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1.
Cell ; 179(5): 1160-1176.e24, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730855

RESUMO

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.


Assuntos
Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/patologia , Antígenos CD/metabolismo , Apirase/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Morte Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Criança , Estudos de Coortes , Colo/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Dipiridamol/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Predisposição Genética para Doença , Homeostase/efeitos dos fármacos , Humanos , Imunoglobulina G/sangue , Memória Imunológica , Inflamação/patologia , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/genética , Interferon Tipo I/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metilprednisolona/farmacologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo
2.
Semin Immunol ; 69: 101809, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37478801

RESUMO

Pyroptosis is a form of programmed cell death associated with activation of inflammasomes and inflammatory caspases, proteolytic cleavage of gasdermin proteins (forming pores in the plasma membrane), and selective release of proinflammatory mediators. Induction of pyroptosis results in amplification of inflammation, contributing to the pathogenesis of chronic cardiovascular diseases such as atherosclerosis and diabetic cardiomyopathy, and acute cardiovascular events, such as thrombosis and myocardial infarction. While engagement of pyroptosis during sepsis-induced cardiomyopathy and septic shock is expected and well documented, we are just beginning to understand pyroptosis involvement in the pathogenesis of cardiovascular diseases with less defined inflammatory components, such as atrial fibrillation. Due to the danger that pyroptosis represents to cells within the cardiovascular system and the whole organism, multiple levels of pyroptosis regulation have evolved. Those include regulation of inflammasome priming, post-translational modifications of gasdermins, and cellular mechanisms for pore removal. While pyroptosis in macrophages is well characterized as a dramatic pro-inflammatory process, pyroptosis in other cell types within the cardiovascular system displays variable pathways and consequences. Furthermore, different cells and organs engage in local and distant crosstalk and exchange of pyroptosis triggers (oxidized mitochondrial DNA), mediators (IL-1ß, S100A8/A9) and antagonists (IL-9). Development of genetic tools, such as Gasdermin D knockout animals, and small molecule inhibitors of pyroptosis will not only help us fully understand the role of pyroptosis in cardiovascular diseases but may result in novel therapeutic approaches inhibiting inflammation and progression of chronic cardiovascular diseases to reduce morbidity and mortality from acute cardiovascular events.


Assuntos
Doenças Cardiovasculares , Piroptose , Animais , Humanos , Piroptose/fisiologia , Gasderminas , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Inflamassomos/metabolismo , Inflamação
3.
Actas Esp Psiquiatr ; 52(4): 445-452, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39129691

RESUMO

BACKGROUND: Lung cancer is a significant health concern, and is often accompanied by comorbid depression, leading to worsened prognosis and decreased quality of life for patients. This study aimed to investigate the potential influence of a diet rich in Omega-3 fatty acids on the quality of life of patients with squamous cell lung cancer and comorbid depression. METHODS: A retroactive analysis of clinical information from patients with squamous cell lung cancer and comorbid depression admitted to Hongqi Hospital Affiliated to Mudanjiang Medical University from June 2022 to June 2023 was conducted. The patients were classified into two groups on the basis of different dietary care approaches: the Routine Dietary Group and the Omega-3 Fatty Acids Group. Baseline characteristics, pulmonary function tests, dietary intake, depression scoring, and quality of life scores were compared between the two groups. RESULTS: 103 patients in total were included, with 51 in the Routine Dietary Group and 52 in the Omega-3 Fatty Acids Group. The Omega-3 Fatty Acids Group exhibited significantly higher ingestion of Omega-3 fatty acids in comparison with the Routine Dietary Group (3.15 ± 0.64 g/day vs. 2.93 ± 0.28 g/day, p = 0.022). Despite similar baseline pulmonary function tests, patients in the Omega-3 Fatty Acids Group showed significantly higher scores in physical (70.17 ± 4.81 vs. 68.18 ± 5.03, p = 0.043) and emotional (71.29 ± 4.58 vs. 69.38 ± 4.25, p = 0.030) functioning, as well as lower scores in insomnia (27.41 ± 4.51 vs. 29.34 ± 4.21, p = 0.027) and constipation (7.34 ± 1.66 vs. 8.43 ± 3.36, p = 0.040). CONCLUSION: The study provided insights into the potential impact of a diet rich in Omega-3 fatty acids on the quality of life of patients with squamous cell lung cancer and complicating depression, suggesting that dietary interventions emphasizing Omega-3 fatty acids may be conducive to improving physical and emotional functioning, as well as symptom management, in this patient population.


Assuntos
Depressão , Ácidos Graxos Ômega-3 , Neoplasias Pulmonares , Qualidade de Vida , Humanos , Ácidos Graxos Ômega-3/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pulmonares/dietoterapia , Neoplasias Pulmonares/complicações , Estudos Retrospectivos , Depressão/dietoterapia , Depressão/epidemiologia , Idoso , Dieta , Carcinoma de Células Escamosas/dietoterapia
4.
Pediatr Res ; 94(6): 1935-1941, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37460708

RESUMO

BACKGROUND: Hirschsprung disease (HSCR) is a congenital intestinal malformation. Previous HSCR animal model needs invasive operation on adult animal. The aim of this study is to establish an early-onset animal model which is consistent with the clinical manifestation of HSCR patients. METHODS: The neonatal mice were randomly divided into the benzalkonium chloride (BAC) group, treated with BAC via enema, and the control group, treated with saline. Weight changes, excretion time of carmine, CT scan, hematoxylin-eosin staining and immunofluorescence staining were used to evaluate the effect of the model. Differentially expressed genes (DEGs) in the HSCR mice were analyzed by using DAVID 6.8 database and compared with DEGs from HSCR patients. RESULTS: The weight of mice was lower and the excretion time of carmine was longer in the BAC group. Moreover, distal colon stenosis and proximal colon enlargement appeared in the BAC group. Neurons in the distal colon decreased significantly after 4 weeks of BAC treatment and almost disappeared completely after 12 weeks. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression. CONCLUSIONS: An economical and reliable HSCR animal model which has similar clinical characteristics to HSCR patients was successfully established. IMPACT: The animal model of Hirschsprung disease was first established in BALB/c mice. This model is an animal model of early-onset HSCR that is easy to operate and consistent with clinical manifestations. Transcriptome profiling of the mouse model and HSCR patients is similar in terms of altered gene expression.


Assuntos
Doença de Hirschsprung , Humanos , Camundongos , Animais , Doença de Hirschsprung/genética , Doença de Hirschsprung/metabolismo , Carmim , Intestinos , Modelos Animais de Doenças
5.
Anal Chem ; 94(25): 9106-9113, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35704448

RESUMO

Herein, a highly efficient electrochemiluminescence (ECL) emitter, luminol/MoS2 quantum dots@zeolitic imidazolate framework-8 (Lu/MoS2 QDs@ZIF-8), with a positive charge was prepared to construct a novel luminol-H2O2-MoS2 QD ternary ECL system for ultrasensitive detection of microRNA-21 (miRNA-21). The porous Lu/MoS2 QDs@ZIF-8 was beneficial for reducing the accessible distance between various participants in the ternary system wherein co-reaction accelerator MoS2 QDs promoted H2O2 to generate superoxide anion radicals (O2•-), which instantaneously reacted with luminol to produce robust ECL signals. Simultaneously, the positively charged Lu/MoS2 QDs@ZIF-8 facilitated the enrichment of O2•- to further improve the ECL efficiency of luminol. Impressively, compared with the traditional binary luminol-H2O2 system, the ECL efficiency of this ternary system was increased by 12.7 times. In the aid of a target-cycled and endogenous adenosine triphosphate-driven signal amplification strategy, the biosensor with Lu/MoS2 QDs@ZIF-8 as an ECL emitter achieved ultrasensitive detection for miRNA-21 with a detection limit of 14.6 aM. This work provides a promising perspective to construct a highly efficient ECL ternary system for biomolecule detection and potential disease diagnosis.


Assuntos
MicroRNAs , Pontos Quânticos , Zeolitas , Humanos , Peróxido de Hidrogênio , Limite de Detecção , Medições Luminescentes , Luminol , Molibdênio
6.
Circ Res ; 127(7): 855-873, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32597702

RESUMO

RATIONALE: Kawasaki disease (KD) is an acute vasculitis of early childhood that can result in permanent coronary artery structural damage. The cause for this arterial vulnerability in up to 15% of patients with KD is unknown. Vascular smooth muscle cell dedifferentiation play a key role in the pathophysiology of medial damage and aneurysm formation, recognized arterial pathology in KD. Platelet hyperreactivity is also a hallmark of KD. We recently demonstrated that uptake of platelets and platelet-derived miRNAs influences vascular smooth muscle cell phenotype in vivo. OBJECTIVE: We set out to explore whether platelet/vascular smooth muscle cell (VSMC) interactions contribute to coronary pathology in KD. METHODS AND RESULTS: We prospectively recruited and studied 242 patients with KD, 75 of whom had documented coronary artery pathology. Genome-wide miRNA sequencing and droplet digital PCR demonstrated that patient with KD platelets have significant induction of miR-223 compared with healthy controls (HCs). Platelet-derived miR-223 has recently been shown to promote vascular smooth muscle quiescence and resolution of wound healing after vessel injury. Paradoxically, patients with KD with the most severe coronary pathology (giant coronary artery aneurysms) exhibited a lack of miR-223 induction. Hyperactive platelets isolated from patients with KD are readily taken up by VSMCs, delivering functional miR-223 into the VSMCs promoting VSMC differentiation via downregulation of PDGFRß (platelet-derived growth factor receptor ß). The lack of miR-223 induction in patients with severe coronary pathology leads to persistent VSMC dedifferentiation. In a mouse model of KD (Lactobacillus casei cell wall extract injection), miR-223 knockout mice exhibited increased medial thickening, loss of contractile VSMCs in the media, and fragmentation of medial elastic fibers compared with WT mice, which demonstrated significant miR-223 induction upon Lactobacillus casei cell wall extract challenge. The excessive arterial damage in the miR-223 knockout could be rescued by adoptive transfer of platelet, administration of miR-223 mimics, or the PDGFRß inhibitor imatinib mesylate. Interestingly, miR-223 levels progressively increase with age, with the lowest levels found in <5-year-old. This provides a basis for coronary pathology susceptibility in this very young cohort. CONCLUSIONS: Platelet-derived miR-223 (through PDGFRß inhibition) promotes VSMC differentiation and resolution of KD induced vascular injury. Lack of miR-223 induction leads to severe coronary pathology characterized by VSMC dedifferentiation and medial damage. Detection of platelet-derived miR-223 in patients with KD (at the time of diagnosis) may identify patients at greatest risk of coronary artery pathology. Moreover, targeting platelet miR-223 or VSMC PDGFRß represents potential therapeutic strategies to alleviate coronary pathology in KD. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Plaquetas/metabolismo , Doença da Artéria Coronariana/etiologia , MicroRNAs/sangue , MicroRNAs/metabolismo , Síndrome de Linfonodos Mucocutâneos/complicações , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Adulto , Fatores Etários , Animais , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Ativação Plaquetária , Estudos Prospectivos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Índice de Gravidade de Doença , Transdução de Sinais , Adulto Jovem
7.
J Sep Sci ; 45(3): 760-770, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34856057

RESUMO

A series of low-cost hyper-crosslinked polymers were prepared by an easy one-step Friedel-Crafts reaction. The synthesized hyper-crosslinked polymers exhibited remarkably porous structure, large surface area, and hydroxyl groups, which can be employed as an ideal adsorbent material for novel sorbent-phase extraction techniques. Based on this, using hyper-crosslinked polymers as sorbent and coating, three novel extraction methods, including micro-solid-phase extraction, dispersive solid-phase extraction, and solid-phase microextraction, were explored and evaluated for simultaneous measurement of five endocrine-disrupting compounds (triclosan and bisphenol A, tetrabromobisphenol A, tetrabromobisphenol A bisallylether, and tetrabromobisphenol A bis(2,3-dibromopropyl ether)) in environment water prior to high-performance liquid chromatography-ultraviolet. The influence of experimental parameters on three extraction techniques such as extraction time, the amount of hyper-crosslinked polymers, extraction temperature, ionic strength, and desorption conditions were optimized. Three previously mentioned methods provided limits of detection ranging from 0.01 to 0.05 µg/L, and high recoveries (85-99%) with relative standard deviations of 1.7-5.6%. This study presented the merits and disadvantages of three proposed extraction methods and their potential for effective monitoring of hazardous pollutants in real water samples.


Assuntos
Polímeros , Poluentes Químicos da Água , Cromatografia Líquida de Alta Pressão , Limite de Detecção , Polímeros/química , Extração em Fase Sólida , Microextração em Fase Sólida/métodos , Água , Poluentes Químicos da Água/análise
8.
J Drug Deliv Sci Technol ; 66: 102738, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36568326

RESUMO

Acute lung injury/inflammation (ALI) is usually caused by various injury factors inside and outside the lung, which can be transformed into acute respiratory distress syndrome (ARDS) in severe cases. Alveolar macrophages play a key role in the pathogenesis of ALI, which regulate inflammatory responses by secreting inflammatory mediators. Therefore, we prepared dexamethasone (DXM)/mannose co-modified branched polyethyleneimine (PEI) (DXM-PEI-mannose, DPM) prodrug nanopartcales, which could effectively target the mannose receptor (MR) on the surface of alveolar macrophages and be used for the treatment of ALI. The DXM-PEI (DP) prodrug was obtained by linking DXM with branched PEI through Schiff base reaction. Subsequently, the pH-responsive DPM prodrug was obtained by using mannose-targeted head modification. The DPM prodrug NPs with a particle size of 115 ± 1 nm, a polydispersity index (PDI) value of 0.054 ± 0.018, and a zeta potential of 31 ± 1 mV were obtained by cross-linking. The drug loading of DPM prodrug NPs measured by the acid hydrolysis method was 51.88%, which had good serum stability and biocompatibility. By comparing the stability and property release of prodrug NPs under different pH (7.4 and 5.0) conditions, it showed that DPM prodrug NPs had certain sensitivity to the micro-acid environment. To study the targeting of mouse mononuclear macrophages, mannose-modified prodrug NPs showed significant in vitro targeting. Moreover, prodrug NPs showed good anti-inflammatory activity in vitro, which was significantly different from free drugs. In vivo biodistribution experiments also showed that it had a long-term lung targeting effect. DPM prodrug NPs also had a good therapeutic effect on ALI. In conclusion, the mannose-modified DXM prodrug NPs delivery system could specifically target lung tissues and have a good therapeutic effect, which might be useful for the treatment of lung diseases.

9.
Mol Pharm ; 17(1): 84-97, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31794225

RESUMO

As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3+ group of CYS after coamorphization. A fluorescence quenching test with a Stern-Volmer plot and density functional theory modeling, phase-solubility study, and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to the solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.


Assuntos
Antipsicóticos/química , Cloridrato de Lurasidona/química , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Cristalização , Cisteína/química , Estabilidade de Medicamentos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Difração de Raios X
10.
AAPS PharmSciTech ; 21(6): 217, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32743738

RESUMO

Currently, there is no specific treatment for acute lung injury (ALI) in clinical practice. In order to efficiently and accurately treat ALI, the advantages of cationic carriers were combined to accelerate the cell uptake. Polycaprolactone-polyethylene glycol carrier (PCL-PEG-COOH, PPC) with good biocompatibility, polycaprolactone-polyethylmethacrylate cationic carrier (PCL-PDMAEMA, PCD), and polycaprolactone-polyethylene glycol carrier connected with high-affinity targeting peptide (Esbp) targeting inflammatory endothelial cells (PCL-PEG-Esbp, PPE) were used to construct the high-molecular polymer micelles (PCD/PPC/PPE). The particle size of the prepared DEX-loaded micelles was 130 ± 4.41 nm, and the Zeta potential was 28.3 ± 0.76 mV. The CMC value of the prepared polymer micelles was 0.643 µg/mL, and it was not easy to depolymerize in the blood circulation. Only about 40% DXM was released from the drug-loaded polymer micelles after 12 h compared with free DXM, indicating that the micelle material had a certain sustained-release performance in vitro release experiments. The safe concentration range of polymer was determined by biocompatibility test. It was recommended that the concentration of polymer micelles should not exceed 0.40 mg/mL to obtain a good compatibility in organisms. The results of cytotoxicity measurement showed that when the content of PCD increased to 50%, the concentration of blank micelles should not exceed 500 µg/mL and the concentration of DXM-loaded micelles should not be higher than 100 µg/mL. It was proved in the cell uptake experiment that the cation carrier of the micelles accelerated the cell uptake. The targeting ability of the targeted micelle group was higher compared with the non-targeted micelle group (P < 0.01, **). Meanwhile, the targeting ability of the non-targeted micelle group was higher compared with the free group (P < 0.001, ***). The targeting ability of the non-targeted micelle group was about 2.30 times and the targeted micelle group was about 3.16 times larger than that of the free group. It was also proved in the in vivo targeting experiments that the targeted micelles had a good targeting ability. The results of in vivo imaging of mice showed that the DXM of the micelle group gathered more in the lungs, and the micelle group had a better targeting ability compared with the free DID group. The order of lung targeting intensity was targeted micelles > non-targeted micelles >> free DID group. The targeting ability of polypeptide Esbp to ALI was confirmed. In conclusion, the prepared PCD/PPC/PPE polymer micelles had obvious in vitro and in vivo targeting ability and good biocompatibility. They could be used as a new targeted delivery system for the treatment of ALI in the future.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Inflamação/tratamento farmacológico , Micelas , Polímeros/administração & dosagem , Animais , Dexametasona/administração & dosagem , Portadores de Fármacos/química , Humanos , Camundongos , Tamanho da Partícula , Polímeros/química , Polímeros/uso terapêutico
11.
Clin Exp Rheumatol ; 37(1): 67-72, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29998838

RESUMO

OBJECTIVES: The aim of this study was to explore the value of serum miRNA for evaluating renal tissue activity in patients with class IV lupus nephritis (LN). METHODS: First, we used a microRNA array to identify miRNAs differentially expressed between class IV LN patients and healthy volunteers (n=4/group). Then, we analysed the association between these identified miRNAs and renal tissue activity in class IV LN patients. Finally, to validate the results, 20 class IV LN patients (confirmed by renal biopsy) and 20 healthy control volunteers were further studied. RESULTS: We found 23 miRNAs to be significantly differentially expressed between the 2 groups. We selected 5 of these miRNAs (miR-3165, miR-4762-5p, miR-146a-5p, miR-151a-3p, and miR-21-5p) for further experiments. In validation experiments, expression of miRNA-151a-3p was significantly down-regulated in the class IV LN group compared to that in the control group (p<0.01) and was negatively correlated with the activity index (AI) in the class IV LN group(r=-0.526, p=0.017); the internal correlation was described with a linear fitting equation (p<0.01). CONCLUSIONS: Serum miR-151a-3p expression was decreased in class IV LN patients compared with healthy control volunteers and was negatively correlated with renal tissue activity. Thus, miR-151a-3p may play a employed for diagnosing class IV LN and evaluating renal tissue activity.


Assuntos
Nefrite Lúpica/metabolismo , MicroRNAs , Estudos de Casos e Controles , Regulação para Baixo , Humanos , Nefrite Lúpica/genética , MicroRNAs/metabolismo
12.
Biochem Biophys Res Commun ; 503(3): 1645-1650, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30055803

RESUMO

Acetylshikonin (AS), a naphthoquinone constituent derived from Lithospermum erythrorhizon, has been revealed various pharmacological activities including anti-oxidative, anti-inflammatory and antifertility effects. Our previous study has illuminated the effects of AS on preventing obesity and hepatic steatosis in db/db mice. However, the effects of AS and the molecular mechanisms for curing non-alcoholic steatohepatitis (NASH) have not yet been studied. Autophagy has been considered as a lysosomal degradative pathway responsible for the removal of cellular lipid droplets through a process called lipophagy, which is recognized as a potential therapeutic approach for NASH. Here we hypothesize that autophagy is involved in the beneficial effects of AS on methionine-choline deficient (MCD) diet-induced NASH of mice. In this study, we observed that AS treatment ameliorated the pathological signs of NASH, and markedly suppressed the levels of hepatic IL-1ß and TNF-α cytokines, and hepatocyte apoptotic cells in MCD diet-induced mice. Moreover, immunological analyses showed that the elevated expression of the fibrotic markers including α-SMA, collegen I, collegen III and fibronectin in MCD diet-induced mice were notably down-regulated by AS treatment. Nevertheless, the beneficial effects of AS on ameliorating NASH were notably counteracted by co-administration of chloroquine, an autophagy inhibitor. Furthermore, our data suggested that AS treatment increased hepatocyte autophagy in MCD diet-induced mice via AMPK/mTOR pathway. These findings suggest that AS could be therapeutically effective in the development of NASH by ameliorating steatosis, inflammation, liver injury and fibrosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antraquinonas/farmacologia , Autofagia/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
13.
Chem Pharm Bull (Tokyo) ; 66(12): 1114-1121, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504628

RESUMO

Tadalafil (TD), a phosphodiesterase-5 (PDE-5) inhibitor with poor oral bioavailability. The aim of the study was to prepare and characterize three crystalline polymorphs of TD (II, III, and IV) and the tadalafil amorphous form (TD-AM). TD polymorphs and TD-AM were prepared and characterized by polarized light microscope (PLM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray powder diffractometry (XRPD), and Fourier-transform (FT)IR, followed by the dissolution testing, physical stabilities and polymorphic transformation studies. TD-I and TD-II were found to be enantiotropically related, while TD-III was monotiotropically related to TD-I with heat release. Among all studied polymorphs, TD-AM demonstrated an extremely high intrinsic dissolution rate with most prolonged higher saturated concentration during dissolution, while TD-II, TD-III, and TD-IV converted to TD-I easily by supersaturation-mediated phase transformation. Upon heating under 60°C for 3 h and storing at long-term stability condition for 3 months, no phase transformation was detected for TD-I, TD-III, and TD-AM, while TD-II and TD-IV easily transformed to TD-I and TD-III, respectively. The higher intrinsic dissolution rate, prolonged supersaturated state during dissolution and favorable physical stability of TD-AM made it to be a very promising candidate for further product development.


Assuntos
Polímeros/química , Tadalafila/química , Cristalização , Conformação Molecular , Tamanho da Partícula , Polímeros/síntese química , Solubilidade , Propriedades de Superfície , Tadalafila/síntese química
14.
Biochem Biophys Res Commun ; 476(4): 560-565, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27264949

RESUMO

Zicao is being highlighted as a promising Chinese medicine due to all the beneficial effects that have been associated with its use. Unfortunately, studies on the toxicity of Zicao in different species are still missing and should be carried out. In this study, we investigated whether Acetylshikonin (AS) from Zicao has an anti-fertility effect through mating experiments and explored its underling mechanism. Sprague-Dawley rats received no treatment or were treated with 120, 360 or 1080 mg/kg AS extract by intragastric administration for 2 weeks. The rat pregnancy rate of the 1080 mg/kg dose group was significantly decreased relative to control group, while it recovered after a month of drug withdrawal, which indicated that the effect of antifertility is reversible. Serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in rat were significantly decreased by AS. The secretion of FSH in rat anterior pituitary cells was decreased but the synthesis was not affected. AS reduced the number of developing follicle and mature follicle in rat ovarian cortical. Maybe all of these resulted from AS decreased the expression of synaptotagmin-1 and SNAP-25 which were the critical proteins of exocytosis. Our data suggested that AS at high dose can suppress the ability of pregnancy of the rats through decreasing serum FSH and LH levels by affecting exocytosis process of gonadotropic hormone (GTH).


Assuntos
Antraquinonas/administração & dosagem , Fertilidade/efeitos dos fármacos , Hormônio Foliculoestimulante/metabolismo , Hormônio Luteinizante/metabolismo , Animais , Antraquinonas/isolamento & purificação , Antraquinonas/toxicidade , Boraginaceae/química , Células Cultivadas , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/toxicidade , Feminino , Fertilidade/fisiologia , Hormônio Foliculoestimulante/sangue , Hormônio Liberador de Gonadotropina/administração & dosagem , Hormônio Luteinizante/sangue , Masculino , Adeno-Hipófise/citologia , Adeno-Hipófise/efeitos dos fármacos , Adeno-Hipófise/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley
15.
Molecules ; 21(8)2016 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-27483220

RESUMO

Zicao (Lithospermum erythrorhizon) has been used in clinics as a traditional Chinese medicine for thousands of years. Acetylshikonin (AS) is the main ingredient of Zicao, Xinjiang, China. The objective of this study was to investigate the anti-obesity and anti-nonalcoholic fatty liver disease (NAFLD) efficacy of AS in a model of spontaneous obese db/db mice. Mice were divided into Wild Type (WT) groups and db/db groups, which received no treatment or treatment with 100 mg/kg/day clenbuterol (CL) hydrochloride or 540 mg/kg/day AS by oral gavage for eight weeks. The results provided the evidence that AS prevented obesity and NAFLD including reduction in body weight, food efficiency ratio, serum triglyceride (TG) and free fatty acid (FFA) levels in db/db mice. Administration of AS markedly suppressed the levels of hepatic alanine aminotransferase (ALT), aspartate aminotransferase (AST) and pro-inflammatory cytokines in treated groups when compared with that of db/db groups. Further investigation of the lipid synthesis-related protein using Western blotting revealed that hepatic protein expression of sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthetase (FAS) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were significantly downregulated by AS treatment. These findings suggest that AS exerts anti-obesity and anti-NAFLD effects through the regulation of lipid metabolism and anti-inflammatory effects.


Assuntos
Antraquinonas/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Peso Corporal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/prevenção & controle , Animais , Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos não Esterificados/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Triglicerídeos/sangue
16.
Contemp Nurse ; 50(1): 26-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26058405

RESUMO

PURPOSES: This study evaluated the effectiveness of cold-gel packing on episiotomy pain among postpartum women who had normal spontaneous deliveries. METHODS: A quasi-randomised control trial was conducted in a maternity ward of a regional teaching hospital in northern Taiwan. Seventy postpartum women were recruited, choosing to be in either the experimental or control group (35 women per group). Subjects in the experimental group received at least six interventions of cold-gel packing applied to the perineal wound and were provided oral analgesics routinely. The subjects in the control group received oral analgesics routinely. FINDINGS: Pain intensity, pain interference on daily activities and satisfaction levels with pain management were assessed using Brief Pain Inventory (BPI) and pain management questionnaire, respectively. The results showed that women in the experimental group reported significantly lower mean pain intensity score, pain interference on daily activities scores at 48 hours post-delivery, and higher level of satisfaction with pain management at 24 and 48 hours post-delivery than the control group after adjusting for demographic and obstetric data. CONCLUSIONS: Cold-gel packing on the perineum is a cost-effective, convenient, easy-to-deploy and non-pharmacologic approach to pain reduction, with an overall positive impact on postpartum recovery for parturients.


Assuntos
Analgésicos/administração & dosagem , Crioterapia , Episiotomia/efeitos adversos , Manejo da Dor/métodos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/terapia , Adulto , Feminino , Géis/uso terapêutico , Humanos , Períneo/cirurgia , Período Pós-Parto , Gravidez , Taiwan
17.
Mol Plant Pathol ; 25(4): e13456, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38619864

RESUMO

The spindle assembly checkpoint (SAC) proteins are conserved among eukaryotes safeguarding chromosome segregation fidelity during mitosis. However, their biological functions in plant-pathogenic fungi remain largely unknown. In this study, we found that the SAC protein MoMad1 in rice blast fungus (Magnaporthe oryzae) localizes on the nuclear envelope and is dispensable for M. oryzae vegetative growth and tolerance to microtubule depolymerizing agent treatment. MoMad1 plays an important role in M. oryzae infection-related development and pathogenicity. The monopolar spindle 1 homologue in M. oryzae (MoMps1) interacts with MoMad1 through its N-terminal domain and phosphorylates MoMad1 at Ser-18, which is conserved within the extended N termini of Mad1s from fungal plant pathogens. This phosphorylation is required for maintaining MoMad1 protein abundance and M. oryzae full virulence. Similar to the deletion of MoMad1, treatment with Mps1-IN-1 (an Mps1 inhibitor) caused compromised appressorium formation and decreased M. oryzae virulence, and these defects were dependent on its attenuating MoMad1 Ser-18 phosphorylation. Therefore, our study indicates the function of Mad1 in rice blast fungal pathogenicity and sheds light on the potential of blocking Mad1 phosphorylation by Mps1 to control crop fungal diseases.


Assuntos
Ascomicetos , Fosforilação , Virulência , Serina
18.
Int J Pharm ; 654: 123944, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38403089

RESUMO

Clarithromycin (CLA) is a high dose antibiotic drug exhibiting poor flowability and tabletability, making the tablet development challenging. This study aims to develop spherulitic CLA by introducing trace amount of polymer in crystallization solution. Its formation mechanism, physicochemical properties and potential for the direct compression (DC) tablets development were also investigated. Morphological analyses and the in situ observation on crystallization process revealed that the CLA spherulites are formed by fractal branching growth from both sides of the threadlike precursor fibers. 1H NMR analysis and nucleation time monitoring indicated that the existence of hydroxypropyl cellulose in solution slowed down the crystal nucleation and growth rate by forming hydrogen bonding interactions with CLA molecules, making the system maintain high supersaturation, providing high driving forces for CLA spherulitic growth. In comparison to commercial CLA, the CLA spherulites exhibit profoundly improved flowability, tabletability and dissolution behaviors. XPS, contact angle and Raman mapping analysis confirmed the presence of a thin HPC layer on the surfaces and interior of CLA spherulitic particles, resulting in increasing powder plasticity, interparticulate bonding strength and powder wettability, thus better tabletability and dissolution performances. The improved flowability and tabletability of CLA spherulites also enabled the successful development of DC tablet formulation with a high CLA loading (82.8 wt%) and similar dissolution profiles to reference listed drug. This study provides a novel solid form of CLA with superior manufacturability for further development.


Assuntos
Claritromicina , Polímeros , Composição de Medicamentos/métodos , Pós/química , Comprimidos/química , Solubilidade
19.
Chem Sci ; 15(33): 13486-13494, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39183916

RESUMO

Nucleophilic substitution is one of the most fundamental chemical reactions, and the pursuit of high reaction rates of the reaction is one of the ultimate goals in catalytic and organic chemistry. The reaction barrier of the nucleophilic substitution originates from the highly polar nature of the transition state that can be stabilized under the electric field created by the solvent environment. However, the intensity of the induced solvent-electric field is relatively small due to the random orientation of solvent molecules, which hinders the catalytic effects and restricts the reaction rates. This work shows that oriented external electric fields applied within a confined nanogap between two nanoscopic tips could accelerate the Menshutkin reaction by more than four orders of magnitude (over 39 000 times). The theoretical calculations reveal that the electric field inside the nanogap reduces the energy barrier to increase the reaction rate. Our work suggests the great potential of electrostatic catalysis for green synthesis in the future.

20.
Int J Pharm ; 642: 123181, 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37364786

RESUMO

As novel green solvents, deep eutectic solvent (DES) with distinct liquid properties has gained increasing interest in pharmaceutical fields. In this study, DES was firstly utilized for improving powder mechanical properties and tabletability of drugs, and the interfacial interaction mechanism was explored. Honokiol (HON), a natural bioactive compound, was used as model drug, and two novel HON-based DESs were synthesized with choline chloride (ChCl) and l-menthol (Men), respectively. The extensive non-covalent interactions were account for DES formation according to FTIR, 1H NMR and DFT calculation. PLM, DSC and solid-liquid phase diagram revealed that DES successfully in situ formed in HON powders, and the introduction of trace amount DES (99:1 w/w for HON-ChCl, 98:2 w/w for HON-Men) significantly improve mechanical properties of HON. Surface energy analysis and molecular simulation revealed that the introduced DES promoted the formation of solid-liquid interfaces and generation of polar interactions, which increase interparticulate interactions, thus better tabletability. Compared to nonionic HON-Men DES, ionic HON-ChCl DES exhibited better improvement effect, since their more hydrogen-bonding interactions and higher viscosity promote stronger interfacial interactions and adhesion effect. The current study provides a brand-new green strategy for improving powder mechanical properties and fills in the blank of DES application in pharmaceutical industry.


Assuntos
Solventes Eutéticos Profundos , Lignanas , Humanos , Masculino , Solventes/química , Pós , Colina/química
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