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1.
Curr Top Med Chem ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503405

RESUMO

Cancer is the second leading cause of human death after cardiovascular disease, and the most used drugs in clinics are cytotoxic agents. However, these drugs have some inherent disadvantages, such as the risk of toxicity, low selectivity, poor solubility, and so on. To overcome these shortcomings, a variety of drug delivery strategies based on prodrugs have been developed. The application of drug delivery systems can optimize ADME properties of cytotoxic agents and improve their selectivity at the target, thereby greatly enhancing the anticancer effect in clinics. At present, it has become mainstream in drug design. This review systematically summarized the studies of prodrug-based drug delivery systems over the past five to ten years, according to four aspects, solubility, controlled release, in situ concentration, and targeting.

2.
Food Funct ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505612

RESUMO

The active compounds in star anise alcohol extractives (SAAE) have potent bioactivity. However, their poor solubility and stability limit their applications. In this study, SAAE/hydroxypropyl-ß-cyclodextrin (HP-ß-CD) inclusion complexes were prepared as a strategy to overcome the abovementioned disadvantages. The phase solubility results indicated that the solubility of the inclusion complex was enhanced. Complexation was confirmed by complementary methods, including Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, scanning electron microscopy, and transmission electron microscopy, which proved to be extremely insightful for studying the inclusion formation phenomenon between SAAE and HP-ß-CD. Despite there being no apparent improvements in the antioxidant capacity and antimicrobial activity, the results of the stability studies presented higher thermal, volatile, and photostability after encapsulation. Further, molecular modeling was used to investigate the factors influencing complex formation and provide the most stable molecular conformation. Thus, based on the obtained results, this study strongly demonstrates the potential of the SAAE/HP-ß-CD inclusion complex in the food industry.

3.
Anal Chim Acta ; 1178: 338847, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34482880

RESUMO

Photodynamic therapy has been generally developed and approved as a promising theranostic technique in recent years, which requires photosensitizers to bear high efficiency of reactive oxygen species production, precisely targeting ability and excellent biocompatibility. The real-time monitoring the microenvironments such as viscosity dynamic involved in mitophagy mediated by photodynamic therapy is significantly important to understand therapeutic process but barely reported. In this work, a pyridinium-functionalized triphenylamine derivative, (E)-4-(2-(4'-(diphenylamino)-[1,1'-biphenyl]-4-yl)vinyl)-1-methylpyridin-1-ium iodide (Mito-I), was exploited as photosensitizer for mitochondria-targeted photodynamic therapy and as fluorescent probe for imaging the mitochondrial viscosity dynamic during mitophagy simultaneously. The results indicated that the additional phenyl ring in Mito-I was beneficial to promote its efficiency of singlet oxygen production. The excellent capability of targeting mitochondria and singlet oxygen generation allowed Mito-I for the specifically mitochondria-targeted photodynamic therapy. Moreover, Mito-I displayed off-on fluorescence response to viscosity with high selectivity and sensitivity. The observed enhancement in fluorescence intensity of Mito-I revealed the increasingly mitochondrial viscosity during mitophagy mediated by the photodynamic therapy of Mito-I. As a result, this work presents a rare example to realize the mitochondria-targeting photodynamic therapy as well as the real-time monitoring viscosity dynamic during mitophagy, which is of great importance for the basic medical research involved in photodynamic therapy.


Assuntos
Mitofagia , Fotoquimioterapia , Mitocôndrias , Fármacos Fotossensibilizantes/farmacologia , Viscosidade
4.
Obesity (Silver Spring) ; 29(1): 108-115, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34494373

RESUMO

OBJECTIVE: This study aimed to evaluate the effects of intermittent energy restriction (IER; only for 2-3 d/wk) versus continuous energy restriction (CER) on weight loss and metabolic outcomes in adults with overweight or obesity. METHODS: Methods included searching databases from the last decade to December 18, 2019, for randomized controlled trials (RCTs) that assessed weight loss and metabolic outcomes in IER and CER. RevMan version 5.3 software was used for statistical analysis of the data. The effect sizes were expressed as weight mean differences and 95% CI. RESULTS: This review included 11 RCTs (n = 850). Meta-analysis showed that IER had greater effects on absolute weight loss, the percentage of weight loss, and improving insulin sensitivity than CER. In the subgroup analysis, short-term (2-3 months) intervention (P < 0.0001) was associated with weight loss. CONCLUSIONS: This systematic review shows that IER (2-3 d/wk) had greater effects on short-term weight loss than CER and that IER results in comparative metabolic improvements. Furthermore, longer RCTs are needed to validate these findings.

5.
Chemosphere ; 283: 131278, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34467945

RESUMO

Production of MCFAs (Medium-chain fatty acids) from simple substrate (i.e., ethanol and acetate) and WAS with chain elongation microbiome was investigated in this study. The results showed that rapid production of MCFAs was observed when simple substrate was utilized. 1889 mg/L of caproate and 3434 mg/L of butyrate were achieved after 10 d's reaction. H2 proportion in the headspace could reach as high as 10.1% on day 8 and then declined quickly. However, when WAS was used, the bacterial consortia was not able to hydrolyze WAS efficiently, which resulted in poor MCFAs production performance. Presence of ethanol could improve the hydrolysis process to a limited degree, which resulted in solubilization of a small fraction of protein and carbohydrate. Around 33.8% and 36.9% of the total detected electrons on day 6 in the 50 mM and 100 mM tests were extracted from WAS respectively. Those results indicate that the chain elongation microbial consortia tended to receive electrons form ethanol directly other than the complex WAS.


Assuntos
Etanol , Esgotos , Elétrons , Ácidos Graxos , Fermentação
6.
Free Radic Biol Med ; 175: 141-154, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474107

RESUMO

AIMS: Chronic inflammation is a primary reason for type 2 diabetes mellitus (T2DM) and its complications, while disordered branched-chain amino acids (BCAA) metabolism is found in T2DM, but the link between BCAA catabolic defects and inflammation in T2DM remains elusive and needs to be investigated. METHODS: The changes in BCAA catabolism, inflammation, organ damage, redox status, and mitochondrial function in db/db mice with treatments of BCAA-overload or BCAA catabolism activator were analyzed in vivo. The changes in BCAA catabolic metabolism, as well as the direct effects of BCAAs/branched-chain alpha-keto acids (BCKAs) on cytokine release and redox status were also analyzed in primary macrophages in vitro. RESULTS: Inactivation of branched-chain ɑ-ketoacid dehydrogenase (BCKDH) complex was found in multiple organs (liver, muscle and kidney) of db/db mice. Long-term high BCAA supplementation further increased BCKA levels, inflammation, tissue fibrosis (liver and kidney), and macrophage hyper-activation in db/db mice, while enhancing BCAA catabolism with pharmacological activator reduced these adverse effects in db/db mice. In vitro, the BCAA catabolism was unchanged in primary macrophages of db/db mice, and elevated BCKAs but not BCAAs promoted the cytokine production in primary macrophages. Moreover, BCKA stimulation was associated with increased mitochondrial oxidative stress and redox imbalance in macrophages and diabetic organs. CONCLUSION: Impaired BCAA catabolism is strongly associated with chronic inflammation and tissue damage in T2DM, and this effect is at least partly due to the BCKAs-induced macrophage oxidative stress. This study highlights that targeting BCAA catabolism is a potential strategy to attenuate T2DM and its complications.

7.
Exp Cell Res ; 407(2): 112823, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506760

RESUMO

Cell transdifferentiation is the conversion of a cell type to another without requiring passage through a pluripotent cell state, and encompasses epithelial- and endothelial-mesenchymal transition (EMT and EndMT). EMT and EndMT are well defined processes characterized by a loss of epithelial/endothelial phenotype and gain in mesenchymal spindle shaped morphology, which results in increased cell migration and decreased apoptosis and cellular senescence. Such cells often develop invasive properties. Physiologically, these processes may occur during embryonic development and can resurface, for example, to promote wound healing in later life. However, they can also be a pathological process. In the eye, EMT, EndMT and cell transdifferentiation have all been implicated in development, homeostasis, and multiple diseases affecting different parts of the eye. Connexins, constituents of connexin hemichannels and intercellular gap junctions, have been implicated in many of these processes. In this review, we firstly provide an overview of the molecular mechanisms induced by transdifferentiation (including EMT and EndMT) and its involvement in eye diseases. We then review the literature for the role of connexins in transdifferentiation in the eye and eye diseases. The evidence presented in this review supports the need for more studies into the therapeutic potential for connexin modulators in prevention and treatment of transdifferentiation related eye diseases, but does indicate that connexin channel modulation may be an upstream and unifying approach for regulating these otherwise complex processes.

8.
Ecotoxicol Environ Saf ; 225: 112752, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34507041

RESUMO

The content of Cd, Cu, Pb, Zn, Cr, Ni and As from 250 soil samples was measured in agricultural soil of Ningxia section of the Yellow River. Positive matrix factorization (PMF) was to identify the main sources of these heavy metals; Sequential Gaussian Simulation (SGS) was to identify their spatial distribution and high-risk areas; and Human Health risk (HHR) model was to measure the health risk. Results showed that the average content of Cd and As exceeds the risk screening value of "Soil Environmental Quality-Agricultural Land Soil Pollution Risk Control Standard" (GB 15618-2018), which belongs to slight-level pollution. Although the content of other types of HMs (Cu, Pb, Zn, Cr, Ni) is below the risk screening value, they are still included heavily in the soil (except Cr). PMF indicated that mixed sources of agriculture and industry accounted for 27.06%, natural sources accounted for 14.12%, industrial sources accounted for 23.04%, traffic sources accounted for 21.50%, and Yellow River sedimentary sources accounted for 14.28%. PMF-HHR showed that the mixed sources of agriculture and industry are the most important factor causing non-carcinogenic risk (HI) to children (accounting for 55.75%). Industrial sources and traffic sources were the two main factors that cause HI to adults (industrial sources accounted for 25.16%, and traffic sources accounted for 28.78%). Mixed sources of agriculture and industry and natural sources were the two main factors that cause carcinogenic risk (CR) (mixed sources of agriculture and industry account for 35.34%, and natural sources account for 33.23%). SGS indicated that 0.64% and 9.32% of the total areas were posing as higher HI areas to children and adults respectively; in particular, 0.68% and 1.12% of the areas were identified as higher HI of As and Cr areas at a critical probability of 0.9.

9.
J Clin Anesth ; 75: 110504, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34509960

RESUMO

STUDY OBJECTIVE: To evaluate the impact of intensive glucose control on diabetic patients undergoing surgery. DESIGN: A systematic review and meta-analysis of randomized controlled trials. PubMed, CENTRAL, EMBASE, ISI Web of Science, and CINAHL databases were searched from inception to 13 December 2020. SETTING: Operating room, postoperative recovery area and ward, up to 30 days after surgery. PATIENTS: Diabetic patients undergoing surgery. INTERVENTIONS: We used Review Manager 5.4 to pool the data with a random-effects model. The quality of evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation system. MEASUREMENTS: The primary outcomes were infectious complications, postoperative mortality, and hypoglycaemia. The secondary outcomes included atrial fibrillation, myocardial infarction, stroke, delirium, renal failure, postoperative mechanical ventilation time, length of intensive care unit (ICU) stay, and hospital stay. MAIN RESULTS: Thirteen studies involving 1582 participants were included. Compared with conventional glucose control, intensive glucose control was associated with a lower risk of infectious complications (risk ratio [RR], 0.35; 95% confidence interval [CI], 0.19-0.63; low-quality evidence), atrial fibrillation (RR, 0.55; 95% CI, 0.42-0.71; high-quality evidence), and renal failure (RR, 0.38; 95% CI, 0.15-0.95; moderate-quality evidence), as well as a shorter length of stay in the ICU (mean difference (MD), -0.55 day; 95% CI, -1.05 to -0.05 days; very-low-quality evidence) and hospital (MD, -1.61 days; 95% CI, -2.78 to -0.44 days; very-low-quality evidence). However, intensive glucose control was associated with a higher risk of hypoglycaemia (RR, 3.00; 95% CI, 1.97-4.55; high-quality evidence). There were no significant differences in postoperative mortality, myocardial infarction, stroke, delirium, or postoperative mechanical ventilation time. CONCLUSIONS: Intensive glucose control in diabetic patients is associated with a reduction in some adverse postoperative outcomes including infectious complications, but also appears to increase the risk of hypoglycaemia. Further well-designed studies may be needed to determine appropriate regimens to reduce hypoglycaemia incidence. PROSPERO REGISTRATION NUMBER: CRD42021226138.

10.
Technol Cancer Res Treat ; 20: 15330338211041191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34520284

RESUMO

Lung cancer is listed as the most common reason for cancer-related death all over the world despite diagnostic improvements and the development of chemotherapy and targeted therapies. MicroRNAs control both physiological and pathological processes including development and cancer. A microRNA-9 to 1 (miR-9 to 1) overexpression model in lung cancer cell lines was established and miR-9 to 1 was found to significantly suppress the proliferation rate in lung cancer cell lines, colony formation in vitro, and tumorigenicity in nude mice of A549 cells. Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) was then identified to direct target of miR-9 to 1. The inhibition of UHRF1 by miR-9 to 1 causes G1 arrest and p15, p16, and p21 were re-expressed in miR-9 to 1 group in mRNA level and protein level. Silence of UHRF1 expression in A549 cells resulted in the similar re-expression of p15, p16, p21 which is similar with miR-9 to 1 infection. Therefore, we concluded that UHRF1 is a new target for miR-9 to 1 to suppress cell proliferation by re-expression of tumor suppressors p15, p16, and p21 mediated by UHRF1.

11.
Org Lett ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533966

RESUMO

Although transition-metal-catalyzed C-C bond activation has been investigated extensively, C-C bond cleavage manipulated by hydrogen transfer has been unexplored. In this work, we disclose a skeleton reorganization of alkene-tethered benzocyclobutenols through Rh-catalyzed C-C bond cleavage coupled with intra- and intermolecular hydrogen transfer. The reaction pathway was well-tuned by the catalytic systems. As a result, divergent benzofurans bearing 4-ß-hydroxy or 4-ß-keto moieties were synthesized under pH- and redox-neutral conditions.

12.
Vet Immunol Immunopathol ; 240: 110316, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34474261

RESUMO

CD4+ helper T cells play key and diverse roles in inducing adaptive immune responses in vertebrates. The CD4 molecule, which is found on the surfaces of CD4+ helper T cells, can be used to distinguish subsets of helper T cells. Teleosts are the oldest living species with bona-fide CD4 coreceptors. Although some components of immune systems of teleosts and mammals appear to be similar, many physiological differences are represented between them. Previous studies have shown that two CD4 paralogs are present in teleosts, whereas only one is present in mammals. Therefore, in this review, the CD4 molecular structure, expression profiles, subpopulations, and biological functions of teleost CD4+ helper T cells were summarized and compared with those of their mammalian counterparts to understand the differences in CD4 molecules between teleosts and mammals. This review provides suggestions for further studies on the CD4 molecular function and regulatory mechanism of CD4+ helper T cells in teleost fish and will help establish therapeutic strategies to control fish diseases in the future.

13.
Medicine (Baltimore) ; 100(36): e27178, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516515

RESUMO

ABSTRACT: Small nucleolar RNA host gene 16 (SNHG16) has recently been reported as a potential biomarker in various cancers. However, the prognostic value of SNHG16 in hepatocellular carcinoma (HCC) has not been investigated yet. Therefore, the purpose of this study was to reveal the association between SNHG16 expression and clinicopathological characteristics of HCC.Standards-compliant literature was retrieved from multiple public databases, and data on overall survival, disease-free survival, and clinicopathological characteristics related to SNGH16 were extracted and meta-analysis was performed. Additionally, the Cancer Genome Atlas data were analyzed through the gene expression profiling interactive analysis database to verify previous results.A total of 5 reports involving 410 patients with HCC were enrolled. The high expression of SNHG16 indicated worse overall survival (hazard ratio, 2.10; 95% CI, 1.22-3.60; P = .007) and disease-free survival (hazard ratio, 3.38; 95% CI, 1.10-10.40; P = .03). Additionally, the high expression of SNHG16 predicted a larger tumor size, metastasis, and advanced TNM stage.SNHG16 could serve as a potential biomarker of poor prognosis in HCC.

14.
Pharm Biol ; 59(1): 1256-1259, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34517743

RESUMO

CONTEXT: Pachymic acid and bavachin are commonly used drugs in the therapy of lung cancer. OBJECTIVE: The co-administration of pachymic acid and bavachin was investigated to evaluate their potential drug-drug interaction. MATERIALS AND METHODS: The pharmacokinetics of bavachin (10 mg/kg) was studied in male Sprague-Dawley (SD) rats in the presence of pachymic acid (5 mg/kg) (n = 6). The rats without pre-treatment of pachymic acid were set as the control and the pre-treatment of pachymic acid was conducted for 7 days before the administration of bavachin. The effect of pachymic acid on the activity of CYP2C9 was also estimated in rat liver microsomes with corresponding probe substrates. RESULTS: Pachymic acid influenced the pharmacokinetic profile of bavachin with the increased AUC (32.82 ± 4.61 vs. 19.43 ± 3.26 µg/L/h), the prolonged t1/2 (3.21 ± 0.65 vs. 2.32 ± 0.28 h), and the decreased CLz/F (307.25 ± 44.35 vs. 523.81 ± 88.67 L/h/kg) in vivo. The metabolic stability of bavachin was enhanced by pachymic acid and the transport of bavachin was inhibited by pachymic acid. Pachymic acid was found to inhibit the activity of CYP2C9 with the IC50 of 21.25 µM as well as the activity of P-gp. DISCUSSION AND CONCLUSION: The interaction between pachymic acid and bavachin results from the inhibition of CYP2C9 and P-gp. The dose of bavachin should be adjusted when combining with pachymic acid. The study design can be generalized to a broader study population with adjustment in the dose.

16.
J Pediatr ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34508748

RESUMO

OBJECTIVE: To determine the effects of maternal periconceptional supplementation with folic acid or multiple micronutrients containing FA on the prevention of fetal congenital heart defects (CHDs). STUDY DESIGN: Data were drawn from a Prenatal Health Care System and a Birth Defects Surveillance System in a district of Beijing, China. A total of 63,969 singleton births, live or stillborn, 308 CHDs among them, during 2013 to 2018 were included. Associations between different patterns of supplementation and risk for total CHDs or main types of CHDs were evaluated with risk ratios (RRs). RESULTS: For FA or MMFA users compared with nonusers, the adjusted risk ratios (ARRs) for total CHDs, critical CHD, and ventricular septal defect (VSD) were 0.60 (95% confidence interval [CI]: 0.44-0.83), 0.41 (95%CI: 0.26-0.67), and 0.47 (95%CI: 0.30-0.74), respectively. When we compared MMFA users with FA users, the ARRs were 0.84 (95%CI: 0.66-1.09), 0.64 (95%CI: 0.41-1.00), and 0.94 (95%-CI: 0.63-1.41) for total CHDs, critical CHD, and VSD, respectively. We also found that compared with supplementation initiated after conception, supplementation initiated before conception was associated with a lower risk for CHDs: the ARRs were 0.68 (95%CI: 0.48-0.95) for total CHDs and 0.26 (95%CI: 0.10-0.71) for critical CHD but 1.08 (95%CI: 0.63-1.83) for VSD. CONCLUSION: Maternal periconceptional supplementation with FA or MMFA appears to reduce the risk for CHDs, especially critical CHD, in offspring. Supplementation confers a greater protective effect when it is initiated before conception. We did not find any difference between FA and MMFA in terms of preventing CHDs.

17.
Sci Prog ; 104(3): 368504211038162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34519556

RESUMO

Fully convolutional networks were developed for predicting optimal dose distributions for patients with left-sided breast cancer and compared the prediction accuracy between two-dimensional and three-dimensional networks. Sixty cases treated with volumetric modulated arc radiotherapy were analyzed. Among them, 50 cases were randomly chosen to conform the training set, and the remaining 10 were to construct the test set. Two U-Net fully convolutional networks predicted the dose distributions, with two-dimensional and three-dimensional convolution kernels, respectively. Computed tomography images, delineated regions of interest, or their combination were considered as input data. The accuracy of predicted results was evaluated against the clinical dose. Most types of input data retrieved a similar dose to the ground truth for organs at risk (p > 0.05). Overall, the two-dimensional model had higher performance than the three-dimensional model (p < 0.05). Moreover, the two-dimensional region of interest input provided the best prediction results regarding the planning target volume mean percentage difference (2.40 ± 0.18%), heart mean percentage difference (4.28 ± 2.02%), and the gamma index at 80% of the prescription dose are with tolerances of 3 mm and 3% (0.85 ± 0.03), whereas the two-dimensional combined input provided the best prediction regarding ipsilateral lung mean percentage difference (4.16 ± 1.48%), lung mean percentage difference (2.41 ± 0.95%), spinal cord mean percentage difference (0.67 ± 0.40%), and 80% Dice similarity coefficient (0.94 ± 0.01). Statistically, the two-dimensional combined inputs achieved higher prediction accuracy regarding 80% Dice similarity coefficient than the two-dimensional region of interest input (0.94 ± 0.01 vs 0.92 ± 0.01, p < 0.05). The two-dimensional data model retrieves higher performance than its three-dimensional counterpart for dose prediction, especially when using region of interest and combined inputs.

18.
Med Sci Monit ; 27: e932725, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34521804

RESUMO

BACKGROUND We designed this study to develop and validate a prevalence model for latent autoimmune diabetes in adults (LADA) among people initially diagnosed with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The study recruited 930 patients aged ≥18 years who were diagnosed with T2DM within the past year. Demographic information, medical history, and clinical biochemistry records were collected. Logistic regression was used to develop a regression model to distinguish LADA from T2DM. Predictors of LADA were identified in a subgroup of patients (n=632) by univariate logistic regression analysis. From this we developed a prediction model using multivariate logistic regression analysis and tested its sensitivity and specificity among the remaining patients (n=298). RESULTS Among 930 recruited patients, 880 had T2DM (96.4%) and 50 had LADA (5.4%). Compared to T2DM patients, LADA patients had fewer surviving b cells and reduced insulin production. We identified age, ketosis, history of tobacco smoking, 1-hour plasma glucose (1hPG-AUC), and 2-hour C-peptide (2hCP-AUC) as the main predictive factors for LADA (P<0.05). Based on this, we developed a multivariable logistic regression model: Y=-8.249-0.035(X1)+1.755(X2)+1.008(X3)+0.321(X4)-0.126(X5), where Y is diabetes status (0=T2DM, 1=LADA), X1 is age, X2 is ketosis (1=no, 2=yes), X3 is history of tobacco smoking (1=no, 2=yes), X4 is 1hPG-AUC, and X5 is 2hCP-AUC. The model has high sensitivity (78.57%) and selectivity (67.96%). CONCLUSIONS This model can be applied to people newly diagnosed with T2DM. When Y ≥0.0472, total autoantibody screening is recommended to assess LADA.

19.
Acta Pharmacol Sin ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522005

RESUMO

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

20.
Environ Sci Technol ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523345

RESUMO

A modified community multiscale air quality model, which can simulate the regional distributions of 2,3-dihydroxy-4-oxopentanoic acid (DHOPA), a marker species for monoaromatic secondary organic aerosol (SOA), was applied to assess the applicability of using the DHOPA to aromatic SOA mass ratio (fSOA) from smog chamber experiments to estimate aromatic SOA during a three-week wintertime air quality campaign in urban Shanghai. The modeled daily DHOPA concentrations based on the chamber-derived mass yields agree well with the organic marker field measurements (R = 0.79; MFB = 0.152; and MFE = 0.440). Two-thirds of the DHOPA are from the oxidation of ARO1 (lumped less-reactive aromatic species; mostly toluene), with the rest from ARO2 (lumped more-reactive aromatic species; mostly xylenes). Modeled DHOPA is mainly in the particle phase under ambient organic aerosol (OA) loading but could exhibit significant gas-particle partitioning when a higher estimation of the DHOPA vapor pressure is used. The modeled fSOA shows a strong dependence on the OA loading when only semivolatile aromatic SOA components are included in the fSOA calculations. However, this OA dependence becomes weaker when non-volatile oligomers and dicarbonyl SOA products are considered. A constant fSOA value of ∼0.002 is determined when all aromatic SOA components are included, which is a factor of 2 smaller than the commonly applied chamber-based fSOA value of 0.004 for toluene. This model-derived fSOA value does not show much spatial variation and is not sensitive to alternative estimates of DHOPA vapor pressures and SOA yields, and thus provides an appropriate scaling factor to assess aromatic SOA from DHOPA measurements. This result helps refine the quantification of SOA attributable to monoaromatic hydrocarbons in urban environments and thereby facilitates the evaluation of control measures targeting these specific precursors.

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