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1.
Thromb J ; 22(1): 27, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38504248

RESUMEN

C-type lectin-like receptor-2 (CLEC-2) is a member of the C-type lectin superfamily of cell surface receptors. The first confirmed endogenous and exogenous ligands of CLEC-2 are podoplanin and rhodocytin, respectively. CLEC-2 is expressed on the surface of platelets, which participates in platelet activation and aggregation by binding with its ligands. CLEC-2 and its ligands are involved in pathophysiological processes, such as atherosclerosis, cancer, inflammatory thrombus status, maintenance of vascular wall integrity, and cancer-related thrombosis. In the last 5 years, different anti- podoplanin antibody types have been developed for the treatment of cancers, such as glioblastoma and lung cancer. New tests and new diagnostics targeting CLEC-2 are also discussed. CLEC-2 mediates thrombosis in various pathological states, but CLEC-2-specific deletion does not affect normal hemostasis, which would provide a new therapeutic tool for many thromboembolic diseases. The CLEC-2-podoplanin interaction is a target for cancer treatment. CLEC-2 may be applied in clinical practice and play a therapeutic role.

2.
Br J Anaesth ; 2024 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-38527923

RESUMEN

BACKGROUND: Numerous models have been developed to predict acute kidney injury (AKI) after noncardiac surgery, yet there is a lack of independent validation and comparison among them. METHODS: We conducted a systematic literature search to review published risk prediction models for AKI after noncardiac surgery. An independent external validation was performed using a retrospective surgical cohort at a large Chinese hospital from January 2019 to October 2022. The cohort included patients undergoing a wide range of noncardiac surgeries with perioperative creatinine measurements. Postoperative AKI was defined according to the Kidney Disease Improving Global Outcomes creatinine criteria. Model performance was assessed in terms of discrimination (area under the receiver operating characteristic curve, AUROC), calibration (calibration plot), and clinical utility (net benefit), before and after model recalibration through intercept and slope updates. A sensitivity analysis was conducted by including patients without postoperative creatinine measurements in the validation cohort and categorising them as non-AKI cases. RESULTS: Nine prediction models were evaluated, each with varying clinical and methodological characteristics, including the types of surgical cohorts used for model development, AKI definitions, and predictors. In the validation cohort involving 13,186 patients, 650 (4.9%) developed AKI. Three models demonstrated fair discrimination (AUROC between 0.71 and 0.75); other models had poor or failed discrimination. All models exhibited some miscalibration; five of the nine models were well-calibrated after intercept and slope updates. Decision curve analysis indicated that the three models with fair discrimination consistently provided a positive net benefit after recalibration. The results were confirmed in the sensitivity analysis. CONCLUSIONS: We identified three models with fair discrimination and potential clinical utility after recalibration for assessing the risk of acute kidney injury after noncardiac surgery.

3.
Anal Chem ; 95(15): 6458-6466, 2023 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-37027511

RESUMEN

The (5 × 5) Moiré pattern resulting from coadsorption of Cu atoms and chloride ions on the Au(111) electrode is one of the most classical structures for underpotential deposition (UPD) in electrochemical surface science. Although two models have been proposed to describe the pattern, the details of the structure remain ambiguous and controversial, leading to a question that remains to be answered. In this work, we investigate the UPD behaviors of Cu on the Au(111) electrode in a chloride-based deep eutectic solvent ethaline by in situ scanning tunneling microscopy (STM). Benefiting from the properties of the ultraconcentrated electrolyte, we directly image not only Cu but also Cl adlayers by finely tuning tunneling conditions. The structure is unambiguously determined for both Cu and Cl adlayers, where an incommensurate Cu layer is adsorbed on the Au(111) surface with a Cu coverage of 0.64, while the Cl coverage is 0.32 (only half of the expected value); i.e., the atomic arrangement of the observed (5 × 5) Moiré pattern in ethaline matches neither of the models proposed in the literature. Meanwhile, STM results confirm the origin of the cathodic peak in the cyclic voltammogram, which indicates that the underpotential shift of Cu UPD in ethaline indeed increases by ca. 0.40 V compared to its counterpart in a sulfuric acid solution, resulting in a significant deviation from the linear relation between the underpotential shift and the difference in work functions proposed in the literature. The unconventional electrochemical behaviors of Cu UPD reveal the specialty of both the bulk and the interface in the chloride-based deep eutectic solvent.

4.
Cancer Control ; 30: 10732748231175017, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37161925

RESUMEN

INTRODUCTION: Neuroblastoma (NB) is one of the children's most common solid tumors, accounting for approximately 8% of pediatric malignancies and 15% of childhood cancer deaths. Somatic mutations in several genes, such as ALK, have been associated with NB progression and can facilitate the discovery of novel therapeutic strategies. However, the differential expression of mutated and wild-type alleles on the transcriptome level is poorly studied. METHODS: This study analyzed 219 whole-exome sequencing datasets with somatic mutations detected by MuTect from paired normal and tumor samples. RESULTS: We prioritized mutations in 8 candidate genes (RIMS4, RUSC2, ALK, MYCN, PTPN11, ALOX12B, ZNF44, and CNGB1) as potential driver mutations. We further confirmed the presence of allele-specific expression of the somatic mutations in NB with integrated analysis of 127 RNA-seq samples (of which 85 also had DNA-seq data available), including MYCN, ALK, and PTPN11. The allele-specific expression of mutations suggests that the same somatic mutation may have different effects on the clinical outcomes of tumors. CONCLUSION: Our study suggests 2 novel variants of ZNF44 as a novel candidate driver gene for NB.


Asunto(s)
Neuroblastoma , ARN , Niño , Humanos , Alelos , Proteína Proto-Oncogénica N-Myc , Neuroblastoma/genética , Proteínas Tirosina Quinasas Receptoras , Canales Catiónicos Regulados por Nucleótidos Cíclicos , Proteínas Portadoras
5.
Exp Cell Res ; 411(2): 113017, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-34998813

RESUMEN

Hypertensive renal injury is accompanied by tubular interstitial fibrosis leading to increased risk for renal failure. This study aimed to explore the influences of miR-122-5p in hypertension-mediated renal fibrosis and damage. 14-week-old male SHR and WKY rats were randomly assigned to treat with rAAV-miR-122-5p or rAAV-GFP for 8 weeks. There were marked increases in miR-122-5p and Kim-1 levels and decreases in FOXO3 and SIRT6 levels in hypertensive rats. Transfection with rAAV-miR-122-5p triggered exacerbation of renal fibrosis, apoptosis and inflammatory injury in SHR, associated with downregulated levels of FOXO3, SIRT6, ATG5 and BNIP3 as well as upregulated expression of Kim-1, NOX4, CTGF, and TGF-ß1. In cultured primary mouse renal tubular interstitial fibroblasts, exposure to angiotensin II resulted in obvious downregulation of FOXO3, SIRT6, ATG5, BNIP3 and nitric oxide levels as well as augmented cellular migration, oxidative stress, and inflammation, which were exacerbated by miR-122-5p mimic while rescued by miR-122-5p inhibitor and rhFOXO3, respectively. Notably, knockdown of FOXO3 strikingly blunted cellular protective effects of miR-122-5p inhibitor. In summary, miR-122-5p augments renal fibrosis, inflammatory and oxidant injury in hypertensive rats by suppressing the expression of FOXO3. Pharmacological inhibition of miR-122-5p has potential therapeutic significance for hypertensive renal injury and fibrosis-related kidney diseases.


Asunto(s)
Proteína Forkhead Box O3/antagonistas & inhibidores , Hipertensión/metabolismo , Hipertensión/patología , Riñón/lesiones , Riñón/metabolismo , MicroARNs/genética , Animales , Apoptosis , Autofagia , Modelos Animales de Enfermedad , Regulación hacia Abajo , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Técnicas de Silenciamiento del Gen , Hipertensión/complicaciones , Riñón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/antagonistas & inhibidores , MicroARNs/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Regulación hacia Arriba
6.
Molecules ; 28(5)2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36903545

RESUMEN

Traditional coupling of ligands for gold wet etching makes large-scale applications problematic. Deep eutectic solvents (DESs) are a new class of environment-friendly solvents, which could possibly overcome the shortcomings. In this work, the effect of water content on the Au anodic process in DES ethaline was investigated by combining linear sweep voltammetry (LSV) and electrochemical impedance spectroscopy (EIS). Meanwhile, we employed atomic force microscopy (AFM) to image the evolution of the surface morphology of the Au electrode during its dissolution and passivation process. The obtained AFM data help to explain the observations about the effect of water content on the Au anodic process from the microscopic perspective. High water contents make the occurrence of anodic dissolution of gold at higher potential, but enhances the rate of the electron transfer and gold dissolution. AFM results reveal the occurrence of massive exfoliation, which confirms that the gold dissolution reaction is more violent in ethaline with higher water contents. In addition, AFM results illustrate that the passive film and its average roughness could be tailored by changing the water content of ethaline.

7.
Cell Commun Signal ; 20(1): 71, 2022 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-35614513

RESUMEN

PURPOSE: Cholecystectomy (XGB) is widely recognized as a risk factor for colon cancer (CC). Continuous exposure of the colonic epithelium to deoxycholic acid (DCA) post-XGB may exert cytotoxic effects and be involved in the progression of CC. However, the functions of the XGB-induced DCA increase and the underlying mechanism remain unclear. METHODS: Colitis-associated CC (CAC) mouse models constructed by AOM-DSS inducement were used to confirm the effect of XGB on the CC progression. Hematoxylin & eosin staining was performed to assess the tumor morphology of CAC mouse models tissues. Various cell biological assays including EdU, live-cell imaging, wound-healing assays, and flow cytometry for cell cycle and apoptosis were used to evaluate the effect of DCA on CC progression. The correlation among XGB, DCA, and CC and their underlying mechanisms were detected with immunohistochemistry, mass spectrometry, transcriptome sequencing, qRT-PCR, and western blotting. RESULTS: Here we proved that XGB increased the plasma DCA level and promoted colon carcinogenesis in a colitis-associated CC mouse model. Additionally, we revealed that DCA promoted the proliferation and migration of CC cells. Further RNA sequencing showed that 120 mRNAs were upregulated, and 118 downregulated in DCA-treated CC cells versus control cells. The upregulated mRNAs were positively correlated with Wnt signaling and cell cycle-associated pathways. Moreover, DCA treatment could reduced the expression of the farnesoid X receptor (FXR) and subsequently increased the levels of ß-Catenin and c-Myc in vitro and in vivo. Moreover, the FXR agonist GW4064 decreased the proliferation of CC cells by repressing the expression of ß-catenin. CONCLUSION: We concluded that XGB-induced DCA exposure could promote the progression of CC by inhibiting FXR expression and enhancing the Wnt-ß-catenin pathway. Video Abstract.


Asunto(s)
Colecistectomía , Neoplasias del Colon , Ácido Desoxicólico , Vía de Señalización Wnt , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular , Colecistectomía/efectos adversos , Colitis/genética , Neoplasias del Colon/etiología , Neoplasias del Colon/patología , Ácido Desoxicólico/metabolismo , Ácido Desoxicólico/farmacología , Regulación Neoplásica de la Expresión Génica , Ratones , beta Catenina/metabolismo
8.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-35269804

RESUMEN

Although pituitary adenomas are histologically benign, they are often accompanied by multiple complications, such as cardiovascular disease and metabolic dysfunction. In the present study, we repositioned the Food and Drug Administration -approved immune regulator tamoxifen to target STAT6 based on the genomics analysis of PAs. Tamoxifen inhibited the proliferation of GH3 and AtT-20 cells with respective IC50 values of 9.15 and 7.52 µM and increased their apoptotic rates in a dose-dependent manner. At the molecular level, tamoxifen downregulated phosphorylated PI3K, phosphorylated AKT and the anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic proteins p53 and Bax in GH3 and AtT-20 cells. Furthermore, tamoxifen also inhibited the migration of both cell lines by reprogramming tumor-associated macrophages to the M1 phenotype through STAT6 inactivation and inhibition of the macrophage-specific immune checkpoint SHP1/SHP. Finally, administration of tamoxifen (20, 50, 100 mg·kg-1·d-1, for 21 days) inhibited the growth of pituitary adenomas xenografts in nude mice in a dose-dependent manner. Taken together, tamoxifen is likely to be a promising combination therapy for pituitary adenomas and should be investigated further.


Asunto(s)
Adenoma , Neoplasias Hipofisarias , Adenoma/genética , Animales , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Humanos , Ratones , Ratones Desnudos , Neoplasias Hipofisarias/patología , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico
9.
J Am Chem Soc ; 143(11): 4311-4318, 2021 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-33625851

RESUMEN

A deficiency of Ca2+ fluxes arising from dysfunctional voltage-gated calcium channels has been associated with a list of calcium channelopathies such as epilepsy, hypokalemic periodic paralysis, episodic ataxia, etc. Apart from analyzing the pathogenic channel mutations, understanding how the channel regulates the ion conduction would be instructive to the treatment as well. In the present work, in relating the free energetics of Ca2+ transport to the calcium channel, we demonstrate the importance of bridging Ca2+ hydration waters, which form hydrogen bonds with channel -COO- and -C═O groups and enable a long-distance effect on the Ca2+ permeation. By firing a terahertz wave which resonates with the stretching mode of either the -COO- or the -C═O group, we obtain significantly enhanced selectivity and conductance of Ca2+. The Ca2+ free energy negatively grows nearly 5-fold. The direct evidence is the reinforced hydrogen bonds. In addition, thanks to forced vibrations, -COO- contributes to raised permeation as well even under a field in resonance with -C═O, and vice versa. Since the resonant terahertz field could manipulate the conduction of calcium channels, it has potential applications in therapeutic intervention such as rectifying a Ca2+ deficiency in degraded calcium channels, inducing apoptosis of tumor cells with overloaded calcium etc.

10.
Am J Physiol Gastrointest Liver Physiol ; 320(3): G351-G365, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33406007

RESUMEN

Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl4-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration, and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.NEW & NOTEWORTHY PHP14 inhibition via adeno-associated virus (AAV)-mediated gene silencing could potently attenuate carbon tetrachloride (CCl4)-induced liver fibrosis. PHP14 could regulate the migration of macrophages to the site of injury in vivo. PHP14 knockdown in vivo influenced the environment of fibrogenesis and relevant signaling pathways, subsequently affecting myofibroblast activation.


Asunto(s)
Cirrosis Hepática/inducido químicamente , Monoéster Fosfórico Hidrolasas/metabolismo , Traslado Adoptivo , Animales , Intoxicación por Tetracloruro de Carbono , Técnicas de Cocultivo , Sistemas de Liberación de Medicamentos , Técnicas de Silenciamiento del Gen , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Macrófagos , Ratones , Ratones Endogámicos C57BL , Monoéster Fosfórico Hidrolasas/genética , Células RAW 264.7 , Regulación hacia Arriba
11.
Cancer Immunol Immunother ; 70(12): 3541-3555, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33903973

RESUMEN

Although the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic.


Asunto(s)
Adenoviridae/inmunología , Inhibidores de Puntos de Control Inmunológico/inmunología , Interleucinas/inmunología , Melanoma/inmunología , Melanoma/terapia , Animales , Línea Celular , Línea Celular Tumoral , Terapia Combinada/métodos , Modelos Animales de Enfermedad , Femenino , Terapia Genética/métodos , Células HEK293 , Humanos , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Viroterapia Oncolítica/métodos , Virus Oncolíticos/inmunología
12.
Basic Res Cardiol ; 116(1): 53, 2021 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-34546460

RESUMEN

We recently identified oncologic miR-182 as a new regulator of pulmonary artery hypertension (PAH) that targets myeloid-associated differentiation marker (Myadm), which is expressed in bone marrow stem cells and multipotent progenitors. Both miR-182 and Myadm are expressed in the cardiopulmonary system and correlated with the balance between the bone morphogenetic protein (BMP) and the transforming growth factor (TGF)-ß signalling pathways, which are disturbed in PAH. We hypothesize that miR-182/Myadm are involved in BMP-TGF-ß-signalling way in PAH. Hypoxia triggered pathological progression in cardiopulmonary PAH in vivo and in vitro; these changes were accompanied by strongly dowregulated BMP/SMAD1/5/8 expression and enhanced TGF-ß/SMAD2/3 signalling pathway, favouring SMAD4/SMAD2 transcript formation and inhibiting the PAH negative regulator Id1 expression. miR-182 gain-of-function significantly inhibited the pathological progression in hypoxia-induced PAH (HPH) in vivo and in vitro, with a restoration of the balance in BMP-TGF-ß signalling pathway. This recovery was abrogated by overexpression of Myadm. Conversely, loss-of-function of miR-182 increased the pathological progression of HPH followed by severe disturbance of BMP and TGF-ß signal transduction and reduced Id1 expression, which was restored by Myadm knockdown. We also showed that the miR-182/Myadm relate BMP-TGF-ß pathway is associated with NOS3/NO/cGMP via the crosstalk between endothelial cells and smooth muscle cells. Our findings further support the therapeutic significance of miR-182/Myadm in PAH via the balance of BMP- and TGF-ß-associated mechanisms.


Asunto(s)
Hipertensión Pulmonar , MicroARNs , Proteínas Morfogenéticas Óseas , Células Endoteliales , Humanos , Hipertensión Pulmonar/genética , Hipoxia , MicroARNs/genética , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito , Arteria Pulmonar , Factor de Crecimiento Transformador beta
13.
Cell Mol Biol Lett ; 26(1): 2, 2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33435886

RESUMEN

BACKGROUND: Iron overload, which is common in patients with haematological disorders, is known to have a suppressive effect on haematogenesis. However, the mechanism for this effect is still unclear. The antioxidant curcumin has been reported to protect against iron overload-induced bone marrow damage through an as-yet-unknown mechanism. METHODS: We established iron overload cell and mouse models. Mitochondrial reactive oxygen species (mROS) levels, autophagy levels and the SIRT3/SOD2 pathway were examined in the models and in the bone marrow of patients with iron overload. RESULTS: Iron overload was shown to depress haematogenesis and induce mitochondrion-derived superoxide anion-dependent autophagic cell death. Iron loading decreased SIRT3 protein expression, promoted an increase in SOD2, and led to the elevation of mROS. Overexpression of SIRT3 reversed these effects. Curcumin treatment ameliorated peripheral blood cells generation, enhanced SIRT3 activity, decreased SOD2 acetylation, inhibited mROS production, and suppressed iron loading-induced autophagy. CONCLUSIONS: Our results suggest that curcumin exerts a protective effect on bone marrow by reducing mROS-stimulated autophagic cell death in a manner dependent on the SIRT3/SOD2 pathway.


Asunto(s)
Médula Ósea/patología , Curcumina/farmacología , Hematopoyesis , Sobrecarga de Hierro/metabolismo , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 3/metabolismo , Superóxido Dismutasa/metabolismo , Acetilación/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Citoprotección/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Humanos , Sobrecarga de Hierro/patología , Ratones
14.
Zhongguo Zhong Yao Za Zhi ; 46(18): 4793-4799, 2021 Sep.
Artículo en Zh | MEDLINE | ID: mdl-34581090

RESUMEN

This study explored the effects of resveratrol(Res) on the expression of phosphatase and tensin homolog deleted on chromosome ten(PTEN) and the fibrosis of rat renal tubular epithelial cells in a high-glucose environment and the possible mechanism underlying the fibrosis reduction. After the pretreatment of rat renal tubular epithelial cells(NRK-52 E) cultured in a high-glucose condition with Res or PTEN inhibitor SF1670, they were divided into several groups, i.e., normal glucose(NG), normal glucose + SF1670(NS), high glucose(HG), high glucose + SF1670(HS), high glucose + Res at different concentrations(5, 10, 25 µmol·L~(-1)). The expression and distribution of E-cadherin and α-SMA in renal tubular epithelial cells were observed by immunofluorescence cytochemistry. The protein expression levels of PTEN, E-cadherin, α-SMA, p-Akt~((Thr308)) and collagen Ⅳ were determined by Western blot. Real-time PCR was employed to detect the expression of PTEN mRNA. Compared with the NG group, the HG group witnessed the reduced expression of PTEN mRNA, PTEN protein and E-cadherin protein, but saw the increased expression of α-SMA, p-Akt~((Thr308)) and collagen Ⅳ proteins. Besides, with the increase in Res concentration, the expression levels of PTEN mRNA, PTEN protein and E-cadherin protein gradually increased, while those of α-SMA, collagen Ⅳ, p-Akt~((Thr308)) proteins gradually decreased in the Res groups, showing a dose-effect dependence, compared with the HG group. No distinct difference was found between the NS group and the NG group. The expression level of E-cadherin was even lower and those of α-SMA, p-Akt~((Thr308)), and collagen Ⅳ were higher in the HS group than in the HG group, with no marked difference shown in the two groups in terms of PTEN mRNA and protein. Although the PTEN inhibitor did not affect PTEN, the expression changes of the other proteins were opposite to the results after Res treatment and the fibrosis was aggravated, which suggested that SF1670 promoted the fibrosis by inhibiting PTEN, activating Akt and increasing the synthesis of collagen Ⅳ and other extracellular matrix. The results show that Res can antagonize the high glucose-mediated fibrosis of renal tubular epithelial cells. This may be achieved via the up-regulation of PTEN and the inhibition of PI3 K/Akt signaling pathway.


Asunto(s)
Células Epiteliales , Fosfohidrolasa PTEN , Animales , Fibrosis , Glucosa , Fosfohidrolasa PTEN/genética , Ratas , Resveratrol/farmacología
15.
Inorg Chem ; 59(10): 7012-7026, 2020 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-32339459

RESUMEN

In this study, zinc-gallium oxynitrides with a Zn:Ga mole ratio of 1:1 [(GaN)0.5(ZnO)0.5] were synthesized from a Zn/Ga/CO3 layered double hydroxide (LDH) precursor. The microstructure and photoactivity of the (GaN)0.5(ZnO)0.5 particles were tuned by adjusting the nitridation conditions of the LDH. It is revealed that the quantity of the LDH, or, equivalently, the partial pressure of the water during nitridation, plays a pivotal role in the defect structure of the obtained oxynitrides. A reduction in the quantity of the LDH precursor can effectively suppress the formation of defects including Ga(Zn)-O bonding, bulk anion vacancies, and surface-deposited Ga/ON···VGa complexes, leading to a better charge-separation efficiency for the photogenerated electron-hole pairs in the oxynitride. Furthermore, a suitable introduction of methane during nitridation would not only increase the crystallinity of the bulk materials but also enhance the density of the surface oxygen vacancy (VO), which would raise the charge-injection efficiency by working as an electron trap and a reaction site to form O2•-. O2•-, as well as photogenerated holes, have been proven to be the dominant active species for the photodegradation of phenol. 25CH4-ZnGaNO, with the lowest density of bulk defects and the highest density of surface VO, exhibited the best photoactivity under visible-light irradiation for the photodegradation of Rhodamine B and phenol. The obtained surface-VO-rich (GaN)0.5(ZnO)0.5 particles can be applied as a high-performance visible-light-driven photocatalyst in the photodegradation of organic pollutants.

16.
Proc Natl Acad Sci U S A ; 114(24): 6376-6381, 2017 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-28559309

RESUMEN

MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adeno-associated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96-mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice.


Asunto(s)
MicroARNs/genética , MicroARNs/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Animales , Visión de Colores/fisiología , Electrorretinografía , Epigénesis Genética , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Visión Nocturna/fisiología , Células Fotorreceptoras de Vertebrados/patología , Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Degeneración Retiniana/genética , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología
17.
Clin Exp Ophthalmol ; 48(8): 1085-1101, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32519377

RESUMEN

Non-coding RNAs (ncRNAs) are key players in variety of biogenesis and biological functions. Their aberrant expression has been implicated in disease progression. NcRNAs can be divided into short ncRNAs whose subtypes are mainly microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA). They are involved in cellular processes, including gene regulation, development and disease. The retina is a remarkably sophisticated instrument with interconnected cell types and is the primary target of many genetic diseases. In addition, in terms of retinal dyshomeostasis and inflammation, ncRNAs seems to play critical roles in many retinal diseases. Here, we provide an overview of ncRNAs in developing retina. We also review how does these ncRNAs function in various retinal diseases including animal and human models. These data indicate that ncRNAs regulate cellular processes including cell proliferation, differentiation, apoptosis and contribute to initiation and progression of retinal diseases.


Asunto(s)
MicroARNs , ARN Largo no Codificante , Enfermedades de la Retina , Animales , Humanos , MicroARNs/genética , ARN Largo no Codificante/genética , ARN no Traducido/genética , Retina , Enfermedades de la Retina/genética
18.
Zhongguo Zhong Yao Za Zhi ; 45(16): 3922-3930, 2020 Aug.
Artículo en Zh | MEDLINE | ID: mdl-32893590

RESUMEN

The aim of this paper was to observe the effect of salvianolic acid B(Sal B) on high-glucose induced renal tubular epithelial-mesenchymal transition(EMT) in rats, and to explore its possible mechanisms of prevention and treatment of diabetic nephropathy. The rat renal tubular epithelial NRK-52 E cells were cultured in vitro. The cells were divided into control group, high glucose group, high glucose+10 µmol·L~(-1)Sal B group(Sal B), the above 3 groups were set at 6, 12, 24 and 48 h for dynamic observation; high glucose+Sal B different concentration(1, 5, 10 µmol·L~(-1)) groups, high glucose+5.0 µmol·L~(-1) pioglitazone group, high glucose+10 µmol·L~(-1)Sal B+5 µmol·L~(-1)GW9662 group. The protein expression levels of PPARγ, PTEN, α-SMA, E-cadherin and PI3 K/Akt signaling molecules were determined by Western blot. The mRNA expression of PPARγ and PTEN were detected by Real-time PCR. The viabi-lity of NRK52 E cells was determined by MTT assay. The results showed that as compared with control group, the mRNA and protein expression levels of PPARγ and PTEN in high glucose group gradually reduced, the protein expression levels of α-SMA and p-Akt~((Thr308))gradually increased, and the protein expression of E-cadherin gradually reduced(P<0.05). As compared with high glucose group, when increases in Sal B doses, the mRNA and protein expression levels of PPARγ, PTEN in high glucose + different concentrations of Sal B groups gradually increased, the protein expression levels of α-SMA and p-Akt~((Thr308)) gradually reduced, and the protein expression of E-cadherin gradually increased(P<0.05), however, the effect of 1 µmol·L~(-1)concentration of Sal B on the expression of PPARγ mRNA and protein and PTEN mRNA was not significantly different. As compared with high glucose group, the mRNA and protein expression levels of PPARγ mRNA(except 6 h) and protein(except 6 h), PTEN mRNA(except 6 h) and protein(except 6, 12 h) kept increasing, the protein expression levels of α-SMA and p-Akt~((Thr308))(except 6 h) continued to reduce, the protein expression of E-cadherin kept increasing in high glucose+10 µmol·L~(-1) Sal B dynamic observation group(P<0.05). As compared with high glucose group, Sal B and the pioglitazone(PIO) can greatly enhance the expression of PPARγ, PTEN at mRNA and protein levels, enhance the expression of E-cadherin at protein levels, and reduce the expression of α-SMA, p-Akt~((Thr308))protein level(P<0.05), there was no significant difference between the two groups. However, the expression levels of PPARγ and PTEN mRNA and protein, E-cadherin, α-SMA and p-Akt(Thr308) protein in the Sal B+GW9662 control group were not statistically significant compared with the high glucose group. The effect of Sal B was blocked by the PPARγ antagonist GW9662. It can be concluded that Sal B can suppress the NRK52 E cells induced by high-glucose EMT. The mechanism may be related to the activation of PPARγ with Sal B, and the up-regulation of PTEN expression, and thereby inhibiting the fibrosis effect of PI3 K/Akt signaling pathway.


Asunto(s)
Transición Epitelial-Mesenquimal , Factor de Crecimiento Transformador beta1 , Animales , Benzofuranos , Células Epiteliales , Glucosa , Ratas
19.
Biol Blood Marrow Transplant ; 25(8): 1592-1596, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30951841

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for patients with ß-thalassemia major (ß-TM). However, the problem of finding a suitable sibling donor with well-matched human leukocyte antigens is still a major obstacle to curing these patients. With the progress in high-resolution HLA typing technology and supportive care, outcomes after allogeneic HSCT from an HLA well-matched unrelated donor (UD) now approach those of well-matched sibling donors. However, UD HSCT is hampered by an increased risk of graft-versus-host disease and transplant-related mortality. Here we report the outcome of transplantation in patients with ß-TM using a novel WZ-14-TM transplant protocol, based on cyclophosphamide, intravenous busulfan, fludarabine, and antithymocyte globulin, in our center. Forty-eight patients between 2 and 11 years of age with ß-TM received HLA well-matched UD peripheral blood stem cell transplantation following the WZ-14-TM protocol. All of the transplanted patients achieved donor engraftment. The incidences of grade II to IV acute and chronic graft-versus-host disease were 8.3% and 8.3%, respectively. The overall survival and thalassemia-free survival rates were both 100%. This encouraging result suggests that the WZ-14-TM protocol is a feasible and safe conditioning regime for patients with ß-TM undergoing UD HSCT.


Asunto(s)
Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante , Donante no Emparentado , Talasemia beta/mortalidad , Talasemia beta/terapia , Enfermedad Aguda , Adulto , Aloinjertos , Suero Antilinfocítico/administración & dosificación , Busulfano/administración & dosificación , Niño , Preescolar , Enfermedad Crónica , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica , Factores de Riesgo , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
20.
Behav Pharmacol ; 30(4): 311-319, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30157036

RESUMEN

Isolation rearing produces significant behavioral and neurochemical dysfunctions in rodents, which resemble the symptoms of schizophrenia. Clozapine, one of the atypical antipsychotics, is widely used in the treatment of schizophrenia patients and in experimental studies. In this study, male Sprague Dawley rats were randomly assigned to either group-reared or isolation-reared conditions during postnatal days (PNDs) 21-34. During PNDs 46-55, the rats were subjected to chronic clozapine (1.0 mg/kg for 10 days) or saline treatment. On PND 56, all rats underwent behavioral testing and then were sacrificed for biochemical testing. The results indicated that adolescent social isolation induced impairments in prepulse inhibition and reversal learning, and clozapine injection improved the prepulse inhibition disruption but not reversal learning ability. Furthermore, clozapine administration reversed the increased brain-derived neurotrophic factor (BDNF) mRNA level in the medial prefrontal cortex (mPFC) that was induced by adolescent isolation. However, clozapine decreased the BDNF mRNA level in the mPFC in group-reared rats. Together, our findings provide additional evidence that a low dose of chronic clozapine treatment could improve information filtering/sensorimotor gating and alterations in the BDNF mRNA level in the mPFC induced by adolescent social isolation.


Asunto(s)
Clozapina/farmacología , Inhibición Prepulso/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/farmacología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Aprendizaje/efectos de los fármacos , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Aprendizaje Inverso/efectos de los fármacos , Esquizofrenia/fisiopatología , Aislamiento Social/psicología
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