Saikosaponin D mitigate pilocarpine-induced astrocyte injury by regulating the NLRP3/caspase-1 signaling pathway.

Studies have shown that saikosaponin D (SSD) has favorable neurotherapeutic effects. Therefore, the objective of this study was to explore the efficacy and possible molecular mechanisms of SSD on pilocarpine (PP)-induced astrocyte injury. Primary astrocytes were isolated from juvenile rats and identified using immunofluorescence. The cells were treated with PP and/or SSD for 6 h and 12 h, respectively, followed by measurement of their viability through 3-(4,5-dimethylthiazol)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Next, quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of Glial fibrillary acidic protein (GFAP), C3, S100 calcium binding protein A10 (S100a10), pentraxin 3 (Ptx3), toll-like receptor 4 (TLR4), and RAG in astrocytes after different treatments. Enzyme-linked immunosorbent assay and biochemical tests were utilized to evaluate the level of inflammatory factors [interleukin (IL)-1ß, IL-6, and tumor necrosis factor alpha (TNF-α)] secreted by cells and the content of oxidative stress-related factors (malondialdehyde [MDA] and glutathione [GSH]) or enzyme activity (catalase [CAT] and glutathione peroxidase [GPX]) in cells. The JC-1 mitochondrial membrane potential (MMP) fluorescence probe was used to measure the MMP in astrocytes. Additionally, western blot was applied to test the expression of proteins related to the nod-like receptor protein 3 (NLRP3)/caspase-1 signaling pathway. PP treatment (1 mM) induced cell injury by significantly reducing the viability of astrocytes and expression of cellular markers. SSD treatment (4 µM) had no toxicity to astrocytes. Besides, SSD (4 µM) treatment could significantly up-regulate the cell viability and marker expression of PP-induced astrocytes. Furthermore, SSD could be employed to inhibit inflammation (reduce IL-1ß, IL-6, and TNF-α levels) and oxidative stress (decrease MDA level, elevate GSH level, the activity of CAT and GPX), and ameliorate mitochondrial dysfunction (upregulate JC-1 ratio) in PP-induced astrocytes. Moreover, further mechanism exploration revealed that SSD treatment significantly reduced the activity of the NLRP3/caspase-1 signaling pathway activated by PP induction. SSD increased cell viability, inhibited inflammation and oxidative stress response, and ameliorated mitochondrial dysfunction in PP-induced astrocyte injury model, thus playing a neuroprotective role. The mechanism of SSD may be related to the inhibition of the NLRP3/caspase-1 inflammasome.

Elucidating the role of Rhodiola rosea L. in sepsis-induced acute lung injury via network pharmacology: emphasis on inflammatory response, oxidative stress, and the PI3K-AKT pathway.

CONTEXT: Sepsis-induced acute lung injury (ALI) is associated with high morbidity and mortality. Rhodiola rosea L. (Crassulaceae) (RR) and its extracts have shown anti-inflammatory, antioxidant, immunomodulatory, and lung-protective effects. OBJECTIVE: This study elucidates the molecular mechanisms of RR against sepsis-induced ALI. MATERIALS AND METHODS: The pivotal targets of RR against sepsis-induced ALI and underlying mechanisms were revealed by network pharmacology and molecular docking. Human umbilical vein endothelial cells (HUVECs) were stimulated by 1 µg/mL lipopolysaccharide for 0.5 h and treated with 6.3, 12.5, 25, 50, 100, and 200 µg/mL RR for 24 h. Then, the lipopolysaccharide-stimulated HUVECs were subjected to cell counting kit-8 (CCK-8), enzyme-linked immunosorbent, apoptosis, and Western blot analyses. C57BL/6 mice were divided into sham, model, low-dose (40 mg/kg), mid-dose (80 mg/kg), and high-dose (160 mg/kg) RR groups. The mouse model was constructed through caecal ligation and puncture, and histological, apoptosis, and Western blot analyses were performed for further validation. RESULTS: We identified six hub targets (MPO, HRAS, PPARG, FGF2, JUN, and IL6), and the PI3K-AKT pathway was the core pathway. CCK-8 assays showed that RR promoted the viability of the lipopolysaccharide-stimulated HUVECs [median effective dose (ED50) = 18.98 µg/mL]. Furthermore, RR inhibited inflammation, oxidative stress, cell apoptosis, and PI3K-AKT activation in lipopolysaccharide-stimulated HUVECs and ALI mice, which was consistent with the network pharmacology results. DISCUSSION AND CONCLUSION: This study provides foundational knowledge of the effective components, potential targets, and molecular mechanisms of RR against ALI, which could be critical for developing targeted therapeutic strategies for sepsis-induced ALI.

3D color multimodality fusion imaging as an augmented reality educational and surgical planning tool for extracerebral tumors.

Extracerebral tumors often occur on the surface of the brain or at the skull base. It is important to identify the peritumoral sulci, gyri, and nerve fibers. Preoperative visualization of three-dimensional (3D) multimodal fusion imaging (MFI) is crucial for surgery. However, the traditional 3D-MFI brain models are homochromatic and do not allow easy identification of anatomical functional areas. In this study, 33 patients with extracerebral tumors without peritumoral edema were retrospectively recruited. They underwent 3D T1-weighted MRI, diffusion tensor imaging (DTI), and CT angiography (CTA) sequence scans. 3DSlicer, Freesurfer, and BrainSuite were used to explore 3D-color-MFI and preoperative planning. To determine the effectiveness of 3D-color-MFI as an augmented reality (AR) teaching tool for neurosurgeons and as a patient education and communication tool, questionnaires were administered to 15 neurosurgery residents and all patients, respectively. For neurosurgical residents, 3D-color-MFI provided a better understanding of surgical anatomy and more efficient techniques for removing extracerebral tumors than traditional 3D-MFI (P < 0.001). For patients, the use of 3D-color MFI can significantly improve their understanding of the surgical approach and risks (P < 0.005). 3D-color-MFI is a promising AR tool for extracerebral tumors and is more useful for learning surgical anatomy, developing surgical strategies, and improving communication with patients.

Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts through regulation of the HOXA6/ZBTB12 axis.

Cancer-associated fibroblasts (CAFs) play critical roles in the tumor microenvironment and exert tumor-promoting or tumor-retarding effects on cancer development. Astragaloside IV has been suggested to rescue the pathological impact of CAFs in gastric cancer. This study aimed to investigate the potential mechanism of astragaloside IV in the regulation of CAF pathological functions in gastric cancer development. Homeobox A6 (HOXA6), and Zinc Finger and BTB Domain Containing 12 (ZBTB12) are highly expressed in gastric CAFs compared with normal fibroblasts (NFs) based on the GSE62740 dataset. We found that astragaloside IV-stimulated CAFs suppressed cell growth, migration, and invasiveness of gastric cancer cells. HOXA6 and ZBTB12 were downregulated after astragaloside IV treatment in CAFs. Further analysis revealed that HOXA6 or ZBTB12 knockdown in CAFs also exerted inhibitory effects on the malignant phenotypes of gastric cells. Additionally, HOXA6 or ZBTB12 overexpression in CAFs enhanced gastric cancer cell malignancy, which was reversed after astragaloside IV treatment. Moreover, based on the hTFtarget database, ZBTB12 is a target gene that may be transcriptionally regulated by HOXA6. The binding between HOXA6 and ZBTB12 promoter in 293T cells and CAFs was further confirmed. HOXA6 silencing also induced the downregulation of ZBTB12 mRNA and protein in CAFs. Astragaloside IV was demonstrated to regulate the expression of ZBTB12 by mediating the transcriptional activity of HOXA6. Our findings shed light on the therapeutic value of astragaloside IV for gastric cancer.

Predicting the emergence of malignant brain oedema in acute ischaemic stroke: a prospective multicentre study with development and validation of predictive modelling.

Background: We aimed to develop and validate a prognostic model for predicting malignant brain oedema in patients with acute ischaemic stroke in a real-world setting of practice. Methods: A prospective multicentre study enrolled adult patients with acute ischaemic stroke with brain CT < 24 h of onset of symptoms admitted to nine tertiary-level hospitals in China between September 2017 and December 2019. Malignant brain oedema was defined as any patient who had decompressive craniectomy, discharge in coma, or in-hospital death attributed to symptomatic brain swelling. The derivation cohort was a consecutive cohort of patients from one centre and the validation cohort was non-consecutive patients from the other centres. Multivariable logistic regression was used to define independent predictors from baseline clinical characteristics, imaging features, complications, and management. A web-based nomogram and a risk score were developed based on the final model. Model performance was assessed for discrimination and calibration in both derivation and validation cohorts. The study is registered, NCT03222024. Findings: Based on the derivation cohort (n = 1627), the model was developed with seven variables including large infarct (adjusted odds ratio [OR] 40.90, 95% CI 20.20-82.80), National Institutes of Health Stroke Scale (NIHSS) score (OR 1.09, 1.06-1.12), thrombolysis (OR 2.11, 1.18-3.78), endovascular treatment (OR 2.87, 1.47-5.59), pneumonia (OR 2.47, 1.53-3.97), brain atrophy (OR 0.57, 0.37-0.86), and recanalisation (OR 0.36, 0.17-0.75). The classification threshold of a predicted probability ≥0.14 showed good discrimination and calibration in both derivation cohort (area under the receiver-operating curve [AUC] 0.90, 0.87-0.92; sensitivity 0.95, 0.92-0.98) and validation cohort (n = 556, AUC 0.88, 0.82-0.95; sensitivity 0.84, 0.73-0.95). The risk score based on this model had a total point that ranged from -1 to 20, with an optimal score of ≥10 showing good discrimination and calibration in both derivation (AUC 0.89, 0.87-0.92; sensitivity 0.95, 0.92-0.98) and validation (AUC 0.88, 0.82-0.95; sensitivity 0.84, 0.73-0.95) cohorts. Interpretation: The INTEP-AR model (i.e. large Infarct, NIHSS score, Thrombolysis, Endovascular treatment, Pneumonia, brain Atrophy, and Recanalisation) incorporating multiple clinical and radiological characteristics has shown good prognostic value for predicting malignant brain oedema after acute ischaemic stroke. Funding: National Natural Science Foundation of China; Science and Technology Department of Sichuan Province; West China Hospital.

Chromosomal aberrations and prognostic analysis of secondary acute myeloid leukemia-a retrospective study.

Background: Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods: The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients' transition to AML (i.e., at S-AML diagnosis). Results: The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20-77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P < 0.05). Conclusion: S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid.

Preparation of MOF/polypyrrole and flower-like MnO2 electrodes by electrodeposition: High-performance materials for hybrid capacitive deionization defluorination.

Fluorine pollution has become a global public health problem due to its adverse health effects. Adsorption is the primary method for removing fluoride from drinking water. However, the adsorption method has disadvantages such as difficulty in recovering the adsorbent, and the need to add additional chemicals for regeneration, thereby causing secondary pollution, which limits further industrial applications. Capacitive deionization (CDI), as an emerging water treatment technology, has attracted widespread attention due to its advantages of simple operation, low energy consumption and less environmental impact. In this study, a polypyrrole (PPy) film was prepared on a graphite substrate by electrodeposition, and then metal-organic framework Ce/Zn-BDC-NH2 (CZBN) was deposited on the PPy film by electrophoretic deposition to obtain CZBN/PPy electrode was obtained. The CZBN/PPy anode was then coupled with the MnO2 cathode for capacitive removal of fluoride in a CDI cell. Both CZBN/PPy and MnO2 electrodes exhibit pseudocapacitive behavior, which can selectively and reversibly intercalate F- (CZBN/PPy) and Na+ (MnO2) ions. As expected, the CZBN/PPy-MnO2 system exhibits excellent fluorine removal performance. In 1.2 V, 100 mg/L F- solution, the F- removal capacity can reach 55.12 mg/g. It has high F- selectivity in the presence of some common anions, and can maintain high F- removal ability even after five adsorption regeneration processes. The mechanism of F- removal was studied by Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). F- was mainly removed by electrostatic interaction and ion exchange with hydroxyl. The excellent defluorination performance of the CZBN/PPy-MnO2 system makes it have good practical application prospects.

The mechanisms underlying the actions of Xuefu Zhuyu decoction pretreatment against neurological deficits after ischemic stroke in mice: The mediation of glymphatic function by aquaporin-4 and its anchoring proteins.

Ischemic stroke (IS) has been associated with an impairment in glymphatic function. Xuefu Zhuyu Decoction (XFZYD) is widely used in the prevention and treatment of ischemic stroke. We hypothesized that Xuefu Zhuyu decoction pretreatment could attenuate early neurological deficits after ischemic stroke by enhancing the function of the glymphatic system. To prove our hypothesis, we carried out temporary middle cerebral artery occlusion and reperfusion surgery on C57BL/6 mice and then measured neurological score, infarct size and performed hematoxylin-eosin staining to assess stroke outcomes after 24 h of reperfusion. Subsequently, we injected fluorescent tracers in to the cisterna magna and evaluated tracer distribution in coronal brain sections. The polarization of aquaporin-4 (AQP4), colocalization of aquaporin-4, α-dystroglycan, ß-dystroglycan and agrin were determined by immunofluorescence. Our research showed that pretreatment with Xuefu Zhuyu decoction significantly alleviated neurological scores, neurological deficits and pathological abnormalities in a mouse model of ischemic stroke. Importantly, Xuefu Zhuyu decoction pretreatment enhanced cerebrospinal fluid influx, protected aquaporin-4 depolarization and promoted the colocalization of aquaporin-4 with its anchoring proteins in the brain. Our findings highlight novel mechanisms underlying the neuroprotective effect of Xuefu Zhuyu decoction pretreatment on ischemic stroke-induced brain damage through the glymphatic system. Xuefu Zhuyu decoction pretreatment may offer a promising approach to slow the onset and progression of ischemic stroke.

Retraction: Down-regulated LncR-MALAT1 suppressed cell proliferation and migration by inactivating autophagy in bladder cancer.

[This retracts the article DOI: 10.1039/C8RA04876B.].

Branched-chain amino acid catabolism breaks glutamine addiction to sustain hepatocellular carcinoma progression.

Branched-chain amino acid (BCAA) catabolism is related to tumorigenesis. However, the underlying mechanism and specific contexts in which BCAAs affect tumor progression remain unclear. Here, we demonstrate that BCAA catabolism is activated in liver cancer cells without glutamine. Enhanced BCAA catabolism leads to BCAA-derived carbon and nitrogen flow toward nucleotide synthesis, stimulating cell-cycle progression and promoting cell survival. Mechanistically, O-GlcNAcylation increases under glutamine-deprivation conditions and stabilizes the PPM1K protein, leading to dephosphorylation of BCKDHA and enhanced decomposition of BCAAs. Dephosphorylation of BCKDHA and high expression of PPM1K promote tumorigenesis in vitro and in vivo and are closely related to the poor prognosis of clinical patients with hepatocellular carcinoma (HCC). Inhibition of BCAA and glutamine metabolism can further retard HCC growth in vivo. These results not only elucidate a mechanism by which BCAA catabolism affects tumorigenesis but also identify pBCKDHA and PPM1K as potential therapeutic targets and predictive biomarkers.

Mechanism of hydroxysafflor yellow A on acute liver injury based on transcriptomics.

Objective: To investigate how Hydroxysafflor yellow A (HSYA) effects acute liver injury (ALI) and what transcriptional regulatory mechanisms it may employ. Methods: Rats were randomly divided into five groups (n = 10): Control, Model, HSYA-L, HSYA-M, and HSYA-H. In the control and model groups, rats were intraperitoneally injected with equivalent normal saline, while in the HSYA groups, they were also injected with different amounts of HSYA (10, 20, and 40 mg/kg/day) once daily for eight consecutive days. One hour following the last injection, the control group was injected into the abdominal cavity with 0.1 ml/100 g of peanut oil, and the other four groups got the same amount of a peanut oil solution containing 50% CCl4. Liver indexes were detected in rats after dissection, and hematoxylin and eosin (HE) dyeing was utilized to determine HSYA's impact on the liver of model rats. In addition, with RNA-Sequencing (RNA-Seq) technology and quantitative real-time PCR (qRT-PCR), differentially expressed genes (DEGs) were discovered and validated. Furthermore, we detected the contents of anti-superoxide anion (anti-O2 -) and hydrogen peroxide (H2O2), and verified three inflammatory genes (Icam1, Bcl2a1, and Ptgs2) in the NF-kB pathway by qRT-PCR. Results: Relative to the control and HSYA groups, in the model group, we found 1111 DEGs that were up-/down-regulated, six of these genes were verified by qRT-PCR, including Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, and Creld2, indicated that these genes were obviously involved in the regulation of HSYA in ALI model. Membrane rafts, membrane microdomains, inflammatory response, regulation of cytokine production, monooxygenase activity, and iron ion binding were significantly enriched in GO analysis. KEGG analysis revealed that DEGs were primarily enriched for PPAR, retinol metabolism, NF-kB signaling pathways, etc. Last but not least, compared with the control group, the anti-O2 - content was substantially decreased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were considerably elevated in the model group. Compared with the model group, the anti-O2 - content was substantially increased, the H2O2 content and inflammatory genes (Icam1, Bcl2a1, and Ptgs2) levels were substantially decreased in the HSYA group (p < 0.05). Conclusion: HSYA could improve liver function, inhibit oxidative stress and inflammation, and improve the degree of liver tissue damage. The RNA-Seq results further verified that HSYA has the typical characteristics of numerous targets and multiple pathway. Protecting the liver from damage by regulating the expression of Tymp, Fabp7, Serpina3c, Gpnmb, Il1r1, Creld2, and the PPAR, retinol metabolism, NF-kappa B signaling pathways.

De Winter electrocardiogram pattern due to type A aortic dissection: a case report.

BACKGROUND: De Winter electrocardiograph (ECG) pattern is an atypical presentation of acute myocardial infarction (AMI) due to severe stenosis of the left anterior descending (LAD). Complications of acute aortic dissection (AD) in the setting of acute myocardial infarction (AMI) with de Winter sign are relatively rare and physicians may easily miss the diagnosis of AD. We report a case of patient with acute chest pain and de Winter ECG pattern due to AD involving the left main coronary artery (LM), LAD and left circumflex artery (LCX). CASE PRESENTATION: A 57-year-old male patient was initially diagnosed with AMI and then the diagnosis of acute AD was supported by transthoracic echocardiograph (TTE). After two stents were implanted respectively into the proximal LM-LAD and LM-LCX, he recovered from cardiogenic shock. Two months later, the patient underwent the surgery of ascending aorta replacement. After the surgery, there was no obvious chest discomfort during follow-up. CONCLUSIONS: When an ECG shows a "de Winter pattern", we should also consider the possibility of AD which result in LAD occlusion. TTE is a useful tool in screening for AD. Further research is needed to prove that percutaneous coronary intervention (PCI) may be a useful treatment strategy in the case of AD leading to severe LAD occlusion and unstable hemodynamics when there's no condition to perform aortic replacement surgery immediately.

CircRNA6783 Inhibits Cell Proliferation and Promotes Apoptosis in Lung Adenocarcinoma.

Purpose: Circular RNA (circRNA) serves an important role in tumour genesis and development. But, little is known about its role in lung adenocarcinoma (LA). This study aimed to investigate circRNA6783 expression in peripheral whole blood (PWB) of LA and controls and explore its effect on proliferation and apoptosis in human lung adenocarcinoma cells (LAC). Patients and Methods: The levels of circRNA6783 in LA cell lines and peripheral whole blood (PWB) of 40 patients and 30 controls were detected by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). In order to explore the effect of circRNA6783 on LA behavior, we overexpressed circRNA6783 in NCI-H1975 cells. The impact on the proliferation of tumor cells was then examined by Cell Counting Kit 8 (CCK8) assay, and the effects on apoptosis in the cell line were detected using flow cytometry. Results: The expression levels of circRNA6783 were significantly higher in LA cell lines and PWB (P < 0.05). The diagnostic value of the area under the receiver operating characteristic curve (AUC) was 0.830, with a sensitivity of 60% and specificity of 96.7%. In addition, functional experiments showed that overexpression of circRNA6783 restrained cell proliferation, significantly increased spontaneous apoptosis. Conclusion: CircRNA6783 was upregulated in LA PWB. In vitro assessment demonstrated that circRNA6783 could act as a potential biomarker for LA diagnosis.

[Immunomodulatory effect of adriamycin in mouse 4T1 model of breast cancer].

To explore the immunomodulatory effect of adriamycin on 4T1 breast cancer. We used a tandem mass tag-based quantitative proteomic method to detect differential proteins in breast cancer tissues, and multiple bioinformatics databases to analyze the differentially expressed proteins in the proteome. Also, we used enzyme-linked immunosorbent assay to detect the effects of adriamycin on helper T cells 1 and 2 in breast cancer tissues, and flow cytometry to detect CD4+ T cells, CD8+ T cells and regulatory T cells. We discovered the immunomodulatory targets of adriamycin in differential proteins. In total 170 differential proteins were significantly up-regulated, whereas 58 were markedly down-regulated. In addition, 73 proteins were involved in immune regulation. Kyoto encyclopedia of genes and genomes enriched important protein pathways related to cytokines and factor receptors, interleukin 17 pathway and cancer transcriptional regulatory pathways. These pathways and important differential proteins related to immunomodulatory functions were ultimately regulated by adriamycin on CD4+ T cells, CD8+ T cells and regulatory T cells, thereby affecting the prognosis of breast cancer. Moreover, adriamycin significantly increased interleukin 2, CD4+ T and CD8+ T (P<0.01) and markedly reduced regulatory T cells (P<0.05). The function of adriamycin against triple-negative breast cancer was closely related to the immunoregulation process of the differential proteins Ighm, Igkc, S100A8, S100A9 and Tmsb4x. Adriamycin could regulate the content of helper T cells 1 cytokines, CD4+ T and CD8+ T lymphocytes in breast cancer and reduce the number of regulatory T cells to produce immunomodulatory effects.

Long Non-coding RNA Expression Patterns in Stomach Adenocarcinoma Serve as an Indicator of Tumor Mutation Burden and Are Associated With Tumor-Infiltrating Lymphocytes and Microsatellite Instability.

Long non-coding RNAs (lncRNAs) are crucial in controlling important aspects of tumor immunity. However, whether the expression pattern of lncRNAs in stomach adenocarcinoma (STAD) reflects tumor immunity is not fully understood. We screened differentially expressed lncRNAs (DElncRNAs) between high and low tumor mutation burden (TMB) STAD samples. Using the least absolute shrinkage and selection operator method, 33 DElncRNAs were chosen to establish a lncRNA-based signature classifier for predicting TMB levels. The accuracy of the 33-lncRNA-based signature classifier was 0.970 in the training set and 0.950 in the test set, suggesting the expression patterns of the 33 lncRNAs may be an indicator of TMB in STAD. Survival analysis showed that a lower classifier index reflected better prognosis for STAD patients, and the index showed correlation with expression of immune checkpoint molecules (PD1, PDL1, and CTLA4), tumor-infiltrating lymphocytes, and microsatellite instability. In conclusion, STAD samples with different tumor mutation burdens have different lncRNA expression patterns. The 33-lncRNA-based signature classifier index may be an indicator of TMB and is associated expression of immune checkpoints, tumor-infiltrating lymphocytes, and microsatellite instability.

The lncRNA XIST/miR-125b-2-3p axis modulates cell proliferation and chemotherapeutic sensitivity via targeting Wee1 in colorectal cancer.

BACKGROUND: Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR-125b-2-3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR-125b-2-3p in advanced CRC under chemotherapy have yet to be elucidated. METHODS: MiR-125b-2-3p expression was detected by real-time PCR (RT-PCR) in CRC tissues. The effects of miR-125b-2-3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR-125b-2-3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. RESULTS: MiR-125b-2-3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR-125b-2-3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR-125b-2-3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR-125b-2-3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR-125b-2-3p inhibited the proliferation and epithelial-mesenchymal transition (EMT) of CRC induced by lncRNA XIST. CONCLUSIONS: Lower miR-125b-2-3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR-125b-2-3p to mediate WEE1 expression. LncRNA XIST-miR-125b-2-3p-WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC.

MYC promotes cancer progression by modulating m6 A modifications to suppress target gene translation.

The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m6 A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m6 A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m6 A controls the translation of MRG mRNA via the specific m6 A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m6 A modifications in selected MRG transcripts promotes cancer progression.

Simplified flow cytometry scoring for diagnosis and prognosis of myelodysplastic symptom.

A flow cytometric score (FCM-score) to diagnose myelodysplastic syndromes (MDS) was proposed in 2012 that used four parameters to distinguish low-grade MDS from non-clonal cytopenias. This study was carried out to further simplify the method for better clinical application. Combinations of antibodies CD34, CD19, CD33 and CD45 were analyzed for the four parameters. Compared with the published method that used low side scatter (SSC) and CD45 expression to separate B lymphocyte progenitor cells and myeloblasts, our method (MFCM-Score) used CD19 and CD33 to separate B lymphocyte progenitor cells and myeloblasts within the CD34+CD45dimm population. Subjects were analyzed and compared using the two schemes. In addition, the relationships between the MFCM-Score and the Revised International Prognostic Scoring System (IPSS-R) for MDS were analyzed. There was no significant difference between the MFCM-score and FCM-score in the diagnosis of MDS (P > 0.05); MFCM-score had a positive correlation with the IPSS-R prognosis classification for MDS (Spearman r = 0.848, P < 0.001). All parameters in the MFCM-score were positively correlated to the IPSS-R grades in MDS (P < 0.01). Our work demonstrates that the FCM score using four parameters is simple and practical for screening MDS patients and the MFCM-score could be used to evaluate the risk of MDS patients.

Myc-mediated SDHA acetylation triggers epigenetic regulation of gene expression and tumorigenesis.

The transcriptional role of cMyc (or Myc) in tumorigenesis is well appreciated; however, it remains to be fully established how extensively Myc is involved in the epigenetic regulation of gene expression. Here, we show that by deactivating succinate dehydrogenase complex subunit A (SDHA) via acetylation, Myc triggers a regulatory cascade in cancer cells that leads to H3K4me3 activation and gene expression. We find that Myc facilitates the acetylation-dependent deactivation of SDHA by activating the SKP2-mediated degradation of SIRT3 deacetylase. We further demonstrate that Myc inhibition of SDH-complex activity leads to cellular succinate accumulation, which triggers H3K4me3 activation and tumour-specific gene expression. We demonstrate that acetylated SDHA at Lys 335 contributes to tumour growth in vitro and in vivo, and we confirm increased tumorigenesis in clinical samples. This study illustrates a link between acetylation-dependent SDHA deactivation and Myc-driven epigenetic regulation of gene expression, which is critical for cancer progression.