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1.
Front Oncol ; 11: 738078, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604081

RESUMO

Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.

3.
Int J Pharm ; 607: 120947, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34358541

RESUMO

With ideal optical properties, semiconducting polymer quantum dots (SPs) have become a research focus in recent years; a considerable number of studies have been devoted to the application of SPs in non-invasive and biosafety phototherapy with near-infrared (NIR) lasers. Nevertheless, the relatively poor stability of SPs in vitro and in vivo remains problematic. PCPDTBT was chosen to synthesize photothermal therapy (PTT) and photodynamic therapy (PDT) dual-model SPs, considering its low band gap and desirable absorption in the NIR window. For the first time, cetrimonium bromide was used as a stabilizer to guarantee the in vitro stability of SPs, and as a template to prepare SP hybrid mesoporous silica nanoparticles (SMs) to achieve long-term stability in vivo. The mesoporous structure of SMs was used as a reservoir for the hypoxia-activated prodrug Tirapazamine (TPZ). SMs were decorated with polyethylene glycol-folic acid (SMPFs) to specifically target activated macrophages in rheumatoid arthritis (RA). Upon an 808 nm NIR irradiation, the SMPFs generate intracellular hyperthermia and excessive singlet oxygen. Local hypoxia caused by molecular oxygen consumption simultaneously activates the cytotoxicity of TPZ, which effectively kills activated macrophages and inhibits the progression of arthritis. This triple PTT-PDT-chemo synergistic treatment suggests that SMPFs realize the in vivo application of SPs and may be a potential nano-vehicle for RA therapy with negligible side-toxicity.


Assuntos
Artrite Reumatoide , Hipertermia Induzida , Nanopartículas , Fotoquimioterapia , Artrite Reumatoide/tratamento farmacológico , Ácido Fólico , Humanos , Fototerapia , Terapia Fototérmica , Polímeros , Dióxido de Silício
4.
Biochem Pharmacol ; 192: 114726, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34389322

RESUMO

Migration and invasion promote tumor cell metastasis, which is the leading cause of cancer death. At present there are no effective treatments. Epidemiological studies have suggested that ω-3 polyunsaturated fatty acids (PUFA) may decrease cancer aggressiveness. In recent studies epoxide metabolites of ω-3 PUFA exhibited anti-cancer activity, although increased in vivo stability is required to develop useful drugs. Here we synthesized novel stabilized ureido-fatty acid ω-3 epoxide isosteres and found that one analogue - p-tolyl-ureidopalmitic acid (PTU) - inhibited migration and invasion by MDA-MB-231 breast cancer cells in vitro and in vivo in xenografted nu/nu mice. From proteomics analysis of PTU-treated cells major regulated pathways were linked to the actin cytoskeleton and actin-based motility. The principal finding was that PTU impaired the formation of actin protrusions by decreasing the secretion of Wnt5a, which dysregulated the Wnt/planar cell polarity (PCP) pathway and actin cytoskeletal dynamics. Exogenous Wnt5a restored invasion and Wnt/PCP signalling in PTU-treated cells. PTU is the prototype of a novel class of agents that selectively dysregulate the Wnt/PCP pathway by inhibiting Wnt5a secretion and actin dynamics to impair MDA-MB-231 cell migration and invasion.


Assuntos
Citoesqueleto/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Transdução de Sinais/fisiologia , Proteína Wnt-5a/antagonistas & inibidores , Proteína Wnt-5a/metabolismo , Animais , Linhagem Celular Tumoral , Citoesqueleto/efeitos dos fármacos , Ácidos Graxos Ômega-3/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
Int J Cardiol ; 338: 196-203, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126132

RESUMO

BACKGROUND: Ischemic heart disease and the resulting heart failure continue to carry high morbidity and mortality, and a breakthrough in our understanding of this disorder is needed. The adult spiny mouse (Acomys cahirinus) has evolved the remarkable capacity to regenerate full-thickness skin tissue, including microvasculature and cartilage, without fibrosis or scarring. We hypothesized that lack of scarring and resulting functional regeneration also applies to the adult Acomys heart. METHODS AND RESULTS: We compared responses of the Acomys heart to CD1 outbred Mus heart following acute left anterior descending coronary artery ligation to induce myocardial infarction. Both Acomys and Mus hearts showed decreased ejection fraction (EF) after ligation. However, Acomys hearts showed significant EF recovery to pre-ligation values over four weeks. Histological analysis showed comparable infarct area 24-h after ligation with a similar collateral flow in both species' hearts, but subsequently, Acomys displayed reduced infarct size, regenerated microvasculature, and increased cell proliferative activity in the infarcted area. CONCLUSIONS: These observations suggest that adult Acomys displays remarkable cardiac recovery properties after acute coronary artery occlusion and may be a useful model to understand functional recovery better. TRANSLATIONAL PERSPECTIVE: Adult Acomys provides a novel mammalian model to further investigate the cardioprotective and regenerative signaling mechanisms in adult mammals. This opens the door to breakthrough treatment strategies for the injured myocardium and help millions of patients with heart failure secondary to tissue injury with irreversible damage.


Assuntos
Regeneração , Pele , Adulto , Animais , Cicatriz , Fibrose , Humanos , Murinae , Pele/patologia
6.
PLoS One ; 16(4): e0249474, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33891596

RESUMO

We reviewed the records of 337 confirmed cases of tuberculosis patients in Monrovia, the capital of Liberia, 2015. The risk factors affecting the survival and multidrug-resistance of tuberculosis patients were examined. Kaplan-Meier analysis and the log-rank test were used to assess the differences in survival among the patients, while Cox regression model was used for multivariate analysis. The qualitative data was tested with chi-square test in the single factor analysis of multidrug-resistant TB. Multivariate analysis was performed using binary logistic regression analysis. The significance level for all the tests were set at 0.05. The mean period of the follow-up of patients was 10 months. In the 337 patients, 33 (9.8%) died, the 21-month survival rate was 90.2%. The results of multivariate Cox regression analysis show that overcrowding (HR = 7.942, 95% CI 3.258-19.356), former smoking (HR = 3.773, 95% CI 1.601-8.889), current smoking (HR = 3.546, 95% CI 1.195-10.521), multidrug-resistance tuberculosis (HR = 4.632, 95% CI 1.913-11.217) were risk factors for death during anti-tuberculosis treatment in TB patients in Liberia. The results of binary logistic regression analysis show that extra-pulmonary (OR = 2.032, 95% CI 1.133-3.644), family history of TB (OR = 2.387, 95% CI 1.186-4.807) and current smoking (OR = 3.436, 95% CI 1.681-7.027) were risk factors for multidrug-resistant tuberculosis. These results can provide insights on local tuberculosis early intervention, increase public health awareness, and strengthen the control of factors that may affect the survival and multidrug-resistance of tuberculosis patients.


Assuntos
Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Adulto , Antituberculosos/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Libéria/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
7.
Cancers (Basel) ; 13(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917287

RESUMO

The effectiveness of immunotherapy against solid tumours is dependent on the appropriate leucocyte subsets trafficking and accumulating in the tumour microenvironment (TME) with recruitment occurring at the endothelium. Such recruitment involves interactions between the leucocytes and the endothelial cells (ECs) of the vessel and occurs through a series of steps including leucocyte capture, their rolling, adhesion, and intraluminal crawling, and finally leucocyte transendothelial migration across the endothelium. The tumour vasculature can curb the trafficking of leucocytes through influencing each step of the leucocyte recruitment process, ultimately producing an immunoresistant microenvironment. Modulation of the tumour vasculature by strategies such as vascular normalisation have proven to be efficient in facilitating leucocyte trafficking into tumours and enhancing immunotherapy. In this review, we discuss the underlying mechanisms of abnormal tumour vasculature and its impact on leucocyte trafficking, and potential strategies for overcoming the tumour vascular abnormalities to boost immunotherapy via increasing leucocyte recruitment.

8.
Adv Sci (Weinh) ; 8(4): 2001961, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33643786

RESUMO

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/ß-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.

9.
Chem Commun (Camb) ; 57(18): 2245-2248, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33554229

RESUMO

A novel peptide nanodrug composed of three functional motifs, bis(pyrene), FFVLK and CREKA, was used as a two-photon excited photosensitizer for precise photodynamic therapy (PDT). The system presented excellent two-photon imaging ability, tumor target effect and high reactive oxygen species productivity for improving treatment precision and efficiency in PDT.


Assuntos
Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Peptídeos/farmacologia , Fotoquimioterapia/métodos , Fótons , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Nanopartículas/química , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/química , Fármacos Fotossensibilizantes/química , Pirenos/química
10.
Molecules ; 25(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33353184

RESUMO

Fungal infections pose a serious threat to human health. Polyoxometalates (POMs) are metal-oxygen clusters with potential application in the control of microbial infections. Herein, the Ag3PW12O40 composites have been synthesized and verified by Fourier transform infrared (FT-IR) spectrum, transmission electron microscopy (TEM), scanning electron microscope (SEM), elemental analysis, and X-ray diffraction (XRD). The antifungal activities of Ag3PW12O40 were screened in 19 Candida species strains through the determination of minimum inhibitory concentration (MIC) by the microdilution checkerboard technique. The minimum inhibitory concentration (MIC50) values of Ag3PW12O40 are 2~32 µg/mL to the Candida species. The MIC80 value of Ag3PW12O40 to resistant clinical isolates C. albicans HL963 is 8 µg/mL, which is lower than the positive control, fluconazole (FLC). The mechanism against C. albicans HL963 results show that Ag3PW12O40 can decrease the ergosterol content. The expressions of ERG1, ERG7, and ERG11, which impact on the synthesis of ergosterol, are all prominently upregulated by Ag3PW12O40. It indicates that Ag3PW12O40 is a candidate in the development of new antifungal agents.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Fósforo/farmacologia , Prata/farmacologia , Compostos de Tungstênio/farmacologia , Antifúngicos/química , Candida/crescimento & desenvolvimento , Farmacorresistência Fúngica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Fósforo/química , Prata/química , Propriedades de Superfície , Compostos de Tungstênio/química
11.
Sensors (Basel) ; 20(21)2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33171820

RESUMO

Component analysis plays an important role in food production, pharmaceutics and agriculture. Nanozymes have attracted wide attention in analytical applications for their enzyme-like properties. In this work, a fluorometric method is described for the determination of thiamine (TH) (vitamin B1) based on hemoglobin-Cu3(PO4)2 nanoflowers (Hb-Cu3(PO4)2 NFs) with peroxidase-like properties. The Hb-Cu3(PO4)2 NFs catalyzed the decomposition of H2O2 into ·OH radicals in an alkaline solution that could efficiently react with nonfluorescent thiamine to fluoresce thiochrome. The fluorescence of thiochrome was further enhanced with a nonionic surfactant, Tween 80. Under optimal reaction conditions, the linear range for thiamine was from 5 × 10-8 to 5 × 10-5 mol/L. The correlation coefficient for the calibration curve and the limit of detection (LOD) were 0.9972 and 4.8 × 10-8 mol/L, respectively. The other vitamins did not bring about any obvious changes in fluorescence. The developed method based on hybrid nanoflowers is specific, pragmatically simple and sensitive, and has potential for application in thiamine detection.


Assuntos
Fluorometria , Peróxido de Hidrogênio , Nanoestruturas , Tiamina/análise , Hemoglobinas , Peroxidase
12.
Proc Natl Acad Sci U S A ; 117(39): 24434-24442, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32917816

RESUMO

Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.


Assuntos
Glucose/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Homeostase , Humanos , Fígado/enzimologia , Masculino , Camundongos , Camundongos Knockout , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Esfingolipídeos/metabolismo
13.
J Inorg Biochem ; 212: 111212, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920432

RESUMO

A new composite, AgPW@PDA@Nisin, with shell-core structure was successfully synthesized by a polydopamine (PDA) surfaced conjugated nisin (an antibacterial 34 amino acid polycyclic peptide) as shell and polyoxometalates (Ag3PW12O40 = AgPW) as core. The composite was characterized by the zeta potential, scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction analysis (XRD), fourier transform infrared (FT-IR). The AgPW@PDA@Nisin showed flower hierarchical structure and potential antibacterial activity against S. aureus ATCC29213. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of it were 4 and 32 µg/mL. AgPW@PDA@Nisin nanoflowers-induced bacterial death bears the characteristic of cell morphology, membrane integrity and permeability changing, nucleotide leakage. It indicated that the AgPW@PDA@Nisin interfere with the cell membrane, resulting in antibacterial activity against S. aureus. The cytotoxicity of the nanoflowers was low on HDF-a (human dermal fibroblasts) cells. A new class of hybrid inorganic-organic nanoflowers based on polyoxometalates and nisin with enhanced antibacterial properties can be developed for food preservation.


Assuntos
Antibacterianos/farmacologia , Nanoestruturas/química , Nisina/química , Compostos de Tungstênio/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Staphylococcus aureus/efeitos dos fármacos
14.
Nanomaterials (Basel) ; 10(8)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32717952

RESUMO

Resistive random access memory (RRAM) devices are receiving increasing extensive attention due to their enhanced properties such as fast operation speed, simple device structure, low power consumption, good scalability potential and so on, and are currently considered to be one of the next-generation alternatives to traditional memory. In this review, an overview of RRAM devices is demonstrated in terms of thin film materials investigation on electrode and function layer, switching mechanisms and artificial intelligence applications. Compared with the well-developed application of inorganic thin film materials (oxides, solid electrolyte and two-dimensional (2D) materials) in RRAM devices, organic thin film materials (biological and polymer materials) application is considered to be the candidate with significant potential. The performance of RRAM devices is closely related to the investigation of switching mechanisms in this review, including thermal-chemical mechanism (TCM), valance change mechanism (VCM) and electrochemical metallization (ECM). Finally, the bionic synaptic application of RRAM devices is under intensive consideration, its main characteristics such as potentiation/depression response, short-/long-term plasticity (STP/LTP), transition from short-term memory to long-term memory (STM to LTM) and spike-time-dependent plasticity (STDP) reveal the great potential of RRAM devices in the field of neuromorphic application.

15.
Metabolites ; 10(6)2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32521763

RESUMO

The number, position, and configuration of double bonds in lipids affect membrane fluidity and the recruitment of signaling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), we observed a marked accumulation of lipids containing a di-unsaturated sphingadiene base in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). The double bonds were localized to positions C4-C5 and C14-C15 of sphingadiene using ultraviolet photodissociation-tandem mass spectrometry (UVPD-MS/MS). Phosphorylation of sphingoid bases by sphingosine kinase 1 (SphK1) or SphK2 forms the penultimate step in the lysosomal catabolism of all sphingolipids. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments in an oligodendrocyte cell line demonstrated that ceramides with a sphingosine base are more rapidly metabolized than those with a sphingadiene base. Since SphK2 is the dominant sphingosine kinase in brain, we propose that the accumulation of sphingadiene-based lipids in SphK2-deficient brains results from the slower catabolism of these lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We have therefore uncovered a previously unappreciated role for SphK2 in lipid quality control.

16.
Antiviral Res ; 179: 104813, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376449

RESUMO

Viruses in the Flaviviridae family such as Zika virus (ZIKV), dengue virus (DENV), and Japanese encephalitis virus (JEV) are major public health concerns. The development of antiviral agents against these viruses is urgently needed. We have previously discovered that the Keggin structured polyoxometalate POM-12 has potent inhibitory activity against hepatitis C virus, another member of the Flaviviridae family. In this study, we tested its antiviral activity of DENV, JEV and ZIKV, and found that POM-12 dramatically inhibited their infection with IC50 value of 1.16 µM, 1.9 µM and 0.64 µM, respectively. Mechanistic studies indicated that POM-12 directly disrupted the integrity of these virions. Moreover, POM-12 also targeted the post-entry steps of viral replication of JEV, but having no similar activities on ZIKV and DENV. The differential actions of POM-12 on these viruses suggest that surface topology and charge of virion may have influence on its drug effect, and thus POM-12 may be modified to more efficiently inhibit these and other similar viruses.


Assuntos
Ânions/farmacologia , Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Polieletrólitos/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Chlorocebus aethiops , Vírus da Dengue/efeitos dos fármacos , Descoberta de Drogas , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Flavivirus/classificação , Flavivirus/fisiologia , Concentração Inibidora 50 , Células Vero , Zika virus/efeitos dos fármacos
17.
Micromachines (Basel) ; 11(4)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218324

RESUMO

Resistive random access memory (RRAM), which is considered as one of the most promising next-generation non-volatile memory (NVM) devices and a representative of memristor technologies, demonstrated great potential in acting as an artificial synapse in the industry of neuromorphic systems and artificial intelligence (AI), due its advantages such as fast operation speed, low power consumption, and high device density. Graphene and related materials (GRMs), especially graphene oxide (GO), acting as active materials for RRAM devices, are considered as a promising alternative to other materials including metal oxides and perovskite materials. Herein, an overview of GRM-based RRAM devices is provided, with discussion about the properties of GRMs, main operation mechanisms for resistive switching (RS) behavior, figure of merit (FoM) summary, and prospect extension of GRM-based RRAM devices. With excellent physical and chemical advantages like intrinsic Young's modulus (1.0 TPa), good tensile strength (130 GPa), excellent carrier mobility (2.0 × 105 cm2∙V-1∙s-1), and high thermal (5000 Wm-1∙K-1) and superior electrical conductivity (1.0 × 106 S∙m-1), GRMs can act as electrodes and resistive switching media in RRAM devices. In addition, the GRM-based interface between electrode and dielectric can have an effect on atomic diffusion limitation in dielectric and surface effect suppression. Immense amounts of concrete research indicate that GRMs might play a significant role in promoting the large-scale commercialization possibility of RRAM devices.

18.
J Neurochem ; 153(2): 173-188, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31742704

RESUMO

Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein-coupled receptors, S1PR1-S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) is a potent S1P receptor agonist that causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties of FTY720 in several neurodegenerative paradigms; however, neuroprotective properties of the native ligand S1P have not been established. We aimed to establish the significance of neurotrophic factor up-regulation by S1P for neuroprotection, comparing S1P with FTY720. S1P induced brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), platelet-derived growth factor B (PDGFB), and heparin-binding EGF-like growth factor (HBEGF) gene expression in primary human and murine astrocytes, but not in neurons, and to a much greater extent than FTY720. Accordingly, S1P but not FTY720 protected cultured neurons against excitotoxic cell death in a primary murine neuron-glia coculture model, and a neutralizing antibody to LIF blocked this S1P-mediated neuroprotection. Antagonists of S1PR1 and S1PR2 both inhibited S1P-mediated neurotrophic gene induction in human astrocytes, indicating that simultaneous activation of both receptors is required. S1PR2 signaling was transduced through Gα13 and the small GTPase Rho, and was necessary for the up-regulation and activation of the transcription factors FOS and JUN, which regulate LIF, BDNF, and HBEGF transcription. In summary, we show that S1P protects hippocampal neurons against excitotoxic cell death through up-regulation of neurotrophic gene expression, particularly LIF, in astrocytes. This up-regulation requires both S1PR1 and S1PR2 signaling. FTY720 does not activate S1PR2, explaining its relative inefficacy compared to S1P.


Assuntos
Astrócitos/metabolismo , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Fatores de Crescimento Neural/biossíntese , Neurônios/metabolismo , Esfingosina/análogos & derivados , Animais , Astrócitos/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Esfingosina/farmacologia , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia
19.
Front Endocrinol (Lausanne) ; 11: 627076, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33633691

RESUMO

Sphingolipids are a class of essential lipids, functioning as both cell membrane constituents and signaling messengers. In the sphingolipid metabolic network, ceramides serve as the central hub that is hydrolyzed to sphingosine, followed by phosphorylation to sphingosine 1-phosphate (S1P) by sphingosine kinase (SphK). SphK is regarded as a "switch" of the sphingolipid rheostat, as it catalyzes the conversion of ceramide/sphingosine to S1P, which often exhibit opposing biological roles in the cell. Besides, SphK is an important signaling enzyme that has been implicated in the regulation of a wide variety of biological functions. In recent years, an increasing body of evidence has suggested a critical role of SphK in type 2 diabetes mellitus (T2D), although a certain level of controversy remains. Herein, we review recent findings related to SphK in the field of T2D research with a focus on peripheral insulin resistance and pancreatic ß-cell failure. It is expected that a comprehensive understanding of the role of SphK and the associated sphingolipids in T2D will help to identify druggable targets for future anti-diabetes therapy.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/enzimologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia
20.
Sci Rep ; 9(1): 14832, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619704

RESUMO

The mimicking enzyme activities of eighteen classic POMs with different structures, Keggin (H3PW12O40, H4SiW12O40, H4GeW12O40, K4GeW12O40, H3PMo12O40, H4SiMo12O40 and Eu3PMo12O40), Wells-Dawson (H6P2Mo18O62, α-(NH4)6P2W18O62 and α-K6P2W18O62·14H2O), lacunary-Keggin (Na8H[α-PW9O34], Na10[α-SiW9O34], Na10[α-GeW9O34] and K8[γ-SiW10O36]), the transition-metal substituted-type (α-1,2,3-K6H[SiW9V3O34] and H5PMo10V2O40), sandwich-type (K10P2W18Fe4(H2O)2O68) and an isopolyoxotungstate (Na10H2W12O42) were screened and compared. The mechanisms and reaction conditions of POMs with mimicking enzyme-like activities were also analyzed. The results shown that the structures, the hybrid atoms, the coordination atoms, the substituted metal atoms, pH and substrate are the effect factors for the enzyme mimic activities of POM. Among the eighteen POMs, H3PW12O40, H4SiW12O40, H4GeW12O40, α-(NH4)6P2W18O62, α-K6P2W18O62·14H2O, Na8H[α-PW9O34], Na10[α-SiW9O34], Na10[α-GeW9O34], K8[γ-SiW10O36], K10P2W18Fe4(H2O)2O68 and Na10H2W12O42 had the peroxidase activities. Eu3PMo12O40, H3PMo12O40, H4SiMo12O40, α-1,2,3-K6H [SiW9V3O34], H6P2Mo18O62 and H5PMo10V2O40 showed the oxidase-like activities. K4GeW12O40 did not show the peroxidase and oxidase activities. The Na8H[α-PW9O34], Na10[α-SiW9O34] and Na10[α-GeW9O34] showed intrinsic enzyme activities at alkaline conditions, which were different from other type of POMs. The sandwich-type K10P2W18Fe4(H2O)2O68 displayed the strongest peroxidase activity, which is similar to natural horseradish peroxidase.

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