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Endoplasmic reticulum (ER) stress, a common cellular stress response induced by various factors that interfere with cellular homeostasis, may trigger cell apoptosis. Autophagy is an important and conserved mechanism for eliminating aggregated proteins and maintaining protein stability of cells, which is closely associated with ER stress and ER stress-induced apoptosis. In this paper, we report for the first time that Hhatl, an ER-resident protein, is downregulated in response to ER stress. Hhatl overexpression alleviated ER stress and ER stress induced apoptosis in cells treated with tunicamycin or thapsigargin, whereas Hhatl knockdown exacerbated ER stress and apoptosis. Further study showed that Hhatl attenuates ER stress by promoting autophagic flux. Mechanistically, we found that Hhatl promotes autophagy by associating with autophagic protein LC3 (microtubule-associated protein 1A/1B-light chain 3) via the conserved LC3-interacting region motif. Noticeably, the LC3-interacting region motif was essential for Hhatl-regulated promotion of autophagy and reduction of ER stress. These findings demonstrate that Hhatl ameliorates ER stress via autophagy activation by interacting with LC3, thereby alleviating cellular pressure. The study indicates that pharmacological or genetic regulation of Hhatl-autophagy signaling might be potential for mediating ER stress and related diseases.
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Autofagia , Estresse do Retículo Endoplasmático , Proteínas Associadas aos Microtúbulos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Humanos , Apoptose/efeitos dos fármacos , Células HEK293 , Células HeLa , Tunicamicina/farmacologiaRESUMO
BACKGROUND: Dynamic interpersonal therapy (DIT) is a brief, structured psychodynamic psychotherapy with demonstrated efficacy in treating major depressive disorder (MDD). The aim of the study was to determine whether DIT is an acceptable and efficacious treatment for MDD patients in China. METHOD: Patients were randomized to 16-week treatments with either DIT plus antidepressant medication (DIT + ADM; n = 66), general supportive therapy plus antidepressant medication (GST + ADM; n = 75) or antidepressant medication alone (ADM; n = 70). The Hamilton Depression Rating Scale (HAMD) administered by blind raters was the primary efficacy measure. Assessments were completed during the acute 16-week treatment and up to 12-month posttreatment. RESULTS: The group × time interaction was significant for the primary outcome HAMD (F = 2.900, df1 = 10, df2 = 774.72, p = 0.001) in the acute treatment phase. Pairwise comparisons showed a benefit of DIT + ADM over ADM at weeks 12 [least-squares (LS) mean difference = -3.161, p = 0.007] and 16 (LS mean difference = -3.237, p = 0.004). Because of the unexpected high attrition during the posttreatment follow-up phase, analyses of follow-up data were considered exploratory. Differences between DIT + ADM and ADM remained significant at the 1-, 6-, and 12-month follow-up (ps range from 0.001 to 0.027). DIT + ADM had no advantage over GST + ADM during the acute treatment phase. However, at the 12-month follow-up, patients who received DIT remained less depressed. CONCLUSIONS: Acute treatment with DIT or GST in combination with ADM was similarly efficacious in reducing depressive symptoms and yielded a better outcome than ADM alone. DIT may provide MDD patients with long-term benefits in symptom improvement but results must be viewed with caution.
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Transtorno Depressivo Maior , Psicoterapia Psicodinâmica , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/uso terapêutico , Resultado do Tratamento , Terapia CombinadaRESUMO
A tandem reaction for the synthesis of phenanthrenes from arynes and α-(bromomethyl)styrenes is reported. The transformation proceeds via an ene reaction of α-(bromomethyl)styrenes with arynes, followed by a [4 + 2] cycloaddition reaction. The reaction generates 9-benzylphenanthrene derivatives in moderate to excellent yields.
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Fenantrenos , Estirenos , Reação de Cicloadição , CiclizaçãoRESUMO
Suitable flowering time can improve fiber yield and quality, which is of great significance for jute biological breeding. In this study, 242 jute accessions were planted in Fujian for 2 consecutive years, and 244,593 SNPs distributed in jute genome were used for genome-wide association analysis of flowering time. A total of 19 candidate intervals (P < 0.0001) were identified by using GLM and FaST-LMM and were significantly associated with flowering time, with phenotypic variation explained (PVE) ranging from 5.8 to 18.61%. Six stable intervals that were repeatedly detected in different environments were further identified by the linkage disequilibrium heatmap. The most likely 7 candidate genes involved to flowering time were further predicted according to the gene functional annotations. Notably, functional analysis of the candidate gene CcPRR7 of the major loci qFT-3-1, a key factor in circadian rhythm in the photoperiodic pathway, was evaluated by linkage, haplotype, and transgenic analysis. ß-glucuronidase (GUS) and luciferase (LUC) activity assay of the promoters with two specific haplotypes confirmed that the flowering time can be controlled by regulating the expression of CcPRR7. The model of CcPRR7 involved in the photoperiod regulation pathway under different photoperiods was proposed. These findings provide insights into genetic loci and genes for molecular marker-assisted selection in jute and valuable information for genetically engineering PRR7 homologs in plants. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01435-8.
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Cultivated jute, which comprises the two species Corchorus capsularis and C. olitorius, is the second most important natural fibre source after cotton. Here we describe chromosome-level assemblies of the genomes of both cultivated species. The C. capsularis and C. olitorius assemblies are each comprised of seven pseudo-chromosomes, with the C. capsularis assembly consisting of 336 Mb with 25,874 genes and the C. olitorius assembly containing 361 Mb with 28 479 genes. Although the two Corchorus genomes exhibit collinearity, the genome of C. olitorius contains 25 Mb of additional sequences than that of C. capsularis with 13 putative inversions, which might give a hint to the difference of phenotypic variants between the two cultivated jute species. Analysis of gene expression in isolated fibre tissues reveals candidate genes involved in fibre development. Our analysis of the population structures of 242 cultivars from C. capsularis and 57 cultivars from C. olitorius by whole-genome resequencing resulted in post-domestication bottlenecks occurred ~2000 years ago in these species. We identified hundreds of putative significant marker-trait associations (MTAs) controlling fibre fineness, cellulose content and lignin content of fibre by integrating data from genome-wide association studies (GWAS) with data from analyses of selective sweeps due to natural and artificial selection in these two jute species. Among them, we further validated that CcCOBRA1 and CcC4H1 regulate fibre quality in transgenic plants via improving the biosynthesis of the secondary cell wall. Our results yielded important new resources for functional genomics research and genetic improvement in jute and allied fibre crops.
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Corchorus , Corchorus/genética , Estudo de Associação Genômica Ampla , Genômica , Lignina , Análise de Sequência de DNARESUMO
Pancreatic cancer is one of the most lethal kinds of cancer; numerous patients die from it every year all over the word. Fewer than 5% of people with pancreatic cancer survive death and recover. Recent evidence suggests that inflammation parameters, such as Th17 cells and Tregs, affect the progression and even the diagnosis and treatment of pancreatic cancer. In the inflammation process, T lymphocytes play an essential role in inflammation intensity, and related cytokines modulate immune responses in the tumor microenvironment. Their function is to establish a balance between destructive inflammation and defense against tumor cells via immune system, and Treg/Th17 imbalance is a common problem in this cancer. The role of microbiota in the development of some cancers is clear; microbiota may also be involved in the pancreatic cancer development. All risk factors for pancreatic cancer, such as chronic pancreatitis-related to microbiota, influence the acute or chronic immune response. Some evidence has been presented regarding the role of the immune response in carcinogenesis. In addition, miRNAs are very important in suppressing and stimulating the growth of cancer cells, and a variety of them have been identified. Some miRNAs are abnormally expressed in many cancers and have main roles as post-transcriptional regulators. They show oncogenic or tumor-suppressive functions by binding to marked mRNAs. In this review, we highlight recent findings regarding the role of Treg/Th17 imbalance, microbiota functions, and miRNAs performance in pancreatic cancer. We also present the evidence regarding therapeutic options.
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MicroRNAs/imunologia , Microbiota/imunologia , Neoplasias Pancreáticas/terapia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Microambiente TumoralRESUMO
Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis.
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Macrófagos/imunologia , Neoplasias/imunologia , Neovascularização Patológica/imunologia , Indutores da Angiogênese/metabolismo , Animais , Citocinas/metabolismo , Progressão da Doença , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Metástase Neoplásica/fisiopatologia , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Microambiente Tumoral/imunologiaRESUMO
Due to aging populations and changes in lifestyle, cardiovascular diseases including cardiomyopathy, hypertension, and atherosclerosis, are the leading causes of death worldwide. The heart is a complicated organ composed of multicellular types, including cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, and immune cells. Cellular specialization and complex interplay between different cell types are crucial for the cardiac tissue homeostasis and coordinated function of the heart. Mounting studies have demonstrated that dysfunctional cells and disordered cardiac microenvironment are closely associated with the pathogenesis of various cardiovascular diseases. In this paper, we discuss the composition and the homeostasis of cardiac tissues, and focus on the role of cardiac environment and underlying molecular mechanisms in various cardiovascular diseases. Besides, we elucidate the novel treatment for cardiovascular diseases, including stem cell therapy and targeted therapy. Clarification of these issues may provide novel insights into the prevention and potential targets for cardiovascular diseases.
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Aterosclerose , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/patologia , Células Endoteliais/metabolismo , Miócitos Cardíacos/patologia , EnvelhecimentoRESUMO
Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.
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Transtorno do Espectro Autista , Modelos Animais de Doenças , Edaravone , Estresse Oxidativo , Ácido Valproico , Animais , Ácido Valproico/farmacologia , Ácido Valproico/administração & dosagem , Edaravone/farmacologia , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/induzido quimicamente , Feminino , Estresse Oxidativo/efeitos dos fármacos , Masculino , Administração Oral , Gravidez , Ratos , Ratos Sprague-Dawley , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/uso terapêutico , Relação Dose-Resposta a Droga , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Interação Social/efeitos dos fármacosRESUMO
The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.
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Extinção Psicológica , Metanfetamina , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Metanfetamina/farmacologia , Feminino , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Camundongos , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Condroitina ABC Liase/farmacologiaRESUMO
Mitochondria-associated endoplasmic reticulum membranes (MAMs) are formed by physical connections of the endoplasmic reticulum and mitochondria. Over the past decades, great breakthroughs have been made in the study of ER-mitochondria communications. It has been identified that MAM compartments are pivotal in regulating neurological function. Accumulating studies indicated that MAMs participate in the development of cardiovascular diseases. However, the specific role of MAMs in heart failure remains to be fully understood. In this article, we first summarize the structural and functional properties of MAM and MAM-associated proteins. We then focus on the roles of MAMs in myocardial infarction, cardiomyopathy and heart failure, and discuss the involvement of MAMs in disease progression and treatment. Elucidating these issues may provide important insights into therapeutic intervention of heart failure.
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The emerging lead halide perovskites show great potential for their use as emitters in electrically driven light-emitting diodes (LEDs) with external quantum efficiency (EQE) over 25%. While the toxicity of lead and inferior device stability are the main obstacles for their commercialization, replacing Pb2+ with low- or non-toxic metal ions to form low- or zero-dimensional structures provides an alternative approach to effectively tackle these issues. Recently, luminescent lead-free metal halides have been increasingly developed toward eco-friendly and highly efficient electroluminescence. In this feature article, we give a brief overview of recent advances in luminescent lead-free metal halides and their applications in electrically driven LEDs. The challenges and prospects in this field are outlined at the end.
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OBJECTIVE: To investigate DNA methylation (DNAm) status of dickkopf-associated protein 1 (DKK-1) in ossified hip capsule synovium and serum among patients with ankylosing spondylitis (AS). METHODS: Western blot was applied to detect the level of DKK-1 protein expression in hip joint capsule tissues from four patients with AS as well as four patients with femoral neck fracture (FNF) caused by trauma as control. DKK-1 gene promoter methylation (GPM) was examined by methylation-specific polymerase chain reaction. Reverse transcription-polymerase chain reaction was performed to examine the messenger RNA (mRNA) levels of DKK-1, ß-catenin, and Wnt3a in both tissue and serum. The DNAm status of serum DKK-1 was measured among 36 patients with AS and syndesmophytes (AS + syndesmophytes group), 40 patients with AS but no syndesmophyte (AS group), and 42 healthy individuals (control group). Also, the serum levels of DKK-1 were measured by enzyme-linked immunosorbent assay. The modified New York criteria (mNYC) together with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were adopted to examine the radiographic progression of AS. The receiver operating characteristic (ROC) curve was applied to investigate the diagnostic value of the methylation rate of DKK-1 with regard to radiographic progression. RESULTS: The expressions of DKK-1 protein and mRNA in hip joint capsule tissues of AS patients were significantly lower, while DKK-1 GPM rate, ß-catenin mRNA, and Wnt3a mRNA were markedly higher when compared with FNF group. For serum samples, the DKK-1 methylation rate was significantly higher in AS+ syndesmophytes group in contrast to AS group and healthy controls. Serum levels of DKK-1 protein and mRNA in AS with syndesmophytes group were markedly decreased, while ß-catenin mRNA and Wnt3a mRNA expressions were significantly increased than AS with no syndesmophyte group and the healthy control group. AS patients in Grade 4 showed a significantly higher serum DKK-1 GPM rate than those in Grade 3 based on mNYC. Serum DKK-1 GPM level was markedly and positively correlated with mSASSS. Serum levels of DKK-1 in AS+ syndesmophytes group were markedly lower compared with AS but no syndesmophyte group and healthy controls. ROC curve analysis indicated that serum DKK-1 methylation rate serves as a decent indicator for AS radiographic progression. CONCLUSION: DNAm of DKK-1 may correlate with pathological bone formation in AS, which may provide new strategies for the treatment of AS abnormal bone formation.
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Espondilite Anquilosante , Humanos , beta Catenina/genética , Metilação de DNA , Osteogênese , Coluna Vertebral/patologia , Espondilite Anquilosante/genéticaRESUMO
Methamphetamine (Meth), a commonly used central nervous system stimulant, is highly addictive. Currently, there is no effective treatment for Meth dependence and abuse, although cell adhesion molecules (CAMs) have been shown to play an important role in the formation and remodeling of synapses in the nervous system while also being involved in addictive behavior. Contactin 1 (CNTN1) is a CAM that is widely expressed in the brain; nevertheless, its role in Meth addiction remains unclear. Therefore, in the present study, we established mouse models of single and repeated Meth exposure and subsequently determined that CNTN1 expression in the nucleus accumbens (NAc) was upregulated in mice following single or repeated Meth exposure, whereas CNTN1 expression in the hippocampus was not significantly altered. Intraperitoneal injection of the dopamine receptor 2 antagonist haloperidol reversed Meth-induced hyperlocomotion and upregulation of CNTN1 expression in the NAc. Additionally, repeated Meth exposure also induced conditioned place preference (CPP) in mice and upregulated the expression levels of CNTN1, NR2A, NR2B, and PSD95 in the NAc. Using an AAV-shRNA-based approach to specifically silence CNTN1 expression in the NAc via brain stereotaxis reversed Meth-induced CPP and decreased the expression levels of NR2A, NR2B, and PSD95 in the NAc. These findings suggest that CNTN1 expression in the NAc plays an important role in Meth-induced addiction, and the underlying mechanism may be related to the expression of synapse-associated proteins in the NAc. The results of this study improved our understanding of the role of cell adhesion molecules in Meth addiction.
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Transtornos Relacionados ao Uso de Anfetaminas , Estimulantes do Sistema Nervoso Central , Metanfetamina , Camundongos , Animais , Metanfetamina/farmacologia , Núcleo Accumbens , Contactina 1/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Encéfalo/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismoRESUMO
Background: The significance of implicit self-schema and other-schema in major depressive disorder (MDD) is highlighted by both cognitive theory and attachment theory. The purpose of the current study was to investigate the behavioral and event-related potential (ERP) characteristics of implicit schemas in MDD patients. Methods: The current study recruited 40 patients with MDD and 33 healthy controls (HCs). The participants were screened for mental disorders using the Mini-International Neuropsychiatric Interview. Hamilton Depression Rating Scale-17 and Hamilton Anxiety Rating Scale-14 were employed to assess the clinical symptoms. Extrinsic Affective Simon Task (EAST) was conducted to measure the characteristics of implicit schemas. Meanwhile, reaction time and electroencephalogram data were recorded. Results: Behavioral indexes showed that HCs responded faster to positive self and positive others than negative self (t = -3.304, p = 0.002, Cohen's d = 0.575) and negative others (t = -3.155, p = 0.003, Cohen's d = 0.549), respectively. However, MDD did not show this pattern (p > 0.05). The difference in other-EAST effect between HCs and MDD was significant (t = 2.937, p = 0.004, Cohen's d = 0.691). The ERP indicators of self-schema showed that under the condition of positive self, the mean amplitude of LPP in MDD was significantly smaller than that in HCs (t = -2.180, p = 0.034, Cohen's d = 0.902). The ERP indexes of other-schema showed that HCs had a larger absolute value of N200 peak amplitude for negative others (t = 2.950, p = 0.005, Cohen's d = 0.584) and a larger P300 peak amplitude for positive others (t = 2.185, p = 0.033, Cohen's d = 0.433). The above patterns were not shown in MDD (p > 0.05). The comparison between groups found that under the condition of negative others, the absolute value of N200 peak amplitude in HCs was larger than that in MDD (t = 2.833, p = 0.006, Cohen's d = 1.404); under the condition of positive others, the P300 peak amplitude (t = -2.906, p = 0.005, Cohen's d = 1.602) and LPP amplitude (t = -2.367, p = 0.022, Cohen's d = 1.100) in MDD were smaller than that in HCs. Conclusion: Patients with MDD lack positive self-schema and positive other-schema. Implicit other-schema might be related to abnormalities in both the early automatic processing stage and the late elaborate processing stage, while the implicit self-schema might be related only to the abnormality in the late elaborate processing stage.
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Background: Many psychotherapy theories emphasise the importance of self-schema and other-schema, but most previous studies focused on the explicit self-schema in major depressive disorder (MDD). However, the limited studies of implicit self-schema in MDD have shown inconsistencies in their findings. Furthermore, only a few studies have investigated the implicit other-schema, and the pathway illustrating how implicit schemas influence depression remains unclear. Aims: The primary aim of our study was to explore the characteristics of implicit self-schema and other-schema in patients with MDD. We also examine the chain-mediating effect of attachment relationships and interpersonal trust. Methods: The present study included 88 patients with MDD and 88 healthy controls (HCs). The Hamilton Depression Rating Scale-17, Experiences in Close Relationships Inventory-Revised Questionnaire, Trust Scale and the Extrinsic Affective Simon Task (EAST) were used to assess depressive symptoms, attachment relationships, interpersonal trust and implicit schemas, respectively. Paired sample t-test was used to compare the reaction time (RT) for positive and negative words within the two groups. Analysis of covariance was used to explore the difference between two groups from the perspective of implicit schemas and interpersonal patterns. The chain mediation model was verified by bootstrap. Results: (1) For interpersonal patterns, patients with MDD scored significantly higher on attachment anxiety (F=82.150, p<0.001) and attachment avoidance (F=23.192, p<0.001) and scored significantly lower on the predictability (F=30.297, p<0.001), dependence (F=39.728, p<0.001) and faith (F=60.997, p<0.001) dimensions of interpersonal trust. (2) As for implicit schemas, no significant difference was found between the RT for positive self-words and negative self-words in patients with MDD (t=-1.056, p=0.294). However, the HC responded faster to positive self-words than negative self-words (t=-3.286, p=0.001). The RT for positive other-words and negative other-words were significantly different in both patients with MDD (t=2.943, p=0.004) and HCs (t=-2.482, p=0.015), with opposite directions. The EAST effect of other-schema in patients with MDD was significantly different from that in HCs (F=13.051, p<0.001). (3) For the total sample, the EAST effect of other-schema significantly correlated with attachment avoidance, interpersonal trust and depressive symptoms. Attachment avoidance and interpersonal trust were the chain mediators between the EAST effect of other-schema and depressive symptoms (95% CI: -0.090 to -0.008). However, no significant results were found for the EAST effect of other-schema when correlation and mediation analyses were performed for HCs and patients with MDD separately. Conclusions: This study verified that patients with MDD have abnormal interpersonal patterns and negative implicit schemas. However, no mediating effect of attachment relationships and interpersonal trust was found.
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"Molecular glue" (MG) is a term coined to describe the mechanism of action of the plant hormone auxin and subsequently used to characterize synthetic small molecule protein degraders exemplified by immune-modulatory imide drugs (IMiDs). Prospective development of MGs, however, has been hampered by its elusive definition and thermodynamic characteristics. Here, we report the crystal structure of a dual-nanobody cannabidiol-sensing system, in which the ligand promotes protein-protein interaction in a manner analogous to auxin. Through quantitative analyses, we draw close parallels among the dual-nanobody cannabidiol sensor, the auxin perception complex, and the IMiDs-bound CRL4CRBN E3, which can bind and ubiquitinate "neo-substrates". All three systems, including the recruitment of IKZF1 and CK1α to CRBN, are characterized by the lack of ligand binding activity in at least one protein partner and an under-appreciated preexisting low micromolar affinity between the two proteinaceous subunits that is enhanced by the ligand to reach the nanomolar range. These two unifying features define MGs as a special class of proximity inducers distinct from bifunctional compounds and can be used as criteria to guide target selection for future rational discovery of MGs.
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Adesivos/química , Canabidiol/química , Nanoestruturas/química , Caseína Quinase Ialfa , Fator de Transcrição Ikaros , Ácidos Indolacéticos , Lenalidomida , Modelos Moleculares , Ligação Proteica , Especificidade por Substrato , UbiquitinaçãoRESUMO
Pancreatic cancer (PC) is a fatal tumor with high mortality. Pyroptosis plays a tumor suppressor role as a novel cell death. However, the influences of the pyroptosis-related lncRNAs (PRlncRNAs) on the prognosis and tumor microenvironment (TME) infiltration have not been fully studied in PC. Using coexpression analysis and univariate Cox regression analysis, we identified seventeen prognostic PRlncRNAs from The Cancer Genome Atlas (TCGA) dataset, which were all expressed differently in normal and tumor samples. A seven-PRlncRNA risk signature was constructed and validated using the least absolute shrinkage and selection operator (LASSO) regression. Furthermore, we verified its independence and created a nomogram to validate the clinical viability of the risk signature. We then identified its relationship with clinical factors and evaluated its values in TME infiltration, functional enrichment, tumor mutation, and therapeutic responses in PC. Lower ImmuneScore, ESTIMATEScore, and advanced tumor stage were connected with high-risk score. The low-risk group was characterized by better OS, elevated immune activation, and higher susceptibility of pazopanib and sunitinib. The high-risk group possessed a worse immune infiltration and poor survival, with higher tumor mutations and lapatinib and paclitaxel that may be better choices in this group. In conclusion, we developed an original seven-PRlncRNA risk signature to predict prognosis, TME infiltration, tumor mutation, and therapeutic options for PC patients.
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Neoplasias Pancreáticas , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Piroptose/genética , Microambiente Tumoral/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias PancreáticasRESUMO
Angiogenesis, a hallmark of cancer, is related to prognosis, tumor progression, and treatment response. Nevertheless, the correlation of angiogenesis-based molecular signature with clinical outcome and immune cell infiltration has not been thoroughly studied in pancreatic cancer. In this study, multiple bioinformatics methods were combined to evaluate prognosis, immune cell infiltration, and the alterations of angiogenesis-related genes (ARGs) in PC samples, and further establish a novel angiogenesis-related gene signature. Moreover, the protein and mRNA expression levels of four angiogenesis risk genes were determined by Human Protein Atlas (HPA) database and qPCR analysis, respectively. Here, we recognized two distinct angiogenesis subtypes and two gene subtypes, and revealed the critical roles of ARGs in the tumor immune microenvironment (TIME), clinical features, and prognosis. Consequently, we established an ARGs score to predict prognosis and therapeutic response of PC patients, and validated its robust predictive ability. Additionally, the ARGs score was markedly associated with clinical outcomes, tumor mutation burden (TMB), and chemotherapeutic drug sensitivity. In brief, our findings imply that the ARGs score is a robust prognostic indicator and may contribute to the development of effective individualized therapies for PC.
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy and lacks effective therapeutic targets. Trametinib is considered to be a promising potential indirectly targeted KRAS inhibitor in PDAC. However, the clinical outcomes were poor. JQ1 displayed a significant synergistic effect when combined with chemotherapy or potential targeted therapy in pancreatic cancer. The impact of Trametinib and JQ1 combination treatment in PDAC remains to be fully elucidated. METHODS: The efficacy of trametinib and JQ1 on cell proliferation and cytotoxicity was assayed in 7 KRAS mutant pancreatic cancer cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using a luminescent cell viability assay. Immunoblot analysis was carried out to investigate changes in p62 and autophagy. RESULTS: We found that either trametinib or JQ1 alone inhibited the proliferation of some pancreatic cancer cell lines with KRAS alterations, irrespective of the mutational loci of KRAS and the aberrant status of the other driver genes. The synergistic effects of combination treatment of trametinib and JQ1 were observed in both trametinib-resistant and trametinib-sensitive cells. In trametinib-sensitive PDAC cells, the combined treatment definitely inhibited p62 expression compared with trametinib alone, while LC3 expression at high levels changed little. In trametinib-resistant PDAC cells, the combination of MEK/BET inhibitor dramatically decreased p62 expression compared with single agent, while p62 expression increased after anti-autophagic therapy was added. CONCLUSIONS: Blocking RAS downstream signaling and epigenetic pathway synergistically increases the antiproliferative activity in KRAS mutant PDAC cells. Combination therapeutic synergism may induce different cell death modes in different pancreatic cancer subtypes.