ABSTRACT
The environmental impact from the waste disposal has been widely concerned around the world. The conversion of wastes to useful resources is important for the sustainable society. As a typical family of wastes, biomass materials basically composed of collagen, protein and lignin are considered as useful resources for recycle and reuse. In recent years, the development of carbon material derived from biomasses, such as plants, crops, animals and their application in electrochemical energy storage have attracted extensive attention. Through the selection of the appropriate biomass, the optimization of the activation method and the control of the pyrolysis temperatures, carbon materials with desired features, such as high-specific surface area, variable porous framework, and controllable heteroatom-doping have been fabricated. Herein, this review summarized the preparation methods, morphologies, heteroatoms doping in the plant/animal-derived carbonaceous materials, and their application as electrode materials for secondary batteries and supercapacitors, and as electrode support for lithium-sulfur batteries. The challenges and prospects for the controllable synthesis and large-scale application of biomass-derived carbonaceous materials have also been outlooked.
ABSTRACT
Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.
Subject(s)
Receptors, G-Protein-Coupled , Synaptic Transmission , Animals , Humans , Brain , Amines , MammalsABSTRACT
BACKGROUND: Timely and systematic professional treatment is crucial in schizophrenia prognosis, but the global rate of mental health service, now, use or help-seeking behavior is low. METHODS: In-depth semi-structured interviews were conducted with 13 participants with the diagnosis of schizophrenia between October to December 2021. The participants were purposively sampled from a psychiatric hospital's. Interviews were recorded and transcribed verbatim into NVivo 12.0. RESULTS: The findings were summarized under 3 themes and 12 subthemes: (1) capability (lack of knowledge due to insufficient mental health literacy or lack of insight, inability to access disease information due to a lack of mental health literacy, and symptoms-related barriers); (2) opportunity (lack of disease information sources, inability to balance work and study during prolonged hospitalization, accessibility and convenience of medical resources, and the acquisition and utilization of social support); and (3) motivation (awareness of the disease and professional treatment, negative experiences of disease episodes, past medical experience, confidence in tcuring the disease, and the fulfillment of daily life and self-worth). CONCLUSION: The medical help-seeking behavior of people with the diagnosis of schizophrenia is the result of the interaction of many barriers and facilitators, and challenges persist today. Interventions can be implemented with the BCW framework and our results to precisely eliminate delays in the diagnosis and treatment of mental problems.
Subject(s)
Help-Seeking Behavior , Mental Health Services , Schizophrenia , Humans , Schizophrenia/diagnosis , Schizophrenia/therapy , Qualitative Research , Mental HealthABSTRACT
BACKGROUND: Sexual health is one of the main areas of health and basic human rights which has been paid less attention in schizophrenia. Most studies have focused on sexual dysfunction rather than the sexual needs of people with schizophrenia. This study explores the sexual needs of people with schizophrenia and identify factors hindering sexual activities. METHODS: We carried out a qualitative study using a descriptive phenomenological approach. Data were collected at a psychiatric hospital in China. In total, 20 patients with schizophrenia were recruited through purposive sampling. Face to face semi-structured in-depth interviews were conducted with them. Interview recordings were transcribed by the research team, and transcripts were analyzed by two independent coders with Colaizzi's descriptive analysis framework by using NVivo 11 software. The consolidated criteria for reporting qualitative research checklist was used for reporting. RESULTS: The data analysis revealed 10 subthemes categorized into 3 macro themes: (1) multiple barriers hinder sexual activity; (2) significance of sex; and (3) conditions for fulfilling sexual needs. CONCLUSION: A poor sexual quality of life may be found in patients with schizophrenia. Furthermore, people with schizophrenia did not lose interest in maintaining an active sex life. Mental health services should address this issue in three areas: sexual knowledge, sexual space, and sexual objects.
Subject(s)
Mental Health Services , Schizophrenia , Humans , Quality of Life , Qualitative Research , Sexual BehaviorABSTRACT
Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.
Subject(s)
Autistic Disorder/genetics , Autistic Disorder/psychology , Disease Models, Animal , Germ-Line Mutation/genetics , Heredity/genetics , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Animals , Animals, Genetically Modified , Anxiety/genetics , Anxiety/psychology , Autistic Disorder/metabolism , Autistic Disorder/physiopathology , Brain/metabolism , Cognition/physiology , Female , Humans , Locomotion/genetics , Locomotion/physiology , Macaca fascicularis , Male , Phenotype , Social Behavior , Sperm Injections, Intracytoplasmic , Transgenes/geneticsABSTRACT
Site-specific DNA double-strand breaks have been used to generate knock-in through the homology-dependent or -independent pathway. However, low efficiency and accompanying negative impacts such as undesirable indels or tumorigenic potential remain problematic. In this study, we present an enhanced reduced-risk genome editing strategy we named as NEO, which used either site-specific trans or cis double-nicking facilitated by four bacterial recombination factors (RecOFAR). In comparison to currently available approaches, NEO achieved higher knock-in (KI) germline transmission frequency (improving from zero to up to 10% efficiency with an average of 5-fold improvement for 8 loci) and 'cleaner' knock-in of long DNA fragments (up to 5.5 kb) into a variety of genome regions in zebrafish, mice and rats. Furthermore, NEO yielded up to 50% knock-in in monkey embryos and 20% relative integration efficiency in non-dividing primary human peripheral blood lymphocytes (hPBLCs). Remarkably, both on-target and off-target indels were effectively suppressed by NEO. NEO may also be used to introduce low-risk unrestricted point mutations effectively and precisely. Therefore, by balancing efficiency with safety and quality, the NEO method reported here shows substantial potential and improves the in vivo gene-editing strategies that have recently been developed.
Subject(s)
Bacterial Proteins/metabolism , Gene Editing/methods , Animals , DNA Breaks, Double-Stranded , DNA-Binding Proteins/metabolism , Female , Gene Knock-In Techniques , Genomics , Homologous Recombination , Humans , INDEL Mutation , Macaca fascicularis , Mice , Rats, Sprague-Dawley , Rec A Recombinases/metabolism , Zebrafish/geneticsABSTRACT
INTRODUCTION: The aim was to analyze the morphological changes of root apex in anterior teeth with periapical periodontitis. METHODS: 32 untreated anterior teeth with periapical periodontitis were enrolled, compared with the healthy contralateral teeth. Two-dimensional measurement of Cone-beam computed tomography was used to determine the location and measure diameter of the apical constriction according to Schell's methods. An open-source software (3D Slicer) was used to reconstruct the teeth. The apical constriction form was analysis according to Schell's topography. The distances of apical constriction to apical foramen and anatomical apex were measured respectively. RESULTS: The difference value between buccolingual and mesiodistal diameter was (0.06 ± 0.09) mm and (0.04 ± 0.04) mm in periapical periodontitis and controls (p < 0.05). The mean distance between apical constriction and anatomical apex was significantly shorter in periapical periodontitis than controls, so was the mean distance of apical constriction to apical foramen. The most common form of apical constriction was flaring (65.6%) in periapical periodontitis. CONCLUSIONS: The anterior teeth with periapical periodontitis had shorter distances of apical constriction to anatomical apex and apical foramen, bigger disparities between the diameters of buccolingual and mesiodistal, and higher proportion of flaring apical constriction.
Subject(s)
Periapical Periodontitis , Cone-Beam Computed Tomography , Humans , Periapical Periodontitis/complications , Periapical Periodontitis/diagnostic imaging , Root Canal Therapy/methods , Tooth Apex/diagnostic imagingABSTRACT
Emerging evidence supports an essential role of trace amine-associated receptor 1 (TAAR1) in neuropsychiatric disorders such as depression and schizophrenia. Stressful events are critical contributors to various neuropsychiatric disorders. This study examined the role of TAAR1 in mediating the negative outcomes of stressful events. In mice that experienced chronic social defeat stress but not acute stress, a significant reduction in the TAAR1 mRNA level was found in the medial prefrontal cortex (mPFC), a brain region that is known to be vulnerable to stress experience. Conditional TAAR1 knockout in the mPFC mimicked the cognitive deficits induced by chronic stress. In addition, chronic treatment with the selective TAAR1 partial agonist RO5263397 ameliorated chronic stress-induced changes in cognitive function, dendritic arborization, and the synapse number of pyramidal neurons in the mPFC but did not affect chronic stress-induced anxiety-like behaviors. Biochemically, chronic stress reduced the ratio of vesicular transporters of glutamate-1 (VGluT1) / vesicular GABA transporter (VGAT) in the mPFCï¼most prominently in the prelimbic cortex, and RO5263397 restored the excitatory-inhibitory (E/I) imbalance. Together, the results of this study reveal an essential role of TAAR1 in mediating chronic stress-induced cognitive impairments and suggest that TAAR1 agonists may be uniquely useful to treat MDD-related cognitive impairments.
Subject(s)
Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Prefrontal Cortex/physiopathology , Receptors, G-Protein-Coupled/metabolism , Stress, Psychological/complications , Animals , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Down-Regulation , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Prefrontal Cortex/metabolism , RNA, Messenger/genetics , Receptors, G-Protein-Coupled/genetics , Stress, Psychological/genetics , Stress, Psychological/metabolism , Stress, Psychological/physiopathologyABSTRACT
Long non-coding RNAs have important roles in the occurrence and progression of various cancers. However, the molecular mechanism of lncRNAs in colorectal cancer (CRC) is not well illustrated. Thus, we used bioinformatics methods to find potential lncRNAs associated with CRC progression, and chose SH3PXD2A-AS1 as a candidate for further analysis. The roles of SH3PXD2A-AS1 in CRC cells were determined by CCK-8, transwell invasion, wound healing and flow cytometry assays. Besides, we established the CRC tumor models in nude mice to study the effect of SH3PXD2A-AS1 on the tumor growth. Based on the ceRNA hypothesis, we used miRDB and miRTarBase websites to identify the SH3PXD2A-AS1-related ceRNA regulatory network, and measured the roles of this network in CRC cells. The results revealed that the expression profiles of SH3PXD2A-AS1 from GEO and TCGA databases showed an aberrant high level in CRC tissues compared with colorectal normal tissues. SH3PXD2A-AS1 over-expression was also found in CRC cells. SH3PXD2A-AS1 knockdown inhibited the CRC cellular proliferation, invasion and migration but induced apoptosis. Besides, SH3PXD2A-AS1 knockdown also suppressed the growth of CRC tumors. Furthermore, SH3PXD2A-AS1 could function as a ceRNA of miR-330-5p. Additionally, UBA2 was proved to be a target gene of miR-330-5p. Moreover, SH3PXD2A-AS1 knockdown downregulated UBA2 expression through sponging miR-330-5p to inactivate the Wnt/ß-catenin signaling pathway, thereby inhibiting the cell growth and promoting apoptosis. Therefore, the SH3PXD2A-AS1/miR-330-5p/UBA2 network could regulate the progression of CRC through the Wnt/ß-catenin pathway. These findings offer new sights for understanding the pathogenesis of CRC and provide potential biomarkers for CRC treatment.
Subject(s)
Colorectal Neoplasms , MicroRNAs , RNA, Long Noncoding , Animals , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Mice , Mice, Nude , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Wnt Signaling PathwayABSTRACT
OBJECTIVE: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. METHODS: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. RESULTS: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. CONCLUSIONS: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.
Subject(s)
Gastrointestinal Microbiome , Inflammation Mediators/metabolism , Metagenome , Metagenomics , Spondylitis, Ankylosing/etiology , Spondylitis, Ankylosing/metabolism , Autoimmunity , Case-Control Studies , Disease Susceptibility , Dysbiosis , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/immunology , Humans , Metagenomics/methods , Spondylitis, Ankylosing/pathologyABSTRACT
INTRODUCTION: The value of postoperative radiotherapy (PORT) for resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial with few studies focusing on whether PORT always plays a part in clinical practice and generates benefits to patients across different time periods. We investigated this issue using the Surveillance, Epidemiology, and End Results Database (SEER) and assessed the temporal trends spanning 27 years. METHODS: Within SEER, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumonectomy and coded as receiving PORT or never receiving radiotherapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival analyses were performed and propensity score matching (PSM) was used in the potentially beneficial subgroup. RESULTS: 45.4% of 5568 eligible patients received PORT. The yearly PORT use rates varied largely from 27.8% to 74.4%. Overall survival (OS) was distinctly improved over the period. The application of PORT had a significant impact on survival only in period 1 and 3. In subgroup analysis, the OS benefit of PORT was significant in each period in patients with 50% or more lymph node ratio (LNR) both before (hazard ratios, and P values of 0.647, P = .002; 0.804, P = .008; 0.721, P < .001 for period 1, 2, 3, respectively) and after PSM (0.642, P = .006; 0.785, P = .004; 0.748, P = .003 for period 1, 2, 3, respectively). CONCLUSIONS: The benefits of PORT are lasting and stable throughout the years in patients with LNR of 50% or more. This might provide a clue on proper patient selection for PORT application.
Subject(s)
Adenocarcinoma of Lung/radiotherapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Squamous Cell/radiotherapy , Lung Neoplasms/radiotherapy , Lymph Nodes/pathology , Pneumonectomy , Adenocarcinoma of Lung/pathology , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Propensity Score , Proportional Hazards Models , Radiotherapy, Adjuvant , SEER Program , Survival RateABSTRACT
The protein acetylation by histone acetyltransferases (HATs) and histone deacetylases (HDACs) plays a significant role in the development and maturation of the nervous system. HDAC6, belonging to class II HDACs, by regulating the survival, differentiation and maturation of neural cells, plays an important role in the development of the nervous system and participates in multiple pathological processes of cerebral ischemic injury. In addition, HDAC6 participates in the regulation of cognition and emotion of the brain. This article summarized the latest research results in recent years and expounded that HDAC6 inhibitors could produce a positive and effective neuroprotective effect on ischemic stroke by reducing the neuronal damage induced by excitotoxicity and oxidative stress, depressing the release of inflammatory mediators, inhibiting the apoptosis of neurons and promoting the growth of nerve and blood vessel.
Subject(s)
Brain Ischemia/drug therapy , Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Stroke/drug therapy , Acetylation , Animals , Apoptosis , Brain , Cell Differentiation , Histone Acetyltransferases , Humans , Neurons , Protein Processing, Post-TranslationalABSTRACT
Treatment of mammalian cells with chemotherapeutic drugs can result in perturbations of nucleotide pools. Monitoring these perturbations in cultured tumor cells from human sources is useful for assessment of the effect of drug therapy and a better understanding of the mechanism of action of these drugs. In this study, three classes of chemotherapeutic drugs with different mechanisms of action were used in the development of drug-treated cell models. The LC-based targeted metabolomics analysis of nucleotides in cells of the control group and the drug-treated group was carried out. Several data processing methods were combined for the identification of potential biomarkers associated with the action of drugs, including one-way analysis of variance, principal component analysis, and receiver operating characteristic curves. Intriguingly, tumor cells of both the control group and the drug-treated groups can be distinguished from each other, and several variables were recognized as potential biomarkers, such as ATP, GMP, and UDP for antimetabolite agents, ATP, GMP, and CTP for DNA-damaging agents, as well as GMP, ATP, UDP, and GDP for the mitotic spindle agents. Further validation of the potential biomarkers was performed using the receiver operating characteristic curve. Considering their corresponding area under the curve, which was larger than 0.9, it can be concluded that GMP and ATP are the best potential biomarkers for DNA-damaging drugs, as well as GMP, ATP, and UDP for the other two classes of drugs. This limited nucleotide approach cannot completely distinguish the mechanisms of the nine drugs, but it provides preliminary evidence for the role of pharmacometabolomics in the preclinical development of drugs at least.
Subject(s)
Antineoplastic Agents/pharmacology , Metabolome , Nucleotides/analysis , Analysis of Variance , Biomarkers, Pharmacological/analysis , Biomarkers, Pharmacological/metabolism , Cell Line, Tumor , Chromatography, Liquid , Humans , Nucleotides/metabolism , Principal Component Analysis , ROC CurveABSTRACT
This study aimed to examine whether ophiopogonin D (OP-D) is capable of protecting cardiomyocytes against DOX-induced injury and the mechanisms involved. H9c2 cells were cultured. MTT assay was used to evaluate cell viability and toxicity. Mito-tracker as fluorescence probe was used to measure ROS content raised from mitochondria. The mRNA and protein expression of ATF6alpha, GRP78 and CHOP were analyzed using real-time PCR and Western blotting, respectively. The results showed that a significant endoplasmic reticulum stress (ERS) was induced upon exposure of H9c2 cells to DOX as indicated by the increase in the expression of ERS related proteins, which was paralleled with the accumulation of reactive oxygen species (ROS) and decrease in the viability of H9c2 cells. Whereas, DOX-induced ROS accumulation and up-regulation of ERS related proteins were partially abolished by pretreatment with OP-D. Consequently, a DOX-induced ERS was mitigated by application of OP-D. Similarly, DOX-induced decrease in cell viability was partially attenuated by either inhibiting CHOP or pretreatment with N-acetylcysteine (NAC), an antioxidant. Moreover, cardiac ultrastructural abnormalities seen in mouse receiving DOX injections were obviously ameliorated by pretreatment of OP-D. Taken together, the present study proved that OP-D protects cardiomyocytes against DOX-induced injury, at least in part, through reducing ROS accumulation and alleviating ERS.
Subject(s)
Doxorubicin/adverse effects , Endoplasmic Reticulum Stress/drug effects , Myocytes, Cardiac/drug effects , Saponins/pharmacology , Spirostans/pharmacology , Acetylcysteine , Activating Transcription Factor 6/metabolism , Animals , Antioxidants , Cell Line , Cell Survival , Endoplasmic Reticulum Chaperone BiP , Heat-Shock Proteins/metabolism , Mice , Mitochondria/metabolism , Rats , Reactive Oxygen Species/metabolism , Transcription Factor CHOP/metabolism , Up-RegulationABSTRACT
BACKGROUND: At present, the clinical mechanisms underlying precocious puberty remain unclear, making effective intervention for children experiencing this condition and rapidly progressive puberty essential. AIM: To explore the effects of Zhibai dihuang pills and gonadotropin-releasing hormone analogue (GnRHa) on growth and ovarian function in girls with precocious puberty. METHODS: The clinical data of 84 adolescent girls with precocious puberty and rapidly progressive puberty from February 2017 to August 2023 were retrospectively analyzed. Girls were divided into a control group and an observation group, with 42 cases in each group. The control group received diet intervention combined with GnRHa treatment, while the observation group received diet intervention combined with Zhibai dihuang pills + GnRHa treatment. Outcomes such as clinical efficacy, growth indicators, ovarian function, and adverse reactions were compared between the two groups. RESULTS: The observation group showed superior clinical efficacy compared to the control group (P < 0.05). Prior to the intervention, no significant differences were found in growth or ovarian function between the groups (P > 0.05). Post-intervention, the observation group exhibited significantly lower rates in growth, height, and bone age, along with reduced levels of progesterone, testosterone, estradiol, prolactin, luteinizing hormone, and follicle-stimulating hormone compared to the control group (P < 0.05). The incidence of adverse reactions was similar across both groups (P > 0.05). CONCLUSION: Combining Zhibai dihuang pills with GnRHa and dietary intervention effectively improves growth, enhances ovarian function, and minimizes adverse reactions in adolescent girls with precocious and rapidly progressive puberty.
ABSTRACT
Patients with EGFR-mutated non-small cell lung cancer (NSCLC) respond poorly to immune checkpoint inhibitors (ICIs). It has been reported that the number of CD8+T cells is reduced in EGFR-mutated NSCLC. However, the extent of heterogeneity and effector function of distinct populations of CD8+T cells has not been investigated intensively. In addition, studies investigating whether a combination of radiotherapy and ICIs can improve the efficacy of ICIs in EGFR-mutated lung cancer are lacking. Single-cell RNA sequencing (scRNA-seq) was used to investigate the heterogeneity of CD8+T cell populations in EGFR-mutated NSCLC. The STING pathway was explored after hypofractionated radiation of EGFR-mutated and wild-type cells. Mice bearing LLC-19del and LLC-EGFR tumors were treated with radiotherapy plus anti-PD-L1. The scRNA-seq data showed the percentage of progenitor exhausted CD8+T cells was lower in EGFR-mutated NSCLC. In addition, CD8+T cells in EGFR-mutated NSCLC were enriched in oxidative phosphorylation. In EGFR-mutated and wild-type cells, 8 Gy × 3 increased the expression of chemokines that recruit T cells and activate the cGAS-STING pathway. In the LLC-19del and LLC-EGFR mouse model, the combination of radiation and anti-PD-L1 significantly inhibited the growth of abscopal tumors. The enhanced abscopal effect was associated with systemic CD8+T cell infiltration. This study provided an intensive understanding of the heterogeneity and effector functions of CD8+T cells in EGFR-mutated NSCLC. We showed that the combination of hypofractionated radiation and anti-PD-L1 significantly enhanced the abscopal responses in both EGFR-mutated and wild-type lung cancer by activating CD8+T cells in mice.
ABSTRACT
The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.
Subject(s)
Adverse Childhood Experiences , Fluoxetine , Humans , Female , Mice , Male , Animals , Fluoxetine/pharmacology , Vortioxetine , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Depression/drug therapyABSTRACT
OBJECTIVE: The effects of four antitussives, including codeine phosphate (CP), moguisteine, levodropropizine (LVDP) and naringin, on airway neurogenic inflammation and enhanced cough were investigated in guinea pig model of chronic cough. METHODS: Guinea pigs were exposed to CS for 8 weeks. At the 7th and 8th week, the animals were treated with vehicle, CP (4.8 mg/kg), moguisteine (24 mg/kg), LVDP (14 mg/kg) and naringin (18.4 mg/kg) respectively. Then the cough and the time-enhanced pause area under the curve (Penh-AUC) during capsaicin challenge were recorded. The substance P (SP) content, NK-1 receptor expression and neutral endopeptidase (NEP) activity in lung were determined. RESULTS: Chronic CS exposure induced a bi-phase time course of cough responsiveness to capsaicin. Eight weeks of CS exposure significantly enhanced the airway neurogenic inflammation and cough response in guinea pigs. Two weeks of treatment with CP, moguisteine, LVDP or naringin effectively attenuated the chronic CS-exposure enhanced cough. Only naringin exerted significant effect on inhibiting Penh-AUC, SP content and NK-1 receptor expression, as well as preventing the declining of NEP activity in lung. CONCLUSIONS: Chronic CS-exposed guinea pig is suitable for studying chronic pathological cough, in which naringin is effective on inhibiting both airway neurogenic inflammation and enhanced cough.
Subject(s)
Antitussive Agents/pharmacology , Cough/metabolism , Neurogenic Inflammation/metabolism , Animals , Capsaicin , Codeine/pharmacology , Cough/chemically induced , Female , Flavanones/pharmacology , Guinea Pigs , Lung/drug effects , Lung/metabolism , Male , Neprilysin/metabolism , Neurogenic Inflammation/chemically induced , Propylene Glycols/pharmacology , Receptors, Neurokinin-1/metabolism , Smoke , Substance P/metabolism , Thiazolidines/pharmacology , NicotianaABSTRACT
22-[N(-7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-23,24-bisnor-5-cholen-3ß-ol (NBD-cholesterol), a fluorescent cholesterol analog, was an extragenous cholesterol tracer used to study cholesterol absorption and metabolism in cultured cells. In order to measure free intracellular cholesterol and its esters, a precise and sensitive method employing high-performance liquid chromatography/fluorescence detection (HPLC-FLD) was developed for the first time. Method validation showed a limit of detection at 30 ng/mL. The calibration curve was linear within the range of 0.0625-10.0 µg/mL (r(2) = 0.999). Accuracy and precision were highlighted by good recovery and low variations. Apart from NBD-cholesteryl oleate, two additional cellular metabolites of NBD-cholesterol, probably an isomer and an oxidation product, were determined in the lipid extracts of Caco-2 human colon adenocarcinoma cells according to mass spectrometry. In AC29 mouse malignant mesothelioma cells overexpressing acyl-CoA:cholesterol acyltransferase-1 (ACAT1) or ACAT2, only the oxidized metabolite was detected. Using the newly developed method, YIC-C8-434, a known ACAT inhibitor, was shown to inhibit ACAT activity in Caco-2 cells, as well as in AC29/ACAT1 or AC29/ACAT2 cells. In conclusion, the sensitive and specific HPLC-FLD method is a powerful tool for simultaneous quantification of intracellular NBD-cholesterol and its oleoyl-ester.
Subject(s)
4-Chloro-7-nitrobenzofurazan/analogs & derivatives , Cholesterol/analogs & derivatives , Chromatography, High Pressure Liquid/methods , Intracellular Space , Spectrometry, Fluorescence/methods , 4-Chloro-7-nitrobenzofurazan/analysis , 4-Chloro-7-nitrobenzofurazan/chemistry , 4-Chloro-7-nitrobenzofurazan/metabolism , Animals , Caco-2 Cells , Cell Line, Tumor , Cholesterol/analysis , Cholesterol/chemistry , Cholesterol/metabolism , Esters/analysis , Esters/chemistry , Esters/metabolism , Humans , Intracellular Space/chemistry , Intracellular Space/metabolism , Linear Models , Mass Spectrometry , Mice , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
PURPOSE: The aim of this study was to evaluate the effects of apical backfilling depth on the apical sealing of different root canal filling qualities and morphologies. METHODS: 3D-printed root canals (A: round, B: oval, C: long oval, D: flat) were used and divided into subgroups by root canal filling quality (a: good, b: poor, c: nonfilling) and backfilling depth (3 mm, 5 mm). A glucose microleakage device was used to measure leakage. RESULTS: (1) 3-mm iRoot BP Plus was filled at the apex, and no obvious leakage occurred in the good root canal filling group, which was significantly smaller than that in the poor/nonfilling groups (P < 0.05). Under good root canal filling conditions in groups A, B, C, and D, no obvious leakage was observed. Under poor/nonfilling root canal filling conditions, there was significant leakage; A and B (P > 0.05) and C and D were compared (P < 0.05). (2) Apical backfilling with 5-mm iRoot BP Plus showed no significant leakage in the poor root canal filling groups with the four morphologies. CONCLUSION: 3-mm iRoot BP Plus was filled at the apex, root canal filling was poor, apical sealing was poor, and root canal morphology affected apical sealing. Apical backfilling with 5-mm iRoot BP Plus improved apical sealing under poor root canal filling conditions, and apical sealing was unaffected by root canal morphology.