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1.
Mol Cancer ; 21(1): 37, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35130920

RESUMO

PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.


Assuntos
Antineoplásicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Carcinoma de Células de Transição/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
2.
RSC Adv ; 12(36): 23240-23251, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-36090389

RESUMO

Cardiac glycosides (CGs) are good candidates as drug leads in the treatment of cancer because of their structural diversities and potent biological activities. In this study, fifteen CGs including three new ones (1-3) were isolated from Digitalis lanata Ehrh. Their structures were elucidated by HRESIMS, NMR spectroscopic methods, including homonuclear and heteronuclear coupling constant analysis, and acid-catalyzed hydrolysis and derivatization analysis of the sugar chain. The cytotoxic activities of these CGs were evaluated against three human cancer cell lines (A549, HeLa and MCF-7 cell lines), and all of them showed strong activities at nanomolar scale. The flow cytometric analysis indicated that compound 1 induced cell cycle arrest in the G2/M phase. Transcriptome analysis revealed a panel of possible targets for compound 1. RT-PCR and western blot experiments showed that 1 significantly inhibited the expression of vasohibin-2 (VASH2). Moreover, compound 1 restrained angiogenesis in a concentration-dependent manner in the chick embryo chorioallantoic membrane (CAM) model.

3.
Front Neurol ; 13: 955271, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36090880

RESUMO

Background: Stroke-associated pneumonia (SAP) contributes to high mortality rates in spontaneous intracerebral hemorrhage (sICH) populations. Accurate prediction and early intervention of SAP are associated with prognosis. None of the previously developed predictive scoring systems are widely accepted. We aimed to derive and validate novel supervised machine learning (ML) models to predict SAP events in supratentorial sICH populations. Methods: The data of eligible supratentorial sICH individuals were extracted from the Risa-MIS-ICH database and split into training, internal validation, and external validation datasets. The primary outcome was SAP during hospitalization. Univariate and multivariate analyses were used for variable filtering, and logistic regression (LR), Gaussian naïve Bayes (GNB), random forest (RF), K-nearest neighbor (KNN), support vector machine (SVM), extreme gradient boosting (XGB), and ensemble soft voting model (ESVM) were adopted for ML model derivations. The accuracy, sensitivity, specificity, and area under the curve (AUC) were adopted to evaluate the predictive value of each model with internal/cross-/external validations. Results: A total of 468 individuals with sICH were included in this work. Six independent variables [nasogastric feeding, airway support, unconscious onset, surgery for external ventricular drainage (EVD), larger sICH volume, and intensive care unit (ICU) stay] for SAP were identified and selected for ML prediction model derivations and validations. The internal and cross-validations revealed the superior and robust performance of the GNB model with the highest AUC value (0.861, 95% CI: 0.793-0.930), while the LR model had the highest AUC value (0.867, 95% CI: 0.812-0.923) in external validation. The ESVM method combining the other six methods had moderate but robust abilities in both cross-validation and external validation and achieved an AUC of 0.843 (95% CI: 0.784-0.902) in external validation. Conclusion: The ML models could effectively predict SAP in sICH populations, and our novel ensemble model demonstrated reliable robust performance outcomes despite the populational and algorithmic differences. This attempt indicated that ML application may benefit in the early identification of SAP.

4.
Shanghai Kou Qiang Yi Xue ; 31(2): 217-220, 2022 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-36110084

RESUMO

PURPOSE: To explore the law of development and existing problems in prosthodontics teaching in the new era, through flipped classroom teaching based on WeChat public platform. METHODS: WeChat public number was applied and WeChat groups were set up among the students of grade 2013, and 93 students were divided into 20 WeChat groups, with 4 to 5 students in each group. The main platform on reform of prosthodontics teaching was WeChat app, supplemented by platforms of Lediaocha and Youkaoshi. Teachers published courseware and learning resources with WeChat public number and WeChat groups. Two-dimensional codes on questionnaires and tests which were generated by Lediaocha and Youkaoshi could be published with WeChat and the final learning effectiveness was compared using SPSS 19.0 software package for t test. RESULTS: The results showed that 59.1% students admitted WeChat teaching effective, only 5.4% students believed ineffective. Based upon partial chapters of prosthodontics, the score of classroom test (91.35±4.45) was significantly higher than that of pre-class test(90.14±5.03, P<0.05). CONCLUSIONS: The reform of flipped classroom based on WeChat platform in prosthodontics have some advantages, such as more flexibility in teaching form and time arrangement, promoting students' learner autonomy, and increasing students' motivation and effects of learning prosthodontics.


Assuntos
Aprendizagem , Prostodontia , Humanos , Estudantes , Inquéritos e Questionários
5.
Int J Biol Macromol ; 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36116598

RESUMO

The golden-needle mushroom Flammulina filiformis is one of the bulk mushroom products in the world. This study obtained complete mitogenomes of 44 wild isolates collected from nine provinces and two artificially bred cultivars of F. filiformis, together with three Flammulina rossica isolates and one Flammulina fennae isolate for comparison. The mitogenome of F. filiformis ranged from 83,540 bp to 90,938 bp, consisting of 14 conserved protein-coding genes (PCGs), two rRNA genes, and 25 tRNA genes. To the best of our knowledge, it contained the highest proportion of intergenic regions compared to the other known Basidiomycota mitogenomes. Introns and intergenic regions were two major contributing factors to the total size of the F. filiformis mitogenome. The conserved PCG cox3 is located in an intron of another conserved PCG, nad5. This is a unique phenomenon in all known fungal mitogenomes. Gain/loss of introns was observed in cox1, nad5, and rnl. Length polymorphism was widely observed in intergenic regions. Accordingly, primers were designed as useful markers for rapid identification of F. filiformis isolates with differentiated mitogenomes. Our findings provide a basis for further studies related to variety identification and population genetics of this economically important mushroom.

6.
PeerJ ; 10: e14028, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36124133

RESUMO

Mycorrhizal fungi can form symbiotic associations with tree species, which not only play an important role in plant survival and growth, but also in soil carbon (C) and nitrogen (N) cycling. However, the understanding of differences in soil C and N cycling patterns among forests with different mycorrhizal types is still incomplete. In order to determine the similarities and differences of soil C and N cycling patterns in different mycorrhizal forest types, three primary forests dominated by ectomycorrhizal (EcM), arbuscular mycorrhizal (AM) and ericoid mycorrhizal (ErM) trees respectively were studied on the eastern Qinghai-Tibetan Plateau. Indicators associated with soil C and N cycling, including leaf litter quality, soil C and N contents, soil C and N fluxes, and soil microbial biomass C and N contents were measured in each mycorrhizal type forest. The results showed that leaf litter quality was significantly lower with high C:N ratio and lignin: N ratio in ErM forest than that in AM and EcM forests. Soil CO2 flux (508.25 ± 65.51 mg m-2 h-1) in AM forest was significantly higher than that in EcM forest (387.18 ± 56.19 mg m-2 h-1) and ErM forest (177.87 ± 58.40 mg m-2 h-1). Furthermore, soil inorganic N content was higher in the AM forest than that in EcM and ErM forests. Soil net N mineralization rate (-0.02 ± 0.03 mg kg-1 d-1) was lower in ErM forest than that in EcM and AM forests. We speculated that AM and EcM forests were relatively characterized by rapid soil C cycling comparing to ErM forest. The soil N cycling in EcM and ErM forests were lower, implying they were 'organic' N nutrition patterns, and the pattern in ErM forest was more obvious.

7.
Bioorg Med Chem ; 73: 117008, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36126445

RESUMO

Quercetin (Que), a polyphenolic flavonoid compound with antioxidant properties has been explicated to have neuroprotective effects on neuronal injury/neurodegenerative diseases. However, low water-solubility, instability and inability to cross the blood-brain barrier (BBB) imped its application. To enhance the neuroprotective effects and improve the potential application of quercetins as a nutraceutical or medicine, we designed and synthesized two types of glycosylated quercetins--Glu-Que and 2Glu-Que through click reaction. Glu-Que and 2Glu-Que improved the water solubility and stability of quercetin, as well as alleviating H2O2-induced neurotoxicity by increasing the cell viability of PC12 cells and reducing the ROS generation. What's more, glycosylated quercetins enhanced neuroprotective effects on cerebral ischemia-reperfusion (I/R). Among the two types of glycosylated quercetin, 2Glu-Que displayed higher neuroprotective potential than Glu-Que. In conclusion, the glycosylated quercetin 2Glu-Que, with better water solubility, bioavailability and brain-targeting ability, significantly enhanced the neuroprotective effects of quercetin, making it a promising nutraceutical or candidate drug in neuroprotection.

8.
Spectrochim Acta A Mol Biomol Spectrosc ; 285: 121842, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36126619

RESUMO

As a mature platform compound, citric acid (CA) is mainly produced by Aspergillus niger (A. niger) through submerged fermentation. However, the CA fermentation process is still regulated based on experience and limited offline data, so real-time monitoring and intelligent precise control of the fermentation process cannot be carried out. In this study, near-infrared (NIR) spectroscopy combined with different chemometrics methods was used to quantify the substrate, product, and cell concentration of CA fermentation online. The predictive performance of total sugar (TS), CA, and dry cell weight (DCW) concentrations were compared between traditional partial least squares (PLS) and intelligent stacked auto-encoder (SAE) modeling methods. Theresults showed that both PLS and SAE models had good performance in predicting TS and CA. The performance, accuracy, and precision of the PLS models are slightly better than those of the SAE models in predicting TS and CA. SAE model was superior to the PLS model in predicting DCW concentration. The SAE modeling method has advantages in predicting the concentration of complex components. In this study, the multi-parameter online prediction was realized in the complex system of CA fermentation, which provided the basis for real-time intelligent control of the fermentation process.

10.
BMC Pulm Med ; 22(1): 347, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114533

RESUMO

BACKGROUND: Few studies have implied the incidence of diaphragmatic hernia (DH) after spontaneous pneumothorax (SP) with unknown mechanisms. The current study aimed to identify whether there is an association between the DH and SP. METHODS: We selected 46,897 patients with SP (SP cohort) and 46,897 without SP (non-SP matched cohort) from the National Health Insurance Database. Patients were frequency matched according to age, sex, and index year. The incidence of DH and its association with SP were assessed after stratifying different characteristics and comorbidities. Statistical analysis including chi-square test, t-test, cox proportional hazard model, and Kaplan-Meier method were used. RESULTS: The results suggested there were significant associations between SP and DH, especially in the subgroup of patients with older age (aged 40-64 years: 2.61-fold in adjusted hazard ratio (aHR), 95% confidence interval (CI): 1.27-5.36; aged > 65 years: 1.97-fold in aHR, 95% CI 1.43-2.71), male sex (2.11-fold in aHR, 95% CI 1.56-2.85), hypertension (2.05-fold in aHR, 95% CI 1.30-3.23), diabetes mellitus (2.58-fold in aHR, 95% CI 1.37-4.86), and smoking-related disease (1.86-fold in aHR, 95% CI 1.28-2.71). The SP cohort has significantly correlated with DH within 5-year follow-up (< 2 years: 3.22-fold in aHR, 95% CI 2.10-4.94; 2-5 years: 1.70-fold in aHR, 95% CI 1.05-2.75). CONCLUSIONS: The SP cohort had a higher incidence of DH than the non-SP matched cohort. A prospective study of indications based on the findings of the current research should be performed.


Assuntos
Hérnia Diafragmática , Pneumotórax , Humanos , Masculino , Pneumotórax/epidemiologia , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco
11.
FASEB J ; 36(10): e22538, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36065631

RESUMO

Antipsychotic agents are clinically utilized to treat schizophrenia and other mental disorders. These drugs induce neurological and metabolic side effects, but their influence on blood vessels remains largely unknown. Here, we show that haloperidol, one of the most frequently prescribed antipsychotic agents, induces vascular defects in bone marrow. Acute haloperidol treatment results in vascular dilation that is specific to hematopoietic organs. This vessel dilation is associated with disruption of hematopoiesis and hematopoietic stem/progenitor cells (HSPCs), both of which are reversible after haloperidol withdrawal. Mechanistically, haloperidol treatment blocked the secretion of vascular endothelial growth factor A (VEGF-A) from HSPCs. Genetic blockade of VEGF-A secretion from hematopoietic cells or inhibition of VEGFR2 in endothelial cells result in similar vessel dilation in bone marrow during regeneration after irradiation and transplantation. Conversely, VEGF-A gain of function rescues the bone marrow vascular defects induced by haloperidol treatment and irradiation. Our work reveals an unknown effect of antipsychotic agents on the vasculature and hematopoiesis with potential implications for drug application in clinic.


Assuntos
Antipsicóticos , Fator A de Crescimento do Endotélio Vascular , Antipsicóticos/farmacologia , Células da Medula Óssea/metabolismo , Células Endoteliais/metabolismo , Haloperidol/metabolismo , Haloperidol/farmacologia , Hematopoese/fisiologia , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Am J Transl Res ; 14(8): 5915-5922, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105043

RESUMO

OBJECTIVE: To retrospectively analyze the effects of dexmedetomidine after induction of anesthesia on intraoperative indices in patients with esophageal cancer. METHODS: The clinical data of 93 patients with esophageal cancer that admitted to our hospital from January 2019 to December 2020 were retrospectively analyzed. The patients were divided into control group (n=31), case group A (n=31, continuous intravenous infusion of 0.3 µg/(kg∙h) dexmedetomidine hydrochloride) and case group B (n=31, continuous intravenous infusion of 0.5 µg/(kg∙h) dexmedetomidine hydrochloride) according to the application condition of dexmedetomidine hydrochloride. Heart rate, blood pressure, arterial blood gas indicators (all measured by blood gas analyzer), respiratory mechanics index (measured by mechanical ventilation), ephedrine and atropine utilization rate of the three groups were compared. RESULTS: The plateau pressure, peak pressure and airway resistance at the end of one-lung ventilation and at chest closure in case groups A and B were lower than those in the control group, and the pulmonary compliance in case group B was higher than that in the control group (P < 0.05). PaO2, P(A-a)O2, and RI before the start of OLV, at the end of OLV, and at chest closure in the three groups were significantly increased compared with those before induction of anesthesia (P < 0.05). Compared with the control group, PaO2 significantly increased, while P(A-a)O2 and RI significantly decreased at the end of OLV and at chest closure in the case group B. CONCLUSION: Dexmedetomidine can improve respiratory dynamics and arterial blood gas indices after anesthesia induction of esophageal cancer, showing high safety and clinical feasibility.

13.
Fish Physiol Biochem ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114399

RESUMO

Magnolia denudata is a well-known ornamental tree in China due to its beautiful blossoms, and it has been used as an analgesic to treat human headaches. This study investigated the anesthetic potential and physiological response of the essential oil of M. denudata flowers on spotted seabass Lateolabrax maculatus. Fish (mean ± SD, 164.16 ± 15.40 g) were individually exposed to different concentrations of M. denudata essential oil (MDO, 10, 20, 40, 60, 80, 100, and 120 mg/L) and eugenol (10, 20, 30, 40, 50, 60, and 70 mg/L) to investigate anesthetic efficacy. Based on the ideal time criterion for anesthetic induction (< 3 min) and recovery (< 10 min), the lowest effective concentration for spotted seabass was 100 mg/L for MDO and 60 mg/L for eugenol. The physiological and histopathological damage in the gill of L. maculatus after using MDO and eugenol was also evaluated at the minimum dose inducing deep anesthesia, and at 0, 6, and 24 h after recovery. The results showed that MDO and eugenol anesthesia alleviated the levels of cortisol and glucose and the lactic dehydrogenase activity induced by handling. Compared with eugenol, MDO also caused secondary stress to the body, but MDO caused minor physiological responses and histological changes in the gills. This study suggests that MDO is an effective anesthetic for spotted seabass.

14.
Cancer Sci ; 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36114749

RESUMO

Lung cancer is one of the leading causes of death among cancer patients worldwide. Carbo-ion radiotherapy is a radical non-surgical treatment with high local control rates and no serious adverse events. N6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic messenger RNAs (mRNAs), which has important effects on the stability, splicing and translation of mRNAs. Recently, the regulatory role of m6A in tumorigenesis has been recognized more and more. However, the dysregulation of m6A and its role in carbo-ion radiotherapy of non-small cell lung cancer (NSCLC) remains unclear. In this study, we found that the level of Methyltransferase-like 3 (METTL3) and its mediated m6A modification were elevated in the NSCLC cells with carbo-ion radiotherapy. Knockdown of METTL3 in NSCLC cells impaired the proliferation, migration, and invasion in vitro and in vivo. Moreover, we found that METTL3 mediated m6A modification mRNA inhibit the decay of H2AX mRNA and enhance its expression, which lead to the enhanced DNA damage repair and cell survival.

15.
Microb Pathog ; : 105765, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36087690

RESUMO

An accumulating trend of research demonstrates that diabetic patients are susceptible to skin infections with Candida albicans, but the mechanism still remains unclear. The intense oxidative stress (OS) responses were occurred in the lesion of diabetic mice footpads after C. albicans infection. Localised skin infections would lead to more severe complications while the severity of the condition worsens or the inadequate treatment. Notably, in this study, through the investigation of murine diabetic footpad C. albicans infection model and molecular biotechnology, including histopathological staining, immunofluorescence (IF) staining, quantitative real-time PCR (qPCR), western blot (WB), flow cytometry (FCM), sandwich enzyme-linked immunosorbent assay (ELISA) assays, we found that intense OS responses in the footpad tissue not only mediated the activation of NF-κB protein complex, but also triggered downstream pyroptosis and apoptosis through NLRP3 inflammasome, which is one of the potential reasons for the severe condition of infectious skin injuries in diabetic mice. Caspase-1, a classical signal pathway protein in pyroptosis, could promote pore formation on cell membranes and the release of the cytokine after NLRP3 inflammasome activation. With intense immune-inflammatory responses, the organism also stimulates immune organs such as the spleen and lymph nodes to produce negative feedback regulation and generate CD4+CD25+Foxp3+ Treg cells to rectify the process. Therefore, combined with the results of this work, it is possible to design and screen relevant drugs for NLRP3 inflammasomes as core targets to keep the OS response at a low level in the footpad tissues.

16.
Clin Res Hepatol Gastroenterol ; 46(8): 101531, 2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36057185

RESUMO

Since the description of the PRSS1 gene encoding the cationic trypsinogen as being involved in dominant hereditary pancreatitis, more than 50 PRSS1 gene variants have been reported. Among those that have been classified as pathogenic, some have a high penetrance and others have a low penetrance. Assessing the clinical relevance of PRSS1 variants is often complicated in the absence of functional evidence and interpretation regarding rare variants is not very easy in clinical practice. The aim of this study was to review the PRSS1 variants and to classify them according to their degree of deleterious effect. This classification was based on the results of in vitro experiments and on population data, in comparing the allelic frequency of each variant in patients with pancreatitis and in unaffected individuals. This review should help geneticists and clinicians in charge of patient's care and genetic counseling to interpret results of genetic studies.

17.
Front Immunol ; 13: 964138, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091018

RESUMO

Macrophages and microglia play important roles in chronic neuroinflammation following spinal cord injury (SCI). Although macrophages and microglia have similar functions, their phagocytic and homeostatic abilities differ. It is difficult to distinguish between these two populations in vivo, but single-cell analysis can improve our understanding of their identity and heterogeneity. We conducted bioinformatics analysis of the single-cell RNA sequencing dataset GSE159638, identifying apolipoprotein E (APOE) as a hub gene in both macrophages and microglia in the subacute and chronic phases of SCI. We then validated these transcriptomic changes in a mouse model of cervical spinal cord hemi-contusion and observed myelin uptake, lipid droplets, and lysosome accumulation in macrophages and microglia following SCI. Finally, we observed that knocking out APOE aggravated neurological dysfunction, increased neuroinflammation, and exacerbated the loss of white matter. Targeting APOE and the related cholesterol efflux represents a promising strategy for reducing neuroinflammation and promoting recovery following SCI.


Assuntos
Microglia , Traumatismos da Medula Espinal , Animais , Apolipoproteínas E/genética , Biologia Computacional , Macrófagos , Camundongos , Doenças Neuroinflamatórias , Traumatismos da Medula Espinal/genética
18.
J Neurosci ; 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109166

RESUMO

Diabetic neuropathic pain (DNP) is a diabetes complication experienced by many patients. Ventrolateral periaqueductal gray (vlPAG) neurons are essential mediators of the descending pain modulation system, yet the role of vlPAG astrocytes in DNP remains unclear. The present study applied a multidimensional approach to elucidate the role of these astrocytes in DNP. We verified the activation of astrocytes in different regions of the PAG in male DNP-model rats. We found that only astrocytes in the vlPAG exhibited increased growth. Furthermore, we described differences in vlPAG astrocyte activity at different time points during DNP progression. After the 14th day of modeling, vlPAG astrocytes exhibited obvious activation and morphological changes. Furthermore, activation of Gq-DREADDs in vlPAG astrocytes in naive male rats induced neuropathic pain-like symptoms and pain-related aversion, whereas activation of Gi-DREADDs in vlPAG astrocytes in male DNP-model rats alleviated sensations of pain and promoted pain-related preference behavior. Thus, bidirectional manipulation of vlPAG astrocytes revealed their potential to regulate pain. Surprisingly, activation of Gi-DREADDs in vlPAG astrocytes also mitigated anxiety-like behavior induced by DNP. Thus, our results provide direct support for the hypothesis that vlPAG astrocytes regulate diabetes-associated neuropathic pain and concomitant anxiety-like behavior.Significance Statement:Many studies examined the association between the vlPAG and neuropathic pain. However, few studies have focused on the role of vlPAG astrocytes in DNP and DNP-related emotional changes. This work confirmed the role of vlPAG astrocytes in DNP by applying a more direct and robust approach. We utilized chemogenetics to bidirectionally manipulate the activity of vlPAG astrocytes and revealed that vlPAG astrocytes regulate DNP and pain-related behavior. In addition, we discovered that activation of Gi-DREADDs in vlPAG astrocytes alleviated anxiety-like behavior induced by DNP. Taken together, these findings provide new insights into DNP and concomitant anxiety-like behavior and supply new therapeutic targets for treating DNP.

19.
Environ Sci Technol ; 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36112513

RESUMO

Arsenic methylation contributes to the formation and diversity of environmental organoarsenicals, an important process in the arsenic biogeochemical cycle. The arsM gene encoding an arsenite (As(III)) S-adenosylmethionine (SAM) methyltransferase is widely distributed in members of every kingdom. A number of ArsM enzymes have been shown to have different patterns of methylation. When incubated with inorganic As(III), Burkholderia gladioli GSRB05 has been shown to synthesize the organoarsenical antibiotic arsinothricin (AST) but does not produce either methylarsenate (MAs(V)) or dimethylarsenate (DMAs(V)). Here, we show that cells of B. gladioli GSRB05 synthesize DMAs(V) when cultured with either MAs(III) or MAs(V). Heterologous expression of the BgarsM gene in Escherichia coli conferred resistance to MAs(III) but not As(III). The cells methylate MAs(III) and the AST precursor, reduced trivalent hydroxyarsinothricin (R-AST-OH) but do not methylate inorganic As(III). Similar results were obtained with purified BgArsM. Compared with ArsM orthologs, BgArsM has an additional 37 amino acid residues in a linker region between domains. Deletion of the additional 37 residues restored As(III) methylation activity. Cells of E. coli co-expressing the BgarsL gene encoding the noncanonical radical SAM enzyme that catalyzes the synthesis of R-AST-OH together with the BgarsM gene produce much more of the antibiotic AST compared with E. coli cells co-expressing BgarsL together with the CrarsM gene from Chlamydomonas reinhardtii, which lacks the sequence for additional 37 residues. We propose that the presence of the insertion reduces the fitness of B. gladioli because it cannot detoxify inorganic arsenic but concomitantly confers an evolutionary advantage by increasing the ability to produce AST.

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