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1.
BMC Psychiatry ; 22(1): 588, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064380

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a common cause of disability and morbidity, affecting about 10% of the population worldwide. Subclinical depression (SD) can be understood as a precursor of MDD, and therefore provides an MDD risk indicator. The pathogenesis of MDD and SD in humans is still unclear, and the current diagnosis lacks accurate biomarkers and gold standards. METHODS: A total of 40 MDD, 34 SD, and 40 healthy control (HC) participants matched by age, gender, and education were included in this study. Resting-state functional magnetic resonance images (rs-fMRI) were used to analyze the functional connectivity (FC) of the posterior parietal thalamus (PPtha), which includes the lateral habenula, as the region of interest. Analysis of variance with the post hoc t-test test was performed to find significant differences in FC and clarify the variations in FC among the HC, SD, and MDD groups. RESULTS: Increased FC was observed between PPtha and the left inferior temporal gyrus (ITG) for MDD versus SD, and between PPtha and the right ITG for SD versus HC. Conversely, decreased FC was observed between PPtha and the right middle temporal gyrus (MTG) for MDD versus SD and MDD versus HC. The FC between PPtha and the middle frontal gyrus (MFG) in SD was higher than that in MDD and HC. Compared with the HC group, the FC of PPtha-ITG (left and right) increased in both the SD and MDD groups, PPtha-MTG (right) decreased in both the SD and MDD groups and PPtha-MFG (right) increased in the SD group and decreased in the MDD group. CONCLUSION: Through analysis of FC measured by rs-fMRI, the altered FC between PPtha and several brain regions (right and left ITG, right MTG, and right MFG) has been identified in participants with SD and MDD. Different alterations in FC between PPtha and these regions were identified for patients with depression. These findings might provide insights into the potential pathophysiological mechanisms of SD and MDD, especially related to PPtha and the lateral habenula.


Assuntos
Transtorno Depressivo Maior , Habenula , Encéfalo , Mapeamento Encefálico , Depressão , Habenula/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos
2.
Oncol Lett ; 24(4): 343, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36072009

RESUMO

Pulmonary sarcomatoid carcinoma (PSC) is a rare form of poorly differentiated non-small-cell lung cancer that is prone to distant metastases. PSC is therapeutically challenging, with low sensitivity to conventional radiotherapy and a poor overall prognosis. The present study reported on the case of a 29-year-old male non-smoker diagnosed with both PSC and lung adenocarcinoma; the cancer had a complex etiology and rapidly metastasized after surgery. The patient presented with an EML4-ALK gene fusion in both tumors with high programmed death ligand-1 (PD-L1) expression. After initial treatment failure, Alectinib, Anlotinib and Tirelizumab were combined, which rapidly resolved the patient's symptoms and led to partial remission of disease at 6 weeks and effective control of the disease 7 months into the treatment. This case exemplifies the efficacy of combining targeted chemotherapy with immunotherapy for patients with PSC. Furthermore, this outcome suggests the usefulness of genetic testing and monitoring PD-L1 expression to identify patients with PSC who may be candidates likely to respond to this combined therapeutic regimen. The present study provides evidence of the success of a novel therapeutic strategy for patients with PSC.

3.
Transl Psychiatry ; 12(1): 359, 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36055984

RESUMO

Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca2+ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca2+ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca2+ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.


Assuntos
Transtorno Bipolar , Disfunção Cognitiva , Animais , Anticonvulsivantes/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Antimaníacos/uso terapêutico , Transtorno Bipolar/psicologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Lamotrigina/farmacologia , Lamotrigina/uso terapêutico , Lítio/farmacologia , Lítio/uso terapêutico , Camundongos , Ácido Valproico
4.
Chem Asian J ; 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071031

RESUMO

Nanopore technology is a burgeoning detection technology for single-molecular sensing and ion rectification. Solid-state nanopores have attracted more and more attention because of their higher stability and tunability than biological nanopores. However, solid-state nanopores still suffer the drawbacks of low signal-to-noise ratio and low resolution, which hinders their practical applications. Thus, developing operatical and useful methods to overcome the shortages of solid-state nanopores is urgently needed. Here, we summarize the recent research on nanopore modification to achieve this goal. Modifying solid-state nanopores with different coating molecules can improve the selectivity, sensitivity, and stability of nanopores. The modified molecules can introduce different functions into the nanopores, greatly expanding the applications of this novel detection technology. We hope that this review of nanopore modification will provide new ideas for this field.

5.
An Acad Bras Cienc ; 94(3): e20211160, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36074406

RESUMO

The aim of this study was to determine the resistance mechanism of Pseudomonas aeruginosa to cefoperazone sodium/sulbactam sodium. We retrospectively analyzed the drug resistance of P.a isolated at the First Affiliated Hospital of Guangxi Medical University. Drug-resistant P.a strains were constructed, then wild-type (WT) and drug-resistant (DR) strains were compared using protein and gene microarrays to determine differences between DR and WT strains. The resistance rates of P. aeruginosa during 2013, 2014 and 2015 were 21.2%, 21.4%, and 24.6% respectively. Among 242 protein peaks of WT and DR bacteriophage proteins, 41 were differentially expressed between the two groups. The expression of 26 and 15 proteins were respectively upregulated and downregulated in the DR compared with the WT group. Gene microarray results revealed 679 mutant loci in the DR group, of which 42 with the top 50 Q values were found in the NCBI database. The rate of P.a resistance to cefoperazone sodium/sulbactam sodium remained high between 2013 and 2015. The numbers of different proteins and genetic variations in the DR strains suggested that the resistance mechanism of P.a to cefoperazone sodium/sulbactam sodium involves multiple genes and proteins that might be key to controlling P.a resistance to cefoperazone sodium/sulbactam sodium.


Assuntos
Cefoperazona , Sulbactam , Antibacterianos/farmacologia , Cefoperazona/farmacologia , China , Humanos , Testes de Sensibilidade Microbiana , Proteômica , Pseudomonas aeruginosa/genética , Estudos Retrospectivos , Sódio , Sulbactam/farmacologia
6.
Adv Sci (Weinh) ; : e2203460, 2022 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-36089657

RESUMO

Respiration signals reflect many underlying health conditions, including cardiopulmonary functions, autonomic disorders and respiratory distress, therefore continuous measurement of respiration is needed in various cases. Unfortunately, there is still a lack of effective portable electronic devices that meet the demands for medical and daily respiration monitoring. This work showcases a soft, wireless, and non-invasive device for quantitative and real-time evaluation of human respiration. This device simultaneously captures respiration and temperature signatures using customized capacitive and resistive sensors, encapsulated by a breathable layer, and does not limit the user's daily life. Further a machine learning-based respiration classification algorithm with a set of carefully studied features as inputs is proposed and it is deployed into mobile clients. The body status of users, such as being quiet, active and coughing, can be accurately recognized by the algorithm and displayed on clients. Moreover, multiple devices can be linked to a server network to monitor a group of users and provide each user with the statistical duration of physiological activities, coughing alerts, and body health advice. With these devices, individual and group respiratory health status can be quantitatively collected, analyzed, and stored for daily physiological signal detections as well as medical assistance.

7.
Curr Neurovasc Res ; 2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36089793

RESUMO

BACKGROUND AND PURPOSE: The aim of this study is to investigate the relationships between the original and modified total cerebral small vessel disease (CSVD) score and gait and balance impairment using quantitative and semi-quantitative tests. METHODS: In our study, patients aged 45 to 85 years were recruited consecutively. CSVD manifestations were identified with brain magnetic resonance imaging (MRI), and the original and modified CSVD scores were calculated based on the results. Gait and balance function were assessed using both gait parameters and clinical rating scales. The correlation between the original and modified total scores of the CSVD and gait and balance dysfunction was demonstrated. RESULTS: 224 patients were enrolled in the study. Gait and balance disorders were associated with both the original and modified CSVD scores. A significant association remained after adjusting for gender, height, age, hypertension, and other relevant risk factors. The binary logistic regression and chi-squared trend tests revealed that impairment of movement function significantly correlated with the modified CSVD score and that the dysfunction was significantly higher for patients with modified CSVD scores of 5-6 than those with scores of 1-2. In receiver operating characteristic (ROC) analysis, modified CSVD scores were more accurate in predicting gait impairment than original CSVD scores. CONCLUSION: We found both original and modified total CSVD scores to be related to gait and balance disorder, and the modified CSVD score was more accurate in identifying movement impairment and should be used as an effective tool in investigating CSVD and motor dysfunction.

8.
Genes Genomics ; 2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36094735

RESUMO

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a frequently-diagnosed malignancy with high potential for proliferation and invasion. Histone methylation is known as a crucial mechanism that regulates pathological processes in various cancers, including OSCC. OBJECTIVE: This study sought to delve into the molecular mechanism of lysine demethylase 3 A (KDM3A) in OSCC cell proliferation and invasion. METHODS: Expression levels of KDM3A, lysin-9 of di-methylated histone H3 (H3K9me2), and doublecortin-like kinase 1 (DCLK1) in cells were determined by reverse-transcription quantitative polymerase chain reaction or Western blot analysis. Cell proliferation and invasion were evaluated by cell counting kit-8, colony formation, and Transwell assays. The enrichment of KDM3A and H3K9me2 on the DCLK1 promoter was determined by chromatin immunoprecipitation assay. The functional rescue experiment was performed with DCLK1 overexpression vector and si-KDM3A in CAL-27 and SCC-9 cells. RESULTS: KDM3A was elevated in OSCC cells. KDM3A knockdown suppressed OSCC proliferation and invasion, along with increased H3K9me2 level in OSCC cells. KDM3A and H3K9me2 were enriched on the DCLK1 promoter and inhibiting H3K9me2 improved DCLK1 expression levels. DCLK1 overexpression neutralized the inhibition of KDM3A knockdown on OSCC proliferation and invasion. CONCLUSIONS: KDM3A facilitated OSCC proliferation and invasion by eliminating H3K9me2 to upregulate DCLK1 expression levels.

9.
Artigo em Inglês | MEDLINE | ID: mdl-36094965

RESUMO

This paper provides a special flexible graphene film based capacitive wireless power transfer (FGCPT) system for powering biomedical sensors of smart wearable devices. The graphene conductive material is flexible, transparent, highly conductive, and impermeable to most gases and liquids. Generally, the coupling structure of capacitive wireless power transfer (CPT) system is consisted of metal plates. However, it is hard to use for the biomedical sensors as the low power density and big volume. The shape of graphene conductive material could be easily built and changed according to the application requirements. In this paper, the power supply of biomedical sensing system could be accomplished by a single graphene film which is acted as the receiver of FGCPT system. The 200 mW power level is achieved with the maximum 9 V output voltage. The theory and calculation are verified by the simulated and experimental results.

10.
Front Plant Sci ; 13: 863626, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36082292

RESUMO

The (E)-ß-farnesene (EßF) is one of the most important secondary metabolites in some plants and provides indirect defense against aphids. However, the direct effect of EßF against pests is still unclear. In this study, various concentrations of EßF (0.16, 0.8, and 4 g/kg) were provided in an artificial diet to determine the direct effects of EßF on Spodoptera exigua. The results showed that an artificial diet containing 4 g/kg of EßF reduced the final survival of the S. exigua larvae and per female fecundity of adults significantly when compared with CK and SC controls (p < 0.05), then ultimately it also significantly affected the intrinsic rate of increase (p < 0.05). Furthermore, the results of the EßF bioassay in an artificial diet also indicated that the proliferation of the S. exigua population was inhibited by the ingestion of EßF in a dose-dependent manner. Combined differential RNA-seq data and RT-qPCR analysis, it was found that four key genes involved in juvenile hormone degradation significantly upregulated in S. exigua larvae treated by EßF at a dose of 0.8 and 4 g/kg when compared with two controls (p < 0.05). This indicated that EßF could disturb the normal function of juvenile hormones and reduce the survival rate of S. exigua larvae. Additionally, two key genes that regulate per fecundity of S. exigua females, including SeVg and SeVgR, were significantly downregulated in adult females (p < 0.05) when they were treated with 0.8 and 4 g/kg of EßF at the larval stage, relative to the expression of these genes after treatment with controls. These findings suggested that EßF first disturbed the normal function of juvenile hormone by upregulating key degradation genes, and then inhibited the expression of SeVg/SeVgR genes and proteins, thus reducing the population size of S. exigua by increasing larval mortality and inhibiting per female fecundity.

11.
Respir Res ; 23(1): 250, 2022 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-36117161

RESUMO

BACKGROUND: No personalized prediction model or standardized algorithm exists to identify those at high risk of death among severe community-acquired pneumonia (SCAP) patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the risk factors and to develop a useful nomogram for prediction of mortality in those patients. METHODS: We performed a retrospective, observational, cohort study in the intensive care unit (ICU) of West China Hospital, Sichuan University with all consecutive SCAP patients with COPD between December 2011 and December 2018. The clinical data within 24 h of admission to ICU were collected. The primary outcome was hospital mortality. We divided the patients into training and testing cohorts (70% versus 30%) randomly. In the training cohort, univariate and multivariate logistic regression analysis were used to identify independent risk factors applied to develop a nomogram. The prediction model was assessed in both training and testing cohorts. RESULTS: Finally, 873 SCAP patients with COPD were included, among which the hospital mortality was 41.4%. In training cohort, the independent risk factors for hospital mortality were increased age, diabetes, chronic renal diseases, decreased systolic blood pressure (SBP), and elevated fibrinogen, interleukin 6 (IL-6) and blood urea nitrogen (BUN). The C index was 0.840 (95% CI 0.809-0.872) in training cohort and 0.830 (95% CI 0.781-0.878) in testing cohort. Furthermore, the time-dependent AUC, calibration plots, DCA and clinical impact curves indicated the model had good predictive performance. Significant association of risk stratification based on nomogram with mortality was also found (P for trend < 0.001). The restricted cubic splines suggested that estimated associations between these predictors and hospital mortality were all linear relationships. CONCLUSION: We developed a prediction model including seven risk factors for hospital mortality in patients with SCAP and COPD. It can be used for early risk stratification in clinical practice after more external validation.


Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Estudos de Coortes , Infecções Comunitárias Adquiridas/diagnóstico , Fibrinogênio , Mortalidade Hospitalar , Humanos , Interleucina-6 , Estudos Retrospectivos
13.
Front Genet ; 13: 880027, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36061201

RESUMO

Cognitive impairment is highly prevalent in patients with major psychiatric disorders (MPDs), including schizophrenia (SCZ), bipolar disorder, major depressive disorder, in whom it can be highly disruptive to community functioning and worsen prognosis. Previously, genetic factors and cognitive impairments in MPD patients have been examined mostly in isolated circuits rather than in the whole brain. In the present study, genetic, neuroimaging, and psychometric approaches were combined to investigate the relationship among genetic factors, alterations throughout the brain, and cognitive impairments in a large cohort of patients diagnosed with SCZ, with a reference healthy control (HC) group. Single nucleotide polymorphisms (SNPs) in SCZ-risk genes were found to be strongly related to cognitive impairments as well as to gray matter volume (GMV) and functional connectivity (FC) alterations in the SCZ group. Annotating 136 high-ranking SNPs revealed 65 affected genes (including PPP1R16B, GBBR2, PDE4B, CANCNA1C, SLC12AB, SATB2, MAG12, and SATB2). Only one, a PDE4B SNP (rs1006737), correlated with GMV (r = 0:19 p = 0.015) and FC (r = 0.21, p = 0.0074) in SCZ patients. GMV and FC alterations correlated with one another broadly across brain regions. Moreover, the present data demonstrate three-way SNP-FC-GMV associations in patients with SCZ, thus providing clues regarding potential genetic bases of cognition impairments in SCZ. SNP-FC-GMV relationships correlated with visual learning and reasoning dimensions of cognition. These data provide evidence that SCZ-related cognitive impairments may reflect genetically underlain whole-brain structural and functional alterations.

14.
Front Behav Neurosci ; 16: 995614, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36062260

RESUMO

Dysphagia is one of the most common manifestations of stroke, which can affect as many as 50-81% of acute stroke patients. Despite the development of diverse treatment approaches, the precise mechanisms underlying therapeutic efficacy remain controversial. Earlier studies have revealed that the onset of dysphagia is associated with neurological damage. Neuroplasticity-based transcranial magnetic stimulation (TMS), a recently introduced technique, is widely used in the treatment of post-stroke dysphagia (PSD) by increasing changes in neurological pathways through synaptogenesis, reorganization, network strengthening, and inhibition. The main objective of this review is to discuss the effectiveness, mechanisms, potential limitations, and prospects of TMS for clinical application in PSD rehabilitation, with a view to provide a reference for future research and clinical practice.

15.
Artigo em Inglês | MEDLINE | ID: mdl-36065263

RESUMO

Excessive reactive oxygen species (ROS) could interfere with the physiological capacities of H9C2 cells and cause cardiomyocyte apoptosis. Glycyrrhetinic acid (GA), one of the main medicinal component of Glycyrrhetinic Radix et Rhizoma, shows toxic and adverse side effects in the clinic setting. In particular, some studies have reported that GA exerts toxic effects on H9C2 cells. The purpose of this study is to assess the effect of GA-induced oxidative stress on cultured H9C2 cells and reveal the relevant signaling pathways. LDH assay was used to assess cell damage. Apoptosis was detected using Hoechst 33242 and a propidium iodide (PI) assay. An Annexin V-fluorescein isothiocyanate/PI double-staining assay was utilized to investigate GA-induced apoptosis in H9C2 cells. The expression level of specific genes/proteins was evaluated by RT-qPCR and Western blotting. Flow cytometry and DCFH-DA fluorescent testing were used to determine the ROS levels of H9C2 cells. The potential mechanism of GA-induced cardiomyocyte injury was also investigated. GA treatment increased ROS generation and mitochondrial membrane depolarization and triggered caspase-3/9 activation and apoptosis. GA treatment also caused the nuclear translocation of NF-E2-related factor 2 after its dissociation from Keap1. This change was accompanied by a dose-dependent decline in the expression of the downstream target gene heme oxygenase-1. The findings demonstrated that GA could regulate the Keap1-Nrf2 signaling axis and induce oxidative stress to promote the apoptosis of H9C2 cells.

16.
Phytomedicine ; 106: 154395, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36103769

RESUMO

BACKGROUND: Sinisan (SNS) consists of four kinds of herbs, which is the core of antidepressant prescription widely used in traditional Chinese medicine clinic treatment for depression induced by early life stress. However, the role and precise mechanism of SNS antidepressant have not yet been elucidated. PURPOSE: This study aimed to investigate the mechanism SNS on antidepressant of regulating mitochondrial function to improve hippocampal synaptic plasticity. METHODS: 90 Sprague-Dawley (SD) rats male pups on Post-Natal Day (PND) 0 were randomly divided into Control group (ddH20), Model group (ddH20), Fluoxetine group (5.0 mg/kg fluoxetine), and SNS-L group (2.5 g/kg SNS), SNS-M group (5.0 g/kg SNS) and SNS-H group (10.0 g/kg SNS), 15 animals per group. Maternal separation (MS) from PND1 to PND21, drug intervention from PND60 to PND90, and behavior tests including sucrose preference test, open field test and forced swimming test from PND83 to PND90 were performed. Synaptic structure and mitochondrial structure were observed by TEM. The expression levels of PSD-95 and SYN were detected by immunohistochemistry and western blot test, the adenosine triphosphate (ATP) content in the hippocampus was detected by assay kits, and the expression levels of Mfn2, Drp1 and Fis1 protein were detected by western bolt test. RESULTS: SNS can alleviate depression-like and anxiety-like behaviors in MS rats, improve the damage of synapses and mitochondria, reduce the decrease of ATP in hippocampus, and reverse the expression levels of PSD-95, SYN, Mfn2, Drp1, and Fis1 proteins. CONCLUSION: SNS reduced the risk of early life stress induced depression disorder via regulating mitochondrial function and synaptic plasticity. Targeting mitochondrial may be a novel prospective therapeutic avenue for antidepressant.

18.
Front Pharmacol ; 13: 919035, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091768

RESUMO

Pancreatic cancer is accompanied by poor prognosis and accounts for a significant number of deaths every year. Since Psoralea corylifolia L. (PCL) possesses a broad spectrum of bioactivities, it is commonly used in traditional Chinese medicine. The study explored potential antitumor agents of PCL and underlying mechanisms in vitro and vivo. Based on network pharmacology, bioinformatics, and molecular docking, we considered isobavachalcone (IBC) as a valuable compound. The activity and potential mechanisms of IBC were investigated by RT-qPCR, immunohistochemistry, immunofluorescence, and flow cytometry. It was confirmed that IBC could inhibit Panc 02 cell proliferation and induce apoptosis via increasing the production of reactive oxygen species. IBC could attenuate the weight of solid tumors, increase CD8+ T cells, and reduce M2 macrophages in the tumor tissue and spleen. Another promising finding was that IBC alleviated the proportion of myeloid-derived suppressor cells (MDSCs) in the tumor tissue but had no change in the spleen. The study of pharmacological effects of IBC was carried out and suggested IBC restrained M2-like polarization of RAW 264.7 cells by inhibiting the expression of ARG1 and MRC1 and suppressed the expression of ARG1 and TGF-ß in bone marrow-derived MDSC. In summary, this research screened IBC as an antineoplastic agent, which could attenuate the growth of pancreatic cancer via activating the immune activity and inducing cell apoptosis. It might be a reference for the antitumor ability of IBC and the treatment of the tumor microenvironment in pancreatic cancer.

19.
Front Genet ; 13: 957023, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36092921

RESUMO

G-quadruplex (G4) has been previously observed to be associated with gene expression. In this study, we performed integrative analysis on G4 multi-omics data from in-silicon prediction and ChIP-seq in human genome. Potential G4 sites were classified into three distinguished groups, such as one group of high-confidence G4-forming locations (G4-II) and groups only containing either ChIP-seq detected G4s (G4-I) or predicted G4 motif candidates (G4-III). We explored the associations of different-confidence G4 groups with other epigenetic regulatory elements, including CpG islands, chromatin status, enhancers, super-enhancers, G4 locations compared to the genes, and DNA methylation. Our elastic net regression model revealed that G4 structures could correlate with gene expression in two opposite ways depending on their locations to the genes as well as G4-forming DNA strand. Some transcription factors were identified to be over-represented with G4 emergence. The motif analysis discovered distinct consensus sequences enriched in the G4 feet, the flanking regions of two groups of G4s. We found high GC content in the feet of high-confidence G4s (G4-II) when compared to high TA content in solely predicted G4 feet of G4-III. Overall, we uncovered the comprehensive associations of G4 formations or predictions with other epigenetic and transcriptional elements which potentially coordinate gene transcription.

20.
J Control Release ; 2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36096364

RESUMO

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral cavity malignancies. However, despite significant advances in the last four decades, little improvement has been achieved in the overall survival rates for OSCC patients. While gambogic acid (GA) is a potential candidate compound for treating a variety of malignancies, its anti-cancer impact on OSCC has yet to be completely investigated. The tumor immune microenvironment (TIME) has been proven to play a crucial role in the prognosis of cancer patients. Although there are few reports on the T cell activation effect of GA, the regulation of GA on the TIME of OSCC has barely been studied yet. In this study, GA was applied to treat OSCC-bearing mice through in situ controlled release. First, GA-loaded mPEG2000-PCL micelles (GA-MIC) were prepared by the thin-film hydration method to improve the aqueous dispersibility of GA. Second, poly(D, l-lactide)-poly(ethylene glycol)-poly(D, l-lactide) (PLEL) was synthesized for thermosensitive hydrogel preparation. Third, GA-MIC was mixed with PLEL to form an injectable therapeutic hydrogel (GA-MIC-GEL). The anti-tumor and TIME regulation effects of GA-MIC-GEL on tumor-bearing mice were next examined in further depth. The results showed that the thermosensitive GA-MIC-GEL with sensitive sol-gel transition characteristics could form hydrogel at 37 °C within 24 s, facilitating the local delivery and sustained GA release. Biochemical analysis, hematology analysis, and pathological tissue analysis proved that GA-MIC-GEL has good biological safety. GA-MIC-GEL promoted an obvious regression of both primary and distant tumors on the OSCC mouse models. Mechanically, GA-MIC-GEL down-regulated the expression of PD-1, increased the frequency of cytotoxic T cells and reduced the immunosuppressive cellular component, which boosted the anti-tumor immunity of OSCC-bearing mice. The constructed thermosensitive hydrogel strategy for local delivery of GA has provided a safe and effective treatment strategy with great potential for OSCC therapy.

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