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BACKGROUND: Pigmented prurigo (PP) is a chronic and recurrent inflammatory skin disease. PP is not common clinically, but it is easily misdiagnosed because of its diversified clinical manifestations in different stages. MATERIALS AND METHODS: We retrospectively analyzed the clinical, histopathological, dermoscopy, and reflectance confocal microscopy (RCM) features of 20 patients diagnosed as PP. RESULTS: The female predominance ratio was revealed with male to female of 1:4. Seven female patients were on a diet (without staple food) and one patient had a history of diabetes. Eight cases were suffered in spring, six cases in winter, three cases in summer, and three cases in autumn. Multiple sites were involved in 13 cases. Four patients had urticarial papules and plaques. Nineteen patients had erythematous papules with reticular distribution, of which 14 cases accompanied reticulate hyperpigmentation, four cases with papulovesicle, and two cases accompanied with pustules. One patient only showed reticulate hyperpigmentation. In the early lesions, dermatoscopy showed pink oval lesions, punctate or linear vessels, and pale yellow rings around the skin lesions. RCM is characterized by spongiosis, spongy vesicle, neutrophils scattered in the epidermis, which was consistent with epidermis spongiosis, neutrophils infiltrating into the upper epidermis and necrotic keratinocytes in histopathology. In the fully developed lesions, dermatoscopy showed pink lesions with brown pigment granules in the center and linear vessels in the edge. RCM showed that demarcation of epidermis and dermis is not clear, and inflammatory cells can be seen in the upper dermis and histopathologically lesions assumed a patchy lichenoid pattern, and the inflammatory cells infiltrating the dermis were dominated by lymphocytes. In the late lesions, dermatoscopy showed grainy grayish-brown or yellowish-brown pigmentation surrounding the hair follicle merging with each other. RCM showed that pigment granules were increased on the ring of basal cells, inflammatory cells were sparsely infiltrated in the dermal papilla and superficial layer, and epidermis slightly hyperplastic, with melanophages and a few lymphocytes infiltrating the superficial dermis in histopathology. CONCLUSION: PP is easily misdiagnosed and not always occurs in those on a restrictive diet. A combination of dermatoscopy and RCM is helpful for its diagnosis of PP.
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Hiperpigmentación , Prurigo , Neoplasias Cutáneas , Humanos , Masculino , Femenino , Prurigo/diagnóstico por imagen , Dermoscopía/métodos , Estudios Retrospectivos , Microscopía Confocal/métodos , Hiperpigmentación/diagnóstico por imagen , Neoplasias Cutáneas/patologíaRESUMEN
Purpose: Developing the ideal drug or dressing is a serious challenge to controlling the occurrence of antibacterial infection during wound healing. Thus, it is important to prepare novel nanofibers for a wound dressing that can control bacterial infections. In our study, the novel self-assembled nanofibers of benzalkonium bromide with bioactive peptide materials of IKVAV and RGD were designed and fabricated. Methods: Different drug concentration effects of encapsulation efficacy, swelling ratio and strength were determined. Its release profile in simulated wound fluid and its cytotoxicity were studied in vitro. Importantly, the antibacterial efficacy, inhibition of biofilm formation effect and wound healing against MRSA infections in vitro and in vivo were performed after observing the tissue toxicity in vivo. Results: It was found that the optimized drug load (0.8%) was affected by the encapsulation efficacy, swelling ratio, and strength. In addition, the novel nanofibers with average diameter (222.0 nm) and stabile zeta potential (-11.2 mV) have good morphology and characteristics. It has a delayed released profile in the simulated wound fluid and good biocompatibility with L929 cells and most tissues. Importantly, the nanofibers were shown to improve antibacterial efficacy, inhibit biofilm formation, and lead to accelerated wound healing following infection with methicillin-resistant Staphylococcus aureus. Conclusion: These data suggest that novel nanofibers could effectively shorten the wound-healing time by inhibiting biofilm formation, which make it promising candidates for treatment of MRSA-induced wound infections.
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Staphylococcus aureus Resistente a Meticilina , Nanofibras , Enfermedades Cutáneas Infecciosas , Infección de Heridas , Antibacterianos/farmacología , Compuestos de Benzalconio/farmacología , Bromuros/farmacología , Humanos , Oligopéptidos/farmacología , Cicatrización de Heridas , Infección de Heridas/microbiologíaRESUMEN
BACKGROUND: A large number of pneumonia cases due to coronavirus disease 2019 (COVID-19) have been first reported in China. Meanwhile, the virus is sweeping all around the world and has infected millions of people. Fever and pulmonary symptoms have been noticed as major and early signs of infection, whereas gastrointestinal symptoms were also observed in a significant portion of patients. The clinical investigation of disease onset was underestimated, especially due to the neglection of cases presenting with gastrointestinal symptoms. AIM: To characterize the clinical features of coronavirus-infected patients with gastrointestinal symptoms as initial symptoms. METHODS: This is a retrospective, single-center case series of the general consecutive hospitalized patients with confirmed COVID-19 at Wuhan Union Hospital from February 2, 2020 to February 13, 2020. According to their initial symptoms, these patients were classified into two groups. Patients in group one presented with pulmonary symptoms (PS) as initial symptoms, and group two presented with gastrointestinal symptoms (GS). Epidemiological, demographic, clinical, laboratory, and treatment data were collected for analysis. RESULTS: Among the 50 patients recruited, no patient has been admitted to intensive care units, and no patient died during the study. The duration of hospitalization was longer in the GS group than in the PS group (12.13 ± 2.44 vs 10.00 ± 2.13, P < 0.01). All of the 50 patients exhibited decreased lymphocytes. However, lymphocytes in the GS group were significantly lower compared to those in the PS group (0.94 ± 0.06 vs 1.04 ± 0.15, P < 0.01). Procalcitonin and hs-CRP were both significantly higher in the GS group than in the PS group. Accordingly, the duration of viral shedding was significantly longer in the GS group compared to the PS group (10.22 ± 1.93 vs 8.15 ± 1.87, P < 0.01). CONCLUSION: COVID-19 patients presenting with gastrointestinal symptoms as initial symptoms need more days of viral shedding and hospitalization than the patients presenting with pulmonary symptoms.
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AIM: To investigate the effects of hydroxychloroquine, sulfasalazine and methotrexate on ischemic stroke in patients with rheumatoid arthritis (RA). METHODS: This population-based retrospective cohort study included 7904 RA patients and 15 808 non-RA patients between 2000 and 2010. All of the participants were sampled from the National Health Insurance Research Database (NHIRD) of Taiwan. Using univariate analyses, these two groups of patients were compared to evaluate the differences in disease-modifying anti-rheumatic drugs usage and demographic variables. Cox proportional hazard models and Schoenfeld residuals test were performed to estimate the hazard ratios for ischemic stroke and proportional hazard assumptions of these drugs, respectively. RESULTS: The mean age of participants was about 53 years old, and about 70% of RA patients were women. The hazard ratio for ischemic stroke was 1.21 (95% CI: 1.10-1.34; P < 0.01) in the case group compared with the control group, and this significant difference persisted throughout the 10-year period. With respect to RA patients, while hydroxychloroquine showed an insignificant protective effect on ischemic stroke, sulfasalazine and methotrexate were found out to have inconsistent effects during these 10 years. The proportional hazard assumption test of methotrexate at > 0.5 defined daily dose (8.75 mg/week) was violated at a significant level after adjustment (P = 0.0002). CONCLUSIONS: At a dosage of > 0.5 defined daily dose, short-term methotrexate might decrease ischemic stroke risk in RA patients, while hydroxychloroquine and sulfasalazine were neutral.
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/administración & dosificación , Accidente Cerebrovascular/prevención & control , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiología , Bases de Datos Factuales , Femenino , Humanos , Hidroxicloroquina/administración & dosificación , Incidencia , Masculino , Persona de Mediana Edad , Factores Protectores , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Sulfasalazina/administración & dosificación , Taiwán/epidemiología , Resultado del TratamientoRESUMEN
BACKGROUND: One- and two-level lumbar interbody fusion with unilateral instrumentation is as effective as that with bilateral instrumentation. The height of the interbody cage influences the operated segment stability and the fusion technique success. The purpose of this research was to determine the effect of the fusion cage height (i.e. long and short) on both the stability (based on flexibility measures) and load sharing of the unilateral and bilateral instrumented transforaminal lumbar interbody fusion (TLIF) technique. METHODS: The flexibility and load sharing tests were performed on seven human lumbar spines. Different configurations combining a long or short cage with a unilateral, bilateral, or no posterior fixation were used to stabilize the operated segment. Two sets of modular cages were designed for each type of test to simulate the long and short cages. During the flexibility test, a pure-moment load of 7.5 Nm was applied. The range of motion (ROM) was recorded for flexion-extension, lateral bending, and axial rotation. During the load sharing test, an axial-compression load of 400 N was applied. The load bearing of the cages was recorded using a cage-embedded load cell. RESULTS: When the fusion cage height decreased 2 mm, the segment flexibility with unilateral fixation showed a significant increase in the ROM for flexion-extension, lateral bending, and axial rotation of 74.9, 83.8, and 175.2% (P < 0.01), respectively. In contrast, for bilateral fixation, the height decrease resulted in no significant change in ROM for flexion-extension (P = 0.686), lateral bending (P = 0.698), and axial rotation (P = 0.133). Using a short fusion cage, the load bearing decreased in 17.1, 21.5, and 54.1% (P < 0.05) for the cage alone, unilateral, and bilateral fixation, respectively. CONCLUSIONS: A cage longer than the intervertebral space should be chosen to increase the stability and intervertebral graft load borne when performing TLIF with unilateral instrumentation.
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Degeneración del Disco Intervertebral/cirugía , Vértebras Lumbares/fisiología , Tornillos Pediculares , Prótesis e Implantes , Fusión Vertebral/instrumentación , Anciano , Fenómenos Biomecánicos , Cadáver , Femenino , Humanos , Degeneración del Disco Intervertebral/diagnóstico por imagen , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Masculino , Persona de Mediana Edad , Diseño de Prótesis , Radiografía , Rango del Movimiento Articular , Fusión Vertebral/métodos , Soporte de Peso/fisiologíaRESUMEN
AIM: To assess the effects of celecoxib and sulfasalazine on cardiovascular risk in patients with ankylosing spondylitis (AS). METHODS: We performed a 10-year population-based retrospective cohort study. A total of 1208 AS patients and 19 328 non-AS patients were sampled from the Taiwan National Health Insurance (NHI) database. We compared these two groups of patients to identify the differences in the exposure of non-steroidal anti-inflammatory drugs and sulfasalazine and their effects on cardiovascular risk. Univariate analyses were performed using Chi-squared tests for dichotomous variables and t-tests for continuous variables. Cox proportional hazard models were conducted to investigate the risk of developing cardiovascular diseases (CVD). RESULTS: AS patients had an adjusted hazard ratio (HR) of 1.72 (CI = 1.46-2.02, P < 0.01) for CVD compared with non-AS controls. The risk increased significantly with the progression of the disease. The use of celecoxib and sulfasalazine provided protective effects against CVD in both groups of patients. Both drugs at high cumulative defined daily doses (DDD) and celecoxib alone at high cumulative DDD showed significant protective effects against CVD in AS patients and the control group, respectively. Sulfasalazine at ≥ 0.5 DDD (1000 mg/day) reduced CVD risk in patients with AS (HR = 0.65, CI = 0.43-0.998, P < 0.05). CONCLUSIONS: In this population-based retrospective cohort study, sulfasalazine at its optimal dose reduced CVD risk in patients with AS. Celecoxib was neutral regarding CVD risk in AS patients.
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Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Celecoxib/uso terapéutico , Espondilitis Anquilosante/tratamiento farmacológico , Sulfasalazina/uso terapéutico , Adolescente , Adulto , Anciano , Antiinflamatorios no Esteroideos/efectos adversos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Celecoxib/efectos adversos , Distribución de Chi-Cuadrado , Bases de Datos Factuales , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores Protectores , Estudios Retrospectivos , Factores de Riesgo , Espondilitis Anquilosante/diagnóstico , Espondilitis Anquilosante/epidemiología , Sulfasalazina/efectos adversos , Taiwán/epidemiología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The growth characteristics of Porites lutea skeleton in east sea area of Hainan Island were studied by CoralXDS software based on X-ray chronology. The growth parameters obtained included extension rate (ER), skeleton density (D), and calcification rate (CR). The results showed that ER varied from 0.49 to 1.10 cm·a-1 with an annual average of 0.76 cm·a-1, D varied from 1.11 to 1.35 g·cm-3 with an annual average of 1.22 g·cm-3, and CR varied from 0.55 to 1.41 g·cm-2·a-1 with an annual average of 0.94 g·cm-2·a-1. Statistical analyses indicated that sea surface temperature (SST) was the key environmental factor that controlled the growth characteristics, as it highly co-varied with ER and CR, less so with D. All of the three growth characteristics increased with the increase of SST. There were other factors that influenced the growth characteristics of the coral column, such as light, water salinity, and hydrodynamics, etc. In addition, typhoon and severe tropical storms also imposed a significant impact on the growth pattern of Porites lutea coral. The change in growth pattern of coral skeleton in east of Hainan Island was a response to complex climate fluctuation. Over the past century, SST of east Hainan Island dramatically increased at a rate of 0.15 â·(10 a)-1. The SST increase trend for the oceanic region could be divided into two stages, early 1940s and early 1980s. The human activities and global warming was the main causes for the increase of SST.
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Antozoos/crecimiento & desarrollo , Calentamiento Global , Animales , China , Islas , Océanos y Mares , Agua de Mar , TemperaturaRESUMEN
AIM: To discover novel hepatitis C virus (HCV) inhibitors and elucidate the mechanism of action of the active compounds. METHODS: HCV subgenomic replicon-based luciferase reporter cell line was used to screen 1200 synthetic compounds with novel structures. Huh7.5.1 cell line stably transfected with HCV NS3/4A protease reporter was established to investigate the anti-HCV mechanism of the active compounds. The active compounds were further examined in an in vitro HCV infection assay to confirm their anti-HCV activity. RESULTS: After two-round screening in the anti-HCV replicon assay, some 2,4-diaminoquinazoline derivatives and carboxamide analogues were found to possess anti-HCV replicon activities (the IC50 values were less than 5 µmol/L). Among them, two representative compounds HZ-1157 and LZ-110618-6 inhibited HCV NS3/4A protease with IC50 values of 1.0 and 0.68 µmol/L, respectively. Furthermore, HZ-1157 and LZ-110618-6 inhibited HCV infection in vitro with IC50 values of 0.82 and 0.11 µmol/L, respectively. CONCLUSION: Some 2,4-diaminoquinazoline derivatives and carboxamide analogues have been identified as novel anti-HCV compounds.
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Antivirales/química , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Quinazolinas/química , Quinazolinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Línea Celular , Evaluación Preclínica de Medicamentos , Hepacivirus/metabolismo , Hepatitis C/virología , Humanos , Proteínas no Estructurales Virales/metabolismoRESUMEN
BACKGROUND: Recapping laminoplasty has become the frequently-used approach to the spinal canal when bone decompression of the vertebral canal is not the goal. However, what changes will occur after surgery, and whether recapping laminoplasty can actually reduce the risk of delayed deformities remains unknown. METHODOLOGY: We designed an animal experiment using a caprine model, and partitioned the animals into in vitro and in vivo surgical groups. We performed recapping laminoplasty on one group and laminectomy on another group. These animals were sacrificed six months after operating, cervical spines removed, biomechanically tested, and these data were compared to determine whether the recapping laminoplasty technique leads to subsequent differences in range of motion. Image data were also obtained before the surgery and when the animals were killed. Besides, we investigated the initial differences in kinetics between recapping laminoplasty and laminectomy. We did this by comparing data obtained from biomechanical testing of in vitro-performed recapping laminoplasty and laminectomy. Finally, we investigated the effect that longitudinal distance has on cervical mechanics. This was determined by performing a two-level recapping laminoplasty, and then extending the laminoplasty to the next level and repeating the mechanical testing at each step. PRINCIPAL FINDINGS: There were three mainly morphological changes at the six months after laminoplasty: volume reduction and bone nonunion of the recapping laminae, irregular fibrosis formation around the facet joints and re-implanted lamina-ligamentous complex. In the biomechanical test, comparing with laminectomy, recapping laminoplasty didn't show significant differences in the immediate postoperative comparison, while recapping laminoplasty demonstrated significantly decreased motion in flexion/extension six months later. Inclusion of additional levels in the laminotomy procedure didn't lead to changes in immediate biomechanics. CONCLUSIONS: Recapping laminoplasty can't fully restore the posterior structure, but still reduced the risk of delayed cervical instability in a caprine model.
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Vértebras Cervicales/cirugía , Descompresión Quirúrgica , Laminoplastia/métodos , Animales , Vértebras Cervicales/fisiopatología , Modelos Animales de Enfermedad , Cabras , Humanos , LaminectomíaRESUMEN
Glial activation-mediated neuroinflammation plays a pivotal role in the process of several neuroinflammatory diseases including stroke, Alzheimer's diseases, Parkinson's diseases, multiple sclerosis and ischemia. Inhibition of microglial activation may ameliorate neuronal degeneration under the inflammatory conditions. In the present study, a number of 5α-cholestan-6-one derivatives were prepared and the anti-inflammatory effects of these compounds were evaluated in LPS-stimulated BV-2 microglia cells. Those derivatives were synthesized from readily available hyodeoxycholic acid (1). Among the tested compounds, several analogs (16-18, 25, 35, 38) exhibited potent inhibitory activities on nitric oxide production with no or weak cell toxicity. Compound 16 also significantly suppressed the expression of TNF-α, interleukin (IL)-1ß, cyclooxygenase (COX-2) as well as inducible nitric oxide synthase (iNOS) in LPS-stimulated BV-2 microglia cells. In addition, compound 16 markedly reduced infarction volume in a focal ischemic mice model.
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Colestanonas/farmacología , Descubrimiento de Drogas , Inflamación/tratamiento farmacológico , Microglía/efectos de los fármacos , Óxido Nítrico/antagonistas & inhibidores , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colestanonas/síntesis química , Colestanonas/química , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Ratones , Microglía/metabolismo , Modelos Moleculares , Estructura Molecular , Óxido Nítrico/biosíntesis , Relación Estructura-ActividadRESUMEN
Bis-triazolyl indoleamine-based chemosensors that respond to copper, and then fluorine as presumably facilitated by the high-affinity interaction between F(-) and the NH-proton of indole, are reported. Remarkable fluorimetric as well as colorimetric alternations upon the specific ligand-ion recognitions were observed.
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Aminas/química , Cobre/análisis , Flúor/análisis , Triazoles/química , Colorimetría , Cobre/química , Flúor/química , Fluorometría , Estructura MolecularRESUMEN
The steroidal enzyme cytochrome P45017alpha catalyzes the conversion of progesterone and pregnenolone into androgens, androstenedione and dehydroepiandrosterone, respectively, the direct precursors of estrogens and testosterone. Dihydrotestosterone is the principal active androgen in the prostate, testosterone is also an active stimulant of the growth of prostatic cancer tissue. Inhibition of this enzyme as a mechanism for inhibiting androgen biosynthesis could be a worthwhile therapeutic strategy for the treatment of PCA. In this paper, four categories of steroidal inhibitors of cytochrome P45017alpha will be reviewed, a diverse range of steroidal inhibitors had been synthesized and shown to be potent inhibitors of P45017alpha.
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Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidores , Androstenodiona/biosíntesis , Androstenos , Androstenoles/síntesis química , Androstenoles/química , Androstenoles/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Deshidroepiandrosterona/biosíntesis , Dihidrotestosterona/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Estructura Molecular , Pregnenolona/metabolismo , Progesterona/metabolismo , Neoplasias de la Próstata/patología , Testosterona/biosíntesisRESUMEN
FIGHTING HCV: Two potent antiviral analogues were developed from a previously identified lead as novel agents against hepatitisâ C virus. Their potency and selectivity (5 n: IC50 =0.013â µM and EC50 =0.018â µM; 5 t: IC50 =0.007â µM and EC50 =0.024â µM) make them good candidates for further development as antiviral agents.
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Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Indazoles/farmacología , Antivirales/síntesis química , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Indazoles/síntesis química , Indazoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
AIM: To investigate the neuroprotective effects of LLDT-67, a novel derivative of triptolide, in MPTP-induced mouse Parkinson's disease (PD) models and in primary cultured astrocytes, and to elucidate the mechanisms of the action. METHODS: In order to induce PD, C57BL/6 mice were injected MPTP (30 mg/kg, ip) daily from d 2 to d 6. MPTP-induced behavioral changes in the mice were examined using pole test, swimming test and open field test. The mice were administered LLDT-67 (1, 2, or 4 mg/kg, po) daily from d 1 to d 11. On d 12, the mice were decapitated and brains were collected for immunohistochemistry study and measuring monoamine levels in the striatum. Primary cultured astrocytes from the cortices of neonatal C57BL/6 mouse pups were prepared for in vitro study. RESULTS: In MPTP-treated mice, administration of LLDT-67 significantly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and ameliorated the behavioral changes. LLDT-67 (4 mg/kg) significantly increased the expression of NGF in astrocytes in the substantia nigra and striatum of the mice. Furthermore, administration of LLDT-67 caused approximately 2-fold increases in the phosphorylation of TrkA at tyrosine 751, and marked increases in the phosphorylation of AKT at serine 473 as compared with the mice model group. In the cultured astrocytes, LLDT-67 (1 and 10 nmol/L) increased the NGF levels in the culture medium by 179% and 160%, respectively. CONCLUSION: The neuroprotective effect of LLDT-67 can be mostly attributed to its ability to enhance NGF synthesis in astrocytes in the midbrain and to rescue dopaminergic neurons indirectly through TrkA activation.
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Diterpenos/farmacología , Factor de Crecimiento Nervioso/genética , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Fenantrenos/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Células Cultivadas , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Diterpenos/administración & dosificación , Neuronas Dopaminérgicas/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/administración & dosificación , Trastornos Parkinsonianos/fisiopatología , Fenantrenos/administración & dosificación , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Sustancia Negra/metabolismo , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Triptolide is a bioactive ingredient in traditional Chinese medicine that exhibits diverse biologic properties, including anticancer properties. Among its many putative targets, this compound has been reported to bind to XPB, the largest subunit of general transcription factor TFIIH, and to cause degradation of the largest subunit Rpb1 of RNA polymerase II (RNAPII). In this study, we clarify multiple important questions concerning the significance and basis for triptolide action at this core target. Triptolide decreased Rpb1 levels in cancer cells in a manner that was correlated tightly with its cytotoxic activity. Compound exposure blocked RNAPII at promoters and decreased chromatin-bound RNAPII, both upstream and within all genes that were examined, also leading to Ser-5 hyperphosphorylation and increased ubiqutination within the Rbp1 carboxy-terminal domain. Notably, cotreatment with inhibitors of the proteasome or the cyclin-dependent kinase CDK7 inhibitors abolished the ability of triptolide to ablate Rpb1. Together, our results show that triptolide triggers a CDK7-mediated degradation of RNAPII that may offer an explanation to many of its therapeutic properties, including its robust and promising anticancer properties.
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Productos Biológicos/farmacología , Muerte Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Diterpenos/farmacología , Neoplasias/patología , Fenantrenos/farmacología , ARN Polimerasa II/metabolismo , Secuencia de Bases , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Cartilla de ADN , Compuestos Epoxi/farmacología , Humanos , Fosforilación , Proteolisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
Triptolide, a principal bioactive ingredient of Tripterygium wilfordii Hook F, has attracted extensive exploration due to its unique structure of a diterpenoid triepoxide and multiple biological activities. This review will focus on the structural modifications, structure-activity relationships, pharmacology, and clinical development of triptolide in the last forty years.
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Antiinflamatorios no Esteroideos , Diterpenos , Fenantrenos , Tripterygium/química , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Compuestos Epoxi/química , Compuestos Epoxi/aislamiento & purificación , Compuestos Epoxi/farmacología , Estructura Molecular , Fenantrenos/química , Fenantrenos/aislamiento & purificación , Fenantrenos/farmacología , Relación Estructura-ActividadRESUMEN
In order to study the constituents and pharmacology of Tripterygium plants (Tripterygium willfordii Hook.f), a variety of chromatography methods were used. Four compounds were isolated from Tripterygium plant and their structures were elucidated by UV, IR, MS, HR-MS, 1H NMR, 13C NMR and 2D-NMR techniques. The isolated compounds were named as triptonide (1), neo-triptetraolide (2), 2alpha-hydroxytriptonide (3), and 15-hydroxytriptonide (4), separately. Compounds 3, 4 belong to new diterpenoids, which can inhibit the growth of K562 cells (leukemia cells) and HL60 cells (acute myeloid leukemia cells).
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Diterpenos/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Plantas Medicinales/química , Tripterygium/química , Proliferación Celular/efectos de los fármacos , Diterpenos/química , Diterpenos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Células HL-60 , Humanos , Células K562 , Estructura Molecular , Raíces de Plantas/química , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
This article offers a novel sequence-based approach to discriminate outer membrane proteins (OMPs). The first step is to use a new representation approach, factor analysis scales of generalized amino acid information (FASGAI) representing hydrophobicity, alpha and turn propensities, bulky properties, compositional characteristics, local flexibility and electronic properties, etc., to characterize sequences of OMPs and non-OMPs. The subsequent data is then transformed into a uniform matrix by the auto cross covariance (ACC). The second step is to develop discrimination predictors of OMPs from non-OMPs using a support vector machine (SVM). The SVM predictors thus successfully produce a high Matthews correlation coefficient (MCC) of 0.916 on 208 OMPs from non-OMPs including 206 α-helical membrane proteins and 673 globular proteins by a fivefold cross validation test. Meanwhile, overall MCC values of 0.923 and 0.930 are obtained for the discrimination OMPs from the α-helical membrane proteins and the globular proteins, respectively. The results demonstrate that the FASGAI-ACC-SVM combination approach shows great prospect of application in the field of bioinformatics or proteomics studies.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/química , Análisis de Secuencia de Proteína/métodos , Biología Computacional , Análisis Factorial , Proteínas de la Membrana/química , Estructura Secundaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α. RESULTS: Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide. CONCLUSIONS: The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1α functions in an unresolved nature or condition.
Asunto(s)
Antineoplásicos/farmacología , Diterpenos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Fenantrenos/farmacología , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Compuestos Epoxi/farmacología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunoprecipitación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Crecimiento Endotelial Vascular/genética , Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The in vitro antitumor activity of bakuchiol was exploited, compared with tamoxifen. The result of biological activities showed that bakuchiol could inhibit human breast cancer and the IC50 values were 2.89 x 10(-5) mol L(-1) and 8.29 x 10(-3) mol L(-1) against the cells line T-47D and MDA-MB-231 respectively. On the other hand, the key intermediate to synthesize bakuchiol was obtained by the method of Ireland-Claisen rearrangement. Comparing with traditional Claisen rearrangement, the reaction conditions are milder and the reaction reagents are safer.