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1.
ACS Nano ; 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33691412

RESUMO

The development of highly efficient catalysts in the cathodes of rechargeable Li-O2 batteries is a considerable challenge. Polyelemental catalysts consisting of two or more kinds of hybridized catalysts are particularly interesting because the combination of the electrochemical properties of each catalyst component can significantly facilitate oxygen evolution and oxygen reduction reactions. Despite the recent advances that have been made in this field, the number of elements in the catalysts has been largely limited to two metals. In this study, we demonstrate the electrochemical behavior of Li-O2 batteries containing a wide range of catalytic element combinations. Fourteen different combinations with single, binary, ternary, and quaternary combinations of Pt, Pd, Au, and Ru were prepared on carbon nanofibers (CNFs) via a joule heating route. Importantly, the Li-O2 battery performance could be significantly improved when using a polyelemental catalyst with four elements. The cathode containing quaternary nanoparticles (Pt-Pd-Au-Ru) exhibited a reduced overpotential (0.45 V) and a high discharge capacity based on total cathode weight at 9130 mAh g-1, which was ∼3 times higher than that of the pristine CNF electrode. This superior electrochemical performance is be attributed to an increased catalytic activity associated with an enhanced O2 adsorbability by the quaternary nanoparticles.

2.
Life Sci ; 267: 118978, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33412209

RESUMO

AIMS: Vascular smooth muscle cell (VSMC) phenotype shift is involved in the pathophysiology of vascular injury or platelet-derived growth factor (PDGF)-induced abnormal proliferation and migration of VSMCs. We aimed to investigate the underlying mechanism involved in PDGF-mediated signaling pathways and autophagy regulation followed by VSMC phenotype shift. MAIN METHODS: The proliferation, migration and apoptosis of cultured rat aortic VSMCs were measured, and cells undergoing phenotype shift and autophagy were examined. Specific inhibitors for target proteins in signaling pathways were applied to clarify their roles in regulating cell functions. KEY FINDINGS: PDGF-BB stimulation initiated autophagy activation and synthetic phenotype transition by decreasing α-smooth muscle-actin (SMA), calponin and myosin heavy chain (MHC) and increasing osteopontin (OPN) expression. However, U0126, a potent extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, decreased PDGF-BB-induced LC3 expression, while rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), increased it. Furthermore, U0126 decreased the expresseion of autophagy-related genes (Atgs) such as beclin-1, Atg7, Atg5, and Atg12-Atg5 complex, indicating that Erk1/2 is a regulator of PDGF-BB-induced VSMC autophagy. Regardless of autophagy inhibition by U0126 or activation by rapamycin, the PDGF-BB-induced decrease in SMA, calponin and MHC and increase in OPN expression were inhibited. Furthermore, PDGF-BB-stimulated VSMC proliferation, migration and proliferating cell nuclear antigen (PCNA) expression were inhibited by U0126 and rapamycin. SIGNIFICANCE: These findings suggest that PDGF-BB-induced autophagy is strongly regulated by Erk1/2, an mTOR-independent pathway, and any approach for targeting autophagy modulation is a potential therapeutic strategy for addressing abnormal VSMC proliferation and migration.


Assuntos
Autofagia/fisiologia , Becaplermina/metabolismo , Músculo Liso Vascular/metabolismo , Animais , Becaplermina/genética , Becaplermina/farmacologia , Proteínas de Ligação ao Cálcio , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas dos Microfilamentos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos de Músculo Liso/metabolismo , Miosinas , Fenótipo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-sis/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
3.
Eur J Pharm Sci ; 158: 105689, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33359482

RESUMO

Sustained-release formulations are important tools to convert efficacious molecules into therapeutic products. Hydrogels enable the rapid assessment of sustained-release strategies, which are important during preclinical development where drug quantities are limited and fast turnaround times are the norm. Most research in hydrogel-based drug delivery has focused around synthesizing new materials and polymers, with limited focus on structural characterization, technology developability and implementation. Two commercially available thermosensitive hydrogel systems, comprised of block copolymers of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PLGA) and poly(lactide-co-caprolactone)-b-poly(ethyleneglycol)-b-poly(lactide-co-caprolactone) (PLCL), were evaluated during this study. The two block copolymers described in the study were successfully formulated to form hydrogels which delayed the release of lysozyme (> 20 days) in vitro. Characterization of formulation attributes of the hydrogels like Tsol-gel temperature, complex viscosity and injection force showed that these systems are amenable to rapid implementation in preclinical studies. Understanding the structure of the gel network is critical to determine the factors controlling the release of therapeutics out of these gels. The structures were characterized via the gel mesh sizes, which were estimated using two orthogonal techniques: small angle X-ray scattering (SAXS) and rheology. The mesh sizes of these hydrogels were larger than the hydrodynamic radius (size) of lysozyme (drug), indicating that release through these gels is expected to be diffusive at all time scales rather than sub-diffusive. In vitro drug release experiments confirm that diffusion is the dominating mechanism for lysozyme release; with no contribution from degradation, erosion, relaxation, swelling of the polymer network or drug-polymer interactions. PLGA hydrogel was found to have a much higher complex viscosity than PLCL hydrogel, which correlates with the slower diffusivity and release of lysozyme seen from the PLGA hydrogel as compared to PLCL hydrogel. This is due to the increased frictional drag experienced by the lysozyme molecule in the PLGA hydrogel network, as described by the hydrodynamic theory.

4.
Acta Pharmacol Sin ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973326

RESUMO

Propionate is a short-chain fatty acid (SCFA) mainly produced from carbohydrates by gut microbiota. Sodium propionate (SP) has shown to suppress the invasion in G protein-coupled receptor 41 (GPR41) and GPR43-overexpressing breast cancer cells. In this study we investigated the effects of SP on the proliferation, apoptosis, autophagy, and antioxidant production of breast cancer cells. We showed that SP (5-20 mM) dose-dependently inhibited proliferation and induced apoptosis in breast cancer cell lines JIMT-1 (ER-negative and HER2-expressing) and MCF7 (ER-positive type), and this effect was not affected by PTX, thus not mediated by the GPR41 or GPR43 SCFA receptors. Meanwhile, we demonstrated that SP treatment increased autophagic and antioxidant activity in JIMT-1 and MCF7 breast cancer cells, which might be a compensatory mechanism to overcome SP-induced apoptosis, but were not sufficient to overcome SP-mediated suppression of proliferation and induction of apoptosis. We revealed that the anticancer effect of SP was mediated by inhibiting JAK2/STAT3 signaling which led to cell-cycle arrest at G0/G1 phase, and increasing levels of ROS and phosphorylation of p38 MAPK which induced apoptosis. In nude mice bearing JIMT-1 and MCF7 cells xenograft, administration of SP (20 mg/mL in drinking water) significantly suppressed tumor growth by regulating STAT3 and p38 in tumor tissues. These results suggest that SP suppresses proliferation and induces apoptosis in breast cancer cells by inhibiting STAT3, increasing the ROS level and activating p38. Therefore, SP is a candidate therapeutic agent for breast cancer.

5.
Bioorg Med Chem Lett ; 30(19): 127466, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763309

RESUMO

RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.

6.
J Orthop Surg (Hong Kong) ; 28(2): 2309499020936848, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32638635

RESUMO

Many studies have shown that surgical management still leads to the best outcomes in elderly patients with hip fractures, with some studies showing non-inferiority of nonsurgical management as compared to surgery in fragility fractures. Evidence-based guidelines on whether to operate on these patients are lacking. A systematic literature search was conducted regarding outcomes of nonoperatively treated hip fractures in elderly patients with various comorbidities. A structured literature review of multiple databases (PubMed, Web of Science, EMBASE, and Cochrane library) referenced articles from 2000 to 2020. A total of 596 patients from 11 published studies were identified. Mean age was 83.3 years. Overall 328 (69.7%) complications occurred in 470 patients with nonsurgical treatment. Pneumonia and urinary tract infections were the most common complications which occurred in 53 (16.1%) and 46 (14.0%) patients, respectively. Hip fracture patients who were treated nonoperatively had a higher in-hospital (17.1% vs. 4.4%; p < 0.001), 30-day (31.4% vs. 10.2%; p < 0.001), and 1-year (48.5% vs. 19.9%; p < 0.001) mortality compared to a matched group of operatively treated patients (n = 1464). Of the 110 patients whose reported cause of death was nonoperative care, 44 (40%) was due to pneumonia. Patients with nonoperative treatment following hip fracture were associated with substantially higher complication and mortality compared with patients who were treated operatively. Our study will help health-care providers and caregivers to enable more informed decision-making for families and patients confronted with a hip fracture.

7.
ACS Appl Mater Interfaces ; 12(29): 32633-32641, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32584023

RESUMO

The rechargeable Li-CO2 battery has attracted considerable attention in recent years because of its carbon dioxide (CO2) utilization and because it represents a practical Li-air battery. As with other battery systems such as the Li-ion, Li-O2, and Li-S battery systems, understanding the reaction pathway is the first step to achieving high battery performance because the performance is strongly affected by reaction intermediates. Despite intensive efforts in this area, the effect of material parameters (e.g., the electrolyte, the cathode, and the catalyst) on the reaction pathway in Li-CO2 batteries is not yet fully understood. Here, we show for the first time that the discharge reaction pathway of a Li-CO2 battery composed of graphene nanoplatelets/beta phase of molybdenum carbide (GNPs/ß-Mo2C) is strongly influenced by the dielectric constant of its electrolyte. Calculations using the continuum solvents model show that the energy of adsorption of oxalate (C2O42-) onto Mo2C under the low-dielectric electrolyte tetraethylene glycol dimethyl ether is lower than that under the high-dielectric electrolyte N,N-dimethylacetamide (DMA), indicating that the electrolyte plays a critical role in determining the reaction pathway. The experimental results show that under the high-dielectric DMA electrolyte, the formation of lithium carbonate (Li2CO3) as a discharge product is favorable because of the instability of the oxalate species, confirming that the dielectric properties of the electrolyte play an important role in the formation of the discharge product. The resulting Li-CO2 battery exhibits improved battery performance, including a reduced overpotential and a remarkable discharge capacity as high as 14,000 mA h g-1 because of its lower internal resistance. We believe that this work provides insights for the design of Li-CO2 batteries with enhanced performance for practical Li-air battery applications.

8.
Injury ; 51(8): 1744-1750, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32487330

RESUMO

BACKGROUND: Femoral nerve palsy caused by iliacus hematoma is an infrequent diagnosis often missed because of its insidious presentation. However, due to potentially devastating outcomes, prompt recognition and management are essential. OBJECTIVES: The aim with this study was to better characterize clinical presentation, diagnosis, treatment, and prognosis of iliacus hematoma. METHODS: We performed a systematic review of recent literature regarding femoral neuropathy secondary to an iliacus hematoma. A structured literature review of multiple databases ((PubMed, Web of Science, EMBASE, and Cochrane library) referenced articles from 2000 to 2019. RESULTS: A total of 25 patients from 25 published studies were identified. The average age of the patients was forty years (range, 12 to 85 years). There were 16 male patients and 9 female patients. The single most important predisposing cause of iliacus hematoma was trauma (14/25), with a pooled percentage of 56%. All patients with spontaneous hematoma were taking antiplatelet medications. Thirteen patients (52%) were treated conservatively with analgesia. Surgical decompression was performed in 10 patients (40%). At the final follow-up, complete resolution of symptoms was achieved in 12 patients (48%). CONCLUSIONS: Although rare, iliacus hematoma syndrome carries significant morbidity. Spontaneous iliacus muscle hematoma should be considered in the differential diagnosis of leg pain in a patient who is on anticoagulation therapy. In patients with an iliacus hematoma and neurology deficit, conservative treatment can be considered initially if there is no progression in the symptoms evident at the time of presentation. However, prompt surgical decompression has been highly recommended in patients with progressive neurological deficits.

9.
Acta Orthop Traumatol Turc ; 54(3): 337-343, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32442123

RESUMO

OBJECTIVE: Internal fixation with cannulated screws for nondisplaced femoral neck fractures in the elderly has substantial reoperation and mortality rates. The selection of either internal fixation or arthroplasty for nondisplaced femoral neck fracture is debatable. METHODS: We performed a systematic review of the literature regarding complications in the internal fixation of nondisplaced femoral neck fractures in elderly (>60 years old) patients. We searched in multiple databases (PubMed, Web of Science, Embase, and Cochrane Library) for articles in this area; there was no limitation over the publication year. RESULTS: A total of 1971 patients were identified from 16 published studies. All these patients were over 60 years old. The minimum follow-up after the surgical procedure was 11 months (range: 11-183 months). A total of 329 fractures (16.7%) with radiographic and clinical failures after fixation were identified with regard to stable femoral neck fractures. The single most common complication after surgery was nonunion (129/329), with a pooled percentage of 39.2%. Osteonecrosis was found to be the second most common cause of revision surgery (31.9%). The overall reoperation rate attributable to surgical complications was 15.2% (300/1971 patients). Conversion to hip arthroplasty was performed in 244 patients (12.4%) after primary fixation. CONCLUSION: Our study elucidated further the complication rate of nondisplaced femoral neck fractures treated with internal screw fixation. Since the failure rate of screw fixation for stable femoral neck fractures in elderly patients is not low, we believe that hemiarthroplasty is a reasonable treatment option in select patients. LEVEL OF EVIDENCE: Level III, Therapeutic study.


Assuntos
Fraturas do Colo Femoral/cirurgia , Fixação Interna de Fraturas , Hemiartroplastia , Complicações Pós-Operatórias , Idoso , Parafusos Ósseos , Pesquisa Comparativa da Efetividade , Fixação Interna de Fraturas/efeitos adversos , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/métodos , Hemiartroplastia/efeitos adversos , Hemiartroplastia/métodos , Humanos , Seleção de Pacientes , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle
10.
J Korean Med Sci ; 35(7): e26, 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32080985

RESUMO

BACKGROUND: We aimed to investigate whether various immune-related plasma proteins, alone or in combination with conventional clinical risk factors, can predict spontaneous preterm delivery (SPTD) and intra-amniotic infection in women with premature cervical dilation or a short cervix (≤ 25 mm). METHODS: This retrospective study included 80 asymptomatic women with premature cervical dilation (n = 50) or a short cervix (n = 30), who underwent amniocentesis at 17-29 weeks. Amniotic fluid (AF) was cultured, and maternal plasma was assayed for interleukin (IL)-6, matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinases (TIMP)-1, and complements C3a and C5a, using enzyme-linked immunosorbent assay (ELISA) kits. The primary outcome measures were SPTD at < 32 weeks and positive AF cultures. RESULTS: The plasma levels of IL-6, C3a, and C5a, but not of MMP-9 and TIMP-1, were significantly higher in women with SPTD at < 32 weeks than in those who delivered at ≥ 32 weeks. The women who delivered at < 32 weeks had more advanced cervical dilatation, and higher rates of antibiotic and tocolytic administration and were less likely to be given vaginal progesterone than those who delivered at ≥ 32 weeks. Using a stepwise regression analysis, a combined prediction model was developed, which included the plasma IL-6 and C3a levels, and cervical dilatation (area under the curve [AUC], 0.901). The AUC for this model was significantly greater than that for any single variable included in the predictive model. In the univariate analysis, plasma IL-6 level was the only significant predictor of intra-amniotic infection. CONCLUSION: In women with premature cervical dilation or a short cervix, maternal plasma IL-6, C3a, and C5a levels could be useful non-invasive predictors of SPTD at < 32 weeks. A combination of these biomarkers and conventional clinical factors may clearly improve the predictability for SPTD, as compared with the biomarkers alone. An increased plasma level of IL-6 predicted intra-amniotic infection.


Assuntos
Biomarcadores , Complemento C3a , Interleucina-6 , Primeira Fase do Trabalho de Parto , Complicações Infecciosas na Gravidez , Nascimento Prematuro , Inibidor Tecidual de Metaloproteinase-1 , Adulto , Amniocentese , Biomarcadores/sangue , Colo do Útero , Complemento C3a/análise , Complemento C5a/análise , Feminino , Humanos , Interleucina-6/sangue , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/imunologia , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/imunologia , Estudos Retrospectivos , Inibidor Tecidual de Metaloproteinase-1/sangue
11.
Solid State Nucl Magn Reson ; 106: 101642, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035327

RESUMO

Characterization of lipid based (SPC/GDO/H2O) liquid crystal (LC) drug delivery system is non-trivial and highly complex, especially when multiple and intermediate phases are present. The phase behavior of such mixtures during hydration or delivery is still poorly understood and therefore, characterizing these systems is crucially important towards controlling their function and enhancing the understanding of their drug release behavior. Current work has established an easy way to identify liquid crystal phases and phase mixtures using deuterium (2H) solid-state nuclear magnetic (NMR) spectroscopy under static conditions without disrupting the three dimensional structure and phases, as magic-angle spinning (MAS) could lead to disruption of the phases. Small angle X-ray scattering (SAXS) technique and optical microscopy were also employed to corroborate the study.

12.
Nanomaterials (Basel) ; 9(10)2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31569757

RESUMO

Graphene powders obtained via the reduction of graphene oxide flakes have been widely used in various applications as they can be synthesized in large quantities with outstanding properties. The electrical conductivity of graphene powders is critical for their uses in fabricating high-performance devices or materials. Here, we investigated the bulk electrical conductivity of reduced graphene oxide (rGO) powders depending on the applied pressure and additional thermal annealing. The electrical conductivity of the rGO powders was correlated with the change in the carbon-to-oxygen ratio via additional thermal reduction. Furthermore, the effect of the morphology of the rGO powders was studied through electromechanical measurements. This study provides a reliable method for the electromechanical characterization of rGO powders and a better understanding of the electrical conductivity of graphene-based materials.

13.
Org Lett ; 21(22): 9198-9202, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31647672

RESUMO

This communication highlights the use of chiral sulfinamides as nitrogen nucleophiles in intermolecular aza-Michael reactions. When chiral sulfinamides are coupled to a chloroethyl group, the corresponding novel annulating reagents can be used to streamline the stereoselective synthesis of complex pyrrolidine-containing molecules. As a result, it has enabled a medicinal chemistry campaign for the synthesis of biologically active RORγt inverse agonists.

14.
Nat Commun ; 10(1): 3620, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399593

RESUMO

Composite metal-organic frameworks (MOFs) tend to possess complex interfaces that prevent facile and rational design. Here we present a joint computational/experimental workflow that screens thousands of MOFs and identifies the optimal MOF pairs that can seamlessly connect to one another by taking advantage of the fact that the metal nodes of one MOF can form coordination bonds with the linkers of the second MOF. Six MOF pairs (HKUST-1@MOF-5, HKUST-1@IRMOF-18, UiO-67@HKUST-1, PCN-68@MOF-5, UiO-66@MIL-88B(Fe) and UiO-67@MIL-88C(Fe)) yielded from our theoretical predictions were successfully synthesized, leading to clean single crystalline MOF@MOF, demonstrating the power of our joint workflow. Our work can serve as a starting point to accelerate the discovery of novel MOF composites that can potentially be used for many different applications.

15.
Injury ; 50(7): 1364-1370, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31182230

RESUMO

BACKGROUND: There has been heightened interest in the effect of osteoanabolic agents on acceleration of fracture healing. OBJECTIVES: The purpose of this study was to identify whether short-term daily teriparatide prescribed for osteoporosis treatment would improve postoperative outcomes including clinical scores, radiographic healing, and complication rates. METHODS: Between 2014 and 2017, we retrospectively assessed 112 patients who underwent closed reduction and internal fixation with proximal femoral nail (PFN) for unstable intertrochanteric fractures. In 60 of 112 patients, patients were treated with a PFN alone (group I). These patients were compared with 52 patients for whom the same device was used and a daily subcutaneous injection of teriparatide (1-34 PTH, Forsteo®) was prescribed postoperatively (group II). Teriparatide was administered by nurses during a hospital stay and then self-injection was monitored by follow-up visits to the outpatient clinic after discharge. Questionnaire surveys were conducted and patients completed a self-report Harris hip score (HHS) and visual analog scale (VAS) scores. RESULTS: Teriparatide therapy significantly increased HHS (p = 0.02) and decreased VAS pain scores (p = 0.008). The mean time to fracture healing post-operatively was 14.8 weeks (SD 7.1) and 12.1 weeks (SD 6.4) in group I and II, respectively (p = 0.002). The frequency of patients reporting postoperative complications was also markedly reduced in the teriparatide-treated groups (p = 0.028). CONCLUSIONS: Short-term daily teriparatide used for osteoporosis treatment improved radiographic fracture healing of a hip fracture and reduced complication rates. However, because of the limited power of the study, additional randomized placebo-controlled trials are needed to determine the potential benefit of PTH as an adjunct to enhance fracture healing and its efficacy in broader populations with varying comorbidities and fracture types.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Consolidação da Fratura/efeitos dos fármacos , Fraturas do Quadril/fisiopatologia , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/fisiopatologia , Teriparatida/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Fixação Interna de Fraturas , Fraturas do Quadril/tratamento farmacológico , Fraturas do Quadril/cirurgia , Humanos , Masculino , Osteoporose/fisiopatologia , Fraturas por Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/cirurgia , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento
16.
J Ethnopharmacol ; 239: 111912, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31029758

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Acer tegmentosum Maxim (AT), the East Asian stripe maple, is an herb used to treat liver disease and is approved as a functional food in Korea. AT protects against hepatic disorders, atopic dermatitis, and diabetes mellitus. AIM OF THE STUDY: We explored the mechanism of the hepatoprotective effects of AT extract in in vitro and in vivo levels. MATERIALS AND METHODS: AT extract from Acer tegmentosum Maxim was extracted by hot water. Hepatoprotective effects of AT extract were confirmed using carbon tetrachloride (CCl4)- or alcohol-induced mouse model, and H2O2- or alcohol-induced HepG2 (liver hepatocellular carcinoma cell line) cells by measuring GOT, GPT, TG, and MDA levels. Hematoxylin and eosin (H&E) staining was used to observe the pathological analysis. Cytotoxicity or protective effect of AT extract was confirmed using MTT assay in HepG2 cells. Antioxidant effect of AT extract was measured using DPPH or H2DCFDA assay. Mechanism study of antioxidant and autophagy was carried out using western blotting and immunofluorescence analysis. RESULTS: AT extract increased the viability of HepG2 cells treated with H2O2 and ethanol, and protected the liver against damage induced by CCl4 and alcohol. The AT extract increased the levels of nuclear respiratory factor 2 (Nrf2) and heme oxygenase-1 (HO-1). The level of microtubule-associated protein light chain 3 (LC3)-Ⅱ, beclin-1, autophagy-related genes (Atg) such as Atg3 and Atg12-5 as markers of autophagy activation was also increased. Moreover, the AT extract increased activation of mitogen-activated protein kinase (MAPK), which regulated autophagy and HO-1. CONCLUSION: Therefore, these results indicate that the AT extract has a hepatoprotective effect by increasing antioxidant activity and inducing autophagy.


Assuntos
Acer , Antioxidantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Tetracloreto de Carbono , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Extratos Vegetais/farmacologia , Caules de Planta , Espécies Reativas de Oxigênio/metabolismo
17.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891145

RESUMO

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

18.
BMC Complement Altern Med ; 19(1): 55, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30841887

RESUMO

BACKGROUND: Mulberry is a Korean medicinal herb that shows effective prevention and treatment of obesity and diabetes. Bioconversion is the process of producing active ingredients from natural products using microorganisms or enzymes. METHODS: In this study, we prepared bioconverted mulberry leaf extract (BMLE) with Viscozyme L, which we tested in insulin-sensitive cells (i.e., skeletal muscle cells and adipocytes) and insulin-secreting pancreatic ß-cells, as well as obese diabetic mice induced by co-administration of streptozotocin (100 mg/kg, IP) and nicotinamide (240 mg/kg, IP) and feeding high-fat diet, as compared to unaltered mulberry leaf extract (MLE). RESULTS: BMLE increased the glucose uptake in C2C12 myotubes and 3 T3-L1 adipocytes and increased glucose-stimulated insulin secretion in HIT-T15 pancreatic ß-cells. The fasting blood glucose levels in diabetic mice treated with BMLE or MLE (300 and 600 mg/kg, PO, 7 weeks) were significantly lower than those of the vehicle-treated group. At the same concentration, BMLE-treated mice showed better glucose tolerance than MLE-treated mice. Moreover, the blood concentration of glycated hemoglobin (HbA1C) in mice treated with BMLE was lower than that in the MLE group at the same concentration. Plasma insulin levels in mice treated with BMLE or MLE tended to increase compared to the vehicle-treated group. Treatment with BMLE yielded significant improvements in insulin resistance and insulin sensitivity. CONCLUSION: These results indicate that in the management of diabetic condition, BMLE is superior to unaltered MLE due to at least, in part, high concentrations of maker compounds (trans-caffeic acid and syringaldehyde) in BMLE.


Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Morus/química , Extratos Vegetais/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Hipoglicemiantes/metabolismo , Resistência à Insulina/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/metabolismo , Folhas de Planta/química
19.
AAPS PharmSciTech ; 19(8): 3462-3480, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30411240

RESUMO

The impact of pharmaceutical materials properties on drug product quality and manufacturability is well recognised by the industry. An ongoing effort across industry and academia, the Manufacturing Classification System consortium, aims to gather the existing body of knowledge in a common framework to provide guidance on selection of appropriate manufacturing technologies for a given drug and/or guide optimization of the physical properties of the drug to facilitate manufacturing requirements for a given processing route. Simultaneously, material scientists endeavour to develop characterisation methods such as size, shape, surface area, density, flow and compactibility that enable a stronger understanding of materials powder properties. These properties are routinely tested drug product development and advances in instrumentation and computing power have enabled novel characterisation methods which generate larger, more complex data sets leading to a better understanding of the materials. These methods have specific requirements in terms of data management and analysis. An appropriate data management strategy eliminates time-consuming data collation steps and enables access to data collected for multiple methods and materials simultaneously. Methods ideally suited to extract information from large, complex data sets such as multivariate projection methods allow simpler representation of the variability contained within the data and easier interpretation of the key information it contains. In this review, an overview of the current knowledge and challenges introduced by modern pharmaceutical material characterisation methods is provided. Two case studies illustrate how the incorporation of multivariate analysis into the material sciences workflow facilitates a better understanding of materials.


Assuntos
Indústria Farmacêutica , Tecnologia Farmacêutica , Desenvolvimento de Medicamentos , Pós
20.
J Orthop Surg (Hong Kong) ; 26(3): 2309499018802485, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30296889

RESUMO

Slow recovery after hip fracture has been associated with negative consequences. Thus, there is medical need to improve healing and functional recovery after intertrochanteric fracture. The aim of this study was to measure whether short-term teriparatide would improve healing in intertrochanteric fractures after internal fixation as measured by (1) clinical scores, (2) radiographic fracture healing, and (3) complication rates. We retrospectively reviewed 96 patients (average age, 82 years) who underwent closed reduction and internal fixation with proximal femoral nail (PFN) for unstable intertrochanteric fractures between 2014 and 2016. Of the 96 patients, 56 patients were treated with a PFN alone (group 1). These patients were compared with 46 patients for whom the same device was used and a weekly subcutaneous injection of PTH 1-34 (teriparatide) was prescribed postoperatively (group 2). Questionnaire surveys or telephone interviews were conducted, and patients completed a self-report Harris hip score and visual analog scale scores. The radiological time to fracture healing was assessed as the primary end point. Postoperative complication rates were compared. Functional outcomes at 6 months after surgery were similar in both groups. There were no differences between groups in the proportion of patients achieving radiographic fracture healing. The frequency of patients reporting adverse events was 20% (10 of 50) in group 1 versus 17% (8 of 46) in group 2 ( p = 0.744). Short-term teriparatide did not improve radiographic signs of fracture healing of an intertrochanteric fracture and reduce the incidence of complications. The effect of teriparatide on fracture healing remains uncertain. Further multicenter prospective studies are needed to demonstrate objective long-term results of parathyroid hormone therapy in patient with hip fracture. LEVEL OF EVIDENCE: Level IV, therapeutic study.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Fixação Interna de Fraturas , Consolidação da Fratura/efeitos dos fármacos , Fraturas do Quadril/cirurgia , Teriparatida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
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