Guanine-Rich RNA Sequence Binding Factor 1 Deficiency Promotes Colorectal Cancer Progression by Regulating PI3K/AKT Signaling Pathway.

Background: Guanine-rich RNA sequence binding factor 1 (GRSF1), part of the RNA-binding protein family, is now attracting interest due to its potential association with the progression of a variety of human cancers. The precise contribution and molecular mechanism of GRSF1 to colorectal cancer (CRC) progression, however, have yet to be clarified. Methods: Immunohistochemistry and Western Blot analysis was carried out to detect the expression of GRSF1 in CRC at both mRNA and protein levels and its subsequent effects on prognosis. A series of functional tests were performed to understand its influence on proliferation, migration, and invasion of CRC cells. Results: The universal downregulation of GRSF1 in CRC was identified, indicating a correlation with poor prognosis. Our functional studies unveiled that the elimination of GRSF1 enhances tumour activities such as proliferation, migration, and invasion of CRC cells, while GRSF1 overexpression curtailed these abilities. Conclusion: Notably, we uncovered that GRSF1 insufficiency modulates the PI3K/Akt signaling pathway and Ras activation in CRC. Therefore, our data suggest GRSF1 operates as a tumor suppressor gene in CRC and may offer promise as a potential biomarker and novel therapeutic target in CRC management.

First-line immunotherapy efficacy in advanced squamous non-small cell lung cancer with PD-L1 expression ≥50%: a network meta-analysis of randomized controlled trials.

Objective: The optimal first-line immunotherapy regimen for patients with PD-L1 expression ≥50% in squamous non-small cell lung cancer (Sq-NSCLC) remains uncertain. This study utilized net-work meta-analysis (NMA) to indirectly compare the efficacy of various first-line immuno-therapy regimens in this patient subset. Methods: Systematic searches were conducted across PubMed, the Cochrane Library, Web of Science, and Embase databases for randomized controlled trials reporting overall survival (OS) and progression-free survival (PFS) outcomes. The search spanned from database inception to November 3, 2023. Bayesian network meta-analysis was employed for a comprehen-sive analysis. To ensure scientific rigor and transparency, this study is registered in the Interna-tional Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022349712. Results: The NMA encompassed 9 randomized controlled trials (RCTs), involving 2170 patients and investigating 9 distinct immunotherapy regimens. For OS, the combination of camrelizumab and chemotherapy demonstrated the highest probability (36.68%) of efficacy, fol-lowed by cemiplimab (33.86%) and atezolizumab plus chemotherapy (23.87%). Regarding PFS, the camrelizumab and chemotherapy combination had the highest probability (39.70%) of efficacy, followed by pembrolizumab (22.88%) and pembrolizumab plus chemotherapy (17.69%). Compared to chemotherapy, first-line treatment with immune checkpoint inhibitors (ICIs) in Sq-NSCLC pa-tients exhibited significant improvements in OS (HR 0.59, 95% CI 0.47-0.75) and PFS (HR 0.44, 95% CI 0.37-0.52). Conclusion: This study suggests that, for Sq-NSCLC patients with PD-L1 expression ≥50%, the first-line immunotherapy regimen of camrelizumab plus chemotherapy provides superior OS and PFS outcomes. Furthermore, ICIs demonstrate enhanced efficacy compared to chemotherapy in this patient population. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD 42022349712.

CircTBC1D22A inhibits the progression of colorectal cancer through autophagy regulated via miR-1825/ATG14 axis.

Distant metastasis is the main cause of death in patients with colorectal cancer (CRC). A better understanding of the mechanisms of metastasis can greatly improve the outcome of patients with CRC. Accumulating evidence suggests that circRNA plays pivotal roles in cancer progression and metastasis, especially acting as a miRNA sponge to regulate the expression of the target gene. A public database bioinformatics analysis found that miR-1825 was highly expressed in CRC tissues. In this study, miR-1825 was highly expressed in CRC tissues, which was positively correlated with lymph node metastasis and distant metastasis. In vitro and in vivo experiments confirmed that miR-1825 was positively correlated with the proliferation and migration of CRC cells. This event can be inhibited by circTBC1D22A. CircTBC1D22A can directly interact with miR-1825 and subsequently act as a miRNA sponge to regulate the expression of the target gene ATG14, which collectively advances the autophagy-mediated progression and metastasis of CRC.

Pathogenic RAB34 variants impair primary cilium assembly and cause a novel oral-facial-digital syndrome.

Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in over 20 genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia. We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families. Affected individuals presented a novel form of OFDS (OFDS-RAB34) accompanied by cardiac, cerebral, skeletal and anorectal defects. RAB34 encodes a member of the Rab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Unlike many genes required for cilium assembly, RAB34 acts selectively in cell types that use the intracellular ciliogenesis pathway, in which nascent cilia begin to form in the cytoplasm. We find that the protein products of these pathogenic variants, which are clustered near the RAB34 C-terminus, exhibit a strong loss of function. Although some variants retain the ability to be recruited to the mother centriole, cells expressing mutant RAB34 exhibit a significant defect in cilium assembly. While many Rab proteins have been previously linked to ciliogenesis, our studies establish RAB34 as the first small GTPase involved in OFDS and reveal the distinct clinical manifestations caused by impairment of intracellular ciliogenesis.

COL10A1-DDR2 axis promotes the progression of pancreatic cancer by regulating MEK/ERK signal transduction.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors with a poor prognosis. Type X collagen α 1 chain (COL10A1), a member of the collagen family, is a gene associated with the progression of a variety of human tumors, but the specific function and molecular mechanism of COL10A1 in pancreatic cancer remain unclear. Our study found that COL10A1 is highly expressed in pancreatic cancer cells and tissues, and its high expression is related to poor prognosis and some clinicopathological features, such as tumor size and differentiation. Biological functional experiments showed that overexpression of COL10A1 enhanced the proliferation and migration of PDAC cells. Interestingly, discoid protein domain receptor 2 (DDR2), the receptor of COL10A1, is regulated by COL10A1. We found that the COL10A1-DDR2 axis activates the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, which leads to epithelial-mesenchymal transformation (EMT) and accelerates the progression of pancreatic cancer. In summary, COL10A1 regulates PDAC cell proliferation and MEK/ERK signaling pathways by binding to DDR2 to promote migration, invasion and EMT. Our study suggested that COL10A1 might be a critical factor in promoting PDAC progression. More research is needed to confirm COL10A1 as a potential biomarker and therapeutic target for PDAC.

Portulaca oleracea L. extracts alleviate 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice.

Atopic dermatitis (AD) is a common chronic allergic skin disease characterized clinically by severe skin lesions and pruritus. Portulaca oleracea L. (PO) is a resourceful plant with homologous properties in medicine and food. In this study, we used two different methods to extract PO, and compared the therapeutic effects of PO aqueous extract (POAE) and PO ultrasound-assisted ethanol extract (POEE) on 2,4-dinitrochlorobenzene (DNCB)-induced AD mice. The results showed that in POAE and POEE, the extraction rates of polysaccharides were 16.95% and 9.85%, while the extraction rates of total flavonoids were 3.15% and 3.25%, respectively. Compared with AD mice, clinical symptoms such as erythema, edema, dryness and ulceration in the back and left ear were alleviated, and pruritus behavior was reduced after POAE and POEE treatments. The thickness of the skin epidermis was thinned, the density of skin nerve fibers labeled with protein gene product 9.5 (PGP9.5) was decreased, and mast cell infiltration was reduced. There was a decrease in blood lymphocytes, eosinophils and basophils, a significant decrease in spleen index and a noticeable decrease in serum immunoglobulin E (Ig E). POEE significantly reduced the concentration of the skin pruritic factor interleukin (Il)-31. POAE and POEE reduced the concentration of skin histamine (His), down-regulated mRNA expression levels of interferon-γ (Ifnγ), tumor necrosis factor-α (Tnf-α), thymic stromal lymphopoietin (Tslp) and Il-4, with an increase of Filaggrin (Flg) and Loricrin (Lor) in skin lesions. These results suggested that POAE and POEE may inhibit atopic response and alleviate the clinical symptoms of AD by inhibiting the expression of immune cells, inflammatory mediators and cytokines. PO may be a potential effective drug for AD-like diseases.

Eu2+ as the structural probe in the phase transformation of CMSA by site-selective occupancy and adjustable multimode white luminescence in Ca2(Mg0.5Al0.5)(Si1.5Al0.5O7) akermanite based on high-aluminum blast furnace slag.

A tunable multimode white emission Ca2(Mg0.5Al0.5)(Si1.5Al0.5O7):Eu2+/Eu3+ phosphor was prepared by doping Eu2O3 in molten high-aluminum blast furnace slag. The structural probe Eu2+ was studied during phase transformation between the glassy state and Ca2(Mg0.5Al0.5)(Si1.5Al0.5O7) crystals based on site-selective Eu2+ occupancy. When the doped Eu2+ ions occupied two different Ca2+ sites in the matrix, blue light (421 nm) and green light (516 nm) emissions were observed corresponding to two types of Eu2+Ca2+, namely Eu2+Ca2+ (Mg2+ → Al3+) and Eu2+Ca2+ (Si4+ → Al3+). The effects of Eu concentration (0.1-2.0 mol%), heat treatment temperature (800-1000 °C), and thermal quenching temperature (30-150 °C) on the structural evolution of the emission unit were studied by differential scanning calorimetry (DSC), photoluminescence spectroscopy (PL) and X-ray diffraction (XRD) analyses. The Eu2+Ca2+ (Mg2+ → Al3+) structure formed by site-selective Eu2+ occupancy possessed better structural stability in the Ca2(Mg0.5Al0.5)(Si1.5Al0.5O7) crystal matrix, in favour of light-emitting diode (LED) illumination and plasma display panels (PDPs).

Scutellarin acts on the AR-NOX axis to remediate oxidative stress injury in a mouse model of cerebral ischemia/reperfusion injury.

BACKGROUND: Oxidative stress plays an important role in the pathology of ischemic stroke. Studies have confirmedthat scutellarin has antioxidant effects against ischemic injury, and we also reported that the involvement of Aldose reductase (AR) in oxidative stress and cerebral ischemic injury, in this study we furtherly explicit whether the antioxidant effect of scutellarin on cerebral ischemia injury is related to AR gene regulation and its specific mechanism. METHODS: C57BL/6N mice (Wild-type, WT) and AR knockout (AR-/-) mice suffered from transient middle cerebral artery occlusion (tMCAO) injury (1 h occlusion followed by 3 days reperfusion), and scutellarin was administered from 2 h before surgery to 3 days after surgery. Subsequently, neurological function was assessed by the modified Longa score method, the histopathological morphology observed with 2,3,5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (Elisa) was used to detect the levels of ROS, 4-hydroxynonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHDG), Neurotrophin-3 (NT-3), poly ADP-ribose polymerase-1 (PARP1) and 3-nitrotyrosine (3-NT) in the ischemic penumbra regions. Quantitative proteomics profiling using quantitative nano-HPLC-MS/MS were performed to compare the protein expression difference between AR-/- and WT mice with or without tMCAO injury. The expression of AR, nicotinamide adenine dinucleotide phosphate oxidases (NOX1, NOX2 and NOX4) in the ipsilateral side of ischemic brain were detected by qRT-PCR, Western blot and immunofluorescence co-staining with NeuN. RESULTS: Scutellarin treatment alleviated brain damage in tMCAO stroke model such as improved neurological function deficit, brain infarct area and neuronal injury and reduced the expression of oxidation-related products, moreover, also down-regulated tMCAO induced AR mRNA and protein expression. In addition, the therapeutic effect of scutellarin on the reduction of cerebral infarction area and neurological function deficits abolished in AR-/- mice under ischemia cerebral injury, which indicated that the effect of scutellarin treatment on tMCAO injury is through regulating AR gene. Proteomic analysis of AR-/- and WT mice indicated AR knockout would affect oxidation reaction even as NADPH related process and activity in mice under cerebral ischemia conditions. Moreover, NOX isoforms (NOX1, NOX2 and NOX4) mRNA and protein expression were significant decreased in neurons of penumbra region in AR-/- mice compared with that in WT mice at 3d after tMCAO injury, which indicated that AR should be the upstream protein regulating NOX after cerebral ischemia. CONCLUSIONS: We first reported that AR directly regulates NOX subtypes (not only NOX2 but also NOX1 and NOX4) after cerebral ischaemic injury. Scutellarin specifically targets the AR-NOX axis and has antioxidant effects in mice with cerebral ischaemic injury, providing a theoretical basis and accurate molecular targets for the clinical application of scutellarin.

LncRNA NEAT1 Promotes Gastric Cancer Progression Through miR-17-5p/TGFßR2 Axis Up-Regulated Angiogenesis.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been indicated to play critical roles in gastric cancer (GC) tumorigenesis and progression. However, their roles in GC remain to be further elucidated. METHODS: RT-qPCR and fluorescence in situ hybridzation (FISH) were conducted to detect the expression of lncRNA NEAT1 in GC tissues and cell lines. Gene Set Enrichment Analysis (GSEA) was performed to screen out potential phenotypes and pathways that NEAT1 may participate in. NEAT1-silenced AGS and MGC803 cells were constructed and a series of functional experiments to investigate the roles of NEAT1 in GC angiogenesis both in vitro and in vivo. RNA pull down and luciferase reporter assays were utilized to illustrate the mechanisms underlying the functions of NEAT1 in GC. RESULTS: We observed that NEAT1 was upregulated in most GC specimens and cell lines. NEAT1 high was correlated with poor prognosis of GC patients. In vitro experiments showed that NEAT1 promoted GC angiogenesis by enhancing proliferation, migration, and tube formation ability of endothelial cells. Mechanism researches revealed that NEAT1 could competitively sponge miR-17-5p which targeted TGFßR2 directly. Subsequently, activate TGFß/Smad pathway by following with upregulation of a series of classical proangiogenic factors especially VEGF. CONCLUSION: The study unveiled that the LncRNA NEAT1/miR-17-5p/TGFßR2 axis is a novel mechanism in GC angiogenesis. Disrupting this axis may be a potential strategy for GC treatment.

Resveratrol induces human colorectal cancer cell apoptosis by activating the mitochondrial pathway via increasing reactive oxygen species.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer­related mortality worldwide according to Global Cancer Statistics 2018. Resveratrol (RSV) is a phenolic compound that possesses anticancer functions against various types of cancer, including breast and gastric cancer. However, the functions and mechanism underlying RSV in CRC are not completely understood. The present study aimed to investigate the anticancer effects and mechanism underlying RSV in CRC cells by conducting Cell Counting Kit­8, apoptosis, reactive oxygen species (ROS) and western blotting assays. The results suggested that RSV dose­dependently inhibited CRC cell viability, and increased cell apoptosis and ROS levels compared with the control group. The protein expression levels of Bax, cytochrome c, cleaved caspase­9 and cleaved caspase­3 were upregulated, whereas Bcl­2 expression levels were downregulated in RSV­treated CRC cells compared with control cells. The results indicated that RSV might activate the mitochondrial apoptotic pathway by increasing ROS release. The present study suggested that RSV possessed antitumour activity against CRC by modulating an ROS­mediated mitochondrial apoptotic pathway.

Analyzing microsatellite instability and gene mutation in circulating cell-free DNA to monitor colorectal cancer progression.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Detection of microsatellite instability (MSI) status and gene mutations may be useful for molecular targeted therapy. The liquid biopsy is a newly developed, non-invasive method for tumor diagnosis and monitoring. In this study, we evaluated the possible clinical value of liquid biopsy by analyzing MSI and gene mutation. METHODS: Next-generation sequencing (NGS) was used to analyze MSI and gene mutation in circulating cell-free DNA (cfDNA) and tissue DNA extracted from 6 CRC patients' plasma and matched primary tumor tissue (MPTT) samples, respectively. RESULTS: A total of 6 patients (4 male, 2 female) were included for analysis, whose stage ranges from stage I through stage III. NGS-based panel of 5 quasi-monomorphic microsatellite markers (MSI-NGS) BAT-25, BAT-26, NR21, NR24 as well as NR27, and 4 mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1) expressions assessed by immunohistochemistry (MMR-IHC) and NGS (MMR-NGS) were used to determine MSI status synergistically. Comprehensive analysis of NGS and IHC results showed that the overall incidences of MSI in plasma and MPTT samples from these patients were 1/6 and 2/6, respectively. 4 patients were defined as microsatellite stable (MSS) in both plasma and MPTT. In the above 6 patients, MSI-NGS detection in cfDNA accurately identified 1/2 of tissue high-level microsatellite instability (MSI-H) and 4/4 of tissue MSS for an overall accuracy of 5/6. Gene mutational profiles in these CRC patients' plasma and MPTT samples were analyzed by NGS. Tumor-specific gene mutations were detected in 2/6 of plasma and 4/4 of MPTT samples. The two mutation-positive plasma samples were from CRC patients at stage IIb and stage IIIc. CONCLUSIONS: Analyzing MSI and gene mutation might be a non-invasive supplementary way to reveal the molecular characteristics of CRC.

Agaricus blazei polypeptide exerts a protective effect on D-galactose-induced aging mice via the Keap1/Nrf2/ARE and P53/Trim32 signaling pathways.

This experiment mainly optimized the extraction technology of Agaricus blazei polypeptide (ABp) and evaluated its protective effect on aging mice. In this study, a novel single component, the M is 3 kD, was isolated and purified from Agaricus blazei. An aging mouse model was established using D-galactose. After the administration of ABp, the contents of total antioxidant capacity (T-AOC), malondialdehyde (MDA), catalase (CAT), and reactive oxygen species were significantly changed. Through immunofluorescence staining, it was observed that ABp can reduce changes in brain tissue. The differential expression of genes was analyzed by RNA-seq. A total of 295 differentially expressed genes were screened out in the ABp group.RT-qPCR verified important genes and showed that the mRNA expression levels of Hsph1, Trim32, HK1, Hnrnpa1, and Grik5 were significantly increased, and those of ApoE, Atp1a3, Stxbp1, and Mapk8ip1 was significantly decreased. Western blotting showed that the protein expression levels of Keap1 and p53 were significantly lower, while the protein expression levels of Nrf2, HO-1, Hsph1, and Trim32 were significantly higher in the ABP group. ABp played an anti-aging role in an aging mouse model. The specific mechanism of action may be related to the regulation of the expression of the Keap1/Nrf2/P53 signaling pathway and related factors. PRACTICAL APPLICATIONS: The research may contribute to the development of ABp as functional foods or dietary supplements for anti-aging in the future.

Mir-20a-5p induced WTX deficiency promotes gastric cancer progressions through regulating PI3K/AKT signaling pathway.

BACKGROUND: The X-linked gene WTX (also called AMER1) has been reported to function as a tumour suppressor gene in Wilms' tumour. In our previous study, WTX expression was shown to be significantly reduced in gastric cancer (GC), but the function and mechanism associated with WTX loss had yet to be fully elucidated. METHODS: WTX expression and clinical significance were father analyzed in GC and control normal gastric tissues, and validated in public databases. The candidate pathway which was regulated by WTX during GC progression was searched by KEGG pathway analysis. The miRNA which monitored WTX expression was screened by miRNA microarray. After verified the pathway and miRNA both in vitro and in vivo, the relationship of miRNA, WTX and the downstream pathway were analyzed by Western blot, immunohistochemistry, RT-PCR, Co-immunoprecipitation (Co-IP), and luciferase analyses. RESULTS: The results showed that WTX serves as a tumour suppressor gene in GC. The loss of WTX which is associated with the aggressiveness of GC by promoting GC cell proliferation in vitro and high metastasis in vivo. Furthermore, WTX expression was positively correlated with the overall survival of GC patients. Microarray assays, bioinformatics analysis, and verification experiments showed that WTX loss activates the PI3K/AKT/mTOR pathway and promotes GC cell proliferation and invasion. And the aberrant miR-20a-5p upregulation contributes to WTX loss in GC, which stimulates PI3K phosphorylation to activate PI3K/AKT/mTOR signaling pathway and promoted GC progression. CONCLUSIONS: The results of the present study elucidated the mechanism of GC progression, which is at least partially caused by aberrant miR-20a-5p upregulation leading to the inhibition of WTX expression and PI3K/AKT/mTOR signaling pathway activation. These findings provide a comprehensive understanding of the action of the miR-20a-5p/WTX/PI3K/AKT/mTOR signaling pathway in the progression and metastasis of GC.

GFPT2 promotes metastasis and forms a positive feedback loop with p65 in colorectal cancer.

As a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation, Glutamine fructose-6-phosphate amidotransferase 2 (GFPT2) is involved in human breast and lung tumorigenesis. However, whether GFTP2 is associated with tumor metastasis remains unclear. Here, we found that GFPT2 promoted the proliferation, migration, invasion and metastasis of colorectal cancer (CRC) cells. Mechanically, p65 acted as an upstream transcription factor of GFPT2 and regulated its expression and function. In turn, GFPT2 enhanced the glycosylation of p65, which led to the nuclear translocation of p65 and then activated NF-κB pathway. Thus, GFTP2 and p65 formed a positive feedback loop to promote the progression of CRC. In addition, GFPT2 was up-regulated in CRC tissues and closely related with liver metastasis (P<0.0001) and tumor stage (P=0.0184). High expression of GFPT2 predicted poor prognosis for CRC patients. Moreover, GFTP2 expression was positively linked with O-linked N-acetylglucosamine transferase in CRC tissues. Our study reveals a new mechanism of GFPT2 in CRC metastasis and provides a new target therapeutic target to deter metastasis.

MicroRNA-451 Aggravates Kainic Acid-induced Seizure and Neuronal Apoptosis by Targeting GDNF.

AIM: Epilepsy is a common and serious neurological disease that causes recurrent episodes, but its molecular mechanism remains unclear. Abnormal miRNA expression is associated with epilepsy, including miR-451. This research investigated the role of miR-451 in seizure and its detailed mechanism. METHODS: The seizure mice model was induced by kainic acid (KA) injection to the right lateral cerebral ventricle. Behavioral changes in mice were observed and evaluated by the Racine Scale. The miR-451 knockout mice were established by adenovirus infection. The in vitro model was performed by miR-451 mimics transfected HEK-293 cells. The amount of neuronal death and morphological changes were evaluated by Nissl staining and H&E staining. RESULTS: The results showed that miR-451 is up regulated in KA-induced seizure models and miR- 451 knockout decreased the behavior score and improved the pathological changes of the hippocampus. Besides, MiR-451 knockout inhibited the apoptosis of hippocampal neurons. Bioinformatics studies have shown that glial cell line-derived neurotrophic factor (GDNF) is a target gene of miR-451. MiR-451 could negatively regulate the expression of GDNF. GDNF overexpression could reverse the effect of miR-451 on KA induced brain injury and neuronal apoptosis. CONCLUSION: This research demonstrates that miR-451 can affect the behavior of KA-induced epilepsy mice and hippocampal neuronal damage by regulating GDNF expression. The results would provide an experimental foundation for further research about the potential contribution of mi- RNAs to epilepsy pathophysiology.

Hydrocortisone Suppresses Early Paraneoplastic Inflammation And Angiogenesis To Attenuate Early Hepatocellular Carcinoma Progression In Rats.

BACKGROUND: Inflammation is implicated in both hepatic cirrhosis development and hepatocellular carcinogenesis, and treatment with long-acting glucocorticoid dexamethasone prevented liver carcinogenesis in mice. However, it is unclear whether glucocorticoids have anti-inflammatory effect on hepatocellular carcinoma (HCC) and if short-acting glucocorticoids (with fewer adverse effects) inhibit paraneoplastic inflammation and HCC progression. METHODS: To investigate whether different types of anti-inflammatory agents attenuate HCC progression, the current study compared effects of treatments with hydrocortisone (a short-acting glucocorticoid) or aspirin on HCC progression. HCC was induced in diethylnitrosamine-treated rats which were randomly divided into 4 groups (n=8), respectively receiving orally once daily vehicle, glucuronolactone, glucuronolactone+hydrocortisone, and glucuronolactone+aspirin. Diethylnitrosamine (DEN) was given to rats in drinking water (100mg/L) to induce HCC. At weeks 12 and 16 post-induction, effects were compared on HCC nodule formation, microvessel density, and macrophage infiltration, and levels of paraneoplastic protein expression of tumor necrosis factor (TNF)-α, p38 mitogen-activated protein kinase (p38), phosphorylated p38 (p-p38), nuclear factor (NF)-κB, interleukin (IL)-10, hepatocyte growth factor (HGF), transforming growth factor (TGF)-ß1 and vascular endothelial growth factor (VEGF). RESULTS: Compared to the model and glucuronolactone alone groups, HCC nodule number and microvessel density in the glucuronolactone+hydrocortisone group were significantly lower at week 12. At week 12 but not week 16, significantly lower levels of macrophages, TNF-α, p-p38, NF-κB, IL-10, HGF, TGF-ß1 and VEGF were observed in the paraneoplastic tissue of the glucuronolactone+hydrocortisone group when compared with the control and glucuronolactone groups. CONCLUSION: The results suggest that hydrocortisone treatment reduces macrophage polarization, expression of inflammatory and anti-inflammatory cytokines, and angiogenesis in paraneoplastic tissue, and attenuates early HCC progression. Although hydrocortisone did not have attenuation effect on advanced solid tumor, the current study shows the potential benefits and supports potential clinical use of hydrocortisone in attenuating early progression of HCC, which is through suppressing paraneoplastic inflammation and angiogenesis.

Overexpression of CENPF correlates with poor prognosis and tumor bone metastasis in breast cancer.

BACKGROUND: Centromere Protein F (CENPF) associates with the centromere-kinetochore complex and influences cell proliferation and metastasis in several cancers. The role of CENPF in breast cancer (BC) bone metastasis remains unclear. METHODS: Using the ONCOMINE database, we compared the expression of CENPF in breast cancer and normal tissues. Findings were confirmed in 60 BC patients through immunohistochemical (IHC) staining. Microarray data from GEO and Kaplan-Meier plots were used analyze the overall survival (OS) and relapse free survival (RFS). Using the GEO databases, we compared the expression of CENPF in primary lesions, lung metastasis lesions and bone metastasis lesions, and validated our findings in BALB/C mouse 4T1 BC models. Based on gene set enrichment analysis (GSEA) and western blot, we predicted the mechanisms by which CENPF regulates BC bone metastasis. RESULTS: The ONCOMINE database and immunohistochemical (IHC) showed higher CENPF expression in BC tissue compared to normal tissue. Kaplan-Meier plots also revealed that high CENPF mRNA expression correlated to poor survival and shorter progression-free survival (RFS). From BALB/C mice 4T1 BC models and the GEO database, CENPF was overexpressed in primary lesions, other target organs, and in bone metastasis. Based on gene set enrichment analysis (GSEA) and western blot, we predicted that CENPF regulates the secretion of parathyroid hormone-related peptide (PTHrP) through its ability to activate PI3K-AKT-mTORC1. CONCLUSION: CENPF promotes BC bone metastasis by activating PI3K-AKT-mTORC1 signaling and represents a novel therapeutic target for BC treatment.

A new cerebroside from cordyceps militaris with anti-PTP1B activity.

Cordyceps militaris (L.) Link (C. militaris) has been used as a folk medicine for treatment of various diseases in China and some other countries. Recent evidence suggests that aqueous extracts of C. militaris have hypoglycemic activity. So the aim of this study was to isolate and characterize compounds with aiti-PTP1B (protein tyrosine phosphatase 1B) activity from C. militaris. As a result, cordycerebroside B (1) together with other three known cerebrosides (2-4) and a disaccharide (5) were isolated by silica gel column chromatography and semi-preparative high performance liquid chromatography (HPLC) and then elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy (MS) and chemical method. Among of which, cordycerebroside B was a new compound and isolated from C. militaris for the first time. The results of the activity assays demonstrated that all these four cerebrosides (compounds 1-4) showed marked inhibition activity against PTP1B with IC50 values of 4.68 ±â€¯0.18, 16.93 ±â€¯1.08, 10.43 ±â€¯0.64 and 18.92 ±â€¯1.65 µM. All the compounds had no discernible cytotoxicity for Rat pheochromocytoma (PC12 cells). These findings suggested that C. militaris or its cerebrosides may be considered as potential useful therapeutic agents for type 2 diabetes.

[Expression of NUF2 in breast cancer and its clinical significance].

OBJECTIVE: To investigate the expression of the cell division- associated gene NUF2 in breast cancer and its clinical significance. METHODS: The expression of NUF2 in breast cancer tissues was analyzed using Oncomine database. The relationship between the expression of NUF2 and the prognosis of breast cancer was analyzed using the Kaplan-Meier Plotter database. Gene set enrichment analysis (GSEA) and GEO database were used to investigate the effect of NUF2 on gene enrichment. The String database was utilized to analyze the proteins associated with NUF2. The TIMER database was analyzed to assess the correlations of NUF2 with BUB1, MAD2L1 and MYC. The expressions of NUF2 mRNA in 8 pairs of breast cancer tissues and adjacent tissues were verified by q-PCR. RESULTS: Compared with that in normal breast tissue, NUF2 was significantly overexpressed in breast cancer (P < 0.001). The overall survival time (HR = 1.52, P = 0.015) and the recurrence-free survival time (HR = 1.85, P = 3.2e-14) of the patients with high NUF2 expression were significantly shorter than those of patients with low NUF2 expression. In patients with high NUF2 expression, the enriched genes were involved mainly in cell cycle, P53, G2/M, DNA repair, MYC, and PI3K-AKT-MTOR signaling pathways, which were associated with tumor proliferation, invasion, metastasis and stemness. Combination of the results of String database, gene enrichment and TIMER database analyses suggested that NUF2 interacted directly with BUB1, MAD2L1, and MYC, which could promote the progression of breast cancer. The results of q-PCR showed that NUF2 expression was up-regulated in 6 cancer tissues and down-regulated in 2 cancer tissues. CONCLUSIONS: NUF2 gene is overexpressed in breast cancer, and its expression level is important in predicting the prognosis of breast cancer.