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1.
Oxid Med Cell Longev ; 2021: 7848027, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33936386

RESUMEN

Abnormal autophagy and oxidative stress contribute to angiotensin II- (Ang II-) induced cardiac hypertrophy and heart failure. We previously showed that Ang II increased Rap1GAP gene expression in cardiomyocytes associated with hypertrophy and autophagy disorders. Using real-time PCR and Western blot, we found that Rap1GAP expression was increased in the heart of Sprague Dawley (SD) rats infused by Ang II compared with saline infusion and in Ang II vs. vehicle-treated rat neonatal cardiomyocytes. Overexpression of Rap1GAP in cultured cardiomyocytes exacerbated Ang II-induced cardiomyocyte hypertrophy, reactive oxygen species (ROS) generation, and cell apoptosis and inhibited autophagy. The increased oxidative stress caused by Rap1GAP overexpression was inhibited by the treatment of autophagy agonists. Knockdown of Rap1GAP by siRNA markedly attenuated Ang II-induced cardiomyocyte hypertrophy and oxidative stress and enhanced autophagy. The AMPK/AKT/mTOR signaling pathway was inhibited by overexpression of Rap1GAP and activated by the knockdown of Rap1GAP. These results show that Rap1GAP-mediated pathway might be a new mechanism of Ang II-induced cardiomyocyte hypertrophy, which could be a potential target for the future treatment of cardiac hypertrophy and heart failure.

2.
Front Endocrinol (Lausanne) ; 12: 601752, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33815272

RESUMEN

Objective: To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies. Methods: According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed. Results: The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E2 and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status. Conclusions: Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI.

3.
Steroids ; 171: 108852, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33887267

RESUMEN

Steriods are well-known scaffolds that have a widespread occurrence in different compounds characterized by extensive biological properties including anticancer activity. Structural modifications on steroids always generate potential lead compounds with superior bioactivity, and creation of steroid hybrids by combining steroid with other anticancer pharmacophores in one molecule, which can exert the anticancer activity through different mechanisms, is one of the most promising strategies to enhance efficiency, overcome drug resistance and reduce side effects. Sugars and azoles, can act on diverse receptors, proteins and enzymes in cancer cells, are pharmacologically significant scaffolds in the development of novel anticancer agents. Therefore, steroid-sugar hybrids cardiac glycosides and steroid-azole hybrids are privileged scaffolds for the discovery of novel anticancer candidates. This review emphasized on the development, the structure-activity relationship and the mechanism of action of cardiac glycosides and steroid-azole hybrids with potential application for fighting against various cancers including drug-resistant forms to facilitate further rational design of novel drug candidates covering articles published between 2015 and 2020.

4.
Spectrochim Acta A Mol Biomol Spectrosc ; 258: 119823, 2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33901945

RESUMEN

Soil organic matter (SOM) is an important index used to evaluate soil fertility and nutrient availability, and it is also an important component of precision agriculture. In this study, in order to quickly and efficiently estimate the SOM content of farmland soil, we took 190 farmland soil samples in Jingbian County and measureed the SOM content of the samples in the lab and collected the corresponding Vis-NIR spectroscopy data. Based on the six pretreatment methods, a competitive adaptive weighting algorithm (CARS) is used for characteristic wavelength selection. Random forest (RF) regression is used to establish the predictive SOM model. The results indicate that after the CARS algorithm screens the different spectral variables, the optimal variable sets of the seven spectral variables are 15, 40, 30, 23, 20, 26, and 23, respectively. The accuracy of the model is improved after the CARS algorithm screens the different spectral variables. A total of 15 characteristic variables from the 2151 spectral wavelengths were used as the optimal spectral variable subset; RF shortened the training time required during the SOM modeling process and dramatically improved the model's accuracy and predictive ability, and the R2 of the validation set increased from 0.21 to 0.96, and the RPD increased from 0.46 to 3.02. The RPIQ increased from 1.25 to 4.41. Among the tested models, the CR-RF model produced the best results. The R2 and RMSE values of the calibration set are 0.91 and 0.49, and the R2, RMSE, RPD, and RPIQ values of the validation set are 0.96, 0.51, 3.02, and 4.41, respectively. Accurate prediction of the SOM of the cultivated layer in the study area was realized.

5.
Biochem Biophys Res Commun ; 553: 172-179, 2021 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-33773140

RESUMEN

BACKGROUND: Cardiac fibrosis will increase wall stiffness and diastolic dysfunction, which will eventually lead to heart failure. Asenapine maleate (AM) is widely used in the treatment of schizophrenia. In the current study, we explored the potential mechanism underlying the role of AM in angiotensin II (Ang II)-induced cardiac fibrosis. METHODS: Cardiac fibroblasts (CFs) were stimulated using Ang II with or without AM. Cell proliferation was measured using the cell counting kit-8 assay and the Cell-Light EdU Apollo567 In Vitro Kit. The expression levels of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were detected using immunofluorescence or western blotting. At the protein level, the expression levels of the components of the transforming growth factor beta 1 (TGFß1)/mitogen-activated protein kinase (MAPK) signaling pathway were also detected. RESULTS: After Ang II stimulation, TGFß1, TGFß1 receptor, α-SMA, fibronectin (Fn), collagen type I (Col1), and collagen type III (Col3) mRNA levels increased; the TGFß1/MAPK signaling pathway was activated in CFs. After AM pretreatment, cell proliferation was inhibited, the numbers of PCNA -positive cells and the levels of cardiac fibrosis markers decreased. The activity of the TGFß1/MAPK signaling pathway was also inhibited. Therefore, AM can inhibit cardiac fibrosis by blocking the Ang II-induced activation through TGFß1/MAPK signaling pathway. CONCLUSIONS: This is the first report to demonstrate that AM can inhibit Ang II-induced cardiac fibrosis by down-regulating the TGFß1/MAPK signaling pathway. In this process, AM inhibited the proliferation and activation of CFs and reduced the levels of cardiac fibrosis markers. Thus, AM represents a potential treatment strategy for cardiac fibrosis.

6.
Nat Commun ; 12(1): 932, 2021 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-33568641

RESUMEN

N-Arylation of NH-sulfoximines represents an appealing approach to access N-aryl sulfoximines, but has not been successfully applied to NH-diaryl sulfoximines. Herein, a copper-catalyzed photoredox dehydrogenative Chan-Lam coupling of free diaryl sulfoximines and arylboronic acids is described. This neutral and ligand-free coupling is initiated by ambient light-induced copper-catalyzed single-electron reduction of NH-sulfoximines. This electron transfer route circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions, increasing the environmental friendliness of this process. Instead, dihydrogen gas forms as a byproduct of this reaction. Mechanistic investigations also reveal a unique autocatalysis process. The C-N coupling products, N-arylated sulfoximines, serve as ligands along with NH-sulfoximine to bind to the copper species, generating the photocatalyst. DFT calculations reveal that both the NH-sulfoximine substrate and the N-aryl product can ligate the copper accounting for the observed autocatalysis. Two energetically viable stepwise pathways were located wherein the copper facilitates hydrogen atom abstraction from the NH-sulfoximine and the ethanol solvent to produce dihydrogen. The protocol described herein represents an appealing alternative strategy to the classic oxidative Chan-Lam reaction, allowing greater substrate generality as well as the elimination of byproduct formation from oxidants.


Asunto(s)
Ácidos Borónicos/química , Catálisis/efectos de la radiación , Fenómenos Químicos , Cobre/química , Luz , Estructura Molecular , Oxidantes/química , Oxidación-Reducción/efectos de la radiación
7.
Eur J Med Chem ; 212: 113153, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33453603

RESUMEN

Metal ion chelators based on 8-hydroxyquinoline (8-HQ) have been widely explored for the treatment of many diseases. When aimed at being developed into potent anticancer agent, a largely unmet issue is how to avoid nonspecific chelation of metal ions by 8-HQ in normal cells or tissues. In the current work, a two-step strategy was employed to both enhance the anticancer activity of 8-HQ and improve its cancer cell specificity. Considering the well-known anticancer activity of nitric oxide (NO), NO donor furoxan was first connected to 8-HQ to construct HQ-NO conjugates. These conjugates were screened for their cytotoxicity, metal-binding ability, and NO-releasing efficiency. Selected conjugates were further modified with a ROS-responsive moiety to afford prochelators. Among all the target compounds, prodrug HQ-NO-11 was found to potently inhibit the proliferation of many cancer cells but not normal cells. The abilities of metal chelation and NO generation by HQ-NO-11 were confirmed by various methods and were demonstrated to be essential for the anticancer activity of HQ-NO-11. In vivo studies revealed that HQ-NO-11 inhibited the growth of SW1990 xenograft to a larger extent than 8-HQ. Our results showcase a general method for designing novel 8-HQ derivatives and shed light on obtaining more controllable metal chelators.


Asunto(s)
Antineoplásicos/farmacología , Quelantes/farmacología , Óxido Nítrico/metabolismo , Oxiquinolina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quelantes/síntesis química , Quelantes/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Oxiquinolina/síntesis química , Oxiquinolina/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
8.
Curr Top Med Chem ; 2020 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-33238856

RESUMEN

The incidence and mortality of cancer continue to grow since the current medical treatments often fail to produce a complete and durable tumor response, and ultimately give rise to therapy resistance and tumor relapse. Heterocycles with potential therapeutic values are of great pharmacological importance, and among them, indazole moiety is privileged struc-ture in medicinal chemistry. Indazole compounds possess potential anticancer activity, and the indazole-based agents Ax-itinib, Lonidamine and Pazopanib have already been applied for cancer therapy, demonstrating indazole compounds are useful templates for the development of novel anticancer agents. The aim of this review is to present the main aspects of exploring anticancer properties, such as the structural modifications, the structure-activity relationship and mechanisms of action, making an effort to highlight the importance and therapeutic potentials of the indazole compounds in the present anticancer agents.

9.
Biomater Sci ; 8(21): 5955-5968, 2020 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-32966382

RESUMEN

The active targeting strategy has achieved inspiring progress for drug accumulation in tumor therapy; however, the insufficient expression level of many potential receptors poses challenges for drug delivery. Poly-γ-glutamic acid (γ-pGluA), a naturally occurring anionic biopolymer, showed high affinity with tumor-associated gamma-glutamyl transpeptidase (GGT), which localized on the cell surface and exhibited intracellular redox homeostasis-dependent expression pattern; thus, GGT was utilized for mediating endocytosis of nanoparticles. Herein, GGT-targeting nanopolyplexes (γ-pGluA-CSO@Fe3+, PCFN) consisting of cationic chitosan and GGT-targeting γ-pGluA blended with iron ion were constructed to load reactive oxygen species-induced menadione (MA) and doxorubicin, which were utilized to investigate the mechanism of GGT up-regulation. Briefly, the pretreated PCFN/MA induced an intracellular oxidative stress environment, which facilitated adjusted up-regulated GGT expression and boosted tumor targeting. Subsequently, the destroyed redox homeostasis sensitized tumors for synergistic therapy. The innovative strategy of augmenting active targeting by disturbing intracellular redox homeostasis offers insight for the application of γ-pGluA-derived nanopolyplexes.

10.
Arch Pharm (Weinheim) ; : e2000266, 2020 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-32986279

RESUMEN

Methicillin-resistant Staphylococcus aureus (MRSA), one of the major and most dangerous pathogens in humans, is a causative agent of severe pandemic of mainly skin and soft tissue and occasionally fatal infections. Therefore, it is imperative to develop potent and novel anti-MRSA agents. Indole derivatives could act against diverse enzymes and receptors in bacteria, occupying a salient place in the development of novel antibacterial agents. Dimerization and hybridization are common strategies to discover new drugs, and a number of indole dimers and hybrids possess potential antibacterial activity against a panel of clinically important pathogens including MRSA. Accordingly, indole dimers and hybrids are privileged scaffolds for the discovery of novel anti-MRSA agents. This review outlines the recent development of indole dimers and hybrids with a potential activity against MRSA, covering articles published between 2010 and 2020. The structure-activity relationship and the mechanism of action are also discussed to facilitate further rational design of more effective candidates.

11.
Autoimmunity ; 53(6): 314-322, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32706318

RESUMEN

Rheumatoid arthritis is a chronic systemic autoimmune disease. In this study, the role of microRNA-340-5p in rheumatoid arthritis was investigated. qRT-PCR was used to detect the expression of microRNA-340-5p in serums, synovial tissues, and fibroblast-like synoviocytes from patients and healthy participants. Cell proliferation rate, cell cycle and apoptotic cell numbers were measured by CCK-8 and flow cytometry assays. The expression of pro-inflammation factors was determined by ELISA. Our data showed that the expression of microRNA-340-5p was greatly suppressed in rheumatoid arthritis serums, synovial tissues and rheumatoid arthritis-fibroblast-like synoviocytes compared to that in healthy controls. Over-expression of microRNA-340-5p greatly suppressed cell proliferation, promoted cell apoptosis, and suppressed the expression of inflammation factors in rheumatoid arthritis fibroblast-like synoviocytes. Additionally, STAT3 was a target of microRNA-340-5. Overexpression of STAT3 could reverse the outcome of microRNA-340-5p on cell proliferation and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes. The findings in our study demonstrated that microRNA-340-5p may serve as a potential target for therapeutic direction for patients with rheumatoid arthritis.

12.
Neural Netw ; 130: 22-32, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32589588

RESUMEN

Heart sound classification plays a vital role in the early detection of cardiovascular disorders, especially for small primary health care clinics. Despite that much progress has been made for heart sound classification in recent years, most of them are based on conventional segmented features and shallow structure based classifiers. These conventional acoustic representation and classification methods may be insufficient in characterizing heart sound, and generally suffer from a degraded performance due to the complicated and changeable cardiac acoustic environment. In this paper, we propose a new heart sound classification method based on improved Mel-frequency cepstrum coefficient (MFCC) features and convolutional recurrent neural networks. The Mel-frequency cepstrums are firstly calculated without dividing the heart sound signal. A new improved feature extraction scheme based on MFCC is proposed to elaborate the dynamic characteristics among consecutive heart sound signals. Finally, the MFCC-based features are fed to a deep convolutional and recurrent neural network (CRNN) for feature learning and later classification task. The proposed deep learning framework can take advantage of the encoded local characteristics extracted from the convolutional neural network (CNN) and the long-term dependencies captured by the recurrent neural network (RNN). Comprehensive studies on the performance of different network parameters and different network connection strategies are presented in this paper. Performance comparisons with state-of-the-art algorithms are given for discussions. Experiments show that, for the two-class classification problem (pathological or non-pathological), a classification accuracy of 98% has been achieved on the 2016 PhysioNet/CinC Challenge database.

13.
Med Sci Monit ; 26: e921039, 2020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32394977

RESUMEN

BACKGROUND At certain frequencies, abdominal naprapathy effectively alleviates functional dyspepsia with spleen deficiency. The present study explored the effects of various frequencies of abdominal naprapathy on gastrointestinal mucosal cells in spleen-deficient rabbits. MATERIAL AND METHODS The model of spleen deficiency was established by the method of bitter cold and catharsis. The rabbits were treated with various frequencies (50 - 100 and 201 - 250 vibrations/min) of abdominal naprapathy.  RESULTS In model rabbits, gastrointestinal mucosal thickness was changed, mucosal epithelial cells were necrotic significantly, a large number of inflammatory cells were infiltrated, and duodenal villus were destroyed. The gastrointestinal mucosal cells had different degrees of regeneration and remodeling under various frequencies of abdominal naprapathy intervention. Among them, the abdominal naprapathy with manipulation frequency of 101 - 150 times/min showed the best effect. CONCLUSIONS The abdominal naprapathy, especially with frequency of 101~150 times/min, repairs gastrointestinal mucosal injury of spleen-deficiency rabbits.

14.
Int J Biol Sci ; 16(11): 2001-2013, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32398966

RESUMEN

Nicotine is proved to be an important factor for cardiac hypertrophy. Autophagy is important cell recycling system involved in the regulation of cardiac hypertrophy. Cilostazol, which is often used in the management of peripheral vascular disease. However, the effects of cilostazol on nicotine induced autophagy and cardiac hypertrophy are unclear. Here, we aim to determine the role and molecular mechanism of cilostazol in alleviating nicotine-induced cardiomyocytes hypertrophy through modulating autophagy and the underlying mechanisms. Our results clarified that nicotine stimulation caused cardiomyocytes hypertrophy and autophagy flux impairment significantly in neonatal rat ventricular myocytes (NRVMs), which were evidenced by augments of LC3-II and p62 levels, and impaired autophagosomes clearance. Interestingly, cathepsin B (CTSB) activity decreased dramatically after stimulation with nicotine in NRVMs, which was crucial for substrate degradation in the late stage of autophagy process, and cilostazol could reverse this effect dramatically. Intracellular ROS levels were increased significantly after nicotine exposure. Meanwhile, p38MAPK and JNK were activated after nicotine treatment. By using ROS scavenger N-acetyl-cysteine (NAC) could reverse the effects of nicotine by down-regulation the phosphorylation of p38MAPK and JNK pathways, and pretreatment of specific inhibitors of p38MAPK and JNK could restore the autophagy impairment and cardiomyocytes hypertrophy induced by nicotine. Moreover, CTSB activity of lysosome regained after the treatment with cilostazol. Cilostazol also inhibited the ROS accumulation and the activation of p38MAPK and JNK, which providing novel connection between lysosome CTSB and ROS/p38MAPK/JNK related oxidative stress pathway. This is the first demonstration that cilostazol could alleviate nicotine induced cardiomyocytes hypertrophy through restoration of autophagy flux by activation of CTSB and inhibiting ROS/p38/JNK pathway, exhibiting a feedback loop on regulation of autophagy and cardiomyocytes hypertrophy.

15.
Int J Nanomedicine ; 15: 2717-2732, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32368051

RESUMEN

Background: Phototherapy is a potential new candidate for glioblastoma (GBM) treatment. However inadequate phototherapy due to stability of the photosensitizer and low target specificity induces the proliferation of neovascular endothelial cells for angiogenesis and causes poor prognosis. Methods: In this study, we constructed c(RGDfk)-modified glycolipid-like micelles (cRGD-CSOSA) encapsulating indocyanine green (ICG) for dual-targeting neovascular endothelial cells and tumor cells, and cRGD-CSOSA/ICG mediated dual effect of PDT/PTT with NIR irradiation. Results: In vitro, cRGD-CSOSA/ICG inhibited cell proliferation and blocked angiogenesis with NIR irradiation. In vivo, cRGD-CSOSA/ICG exhibited increased accumulation in neovascular endothelial cells and tumor cells. Compared with that of CSOSA, the accumulation of cRGD-CSOSA in tumor tissue was further improved after dual-targeted phototherapy pretreatment. With NIR irradiation, the tumor-inhibition rate of cRGD-CSOSA/ICG was 80.00%, significantly higher than that of ICG (9.08%) and CSOSA/ICG (42.42%). Histological evaluation showed that the tumor vessels were reduced and that the apoptosis of tumor cells increased in the cRGD-CSOSA/ICG group with NIR irradiation. Conclusion: The cRGD-CSOSA/ICG nanoparticle-mediated dual-targeting phototherapy could enhance drug delivery to neovascular endothelial cells and tumor cells for anti-angiogenesis and improve the phototherapy effect of glioblastoma, providing a new strategy for glioblastoma treatment.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Glioblastoma/terapia , Verde de Indocianina/administración & dosificación , Nanopartículas/administración & dosificación , Neovascularización Patológica/tratamiento farmacológico , Fototerapia/métodos , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Glioblastoma/patología , Glucolípidos/química , Humanos , Verde de Indocianina/química , Ratones Desnudos , Micelas , Nanopartículas/química , Oligopéptidos/química , Fármacos Fotosensibilizantes/administración & dosificación , Fármacos Fotosensibilizantes/farmacología , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Medicine (Baltimore) ; 99(9): e19155, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32118718

RESUMEN

BACKGROUND: The potential association between antibiotic use and the risk of rheumatoid arthritis (RA) has drawn significant attention from clinicians and researchers in recent years due to the wild usage of antibiotic. This study aimed to perform a systematic review and meta-analysis of the literature to determine if antibiotic use is associated with an increased risk of RA, so as to provide an important reference for clinical decision-making. METHODS: Case-control and nest case-control studies of assessing whether antibiotic use is associated with the onset of RA will be identified in searches of 4 databases from their inception to August 2019. All data were assessed and extracted by 2 authors independently. The Newcastle-Ottawa scale was used to assess the quality of the selected studies. Manager Software 5.3 from Cochrane Collaboration (London, UK) and Stata 15.1 (Stata Corp, College Station, TX) will be used to conduct meta-analysis, determining pooled odds ratios and evaluating heterogeneity between studies. RESULT: The results of this systemic review and meta-analysis will be submitted to a recognized journal for publication. CONCLUSION: This systemic review and meta-analysis will determine if antibiotic use is associated with an increased risk of RA. We hope this study can make a definitive conclusion for the association.


Asunto(s)
Antibacterianos/efectos adversos , Artritis Reumatoide/inducido químicamente , Humanos , Revisiones Sistemáticas como Asunto
17.
Food Funct ; 11(4): 3112-3125, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32196541

RESUMEN

Diabetes is the main chronic disease that greatly affects human life. Up to now, many measures have been taken to cope with the disease, among which natural products with hypoglycemic effects have aroused great interest. The objective of this study was to evaluate the hypoglycemic effects of Morus abla L. cv. longsang 1 leaf-derived water extract in vitro and in vivo. These leaves were firstly subjected to water extraction, and the obtained products were further isolated for polysaccharides, flavonoids and alkaloids. The α-glucosidase activity and anti-protein glycosylation activity of the aqueous extracts were examined in vitro. Hyperglycemic mouse models were used to evaluate the hypoglycemic effects of the aqueous extract by blood biochemical parameters, intestinal microbiota, and pathological changes to the kidneys. The results showed that the main hypoglycemic components in the aqueous extracts were flavonoids and alkaloids and their inhibition rates against α-glucosidase activity were 86.12 ± 1.79% and 87.29 ± 1.32%, respectively. High-dose mulberry leaf water extracts can reduce the blood glucose of diabetic mice by 28.17% and improve glucose tolerance by 19.02%. Furthermore, mulberry leaf water extracts could reduce the serum free fatty acid (FFA), tumor necrosis factor-α (TNF-α), insulin and glycated serum protein content, while alleviating kidney damage and improving intestinal microbiota. These results indicated that the synergistic effects among the different components of mulberry leaves might explain their alleviating effects on diabetic syndrome and thus provide a simple, convenient way to obtain the hypoglycemic components from mulberry leaves.

18.
J Pain Res ; 13: 131-142, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32021402

RESUMEN

Purpose: Chronic pain is one of the most common complications of postmenopausal osteoporosis. Since oxidative stress is involved in the pathogenesis of postmenopausal osteoporosis, we explored whether oxidative stress contributes to postmenopausal osteoporotic pain. Methods: Osteoporosis was induced in mice by ovariectomy (OVX). Pain-related behaviours were assessed by measuring sensitivity to mechanical, thermal and cold stimulation. The expression of pain-related transcripts, such acid-sensing ion channel 3 (ASIC3), transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP), was evaluated. Plasma markers of oxidative stress were also measured. In addition, the effects of the reactive oxygen species scavenger phenyl N-tert-butylnitrone (PBN) on these parameters were assessed. Results: The OVX mice presented hyperalgesia, as demonstrated by decreased paw withdrawal thresholds to mechanical stimulation and withdrawal latencies to thermal and cold stimulation, along with upregulated expression of ASIC3, TRPV1 and CGRP in the dorsal root ganglia, spinal cord and thalamus tissue. OVX elevated the plasma levels of malondialdehyde (MDA) and advanced oxidation protein products (AOPPs). However, the administration of PBN alleviated these effects. Conclusion: Our results indicated that oxidative stress contributes to hyperalgesia in OVX mice. Enhanced oxidative stress may be associated with osteoporotic pain. Antioxidant treatment could help alleviate chronic pain in postmenopausal osteoporotic patients.

19.
Exp Ther Med ; 19(1): 459-466, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31885695

RESUMEN

Congenital hypothyroidism (CH) is an endocrine disease caused by congenital thyroid hormone (TH) deficiency. MicroRNAs (miRNAs or miRs) have been reported to inhibit the progression of congenital hypothyroidism. However, the expression and role of miR-1236-3p in CH remains unclear. To address this, 12 day old Sprague-Dawley rats were divided into five groups: Control; Congenital hypothyroidism (CH), miR-1236-3p inhibitor control (inhibitor control); miR-1236-3p inhibitor (inhibitor); and miR-1236-3p inhibitor + translationally-controlled tumor protein 1 (TPT1)-small interfering (si)RNA (inhibitor + siRNA). Propylthiouracil (50 mg/day) was injected intraperitoneally into pregnant rats to generate pups with CH. The levels of miR-1236-3p and TPT1 were detected via reverse transcription-quantitative PCR and western blot analysis. Bioinformatics analysis was performed to predict the targets of miR-1236-3p, which was confirmed using dual luciferase reporter assay. Flow cytometry and MTT assay were used to measure neuronal cell apoptosis and cell viability, whereas western blotting was applied to detect the expression of Pim-3, p-Bad (Ser112), Bad and Bcl-xL, proteins associated with apoptosis. The results revealed that miR-1236-3p expression was significantly upregulated, whilst TPT1 expression was significantly downregulated in the hippocampus tissues of CH rats compared with the control group. TPT1 was confirmed as a target of miR-1236-3p. MiR-1236-3p inhibitor prevented hippocampal neuron apoptosis induced by CH induction, which was reversed by TPT1-siRNA transfection. In addition, following miR-1236-3p inhibitor transfection, neuronal cell apoptosis significantly reduced compared with the control group, which was accompanied by significantly increased expressions of Pim-3, p-Bad (Ser112) and Bcl-xL expression. These effects were reversed by TPT1-siRNA co-transfection. These results indicated that inhibition of miR-1236-3p expression inhibited neuron apoptosis in vivo and in vitro by targeting TPT1, serving a protective role in CH.

20.
Carbohydr Polym ; 229: 115435, 2020 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-31826424

RESUMEN

Micelles are one of the most investigated nanocarriers for drug delivery. In this study, polymeric micelles based on chitosan were prepared to explore the delivery mechanism which was critical for enhancing tumor targeting but still remain elusive. The chitosan polymer COSA was synthesized and the polymeric micelles showed good self-assembly ability, good dispersion stability and low toxicity. After being intravenously administered, the micelles were selectively taken up by circulating monocytes in a receptor-mediated way (almost 94% uptake in Ly-6Chi monocytes, below 7% in all other circulating cells) and reach the tumor with the subsequent travel of these cells. In addition, the micelles in macrophages (differentiated from circulating monocytes) can be exocytosed and subsequently taken up by cancer cells. The delivery mechanism of COSA micelles is directional for the novel strategies to enhance tumor targeting and the micelles are promising candidates for diseases in which monocytes are directly implicated.


Asunto(s)
Quitosano/metabolismo , Portadores de Fármacos/metabolismo , Micelas , Monocitos/metabolismo , Animales , Antineoplásicos/farmacología , Doxorrubicina/farmacología , Liberación de Fármacos , Endocitosis , Exocitosis , Femenino , Ratones , Ratones Endogámicos BALB C , Neoplasias/metabolismo , Células RAW 264.7
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