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1.
Aging (Albany NY) ; 122020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-32200357

RESUMO

Major abdominal procedures could induce dysfunction in the immune system and lead to postoperative immunosuppression. Sleep dysfunction is associated with impaired immune activity. However, the effects of postoperative sleep dysfunction on postoperative immune function remain unclear. In this study, we found that sleep-restriction (SR) after surgery increased the spleen weight and the percentage of myeloid-derived suppressor cells (MDSCs) in the spleen, and inhibited splenic CD8+ T cells activity, which was via inhibiting subdiaphragmatic vagus nerve (SVN)-mediated trefoil factor 2 (TFF2) expression in the spleen of aged mice. Dexmedetomidine could alleviate SR-induced these changes via modulating gut microbiota, which acted through SVN. Moreover, we showed essential roles of splenic TFF2 in attenuating SR-induced reduced protective ability against Escherichia coli (E. coli) pneumonia, increased expression of IL-4 and IL-13 in the lung and M2 polarization of alveolar macrophages (AMs), and decreased phagocytic activity of AMs. Dexmedetomidine improved SR-induced reduced protective ability against E. coli pneumonia via splenic TFF2, and subsequently decreasing IL-4 and IL-13 expression in the lung via modulating gut microbiota/SVN, increasing the compromised phagocytic activity of AMs, and ultimately decreasing M2 polarization of AMs. Taken together, dexmedetomidine-induced increase in splenic TFF2 expresssion could alleviate SR-induced exaggeration of postoperative immunosuppression.

2.
Oncogene ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32205869

RESUMO

Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.

3.
Mol Oncol ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32112500

RESUMO

Non-small-cell lung carcinoma (NSCLC) accounts for the majority of lung cancer deaths, and thus there is a clinical need to understand the molecular mechanisms underlying this malignancy. Tumor-initiating cells (TICs) have been accepted to be closely related to tumor reoccurrence after surgery, and circular RNAs (circRNAs) play a crucial function in the tumorigenesis and development of human cancers. Here, we examined the role of the circular RNA hsa_circ_0131457 (circ-SOX4) in lung TICs. We report that circ-SOX4 is upregulated and exists as a covalently closed loop structure in CD133+ cancer cells. Subsequent functional assays showed that circ-SOX4 downregulation suppresses lung TIC proliferation, self-renewal, migration and invasion. Circ-SOX4 upregulation facilitates in vitro development of CD133- cancer cells, and circ-SOX4 deficiency represses in vivo malignancy of CD133+ cells. Additionally, circ-SOX4 was shown to interact with c-MYC by activating the Wnt/ß-catenin pathway in NSCLC. In summary, circ-SOX4 expedites NSCLC progression by activating the Wnt/ß-catenin pathway, and this finding may facilitate the identification of effective therapeutic targets for NSCLC.

4.
FASEB J ; 34(3): 4178-4188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950551

RESUMO

Telomerase plays a pivotal role in tumorigenesis by maintaining telomere homeostasis, a hallmark of cancer. However, the mechanisms by which telomerase is reactivated or upregulated during tumorigenesis remain incompletely understood. Here, we report that the Hippo pathway effector Yes-associated protein (YAP) regulates the expression of human telomerase reverse transcriptase (hTERT). Ectopic expression or physiological activation of YAP increases hTERT expression, whereas knockdown of YAP decreases the expression of hTERT. YAP binds to the hTERT promoter through interaction with the TEA domain family transcription factors and activates hTERT transcription. Furthermore, sustained YAP hyperactivation promotes telomerase activity and extends telomere length, with increased hTERT expression. In addition, we show that hTERT expression is positively correlated with YAP activation in human liver cancer tissues. Together, our results demonstrate that YAP promotes hTERT expression, which could contribute to tumor progression.

5.
Muscle Nerve ; 61(4): 535-541, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31950518

RESUMO

INTRODUCTION: In this study we investigated whether burst-modulated wide-pulse neuromuscular electrical stimulation (NMES) can improve the H-reflex and activation efficiency of sensory fibers. METHODS: NMES-induced electromyography (EMG) was recorded from hindpaw plantar muscles in 11 anesthetized rats. A burst-modulated wide pulse (mWP) with three carrier frequencies (2 kHz, 5 kHz, and 10 kHz) and a continuous wide-pulse (WP) were delivered to the tibial nerve of each rat. The evoked Hoffman (H)-reflexes were measured to evaluate nerve activation efficiency using the H-reflex recruitment curve (HRC). RESULTS: Relative to WP simulation, mWP stimulation required less electrical charge to excite sensory fibers and improved the H-reflex recruitment. Greater electrical charge and smaller recruitment gains were obtained with increased carrier frequency of mWP. DISCUSSION: mWP NMES can improve stimulation efficiency and improve recruitment of sensory fibers on tibial nerve stimulation, which may help to optimize NMES stimulus parameters.

6.
Nat Biomed Eng ; 4(2): 159-171, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31659307

RESUMO

Mechanical mismatches between implanted electronics and biological tissues can lead to inaccurate readings and long-term tissue damage. Here, we show that functionalized multi-walled carbon nanotubes twisted into helical fibre bundles that mimic the hierarchical structure of muscle can monitor multiple disease biomarkers in vivo. The flexible fibre bundles are injectable, have a low bending stiffness and display ultralow stress under compression. As proof-of-concept evidence of the sensing capabilities of these fibre bundles, we show that the fibre bundles enable the spatially resolved and real-time monitoring of H2O2 when implanted in tumours in mice, and that they can be integrated with a wireless transmission system on an adhesive skin patch to monitor calcium ions and glucose in the venous blood of cats for 28 d. The versatility of the helical fibre bundles as chemically functionalized electrochemical sensors makes them suitable for multiple sensing applications in biomedicine and healthcare.

7.
Lasers Med Sci ; 35(2): 365-372, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31222480

RESUMO

The post-stimulation response of neural activities plays an important role to evaluate the effectiveness and safety of neural modulation techniques. Previous studies have established the capability of infrared neural modulation (INM) on neural firing regulation in the central nervous system (CNS); however, the dynamic neural activity after the laser offset has not been well characterized yet. We applied 980-nm infrared diode laser light to irradiate the primary motor cortex of rats, and tungsten electrode was inserted to record the single-unit activity of neurons at the depth of 800-1000 µm (layer V of primary motor cortex). The neural activities were assessed through the change of neural firing rate and firing pattern pre- and post-stimulation with various radiant exposures. The results showed that the 980-nm laser could modulate the firing properties of neurons in the deep layer of the cortex. More neurons with post-stimulation response (78% vs. 83%) were observed at higher stimulation intensity (0.803 J/cm2 vs. 1.071 J/cm2, respectively). The change of firing rate also increased with radiant exposures increasing, and the response lasted up to 4.5 s at 1.071 J/cm2, which was significantly longer than the theoretical thermal relaxation time. Moreover, the increasing Fano factors indicated the irregularity firing pattern of post-stimulation response. Our results confirmed that neural activity maintained a prolonged post-stimulation response after INM, which may provide necessary measurable data for optimization of INM applications in CNS.

8.
Front Psychol ; 10: 2557, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824373

RESUMO

Previous studies have indicated that social evaluations rely heavily on the outcome of an actor's behavior toward a recipient. These studies focused on interactions in which two agents are connected by an external goal (i.e., object-mediated social interaction) and revealed that the intent behind an action has a privileged role in evaluating the valence of a social interaction. The current study investigated whether the intent behind an action influences evaluation of contingent social interactions wherein one agent responds to another without referring to a specific target. To clarify this, we operationalized intent as harmful or harmless when one agent hit another (i.e., recipient), and manipulated the action's outcome by determining to what extent it changed the recipient's state (i.e., falling down or moving slightly). Results showed that in contingent interactions with both direct launching (i.e., the actor directly caused the change) and extended launching (i.e., the actor caused the change through a mediated block), when the action significantly affected the recipient, the agents were evaluated as having a more negative social interaction than when the influence was small; this effect was independent of the intent behind the action. Such findings demonstrated that evaluations of contingent social interactions are primarily influenced by an actor's causal role in the outcome, not the intent behind an action. This null effect of intent when evaluating social interaction contrasts with findings on object-mediated social interaction, which is consistent with human social evaluations relying on two dissociable systems: causal and intentional components.

9.
PLoS Negl Trop Dis ; 13(11): e0007846, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751335

RESUMO

Angiostrongylus cantonensis (rat lungworm) is the etiological agent of angiostrongyliasis, mainly causing eosinophilic meningitis or meningoencephalitis in human. Although the biology of A. cantonensis is relatively well known, little is understood about the mechanisms of the parasite's development and survival in definitive hosts, or its adaptation to a broad range of snail intermediate hosts. Here, we generate a high-quality assembly of a well-defined laboratory strain of A. cantonensis from Guangzhou, China, by using Illumina and PacBio sequencing technologies. We undertake comparative analyses with representative helminth genomes and explore transcriptomic data throughout key developmental life-cycles of the parasite. We find that part of retrotransposons and gene families undergo multiple waves of expansions. These include extracellular superoxide dismutase (EC-SOD) and astacin-like proteases which are considered to be associated with invasion and survival of the parasite. Furthermore, these paralogs from different sub-clades based on phylogeny, have different expression patterns in the molluscan and rodent stages, suggesting divergent functions under the different parasitic environment. We also find five candidate convergent signatures in the EC-SOD proteins from flukes and one sub-clade of A. cantonensis. Additionally, genes encoding proteolytic enzymes, involved in host hemoglobin digestion, exhibit expansion in A. cantonensis as well as two other blood-feeding nematodes. Overall, we find several potential adaptive evolutionary signatures in A. cantonensis, and also in some other helminths with similar traits. The genome and transcriptomes provide a useful resource for detailed studies of A. cantonensis-host adaptation and an in-depth understanding of the global-spread of angiostrongyliasis.


Assuntos
Adaptação Biológica , Angiostrongylus cantonensis/classificação , Angiostrongylus cantonensis/genética , Evolução Molecular , Genoma Helmíntico , Infecções por Strongylida/parasitologia , Infecções por Strongylida/veterinária , Angiostrongylus cantonensis/isolamento & purificação , Animais , China , Biologia Computacional , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Roedores , Trematódeos
10.
Theranostics ; 9(26): 8206-8220, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754391

RESUMO

Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.

11.
Neurophotonics ; 6(3): 035009, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31482103

RESUMO

Near-infrared radiation (NIR) has been described as one of the highest-resolution tools for neuromodulation. However, the poor tissue penetration depth of NIR has limited its further application on some of the deeper layer neurons in vivo. A 980-nm short-wavelength NIR (SW-NIR) with high penetration depth was employed, and its inhibitory effect on neurons was investigated in vivo. In experiments, SW-NIR was implemented on the rat's cochlear nucleus (CN), the auditory pathway was activated by pure-tones through the rat's external auditory canal, and the neural responses were recorded in the inferior colliculus by a multichannel electrode array. Neural firing rate (FR) and the first spike latency (FSL) were analyzed to evaluate the optically induced neural inhibition. Meanwhile, a two-layered finite element, consisting of a fluid layer and a gray matter layer, was established to model the optically induced temperature changes in CN; different stimulation paradigms were used to compare the inhibitory efficiency of SW-NIR. Results showed that SW-NIR could reversibly inhibit acoustically induced CN neural activities: with the increase of laser radiant exposures energy, neural FR decreased significantly and FSL lengthened steadily. Significant inhibition occurred when the optical pulse stimulated prior to the acoustic stimulus. Results indicated that the inhibition relies on the establishment time of the temperature field. Moreover, our preliminary results suggest that short-wavelength infrared could regulate the activities of neurons beyond the neural tissues laser irradiated through neural networks and conduction in vivo. These findings may provide a method for accurate neuromodulation in vivo.

12.
Curr Eye Res ; 44(12): 1393-1398, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31256683

RESUMO

Aims: Wavefront aberration (WA) has become one of the important indicators for measuring the visual quality. Whether strabismus surgery affects the WA remain controversial. This study aims to investigate the postoperative alterations of WA in patients who underwent horizontal rectus muscle surgery.Methods: A total of 34 patients were enrolled and divided into two groups: bilateral lateral rectus recession (BLR) group and unilateral lateral rectus recession and medial rectus resection (R&R) group. The WA was examined 1 day before surgery, 3 days, and 6 weeks after surgery using the iTrace Visual Function Analyzer (Tracey Technologies).Results: Significant increases in total WA, lower-order aberration (LOA) and higher-order aberration (HOA) of both groups were detected in 3 days after surgery (P < 0.05), while no significant differences in 6 weeks after surgery. Significant increases in astigmatism, secondary astigmatism, and trefoil of both groups were detected in 3 days after surgery (P < 0.05), while no significant differences in individual order of LOA and HOA in 6 weeks postoperatively. Z22, Z33, and Z42 of both groups increased significantly 3 days after surgery (P < 0.05) and returned to baseline level 6 weeks after surgery, while the rest Zernike coefficients remained the same postoperatively. When comparing the differences between the two groups, there were no statistically significant differences in these parameters between baseline and each follow-up visit postoperatively.Conclusions: The increase of WA restored to pre-operative level in 6 weeks after surgery, indicating the influences of horizontal rectus muscle surgery to WA were transient and reversible.

13.
Theranostics ; 9(13): 3840-3852, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281517

RESUMO

Background and aims: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism. Methods: We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and AML12 cell lines in vitro. We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration in vivo. Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of Yap in AML12 cells. Furthermore, we used Yap overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins. Results: In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes in vivo and mouse AML12 cell lines in vitro. By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway in vivo. Furthermore, the study showed that Yap knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas Yap overexpression promoted Notch1-NICD signals. Specific overexpression of Yap in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury. Conclusion: These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.

14.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(5): 528-534, 2019 May 28.
Artigo em Chinês | MEDLINE | ID: mdl-31303616

RESUMO

OBJECTIVE: To explore the role of P53, pairing box gene 8 antibody (PAX8), and calcium omentum protein (Calretinin) in the origin of epithelial ovarian cancer.
 Methods: A total of 63 tissue samples of ovarian tumor and fallopian tubes were collected. Immunohistochemistry methods were used to analyze the expression of P53, PAX8, and Calretinin. The relationship between these protein levels and the classification of ovarian tumors was evaluated.
 Results: In epithelial ovarian cancer, the P53 or PAX8 was correlated with the occurrence of high-grade carcinoma, while the calretinin was correlated with the occurrence of low-grade carcinoma (P<0.05). The combination of PAX8 with Calretinin was correlated with the grade of ovarian tumor (P<0.05). The combination of P53 with Calretinin was correlated with the grade of tumor (P<0.05). The combination of P53 with PAX8 was correlated with the grade of tumor (P<0.05). The expression of P53 in fallopian tubes was correlated with the malignant degree of epithelial ovarian cancer (P<0.05). The degree of fallopian tube lesions in patients with ovarian cancer was correlated with epithelial ovarian cancer. The malignant lesions of tubal epithelium was correlated with high-grade carcinoma, while the normal or atypical hyperplasia of tubal epithelium was correlated with low-grade carcinoma (P<0.05).
 Conclusion: P53 and Calretinin combined with PAX8 show a synergistic effect on the differentiation of epithelial ovarian cancer grade. The morphology of HE and the expression of TP53 in the fallopian tube epithelium play an auxiliary role in the diagnosis of epithelial ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Epitélio , Tubas Uterinas , Feminino , Humanos , Fator de Transcrição PAX8
15.
PeerJ ; 7: e6998, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179186

RESUMO

Objective: To study the one-year effect of wearing orthokeratology (OK) lenses on the visual quality of juvenile myopia. Methods: The right eyes of 36 juvenile myopias were retrospectively studied in this work. Q-value, e-value, corneal curvature, strehl ratio (SR), modulation transfer function (MTF) and wavefront aberration (WA) were compared before and at 1, 3 and 12 months after wearing OK lenses. The SR, MTF and WA of cornea, internal optic and ocular were analyzed separately. The spherical and cylinder diopter, vision acuity, compensating factor (CF) and compensative rate (CF%) were compared before and at 12 months after wearing OK lenses. Results: (1) The vision of LogMAR increased and the corneal curvature decreased significantly after wearing OK lenses. There was no significant difference for the e-value before and after wearing OK lenses. The Q-value increased at 1 month but decreased at 3 and 12 months remarkably. (2) The ocular and internal optic SR and MTF increased significantly at 1 month and then remained stable. The MTF in different spacial frequencies increased after wearing OK lenses. There was no significant difference for the corneal SR before and after wearing OK lenses, and the corneal MTF decreased significantly after wearing OK lenses. (3) For the ocular, the total higher order aberration (HOA), spherical, coma and trefoil aberrations increased, and the total aberration, total lower order aberration (LOA) and defocus aberration decreased obviously except astigmatism. The corneal aberrations increased significantly after wearing OK lenses except astigmatism. For the internal optic, the total aberration, total LOA and defocus aberration decreased, and the total HOA, coma and trefoil aberration increased significantly except the astigmatism and spherical aberrations. (4) The CF and CF% of total aberration, total LOA, total HOA and coma aberrations increased, and those of astigmatism and spherical decreased at 12 months. Conclusions: Orthokeratology is effective in correcting the refractive error and improving the vision quality of juvenile myopia over the one-year follow-up period.

16.
Neuropsychiatr Dis Treat ; 15: 1429-1438, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213817

RESUMO

Objective: To investigate the therapeutic effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) on the expression of 5-hydroxytryptamine (5-HT)/5-HT receptor 2A (5-HT2A), 5-HT transporter (5-HTT), and uncoupling protein 4 (UCP4) after cerebral ischemia/reperfusion (I/R) injury. Methods: Sprague-Dawley rats were randomly divided into control, model and 125 (low-dose), 250 (middle-dose), and 500 (high-dose) mg/mL TSG groups. Rat cerebral I/R injury model was established by middle cerebral artery occlusion (MCAO). After successful establishment of rat MCAO model, rats in control and model groups were decapitated immediately. Rats in TSG group were orally administered 125, 250, and 500 mg/mL TSG in corresponding groups at a dose of 1 mL/100 g per day for 7 continuous days, and then the rats were decapitated. The infarct size was determined using triphenyl tetrazolium chloride staining and the expression of UCP4 and 5-HT2A in the hippocampus and thalamic nucleus was detected using immunohistochemistry and western blot assay. The expression of 5-HTT in brain tissue was detected using western blot assay. Serum 5-HT levels were detected using ELISA. Results: After treatment, the infarct size due to cerebral I/R injury decreased with increased concentrations of TSG. Synchronous reduction of 5-HT in the blood and 5-HTT in the brain was observed, and 5-HT2A was expressed in normal brain tissue but its level was increased in rats after cerebral I/R injury. A high level of UCP4 was found in normal brain tissue, which rose by 6 hrs after cerebral I/R injury but reduced to minimal levels 24 hrs after injury. With increasing TSG concentration, the levels of 5-HT, 5HTT, and UCP4 were increased, while the level of 5-HT2A was decreased. Conclusion: TSG is effective in treating cerebral I/R injury in rats, and its mechanism may be implemented through the 5-HT/5-HTR pathway, by increasing 5-HT release, enhancing the activity of 5-HTT, increasing expression of UCP4, and inhibiting 5-HT2A activity.

17.
Proc Natl Acad Sci U S A ; 116(21): 10382-10391, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31072927

RESUMO

During skeletal muscle regeneration, muscle stem cells (MuSCs) respond to multiple signaling inputs that converge onto mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. mTOR function is essential for establishment of the differentiation-committed progenitors (early stage of differentiation, marked by the induction of myogenin expression), myotube fusion, and, ultimately, hypertrophy (later stage of differentiation). While a major mTORC1 substrate, p70S6K, is required for myotube fusion and hypertrophy, an mTORC1 effector for the induction of myogenin expression remains unclear. Here, we identified Per-Arnt-Sim domain kinase (PASK) as a downstream phosphorylation target of mTORC1 in MuSCs during differentiation. We have recently shown that the PASK phosphorylates Wdr5 to stimulate MuSC differentiation by epigenetically activating the myogenin promoter. We show that phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exit from self-renewal, and induction of the myogenesis program. Our studies reveal that mTORC1-PASK signaling is required for the rise of myogenin-positive committed myoblasts (early stage of myogenesis), whereas mTORC1-S6K signaling is required for myoblast fusion (later stage of myogenesis). Thus, our discoveries allow molecular dissection of mTOR functions during different stages of the myogenesis program driven by two different substrates.

18.
Int J Ophthalmol ; 12(5): 717-724, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131228

RESUMO

AIM: To evaluate the feasibility of mesenchymal stem cells (MSCs) to differentiate into corneal epithelial cells after being seeded on the decellularized small incision lenticule extraction (SMILE)-derived lenticules. METHODS: The fresh lenticules procured from patients undergoing SMILE for the correction of myopia were decellularized. The MSCs were subsequently cultivated on those denuded lenticules. The MSCs without lenticules were used as a control. The proliferation activity of the MSCs after seeding 24h was quantitatively determined with the Cell Counting Kit-8 (CCK-8) assay. Immunofluorescence staining and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to assess the marker expression in differentiated MSCs. RESULTS: The data showed that both fresh and decellularized lenticules could significantly promote the proliferation of MSCs, compared to that in control (P=0.02 for fresh lenticules, P=0.001 for decellularize ones, respectively). The MSCs seeded on both lenticules were positive for cytokeratin 3 (CK3) staining. The expression of CK3 increased 5-fold in MSCs seeded on fresh lenticules and 18-fold on decellularized ones, compared to that in control. There was a significant difference in the expression of CK3 in MSCs seeded on fresh and decellularized lenticules (P<0.001). The expression of CK8 and CK18 was similar in pure MSCs and MSCs seeded on fresh lenticules (P>0.05), while the expression of these markers was decreased in MSCs seeded on decellularized ones. CONCLUSION: These results suggest that the decellularized lenticules might be more suitable for MSCs to differentiate into corneal epithelial cells, which offers the prospect of a novel therapeutic modality of SMILE-derived lenticules in regenerative corneal engineering.

19.
Life Sci ; 228: 72-84, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31034839

RESUMO

AIMS: Calcific aortic valve disease (CAVD) emerges as a challenging clinical issue, which is associated with high cardiovascular mortality. It has been demonstrated that osteoblastic transformation of AVICs is a key mechanism of CAVD and C-C motif chemokine receptors (CCRs) may favor this process. Thus, we aimed to investigate whether CCRs were involved in osteoblastic transformation of AVICs during the development CAVD. MAIN METHODS: We first analyzed microarray data (GSE51472 and GSE12644) to identify differentially expressed genes between CAVD aortic valve tissue and normal samples, followed by verification of immunohistochemistry, qPCR and western blotting. Primary aortic valvular interstitial cells (AVICs) were incubated with specific inhibitors and/or siRNA of CCR2 and CCL2 under pro-calcifying medium. The levels of CCL2 in the medium were measured by ELISA. In addition, we used recombinant CCL2 to activate CCR2 in calcifying AVICs. Alizarin red S staining and calcium deposition were used to evaluate the degree of calcification. Western blotting was used to determine osteoblastic transformation of AVIC and total Akt and phosphorylated Akt expression. KEY FINDING: CCR2 levels were remarkably up-regulated in calcified aortic valve and calcifying AVICs. Silencing CCR2 inhibited the osteoblastic transformation and calcification of AVICs. In addition, recombinant CCL2 activated CCR2 and accelerated AVICs calcification through PI3K/Akt pathway. SIGNIFICANCE: We characterize abnormal activation of CCL2/CCR2 axis as a promoter of AVICs osteoblastic transformation and calcification. Our findings implicate the CCL2/CCR2-PI3K/Akt pathway as a potential target for treatment of CAVD.


Assuntos
Estenose da Valva Aórtica/patologia , Valva Aórtica/patologia , Calcinose/patologia , Osteoblastos/patologia , Receptores CCR2/metabolismo , Adulto , Idoso , Animais , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Calcinose/genética , Calcinose/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoblastos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos Sprague-Dawley , Receptores CCR2/análise , Receptores CCR2/genética , Transdução de Sinais , Transcriptoma , Regulação para Cima
20.
J Clin Nurs ; 28(15-16): 2824-2832, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30938890

RESUMO

AIMS AND OBJECTIVES: To validate the Chinese version of the Critical-Care Pain Observation Tool (CPOT) in nonintubated and intubated ICU patients. BACKGROUND: While CPOT was found to have the best psychometric properties among objective pain assessment scales, there is no Chinese version CPOT for nonintubated patients. DESIGN: Cross-sectional design was used in these two observational studies. METHODS: Seventy-six nonintubated patients and 53 intubated patients were assessed to examine internal consistency, criterion-related and discriminative validity of CPOT in the first study. Pain assessment during low pain condition as well as increased pain condition was performed by Numeric Rating Scale (NRS) and the Chinese version COPT. Forty nonintubated patients and 43 intubated patients were assessed to examine inter-rater reliability in the second study. A bedside nurse and a researcher independently executed paired pain assessments with CPOT in the same conditions. The STROBE Statement was followed to guide these studies. RESULTS: The Cronbach's α in nonintubated patients and intubated patients was 0.903-0.930 and 0.868-0.870. The intraclass correlation coefficients (ICCs) in nonintubated patients ranged from 0.959-0.982, and the ICC in intubated patients ranged from 0.947-0.959, confirming the inter-rater reliability. The moderately positive Pearson's correlations between CPOT and NRS scores (r = 0.757-0.838 in nonintubated patients, r = 0.574-0.705 in intubated patients) indicated the criterion-related validity. A significant increase in CPOT scores in the increased pain condition compared with those acquired in the low pain condition verified the discriminative validity. CONCLUSIONS: The Chinese version of CPOT was presented to be valid and reliable for both nonintubated and intubated critically ill adults, which could be applicable for pain assessment in patients in ICU. RELEVANCE TO CLINICAL PRACTICE: This study provides an applicable pain assessment tool for both nonintubated patients and intubated patients in ICU.


Assuntos
Enfermagem de Cuidados Críticos/métodos , Intubação/efeitos adversos , Medição da Dor/instrumentação , Adulto , Idoso , China , Estudos Transversais , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
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