Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 197
Filtrar
1.
J Chem Inf Model ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33629839

RESUMO

The development of efficient models for predicting specific properties through machine learning is of great importance for the innovation of chemistry and material science. However, predicting global electronic structure properties like Frontier molecular orbital highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels and their HOMO-LUMO gaps from the small-sized molecule data to larger molecules remains a challenge. Here, we develop a multilevel attention neural network, named DeepMoleNet, to enable chemical interpretable insights being fused into multitask learning through (1) weighting contributions from various atoms and (2) taking the atom-centered symmetry functions (ACSFs) as the teacher descriptor. The efficient prediction of 12 properties including dipole moment, HOMO, and Gibbs free energy within chemical accuracy is achieved by using multiple benchmarks, both at the equilibrium and nonequilibrium geometries, including up to 110,000 records of data in QM9, 400,000 records in MD17, and 280,000 records in ANI-1ccx for random split evaluation. The good transferability for predicting larger molecules outside the training set is demonstrated in both equilibrium QM9 and Alchemy data sets at the density functional theory (DFT) level. Additional tests on nonequilibrium molecular conformations from DFT-based MD17 data set and ANI-1ccx data set with coupled cluster accuracy as well as the public test sets of singlet fission molecules, biomolecules, long oligomers, and protein with up to 140 atoms show reasonable predictions for thermodynamics and electronic structure properties. The proposed multilevel attention neural network is applicable to high-throughput screening of numerous chemical species in both equilibrium and nonequilibrium molecular spaces to accelerate rational designs of drug-like molecules, material candidates, and chemical reactions.

2.
Clin Neurol Neurosurg ; 202: 106523, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33581615

RESUMO

OBJECTIVE: To understand the distribution of Parkinson's disease questionnaire-39 (PDQ-39) scores in Parkinson's disease (PD) patients with or without depression, and to analyze the factors that influence the quality of life of PD patients. MATERIALS AND METHODS: 300 PD patients were enrolled. Patients' general information and the results of assessments including UPDRS, H-Y, HAMD, HAMA, ADL and PDQ-39 were collected. They were divided into depression group and non-depression group according to HAMD score. The relationship between PD-related depression and quality of life and the factors that influence the quality of life of PD patients were analyzed based on PDQ-39 score. RESULTS: 111 patients with depression (37.0 %) and 189 patients without depression (63.0 %) were enrolled. The scores of PDQ-39 summary index (PDQ-39 SI) in the depression group were significantly higher than those in the non-depression group in all domains (P < 0.05). Patients in the depression group had a longer disease duration (6.89 ± 4.70 vs. 5.52 ± 4.12, P < 0.038), a higher UPDRS-III score (30.1 ± 13.55 vs. 25.2 ± 11.73, P < 0.001), and a higher H-Y stage level (2.41 ± 0.853 vs. 2.13 ± 0.707, P < 0.001), compared with patients in the non-depression group. All factors including age, disease duration, UPDRS-III, H-Y stage, HAMD score and HAMA score, may independently affected PDQ-39SI in PD patients, among which HAMD had the greatest effect. HAMD and HAMA were correlated with PDQ-39 in its all eight domains. CONCLUSION: PD patients with psychological problems such as anxiety and depression may lead to a significant decline in the quality of life of patients in all domains.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33576578

RESUMO

OBJECTIVE: This study aimed to investigate mitochondrial changes and the mitochondrial antiviral-signaling protein (MAVS)-type I interferon (IFN1) signaling pathway in the muscles of anti-melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients. METHODS: Eleven anti-MDA5 DM and ten antibody-negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN-stimulated gene 15, which are components of the MAVS-IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed. RESULTS: Anti-MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P < 0.05) than antibody-negative DM, including perifascicular fiber atrophy, inflammation, and vasculopathy. Mitochondrial abnormalities in anti-MDA5 patients revealed a high incidence of (8/11,72.7%) and different pattern from that in antibody-negative DM. MDA5, MAVS, IFN regulatory factor 7, and IFN stimulated gene 15 expression levels in the muscles of anti-MDA5 DM patients were higher than those of the controls (P < 0.05) but lower than those of antibody-negative DM patients (P < 0.05). The MAVS levels negatively correlated with manual muscle test 8 scores (r = 0.701, P = 0.016). CONCLUSIONS: Compared to antibody-negative DM, we presented a different distribution of the mitochondrial pathology and less severe morphology in anti-MDA5 DM. We also revealed the enhanced but less intensive MAVS-IFN1 signaling pathway activity in muscles of anti-MDA5 DM. Such disparity suggested the potentially different mechanism of muscle injury in two DM groups.

4.
Cancer Res ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558336

RESUMO

Insights into oncogenesis derived from cancer susceptibility loci (single nucleotide polymorphisms, SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, while both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of pro-survival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacological inhibition of the pro-survival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.

5.
J Ethnopharmacol ; : 113926, 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33596472

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Jiang-Zhi-Ning (JZN) is a traditional Chinese medicine formula, which has the effect of lowering blood lipid level and softening blood vessels. It is clinically used in the treatment of hyperlipidemia with significant curative effect. AIM OF THE STUDY: This study aims to screen the active components of JZN that are responsible for its blood lipids lowering effect and lay the foundation for elucidating pharmacodynamic material basis of the hypolipidemic effect of the formula. MATERIALS AND METHODS: The hyperlipidemia model was used to evaluate the efficacy of the JZN effective extraction with the TC and TG of rat plasma as evaluation index. Then the established ultra-high performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry (UPLC-ESI-Q-TOF-MSn) method was utilized to analyze the components of JZN effective extraction and the absorbed components in rat plasma, the potential active components were screened by using the combined analysis results of in vivo and in vitro component identification. Then an established ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QqQ-MSn) method was used to determine the content of potential active components and its natural ratio in JZN effective extraction, and a potential active components combination (PACC) was formed accordingly. Then a HepG2 cell hyperlipidemia model induced by sodium oleate was used to study the hypolipidemic activity of PACC by detecting the content of TG level in the model. Meanwhile, the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to conduct preliminary research on its hypolipidemic mechanism. Then combined with the concept of "combination index" in the "median-effect principle", to calculate the half inhibitory concentration (IC50) values of PACC and each monomer component on inhibiting the TG level in the cell model. Subsequently, the "activity contribution study" was carried out, and the components with the sum of the "activity contribution value" of 85% were finally selected as the hypolipidemic active components of JZN. RESULTS: The pharmacodynamics results showed that JZN effective extraction has displayed a good hypolipidemic effect. 45 components were identified in vitro, 108 components were identified from rat plasma, and 17 potential active components were screened out. The content determination result showed that the ratio of each potential active components in PACC as following: cassiaside C: rubrofusarin-6-O-gentiobioside: aurantio-obtusin-6-O-glucoside: hyperoside: isoquercitrin: quercetin-3-O-glucuronide: (E)-2,3,5,4'-tetrahydroxystilbene-2-O-glucoside: rutin: emodin-8-O-glucoside: astragalin: armepavine: N-nornuciferine: coclaurine: O-nornuciferine: nuciferine: N-norarmepavine: higenamine = 3.30: 16.06: 9.15: 23.94: 98.40: 417.45: 189.68: 8.62: 1.28: 5: 3.51: 14.57: 1.06: 1.35: 1: 5.64: 6.06, and the activity study results showed that it has displayed a good hypolipidemic activity. Finally, the hypolipidemic active components screened out by the "activity contribution study" were: quercetin-3-O-glucuronide, (E)-2,3,5,4'-tetrahydroxystilbene-2-O-glucoside, isoquercitrin, O-nornuciferine, hyperoside and rubrofusarin-6-O-gentiobioside. CONCLUSIONS: A scientific and rational approach of screening the hypolipidemic active ingredients of JZN has been developed in the current study. In addition, the research revealed the blood lipid lowering mechanism of those ingredients, which provide a solid basis for further elucidating the hypolipidemic pharmacodynamic material basis and action mechanism of JZN.

6.
Parasite ; 28: 1, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33416489

RESUMO

Schistosoma japonicum infection causes pathological injury to the host. Multiple studies have shown that intestinal helminth infection causes dysbiosis for the gut microbial community and impacts host immunology. However, the effect of acute S. japonicum infection on the gut microbiome structure (abundance and diversity) is still unclear. We collected fecal samples from healthy and infected patients from a single hospital in Hunan Province, China. The bacterial community was analyzed using 16S ribosomal RNA gene sequencing of the V4 hypervariable region using the HiSeq platform. Compared with healthy subjects, infected patients exhibited an increase in relative abundance of the TM7 phylum. At the genus level, there were seven differentially abundant genera between groups. The most significant finding was a Bacteroides enterotype in patients with acute schistosomiasis. These results suggest that S. japonicum infection has a significant effect on microbiome composition characterized by a higher abundance of the TM7 phylum and development of a Bacteroides enterotype.

7.
J Ethnopharmacol ; 271: 113833, 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33465437

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Miao-Yong-An decoction (SMYAD), a classical traditional Chinese medicine (TCM) formula, has been used to treat various cardiovascular diseases in clinics. AIM OF THE STUDY: The aim of this study is to investigate the effective combinatorial components from SMYAD and its mechanism regarding the intervention on myocardial hypertrophy. MATERIALS AND METHODS: SMYAD constituents absorbed in rat plasma and heart were identified using UHPLC Q-Exactive-Orbitrap MS/MS. The identified constituents in SMYAD were further analyzed using ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction and molecular docking. The effective constituents were identified using isoproterenol (ISO)-induced H9c2 cardiomyocyte hypertrophy, and neochlorogenic acid (NCA), chlorogenic acid (CA), cryptochlorogenic acid (CCA), isochlorogenic acid C (ICAC), angoroside C (AGDC), isochlorogenic acid A (ICAA), sweroside (SRD), and harpagide (HPD) in SMYAD extract were quantified by HPLC for compatibility. Finally, anti-hypertrophic activities of candidate effective combinatorial components, which were prepared according to the determined molar concentration ratio of effective constituents using reference substance solution, were analyzed using immunofluorescence staining and Quantitative real-time PCR. The expression levels of PI3Kα, p-ERK, p-Akt, Akt, p-mTOR, mTOR and HIF-1α were measured using Western blot. RESULTS: 32 prototypes of SMYAD were identified from plasma and heart tissue of rat. Combining with ADMET prediction, 31 dominant constituents were focused. Based on HIF-1 pathway identified in preliminary result, 17 targets were focused, which were used to dock with 31 constituents. 27 constituents were therefore hit as the potential effective constituents of SMYAD in inhibiting myocardial hypertrophy. Bioactivity evaluation showed that NCA, CA, CCA, ICAC, AGDC, ICAA, SRD, and HPD significantly inhibited the increase of H9c2 cell surface area induced by ISO. Except for ICAA and AGDC, the remaining 6 effective constituents, showing a certain inhibitory effect on ISO-induced ANP mRNA overexpression at high and low concentrations, participated in compatibility based on the molar concentration ratio determined by HPLC. Effective combinatorial components composed of the 6 effective constituents (effective combinatorial components ABC) showed significant inhibitory effect on the increase of cell surface area, and the overexpression of ANP and ß-MHC mRNA in H9c2 cells induced by ISO. Moreover, effective combinatorial components ABC significantly inhibited the protein overexpressions of p-Akt, p-mTOR and HIF-1α. Based on the results, we put forward the strategy of "Focusing constituents" and "Focusing targets" for the effective constituents research of TCM formula. CONCLUSION: Effective combinatorial components ABC composed of NCA, CA, CCA, ICAC, SRD and HPD from SMYAD inhibited ISO-induced cardiomyocyte hypertrophy and down-regulated expression of ANP and ß-MHC mRNA through the inactivation of Akt/mTOR/HIF-1α pathway.

8.
J Ethnopharmacol ; 270: 113831, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33476714

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Clematis chinensis Osbeck (C. chinensis), Clematis hexapetala Pall (C. hexapetala) and Clematis terniflora var. mandshurica Rupr (C. mandshurica) are collectively referred to as Clematidis Radix et Rhizome (CRR) in China. CRR is widely distributed in China, which is used as a traditional Chinese medicine to treat rheumatic arthralgia, limb numbness, tendon constriction and inconvenience in flexion and extension. AIMS OF THIS REVIEW: This review systematically summarized the research progress on uses, chemical components, pharmacological activities and toxicology of CRR, listed the chemical structures of main compounds for clarifying the differences in chemical compositions. Meanwhile, the review will provide a theoretical and practical basis for the further research and development of CRR. MATERIALS AND METHODS: The available information on CRR was collected using published materials and electronic databases, including ancient and modern books, Chinese Pharmacopoeia, Ph.D. and M. Sc. dissertations, CNKI, SciFinder, WanFang data, PubMed, ScienceDirect and Web of Science. The starting and ending years of references is 1965-2020, the search strategy was conducted by key words such as uses, chemical components, pharmacology and toxicology of CRR. RESULTS: Up to now, CRR has been used to treat various diseases/disorders, such as relieving rheumatism pain, treating cervical spondylopathy and scapulohumeral periarthritis, treating hepatic carcinoma and gastrointestinal, etc. In addition, more than 200 compounds have been isolated from the three plant species of Clematidis. Moreover, the crude extracts and isolated compounds of CRR have been reported to have a wide range of pharmacological activities, such as anti-inflammatory, anti-tumor, antimicrobial and antioxidant activities, etc. Toxicity studies have shown that CRR can cause oral burning, swelling, abdominal pain or severe diarrhea, difficulty breathing, dilated pupils, renal tissue structural changes, and severe death. CONCLUSIONS: Researches in recent years mainly focused on C. chinensis and C. mandshurica, while there are a few reports on the pharmacological studies of C. hexapetala. Therefore, it is necessary to conduct further research on C. hexapetala. Meanwhile, it is important to pay attention to pursue research on the similarities and differences between the three plant species of Clematidis to find their respective advantages and make rational use of CRR. In addition, there is no report on the mechanism of toxicity research, which needs more attention.

9.
Nano Res ; : 1-23, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33500771

RESUMO

Globally, millions of people die of microbial infection-related diseases every year. The more terrible situation is that due to the overuse of antibiotics, especially in developing countries, people are struggling to fight with the bacteria variation. The emergence of super-bacteria will be an intractable environmental and health hazard in the future unless novel bactericidal weapons are mounted. Consequently, it is critical to develop viable antibacterial approaches to sustain the prosperous development of human society. Recent researches indicate that transition metal sulfides (TMSs) represent prominent bactericidal application potential owing to the meritorious antibacterial performance, acceptable biocompatibility, high solar energy utilization efficiency, and excellent photo-to-thermal conversion characteristics, and thus, a comprehensive review on the recent advances in this area would be beneficial for the future development. In this review article, we start with the antibacterial mechanisms of TMSs to provide a preliminary understanding. Thereafter, the state-of-the-art research progresses on the strategies for TMSs materials engineering so as to promote their antibacterial properties are systematically surveyed and summarized, followed by a summary of the practical application scenarios of TMSs-based antibacterial platforms. Finally, based on the thorough survey and analysis, we emphasize the challenges and future development trends in this area.

10.
J Ethnopharmacol ; 266: 113404, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32976970

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Danqi Pill, composed of the root of Salvia miltiorrhiza Bunge and the root of Panax notoginseng, is effective in the clinical treatment of myocardial ischemia in coronary heart diseases. A number of studies have shown that autophagy plays an essential role in cardiac function and energy metabolism, and disordered autophagy is associated with the progression of heart failure. However, the effect and mechanism of Danqi pill on autophagy have not been reported yet. AIM OF THE STUDY: This study aims to elucidate whether Danqi pill restores autophagy to protect against HF and its potential mechanism. MATERIALS AND METHODS: Left anterior descending ligation was established to induce an HF rat model, H2O2-stimulated H9C2 cells model was conducted to clarify the effects and potential mechanism of Danqi pill. In vivo, Danqi pill (1.5 g/kg) were orally administered for four weeks and Fenofibrate (10 mg/kg) was selected as a positive group. In vitro, Danqi pill (10-200 µg/mL) was pre-cultured for 24 h and co-cultured with H2O2 stimulation for 4 h. Importantly, transmission electron microscopy and fluorescence GPF-mRFP-LC3 reporter system were combined to monitor autophagy flux. Furtherly, we utilized Compound C, a specific AMPK inhibitor, to validate whether the autophagy was mediated by AMPK-TSC2-mTOR pathway. RESULTS: Danqi pill significantly improved cardiac function and myocardial injury in HF rats. Intriguingly, Danqi pill potently regulated autophagy mainly by promoting the formation of autophagosomes in vivo. Further results demonstrated that expressions of p-AMPK (P < 0.001) and p-TSC2 (P < 0.001) in cardiac tissue were upregulated by Danqi pill, accompanied with downregulation of p-mTOR (P < 0.01) and p-ULK1(P < 0.01). In parallel with the vivo experiment, in vitro study indicated that Danqi pill dramatically restored autophagy flux and regulated expressions of critical autophagy-related molecules. Finally, utilization of Compound C abrogated the effects of Danqi pill on autophagy flux and the expressions of p-TSC2 (P < 0.05), p-mTOR (P < 0.01) and p-ULK1 (P < 0.05). CONCLUSION: Danqi pill could improve cardiac function and protect against cardiomyocytes injury by restoring autophagy via regulating the AMPK-TSC2-mTOR signaling pathway.


Assuntos
Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Insuficiência Cardíaca/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Insuficiência Cardíaca/etiologia , Masculino , Infarto do Miocárdio/complicações , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
11.
Front Cell Infect Microbiol ; 10: 614053, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33324584

RESUMO

Cryptosporidium and Giardia are two important zoonotic intestinal protozoa responsible for diarrheal diseases in humans and animals worldwide. Feces from infected hosts, water and food contaminated by Cryptosporidium oocysts and Giardia cysts as well as predictors such as poverty have been involved in their transmission. Myanmar is one of the world's most impoverished countries. To date, there are few epidemiological studies of Cryptosporidium and Giardia in humans. To understand the prevalence and genetic characterization of Cryptosporidium spp. and Giardia duodenalis in humans in Myanmar, a molecular epidemiological investigation of the two protozoa was conducted in four villages of Shan State. 172 fecal specimens were collected from Wa people (one each) and identified for the presence of Cryptosporidium spp. and G. duodenalis by sequence analysis of their respective small subunit ribosomal RNA genes. 1.74% of investigated people were infected with Cryptosporidium spp.-C. andersoni (n = 2) and C. viatorum (n = 1) while 11.05% infected with G. duodenalis-assemblages A (n = 6) and B (n = 13). By sequence analysis of 60-kDa glycoprotein gene, the C. viatorum isolate belonged to a novel subtype XVcA2G1c. DNA preparations positive for G. duodenalis were further subtyped. Five of them were amplified and sequenced successfully: different assemblage B sequences (n = 2) at the triosephosphate isomerase (tpi) locus; sub-assemblage AII sequence (n = 1) and identical assemblage B sequences (n = 2) at the ß-giardin (bg) locus. This is the first molecular epidemiological study of Cryptosporidium spp. and G. duodenalis in humans in Myanmar at both genotype and subtype levels. Due to unclear transmission patterns and dynamics of Cryptosporidium spp. and G. duodenalis, future research effort should focus on molecular epidemiological investigations of the two parasites in humans and animals living in close contact in the investigated areas, even in whole Myanmar. These data will aid in making efficient control strategies to intervene with and prevent occurrence of both diseases.

12.
J Infect Dev Ctries ; 14(10): 1106-1110, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33175703

RESUMO

The coronavirus pandemic is the biggest in the past 100 years, affected over 200 countries and killed over 300 thousand people. To better understand the epidemics in different areas, the progress percentage was generated in this study by dividing everyday total confirmed case number by the up-to-date total case number, so data obtained from different countries and territories can be put together and compared directly regardless of the large difference in the magnitude of numbers. The global outbreak data were analyzed and categorized into 4 groups based on different epidemic curve stages. The grouping pattern suggests that the geographical position may not play a critical role in the progress of COVID-19 epidemic. In this report, we also used a mathematic model to predict the progress of COVID-19 outbreak in UK, USA and Canada in Group 3, providing valuable information for assessing the risk in these countries and the timing of reopening business.


Assuntos
Infecções por Coronavirus/epidemiologia , Modelos Teóricos , Pneumonia Viral/epidemiologia , Betacoronavirus , Previsões , Saúde Global , Humanos , Pandemias
13.
Sci Rep ; 10(1): 18801, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139790

RESUMO

Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region. However, the contribution of hypo-innervation to electrophysiological remodeling, independent from MI-induced ischemia and fibrosis, has not been comprehensively investigated. We present a novel mouse model of regional cardiac sympathetic hypo-innervation utilizing a targeted-toxin (dopamine beta-hydroxylase antibody conjugated to saporin, DBH-Sap), and measure resulting electrophysiological and Ca2+ handling dynamics. Five days post-surgery, sympathetic nerve density was reduced in the anterior left ventricular epicardium of DBH-Sap hearts compared to control. In Langendorff-perfused hearts, there were no differences in mean action potential duration (APD80) between groups; however, isoproterenol (ISO) significantly shortened APD80 in DBH-Sap but not control hearts, resulting in a significant increase in APD80 dispersion in the DBH-Sap group. ISO also produced spontaneous diastolic Ca2+ elevation in DBH-Sap but not control hearts. In innervated hearts, sympathetic nerve stimulation (SNS) increased heart rate to a lesser degree in DBH-Sap hearts compared to control. Additionally, SNS produced APD80 prolongation in the apex of control but not DBH-Sap hearts. These results suggest that hypo-innervated hearts have regional super-sensitivity to circulating adrenergic stimulation (ISO), while having blunted responses to SNS, providing important insight into the mechanisms of arrhythmogenesis following sympathetic nerve loss.

14.
J Physiol ; 598(21): 4941-4955, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32864736

RESUMO

KEY POINTS: Stress triggers and exacerbates the symptoms of functional gastrointestinal disorders, such as delayed gastric emptying and impaired gastric motility. Understanding the mechanisms by which the neural circuits, impaired by stress, are restored may help to identify potential targets for more effective therapeutic interventions. Oxytocin administration or release ameliorates the stress-induced delayed gastric emptying and motility. However, is it unclear whether the effects are mediated via the hypothalamic-pituitary-adrenocortical axis or the oxytocinergic projections from the paraventricular nucleus of the hypothalamus to brainstem neurones of the dorsal vagal complex. We used Cre-inducible designer receptors exclusively activated by designer drugs to demonstrate the fundamental role of the oxytocinergic hypothalamic-vagal projections in the gastric adaptation to stress. ABSTRACT: Stress triggers and exacerbates the symptoms of functional gastrointestinal (GI) disorders, such as delayed gastric emptying and impaired gastric motility. The prototypical anti-stress hormone, oxytocin (OXT), plays a major role in the modulation of gastric emptying and motility following stress. It is not clear, however, whether the amelioration of dysregulated GI functions by OXT is mediated via an effect on the hypothalamic-pituitary-adrenocortical axis or the oxytocinergic projections from the paraventricular nucleus of the hypothalamus (PVN) to neurones of the dorsal vagal complex (DVC). In the present study we tested the hypothesis that the activity of hypothalamic-vagal oxytocinergic neurocircuits plays a major role in the gastric adaptation to stress. Cre-inducible designer receptors exclusively activated by designer drugs (DREADDs) were injected into the DVC of rats and retrogradely transported to allow selective expression in OXT neurones in the PVN. Following acute stress and either chronic heterotypic (CHe) or chronic homotypic (CHo) stress, gastric emptying was assessed via the [13 C]-octanoic acid breath test, and gastric tone and motility were assessed via strain gauges sewn on the surface of the stomach. Activation of the hypothalamic-vagal oxytocinergic neurocircuitry, by DREADD agonist clozapine-N-oxide (CNO), prevented the delayed gastric emptying observed following acute or CHe stress, and 4th ventricular administration of CNO increased gastric tone and motility. Conversely, CNO-mediated inhibition of the hypothalamic-vagal oxytocinergic neurocircuitry prevented the CHo-induced adaptation in gastric emptying, and an increase in gastric tone and motility. Taken together, the data support the hypothesis that hypothalamic-vagal oxytocinergic neurocircuits play a major role in the modulation of gastric emptying and motility following stress.

15.
Front Vet Sci ; 7: 430, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903723

RESUMO

Cryptosporidiosis is a major public health problem in humans and animals. Information on the prevalence and molecular diversity of Cryptosporidium in farmed deer in northeastern China is limited. In this study, the prevalence of these parasites was investigated in four farmed deer species, including 125 reindeer, 109 red deer, 86 sika deer, and 18 Siberian roe deer by nested PCR amplification of the partial small subunit of ribosomal RNA (SSU rRNA) gene. C. ubiquitum isolates were subtyped using nested PCR and sequence analysis of the 60-kDa glycoprotein (gp60) gene. The overall prevalence of Cryptosporidium was 7.1%, with 15.1% for sika deer, 4.0% for reindeer, 4.6% for red deer, and 5.6% for roe deer. C. ubiquitum (n = 4), C. xiaoi (n = 2), and Cryptosporidium deer genotype (n = 18) were identified. All four C. ubiquitum isolates belonged to the XIIa subtype (n = 4). This study confirms that Cryptosporidium deer genotype is widely occurring in deer in the investigated areas. Presence of zoonotic C. ubiquitum XIIa subtype indicates that farmed deer represent potential source of zoonotic cryptosporidia and might pose a threat to human health.

16.
Drug Dev Ind Pharm ; 46(11): 1809-1818, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32903067

RESUMO

Arsenic trioxide (ATO) is first-line drug for acute promyelocytic leukemia. Clinically, the continuously slow intravenous infusion is adopted to maintain effective blood concentration and reduce toxic effects, but it causes poor patient' compliance for a considerable infusion period. To overcome these disadvantages, we developed an oral ATO sustained-release preparation which was constructed via the ATO core pellets prepared by extrusion spheronization and followed by a coating membrane by fluid-bed technology. The prepared coated pellets displayed a round surface and uniform particle size. All in vitro release profiles of ATO pellets in different pH media and rotation speeds had no statistical difference. Importantly, the coated pellets can release completely in 12 h without obvious burst release. There was no distinct change in appearance and release behaviors in stability experiments. In vivo pharmacokinetics was studied by one-time intragastric administration of rats. Compared with free drug, the AUC0-∞ of the ATO coated pellets was 2.3-fold higher, indicating the oral bioavailability was significantly increased. Cmax decreased by about a half and Tmax extended about 15 h. In particularly, the ATO level at 96 h only decreased about 20% of Cmax , suggesting that the ATO sustained-release preparation could not only decrease the peak concentration, but also maintain a relatively constant blood concentration for a long period. Further, the in vivo absorption could be well predicted by in vitro release experiments. Therefore, the ATO sustained-release preparation formulated by the mature preparation technology, possessing satisfactory stability and improving bioavailability, had great application potentials for industrialization.

17.
AAPS PharmSciTech ; 21(7): 259, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32914285

RESUMO

Nanomedicines such as liposomes have been widely exploited in the treatment of tumors, and are also involved in combination therapies to enhance anti-tumor efficacy and reduce side effects. However, few studies have systematically discussed the significance and optimized regimens for nanomedicine-based combination therapy. In this study, we used anti-inflammatory and anti-tumor liposomes for co-administration, and compared three regimens: intermittent, metronomic, or sequential administration (IA, MA, and SA). The anti-inflammatory liposome HA/TN-CCLP was constructed in our previous research, which co-loaded curcumin (CUR) and celecoxib (CXB), modified with TAT-NBD peptide (TN) and finally coated with hyaluronic acid (HA), thereby inhibiting NF-κB and STAT3 pathways in the treatment of metastatic breast cancer. Furthermore, doxorubicin liposomes with and without TN modification (namely TN-DOXLP and DOXLP) were constructed and administrated with HA/TN-CCLP. The anti-tumor and anti-metastasis efficacy of different regimens was investigated. Results showed that in vitro cytotoxicity of DOXLP and TN-DOXLP was significantly enhanced when combined with HA/TN-CCLP. In vivo experiments also revealed the superiority of three combination therapies in inhibiting tumor growth, prolonging the survival of tumor-bearing mice, inducing apoptosis, and reducing lung metastases. In particular, the combination therapy could reduce MDSCs (Gr-1+/CD11b+) and CSCs (CD44+/CD24+) infiltration, which are two important factors in tumor metastasis and recurrence. Among three regimens, sequential administration (SA) showed the best therapeutic outcome and was especially effective for the inhibition of CSCs. In general, the results demonstrated that combination therapy, particularly the sequential administration of anti-inflammatory and anti-tumor liposome, was superior to monotherapy in inhibiting the development and metastasis of inflammation-related tumors.

18.
Curr Drug Metab ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32735517

RESUMO

OBJECTIVE: Study on the compatibility regularity of Simiao Yong'an Decoction by determination the plasma protein binding rate with the constituents in Simiao Yong'an Decoction. Preliminary clarify the effects of the compatibility on plasma protein binding rate of different components. METHODS: Based on the equilibrium dialysis method, high-performance liquid chromatography was used to determine the contents of six constituents, which were divided into single group and combination groups, in Simiao Yong'an Decoction in the internal and external dialysis solutions. The obtained plasma protein binding rate through calculations was as index to evaluate the binding of the above components to plasma protein in different conditions. RESULTS: Harpagide, harpagoside, sweroside and loganin had low plasma protein binding rates, ferulic acid had moderate plasma protein binding rate, and glycyrrhizic acid had high plasma protein binding rate. The compatibility study showed that glycyrrhizic acid promoted the binding of ferulic acid to plasma protein. Glycyrrhizic acid and ferulic acid were the key compounds to promote the binding of harpagide to plasma protein. Glycyrrhizic acid, harpagide, harpagoside and loganin had a significant inhibitory effects on the binding of sweroside to plasma protein. The plasma protein binding capacities of harpagoside and loganin were reduced by the other five constituents. Glycyrrhizic acid had the strongest plasma protein binding effect, and the binding effect was not affected by other components. CONCLUSIONS: This study explores the effects of compound compatibility on effective components from the perspective of plasma protein binding by high-performance liquid chromatography combined with equilibrium dialysis method, and lays a foundation for clarifying the compatibility rule of Simiao Yong'an Decoction and also provides a new idea for the study of compatibility of traditional Chinese medicine formulas.

19.
J Cell Mol Med ; 24(18): 10677-10692, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32757377

RESUMO

Heart failure (HF) represents a major public health burden. Inflammation has been shown to be a critical factor in the progression of HF, regardless of the aetiology. Disappointingly, the majority of clinical trials targeting aspects of inflammation in patients with HF have been largely negative. Many clinical researches demonstrate that danshen has a good efficacy on HF, and however, whether danshen exerts anti-inflammatory effects against HF remains unclear. In our study, the employment of a water extracted and alcohol precipitated of danshen extract attenuated cardiac dysfunction and inflammation response in acute myocardial infarction-induced HF rats. Transcriptome technique and validation results revealed that TLR4 signalling pathway was involved in the anti-inflammation effects of danshen. In vitro, danshen reduced the release of inflammatory mediators in LPS-stimulated RAW264.7 macrophage cells. Besides, the LPS-stimulated macrophage conditioned media was applied to induce cardiac H9C2 cells injury, which could be attenuated by danshen. Furtherly, knock-down and overexpression of TLR4 were utilized to confirm that danshen ameliorated inflammatory injury via MyD88-dependent TLR4-TRAF6-NF-κB signalling pathway in cardiomyocytes. Furthermore, by utilizing co-immunoprecipitation, danshen was proved to suppress MD2/TLR4 complex formation and MyD88 recruitment. In conclusion, our results demonstrated that danshen ameliorates inflammatory injury by controlling MD2/TLR4-MyD88 complex formation and TLR4-TRAF6-NF-κB signalling pathway in acute myocardial infarction-induced HF.

20.
Parasit Vectors ; 13(1): 367, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698833

RESUMO

BACKGROUND: Enterocytozoon bieneusi is the most frequently detected microsporidian species in humans and animals. Currently, to the best of our knowledge, no information on E. bieneusi infection in Himalayan marmots (Marmota himalayana) and Alashan ground squirrels (Spermophilus alashanicus) is available worldwide. The aim of the present study was to understand the occurrence and genetic characterizations of E. bieneusi in Himalayan marmots and Alashan ground squirrels in the Qinghai-Tibetan Plateau area (QTPA), Gansu Province, China. METHODS: A total of 498 intestinal contents were collected from 399 Himalayan marmots and 99 Alashan ground squirrels in QTPA. These samples were screened for the presence of E. bieneusi by using nested polymerase chain reaction and sequencing of the internal transcribed spacer (ITS) region of the ribosomal RNA (rRNA) gene. The ITS-positive sequences were aligned and phylogenetically analyzed to determine the genotypes of E. bieneusi. RESULTS: The average infection rate of E. bieneusi was 10.0% (50/498), with 11.8% (47/399) in Himalayan marmots and 3.0% (3/99) in Alashan ground squirrels. A total of 7 distinct E. bieneusi genotypes were confirmed: 1 known genotype, YAK1 (n = 18) and 6 novel genotypes, named as ZY37 (n = 27), HN39 (n = 1), HN96 (n = 1), SN45 (n = 1), XH47 (n = 1) and ZY83 (n = 1). All the genotypes obtained in the present study were classified into group 1. CONCLUSIONS: To our knowledge, this is the first report of E. bieneusi in Himalayan marmots and Alashan ground squirrels in China. The identification of genotype YAK1 in the two rodent species expanded the host range of this genotype. All the seven genotypes were clustered into zoonotic group 1, suggesting that these animal species can be potential epidemiological vectors of zoonotic microsporidiosis caused by E. bieneusi and pose a threat to ecological security. It is necessary to strengthen management practices and surveillance in the investigated areas to reduce the risk of E. bieneusi infection from the two rodent species to humans.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA