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Pharmacokinetic studies were conducted on rats for protopine, corynoline, 7'-(3',4'-dihydroxyphenyl)-N-[(4-methoxyphenyl)-ethyl]propenamide, acetylcorynoline, and 8-oxocorynoline, five main active components from Corydalis bungeana Turcz (C. bungeana Turcz). An ultra high performance liquid chromatography with tandem mass spectrometry method has been developed and validated for the simultaneous determination of the pharmacokinetic characteristics of these components in rat plasma. Chromatographic separation was achieved on an Agilent SB-C18 column (1.8 µm, 150 × 2.1 mm) using a gradient elution program with a mobile phase consisting of acetonitrile and water containing 0.1% acetic acid at a flow rate of 0.3 mL/min. The analytes were detected in the multiple reaction monitoring mode with positive electrospray ionization. Lower limits of quantification were >0.680 ng/mL and matrix effects ranged from 91.26 to 100.38%. The mean extraction recoveries of quality control samples were less than 79.32%, and the precision and accuracy were within the acceptable limits. All analytes were proven to be stable during sample storage and analysis procedures. The validated method was successfully applied to the pharmacokinetic study of five alkaloid components after oral administration of C. bungeana Turcz extract to rats. The obtained results may be helpful to reveal the mechanism of action and to guide the clinical application of C. bungeana Turcz.
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Alcaloides/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Alcaloides/administração & dosagem , Alcaloides/sangue , Animais , Corydalis/química , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
AIM: Connexin 43 (Cx43) is a member of connexin family mainly expressed in astrocytes, which forms gap junctions and hemichannels and maintains the normal shape and function of astrocytes. In this study we investigated the role of Cx43 in astrocytes in facilitating neuronal recovery during ischemic stroke. METHODS: Primary culture of astrocytes or a mixed culture of astrocytes and cortical neurons was subjected to oxygen glucose deprivation and reperfusion (OGD/R). The expression of Cx43 and Ephrin-A4 in astrocytes was detected using immunocytochemical staining and Western blot assays. Intercellular Ca(2+) concentration was determined with Fluo-4 AM fluorescent staining. Middle cerebral artery occlusion (MCAO) model rats were used for in vivo studies. RESULTS: OGD/R treatment of cultured astrocytes caused a decrement of Cx43 expression and translocation of Cx43 from cell membrane to cytoplasm, accompanied by cell retraction. Furthermore, OGD/R increased intracellular Ca(2+) concentration, activated CaMKII/CREB pathways and upregulated expression of Ephrin-A4 in the astrocytes. All these changes in OGD/R-treated astrocytes were alleviated by overexpression of Cx43. In the cortical neurons cultured with astrocytes, OGD/R inhibited the neurite growth, whereas overexpression of Cx43 or knockdown of Ephrin-A4 in astrocytes restored the neurite growth. In MCAO model rats, neuronal recovery was found to be correlated with the recuperation of Cx43 and Ephrin-A4 in astrocytes. CONCLUSION: Cx43 can stabilize astrocytes and facilitate the resistance to the deleterious effects of a stroke-like milieu and promote neuronal recovery.
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Astrócitos/metabolismo , Conexina 43/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Neurônios/metabolismo , Animais , Astrócitos/citologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Efrina-A4/metabolismo , Glucose/metabolismo , Masculino , Neurônios/citologia , Oxigênio/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de SinaisRESUMO
A phytochemical investigation on crude extract of Gentianella azurea led to the isolation of ten new (1-10) and one known (11) secoiridoid glycosides. Their structures were unambiguously elucidated by analysis of 1D and 2D NMR. Compounds 2, 5 and 11 were found to inhibit nitric oxide (NO) production in RAW 264.7 macrophages with IC50 values of 52.78 ± 8.61, 0.69 ± 0.23 and 5.18 ± 1.33, respectively, while indomethacin, the positive control, showed an IC50 value of 1.25 ± 0.52 µM.
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Anti-Inflamatórios/química , Gentianella/química , Glicosídeos Iridoides/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Linhagem Celular , Gentianella/metabolismo , Humanos , Glicosídeos Iridoides/isolamento & purificação , Glicosídeos Iridoides/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Conformação Molecular , Óxido Nítrico/metabolismoRESUMO
Thirteen new dammarane-type triterpenoids (1-13) and four known analogues, gentirigenic acid (14) and the gentirigeosides A, B, and E (15-17), were isolated from Gentianella azurea. Their structures were elucidated by detailed analysis of the NMR, MS, and X-ray crystallographic data. This is the first report of dammarane-type triterpenoids in the Gentianella genus. In addition, the known structures of gentirigenic acid (14) and the gentirigeosides A, B, and E (15-17) were revised based on the X-ray diffraction analysis. Gentirigeoside A (15) was found to inhibit nitric oxide production in RAW 264.7 macrophages with an IC50 value of 6.6 ± 2.1 µM.
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Medicamentos de Ervas Chinesas/isolamento & purificação , Gentianella/química , Triterpenos/isolamento & purificação , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Ressonância Magnética Nuclear Biomolecular , Triterpenos/química , Triterpenos/farmacologia , DamaranosRESUMO
The objective of this study was to develop an effective ultra-rapid vitrification method and evaluate its effect on maturation, developmental competence and development-related gene expression in bovine immature oocytes. Bovine cumulus oocyte complexes were randomly allocated into three groups: (1) controls, (2) liquid nitrogen vitrification, and (3) liquid helium vitrification. Oocytes were vitrified and then warmed, the percentage of morphologically normal oocytes in liquid helium group (89.0%) was significantly higher (P<0.05) than that of the liquid nitrogen group (81.1%). When the vitrified-thawed oocytes were matured in vitro for 24h, the maturation rate in liquid helium group (50.6%) was higher (P<0.05) than liquid nitrogen group (42.6%). Oocytes of liquid helium vitrification had higher cleavage and blastocyst rates (41.1% and 10.0%) than that of liquid nitrogen vitrification (33.0% and 4.5%; P<0.05) after in vitro fertilization. Moreover, the expression of GDF9 (growth/differentiation factor-9), BAX (apoptosis factor) and ZAR1 (zygote arrest 1) was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) when the vitrified-thawed oocytes were matured 24h. The expression of these genes was altered after vitrification. Expression of GDF9 and BAX in the liquid helium vitrification group was not significantly different from that of the control, however there were significant differences between the liquid nitrogen vitrification group and control. In conclusion, it was feasible to use liquid helium for vitrifying bovine immature oocytes. There existed an association between the compromised developmental competence and the altered expression levels of these genes for the vitrified oocytes.
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Bovinos/fisiologia , Criopreservação/veterinária , Hélio , Oócitos/citologia , Vitrificação , Animais , Bovinos/embriologia , Criopreservação/métodos , Desenvolvimento Embrionário , Feminino , Fertilização in vitro , Regulação da Expressão Gênica no Desenvolvimento , Hélio/química , Masculino , Oócitos/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
AIMS: We aimed to evaluate the potential of a novel selective α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) potentiator, LT-102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action. METHODS: The activity of LT-102 was examined by Ca2+ influx assays and patch-clamp in rat primary hippocampal neurons. The structure of the complex was determined by X-ray crystallography. The selectivity of LT-102 was evaluated by hERG tail current recording and kinase-inhibition assays. The electrophysiological characterization of LT-102 was characterized by patch-clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests. RESULTS: LT-102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT-102 facilitated long-term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine-induced mouse model. Additionally, LT-102 treatment increased the protein level of brain-derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues. CONCLUSION: We conclude that LT-102 ameliorates cognitive impairments in a phencyclidine-induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.
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Disfunção Cognitiva , Propionatos , Esquizofrenia , Animais , Camundongos , Ratos , Fenciclidina , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , IsoxazóisRESUMO
Background: Elevated platelet count (PLTc) is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis. However, the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear. Aims: We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables. Methods: A total of 2985 patients with schizophrenia were randomised into seven groups. Each group received one of seven antipsychotic treatments and was assessed at 2, 4 and 6 weeks. Clinical symptoms were evaluated using the positive and negative syndrome scale (PANSS). Additionally, we measured blood cell counts and metabolic parameters, such as blood lipids. Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes, while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes. Results: PLTc significantly increased in patients treated with aripiprazole (F=6.00, p=0.003), ziprasidone (F=7.10, p<0.001) and haloperidol (F=3.59, p=0.029). It exhibited a positive association with white blood cell count and metabolic indicators. Higher baseline PLTc was observed in non-responders, particularly in those defined by the PANSS-negative subscale. In the structural equation model, PLTc, white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores. Moreover, higher baseline PLTc was observed in individuals with less metabolic change, although this association was no longer significant after accounting for baseline metabolic values. Conclusions: Platelet parameters, specifically PLTc, are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia. Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation. Given PLTc's easy measurement and clinical relevance, it warrants increased attention from psychiatrists. Trial registration number: ChiCTR-TRC-10000934.
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BACKGROUND AND PURPOSE: Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. KEY RESULTS: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1ß pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway. CONCLUSION AND IMPLICATIONS: This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
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Disfunção Cognitiva , Esquizofrenia , Animais , Ratos , Masculino , Fenciclidina/toxicidade , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo , Ratos Sprague-Dawley , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Citocinas , Modelos Animais de DoençasRESUMO
Manipulating interface defects can minimize interfacial nonradiative recombination, thus increasing the stability and performance of perovskite solar cells (PSCs). Here, copper acetylacetonate [Cu(acac)2] as a passivator is used to treat the interface between Spiro-OMeTAD and perovskite. Owing to the strong chelation, the uncoordinated Pb2+ could react with -CâO/-COH functional groups, firmly anchoring acetylacetonate at this interface or the grain boundaries (GBs) of perovskite films to construct multiple ligand bridges, accompanied by the p-type copper iodide formation with copper substituting lead. Simultaneously, Cu+-Cu2+ pairs transfer electrons from Pb0 to I0, suppressing deep level defects of Pb0 and I0 near the perovskite interface. These can be beneficial to hole-transferring. Moreover, the Schiff base complexes with hydrophobicity, from the reaction of acetylacetonate with perovskite, can lead to tightly packed adjacent perovskite surfaces and self-seal the GBs of the perovskite, inhibiting moisture diffusion for long-term stability. Consequently, the Cu(acac)2-based PSC has achieved more than 24% champion efficiency while retaining ca. 92% of the initial power conversion efficiency after 1680 h of storage.
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Major depressive disorder is a common psychiatric disorder, with â¼30% of patients suffering from treatment-resistant depression. Based on preclinical studies on ketamine, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation may be a promising therapeutic approach. In this study, we synthesized a series of novel 3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs and analyzed their potential as AMPAR potentiators. Compounds 5aa and 7k exhibited high potentiation with little agonist activity in a high-throughput screen using a calcium influx assay in cultured hippocampal primary neurons. In rats, compound 7k had better pharmacokinetic properties and oral bioavailability (F = 67.19%); it also exhibited an acceptable safety profile in vital internal organs based on hematoxylin and eosin staining. We found that 7k produced a rapid antidepressant-like effect in chronic restraint stress-induced mice 1 h after intraperitoneal administration. Our study presented a series of novel AMPAR potentiators and identified 7k as a promising drug-like candidate against major depressive disorders.
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Transtorno Depressivo Maior , Ketamina , Ratos , Camundongos , Animais , Receptores de AMPA , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/farmacologia , Ketamina/farmacologia , NeurôniosRESUMO
Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ.
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Metilação de DNA , Esquizofrenia , Humanos , Metilação de DNA/genética , Leucócitos Mononucleares/metabolismo , Esquizofrenia/genética , Interneurônios/metabolismo , Interneurônios/patologia , DNA/metabolismo , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Proteínas do Tecido Nervoso/genéticaRESUMO
Porous structure design and the content regulation of heteroelements have been proved to be effective strategies to boost photocatalytic H2 generation activity of graphitic carbon nitride (g-C3N4) based photocatalyst. Herein, a series of porous graphitic carbon nitride with high concentration of oxygen (g-C3N4-O) photocatalysts were synthesized via in situ polymerization process using colloidal SiO2 as oxygen source. The content of oxygen within the g-C3N4-O photocatalysts could be tuned by adjusting the amount of added colloidal SiO2 during the preparation procedure. The introduced oxygen replaced two-coordinated nitrogen atom, influencing band edge position and localized electron distribution, thereby enhancing visible light harvesting and photoelectric conversion. As a result, the g-C3N4-O photocatalyst with an optimal oxygen content (8.39 wt%) showed 10.5 fold enhancement in H2 evolution rate compared to that of bulk g-C3N4, attributed to the porous structure and high concentration of incorporated oxygen.
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We evaluated the effects of different vitrification temperatures (VTs) and cryoprotective agent concentrations (CPAs) on the viability and expressions of long non-coding RNA (lncRNA) in bovine oocytes following vitrification at the germinal vesicle (GV) stage. Our findings provide a theoretical support for improvement of the cryopreservation technology of bovine immature oocytes (BIOs). Bovine cumulus oocyte complexes (COCs) were collected and randomized into five groups: fresh oocytes (control), oocytes vitrified in liquid helium (LHe; -269 °C) with 5.6 M CPAs (LHe 5.6 M), oocytes vitrified in LHe with 6.6 M CPAs (LHe 6.6 M), oocytes vitrified in liquid nitrogen (LN; -196 °C) with 5.6 M CPAs (LN 5.6 M), and oocytes vitrified in LN with 6.6 M CPAs (LN 6.6 M). Of the four vitrification groups, the LHe 5.6 M group exhibited the highest blastocyst rate (13.22%), followed by the LHe 6.6 M group (10.19%) and LN 6.6 M group (9.77%), while the LN 5.6 M group had the lowest blastocyst rate (1.87%). Then, lncRNA expressions in the five groups were profiled. A total of 18,271 lncRNAs were identified, of which 2,158 were differentially expressed lncRNAs (DELs) in the vitrified groups, compared to the fresh group (P < 0.05; fold-change > 2). Co-location (cis) and co-expression (trans) prediction revealed 14 differentially expressed target genes (DETGs), which corresponded to 17 DELs. Based on grouping data and expression profiles of the DELs, we demonstrated that different VTs (-269 °C vs. -196 °C) can affect the expressions of MSTRG.12295.5, MSTRG.37123.1, MSTRG.37930.2, MSTRG.40464.9, MSTRG.8869.3 and MSTRG.26680.6. Expressions of these lncRNAs were affected by CPAs only in the condition of vitrification with LHe (-269 °C). Expressions of MSTRG.35129.6 were associated with exposures to both VTs and CPAs; while expressions of MSTRG.3578.3, MSTRG.40576.3, MSTRG.6723.5, MSTRG.32862.4, MSTRG.1184.4, MSTRG.33110.3, MSTRG.40454.2, MSTRG.41073.2, MSTRG.44732.4 and MSTRG.6729.3 might be related to vitrification. Co-expression analysis showed that MSTRG.12295.5, MSTRG.37930.2, MSTRG.40454.2, MSTRG.8869.3 and MSTRG.6723.5 expressions affect oocyte development after vitrification by regulating target gene expressions. Taken together, improvement of the developmental ability of BIOs after LHe vitrification maybe attributed to changes in expressions of some lncRNAs. Our findings elucidate on the molecular mechanisms underlying the development of BIOs under different VTs and CPAs.
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RNA Longo não Codificante , Vitrificação , Animais , Bovinos , Criopreservação/veterinária , Crioprotetores/farmacologia , Oócitos/fisiologia , RNA Longo não Codificante/genética , TemperaturaRESUMO
Flavonoids, found in a wide variety of foods and plants, are considered to play an important role in the prevention and treatment of osteoporosis. Our previous studies demonstrated that Erythrina cortex extract (EC) rich in prenylated isoflavonoids exerted bone protective effects in ovariectomized (OVX) rats. The present study aimed to investigate the interactions of gut microbiota with the EC extract to explore the underlying mechanisms involved in its beneficial effects on bone. Sprague-Dawley female rats of 3-months-old were ovariectomized and treated with EC extract for 12 weeks. EC extract reversed ovariectomy-induced deterioration of bone mineral density and bone microarchitecture as well as downregulated cathepsin K (Ctsk) and upregulated runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) in the tibia of OVX rats. Its protective effects on bone were correlated with changes in microbial richness and the restorations of several genera. EC increased the serum circulating levels of acetate and propionate in OVX rats. We conclude that the bone protective effects of EC extract were associated with the changes in microbial compositions and serum short chain fatty acids (SCFAs) in OVX rats.
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Densidade Óssea/efeitos dos fármacos , Erythrina , Flavonoides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Osteoporose/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Ovariectomia , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Schizophrenia, bipolar disorder (BD), and major depressive disorder are three common mental disorders. Although their diagnosis and treatment differ, they partially overlap. METHODS: To explore the similarities and characteristics of these three psychiatric diseases, an intelligence quotient (IQ) assessment was performed to evaluate cognitive deficits. Relative catechol-O-methyltransferase (COMT) expression in peripheral blood mononuclear cells was examined in all three groups compared with healthy controls (HCs). RESULTS: The results indicated that patients with any of the three psychiatric diseases presented IQ deficits, and that the first-episode schizophrenia (FES) group had even lower cognitive function than the other two groups. The relative COMT expression decreased in the FES group and increased in the BD group compared with the HC group. The correlation analysis of COMT expression level and IQ scores showed a positive correlation between relative COMT expression and full-scale IQ in the HC group. However, this correlation disappeared in all three psychiatric diseases studied. CONCLUSION: In conclusion, this cross-disease strategy provided important clues to explain lower IQ scores and dysregulated COMT expression among three common mental illnesses.
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ABSTRACT: Major depressive disorder (MDD) is a common disease with both affective and cognitive disorders. Alterations in metabolic systems of MDD patients have been reported, but the underlying mechanisms still remains unclear. We sought to identify abnormal metabolites in MDD by metabolomics and to explore the association between differential metabolites and neurocognitive dysfunction.Plasma samples from 53 MDD patients and 83 sex-, gender-, BMI-matched healthy controls (HCs) were collected. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) system was then used to detect metabolites in those samples. Two different algorithms were applied to identify differential metabolites in 2 groups. Of the 136 participants, 35 MDD patients and 48 HCs had completed spatial working memory test. Spearman rank correlation coefficient was applied to explore the relationship between differential metabolites and working memory in these 2 groups.The top 5 metabolites which were found in sparse partial least squares-discriminant analysis (sPLS-DA) model and random forest (RF) model were the same, and significant difference was found in 3 metabolites between MDD and HCs, namely, gamma-glutamyl leucine, leucine-enkephalin, and valeric acid. In addition, MDD patients had higher scores in spatial working memory (SWM) between errors and total errors than HCs. Valeric acid was positively correlated with working memory in MDD group.Gamma-glutamyl leucine, leucine-enkephalin, and valeric acid were preliminarily proven to be decreased in MDD patients. In addition, MDD patients performed worse in working memory than HCs. Dysfunction in working memory of MDD individuals was associated with valeric acid.
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Transtorno Depressivo Maior/sangue , Memória de Curto Prazo/fisiologia , Navegação Espacial/fisiologia , Adolescente , Adulto , Fatores Etários , Algoritmos , Índice de Massa Corporal , Cromatografia Líquida , Transtorno Depressivo Maior/fisiopatologia , Dipeptídeos/sangue , Encefalina Leucina/sangue , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Ácidos Pentanoicos/sangue , Escalas de Graduação Psiquiátrica , Fatores Sexuais , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
A ratiometric fluorescent pH sensor was facilely constructed by covalent modification of amino-terminated silicon nanodots (SiND) with pH-sensitive fluorescein isothiocyanate (FITC). After optimization, the SiND-FITC(40:1) material with a SiND:FITC initial mass ratio of 40:1 was selected for the sensing of hydrogen ions. It was observed that the material inherits the unique features of SiND and FITC, and there is significant improvement of SiND acid-base stability, which is a favorable factor in terms of providing fluorescence reference signal. The SiND-FITC(40:1) material displays not only high pH sensitivity, but also good stability and anti-interference ability, and the response process is highly reversible. Deploying the SiND-FITC(40:1) material, we have made available a simple, sensitive, and precise approach for pH sensing. In aqueous solutions, the I517/I466 fluorescence intensity ratio of SiND-FITC(40:1) increases linearly in the pH range of 5.40-7.76. This dual emission nanosensor was successfully applied for pH sensing and cellular fluorescence imaging.
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Técnicas Biossensoriais , Fluoresceína-5-Isotiocianato/química , Imageamento Tridimensional , Nanopartículas/química , Silício/química , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Nanopartículas/ultraestrutura , Concentração Osmolar , Espectrometria de FluorescênciaRESUMO
The present study aimed to investigate the effect of vitrification temperature (VT) and cryoprotective agent concentrations (CPAs) on the mRNA transcriptome of bovine mature oocytes after vitrifying at immature stage. Cumulus oocyte complexes (COCs) were randomly divided into the following five groups: fresh oocytes (control), oocytes vitrified in liquid helium (LHe; -269 °C) with 5.6 M CPAs (LHe 5.6 M), oocytes vitrified in LHe with 6.6 M CPAs (LHe 6.6 M), oocytes vitrified in liquid nitrogen (LN; -196 °C) with 5.6 M CPAs (LN 5.6 M), and oocytes vitrified in LN with 6.6 M CPAs (LN 6.6 M). We performed two experiments in this study. In experiment 1, after vitrification and thawing, oocytes of vitrified and control groups were subjected to in vitro maturation (IVM), in vitro fertilization (IVF) and in vitro culture (IVC). The rates of normal morphology, maturation, cleavage, and blastocyst formation in LHe 5.6 M were higher than those in LN 5.6 M (P < 0.05). The rates of normal morphology and cleavage in LHe 6.6 M were higher than those in LN 6.6 M (P < 0.05). However, the maturation and blastocyst rates were similar (P > 0.05) between LHe 6.6 M and LN 6.6 M. The blastocyst rate of 13.31% in LHe 5.6 M was the highest among all vitrified groups (P < 0.05). In experiment 2, the mRNA transcriptome of each sample was analyzed by Smart-Seq4, and the differentially expressed genes (DEGs) were detected by edgeR (P ≤ 0.05; fold-change ≥ 2). A total of 505 DEGs (342 upregulated and 163 downregulated genes) were detected in LHe 5.6 M; 609 DEGs (493 upregulated and 116 downregulated genes) were detected in LHe 6.6 M; 218 DEGs (101 upregulated and 117 downregulated genes) were determined in LN 5.6 M; and 221 DEGs (104 upregulated and 117 downregulated genes) were detected in LN 6.6 M. LHe vitrification affected the mRNA transcriptome of bovine mature oocytes after vitrifying at immature stage mainly by upregulating gene expression. Decreased CPAs (5.6 M) reduced the effect of vitrification on mRNA transcriptome when LHe vitrification was used. Among the DEGs closely related to bovine oocytes, the genes possibly related to VT were ND2, MPV17L2, PIF1, LPIN1, IMP3, BRD1, DCTN3, DERA, ATP7B, NEK5, HVCN1, and MARK2. The gene that may be associated with CPAs is CC2D2A. Genes that may be affected by VT and CPAs included PGK1, SLC7A3, FITM2, NPM3, ISCU, CWC15, and PSAP.
Assuntos
Criopreservação/veterinária , Crioprotetores/farmacologia , Oócitos/fisiologia , RNA Mensageiro/metabolismo , Transcriptoma/fisiologia , Vitrificação , Animais , Bovinos , Crioprotetores/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , RNA Mensageiro/genéticaRESUMO
The amygdala plays an important role in emotion processing. Several studies have proved that its activation can be regulated by real-time functional magnetic resonance imaging (rtfMRI)-based neurofeedback training. However, although studies have found brain regions that are functionally closely connected to the amygdala in the cortex, it is not clear whether these brain regions and the amygdala are structurally closely connected, and if they show the same training effect as the amygdala in the process of emotional regulation. In this paper, we instructed subjects to up-regulate the activation of the left amygdala (LA) through rtfMRI-based neurofeedback training. In order to fuse multimodal imaging data, we introduced a network analysis method called the -Louvain clustering algorithm. This method was used to integrate multimodal data from the training experiment and construct an LA-cortical network. Correlation analysis and main-effect analysis were conducted to determine the signal covariance associated with the activation of the target area; ultimately, we identified the left temporal pole superior as the amygdaloidal-cortical network region. As a deep nucleus in the brain, the treatment and stimulation of the amygdala remains challenging. Our results provide new insights for the regulation of activation in a deep nucleus using more neurofeedback techniques.
Assuntos
Algoritmos , Tonsila do Cerebelo/fisiologia , Mapeamento Encefálico/métodos , Córtex Cerebral/fisiologia , Rede Nervosa/fisiologia , Análise por Conglomerados , Sistemas Computacionais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Neurorretroalimentação , Espectroscopia de Luz Próxima ao Infravermelho , Adulto JovemRESUMO
Oligodendrocytes are a type of glial cells that ensheath multiple neuronal axons and form myelin. Under pathological conditions, such as multiple sclerosis (MS), inflammatory damage to myelin and oligodendrocytes leads to demyelination. Although the demyelinated regions can partially resolve functional deficits through remyelination, however, as the disease progresses, remyelination typically becomes incomplete and ultimately fails. One possible explanation for this failure is the activation of the Notch pathway in MS lesions, which impedes oligodendrocyte precursor cells (OPCs) at maturation. This leads to a potential target for remyelination. Here, we have identified a compound Yhhu4952 that promoted the maturation of cultured OPCs in a dose-dependent and time-dependent manner. Neonatal rats showed a significant increase in the expression of myelin basic protein (MBP) and the prevalence of mature oligodendrocytes in the corpus callosum after Yhhu4952 treatment. The compound was also effective in promoting remyelination in cuprizone-induced demyelination model and improving severity scores in experimental autoimmune encephalomyelitis (EAE) model. Mechanism studies revealed that Yhhu4952 promotes OPC differentiation through the inhibition of the Jagged1-Notch1 pathway. These findings suggest Yhhu4952 is potentially useful for proceeding oligodendrocyte differentiation and remyelination.