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Previous studies have found a possible association between nickel and metabolic syndrome (MetS), but with conflicting results. No studies have determined whether nickel exposure increases the prevalence of MetS in the general U.S. population. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) to assess the association between urinary nickel and MetS. Since urinary nickel levels were presented as a skewed distribution, they were normalized using a logarithmic transformation. Weighted multivariate logistic models, restricted cubic spline, threshold effect analysis, and subgroup analyses were used to examine the association between urinary nickel concentration and the risk of MetS and its components. Based on data from 1577 participants, individuals in the second, third, and fourth quartiles of urinary nickel had an adjusted OR for MetS of 1.42 (95% CI: 0.88, 2.28), 2.00 (95% CI: 1.22, 3.28), and 1.68 (95% CI: 1.05, 2.70), respectively, representing an inverted "L"-shaped nonlinear dose-response relationship with an inflection point at 0.2141 ng/L. Patients over the age of 40, males, less educated, and smokers are more susceptible to nickel exposure. In addition, there were significant associations between nickel and most components of the MetS, with the strongest to weakest correlations being high fasting glucose, reduced high-density lipoprotein, abdominal obesity, and elevated blood pressure; however, there was no significant correlation between nickel and hyperlipidemia. In conclusion, environmental nickel exposure increases the prevalence of MetS in U.S. adults, particularly in males over 40 years of age, those with less education, and smokers.
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BACKGROUND: Major depressive disorder (MDD) is the most frequent reason of disabled people in the world, as reported by the World Health Organization. However, the diagnosis of MDD is mainly based on clinical symptoms. CASE SUMMARY: The clinical, genetic, and molecular characteristics of two Chinese families with MDD are described in this study. There were variable ages of onset and severity in depression among the families. Both Chinese families had a very low pre-valence of MDD. The mitochondrial genomes of these pedigrees were sequenced and indicated a homoplasmic T3394C (Y30H) mutation, with the polymorphism located at a highly conserved tyrosine at position 30 of ND1. The analysis also revealed unique sets of mitochondrial DNA (mtDNA) polymorphisms orig-inating from haplogroups M9a3 and M9a. CONCLUSION: This finding of the T3394C mutation in two unrelated depressed patients provides strong evidence that this mutation may have a part in the etiology of MDD. However, In these two Chinese families having the T3394C mutation, no functional mtDNA mutation was observed. Therefore, T3394C mutations are related with MDD, and the phenotypic manifestation of these mutations may be affected by changes in nuclear genes or environmental factors.
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Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.
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Inmunidad Innata , Enfermedades Inflamatorias del Intestino , Nucleotidiltransferasas , Animales , Ratones , ADN/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Nucleotidiltransferasas/antagonistas & inhibidores , Transducción de Señal , Pirroles/química , Pirroles/farmacología , Pirazinas/química , Pirazinas/farmacologíaRESUMEN
Hyperglycemia-induced myelopoiesis and atherosclerotic progression occur in mice with type I diabetes. However, less is known about the effects of metabolites on myelopoesis in type 2 diabetes. Here, we use fluorescence-activated cell sorting to analyze the proliferation of granulocyte/monocyte progenitors (GMP) in db/db mice. Using targeted metabolomics, we identify an increase in inosine monophosphate (IMP) in GMP cells of 24-week-old mice. We show that IMP treatment stimulates cKit expression, ribosomal S6 activation, GMP proliferation, and Gr-1+ granulocyte production in vitro. IMP activates pAkt in non-GMP cells. In vivo, using an established murine acute pancreatitis (AP) model, administration of IMP-treated bone marrow cells enhances the severity of AP. This effect is abolished in the presence of a pAkt inhibitor. Targeted metabolomics show that plasma levels of guanosine monophosphate are significantly higher in diabetic patients with AP. These findings provid a potential therapeutic target for the control of vascular complications in diabetes.
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Diabetes Mellitus Tipo 2 , Pancreatitis , Enfermedad Aguda , Animales , Guanosina Monofosfato , Inosina Monofosfato , Ratones , Mielopoyesis , Purinas/metabolismo , Purinas/farmacologíaRESUMEN
Precious Tibetan medicine formula is a characteristic type of medicine commonly used in the clinical treatment of central nervous system diseases. Through the summary of modern research on the precious Tibetan medicine formulas such as Ratnasampil, Ershiwuwei Zhenzhu Pills, Ershiwewei Shanhu Pills, and Ruyi Zhenbao Pills, it is found that they have obvious advantages in the treatment of stroke, Alzheimer's disease, epilepsy, angioneurotic headache, and vascular dementia. Modern pharmacological studies have shown that the mechanisms of precious Tibetan medicine formulas in improving central nervous system diseases are that they promote microcirculation of brain tissue, regulate the permeability of the blood-brain barrier, alleviate inflammation, relieve oxidative stress damage, and inhibit nerve cell apoptosis. This review summarizes the clinical and pharmacological studies on precious Tibetan medicine formulas in prevention and treatment of central nervous system diseases, aiming to provide a reference for future in-depth research and innovative discovery of Tibetan medicine against central nervous diseases.
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Enfermedades del Sistema Nervioso Central , Accidente Cerebrovascular , Barrera Hematoencefálica , Encéfalo , Humanos , Medicina Tradicional Tibetana , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
The present study investigated the mechanism of the Tibetan medicine Ershiwuwei Songshi Pills(ESP) against the liver injury induced by acetaminophen(APAP) in mice based on the kelch-like ECH-associated protein 1(Keap1)/nuclear transcription factor E2 related factor 2(Nrf2) and Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) p65 signaling pathways. Kunming mice were randomly divided into a blank control group, a model group, an N-acetyl-L-cysteine(NAC) group, and high-(400 mg·kg~(-1)), medium-(200 mg·kg~(-1)), and low-dose(100 mg·kg~(-1)) ESP groups. After 14 days of continuous administration, except for those in the control group, the mice were intraperitoneally injected with 200 mg·kg~(-1) APAP. After 12 h, the serum and liver tissues of mice were collected. Hematoxylin-eosin(HE) staining was performed on pathological sections of the liver, and the levels of aspartate aminotransferase(AST) and alanine aminotransferase(ALT) in the serum and the levels of glutathione(GSH), malondialdehyde(MDA), superoxide dismutase(SOD), catalase(CAT), myeloperoxidase(MPO), and total antioxidant capacity(T-AOC) in liver tissue homogenate were detected to observe and analyze the protective effect of ESP on APAP-induced liver injury in mice. The serum levels of tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1ß), and interleukin-6(IL-6) were determined by enzyme-linked immunosorbent assay(ELISA). The protein expression of Nrf2, Keap1, TLR4, and NF-κB p65 in the liver was determined by Western blot. Quantitative real-time was used to determine the mRNA expression of glutamate-cysteine ligase catalytic subunit(GCLC), glutamate-cysteine ligase regulatory subunit(GCLM), heme oxygenase-1(HO-1), and NAD(P)H dehydrogenase quinone 1(NQO-1) in the liver to explore the mechanism of ESP in improving APAP-induced liver damage in mice. As revealed by results, compared with the model group, the ESP groups showed improved liver pathological damage, decreased ALT and AST levels in the serum and MDA and MPO content in the liver, increased GSH, SOD, CAT, and T-AOC in the liver, reduced TNF-α and IL-6 levels in the serum, down-regulated expression of Keap1 in the liver cytoplasm and NF-κB p65 in the liver nucleus, up-regulated expression of Nrf2 in the liver nucleus, insignificant change in TLR4 expression, and elevated relative mRNA expression levels of antioxidant genes GCLC, GCLM, HO-1, and NQO-1. ESP can reduce the oxidative damage and inflammation caused by APAP, and the mechanism may be related to the Keap1/Nrf2 signaling pathway and the signal transduction factors on the TLR4/NF-κB p65 pathway.
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Acetaminofén , Factor 2 Relacionado con NF-E2 , Acetaminofén/toxicidad , Animales , Antioxidantes/farmacología , Glutamato-Cisteína Ligasa/metabolismo , Glutamato-Cisteína Ligasa/farmacología , Glutatión , Interleucina-6/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Hígado , Medicina Tradicional Tibetana , Ratones , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal , Superóxido Dismutasa/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The present study investigated the mechanism of the Tibetan patent medicine Ershiwuwei Shanhu Pills(ESP) in alleviating Alzheimer's disease in mice via Akt/mTOR/GSK-3ß signaling pathway. BALB/c mice were randomly assigned into a blank control group, a model group, low(200 mg·kg~(-1)), medium(400 mg·kg~(-1)) and high(800 mg·kg~(-1)) dose groups of ESP, and donepezil hydrochloride group. Except the blank control group, the other groups were given 20 mg·kg~(-1) aluminum chloride by gavage and 120 mg·kg~(-1) D-galactose by intraperitoneal injection for 56 days to establish Alzheimer's disease model. Morris water maze was used to detect the learning and memory ability of mice. The level of p-tau protein in mouse hippocampus and the levels of superoxide dismutase(SOD), malondialdehyde(MDA), catalase(CAT), and total antioxidant capacity(T-AOC) in hippocampus and serum were detected. Hematoxylin-eosin staining and Nissl staining were performed for the pathological observation of whole brain in mice. TdT-mediated dUTP nick-end labeling(TUNEL) staining was employed for the observation of apoptosis in mouse cortex. Western blot was adopted to detect the protein levels of p-mTOR, p-Akt, and GSK-3ß in the hippocampus. Compared with the model group, the ESP groups showcased alleviated pathological damage of the whole brain, decreased TUNEL positive cells, reduced level of p-tau protein in hippocampus, and risen SOD, CAT, and T-AOC levels and declined MDA level in hippocampus and serum. Furthermore, the ESP groups had up-regulated protein levels of p-mTOR and p-Akt while down-regulated protein level of GSK-3ß in hippocampus. Therefore, ESP can alleviate the learning and memory decline and oxidative damage in mice with Alzheimer's disease induced by D-galactose combined with aluminum chloride, which may be related to Akt/mTOR/GSK-3ß signaling pathway.
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Enfermedad de Alzheimer , Cloruro de Aluminio/efectos adversos , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Galactosa/efectos adversos , Galactosa/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Superóxido Dismutasa/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas tauRESUMEN
This study aims to investigate the mechanism of the Tibetan medicine Ershiwuwei Shanhu Pills(ESP) in improving scopolamine-induced learning and memory impairment in mice based on Keap1/Nrf2/HO-1 signaling pathway. ICR mice were randomized into blank group, model group, low-dose(200 mg·kg~(-1)), medium-dose(400 mg·kg~(-1)), and high-dose(800 mg·kg~(-1)) ESP groups, and donepezil hydrochloride group. The learning and memory impairment was induced in mice by intraperitoneal injection of scopola-mine. The learning and memory abilities of mice were detected by Morris water maze test, and the damage of hippocampal neurons and cortical neurons was detected based on Nissl staining. The expression of neuron specific nuclear protein(NeuN) in hippocampus and cortex of mice was determined by immunofluorescence assay, and the content of acetylcholine(Ach) and the activity of acetylcholines-terase(AchE) in hippocampus of mice by kits. Moreover, the content of superoxide dismutase(SOD), malondialdehyde(MDA), catalase(CAT), and total antioxidant capacity(T-AOC) in serum of mice was detected. The content of Kelch-like ECH-associated protein 1(Keap1), nuclear factor erythroid 2-related factor 2(Nrf2), and heme oxygenase 1(HO-1) in hippocampus was determined by Western blot. The results showed that there were significant differences in the trajectory map of mice among different groups in the behavioral experiment. Moreover, the latency of ESP groups decreased significantly compared with that in the model group. The hippocampal neurons in the high-dose ESP group were significantly more than those in the model group and the cortical neurons in the high-dose and medium-dose ESP groups were significantly more than those in the model group. The expression of NeuN in the model group was significantly decreased compared with that in the blank group, and the expression in the ESP groups was significantly higher than that in the model group. The AchE activity and MDA level were significantly decreased, and Ach content and levels of SOD, CAT, and T-AOC in the ESP groups were significantly increased in the ESP groups compared with those in the model group. The expression of Keap1 in the model group was significantly increased compared with that in the blank group, and the Keap1 expression increased insignificantly in ESP groups compared with that in the model group. The expression of Nrf2 and HO-1 was significantly lower in the model group than in the blank group, and the expression was significantly higher in the medium-dose ESP group than in the model group. In conclusion, ESP protected mice against the scopolamine-induced learning and memory impairment by regulating the Keap1/Nrf2/HO-1 signaling pathway.
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Factor 2 Relacionado con NF-E2 , Escopolamina , Animales , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Medicina Tradicional Tibetana , Ratones , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Extractos Vegetales , Escopolamina/efectos adversos , Transducción de Señal , Superóxido Dismutasa/metabolismoRESUMEN
Acute pancreatitis (AP) is one of the leading causes of hospital admission, 20% of which could progress to the severe type with extensive acinar cell necrosis. Clinical studies have reported that diabetes is an independent risk factor of the incidence of AP and is associated with higher severity than nondiabetic subjects. However, how diabetes participates in AP progression is not well defined. To investigate this question, wild-type (wt) and diabetic db/db mice at the age of 16 weeks were used in the study. AP was induced in wt recipients by 10 injections of 50 µg/kg caerulein with a 1 h interval. One hour after the last caerulein injection, bone marrow cells (BMC) isolated from wt and db/db mice were injected intraperitoneally into the recipients (1 × 107cells/recipient). The recipients with no BMC injection served as controls. Thirteen hours after BMC injection, serum lipase activity was 1.8- and 1.3-folds higher in mice that received db/db BMC, compared with those with no injection and wt BMC injection, respectively (p ≤ 0.02 for both). By H&E staining, the overall severity score was 14.7 for no cell injection and 16.6 for wt BMC injection and increased to 22.6 for db/db BMC injection (p ≤ 0.002 for both). In particular, mice with db/db BMC injection developed more acinar cell necrosis and vacuolization than the other groups (p ≤ 0.03 for both). When sections were stained with an antibody against myeloperoxidase (MPO), the density of MPO+ cells in pancreatitis was 1.9- and 1.6-folds higher than wt BMC and no BMC injection groups, separately (p ≤ 0.02 for both). Quantified by ELISA, db/db BMC produced more IL-6, GM-CSF, and IL-10 compared with wt BMC (p ≤ 0.04 for all). In conclusion, BMC of db/db mice produced more inflammatory cytokines. In response to acinar cell injury, diabetic BMC aggravated the inflammation cascade and acinar cell injury, leading to the progression of acute pancreatitis.
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Células de la Médula Ósea/inmunología , Complicaciones de la Diabetes/inmunología , Pancreatitis/inmunología , Animales , Células de la Médula Ósea/metabolismo , Trasplante de Médula Ósea , Ceruletida/administración & dosificación , Ceruletida/toxicidad , Citocinas/metabolismo , Complicaciones de la Diabetes/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Inyecciones Intraperitoneales , Masculino , Ratones , Necrosis , Páncreas/efectos de los fármacos , Páncreas/inmunología , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/patologíaRESUMEN
Cardiomyopathy and fibrosis are the main causes of heart failure in diabetes patients. For therapeutic purposes, a delivery system is required to enhance antidiabetic drug efficacy and specifically target profibrotic pathways in cardiomyocytes. Nanoparticles (NPs) have distinct advantages, including biocompatibility, bioavailability, targeting efficiency, and minimal toxicity, which make them ideal for antidiabetic treatment. In this review, we overview the latest information on the pathogenesis of cardiomyopathy and fibrosis in diabetes patients. We summarize how NP applications improve insulin and liraglutide efficacy and their sustained release upon oral administration. We provide a comprehensive review of the results of NP clinical trials in diabetes patients and of animal studies investigating the effects of NP-mediated anti-fibrotic treatments. Collectively, the application of advanced NP delivery systems in the treatment of cardiomyopathy and fibrosis in diabetes patients is a promising and innovative therapeutic strategy.
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Sistemas de Liberación de Medicamentos , Hipoglucemiantes/administración & dosificación , Nanopartículas , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Complicaciones de la Diabetes/fisiopatología , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/fisiopatología , Fibrosis , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Humanos , Hipoglucemiantes/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patologíaRESUMEN
Macrophage proliferation and skewed myelopoiesis-induced monocytosis, as well as neutrophils, enhance the generation of atherogenic inflammatory cells in a lesion area, leading to plaque formation and Cardiovascular Disease (CVD). Among all risk factors, accumulated data have shown that hyperlipidemia activates Hematopoietic Stem/Progenitor Cells (HSPCs) in the Bone Marrow (BM) niche. Recently, proliferation of Granulocyte-Monocyte Progenitors (GMPs) has been demonstrated to drive skewed myelopoiesis, while HSPCs remain quiescent. In this review, we discuss how HSPCs and GMPs participate in atherosclerosis of mice in terms of proliferation and cell mobilization from BM to peripheral blood and the lesion area. We also describe how the spleen, an extramedullary organ, is involved in skewed myelopoiesis and inflammation in atherosclerosis. We further summarize the clinical evidence of the relationship of HSPCs with coronary stenoses in patients with CVD. Ultimately, this review facilitates understanding the pathological roles of HSPCs and GMPs in atherosclerosis for future treatments.
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Enfermedades Cardiovasculares , Trasplante de Células Madre Hematopoyéticas , Animales , Enfermedades Cardiovasculares/terapia , Células Madre Hematopoyéticas , Humanos , Ratones , Ratones Endogámicos C57BL , MielopoyesisRESUMEN
A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallographic profiles of the "short" inverse agonist 6. With the increase in the size of the 6-position substituents, the "short" inverse agonist 6 first reversed its function to agonists and then to "long" inverse agonists. The cocrystal structures of RORγt complexed with the representative "short" inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the "long" inverse agonist 7h (PDB: 6LO9) were revealed by X-ray analysis. However, minor differences were found in the binding modes of "short" inverse agonist 6 and "long" inverse agonist 7h. To further reveal the molecular mechanisms of different RORγt inverse agonists, we performed molecular dynamics simulations and found that "short" or "long" inverse agonists led to different behaviors of helixes H11, H11', and H12 of RORγt. The "short" inverse agonist 6 destabilizes H11' and dislocates H12, while the "long" inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms.
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Carbazoles/farmacología , Cristalografía , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Receptores de Ácido Retinoico/agonistas , Carbazoles/síntesis química , Simulación de Dinámica Molecular , Estructura Molecular , Relación Estructura-Actividad , Receptor de Ácido Retinoico gammaRESUMEN
OBJECTIVE: The objective of this study was to explore the association between periodontitis and systemic lupus erythematosus (SLE). METHODS: To identify eligible studies, the PubMed, EMBASE and Web of Science databases were searched from inception to 19 September 2019. Associations of periodontitis, and other periodontal parameters, with SLE were assessed. RESULTS: Ten studies involving 80,633 subjects were included in this meta-analysis. Pooled data showed a significant association between periodontitis and SLE (odds ratio=5.32, 95% confidence interval (CI) 1.69-16.78, p = 0.004). In addition, SLE patients had a higher prevalence of bleeding on probing (mean difference = 0.03, 95% CI 0.00-0.06, p = 0.02) and higher mean clinical attachment loss (mean difference = 0.69, 95% CI 0.39-1.00, p < 0.001). However, there were no significant differences between SLE and reference subjects in mean plaque index, gingival index, pocket depth or decayed, missing or filled teeth. CONCLUSIONS: This study demonstrates a significant association between periodontitis and SLE, which indicates that avoidance of periodontitis by maintaining oral health may be a simple and economical way to prevent SLE.
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Lupus Eritematoso Sistémico/complicaciones , Periodontitis/complicaciones , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Cascade analysis is an effective method to analyze the processing data of an event, such as a provided service or a series of examinations. This study aimed to develop a primary cervical cancer screening cascade in China to promote the quality of the screening process. METHODS: We designed a cervical cancer screening cascade in China according to the program flow chart. It had three stages, each with two steps and one result. Data from 117,522 women aged 35 to 64 years in the Rural Cervical Cancer Surveillance Project from January 1, 2014, to December 31, 2014, were collected to analyze the main results of the cascade. The data and proportion are used to describe the follow-up of cervical cancer and pre-cancer detection rate. RESULTS: In 2014, 117,522 (80.94% of all cases reported by the Rural Cervical Cancer Surveillance Project) women aged 35 to 64 years had not received cervical cytology in the previous 3 years. The pre-cancer and cancer detection rates were 256.12/100,000 and 16.16/100,000, respectively. A total of 3031 cases failed to follow-up through the screening process, and 1189, 1555, and 287 cases were lost at cervical cytology, colposcopy, and histopathological screening stages, respectively. The estimated cases of pre-cancer and cancer cases would have been 544 and 34, respectively, and the estimated detection rates of pre-cancer and cancer would have been 462.89/100,000 and 28.93/100,000, respectively. CONCLUSION: In order to increase the detection rate of cervical cancer, cervical cancer screening staff should focus on increasing the rate of follow-up of those who are positive for cervical cancer screening (ie, those with positive cytology results), especially for the 40 to 44 years age range.
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Detección Precoz del Cáncer/métodos , Tamizaje Masivo/métodos , Neoplasias del Cuello Uterino/diagnóstico , Adulto , China , Colposcopía , Femenino , HumanosRESUMEN
Four new acylated triterpene glycosides with aliphatic chains (4-7) as well as five known triterpenoids were isolated from the flower buds of Staphylea bumalda with bioassay guidance. Their structures were determined on the basis of spectral techniques, including IR, 1D and 2D NMR, and HR-APCI-MS. Most compounds (except 8) were isolated from S. bumalda for the first time. Additionally, the neuroprotective effects of 1 and 4-9 on suckling rat primary cultured hippocampal neurons against H2O2-induced injury were evaluated in vitro. The four new triterpenoids (4-7) showed neuroprotective effects, which increased the cell viability to over 74% at different concentrations, which was higher than the negative control (59%), while compounds 1 and 8-9 exhibited cytotoxic activity.
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Glicósidos/farmacología , Hipocampo/efectos de los fármacos , Peróxido de Hidrógeno/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Triterpenos/farmacología , Animales , Flores/química , Glicósidos/química , Glicósidos/aislamiento & purificación , Hipocampo/patología , Peróxido de Hidrógeno/farmacología , Magnoliopsida/química , Neuronas/patología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
CONTEXT: Tai Chi exercise has been shown to improve cancer-related fatigue (CRF) and autonomic nervous system (ANS) balance in some cancer patients or survivors; however, such effects are yet to be verified in nasopharyngeal carcinoma (NPC) patients undergoing chemoradiotherapy. OBJECTIVES: To explore the effects of Tai Chi exercise on CRF in NPC patients undergoing chemoradiotherapy and then to evaluate ANS information indicated by heart rate variability parameters and their association with CRF. METHODS: A randomized controlled trial of Tai Chi exercise was conducted from January 2014 to August 2015. Participants in the Tai Chi group practiced Tai Chi a one-hour session, five sessions/week during chemoradiotherapy. Participants in the control group received usual care. The primary end points were scores of the multidimensional fatigue symptom inventory-short form (MFSI-SF). Secondary end points were heart rate variability parameters, including normalized low-frequency (nLF) power, normalized high-frequency (nHF) power, and the nLF/nHF ratio, and their association with CRF. RESULTS: One hundred fourteen patients were recruited in this study, and 83 patients completed the trial. The Tai Chi group and the control group had comparable baseline characteristics. After chemoradiotherapy, the Tai Chi group exhibited lower MFSI-SF total score and three negative subscale (general, physical, and emotional fatigue) scores and higher vigor score compared with the control group (P < 0.01 for all). The nLF/nHF ratio was significantly lower in the Tai Chi group compared to the control group after chemoradiotherapy. The MFSI-SF total score was markedly correlated with the nLF/nHF ratio. CONCLUSION: Tai Chi exercise is conducive to alleviate CRF in NPC patients undergoing chemoradiotherapy. The improvement in ANS balance might fit into the process of Tai Chi for CRF management in this population.
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Quimioradioterapia , Fatiga/etiología , Fatiga/terapia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Taichi Chuan , Adulto , Fatiga/fisiopatología , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/complicaciones , Carcinoma Nasofaríngeo/fisiopatología , Neoplasias Nasofaríngeas/complicaciones , Neoplasias Nasofaríngeas/fisiopatología , Datos Preliminares , Resultado del TratamientoRESUMEN
In an attempt to arrive at a more potent cytotoxic agent than the parent compound α-hederagenin (H), 24 α-hederagenin derivatives (5-8, 11-24, 27-28, 31-32, and 35-36) were synthesized in a concise and efficient strategy and screened for in vitro cytotoxicity against the human cancer cell lines MKN45 and KB. Among these compounds, the polyamine derivative 15 exhibited more potency than the parent compound with IC50 values in the range of 4.22 µM-8.05 µM. Compound 15 increased Bax/bcl-2 ratio that disrupted the mitochondrial potential and induced apoptosis. Therefore, the present studies highlight the importance of polyamine derivatives of α-hederagenin in the discovery and development of novel anticancer agents.
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Antineoplásicos/farmacología , Diseño de Fármacos , Ácido Oleanólico/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Ácido Oleanólico/síntesis química , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
The Transport protein particle (TRAPP) complex is a tethering factor for COPII vesicle. Of three forms of TRAPP (TRAPPI, II and III) complexes identified so far, TRAPPIII has been largely considered to play a role in autophagy. While depletion of TRAPPIII specific subunits caused defects in the early secretory pathway and TRAPPIII might interact with components of the COPII vesicle coat, its exact role remains to be determined. In this study, we studied the function of TRAPPIII in early secretory pathway using a TRAPPIII-specific subunit, TRAPPC12, as starting point. We found that TRAPPC12 was localized to the ER exit sites and ERGIC. In cells deleted with TRAPPC12, ERGIC and to a lesser extent, the Golgi became dispersed. ER-to-Golgi transport was also delayed. TRAPPC12, but not TRAPPC8, bound to Sec13/Sec31A tetramer but each Sec protein alone could not interact with TRAPPC12. TRAPPIII positively modulated the assembly of COPII outer layer during COPII vesicle formation. These results identified a novel function of TRAPPIII as a positive modulator of the outer layer of the COPII coat.
Asunto(s)
Proteínas Portadoras/metabolismo , Vesículas Secretoras/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animales , Células COS , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Unión ProteicaRESUMEN
BACKGROUND: Chemical toxicity is an important reason for late-stage failure in drug R&D. However, it is time-consuming and expensive to identify the multiple toxicities of compounds using the traditional experiments. Thus, it is attractive to build an accurate prediction model for the toxicity profile of compounds. MATERIALS AND METHODS: In this study, we carried out a research on six types of toxicities: (I) Acute Toxicity; (II) Mutagenicity; (III) Tumorigenicity; (IV) Skin and Eye Irritation; (V) Reproductive Effects; (VI) Multiple Dose Effects, using local lazy learning (LLL) method for multi-label learning. 17,120 compounds were split into the training set and the test set as a ratio of 4:1 by using the Kennard-Stone algorithm. Four types of properties, including molecular fingerprints (ECFP_4 and FCFP_4), descriptors, and chemical-chemical-interactions, were adopted for model building. RESULTS: The model 'ECFP_4+LLL' yielded the best performance for the test set, while balanced accuracy (BACC) reached 0.692, 0.691, 0.666, 0.680, 0.631, 0.599 for six types of toxicities, respectively. Furthermore, some essential toxicophores for six types of toxicities were identified by using the Laplacian-modified Bayesian model. CONCLUSION: The accurate prediction model and the chemical toxicophores can provide some guidance for designing drugs with low toxicity.
Asunto(s)
Carcinógenos/toxicidad , Simulación por Computador , Descubrimiento de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Modelos Biológicos , Mutágenos/toxicidad , Preparaciones Farmacéuticas , Algoritmos , Animales , Carcinógenos/química , Bases de Datos Farmacéuticas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Ojo/efectos de los fármacos , Humanos , Aprendizaje Automático , Mutágenos/química , Preparaciones Farmacéuticas/química , Relación Estructura-Actividad Cuantitativa , Reproducción/efectos de los fármacos , Piel/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Hand, foot and mouth disease (HFMD) is a serious, highly contagious disease. HFMD caused by Enterovirus 71 (EV71), results in severe complications and even death. The pivotal role of EV71 3Cpro in the viral life cycle makes it an attractive target for drug discovery and development to treat HFMD. In this study, we identified novel EV71 3Cpro inhibitors by docking-based virtual screening. Totally 50 compounds were selected to test their inhibitory activity against EV71 3Cpro. The best inhibitor DC07090 exhibited the inhibition potency with an IC50 value of 21.72 ± 0.95 µM without apparent toxicity (CC50 > 200 µM). To explore structure-activity relationship of DC07090, 15 new derivatives were designed, synthesized and evaluated in vitro enzyme assay accordingly. Interestingly, four compounds showed inhibitory activities against EV71 3Cpro and only DC07090 inhibited EV71 replication with an EC50 value of 22.09 ± 1.07 µM. Enzyme inhibition kinetic experiments showed that the compound was a reversible and competitive inhibitor. The Ki value was determined to be 23.29 ± 12.08 µM. Further molecular docking, MD simulation and mutagenesis studies confirmed the binding mode of DC07090 and EV71 3Cpro. Besides, DC07090 could also inhibit coxsackievirus A16 (CVA16) replication with an EC50 value of 27.76 ± 0.88 µM. Therefore, DC07090 represents a new non-peptidyl small molecule inhibitor for further development of antiviral therapy against EV71 or other picornaviruses.