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1.
Biotechnol Biofuels ; 14(1): 195, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598723

RESUMO

BACKGROUND: Xylanase, an important accessory enzyme that acts in synergy with cellulase, is widely used to degrade lignocellulosic biomass. Thermostable enzymes with good catalytic activity at lower temperatures have great potential for future applications in the feed and fuel industries, which have distinct demands; however, the potential of the enzymes is yet to be researched. RESULTS: In this study, a structure-based semi-rational design strategy was applied to enhance the low-temperature catalytic performance of Bispora sp. MEY-1 XYL10C_∆N wild-type (WT). Screening and comparisons were performed for the WT and mutant strains. Compared to the WT, the mutant M53S/F54L/N207G exhibited higher specific activity (2.9-fold; 2090 vs. 710 U/mg) and catalytic efficiency (2.8-fold; 1530 vs. 550 mL/s mg) at 40 °C, and also showed higher thermostability (the melting temperature and temperature of 50% activity loss after 30 min treatment increased by 7.7 °C and 3.5 °C, respectively). Compared with the cellulase-only treatment, combined treatment with M53S/F54L/N207G and cellulase increased the reducing sugar contents from corn stalk, wheat bran, and corn cob by 1.6-, 1.2-, and 1.4-folds, with 1.9, 1.2, and 1.6 as the highest degrees of synergy, respectively. CONCLUSIONS: This study provides useful insights into the underlying mechanism and methods of xylanase modification for industrial utilization. We identified loop2 as a key functional area affecting the low-temperature catalytic efficiency of GH10 xylanase. The thermostable mutant M53S/F54L/N207G was selected for the highest low-temperature catalytic efficiency and reducing sugar yield in synergy with cellulase in the degradation of different types of lignocellulosic biomass.

2.
Neuroscience ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34626750

RESUMO

Cognitive control and working memory (WM) processes are essential for goal-directed behaviour. Cognitive control and WM are probably based on overlapping neurophysiological mechanisms. For example, theta-band activity (TBA) plays an important role in both functions. For cognitive control processes, it is known that different aspects of information about stimulus content, motor processes and stimulus-response relationships are encoded simultaneously in the TBA. All this information is probably processed during WM gating processes and must be controlled during them. However, direct data for this are lacking. This question is investigated in this study by combining methods of EEG temporal signal decomposition, time-frequency decomposition and beamforming. We show that portions of stimulus-related information, motor response-related information and information related to the interaction between the stimulus and motor responses in the TBA are influenced in parallel and to a similar extent by WM gate opening and gate closing processes. Nevertheless, it is stimulus-related information in the theta signal in particular that modulates behavioural performance in WM-gating. The data suggest that the identified processes are implemented in specific neuroanatomical structures. In particular, the medial frontal cortex, temporal cortical regions and insular cortex are involved in these dynamics. The study shows that principles of information coding relevant to cognitive control processes are also crucial for understanding WM gating.

3.
Nat Plants ; 7(10): 1335-1346, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34621047

RESUMO

Plants live as sessile organisms with large-scale gene duplication events and subsequent paralogue divergence during evolution. Notably, plant paralogues are expressed tissue-specifically and fine-tuned by phytohormones during various developmental processes. The coat protein complex II (COPII) is a highly conserved vesiculation machinery mediating protein transport from the endoplasmic reticulum to the Golgi apparatus in eukaryotes1. Intriguingly, Arabidopsis COPII paralogues greatly outnumber those in yeast and mammals2-6. However, the functional diversity and underlying mechanism of distinct COPII paralogues in regulating protein endoplasmic reticulum export and coping with various adverse environmental stresses are poorly understood. Here we characterize a novel population of COPII vesicles produced in response to abscisic acid, a key phytohormone regulating abiotic stress responses in plants. These hormone-induced giant COPII vesicles are regulated by an Arabidopsis-specific COPII paralogue and carry stress-related channels/transporters for alleviating stresses. This study thus provides a new mechanism underlying abscisic acid-induced stress responses via the giant COPII vesicles and answers a long-standing question on the evolutionary significance of gene duplications in Arabidopsis.

4.
Acta Pharmacol Sin ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480112

RESUMO

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are known as the common causes of respiratory failure in critically ill patients. Myeloid differentiation 2 (MD2), a co-receptor of toll like receptor 4 (TLR4), plays an important role in LPS-induced ALI in mice. Since MD2 inhibition by pharmacological inhibitors or gene knockout significantly attenuates ALI in animal models, MD2 has become an attractive target for the treatment of ALI. In this study we identified two chalcone-derived compounds, 7w and 7x, as new MD2 inhibitors, and investigated the therapeutic effects of 7x and 7w in LPS-induced ALI mouse model. In molecular docking analysis we found that 7w and 7x, formed pi-pi stacking interactions with Phe151 residue of the MD2 protein. The direct binding was confirmed by surface plasmon resonance analysis (with KD value of 96.2 and 31.2 µM, respectively) and by bis-ANS displacement assay. 7w and 7x (2.5, 10 µM) also dose-dependently inhibited the interaction between lipopolysaccharide (LPS) and rhMD2 and LPS-MD2-TLR4 complex formation. In mouse peritoneal macrophages, 7w and 7x (1.25-10 µM) dose-dependently inhibited LPS-induced inflammatory responses, MAPKs (JNK, ERK and P38) phosphorylation as well as NF-κB activation. Finally, oral administration of 7w or 7x (10 mg ·kg-1 per day, for 7 days prior LPS challenge) in ALI mouse model significantly alleviated LPS-induced lung injury, pulmonary edema, lung permeability, inflammatory cells infiltration, inflammatory cytokines expression and MD2/TLR4 complex formation. In summary, we identify 7w and 7x as new MD2 inhibitors to inhibit inflammatory response both in vitro and in vivo, proving the therapeutic potential of 7w and 7x for ALI and inflammatory diseases.

5.
Q J Exp Psychol (Hove) ; : 17470218211048193, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34507509

RESUMO

We report a boundary paradigm eye movement experiment to investigate whether the predictability of the second character of a two-character compound word affects how it is processed prior to direct fixation during reading. The boundary was positioned immediately prior to the second character of the target word, which itself was either predictable or unpredictable. The preview was either a pseudocharacter (nonsense preview) or an identity preview. We obtained clear preview effects in all conditions, but more importantly, skipping probability for the second character of the target word and the whole target word from pretarget was greater when it was predictable than when it was not predictable from the preceding context. Interactive effects for later measures on the whole target word (gaze duration and go-past time) were also obtained. These results demonstrate that predictability information from preceding sentential context and information regarding the likely identity of upcoming characters are used concurrently to constrain the nature of lexical processing during natural Chinese reading.

6.
Bioresour Technol ; 342: 125962, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34563821

RESUMO

Lignocellulosic biorefining for producing biofuels poses technical challenges. It is usually conducted over a long time using heat, making it energy intensive. In this study, we lowered the energy consumption of this process through an optimized enzyme and pretreatment strategy. First, the dominant mutant M137E/N269G of Bispora sp. MEY-1XYL10C_ΔN was obtained by directed evolution with highcatalytic efficiency (970 mL/s∙mg)and specific activity (2090 U/mg)at 37 °C, and thermostability was improved (T50 increased by5 °C). After pretreatment with seawater immersionfollowing steam explosion,bagasse was co-treated with cellulase and M137E/N269G under mild conditions (37 °C), the resulting highest yield of fermentable sugars reached 219 µmol/g of bagasse,46% higher than that of the non-seawater treatment group, with the highest degree of synergy of 2.0. Pretreatment with seawater following steam explosion and synergistic hydrolysis through high activity xylanase and cellulase helped to achieve low energy degradation of lignocellulosic biomass.

7.
Life Sci ; 285: 119944, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34509465

RESUMO

AIMS: Chronic cerebral hypoperfusion (CCH) is a state of chronic cerebral blood flow reduction, and it is the main cause of cognitive impairment and neurodegenerative diseases. The abnormal upregulation of legumain, a lysosomal cysteine protease, trigger synaptic plasticity impairment and neuroinflammation, which are involved in the underlying pathophysiology of CCH. At present, few studies have reported the role of legumain in cognitive impairment caused by CCH. In our study, we aimed to investigate the involvement of legumain knockout in cognitive function and neuroinflammation in a CCH mouse model. MAIN METHODS: In this study, right unilateral common carotid artery occlusion (rUCCAO) was used to simulate the pathological state of cerebral ischemic injury. Various behavioural tests were executed to assess cognitive performance. In vivo electrophysiological recordings were used to measure synaptic functions. Western blotting, Golgi staining, haematoxylin/eosin staining, and immunofluorescence assays were conducted to examine pathological changes and molecular mechanisms. KEY FINDINGS: The data showed that the level of legumain was significantly increased in the hippocampus of mice subjected to rUCCAO. Legumain knockout significantly improved cognitive function and synaptic plasticity induced by rUCCAO, suggesting that legumain knockout-regulation effectively protected against CCH-induced behavioural dysfunctions. Moreover, legumain knockout suppressed rUCCAO-induced microglial activation, reduced the abnormal expression of inflammatory cytokines and the inflammasome complex, and impeded the activation of P65 and pyroptosis. SIGNIFICANCE: These findings suggest that legumain is an effective regulator of CCH, and may be an ideal target for the development of cerebral ischemia treatments in the future.

8.
Stem Cell Res ; 55: 102501, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34450529

RESUMO

A 74-year-old Alzheimer's Disease (AD) woman patient donated her peripheral blood mononuclear cells (PBMC). Non-integrating episomal vector system were used to reprogram their PBMCs with human OKSM (OCT3/4, KLF4, SOX2, and c-MYC) transcription factors. Immunocytochemistry and flow cytometry for pluripotency makers confirmed the pluripotency of transgene-free iPSCs. Pluripotency was confirmed by the ability of iPSCs to spontaneously differentiate three germ layers in vitro as well. The newly generated human iPSC from PBMCs of a 74 year-old Alzheimer's disease woman can be used for studying further disease mechanisms of Alzheimer's Disease (AD).

9.
ACS Appl Mater Interfaces ; 13(32): 38127-38137, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34347422

RESUMO

Combination therapy has attracted extensive interest in alleviating the shortcomings of monotherapy and enhancing the treatment efficacy. In this work, hollow mesoporous silica nanoparticles (HMSNs) play the role of nanocarriers in the delivery of Cu(II)-doped polydopamine (PDA), termed as HMSNs@PDA-Cu, for synergistic therapy. PDA acts as a traditional photothermal agent to realize photothermal treatment (PTT). Chemodynamic therapy (CDT) is realized by the reaction of Cu(II) with intracellular glutathione (GSH), and subsequently, the generated Cu(I) reacts with H2O2 to produce toxic hydroxyl radical (•OH) through a Fenton-like reaction. The photothermal performance of PDA is improved after its coordination with Cu(II). On the other hand, PDA exhibits superoxide dismutase (SOD)-mimicking activity. PDA converts O2•- to H2O2 and improves the production of H2O2, which promotes the therapeutic effect of CDT. Moreover, the high temperature caused by PTT further enhances the yield of •OH for CDT. This nanotheranostic platform perfectly applied to the tumor depletion of mice, presenting great potential for cancer metastasis therapy in vitro and in vivo.

10.
J Environ Manage ; 298: 113535, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34391105

RESUMO

Blending flue gas desulfurization (FGD) gypsum with surface sodic soil is a universally recognized method for the rapid amelioration of sodic soils; however, little information is available on whether other application methods (band application) will reclaim sodic soil. Three FGD gypsum application methods (single-band, dual-band and blend applications) and a control treatment (non-FGD gypsum) were carried out using sodic soil in soil bins to investigate the effects of the application method on the wetting front, major cations in the leachate during the process of water infiltration and soluble and exchangeable cations in the soil profile after infiltration. The results showed that the wetting fronts in the band treatments were denser in the horizontal direction than in the vertical direction, but the blend and control treatments only had vertical migration. The main channel of the stream in the band treatment was concentrated below the application site of FGD gypsum. The orders of desalting capacity were blend treatment, dual-band treatment and single-band treatment for the same volume of outlet water. There was no water outflow in the control treatment even after 115 days of leaching. The dual-band treatment significantly decreased the soil sodicity of the 0-40 cm soil profile, while the single-band treatment only effectively reclaimed (horizontally) half of the soil. In the blend treatment, the exchangeable sodium percentages were 21.3 % and 34.7 % at depths of 30-35 cm and 35-40 cm, respectively, and were close to zero at a depth of 0-30 cm. Compared with blend treatment, band application could be a better way to reclaim sodic soil with FGD gypsum due to its advantages of long-term and efficient amelioration with low consumption.


Assuntos
Poluentes do Solo , Solo , Sulfato de Cálcio , Rios , Água
11.
Chemosphere ; 286(Pt 3): 131963, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34426263

RESUMO

BACKGROUND: Exposure to air pollution has been linked with altered immune function in adults, but little is known about its effects on early life. This study aimed to investigate the effects of exposure to air pollution during prenatal and postnatal windows on cell-mediated immune function in preschoolers. METHODS: Pre-school aged children (2.9 ± 0.5 y old, n = 391) were recruited from a mother-child cohort study in Wuhan, China. We used a spatial-temporal land use regression (LUR) model to estimate exposures of particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) and ≤10 µm (PM10), and nitrogen dioxide (NO2) during the specific trimesters of pregnancy and the first two postnatal years. We measured peripheral blood T lymphocyte subsets and plasma cytokines as indicators of cellular immune function. We used multiple informant models to examine the associations of prenatal and postnatal exposures to air pollution with cell-mediated immune function. RESULTS: Prenatal exposures to PM2.5, PM10, and NO2 during early pregnancy were negatively associated with %CD3+ and %CD3+CD8+ cells, and during late pregnancy were positively associated with %CD3+ cells. Postnatal exposures to these air pollutants during 1-y or 2-y childhood were positively associated with IL-4, IL-5, IL-6, and TNF-α. We also observed that the associations of prenatal or postnatal air pollution exposures with cellular immune responses varied by child's sex. CONCLUSIONS: Our results suggest that exposure to air pollution during different critical windows of early life may differentially alter cellular immune responses, and these effects appear to be sex-specific.

12.
Sci Total Environ ; 799: 149145, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34365270

RESUMO

This study investigates the drivers of water use efficiency (WUE), a key metric of water resources management, and its changes over eight regions across China from 1982 to 2015 based on gross primary production (GPP) and actual evapotranspiration (AET) datasets. The order of seasonal change of WUE from large to small is autumn, summer, spring and winter. The drivers include seven variables, air temperature, specific humidity, precipitation, short-wave radiation, Normalized Difference Vegetation Index (NDVI), soil moisture and CO2. Our analysis suggests that the sensitivity of annual average NDVI to WUE changes was high nationwide, but there were some differences in seasonal scales. The annual average contribution of air temperature and CO2 affecting WUE change was relatively high in China's largest area (SW, SE, E, NP). Other influencing factors were only relatively high in the local area. Seasonally, NDVI is the driving factor with the highest contribution rate in summer and autumn for NC and NW region. The seasonal contribution rates of driving factors in other regions are significantly different. For the study period (1982-2015), the shrubland ecosystem had the highest annual WUE followed by forest and cropland. The WUE of the farmland ecosystem was higher than that of the grassland ecosystem in most areas.


Assuntos
Ecossistema , Água , China , Florestas , Solo
13.
J Youth Adolesc ; 50(10): 2079-2095, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34259955

RESUMO

Ample evidence suggested that parental responsiveness, demandingness, and autonomy granting protect adolescents from depressive symptoms. However, what is less well understood is how parenting practices reduce the risk of depressive symptoms. This study tested the protective effects of parenting practices and inhibitory control on depressive symptoms, along with the mediating role of inhibitory control and the moderating role of the COMT gene in linking parenting practices to depressive symptoms. The study utilized cross-sectional data from a community sample of Chinese Han adolescents (N = 943, Mage = 15.25 years, SD = 0.70 years; 51.9% girls). Results showed that parental responsiveness and autonomy granting promoted higher inhibitory control, which in turn was associated with lower depressive symptoms. Further, the mediation effects were moderated by the COMT gene. For adolescents with ValVal homozygotes, both responsiveness and autonomy granting were related to higher levels of inhibitory control, which reduced risk for depressive symptoms, but the mediation effects were not observed among Met allele carriers. The mediating role of inhibitory control did not hold in the parental demandingness model. Findings support the cognitive theory that inhibitory control is a proximal factor linking parenting practices to depressive symptoms exclusively in ValVal homozygotes. These results also suggested that differentiating different dimensions of parenting practices may help to further clarify the processes by which parenting practices eventuate depressive symptoms.


Assuntos
Catecol O-Metiltransferase , Poder Familiar , Adolescente , Catecol O-Metiltransferase/genética , Criança , Educação Infantil , Estudos Transversais , Depressão/genética , Feminino , Humanos , Masculino
14.
Behav Brain Res ; 413: 113464, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34265317

RESUMO

Emotional and cognitive impairment has been recognized as a central feature of depression, which is closely related to hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis caused by down-regulation of glucocorticoid receptor (GR) expression in patients. A decrease in GR expression can cause pathological changes and lead to the impairment of synaptic plasticity. Legumain, a lysosomal cysteine protease, plays an important role in neurological diseases. It is reported that legumain activates the MAPK signaling pathway, which modifies the GR. Therefore, we hypothesize that regulation of the GR by legumain plays a crucial role in the pathological process of depression. The relationships between legumain, GR, synaptic plasticity and emotional and cognitive deficits were explored in this study. The results demonstrated that repeated corticosterone (CORT) injections (3 weeks) induced emotional and cognitive deficits in mice, based on behavioral experiments and the detection of synaptic plasticity. Furthermore, CORT injections decreased the expression of hippocampal synapse-related proteins, cell density and dendritic spine density in the hippocampus, accompanied by increased protein expression in the MAPK signaling pathway and decreased expression of the GR. In conclusion, our results demonstrated that legumain knockout up-regulated expression of the GR by reducing protein expression in the MAPK signaling pathway, thereby improving hippocampal synaptic plasticity as well as the emotional and cognitive impairment of model mice. This suggests that legumain may be an effective therapeutic target for emotional and cognitive deficits.

15.
Immunobiology ; 226(4): 152109, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34252840

RESUMO

Macrophages have a variety of functions, such as secreting cytokines, phagocytosis, et al. Tripartite motif containing 59 (TRIM59) protein is highly expressed in tumor cells. It can regulate proliferation of tumor cells and promote tumor progression. Recent studies shown that the expression of TRIM59 was different in macrophages when stimulated by different stimuli, however, the effects of TRIM59 on macrophage gene expression profiles and functions are still unknown. In our study, we constructed RAW264.7 macrophages with high and low expression of TRIM59, and used next generation sequencing to explore the effects of TRIM59 on macrophage gene expression profiles. Results showed that TRIM59 affected an abundant number of genes, and may affect phagocytosis and cell cycles. We also examined the expression of surface molecules, secretion of cytokines, phagocytosis, proliferation, and apoptosis of macrophages, and confirmed that TRIM59 increased the expression of FcγRs CD16/32, CD64 and the secretion of TNF-α and IL-10, promoted phagocytosis and proliferation of RAW264.7 cells, inhibited the expression of complement receptor CD11b and antigen presentation related receptors (MHCII, CD80), but TRIM59 had no significant effect on apoptosis. Our study explored the effect of TRIM59 on the gene expression and function of macrophages comprehensively.

16.
Sci Rep ; 11(1): 14640, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282234

RESUMO

Many efforts have been devoted to investigating the effect of the interaction between the serotonin transporter gene (5-HTTLPR) and environment (G × E) on depression, but they yield mixed results. The inconsistency has suggested that G × E effects may be more complex than originally conceptualized, and further study is warranted. This study explored the association among 5-HTTLPR, peer victimization and depressive symptoms and the underlying mediating role of inhibitory control in this association. A total of 871 Chinese Han adolescents (Mage = 15.32 years, 50.3% girls) participated and provided saliva samples from which the 5-HTTLPR was genotyped. This study found that 5-HTTLPR interacted with peer victimization in predicting depressive symptoms. Adolescents carrying L allele reported more depressive symptoms than SS carriers when exposed to higher level of peer victimization. Furthermore, adolescents' inhibitory control deficits mediated the association between 5-HTTLPR × peer victimization and depressive symptoms. These findings suggested that one pathway in which G × E may confer vulnerability to depressive symptoms is through disruptions to adolescents' inhibitory control system.

17.
Child Dev ; 92(5): 1836-1854, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34196997

RESUMO

The present longitudinal study examined how and why classroom-level victimization moderates the prospective association between peer victimization and depressive symptoms with 2,643 third- and fourth-graders (Mage  = 10.01 years) in China. Multilevel modeling revealed that peer victimization was more strongly associated with increasing depressive symptoms in classrooms with lower classroom-level victimization. Moreover, two mechanisms were identified to explain the moderating effect of classroom-level victimization. First, low classroom-level victimization reduced victimized children's received friendship nominations from peers, thereby leading to increases in depressive affect. Second, low classroom-level victimization affected victimized children's depressive symptoms through damage to their social self-concept. These findings provide support for the "healthy context paradox" in the Chinese culture, and highlight the mechanisms of this phenomenon.

18.
Biomed Pharmacother ; 139: 111665, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243607

RESUMO

Multicomponent herbal formulas (MCHFs) have earned a wide reputation for their definite efficacy in preventing or treating chronic complex diseases. However, holistic elucidation of the causal relationship between the bioavailable ingredients of MCHFs and their multitarget interactions is very challenging. To solve this problem, pharmacokinetics/pharmacometabolomics-pharmacodynamics (PK/PM-PD) combined with a multivariate biological correlation-network strategy was developed and applied to a classic MCHF, Baoyuan decoction (BYD), to clarify its active components and synergistic mechanism against cardiac hypertrophy (CH). First, multiple plasma metabolic biomarkers for ß-adrenergic agonist-induced CH rats were identified by using untargeted metabolomic profiling, and then, these CH-associated endogenous metabolites and the absorbed BYD-compounds in plasma at different treatment stages after oral administration of BYD were analyzed by using targeted PK and PM. Second, the dynamic relationship of BYD-related compounds and CH-associated endogenous metabolites and signaling pathways was built by using multivariate and bioinformatic correlation analysis. Finally, metabolic-related PD indicators were predicted and further verified by biological tests. The results demonstrated that the bioavailable BYD-compounds, such as saponins and flavonoids, presented differentiated and distinctive metabolic features and showed positive or negative correlations with various CH-altered metabolites and PD-indicators related to gut microbiota metabolism, amino acid metabolism, lipid metabolism, energy homeostasis, and oxidative stress at different treatment stages. This study provides a novel strategy for investigating the dynamic interaction between BYD and the biosystem, providing unique insight for disclosing the active components and synergistic mechanisms of BYD against CH, which also supplies a reference for other MCHF related research.


Assuntos
Cardiomegalia/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/farmacocinética , Extratos Vegetais/farmacologia , Extratos Vegetais/farmacocinética , Aminoácidos/metabolismo , Animais , Biomarcadores/metabolismo , Cardiomegalia/metabolismo , Sinergismo Farmacológico , Flavonoides/farmacocinética , Flavonoides/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Saponinas/farmacocinética , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos
19.
Pharmacopsychiatry ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34293810

RESUMO

Depression is the leading cause of disability worldwide, making antidepressant drugs the most used psychiatric drugs in the USA. Withdrawal effects and rebound symptoms frequently occur after the reduction and/or discontinuation of these drugs. Although these phenomena have been investigated with respect to the clinical symptomatology, no studies have systematically investigated the effects of withdrawal/rebound on general cognition. We present a novel framework based on the idea of allostatic adaptation, which allows to predict how different antidepressants likely impair different cognitive processes as a result of withdrawal and rebound effects. This framework relies on the assumptions that the type of cognitive impairments evoked by an antidepressant is determined by the targeted neurotransmitter systems, while the severity of deficits depends on its half-life. Our model predicts that the severity of detrimental cognitive withdrawal and rebound effects increases with a shorter half-life of the discontinued antidepressant drug. It further proposes drug-specific effects: antidepressants mainly targeting serotonin should primarily impair aversive and emotional processing, those targeting norepinephrine should impair the processing of alerting signals, those targeting dopamine should impair motivational processes and reward processing, and those targeting acetylcholine should impair spatial learning and memory. We hope that this framework will motivate further research to better understand and explain cognitive changes as a consequence of antidepressant discontinuation.

20.
EMBO J ; 40(14): e105985, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34121209

RESUMO

Autophagy is a process through which intracellular cargoes are catabolised inside lysosomes. It involves the formation of autophagosomes initiated by the serine/threonine kinase ULK and class III PI3 kinase VPS34 complexes. Here, unbiased phosphoproteomics screens in mouse embryonic fibroblasts deleted for Ulk1/2 reveal that ULK loss significantly alters the phosphoproteome, with novel high confidence substrates identified including VPS34 complex member VPS15 and AMPK complex subunit PRKAG2. We identify six ULK-dependent phosphorylation sites on VPS15, mutation of which reduces autophagosome formation in cells and VPS34 activity in vitro. Mutation of serine 861, the major VPS15 phosphosite, decreases both autophagy initiation and autophagic flux. Analysis of VPS15 knockout cells reveals two novel ULK-dependent phenotypes downstream of VPS15 removal that can be partially recapitulated by chronic VPS34 inhibition, starvation-independent accumulation of ULK substrates and kinase activity-regulated recruitment of autophagy proteins to ubiquitin-positive structures.

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