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Two novel bis-tridentate imidazole derivatives were conveniently synthesized using a 'one-pot' method. Their dinuclear (Cu2L1Cl4, Cu2L2Cl4) and mononuclear (CuL1Cl2, CuL2Cl2âH2O) copper (II) complexes were synthesized to comparably evaluate their reactivities in the hydrolytic cleavage of 2-hydroxypropyl p-nitrophenyl phosphate (HPNP) as a classic RNA model. Single crystals of Cu2L1Cl4 and Cu2L2Cl4 indicate that both of them are centrosymmetric, and each central copper ion is penta-coordinated. Regarding the transesterification of HPNP, both of dinuclear ones exhibited excess one order of magnitude rate enhancement in contrast with auto-hydrolysis reaction. Under comparable conditions, dinuclear complexes displayed no more than twofold increase in activity over their mononuclear analogues, which verifies the lack of binuclear cooperation effect due to long Cu-to-Cu space.
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Cobre , Nitroimidazoles , Cobre/química , ARN/química , Imidazoles , LigandosRESUMEN
Schizophrenia (SCZ) is a debilitating neuropsychiatric disorder with high heritability and complex inheritance. In the past decade, successful identification of numerous susceptibility loci has provided useful insights into the molecular etiology of SCZ. However, applications of these findings to clinical classification and diagnosis, risk prediction, or intervention for SCZ have been limited, and elucidating the underlying genomic and molecular mechanisms of SCZ is still challenging. More recently, multiple Omics technologies - genomics, transcriptomics, epigenomics, proteomics, metabolomics, connectomics, and gut microbiomics - have all been applied to examine different aspects of SCZ pathogenesis. Integration of multi-Omics data has thus emerged as an approach to provide a more comprehensive view of biological complexity, which is vital to enable translation into assessments and interventions of clinical benefit to individuals with SCZ. In this review, we provide a broad survey of the single-omics studies of SCZ, summarize the advantages and challenges of different Omics technologies, and then focus on studies in which multiple omics data are integrated to unravel the complex pathophysiology of SCZ. We believe that integration of multi-Omics technologies would provide a roadmap to create a more comprehensive picture of interactions involved in the complex pathogenesis of SCZ, constitute a rich resource for elucidating the potential molecular mechanisms of the illness, and eventually improve clinical assessments and interventions of SCZ to address clinical translational questions from bench to bedside.
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Esquizofrenia , Epigenómica , Genómica , Humanos , Metabolómica , Proteómica , Esquizofrenia/genéticaRESUMEN
Methamphetamine (METH), a widely abused stimulant drug, induces psychosis in approximately half of abusers; this effect is becoming a major concern for society. Although the Notch1 signalling pathway has been shown to play a part in the pathogenesis of some psychiatric disorders, its role in METH-induced psychosis (MIP) is still unknown. Here, the METH-induced locomotor sensitization model in rodents is considered to represent the underlying neurochemical changes driving psychoses. We found that the Notch1 signalling was downregulated in the medial prefrontal cortex (mPFC) in sensitized mice. Direct genetic and pharmacological manipulations of Notch1 signalling bidirectionally altered METH-induced locomotor sensitization and other MIP-related behaviours through governing neuronal activity in the mPFC. Moreover, Notch1 signalling negatively regulated GABAB1 receptor expression in the mPFC of METH-sensitized mice through Hes1, a transcriptional repressor in Notch1 signalling. Further, we show that Hes1 can directly bind to the GABAB1 receptor promoter. Notably, pharmacological regulation of the GABAB receptor in the mPFC reversed the changes in METH-induced locomotor sensitization caused by the dysfunction of Notch1 signalling. Together, our findings uncover a previously unrecognised Notch1-Hes1-GABAB1 receptor-dependent mechanism involved in regulating mPFC neuronal activity and behavioural phenotypes in MIP. Our work provides mechanistic insight into the aetiology and pathophysiology of MIP.
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Estimulantes del Sistema Nervioso Central , Metanfetamina , Trastornos Psicóticos , Receptores de GABA-B , Receptores Notch , Factor de Transcripción HES-1 , Animales , Ratones , Estimulantes del Sistema Nervioso Central/farmacología , Metanfetamina/farmacología , Actividad Motora , Corteza Prefrontal/metabolismo , Trastornos Psicóticos/metabolismo , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Factor de Transcripción HES-1/genética , Factor de Transcripción HES-1/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismoRESUMEN
Methamphetamine (METH) -induced behavioral sensitization depends on long-term neuroplasticity in the mesolimbic dopamine system, especially in the nucleus accumbens (NAc). miR-128, a brain enriched miRNA, was found to have abilities in regulating neuronal excitability and formation of fear-extinction memory. Here, we aim to identify the role of miR-128 on METH-induced locomotor sensitization of male mice. We identified a significant increase of miR-128 in the NAc of mice upon repeated-intermittent METH exposure but not acute METH administration. Microinjection of adeno-associated virus (AAV)-miR-128 over-expression and inhibition constructs into the NAc of mice resulted in enhanced METH-induced locomotor sensitization and attenuated effects of METH respectively. Isobaric tags for relative and absolute quantification (iTRAQ) technology and ingenuity pathway analysis (IPA) were carried out to uncover the potential molecular mechanisms underlying miR-128-regulated METH sensitization. Differentially expressed proteins, including 25 potential targets for miR-128 were annotated in regulatory pathways that modulate dendritic spines, synaptic transmission and neuritogenesis. Of which, Arf6, Cpeb3 and Nlgn1, were found to be participating in miR-128-regulated METH sensitization. Consistently, METH-induced abnormal changes of Arf6, Cpeb3 and Nlgn1 in the NAc of mice were also detected by qPCR and validated by western blot analysis. Thus, miR-128 may contribute to METH sensitization through controlling neuroplasticity. Our study suggested miR-128 was an important regulator of METH- induced sensitization and also provided the potential molecular networks of miR-128 in regulating METH-induced sensitization.
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Estimulantes del Sistema Nervioso Central/farmacología , Metanfetamina/farmacología , MicroARNs/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Animales , Aprendizaje/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacosRESUMEN
WBP1L is a target of microRNA 137 (miR-137) and has been considered a candidate gene for schizophrenia (SCZ). To investigate the relationships between WBP1L and SCZ and its related symptom scales, a total of 5,993 Chinese Han subjects, including 2,128 SCZ patients and 3,865 controls, were enrolled. In addition, an independent sample set for replication study including 1,052 SCZ patients and 2,124 controls were also recruited. Thirty-two tag single nucleotide polymorphisms (SNPs) located within gene region of WBP1L were selected for genotyping and analyzing. The expression quantitative trait loci (eQTL) effects for the targeted SNPs were investigated with gene expression data from multiple human tissues. Rs4147157 (OR = 0.84, p = 1.51 × 10-5 ) and rs284854 (OR = 1.14, p = 7.00 × 10-4 ) were significantly associated with SCZ disease status and these association signals were replicated in our replication sample. A significant association was identified between rs4147157 and the general (ß = -.66, p = .001) and total (ß = -.8, p = .0042) scores of positive and negative syndrome scale scores in SCZ patients. Both SNPs were significant eQTL for genes around WBP1L in human brain tissues including ARL3 and AS3MT. To conclude, SNPs rs4147157 and rs284854 were associated with SCZ in the Chinese Han population. Additionally, rs4147157 was significantly associated with specific symptom features of SCZ.
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Proteínas de la Membrana/genética , Escalas de Valoración Psiquiátrica , Esquizofrenia/genética , Dominios WW , Adulto , Alelos , Encéfalo/metabolismo , Estudios de Casos y Controles , China , Biología Computacional , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Adulto JovenRESUMEN
microRNA (miRNA) play important roles in drug addiction and act as a post-transcriptional regulator of gene expression. We previously reported extensive downregulation of miRNAs in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice. However, the regulatory mechanism of this METH-induced downregulation of miRNAs has yet to be elucidated. Thus, we examined METH-induced changes in the expression of miRNAs and their precursors, as well as the expression levels of mRNA and the proteins involved in miRNA biogenesis such as Dicer1 and Ago2, in the nucleus accumbens of METH-induced locomotor sensitized mice. miRNAs and Ago2 were significantly downregulated, while the expression of miRNA precursors remained unchanged or upregulated, which suggests that the downregulation of miRNAs was likely due to a reduction in Ago2-mediated splicing but unlikely to be regulated at the transcription level. Interestingly, the expression level of Dicer1, which is a potential target of METH-induced decreased miRNAs, such as miR-124, miR-212 and miR-29b, was significantly increased. In conclusion, this study indicates that miRNA biogenesis (such as Ago2 and Dicer1) and their miRNA products may have a role in the development of METH addiction.
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Proteínas Argonautas/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , ARN Helicasas DEAD-box/fisiología , Locomoción/efectos de los fármacos , Metanfetamina/farmacología , MicroARNs/metabolismo , Ribonucleasa III/fisiología , Trastornos Relacionados con Anfetaminas/fisiopatología , Animales , Regulación hacia Abajo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Núcleo Accumbens/efectos de los fármacosRESUMEN
Blebbistatin is a potent and specific inhibitor of the motor functions of class II myosins, including striated muscle myosin and nonmuscle myosin-2 (NM2). However, the blebbistatin inhibition of NM2c has not been assessed and remains controversial with respect to its efficacy with smooth muscle myosin (SmM), which is highly homologous to NM2. To clarify these issues, we analyzed the effects of blebbistatin on the motor activities of recombinant SmM and three NM2s (NM2a, -2b, and -2c). We found that blebbistatin potently inhibits the actin-activated ATPase activities of SmM and NM2s with following IC50 values: 6.47 µM for SmM, 3.58 µM for NM2a, 2.30 µM for NM2b, and 1.57 µM for NM2c. To identify the blebbistatin-resistant myosin-2 mutant, we performed mutagenesis analysis of the conserved residues in the blebbistatin-binding site of SmM and NM2s. We found that the A456F mutation renders SmM and NM2s resistant to blebbistatin without greatly altering their motor activities or phosphorylation-dependent regulation, making A456F a useful mutant for investigating the cellular function of NM2s.
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Proteínas Aviares/antagonistas & inhibidores , Proteínas Aviares/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Miosina Tipo IIB no Muscular/antagonistas & inhibidores , Miosina Tipo IIB no Muscular/química , Miosinas del Músculo Liso/antagonistas & inhibidores , Miosinas del Músculo Liso/química , Sustitución de Aminoácidos , Animales , Proteínas Aviares/genética , Proteínas Aviares/metabolismo , Pollos , Humanos , Ratones , Mutación Missense , Miosina Tipo IIB no Muscular/genética , Miosina Tipo IIB no Muscular/metabolismo , Miosinas del Músculo Liso/genética , Miosinas del Músculo Liso/metabolismoRESUMEN
A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable (13)C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was â¼100 liters. The clearance was â¼0.8 l/h (13 ml/min), supporting that odanacatib is a low-extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.
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Compuestos de Bifenilo/farmacocinética , Interacciones Alimento-Droga , Posmenopausia , Administración Oral , Anciano , Área Bajo la Curva , Disponibilidad Biológica , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/sangre , Estudios Cruzados , Femenino , Semivida , Humanos , Infusiones Intravenosas , Persona de Mediana EdadRESUMEN
Hydrogen sulfide (H2S) is a pervasive gaseous pollutant that emits the characteristic odor of rotten gas, even at low concentrations. It is generated during various industrial processes, including petroleum and natural gas refining, mining operations, wastewater treatment activities, and refuse disposal practices. According to statistics from the World Health Organization (WHO), over 70 occupations are exposed to H2S, rendering it a key monitoring factor in occupational disease detection. Although H2S has legitimate uses in the chemical, medical, and other fields, prolonged exposure to this gas can cause severe damage to the respiratory and central nervous systems, as well as other organs in the human body. Moreover, the substantial release of H2S into the environment can lead to significant pollution. This noxious substance has the potential to impair soil, water, and air quality, while disrupting the equilibrium of the surrounding ecosystems. Therefore, sulfide has become one of the most commonly measured substances for environmental monitoring worldwide. Achieving the stable enrichment and accurate detection of low-level H2S is of great significance. Common methods for detecting this gas include spectrophotometry, chemical analysis, gas chromatography, rapid field detection, and ion chromatography. Although these methods provide relatively reliable results, they suffer from limitations such as high detection cost, low recovery, lack of environmental friendliness, and imprecise quantification of low-concentration H2S. Furthermore, the sampling processes involved in these methods are complex and require specialized equipment and electrical devices. Additionally, approximately 20% of the sulfides in a sample are lost after 2 h in a conventional alkaline sodium hydroxide solution, causing difficulties in preservation and detection. In this study, an accurate, efficient, and cost-saving method based on ion chromatography-pulse amperometry was developed for H2S determination. A conventional IonPac AS7 (250 mm×4 mm) anion-exchange column was employed, and a new eluent based on sodium hydroxide and sodium oxalate was used to replace the original sodium hydroxide-sodium acetate eluent. The main factors influencing the separation and detection performance of the proposed method, including the pulse amperage detection potential parameters and integration time, as well as the type and content of additives in the stabilizing solution, were optimized. The results showed that the proposed method had a good linear relationship between 10 and 3000 µg/L, with correlation coefficients (r2) of up to 0.999. The limits of detection (S/N=3) and quantification (S/N=10) were 1.53 and 5.10 µg/L, respectively. The relative standard deviations (RSDs) of the peak area and retention time of sulfides were less than 0.2% (n=6). The new method exhibited excellent stability, with up to 90% reduction in reagent costs. Compared with conventional ion chromatography-pulse amperometry, this method is more suitable for detecting low concentrations of sulfides in actual samples. Sulfides in a 250 mmol/L sodium hydroxide-0.8% (mass fraction) ethylenediaminetetraacetic acid disodium salt solution were effectively maintained for over 10 h. The new stabilizer significantly improved the reliability of both large-scale and long-term detection. The recovery of the proposed method was investigated by combining the system with a badge-type passive sampler. This sampling method requires no power devices; it is inexpensive, simple to operate, and can realize long-term sampling without the need for skilled personnel. Moreover, it can overcome the influence of short-term changes in pollutant concentration. The sampling results have high reference value for large-scale intervention-less pollutant monitoring in ultraclean rooms, museum counters, and other places. The results demonstrated that the recovery of the proposed method was greater than 95% for the blank sample and 80% for the sample plus standard solution. Finally, the newly established method was applied to determine H2S levels in air samples collected via passive sampling at school garbage stations. The measured results did not exceed the national limit.
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Contaminantes Atmosféricos , Sulfuro de Hidrógeno , Sulfuro de Hidrógeno/análisis , Contaminantes Atmosféricos/análisis , Monitoreo del Ambiente/métodos , Cromatografía por Intercambio Iónico/métodosRESUMEN
Locust (Locusta migratoria) has a single striated muscle myosin heavy chain (Mhc) gene, which contains 5 clusters of alternative exclusive exons and 1 differently included penultimate exon. The alternative exons of Mhc gene encode 4 distinct regions in the myosin motor domain, that is, the N-terminal SH3-like domain, one lip of the nucleotide-binding pocket, the relay, and the converter. Here, we investigated the role of the alternative regions on the motor function of locust muscle myosin. Using Sf9-baculovirus protein expression system, we expressed and purified 5 isoforms of the locust muscle myosin heavy meromyosin (HMM), including the major isoform in the thorax dorsal longitudinal flight muscle (FL1) and 4 isoforms expressed in the abdominal intersegmental muscle (AB1 to AB4). Among these 5 HMMs, FL1-HMM displayed the highest level of actin-activated adenosine triphosphatase (ATPase) activity (hereafter referred as ATPase activity). To identify the alternative region(s) responsible for the elevated ATPase activity of FL1-HMM, we produced a number of chimeras of FL1-HMM and AB4-HMM. Substitution with the relay of AB4-HMM (encoded by exon-14c) substantially decreased the ATPase activity of FL1-HMM, and conversely, the relay of FL1-HMM (encoded by exon-14a) enhanced the ATPase activity of AB4-HMM. Mutagenesis showed that the exon-14a-encoded residues Gly474 and Asn509 are responsible for the elevated ATPase activity of FL1-HMM. Those results indicate that the alternative relay encoded by exon-14a/c play a key role in regulating the ATPase activity of FL1-HMM and AB4-HMM.
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Locusta migratoria , Músculo Estriado , Animales , Locusta migratoria/genética , Locusta migratoria/metabolismo , Secuencia de Aminoácidos , Miosinas/química , Miosinas/genética , Miosinas/metabolismo , Isoformas de Proteínas/genética , Cadenas Pesadas de Miosina/química , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Músculo Estriado/metabolismoRESUMEN
Infantile primary hyperoxaluria type 1 (PH1) is the most devastating primary hyperoxaluria (PH) subtype as it leads to early end-stage kidney disease (ESKD) associated with high mortality. We report a case of a three-month-old female Chinese infant who was diagnosed with PH1 by renal biopsy and genetic studies. She carried two heterozygous mutations in the alanine-glyoxylate and serine pyruvate aminotransferase (AGXT) gene, one of which has never been previously reported. The patient had multiple organ failures caused by kidney failure, which was improved by extracorporeal membrane oxygenation and continuous renal replacement therapy. However, her primary disease responded poorly to conservative treatment. Fortunately, after waiting for four months, the patient underwent a successful combined liver-kidney transplantation and has progressed well so far. This case highlights the importance of suspecting PH in infant patients with ESKD of uncertain etiology, as early initiation of therapy prevents poor outcomes.
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Hiperoxaluria Primaria , Fallo Renal Crónico , Trasplante de Riñón , Lactante , Humanos , Femenino , Hiperoxaluria Primaria/diagnóstico , Riñón , Trasplante de Riñón/efectos adversos , Fallo Renal Crónico/complicacionesRESUMEN
A novel fluorescent dye molecule - triphenylamine (TPA)-benzothiazole (BZT) - based on excited state intramolecular proton transfer (ESIPT) was prepared by the Suzuki coupling reaction. The photophysical property assay indicates that BZT-TPA appeared in distinguishable colors in mixed solvents with different water contents. Moreover, BZT-TPA exhibited observable AIE behavior. On this basis, a fluorescent probe BZT-TPA-BO was synthesized for detecting H2O2. This probe molecule was found to have excellent selectivity, rapid response, and good linear relationship (R2 = 0.989) for detecting H2O2 in aqueous medium. Through DFT calculation, fluorescence spectrum, nuclear magnetic titration and HR-MS, the mechanism of recognition of H2O2 by the probe BZT-TPA-BO is proposed. In addition, the probe BZT-TPA-BO to some extent exhibited better performance for detecting exogenous H2O2 in HeLa cells.
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Reperfusion therapy, the standard treatment for acute myocardial infarction (MI), can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, molecular mechanisms that regulate cardiomyocyte death remain largely unknown. The abnormal expression of lncRNA MIR22HG has been found in types of diseases. The current study was aimed at exploring the function and mechanism of MIR22HG in I/R injury. In this study, mouse myocardial cells (HL-1) treated with oxygen-glucose deprivation and reoxygenation (OGD/R) were used as the in vitro models, and myocardial ischemia reperfusion injury (MIRI) animal models in vivo were established in male C57BL/6 mice. Experiments including CCK-8, flow cytometry, TUNEL, HE staining, RT-qPCR, western blotting, and luciferase reporter assays were performed to explore the function and potential mechanism of MIR22HG in MIRI in vitro and in vivo. Bioinformatics analysis was performed to predict the binding site between miR-9-3p and MIR22HG (or SH2B3). Our results indicated that the MIR22HG level was upregulated in cardiomyocytes after OGD/R treatment. The knockdown of MIR22HG promoted cell viability and inhibited apoptosis and extracellular matrix (ECM) production in OGD/R-treated HL-1 cells. In mechanism, MIR22HG binds to miR-9-3p, and miR-9-3p targets the SH2B3 3' untranslated region (UTR). Moreover, SH2B3 expression was positively regulated by MIR22HG but negatively modulated by miR-9-3p. Rescue assays suggested that the suppressive effect of MIR22HG knockdown on cell viability, apoptosis, and ECM accumulation was reversed by the overexpression of SH2B3. The in vivo experiments demonstrated that MIR22HG knockdown alleviated cardiomyocyte apoptosis and reduced myocardial infarct size in MIRI mice. In summary, MIR22HG knockdown alleviates myocardial injury through the miR-9-3p/SH2B3 axis.
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MicroARNs , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Animales , Apoptosis , Glucosa , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Oxígeno/metabolismo , Oxígeno/farmacologíaRESUMEN
PURPOSE: Cerebral ischemia is related to insufficient blood supply and is characterized by abnormal reactive oxygen species (ROS) production and cell apoptosis. Previous studies have revealed a key role for basic helix-loop-helix family member e40 (Bhlhe40) in oxidative stress and cell apoptosis. This study aimed to investigate the roles of miR-494-3p in cerebral ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: A mouse middle cerebral artery occlusion (MCAO/R) model was established to mimic cerebral ischemia in vivo. Brain infarct area was assessed using triphenyl tetrazolium chloride staining. Oxygen-glucose deprivation/reoxygenation (OGD/R) operation was adopted to mimic neuronal injury in vitro. Cell apoptosis was analyzed by flow cytometry. The relationship between miR-494-3p and Bhlhe40 was validated by luciferase reporter and RNA immunoprecipitation assays. RESULTS: Bhlhe40 expression was downregulated both in MCAO/R animal models and OGD/R-induced SH-SY5Y cells. Bhlhe40 overexpression inhibited cell apoptosis and reduced ROS production in SH-SY5Y cells after OGD/R treatment. MiR-494-3p was verified to bind to Bhlhe40 and negatively regulate Bhlhe40 expression. Additionally, cell apoptosis and ROS production in OGD/R-treated SH-SY5Y cells were accelerated by miR-494-3p overexpression. Rescue experiments suggested that Bhlhe40 could reverse the effects of miR-494-3p overexpression on ROS production and cell apoptosis. CONCLUSION: MiR-494-3p exacerbates brain injury and neuronal injury by regulating Bhlhe40 after I/R.
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Lesiones Encefálicas , Isquemia Encefálica , MicroARNs , Daño por Reperfusión , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Isquemia Encefálica/genética , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Daño por Reperfusión/genética , Daño por Reperfusión/metabolismo , Regulación hacia ArribaRESUMEN
Background & Aims: Acetaminophen (APAP)-induced acute liver injury (ALI) is a global health issue characterised by an incomplete understanding of its pathogenesis and unsatisfactory therapies. NEK7 plays critical roles in both cell cycle regulation and inflammation. In the present study, we investigated the role and mechanism of NEK7 in APAP-induced ALI. Methods: In mice with NEK7 overexpression (hydrodynamic tail vein injection of NEK7 plasmids), hepatocyte-specific NEK7 knockout (cKO), and inducible NEK7 knockout (iKO), an overdose of APAP was administered to induce ALI. Liver injury was determined by an analysis of serum liver enzymes, pathological changes, inflammatory cytokines, and metabonomic profiles. In vitro, hepatocyte damage was evaluated by an analysis of cell viability, the reactive oxygen species levels, and mitochondrial function in different cell lines. Hepatocyte proliferation and the cell cycle status were determined by Ki-67 staining, EdU staining, and the cyclin levels. Results: NEK7 was markedly downregulated in APAP-induced injured liver and damaged hepatocytes. NEK7 overexpression in the liver significantly alleviated APAP-induced liver injury, as shown by the restored liver function, reduced pathological injury, and decreased inflammation and oxidative stress, which was confirmed in a hepatocyte cell line. Moreover, both NEK7 cKO and iKO mice exhibited exacerbation of APAP-induced ALI. Finally, we determined that cyclin B1-mediated cell cycle progression could mediate the protective effect of NEK7 against APAP-induced ALI. Conclusions: Reduced NEK7 contributes to APAP-induced ALI, possibly by dysregulating cyclins and disturbing cell cycle progression. Lay summary: Acetaminophen-induced acute liver injury is one of the major global health issues, owing to its high incidence, potential severity, and limited therapeutic options. Our current understanding of its pathogenesis is incomplete. Herein, we have shown that reduced NEK7 (a protein with a key role in the cell cycle) exacerbates acetaminophen-induced acute liver injury. Hence, NEK7 could be a possible therapeutic target for the prevention or treatment of this condition.
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BACKGROUND: Renal stone disease (RSD) is a common disease of the human urinary system and is regarded as a multifactorial condition affected by environmental and genetic factors. RGS14 encodes a complex scaffolding protein, known as regulator of G protein signaling 14, which is enriched in hippocampal area CA2 dendritic spines. AIM OF THE STUDY: We aimed to investigate the association between genetic polymorphisms in RGS14 and the risk of RSD based on a large sample of the Chinese Han population. METHODS: A total of 1,436 subjects, comprising 506 patients with RSD and 920 controls, were enrolled in the study. Ten tag SNPs located in the RGS14 gene region were chosen for genotyping. Genetic associations were evaluated at both the single marker and haplotype levels. Genotypic (χ2 test) and allelic analyses (Cochran-Armitage test for trend) were performed for single marker-based association. Two bioinformatics tools, RegulomeDB and GTEx, were used to examine the functional consequences of the target SNP. RESULTS: SNP rs11746443 was found to be significantly associated with disease status (χ2 = 12.60, p = 0.0018). Moreover, the A allele of this SNP was significantly associated with an increased risk of RSD (OR [95%CI] = 1.36 [1.13-1.65]). Multiple significant eQTL signals of rs11746443 on RGS14 were identified. CONCLUSIONS: This study replicated the association signal of RGS14 with RSD in a large sample of the Chinese Han population. The results suggest that the SNP rs11746443 of RGS14 might increase the risk of RSD by regulating the Ca2+ levels in humans.
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Cálculos Renales/genética , Proteínas RGS/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
The SNAP25 gene is involved in the development of antipsychotic-induced weight gain (AIWG) or metabolic syndrome during antipsychotics use in Americans and Europeans, but its role in Asians remains unknown. To identify common variants in SNAP25 associated with schizophrenia and evaluate their effects on AIWG and antipsychotic responses in Han Chinese individuals with schizophrenia, we conducted a two-stage case-control study of 3,243 patients and 6,154 healthy controls. 2128 inpatients in the replication stage have received conventional treatment with an antipsychotic monotherapy (Haloperidol, Olanzapine or Risperidone) for 10â¯weeksâ¯at least. Weight change, antipsychotic responses and metabolic indices change were assessed during treatments. Three SNPs were significantly associated with schizophrenia in samples (rs6039769, Pâ¯=â¯6.64â¯×â¯10-7; rs3787283, Pâ¯=â¯0.004283; rs3746544, Pâ¯=â¯2.51â¯×â¯10-6). Of these, rs6039769 is a novel schizophrenia-associated SNP and is uncorrelated with the other two variants, which have previously been associated with schizophrenia in European-ancestry samples. Rs6039769 was significantly associated with AIWG (Pâ¯<â¯0.001), but not with antipsychotic responses or metabolic indices. Another two SNPs were not associated with AIWG or antipsychotic responses or metabolic indices. Overall, there were significant differences in antipsychotic responses and metabolic indices among the three treatment groups. Our findings suggest that SNAP25 gene may contribute to the susceptibility of AIWG and even metabolic disturbances. A prior identification of high-risk of patients with rs6039769 would contribute to a better precision of the pharmacological treatment.
Asunto(s)
Antipsicóticos/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Proteína 25 Asociada a Sinaptosomas/genética , Aumento de Peso/efectos de los fármacos , Aumento de Peso/genética , Adulto , Antipsicóticos/efectos adversos , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Phenamacril is a Fusarium-specific fungicide used for Fusarium head blight management. The target of phenamacril is FgMyo1, the sole class I myosin in Fusarium graminearum. The point mutation S217L in FgMyo1 is responsible for the high resistance of F. graminearum to phenamacril. Recent structural studies have shown that phenamacril binds to the 50 kDa cleft of the FgMyo1 motor domain, forming extensive interactions, including a hydrogen bond between the cyano group of phenamacril and the hydroxyl group of S217. Here, we produced FgMyo1IQ2, a truncated FgMyo1 composed of the motor domain and two IQ motifs complexed with the F. graminearum calmodulin in insect Sf9 cells. Phenamacril potently inhibited both the basal and the actin-activated ATPase activities of FgMyo1IQ2, with an IC50 in a micromolar range. S217 mutations of FgMyo1IQ2 substantially increased the IC50 of phenamacril. S217T or S217L each increased the IC50 of phenamacril for â¼60-fold, while S217A only increased the IC50 for â¼4-fold. These results indicate that the hydroxyl group of S217 plays an important, but nonessential role in phenamacril binding and that the bulky side chain at the position 217 sterically hinders phenamacril binding. On the other hand, S217P, which might alter the local conformation of the phenamacril-binding site, completely abolished the phenamacril inhibition. Because the cyano group of phenamacril does not form discernible interactions with FgMyo1 other than the nonessential hydrogen bond with the S217 hydroxyl group, we propose the cyano group of phenamacril as a key modification site for the development of novel fungicides.
Asunto(s)
Estimulantes del Sistema Nervioso Central , Metanfetamina , Psicosis Inducidas por Sustancias , Trastornos Psicóticos , Esquizofrenia , Humanos , Metanfetamina/efectos adversos , Trastornos Psicóticos/etiología , Estimulantes del Sistema Nervioso Central/efectos adversos , Psicosis Inducidas por Sustancias/etiologíaRESUMEN
Altered cholinergic neural transmission is hypothesized to increase susceptibility to cognitive deficits in psychotic disorders such as schizophrenia (SCZ). The nicotinic acetylcholine receptor α5 subunit gene (CHRNA5) is reported to be associated with cognitive function in nicotine-dependent populations and SCZ in non-smoking SCZ patients. Nevertheless, it is still not clear whether the CHRNA5 gene contributes to susceptibility to the cognitive deficits of SCZ without smoking. To further clarify the role of CHRNA5, we designed a two-stage, case-control study to examine the association between CHRNA5 and SCZ and its clinical features adjusted for smoking status in early-onset SCZ patients. A total of 15 tag single nucleotide polymorphisms (SNPs) on CHRNA5 were genotyped in the discovery stage, which included 485 early-onset SCZ patients and 1018 controls, and then, we replicated this association in a confirmatory population of 674 patients and 1886 controls. The rs16969968 SNP was identified as significantly associated with SCZ in both datasets. In addition, the severity of psychotic symptoms and cognitive deficits was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Wisconsin Card Sorting Test (WCST). The rs16969968 SNP was associated with psychotic symptoms in patients and with cognitive function in patients and controls. Our results show that rs16969968 on CHRNA5 is tightly linked to genetic susceptibility, psychotic symptoms and cognitive deficits in SCZ in an early-onset Chinese population, suggesting that CHRNA5 may play an important role in the etiology of SCZ.