR-loaded PLs showed a smooth BBR-embedded film around micron-scale carrier particles (mannitol). The reconstituted BBR-loaded liposomes had a nano-scale average size (116.6 ± 5.8 nm), narrow size distribution (polydispersity index, PDI 0.269 ± 0.038), and high EE (87.8 ± 1.0%). The oral bioavailability of reconstituted BBR-loaded liposomes at a dose of 100 mg/kg in rats was increased even 628% compared to that obtained with pure BBR (according to 90% confidence interval). The BBR-loaded liposomes at the daily oral dose 100 mg/kg in P-407- reduced total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) in hyperlipidemic mice by 15.8%, 38.2%, and 57.0%, respectively.
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Berberina , Animais , Berberina/química , Colesterol , LDL-Colesterol , Modelos Animais de Doenças , Lipossomos/química , Camundongos , RatosRESUMO
Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti-HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.
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Vacinas contra a AIDS/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Mutação , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/genética , Anticorpos Amplamente Neutralizantes/genética , Anticorpos Anti-HIV/genética , HIV-1/genética , Humanos , Produtos do Gene env do Vírus da Imunodeficiência Humana/genéticaRESUMO
AIM AND OBJECTIVE: The current study aimed to investigate the effect of two nonsurgical periodontal treatment modalities on clinical periodontal parameters and glycemic control. MATERIALS AND METHODS: A randomized clinical trial was conducted with a sample of 64 type 2 diabetes mellitus (T2DM) patients with chronic periodontitis. Subjects were randomly assigned into two groups. Group I received oral hygiene instructions (OHI) at baseline and each recall visit. Group II received one-stage full-mouth scaling and root planning (SRP) combining OHI. At baseline, third month, and sixth month the plaque index (PlI), gingival index (GI), probing pocket depth (PPD), clinical attachment loss (CAL), and glycated hemoglobin (HbA1c) were recorded and analyzed. RESULTS: After treatment, two groups showed signiï¬cant differences for all parameters at both assessed times (p <0.05). The OHI alone only demonstrated a slight reduction in GI in third month, with no significant changes for PlI and PPD indexes. However, Group I recorded the increased HbA1c and CAL values at 6-month follow-up (p <0.05). The combination of OHI and SRP exhibited a significant improvement in all periodontal values (p <0.05). Also, the HbA1C levels of Group II showed a significant reduction after treatment and were lower than those of Group I. CONCLUSIONS: Oral hygiene instructions only resulted in a better gingival condition of diabetic patients in the initial time. The nonsurgical periodontal therapy by combining SRP and OHI significantly improved both periodontal health and glycemic control. CLINICAL SIGNIFICANCE: Diabetic patients should be supplied with an effective OHI modality and a professional dental debridement.
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Periodontite Crônica , Diabetes Mellitus Tipo 2 , Periodontite Crônica/complicações , Periodontite Crônica/terapia , Raspagem Dentária/métodos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas/análise , Humanos , Aplainamento Radicular/métodosRESUMO
Cassaine diterpenoids as erythrofordins A-C (1-3), pseudo-erythrosuamin (4), and erythrofordin U (5) isolated from the leaves of Vietnamese Erythrophleum fordii Oliver were tested cytotoxic activity against human leukemia cancer cells. The results showed that these metabolites exhibited dose-dependent cytotoxicity against human leukemia HL-60 and KG cells with IC50 values ranging from 15.2 ± 1.5 to 42.2 ± 3.6 µM. Treatment with erythrofordin B led to the apoptosis of HL-60 and KG cells due to the activation of caspase 3, caspase 9, and poly (ADP-ribose) polymerase (PARP). Erythrofordin B significantly increased Bak protein expression, but downregulated the anti-apoptotic protein Bcl-2, in HL-60 cells. In silico results demonstrated that erythrofordin B can bind to both the procaspase-3 allosteric site and the PARP-1 active site, with binding energies of -7.36 and -10.76 kcal/mol, respectively. These results indicated that the leaves of Vietnamese E. fordii, which contain cassaine diterpenoids, can induce the apoptosis of human leukemia cancer cells.
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Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Fabaceae/química , Extratos Vegetais/farmacologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Balanophora laxiflora Hemsl. (Balanophoraceae) is a traditional medicinal plant with a diverse array of biological activities. In our exploration of new bioactive constituents from B. laxiflora, we isolated five compounds, including a new lignan, balanophorone (5), and four known phenolic compounds (1–4). The chemical structures of these compounds were determined by extensive spectroscopic analyses, including 1D and 2D NMR, HR-ESI-MS, and CD. In addition, we evaluated the effects of each of the isolates (1–5) on the messenger RNA expression levels of tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells. Compound 2 showed significant inhibition of LPS-induced COX-2 and TNF-α expression in RAW 264.7 macrophages, while compound 4 showed moderate cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells, with IC 50 values of 18.3 and 30.7 μM, respectively. No significant effects on the viability of normal mammary epithelial cells were observed.
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Balanophora laxiflora Hemsl. (Balanophoraceae) is a traditional medicinal plant with a diverse array of biological activities. In our exploration of new bioactive constituents from B. laxiflora, we isolated five compounds, including a new lignan, balanophorone (5), and four known phenolic compounds (1–4). The chemical structures of these compounds were determined by extensive spectroscopic analyses, including 1D and 2D NMR, HR-ESI-MS, and CD. In addition, we evaluated the effects of each of the isolates (1–5) on the messenger RNA expression levels of tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells. Compound 2 showed significant inhibition of LPS-induced COX-2 and TNF-α expression in RAW 264.7 macrophages, while compound 4 showed moderate cytotoxicity against MCF-7 and MDA-MB-231 breast cancer cells, with IC 50 values of 18.3 and 30.7 μM, respectively. No significant effects on the viability of normal mammary epithelial cells were observed.
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BACKGROUND: Based on the prevalence studies, the number of people suffering from dementia will almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050, assuming no changes in mortality, effective preventative measures, definitive diagnostic guidelines or curative treatment. From the abovementioned epidemiological data, it is obvious that dementia constitutes a major public health problem not only at present, but unfortunately also in the future. OBJECTIVES AND METHODS: Several N-alkylated tacrine (THA) derivatives have already been synthesized by Pomponi et al., in 1997. However, these compounds were tested for their anti-AChE activity using enzyme isolated from Electrophorus electricus. For this reason, we have decided to extend the previously reported series of THA derivatives and consequently test them in the battery of experiments, the results of which have served to more relevant evaluation of these compounds from the perspective of Alzeimer´s disease compared to that published by Pomponi. RESULTS AND CONCLUSION: In summary, all compounds of interest effectively inhibited ChEs in vitro. One of the most promising derivatives 8 bearing an N-octyl chain showed 2.5-fold higher AChE inhibitory activity in relation to tacrine. With respect to blood-brain barrier (BBB) penetration, it can be claimed that synthesized analogues are presumably able to cross the BBB. From the point of view of hepatotoxicity, selected Nalkylated tacrine derivatives exerted worse results compared to tacrine. However, in vitro results are only illustrative, therefore, only in vivo experiments could determine the real value of selected N-alkylated THA derivatives.
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Doença de Alzheimer , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Tacrina/análogos & derivados , Tacrina/farmacologia , Células Hep G2 , HumanosRESUMO
The current objective was to evaluate six groups of titanium membranes in a rat calvarial defect model, regarding the surface treatment with or without calcium-phosphate coating and surface topography with no, small, or large holes. Critical size defects (Ф = 8 mm, n = 42) were surgically created in rat calvaria, and then were treated by one of the six groups. Biopsies were obtained at 4 weeks (n = 5 per group) for micro-computed tomography and histomorphometric analyses. Fluorochrome bone markers were injected in two rats each group at 1 (Alizarin red), 3 (Calcein green) and 5 weeks (Oxytetracyclin yellow), followed by histological examination at 7 weeks to assess bone regeneration dynamic. At 4 weeks, the highest bone volume was observed in no-hole groups independent of surface treatment (p < 0.05). Treated groups with no-hole and large-hole membranes showed increased bone mineral density than with respective non-treated groups (p < 0.05). Histology exhibited an intimate bone formation onto the treated membranes, whereas non-treated ones demonstrated interposition of connective tissue, which was confirmed through bone contact percentages. The results suggest that occlusive membranes showed more bone formation than other perforated ones, and calcium-phosphate treatment induces intimate bone formation toward the membrane.