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1.
Carbohydr Polym ; 232: 115822, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952617

RESUMO

Chondroitin sulfate is a linear glycosaminoglycan widely distributed as an important extracellular matrix component of mammalian cells. It participates in numerous pathological processes, however, illustration of its diverse biological roles is hampered by the unavailability of structurally defined chondroitin polymers and their derivatives. Herein, we report a novel homogeneous chondroitin polymers synthetic strategy which combines stepwise oligosaccharides synthesis with one-pot homogeneous chondroitin chain polymerization. Exogenous trisaccharide was proved to be the necessary acceptor for PmCS-catalyzed homogeneous chondroitin polymers synthetic reactions. The strategy exhibited a well-controlled relationship between the final sugar chain length and the molar ratios of reaction substrates that could synthesize homogenous chondroitin polymers with unprecedented narrow molecular weight distribution. More importantly, the strategy was further expanded to synthesis of unnatural zwitterionic and N-sulfonated chondroitin polymers by incorporation of sugar nucleotide derivatives into the synthetic approach.


Assuntos
Condroitina/biossíntese , N-Acetilgalactosaminiltransferases/metabolismo , Polímeros/metabolismo , Configuração de Carboidratos , Condroitina/análogos & derivados , Condroitina/química , Pasteurella multocida/enzimologia , Polimerização , Polímeros/química
2.
Yakugaku Zasshi ; 139(12): 1495-1500, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787635

RESUMO

The roles of chondroitin sulfate (CS) and dermatan sulfate (DS) have been demonstrated in various biological events such as the construction of the extracellular matrix, tissue development, and cell signaling through interactions with extracellular matrix components, morphogens, and growth factors. Human genetic diseases, including skeletal abnormalities, connective tissue diseases, and heart defects, were reported to be caused by mutations in the genes encoding glycosyltransferases, epimerases, and sulfotransferases that are responsible for the biosynthesis of CS and DS. Glycobiological approaches revealed that mutations in CS- and DS-biosynthetic enzymes led to reductions in their enzymatic activities and in the levels of CS and DS. Furthermore, CS at the surface of tumor cells plays a key role in pulmonary metastasis. A receptor for advanced glycation end-products (RAGE) was predominantly expressed in the lung, and was identified as a functional receptor for CS chains. CS and anti-RAGE antibodies inhibited the pulmonary metastasis of not only Lewis lung carcinoma but also B16 melanoma cells. Hence, RAGE and CS are potential targets of drug discovery for pulmonary metastasis and a number of other pathological conditions involving RAGE in the pathogenetic mechanism. This review provides an overview of glycobiological studies on characterized genetic disorders caused by the impaired biosynthesis of CS, as well as DS, and on the pulmonary metastasis of Lewis lung carcinoma cells involving CS and RAGE.


Assuntos
Doenças Ósseas/etiologia , Doenças Ósseas/genética , Carcinoma Pulmonar de Lewis/etiologia , Carcinoma Pulmonar de Lewis/secundário , Condroitina/biossíntese , Dermatan Sulfato/biossíntese , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/secundário , Receptor para Produtos Finais de Glicação Avançada , Dermatopatias/etiologia , Dermatopatias/genética , Animais , Carcinoma Pulmonar de Lewis/genética , Humanos , Neoplasias Pulmonares/genética , Camundongos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo
3.
Clin Rheumatol ; 38(12): 3595-3607, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31376086

RESUMO

OBJECTIVES: This study aims to evaluate the efficacy of treatments for Kashin-Beck disease (KBD). METHOD: We searched PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science, SinoMed, Chinese National Knowledge Infrastructure, reference lists and published systematic reviews and registries of ongoing trials through May 2015 for randomised controlled trials (RCTs) of treatments for KBD. Outcomes of interest were pain, function, stiffness, overall clinical improvement, radiographic improvement (X-ray) and adverse events. Frequentist network meta-analyses were conducted using random-effects consistency model to assess the efficacy of treatments for KBD. RESULTS: Forty-four RCTs with 9815 participants were included in the review. In children or adolescents, selenium (risk ratio 1.88, 95% confidence interval (CI) 1.51-2.33), vitamin C (2.03, 1.40-2.95) and aspirin (2.14, 1.12-4.08) were effective for radiographic structure improvement. In adults, chondroitin plus glucosamine was the best for pain (standardised mean difference 1.46, 95% CI 1.07-1.85), followed by intra-articular injection of hyaluronic acid (IAH) (1.09, 0.70-1.48), chondroitin (0.84, 0.47-1.21), diclofenac (0.63, 1.18-1.08), naproxen (0.55, 0.12-0.98), meloxicam (0.52, 0.03-1.01) and glucosamine (0.40, 0.13-0.67) compared to placebo, with similar results for other clinical outcomes in adults. However, the strength of most evidence was limited by the small number of trials with low to moderate quality. CONCLUSIONS: Selenium supplement has demonstrated some benefits for structural improvement of the disease in children. Chondroitin, glucosamine, IAH and nonsteroid anti-inflammatory drugs are effective for symptom improvements of KBD in adults. Evidence of surgical and complementary treatments for symptoms and aspirin and vitamin C for structure has yet to be established.Key Points• There were 23 nutraceuticals, pharmaceuticals and surgical and complementary treatments assessed for Kashin-Beck disease (KBD) in randomised trials.• Among the 23 treatments, chondroitin, glucosamine, IAH and non-steroid anti-inflammatory drugs are more effective than placebo to relieve symptoms for adults with KBD.• Selenium supplement is more effective than placebo for radiographic improvement in children or adolescents.• The efficacy of surgeries, aspirin, vitamin C and complementary treatments for KBD has not been established yet.


Assuntos
Doença de Kashin-Bek/terapia , Condroitina/uso terapêutico , Suplementos Nutricionais , Glucosamina/uso terapêutico , Humanos , Manejo da Dor , Selênio/uso terapêutico
4.
Appl Microbiol Biotechnol ; 103(16): 6771-6782, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222385

RESUMO

Heparin and chondroitin sulfate are used as anti-thrombic and anti-osteoarthritis drugs, respectively, but their pharmacological actions depend on their structural characteristics such as their sulfation grade and their molecular weight. In the last years, new fermentation-based biotechnological approaches have tried to obtain heparin and chondroitin sulfate starting from the heparosan and chondroitin-like capsular polysaccharides produced by Escherichia coli K5 and K4. The study of the microbial capsular polysaccharide molecular weight is critical to obtain nature-like or structural tailor cut glycosaminoglycan homologues. However, so far, it has been scarcely investigated. In this paper, for the first time, a new protocol was set up to determine the molecular weights of the capsular polysaccharides of three wild-type and three engineered E. coli K5 and K4 strains. The protocol includes a small-scale downstream train to purify the intact polysaccharides, directly from the fermentation broth supernatants, by using ultrafiltration membranes and anion exchange chromatography, and it couples size exclusion chromatography analyses with triple detector array. In the purification high recovery (> 85.0%) and the removal of the main contaminant, the lipopolysaccharide, were obtained. The averaged molecular weights of the wild-type capsular polysaccharides ranged from 51.3 to 90.9 kDa, while the engineered strains produced polysaccharides with higher molecular weights, ranging from 68.4 to 130.6 kDa, but with similar polydispersity values between 1.1 and 1.5.


Assuntos
Condroitina/química , Dissacarídeos/química , Escherichia coli/química , Engenharia Metabólica , Polissacarídeos Bacterianos/química , Condroitina/metabolismo , Cromatografia em Gel , Meios de Cultura/química , Dissacarídeos/metabolismo , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Peso Molecular , Polissacarídeos Bacterianos/metabolismo , Ultrafiltração
5.
Biochimie ; 166: 173-183, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30981871

RESUMO

Formation of new blood vessels from preexisting ones, a process known as angiogenesis, is one of the limiting steps for success in treatment of ischemic disorders. Therefore, efforts to understanding and characterize new agents capable to stimulate neovascularization are a worldwide need. Crataeva tapia bark lectin (CrataBL) has been shown to have chemoattractant properties for endothelial cells through the stimulation of migration and invasiveness of human umbilical vein endothelial cells (HUVEC) because it is a positively charged protein with high affinity to glycosaminoglycan. In addition, CrataBL increased the production of chondroitin and heparan sulfate in endothelial cells. These findings orchestrated specific adhesion on collagen I and phosphorylation of tyrosine kinase receptors, represented by vascular endothelial growth factor receptor-2 (VEGFR-2) and fibroblast growth factor receptor (FGFR), whose downstream pathways trigger the angiogenic cascade increasing cell viability, cytoskeleton rearrangement, cell motility, and tube formation. Moreover, CrataBL inhibited the activity of matrix metalloproteases type 2 (MMP-2), a protein related to tissue remodeling. Likewise, CrataBL improved wound healing and increased the number of follicular structures in lesioned areas produced in the dorsum-cervical region of C57BL/6 mice. These outcomes altogether indicate that CrataBL is a pro-angiogenic and healing agent.


Assuntos
Indutores da Angiogênese/farmacologia , Condroitina/metabolismo , Heparitina Sulfato/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Lectinas de Plantas/farmacologia , Animais , Capparaceae/metabolismo , Movimento Celular/efeitos dos fármacos , Fatores Quimiotáticos/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cicatrização/efeitos dos fármacos
6.
Int J Biol Macromol ; 133: 702-711, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31022484

RESUMO

Polysaccharide K4 expressed from E. coli K4 has a similar structure with chondroitin, which can be used as a precursor to produce chondroitin sulfates. Here, we investigated the structure, conformation and biological activity of K4 from an engineered strain with high productivity. The NMR analysis suggested that K4 from wild-type strain with a low yield was a partially fructosylated chondroitin. While K4 from engineered strain was a fully fructosylated chondroitin. Light scattering analysis gave the Mw values of 6.15 × 104, 8.23 × 104 and 1.92 × 104 for K4-1, K4-2 and defructosylated K4 (DK4), respectively. The exponents of functions z1/2 = f(Mw) were in the range of 0.643-0.608, suggesting a random coil conformation for K4 and DK4. And the random coils K4 easily self-assembled into sphere-like aggregates in the dilute aqueous solution. Both K4 and DK4 exhibited significant immunomodulatory activities on RAW 264.7 cells at the dosage range of 5-500 µg/mL.


Assuntos
Condroitina/química , Condroitina/farmacologia , Escherichia coli/genética , Frutose/química , Engenharia Genética , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Animais , Configuração de Carboidratos , Proliferação de Células/efeitos dos fármacos , Condroitina/genética , Citocinas/biossíntese , Fatores Imunológicos/metabolismo , Camundongos , Peso Molecular , Óxido Nítrico/biossíntese , Fagocitose/efeitos dos fármacos , Células RAW 264.7
7.
Int J Biol Macromol ; 131: 812-820, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30880057

RESUMO

Hyaluronic acid (HA) cross-linked with 1,4-butanediol diglycidyl ether (BDDE) are hydrogels with many biomedical applications. Degree of substitution, cross-linking and substitution position of the cross-linker might influence the properties of the hydrogels. We showed earlier that the most common substitution position of the cross-linker on the hyaluronan chain was the 4-hydroxyl of N-acetylglucosamine. This result has led us to investigate unsulfated chondroitin (CN) which only differ from HA in the primary structure by the configuration at C4 of the aminoglycan. In the present study, we have investigated (i) the substitution positions of the cross-linker in CN using NMR and LC-MS and compared the results to the data obtained for HA (ii) the effect of alkali on the 13C and 1H chemical shifts in CN and HA (iii) the temperature coefficients and chemical shifts of hydroxyl protons in CN and HA. In CN, the 2-hydroxyl of glucuronic acid and 6-hydroxyl of N-acetylgalactosamine were found to be the major sites of substitution by BDDE. Moreover, while chondroitinase was not able to cleave HA tetrasaccharide substituted at the 4-hydroxyl GlcNAc reducing end by BDDE, it is able to degrade CN-BDDE down to disaccharide units.


Assuntos
Butileno Glicóis/química , Condroitina/química , Ácido Hialurônico/química , Cromatografia Líquida , Reagentes para Ligações Cruzadas/química , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
8.
PLoS One ; 14(2): e0211999, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794553

RESUMO

OBJECTIVE: This pilot study assessed the efficacy of a knee guard device, which used magnetophoresis to transdermally deliver Glucosamine, Chondroitin and Hyaluronic Acid in a cohort of individuals with prior knee injury. The aim was to determine if the change in physical function and pain with the knee guard device was equivalent to the change produced by an established topical NSAID formulation containing diclofenac sodium 1%. METHODS: A randomized, controlled, equivalence trial evaluated outcomes following treatment with the knee guard device or NSAID formulation. The study recruited 114 male participants (aged 40-55 years). Participants were randomly allocated to wear the knee guard device or to use a NSAID gel daily for two weeks. The primary outcomes were the knee injury osteoarthritis function score (KOOS-F) and an aggregated function score (AFS). The lower extremity functional scale (LEFS), pain numerical rating scale (PNRS), global rating of change (GROC) and other KOOS scores were also evaluated. RESULTS: Multiple linear regression analyses indicated that there were no significant differences between the interventions for changes in the primary outcomes of AFS and KOOS_F. The 95% confidence interval (-2.89 to 5.15) of the estimated treatment difference for KOOS-F was within the lower (-5.61) and upper (5.61) bounds of the 7% equivalence margin for that measure, The mean value for the AFS was within, but the 95% CI (-3.11 to 7.37) exceeded the 7% equivalence margin (-2.97 to 2.97) for that measure. There was a significant difference in PNRS, which favored the knee guard device. CONCLUSION: The knee guard device demonstrated equivalence for the KOOS-F measure but not the AFS measure of function over the two week trial period when compared to a widely available NSAID gel that has been shown to be superior to placebo. The knee guard produced a greater reduction in pain report (p = 0.002) than the NSAID gel. Users of the knee guard device experienced more skin irritation than participants using the NSAID gel. Further research is required to fully evaluate the therapeutic potential of this innovative treatment approach.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Desenho de Equipamento/instrumentação , Traumatismos do Joelho/terapia , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Condroitina/administração & dosagem , Condroitina/uso terapêutico , Composição de Medicamentos , Glucosamina/administração & dosagem , Glucosamina/uso terapêutico , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/uso terapêutico , Fenômenos Magnéticos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Projetos Piloto , Resultado do Tratamento
10.
J Microbiol Biotechnol ; 29(3): 392-400, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691254

RESUMO

Chondroitin, the precursor of chondroitin sulfate, which is an important polysaccharide, has drawn significant attention due to its applications in many fields. In the present study, a heterologous biosynthesis pathway of chondroitin was designed in a GRAS (generally recognized as safe) strain C. glutamicum. CgkfoC and CgkfoA genes with host codon preference were synthesized and driven by promoter Ptac, which was confirmed as a strong promoter via GFPuv reporter assessment. In a lactate dehydrogenase (ldh) deficient host, intracellular chondroitin titer increased from 0.25 to 0.88 g/l compared with that in a wild-type host. Moreover, precursor enhancement via overexpressing precursor synthesizing gene ugdA further improved chondroitin titers to 1.09 g/l. Chondroitin production reached 1.91 g/l with the engineered strain C. glutamicum ΔL-CgCAU in a 5-L fed-batch fermentation with a single distribution Mw of 186 kDa. This work provides an alternative, safe and novel means of producing chondroitin for industrial applications.


Assuntos
Vias Biossintéticas , Condroitina/biossíntese , Condroitina/genética , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Engenharia Metabólica , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Técnicas de Cultura Celular por Lotes/métodos , Reatores Biológicos , Vias Biossintéticas/genética , Condroitina/análise , Corynebacterium glutamicum/crescimento & desenvolvimento , DNA Bacteriano , Fermentação , Regulação Bacteriana da Expressão Gênica , Técnicas de Inativação de Genes , Genes Bacterianos/genética , Glucose/metabolismo , Microbiologia Industrial , L-Lactato Desidrogenase/genética
11.
FASEB J ; 33(2): 2252-2262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30339470

RESUMO

Glycosaminoglycans such as chondroitin sulfate (CS) and dermatan sulfate (DS) are long chains of repeating disaccharide units, covalently linked to core proteins to form proteoglycans. Proteoglycans can be cell membrane-bound or are part of the extracellular matrix. They are important in a wide range of biologic processes, including development, synaptic plasticity, and regeneration after injury, as well as modulation of growth factor signaling, cell migration, survival, and proliferation. Synthesis of CS and DS in the Golgi apparatus is mediated by sulfotransferases that modify sugar chains through transfer of sulfate groups to specific positions on the sugar moieties. To clarify the functions of CS and DS during nervous system regeneration, we studied the effect of chondroitin 4- O-sulfotransferase-1/carbohydrate sulfotransferase-11 (C4ST-1/Chst-11) and dermatan 4- O-sulfotransferase-1/Chst-14 (D4ST-1/Chst-14) down-regulation on spinal cord regeneration in larval and adult zebrafish. In our study, knockdown of C4ST1/Chst-11 accelerated regeneration after spinal cord injury in larval and adult zebrafish and knockdown of D4ST1/Chst-14 did not alter regenerative capacity. From these and previous observations, we drew the conclusion that different CS and DS expression patterns can be growth permitting, growth inhibiting, or neutral for regrowing or sprouting axons, depending on the tissue environment of a particular animal species.-Sahu, S., Li, R., Loers, G., Schachner, M. Knockdown of chondroitin-4-sulfotransferase-1, but not of dermatan-4-sulfotransferase-1, accelerates regeneration of zebrafish after spinal cord injury.


Assuntos
Condroitina/metabolismo , Traumatismos da Medula Espinal/genética , Sulfotransferases/metabolismo , Animais , Técnicas de Silenciamento de Genes , Sulfotransferases/genética , Peixe-Zebra
12.
Clin Interv Aging ; 13: 2119-2126, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498336

RESUMO

Purpose: Osteoarthritis (OA) is an age-related disease caused by the wear and tear of the joints. Presently, there is no known cure for OA, but its management involves the use of high doses of pain killers and antiinflammatory agents with different side and dependency effects. Alternative management strategies involve the use of high doses of glucosamine-chondroitin (GC). This study was carried out to evaluate the efficacy of Q-Actin™, an aqueous extract of Cucumis sativus (cucumber; CSE) against GC in the management of moderate knee OA. Patients and methods: Overall, 122 patients (56 males and 66 females) aged between 40 and 75 years and diagnosed with moderate knee OA were included in this randomized double-blind, parallel-group clinical trial that took place in three different centers. The 180 day intervention involved two groups of 61 participants in each: the GC group, which received orally the generally prescribed dose of 1,350 mg of GC twice daily and the CSE group, which received orally10 mg twice daily of CSE. The Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), Visual Analog scale, and Lequesne's Functional Index were used to evaluate pain, stiffness, and physical function of knee OA in participants at baseline (Day 0) and on Days 30, 60, 90, 120, 150, and 180. Results: In the CSE group, the WOMAC score was decreased by 22.44% and 70.29% on Days 30 and 180, respectively, compared to a 14.80% and 32.81% decrease in the GC group. Similar trends were observed for all the other pain scores. No adverse effect was reported during the trial period. Conclusion: The use of 10 mg CSE, twice daily, was effective in reducing pain related to moderate knee OA and can be potentially used in the management of knee pain, stiffness, and physical functions related to OA.


Assuntos
Condroitina/uso terapêutico , Cucumis sativus/química , Glucosamina/uso terapêutico , Dor Musculoesquelética/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/etiologia , Osteoartrite do Joelho/complicações , Medição da Dor , Fitoterapia , Resultado do Tratamento , Escala Visual Analógica
14.
Nanomedicine (Lond) ; 13(16): 2015-2035, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30191764

RESUMO

AIM: The use of inhalable nanomedicines can overcome the Enhanced permeation and retention effect (EPR)-associated drawbacks in lung cancer therapy via systemic nanomedicines. METHODS: We developed a lactoferrin-chondroitin sulfate nanocomplex for the co-delivery of doxorubicin and ellagic acid nanocrystals to lung cancer cells. Then, the nanocomplex was converted into inhalable nanocomposites via spray drying. RESULTS: The resulting 192.3 nm nanocomplex exhibited a sequential faster release of ellagic acid, followed by doxorubicin. Furthermore, the nanocomplex demonstrated superior cytotoxicity and internalization into A549 lung cancer cells mediated via Tf and CD44 receptors. The inhalable nanocomposites exhibited deep lung deposition (89.58% fine particle fraction [FPF]) with powerful antitumor efficacy in lung cancer bearing mice. CONCLUSION: Overall, inhalable lactoferrin-chondroitin sulfate nanocomposites would be a promising carrier for targeted drug delivery to lung cancer.


Assuntos
Condroitina/química , Doxorrubicina/uso terapêutico , Ácido Elágico/uso terapêutico , Lactoferrina/química , Neoplasias Pulmonares/tratamento farmacológico , Nanocompostos/química , Nanopartículas/química , Células A549 , Animais , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Ácido Elágico/administração & dosagem , Ácido Elágico/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
15.
Curr Rheumatol Rep ; 20(11): 72, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30232562

RESUMO

PURPOSE OF REVIEW: Osteoarthritis, the most common joint disease, is associated with substantial medical costs, lost productivity, and reduced quality of life. However, available pharmaceutical treatments have limitations in terms of efficacy and long-term safety. RECENT FINDINGS: In vitro evidence suggests that some natural products may possess anti-inflammatory and anti-oxidative properties and may inhibit the release of key osteoarthritis-related cytokines. There is, therefore, ongoing interest in identifying natural products that safely promote joint health and treat osteoarthritis. Numerous plant extracts, including curcumin, Boswellia extract, and pycnogenol, have shown effect sizes (ES) for reducing pain and functional disability larger than those observed with analgesics and products such as glucosamine and chondroitin. The ES for methylsulfonylmethane and avocado/soybean unsaponifiables are also considered to be clinically relevant. Data from a small number of studies using natural products for treating osteoarthritis are promising but require confirmation in further well-designed clinical trials.


Assuntos
Produtos Biológicos/uso terapêutico , Osteoartrite/terapia , Fitoterapia/métodos , Anti-Inflamatórios não Esteroides/uso terapêutico , Boswellia , Condroitina/uso terapêutico , Curcumina/uso terapêutico , Suplementos Nutricionais , Dimetil Sulfóxido/uso terapêutico , Flavonoides/uso terapêutico , Glucosamina/uso terapêutico , Humanos , Manejo da Dor , Extratos Vegetais/uso terapêutico , Salix , Sulfonas/uso terapêutico
16.
J Orthop Surg Res ; 13(1): 170, 2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29980200

RESUMO

OBJECTIVE: To assess the symptomatic effectiveness and safety of oral symptomatic slow-acting drugs (SYSADOAs) on the treatment of knee and/or hip osteoarthritis, such as chondroitin, glucosamine, and combination treatment with chondroitin plus glucosamine. METHODS: We searched electronic database including PubMed, Embase, Cochrane Library, and the reference lists of relevant articles published from inception to May 22, 2018. An updated meta-analysis was performed to assess the effectiveness of these slow-acting drugs for osteoarthritis. RESULTS: Twenty-six articles describing 30 trials met our inclusion criteria and were included in the meta-analysis. The estimates between chondroitin and placebo showed that chondroitin could alleviate pain symptoms and improve function. Compared with placebo, glucosamine proved significant effect only on stiffness improvement. However, the combination therapy did not have enough evidence to be superior to placebo. Additionally, there was no significant difference in the incidence of AEs and discontinuations of AEs when compared with placebo. CONCLUSIONS: Given the effectiveness of these symptomatic slow-acting drugs, oral chondroitin is more effective than placebo on relieving pain and improving physical function. Glucosamine showed effect on stiffness outcome. Regarding on the limited number of combination therapy, further studies need to investigate the accurate effectiveness. This information accompanied with the tolerability and economic costs of included treatments would be conducive to making decisions for clinicians.


Assuntos
Condroitina/uso terapêutico , Glucosamina/uso terapêutico , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Quimioterapia Combinada , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
Regen Med ; 13(5): 519-530, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30039738

RESUMO

AIM: To evaluate different intratracheal flow rates on extracellular matrix content and lung mechanics in an established lung decellularization protocol. MATERIALS & METHODS: Healthy mice were used: 15 for decellularization and five to serve as controls. Fluids were instilled at 5, 10 and 20 ml/min flow rates through tracheal cannula and right ventricular cavity (0.5 ml/min) in all groups. RESULTS: The 20 ml/min rate better preserved collagen content in decellularized lungs. Elastic fiber content decreased at 5 and 10 ml/min, but not at 20 ml/min, compared with controls. Chondroitin, heparan and dermatan content was reduced after decellularization. CONCLUSION: An intratracheal flow rate of 20 ml/min was associated with lower resistance and greater preservation of collagen to that observed in ex vivo control lungs.


Assuntos
Condroitina/química , Dermatan Sulfato/química , Matriz Extracelular/química , Heparitina Sulfato/química , Pulmão/química , Animais , Feminino , Camundongos , Perfusão
18.
PLoS One ; 13(4): e0196572, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29708992

RESUMO

Age is a major risk factor for diseases caused by ischemic hypoxia, such as stroke and coronary artery disease. Endothelial progenitor cells (EPCs) are the major cells respond to ischemic hypoxia through angiogenesis and vascular remodeling. However, the effect of aging on EPCs and their responses to hypoxia are not well understood. CD34+ EPCs were isolated from healthy volunteers and aged by replicative senescence, which was to passage cells until their doubling time was twice as long as the original cells. Young and aged CD34+ EPCs were exposed to a hypoxic environment (1% oxygen for 48hrs) and their gene expression profiles were evaluated using gene expression array. Gene array results were confirmed using quantitative polymerase chain reaction, Western blotting, and BALB/c female athymic nude mice hindlimb ischemia model. We identified 115 differentially expressed genes in young CD34+ EPCs, 54 differentially expressed genes in aged CD34+ EPCs, and 25 common genes between normoxia and hypoxia groups. Among them, the expression of solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) increased the most by hypoxia in young cells. Gene set enrichment analysis indicated the pathways affected by aging and hypoxia most, including genes "response to oxygen levels" in young EPCs and genes involved "chondroitin sulfate metabolic process" in aged cells. Our study results indicate the key factors that contribute to the effects of aging on response to hypoxia in CD34+ EPCs. With the potential applications of EPCs in cardiovascular and other diseases, our study also provides insight on the impact of ex vivo expansion might have on EPCs.


Assuntos
Hipóxia Celular , Senescência Celular , Células Progenitoras Endoteliais/citologia , Perfilação da Expressão Gênica , Neovascularização Patológica , Adulto , Fatores Etários , Animais , Antígenos CD34/metabolismo , Técnicas de Cultura de Células , Condroitina/metabolismo , Feminino , Regulação da Expressão Gênica , Voluntários Saudáveis , Membro Posterior/irrigação sanguínea , Humanos , Isquemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Animais , Análise de Sequência com Séries de Oligonucleotídeos , Sulfitos/metabolismo , Fatores de Tempo , Remodelação Vascular , Adulto Jovem
19.
Metab Eng ; 47: 314-322, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29654832

RESUMO

Microbial production of chondroitin and chondroitin-like polysaccharides from renewable feedstock is a promising and sustainable alternative to extraction from animal tissues. In this study, we attempted to improve production of fructosylated chondroitin in Escherichia coli K4 by balancing intracellular levels of the precursors UDP-GalNAc and UDP-GlcA. To this end, we deleted pfkA to favor the production of Fru-6-P. Then, we identified rate-limiting enzymes in the synthesis of UDP-precursors. Third, UDP-GalNAc synthesis, UDP-GlcA synthesis, and chondroitin polymerization were combinatorially optimized by altering the expression of relevant enzymes. The ratio of intracellular UDP-GalNAc to UDP-GlcA increased from 0.17 in the wild-type strain to 1.05 in a 30-L fed-batch culture of the engineered strain. Titer and productivity of fructosylated chondroitin also increased to 8.43 g/L and 227.84 mg/L/h; the latter represented the highest productivity level achieved to date.


Assuntos
Condroitina/biossíntese , Escherichia coli , Frutosefosfatos , Açúcares de Uridina Difosfato , Condroitina/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Frutosefosfatos/genética , Frutosefosfatos/metabolismo , Deleção de Genes , Glicosilação , Humanos , Açúcares de Uridina Difosfato/genética , Açúcares de Uridina Difosfato/metabolismo
20.
Biopharm Drug Dispos ; 39(4): 205-217, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29488228

RESUMO

Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 µM, indicating very weak potential in inhibiting CYP2C9. In silico docking postulated no interaction with CYP2C9 for chondroitin and weak bonding for glucosamine. On the other hand, diacerein exhibited mixed-type inhibition with IC50 value of 32.23 µM and Ki value of 30.80 µM, indicating moderately weak inhibition. Diacerein's main metabolite, rhein, demonstrated the same mode of inhibition as diacerein but stronger potency, with IC50 of 6.08 µM and Ki of 1.16 µM. The docking of both compounds acquired lower CDOCKER interaction energy values, with interactions dominated by hydrogen and hydrophobic bondings. The ranking with respect to inhibition potency for the investigated compounds was generally the same in both in vitro enzyme assay and in silico modeling with order of potency being diacerein/rhein > various glucosamine/chondroitin forms. In vitro-in vivo extrapolation of inhibition kinetics (using 1 + [I]/Ki ratio) demonstrated negligible potential of diacerein to cause interaction in vivo, whereas rhein was predicted to cause in vivo interaction, suggesting potential interaction risk with the CYP2C9 drug substrates.


Assuntos
Anti-Inflamatórios/farmacologia , Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Antraquinonas/farmacologia , Artrite/tratamento farmacológico , Condroitina/farmacologia , Citocromo P-450 CYP2C9/química , Interações Medicamentosas , Glucosamina/farmacologia , Simulação de Acoplamento Molecular , Sulfafenazol/farmacologia , Valsartana/farmacologia
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