Using molecular signatures, previous studies have defined glioblastoma (GBM) subtypes with different phenotypes, such as the proneural (PN), neural (NL), mesenchymal (MES) and classical (CL) ...subtypes. However, the gene programmes underlying the phenotypes of these subtypes were less known. We applied weighted gene co‐expression network analysis to establish gene modules corresponding to various subtypes. RNA‐seq and immunohistochemical data were used to validate the expression of identified genes. We identified seven molecular subtype‐specific modules and several candidate signature genes for different subtypes. Next, we revealed, for the first time, that radioresistant/chemoresistant gene signatures exist only in the PN subtype, as described by Verhaak et al, but do not exist in the PN subtype described by Phillips et al PN subtype. Moreover, we revealed that the tumour cells in the MES subtype GBMs are under ER stress and that angiogenesis and the immune inflammatory response are both significantly elevated in this subtype. The molecular basis of these biological processes was also uncovered. Genes associated with alternative RNA splicing are up‐regulated in the CL subtype GBMs, and genes pertaining to energy synthesis are elevated in the NL subtype GBMs. In addition, we identified several survival‐associated genes that positively correlated with glioma grades. The identified intrinsic characteristics of different GBM subtypes can offer a potential clue to the pathogenesis and possible therapeutic targets for various subtypes.
ObjectivePatients with increased PD-L1+ host cells in tumours are more potent to benefit from antiprogrammed death-1/programmed death ligand-1 (PD-L1) treatment, but the underlying mechanism is still ...unclear. We aim to elucidate the nature, regulation and functional relevance of PD-L1+ host cells in hepatocellular carcinoma (HCC).DesignA total of untreated 184 HCC patients was enrolled randomly. C57BL/6 mice are given injection of Hepa1-6 cells to form autologous hepatoma. ELISpot, flow cytometry and real-time PCR are applied to analyse the phenotypic characteristics of PD-L1+ cells isolated directly from HCC specimens paired with blood samples or generated from ex vivo and in vitro culture systems. Immunofluorescence and immunohistochemistry are performed to detect the presence of immune cells on paraffin-embedded and formalin-fixed samples. The underlying regulatory mechanisms of metabolic switching are assessed by both in vitro and in vivo studies.ResultsWe demonstrate that PD-L1+ host macrophages, which constructively represent the major cellular source of PD-L1 in HCC tumours, display an HLA-DRhighCD86high glycolytic phenotype, significantly produce antitumourigenic IL-12p70 and are polarised by intrinsic glycolytic metabolism. Mechanistically, a key glycolytic enzyme PKM2 triggered by hepatoma cell derived fibronectin 1, via a HIF-1α-dependent manner, concurrently controls the antitumourigenic properties and inflammation-mediated PD-L1 expression in glycolytic macrophages. Importantly, although increased PKM2+ glycolytic macrophages predict poor prognosis of patients, blocking PD-L1 on these cells eliminates PD-L1-dominant immunosuppression and liberates intrinsic antitumourigenic properties.ConclusionsSelectively modulating the ‘context’ of glycolytic macrophages in HCC tumours might restore their antitumourigenic properties and provide a precise strategy for anticancer therapy.
Hepatic insulin resistance is a major characteristic of type 2 diabetes mellitus. LncRNA MEG3 has been shown to correlate to hepatic glucose production; however, the underlying mechanism remains ...unclear. This study aims to investigate the role of MEG3 in hepatic insulin resistance.
High-fat diet mice, ob/ob mice and mice primary hepatocytes were used in this study. Expression of MEG3, FoxO1, G6pc and Pepck were determined by real-time PCR. FoxO1, G6pc, Pepck, HDAC1 and HDAC3 protein levels were analyzed by western blotting. Hepatic gluconeogenesis, glycogen accumulation, triglyceride and glycogen contents were measured by corresponding assay or kit, and body weight was monitored after an overnight fast.
Gene expression of MEG3 was upregulated in high-fat diet and ob/ob mice and increased by palmitate, oleate or linoleate. MEG3 overexpression significantly increased FoxO1, G6pc, Pepck mRNA expressions and hepatic gluconeogenesis and suppressed insulin-stimulated glycogen synthesis in primary hepatocytes, whereas palmitate-induced increase of FoxO1, G6pc and Pepck protein expressions could be reversed by MEG3 interference. In addition, high fat enhanced expression of lncRNA MEG3 in hepatocytes through histone acetylation. Furthermore, MEG3 interference could reverse the up-regulation of triglyceride as well as impaired glucose tolerance and down-regulation of glucogen content in high-fat diet mice or ob/ob mice.
Upregulation of lncRNA MEG3 enhances hepatic insulin resistance via increasing foxO1expression, suggesting that MEG3 may be a potential target and therapeutic strategy for diabetes.
•MEG3 expression is upregulated in high-fat diet and ob/ob mice and by palmitate, oleate or linoleate.•MEG3 affects FoxO1, G6pc and Pepck expression, hepatic gluconeogenesis and glycogen synthesis.•High fat enhances expression of lncRNA MEG3 in hepatocytes through histone acetylation.•MEG3 interference recovers upregulation of triglyceride and downregulation of glucogen content.•MEG3 interference attenuates glucose tolerance in high-fat diet mice and ob/ob mice.
Abstract
Licorice is one of the oldest and most frequently used herbs in traditional Chinese medicine. It contains more than 20 triterpenoids and 300 flavonoids. In recent years, a lot of studies ...have reported that the active compounds isolated from licorice possess antitumor, antimicrobial, antiviral, anti-inflammatory, immunoregulatory, and several other activities that contribute to the recovery and protection of the nervous, alimentary, respiratory, endocrine, and cardiovascular systems. In this paper, nine different pharmacological activities of licorice are summarized. The active compounds responsible for these pharmacological activities, the molecular mechanisms, and
in vivo
and
in vitro
studies are listed in detail. Furthermore, the clinical therapeutics and toxicity studies of licorice are also discussed. We hope this work can provide a basis for further studies concerning with the safe and effective use of licorice.
Objective: Transcranial focused ultrasound (tFUS) is regarded as a promising non-invasive stimulation tool for modulating brain circuits. The aim of this study is to explore the feasibility of tFUS ...stimulation for analgesia applications. Methods: 50 µl of 3% formalin solution was injected into the rat's left hindpaw to build a pain model, and then the local field potential (LFP) activities of the dorsal horn were tracked after a recording electrode was placed in the spinal cord. Rats were randomly divided into two groups: control group and tFUS group. At the 30 th minute after formalin injection, tFUS (US-650 kHz, PD = 1 ms, PRF = 100 Hz, 691 mW/cm 2 ) was conducted to stimulate the periaqueductal gray (PAG) for 5 minutes (on 5 s and off 5 s) in the tFUS group, but there was no treatment in the control group. In addition, the analgesia mechanism (LFP recording from the PAG) and safety assessment (histology analysis) were carried out. Results: The tFUS stimulation of the PAG can suppress effectively the nociceptive activity generated by formalin. The findings of the underlying mechanism exploration indicated that the tFUS stimulation was able to activate the PAG directly without causing notable temperature change and tissue injury. Conclusion: The results illustrated that the tFUS stimulation of the PAG can achieve the effect of analgesia. Significance: This work provides new insights into the development of non-invasive analgesic technology in the future.
To analyze the relationship between olanzapine blood concentration and clinical efficacy in schizophrenia patients, which has been expected to provide a scientific reference basis for improving the ...treatment effect of olanzapine in schizophrenia patients. Four hundred eighty-six psychiatric inpatients were randomly selected from October 31, 2019, to October 31, 2020, and all enrolled patients were given olanzapine treatment, and the treatment effect of schizophrenia patients was assessed according to the Positive and Negative Symptom Scale subtraction rate, and divided into treatment effective and ineffective groups at 1, 2, and 3 weeks of treatment, respectively. The olanzapine blood concentration in the body was monitored at 1, 2, and 3 weeks of treatment, and the relationship between olanzapine blood concentration and treatment effect at different time points was analyzed. Patients in the ineffective group had lower olanzapine blood concentrations than the effective group in treatment 1, 2, and 3 weeks and lower Positive and Negative Symptom Scale score reduction rates than the effective group (P < .05); the differences in other baseline information between the groups were not statistically significant (P > .05). Logistic regression analysis showed that olanzapine blood concentration at different times of treatment was related to the treatment effect (odds ratio > 1, P < .05); the results of the bivariate Spearman linear correlation test showed that olanzapine blood concentration at different times of treatment was positively related to the treatment effect of schizophrenia patients (R > 0, P < .05). In schizophrenia patients treated with olanzapine, the higher the olanzapine blood concentration in patients, the better the clinical treatment effect. Accordingly, the clinical can develop individualized medication regimens based on the results of blood concentration testing in the body under the premise of ensuring safety, aiming to ensure maximum efficacy.
Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In ...this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion.
To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated
and
.
Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization
the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion
the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs.
This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion
M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.
Recent discoveries of two-dimensional transitional metal based materials have emerged as an excellent candidate for fabricating nanostructured flame-retardants. Herein, we report an eco-friendly ...flame-retardant for flexible polyurethane foam (PUF), which is synthesised by hybridising MXene (TiFormula: see text) with biomass materials including phytic acid (PA), casein, pectin, and chitosan (CH). Results show that coating PUFs with 3 layers of CH/PA/TiFormula: see text via layer-by-layer approach reduces the peak heat release and total smoke release by 51.1% and 84.8%, respectively. These exceptional improvements exceed those achieved by a CH/TiFormula: see text coating. To further understand the fundamental flame and smoke reduction phenomena, a pyrolysis model with surface regression was developed to simulate the flame propagation and char layer. A genetic algorithm was utilised to determine optimum parameters describing the thermal degradation rate. The superior flame-retardancy of CH/PA/TiFormula: see text was originated from the shielding and charring effects of the hybrid MXene with biomass materials containing aromatic rings, phenolic and phosphorous compounds.
METTL3 is known to be involved in all stages in the life cycle of RNA. It affects the tumor formation by the regulation the m6A modification in the mRNAs of critical oncogenes or tumor suppressors. ...In bladder cancer, METTL3 could promote the bladder cancer progression via AFF4/NF-κB/MYC signaling network by an m6A dependent manner. Recently, METTL3 was also found to affect the m6A modification in non-coding RNAs including miRNAs, lincRNAs and circRNAs. However, whether this mechanism is related to the proliferation of tumors induced by METTL3 is not reported yet.
Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of METTL3 in bladder cancer. The survival analysis was adopted to explore the association between METTL3 expression and the prognosis of bladder cancer. Bladder cancer cells were stably transfected with lentivirus and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of METTL3 in bladder cancer. RNA immunoprecipitation (RIP), co-immunoprecipitations and RNA m6A dot blot assays were conducted to confirm that METTL3 interacted with the microprocessor protein DGCR8 and modulated the pri-miR221/222 process in an m6A-dependent manner. Luciferase reporter assay was employed to identify the direct binding sites of miR221/222 with PTEN. Colony formation assay and CCK8 assays were conducted to confirm the function of miR-221/222 in METTL3-induced cell growth in bladder cancer.
We confirmed the oncogenic role of METTL3 in bladder cancer by accelerating the maturation of pri-miR221/222, resulting in the reduction of PTEN, which ultimately leads to the proliferation of bladder cancer. Moreover, we found that METTL3 was significantly increased in bladder cancer and correlated with poor prognosis of bladder cancer patients.
Our findings suggested that METTL3 may have an oncogenic role in bladder cancer through interacting with the microprocessor protein DGCR8 and positively modulating the pri-miR221/222 process in an m6A-dependent manner. To our knowledge, this is the first comprehensive study that METTL3 affected the tumor formation by the regulation the m6A modification in non-coding RNAs, which might provide fresh insights into bladder cancer therapy.
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