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1.
Front Immunol ; 12: 705751, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621265

RESUMO

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-ß-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.

2.
Sensors (Basel) ; 21(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34640809

RESUMO

Many environmental monitoring applications that are based on the Internet of Things (IoT) require robust and available systems. These systems must be able to tolerate the hardware or software failure of nodes and communication failure between nodes. However, node failure is inevitable due to environmental and human factors, and battery depletion in particular is a major contributor to node failure. The existing failure detection algorithms seldom consider the problem of node battery consumption. In order to rectify this, we propose a low-power failure detector (LP-FD) that can provide an acceptable failure detection service and can save on the battery consumption of nodes. From simulation experiments, results show that the LP-FD can provide better detection speed, accuracy, overhead and battery consumption than other failure detection algorithms.


Assuntos
Internet das Coisas , Algoritmos , Simulação por Computador , Fontes de Energia Elétrica , Monitoramento Ambiental , Humanos
3.
Molecules ; 26(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34641427

RESUMO

O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-ß-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g's neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.

4.
ACS Nano ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34529415

RESUMO

Lithium-sulfur (Li-S) batteries have attracted widespread attention due to their high theoretical energy density. However, their practical application is still hindered by the shuttle effect and the sluggish conversion of lithium polysulfides (LiPSs). Herein, monodisperse molybdenum (Mo) nanoparticles embedded onto nitrogen-doped graphene (Mo@N-G) were developed and used as a highly efficient electrocatalyst to enhance LiPS conversion. The weight ratio of the electrocatalyst in the catalyst/sulfur cathode is only 9%. The unfilled d orbitals of oxidized Mo can attract the electrons of LiPS anions and form Mo-S bonds during the electrochemical process, thus facilitating fast conversion of LiPSs. Li-S batteries based on the Mo@N-G/S cathode can exhibit excellent rate performance, large capacity, and superior cycling stability. Moreover, Mo@N-G also plays an important role in room-temperature quasi-solid-state Li-S batteries. These interesting findings suggest the great potential of Mo nanoparticles in building high-performance Li-S batteries.

5.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360755

RESUMO

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.


Assuntos
Achyranthes/química , Hipocampo/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores , Peptídeos , Proteínas de Plantas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Ann Am Thorac Soc ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34288830

RESUMO

RATIONALE: The etiology of acute respiratory distress syndrome (ARDS) may play an important role in the failure of noninvasive ventilation (NIV). OBJECTIVES: To explore the association between ARDS etiology and risk of noninvasive ventilation failure. METHODS: A multicenter prospective observational study was performed in 17 ICUs in China from September 2017 to December 2019. Patients with ARDS who used NIV as a first-line therapy were enrolled. The etiology of ARDS was recorded at study entry. RESULTS: A total of 306 patients were enrolled. Of the patients, 146 were classified as having pulmonary ARDS (ARDSp) and 160 were classified as having extrapulmonary ARDS (ARDSexp). From initiation to 24 h of NIV, the respiratory rate, heart rate, PaO2/FiO2, and PaCO2 improved slower in patients with ARDSp than those with ARDSexp. Patients with ARDSp experienced more NIV failure (55% vs. 28%; p < 0.01) and higher 28-day mortality (47% vs. 14%; p < 0.01). The adjusted odds ratio of NIV failure and 28-day mortality were 5.47 (95%CI: 3.04-9.86) and 10.13 (95%CI: 5.01-20.46), respectively. In addition, we combined the presence of ARDSp, presence of septic shock, age, non-pulmonary SOFA score, respiratory rate at 1-2 h of NIV, and PaO2/FiO2 at 1-2 h of NIV to develop a risk score of NIV failure. With the increase of the risk score, the rate of NIV failure increased. Using 5.5 as cutoff value to predict NIV failure, the sensitivity and specificity was good both in training and validation cohorts. CONCLUSIONS: Among patients with ARDS who used NIV as a first-line therapy, ARDSp was associated with slower improvement, more NIV failure, and higher 28-day mortality than ARDSexp. The risk score combined presence of ARDSp, presence of septic shock, age, non-pulmonary SOFA score, respiratory rate at 1-2 h of NIV, and PaO2/FiO2 at 1-2 h of NIV has high accuracy to predict NIV failure among ARDS population.

7.
Acta Biomater ; 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34289422

RESUMO

Our previous studies have shown that extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth of sensory and motor neurons in vitro. This study was aimed at generating an artificial nerve graft incorporated with SKP-SC-EVs to examine in vivo effects of SKP-SC-EVs on peripheral nerve regeneration. Here SKP-SC-EVs were isolated and then identified by morphological observation and phenotypic marker expression. Following co-culture with SCs or motoneurons, SKP-SC-EVs were internalized, showing the capability to enhance SC viability or motoneuron neurite outgrowth. In vitro, SKP-SC-EVs released from Matrigel could maintain cellular uptake property and neural activity. Nerve grafts were developed by incorporating Matrigel-encapsulated SKP-SC-EVs into silicone conduits. Functional evaluation, histological investigation, and morphometric analysis were performed to compare the nerve regenerative outcome after bridging the 10-mm long sciatic nerve defect in rats with our developed nerve grafts, silicone conduits (filled with vehicle), and autografts respectively. Our developed nerve grafts significantly accelerated the recovery of motor, sensory, and electrophysiological functions of rats, facilitated outgrowth and myelination of regenerated axons, and alleviated denervation-induced atrophy of target muscles. Collectively, our findings suggested that incorporation of SKP-SC-EVs into nerve grafts might represent a promising paradigm for peripheral nerve injury repair. STATEMENT OF SIGNIFICANCE: Nerve grafts have been progressively developed to meet the increasing requirements for peripheral nerve injury repair. Here we reported a design of nerve grafts featured by incorporation of Matrigel-encapsulated extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs), because SKP-SC-EVs were found to possess in vitro neural activity, thus raising the possibility of cell-free therapy. Our developed nerve grafts yielded the satisfactory outcome of nerve grafting in rats with a 10-mm long sciatic nerve defect, as evaluated by functional and morphological assessments. The promoting effects of SKP-SC-EVs-incorporating nerve grafts on peripheral nerve regeneration might benefit from in vivo biological cues afforded by SKP-SC-EVs, which had been released from Matrigel and then internalized by residual neural cells in sciatic nerve stumps.

8.
Biosens Bioelectron ; 192: 113488, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34265522

RESUMO

Screening inhibitors of flavin monooxygenase 3 (FMO3) is very important for treating trimethylamine N-oxide (TMAO) derived thrombotic diseases. Herein, focusing on Xuefu Zhuyu decoction (XFZYD) as a Chinese traditional medicine with antithrombotic efficacy, a facile and label-free fluorescence strategy was developed for evaluating the influence of the bioactive ingredients in XFZYD on FMO3 activity through indicator displacement assay. To this end, the optimized supramolecular host-guest (p-sulfonatocalix[4]arene-oxazine 1) reporter pair and FMO3 catalytic system were exploited to determine the influence of the bioactive compounds in XFZYD on the conversion from TMA to TMAO. From the nine compounds tested, naringin, paeoniflorin, ß-ecdysterone, 18ß-glycyrrhizic acid, amygdalin, albiflorin, and saikosaponin A downregulated FMO3 activity and reduced TMAO biosynthesis. Moreover, molecular docking was successfully applied to simulate the optimal conformation of a receptor-ligand complex between FMO3 and all tested compounds except for ß-ecdysterone. Therefore, this approach provides a novel and promising strategy for screening FMO3 inhibitors from Chinese traditional medicine by supramolecular sensing.


Assuntos
Técnicas Biossensoriais , Trombose , Humanos , Metilaminas , Simulação de Acoplamento Molecular , Oxigenases
9.
Am J Med Genet A ; 185(10): 3074-3082, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34047005

RESUMO

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome caused by mutations in PSTPIP1 is a rare inflammatory disorder that can be easily misdiagnosed. It is characterized by anemia, arthritis, cutaneous inflammation, recurrent infections, growth failure, hepatosplenomegaly, lymphadenopathy, hyperzincemia/hypercalprotectinemia, neutropenia, thrombocytopenia, and elevated inflammatory indicators. This study describes the cases of two pediatric female patients with long-standing recurrent arthralgia in different parts of the extremities and severe anemia, respectively, who were misdiagnosed and treated for aseptic necrosis of the femoral head and severe autoimmune hemolytic anemia, respectively. High-throughput sequencing analysis revealed a de novo heterozygous missense mutation (c.748G > A, p. Glu250Lys) in exon 11 of PSTPIP1 (NM_003978.5) in both patients, which supported a diagnosis of PAMI. The patients were treated with prednisone and etanercept, which improved their symptoms, but neutropenia remained unchanged. These cases highlight the importance of genetic assessment for the accurate diagnosis of PAMI and to ensure adequate and timely treatment of these patients.

10.
Nano Lett ; 21(10): 4394-4402, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33998787

RESUMO

The high demand for acute kidney injury (AKI) therapy calls the development of multifunctional nanomedicine for renal management with programmable pharmacokinetics. Here, we developed a renal-accumulating DNA nanodevice with exclusive kidney retention for longitudinal protection of AKI in different stages in a renal ischemia-reperfusion (I/R) model. Due to the prolonged kidney retention time (>12 h), the ROS-sensitive nucleic acids of the nanodevice could effectively alleviate oxidative stress by scavenging ROS in stage I, and then the anticomplement component 5a (aC5a) aptamer loaded nanodevice could sequentially suppress the inflammatory responses by blocking C5a in stage II, which is directly related to the cytokine storm. This sequential therapy provides durable and pathogenic treatment of kidney dysfunction based on successive pathophysiological events induced by I/R, which holds great promise for renal management and the suppression of the cytokine storm in more broad settings including COVID-19.


Assuntos
Injúria Renal Aguda , COVID-19 , Traumatismo por Reperfusão , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Humanos , Rim/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/tratamento farmacológico , SARS-CoV-2
11.
Adv Sci (Weinh) ; 8(14): e2101182, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34032382

RESUMO

Lithium-sulfur (Li-S) batteries, as part of the post-lithium-ion batteries (post-LIBs), are expected to deliver significantly higher energy densities. Their power densities, however, are today considerably worse than that of the LIBs, limiting the Li-S batteries to very few specific applications that need low power and long working time. With the rapid development of single cell components (cathode, anode, or electrolyte) in the last few years, it is expected that an integrated approach can maximize the power density without compromising the energy density in a Li-S full cell. Here, this goal is achieved by using a novel biomass porous carbon matrix (PCM) in the anode, as well as N-Co9 S8 nanoparticles and carbon nanotubes (CNTs) in the cathode. The authors' approach unlocks the potential of the electrodes and enables the Li-S full pouch cells with unprecedented power densities and energy densities (325 Wh kg-1 and 1412 W kg-1 , respectively). This work addresses the problem of low power densities in the current Li-S technology, thus making the Li-S batteries a strong candidate in more application scenarios.

12.
Eur J Med Chem ; 218: 113384, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33799070

RESUMO

Herein we reported the synthesis of twenty new organoselenium compounds (2a-2j and 3a-3j) based on the hybridization of nonsteroidal antiinflammatory drugs (NSAIDs) skeleton and organoselenium motif (-SeCN and -SeCF3), the anticancer activity was evaluated against four types of cancer cell lines, Caco-2 (human colon adenocarcinoma cells), BGC-823 (human gastric cancer cells), MCF-7 (human breast adenocarcinoma cells), PC-3 (human prostatic cancer cells). Interestingly, the introduction of the -SeCN or -SeCF3 moiety in corresponding parent NSAIDs results in the significant effect on cancer cell lines. Moreover, the most active compound 3a showed IC50 values lower than 5 µM against the four cancer cell lines, particularly to BGC-823 and MCF-7 with IC50 values of 2.5 and 2.7 µM, respectively. Furthermore, three compounds 3a, 3g and 3i were selected to investigate their ability to induce apoptosis in BGC-823 cells via modulating the expression of anti-apoptotic Bcl-2 protein, pro-inflammatory cytokines (IL-2) and proapoptotic caspase-8 protein. The redox properties of the NSAIDs-Se derivatives prepared herein were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), bleomycin dependent DNA damage and glutathione peroxidase (GPx)-like assays. Finally, molecular docking study revealed that an interaction with the active site of thioredoxin reductase 1 (TrxR1) and predicted the anticancer activity of the synthesized candidates. Overall, these results could serve a promising launch point for further design of NSAIDs-Se derivatives as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Compostos Organosselênicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
BMC Mol Cell Biol ; 22(1): 21, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827416

RESUMO

BACKGROUND: Schwann cells (SCs) play a crucial role in the repair of peripheral nerves. This is due to their ability to proliferate, migrate, and provide trophic support to axon regrowth. During peripheral nerve injury, SCs de-differentiate and reprogram to gain the ability to repair nerves. Cysteine-rich 61 (Cyr61/CCN1) is a member of the CCN family of matrix cell proteins and have been reported to be abundant in the secretome of repair mediating SCs. In this study we investigate the function of Cyr61 in SCs. RESULTS: We observed Cyr61 was expressed both in vivo and in vitro. The promoting effect of Cyr61 on SC proliferation and migration was through autocrine and paracrine mechanisms. SCs expressed αvß3 integrin and the effect of Cyr61 on SC proliferation and migration could be blocked via αvß3 integrin. Cyr61 could influence c-Jun protein expression in cultured SCs. CONCLUSIONS: In this study, we found that Cyr61 promotes SC proliferation and migration via αvß3 integrin and regulates c-Jun expression. Our study contributes to the understanding of cellular and molecular mechanisms underlying SC's function during nerve injury, and thus, may facilitate the regeneration of peripheral nerves after injury.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteína Rica em Cisteína 61/farmacologia , Integrina alfaVbeta3/metabolismo , Células de Schwann/efeitos dos fármacos , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Proteína Rica em Cisteína 61/genética , Proteína Rica em Cisteína 61/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
14.
Neuroreport ; 32(6): 518-524, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33788819

RESUMO

Achyranthes bidentata polypeptide k (ABPPk), a powerful active component from a traditional Chinese medicinal herb-Achyranthes bidentata Bl., has exhibited promising neuroprotective activity due to its multiple-targeting capability. However, the effect of ABPPk on the survival, growth and axonal regeneration of spinal cord motor neurons remains unclear. Here, a modified method, which is more optimized for embryonic cells in ambient carbon dioxide levels, was used for acquisition of rat embryonic spinal cord motor neurons with high survival and purity. ABPPk concentration-dependently enhanced the neuronal viability and promoted the neurite outgrowth. Co-culture of motor neurons and skeletal myocytes model indicated that ABPPk enhanced the neuromuscular junction development and maturation. A microfluidic axotomy model was further established for the axonal disconnection, and ABPPk significantly accelerated the axonal regeneration of motor neurons. Furthermore, we demonstrated that the upregulation of three neurofilament protein subunits in motor neurons might be relevant to the mechanisms of the growth-promoting effect of ABPPk. Our findings provide an experimental and theoretical basis for the development of ABPPk as a potential application in the development of treatment strategy for nerve injury diseases.

15.
Carbohydr Polym ; 259: 117734, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33673995

RESUMO

Oligosaccharides are one of the most important components in mammalian milk. Milk oligosaccharides can promote colonization of gut microbiota and protect newborns from infections. The diversity and structures of MOs differ among mammalian species. MOs in human and farm animals have been well-documented. However, the knowledge on MOs in rat and mouse have been very limited even though they are the most-widely used models for studies of human physiology and disease. Herein, we use a high-sensitivity online solid-phase extraction and HILIC coupled with electrospray tandem mass spectrometry to analyze the acidic MOs in rat and mouse. Among the fifteen MOs identified, twelve were reported for the first time in rat and mouse together with two novel sulphated oligosaccharides. The complete list of acidic oligosaccharides present in rat and mouse milk is the baseline information of these animals and should contribute to biological/biomedical studies using rats and mice as models.


Assuntos
Leite/metabolismo , Oligossacarídeos/análise , Espectrometria de Massas por Ionização por Electrospray , Animais , Cromatografia Líquida de Alta Pressão , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Oligossacarídeos/isolamento & purificação , Ratos , Extração em Fase Sólida
16.
Adv Drug Deliv Rev ; 173: 141-163, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33774116

RESUMO

Optical imaging has played a vital role in development of biomedicine and image-guided theragnostic. Nevertheless, the clinical translation of optical molecular imaging for deep-tissue visualization is still limited by poor signal-to-background ratio and low penetration depth owing to light scattering and tissue autofluorescence. Hence, to facilitate precise diagnosis and accurate surgery excision in clinical practices, the responsive optical probes (ROPs) are broadly designed for specific reaction with biological analytes or disease biomarkers via chemical/physical interactions for photoacoustic and second near-infrared fluorescence (NIR-II, 900-1700 nm) fluorescence imaging. Herein, the recent advances in the development of ROPs including molecular design principles, activated mechanisms and treatment responses for photoacoustic and NIR-II fluorescence imaging are reviewed. Furthermore, the present challenges and future perspectives of ROPs for deep-tissue imaging are also discussed.

17.
Biochem Biophys Res Commun ; 548: 148-154, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33640608

RESUMO

Endocrine therapy is a promising treatment for endometrial cancer (EC) that preserves fertility, however, progesterone-resistance is currently the major challenges. The Cancer Genome Atlas (TCGA) database analysis showed that CNR1 was closely have a negative correlation with overall survival (OS) and relapse-free survival (RFS) in endometrial cancer. To explore the role of CNR1 in progesterone resistance and possible molecular regulation mechanism, we established stable progesterone-resistant cell lines (IshikawaPR) via progesterone tolerance of ordinary cancer cells (Ishikawa). The difference of CNR1 level in two cell lines was assessed by MTT, RT-PCR, Western blot, immunofluorescence. Then, lentiviruses constructed CNR1-knockdown with GV248 as the tool vector were used to transfect IshikwaPR cells, and the changes of biological behavior and progesterone sensitivity was verified respectively through plate cloning experiment, EdU assay, flow cytometry cycle analysis, transwell, Scratch test, etc. We founded after CNR1 was knocked down, the proliferative activity and ability to migrate of IshikawaPR cells decreased, progesterone-response sensitivity could be improved. Moreover, knockdown of CNR1 can also down-regulate ERK and NFκ B expression and activation. Furthermore, subcutaneous xenograft in nude mice was tested similarly in vivo. The above datas suggest that targeting CNR1 may reverse the progesterone resistance in endometrial cancer and may coordinate the role of ERK pathway activation.


Assuntos
Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Endométrio/anormalidades , Sistema de Sinalização das MAP Quinases , Receptor CB1 de Canabinoide/metabolismo , Doenças Uterinas/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Neoplasias do Endométrio/genética , Endométrio/metabolismo , Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Medroxiprogesterona/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor CB1 de Canabinoide/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Doenças Uterinas/genética , Doenças Uterinas/patologia
18.
Clin Biochem ; 90: 50-57, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33539806

RESUMO

BACKGROUND: Parathyroid hormone (PTH) and vitamin D plays a major role in calcium (Ca) homeostasis and bone turnover. The purpose of this study was to assess which factors (sex, age, time of blood sampling, season of the year, temperature and sunshine hours (SHH)) had the greatest impact on plasma PTH, 25-OH-VitD, and Ca levels, and then whether these effects were clinically acceptable in a large number of Southwestern Chinese subjects. METHOD: The data was from West China Hospital Health Examination Center, Sichuan University from April 1, 2018 to June 30, 2019. A total of 18,664 physical examination subjects were included. PTH and 25-OH-VitD were measured by a Roche Cobas e 601, and Ca was measured by a Roche Cobas 8000. Linear regression models were used to assess correlations between PTH, 25-OH-VitD, Ca and the above factors. RESULTS: The concentrations of serum PTH in females were significantly higher than those in males, while the 25-OH-VitD and Ca were opposite. The concentration of PTH in data collection decreased in summer and increased in spring. The concentration of 25-OH-VitD decreases in spring and increases in autumn. PTH concentrations were negatively correlated with last month temperature and SHH, while 25-OH-VitD were opposite. Linear regression showed that season may be the main factor affecting serum PTH and 25-OH-VitD levels, and these effects were not clinically acceptable. CONCLUSION: In order to avoid influencing clinicians' investigation of suspected hyperparathyroidism and hypovitaminosis, reference intervals for PTH, 25-OH-VitD, and Ca should be established, taking into account sex, age and the season.


Assuntos
Cálcio/sangue , Hormônio Paratireóideo/sangue , Vitamina D/sangue , Adolescente , Adulto , Fatores Etários , Idoso , China/epidemiologia , Mineração de Dados , Feminino , Humanos , Hiperparatireoidismo/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estações do Ano , Fatores Sexuais , Luz Solar , Temperatura , Deficiência de Vitamina D/sangue , Vitaminas/sangue , Adulto Jovem
19.
Stem Cell Res Ther ; 12(1): 80, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33494833

RESUMO

BACKGROUND: Patients with peripheral nerve injury (PNI) often suffer from hypoxic ischemic impairments, in particular when combined with vascular damage, causing neuronal dysfunction and death. Increasing attention has been paid on skin precursor-derived Schwann cells (SKP-SCs), and previous study has shown that SKP-SCs could promote sensory recovery after cell therapy for PNI, resembling the effect of naive SCs, and SKP-SC-derived extracellular vesicles (SKP-SC-EVs) are putatively supposed to be promising therapeutic agents for neural regeneration. METHODS: SKPs were induced to differentiate towards SCs with cocktail factors (N2, neuregulin-1ß, and forskolin) in vitro. SKP-SC-EVs were isolated by exoEasy Maxi Kit and characterized by morphology and phenotypic markers of EVs. Rat sensory neurons from dorsal root ganglions (DRGs) were primarily cultured in regular condition or exposed to oxygen-glucose-deprivation (OGD) condition. SKP-SC-EVs were applied to DRGs or sensory neurons, with LY294002 (a PI3K inhibitor) added; the effect on neurite outgrowth and cell survival was observed. Moreover, microRNA (miR) candidate contained in SKP-SC-EVs was screened out, and miR-mimics were transfected into DRG neurons; meanwhile, the negative regulation of PTEN/PI3K/Akt axis and downstream signaling molecules were determined. RESULTS: It was shown that SKP-SC-EVs could improve the neurite outgrowth of DRGs and sensory neurons. Furthermore, SKP-SC-EVs enhanced the survival of sensory neurons after OGD exposure by alleviating neuronal apoptosis and strengthening cell viability, and the expression of GAP43 (a neuron functional protein) in neurons was upregulated. Moreover, the neuro-reparative role of SKP-SC-EVs was implicated in the activation of PI3K/Akt, mTOR, and p70S6k, as well as the reduction of Bax/Bcl-2 ratio, that was compromised by LY294002 to some extent. In addition, transferring miR-21-5p mimics into sensory neurons could partly protect them from OGD-induced impairment. CONCLUSIONS: Sum up, SKP-SC-EVs could improve neurite outgrowth of DRG sensory neurons in physiological and pathological condition. Moreover, the in vitro therapeutic potential of SKP-SC-EVs on the survival and restoration of OGD-injured sensory neurons was evidenced to be associated with miR-21-5p contained in the small EVs and miR-21-5p/PTEN/PI3K/Akt axis.


Assuntos
Vesículas Extracelulares , MicroRNAs , Animais , Humanos , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Ratos , Células de Schwann , Células Receptoras Sensoriais
20.
Adv Mater ; 33(9): e2006116, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33501743

RESUMO

Immunotherapy is recognized as one of the most promising approaches to treat cancers. However, its effect in glioblastoma (GBM) treatment is insufficient, which can in part be attributed to the immunosuppressive tumor microenvironment (TME). Microglia and macrophages are the main immune infiltrating cells in the TME of GBM. Unfortunately, instead of initiating the anti-tumor response, GBM-infiltrating microglia and macrophages switch to a tumor-promoting phenotype (M2), and support tumor growth, angiogenesis, and immunosuppression by the release of cytokines. In this work, a virus-mimicking membrane-coated nucleic acid nanogel Vir-Gel embedded with therapeutic miRNA is developed, which can reprogram microglia and macrophages from a pro-invasive M2 phenotype to an anti-tumor M1 phenotype. By mimicking the virus infection process, Vir-Gel significantly enhances the targetability and cell uptake efficiency of the miR155-bearing nucleic acid nanogel. In vivo evaluations demonstrate that Vir-Gel apparently prolongs the circulation lifetime of miR155 and endows it with an active tumor-targeting capability and excellent tumor inhibition efficacy. Owing to its noninvasive feature and effective delivery capability, the virus-mimicking nucleic acid nanogel provides a general and convenient platform that can successfully treat a wide range of diseases.

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