Objective
This study was performed to assess the anti‐inflammatory and anti‐apoptotic effects of the combination of Ligusticum chuanxiong and Radix Paeoniae (XS) on focal cerebral ischaemic stroke.
...Methods
MCAO rats were used to evaluate the effect of XS on stroke. Cerebral water content was measured, and the levels of IFN‐γ, IL‐1β, IL‐6 and IL‐12 in serum and brain were assessed by ELISA kits. Protein expressions including p‐p38, p‐38, TLR‐4, p‐ERK, ERK, TLR‐5, NF‐κBp65, Myd88, Caspase‐3 and Caspase‐12 were examined by WB and IHC. Q‐PCR was applied to examine IL‐1β and IL‐6 mRNA levels in the rat brain of each group.
Key findings
XS treatment remarkedly decreased the levels of IFN‐γ, IL‐1β, IL‐6 and IL‐12 in serum and brain tissues of MCAO rats. In the ischaemic brain, the expressions of TLR‐4, TLR‐5, p‐p38, p‐ERK, Myd88, NF‐κBp65, Caspase‐3 and Caspase‐12 were increased significantly, while the treatment attenuated the activated expressions by MCAO. XS also downregulated Caspase‐3 and Caspase‐12 expressions. IL‐1β and IL‐6 mRNA levels in MCAO brain tissue were decreased by XS treatment.
Conclusions
XS could protect MCAO rats by anti‐inflammation and anti‐apoptosis through TLR4/MyD88/MAPK/NF‐κB signalling pathway. Furthermore, the combination has a more meaningful improvement on focal cerebral ischaemic stroke.
Metastasis causes the vast majority of colorectal carcinoma (CRC)-related deaths. However, little is known about the specific traits and underlying mechanisms of metastasis-initiating cells in ...primary CRC. And whether or not circular RNAs (circRNAs) take part in this particular event remain not adequately stated yet.
A screening method based on Transwell assay was first applied to build CRC subgroups with different metastatic potential. High throughput RNA sequencing was used to find out novel metastatic drivers in CRC metastasis-initiating step. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of circRNAs in CRC metastasis.
A circRNA consisting of exon 8-11 of LONP2, termed as circLONP2, was upregulated in metastasis-initiating CRC subgroups. Aberrant higher expression of circLONP2 was observed in primary CRC tissues with established metastasis, and along the invasive margin in metastatic site. High expression of circLONP2 predicted unfavorable overall survival. Functional studies revealed that circLONP2 could enhance the invasiveness of CRC cells in vitro, and targeting circLONP2 through anti-sense oligonucleotide (ASO) dramatically reduced the penetrance of metastasis to foreign organs in vivo. Mechanically, circLONP2 directly interacted with and promoted the processing of primary microRNA-17 (pri-miR-17), through recruiting DiGeorge syndrome critical region gene 8 (DGCR8) and Drosha complex in DDX1-dependent manner. Meanwhile, upregulated mature miR-17-5p could be assembled into exosomes and internalized by neighboring cells to enhance their aggressiveness.
Our data indicate that circLONP2 acts as key metastasis-initiating molecule during CRC progression through modulating the intracellular maturation and intercellular transfer of miR-17, resulting in dissemination of metastasis-initiating ability in primary site and acceleration of metastasis formation in foreign organs. circLONP2 could serve as an effective prognostic predictor and/or novel anti-metastasis therapeutic target in CRC treatment.
DNA high methylation is one of driving force for colorectal carcinoma (CRC) pathogenesis. Transcription factors (TFs) can determine cell fate and play fundamental roles in multistep process of ...tumorigenesis. Dysregulation of DNA methylation of TFs should be vital for the progression of CRC. Here, we demonstrated that TBX20, a T‐box TF family protein, was downregulated with hypermethylation of promoter in early‐stage CRC tissues and correlated with a poor prognosis for CRC patients. Moreover, we identified PDZRN3 as the E3 ubiquitin ligase of TBX20 protein, which mediated the ubiquitination and degradation of TBX20. Furthermore, we revealed that TBX20 suppressed cell proliferation and tumor growth through impairing non‐homologous DNA end joining (NHEJ)‐mediated double‐stranded break repair by binding the middle domain of both Ku70 and Ku80 and therefore inhibiting their recruitment on chromatin in CRC cells. Altogether, our results reveal the tumor‐suppressive role of TBX20 by inhibiting NHEJ‐mediated DNA repair in CRC cells, and provide a potential biomarker for predicting the prognosis of patients with early‐stage CRC and a therapeutic target for combination therapy.
Our study highlights the dysregulation of TBX20 in early‐stage CRC tissues and the mechanism suppressing NHEJ‐mediated DSBs repair by inhibiting the interaction of Ku70 and Ku80, which indicates the potential of TBX20 as an effective biomarker for predicting the prognosis of patients with early‐stage CRC.
Herb couple Rehmannia glutinosa Libosch and Cornus officinalis Sieb (RC), originated from "Liuwei Dihuang Pill" which recorded in Key to Therapeutics of Children's Diseases. Traditionally, they have ...been used widely for their ability to nourish yin and energize the kidneys. Our previous study indicated that the RC could protect against adenine induced Chronic kidney disease (CKD) rats. Nevertheless, there is still no clear explanation of the mechanisms by which RC affects renal interstitial fibrosis in CKD rats.
Current Work aims to explore the amelioration and potential mechanism of RC on renal interstitial fibrosis in CKD rats.
CKD rats were induced by adenine. Two weeks after administration, blood, urine, and kidney tissue were collected for biochemical analysis. Observing the physiological state of rats through the changes of rat body weight and renal index. The pro-inflammatory cytokines were measured by enzyme linked immunosorbent assay (ELISA), while renal tissue damage and fibrosis were assessed with Hematoxylin-eosin staining (H&E) and Masson's trichrome staining. In order to determine the levels of indicators and proteins associated with fibrosis signaling pathways, real time PCR (Rt-PCR), Western blot (WB), and immunofluorescence were employed.
The renal interstitial fibrosis led to impaired cellular functions with increased the levels of Blood Urea Nitrogen (BUN), Urine protein (UP), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor alpha (TNF-α). and simultaneous up-regulated collagenⅠ(COL-1), fibronection (FN), α-smooth muscle actin (a-SMA), transforming growth factor-β1 (TGF-β1), c-Jun N-terminal kinase (JNK), p38 and extracellular regulated protein kinases (ERK), down-regulated the expression of the E-cadherin proteins. RC notably improved renal dysfunction in CKD rats as indicated by decreases in BUN, UP, and renal index. In addition, consistent with the morphological changes of renal tissue, renal interstitial fibrosis in CKD rats after RC intervention was significantly improved, mainly manifested by a decrease in the positive expression of COL-1, FN, and a-SMA, and increased levels of E-cadherin protein. Meanwhile, RC reduced the classical pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in adenine-induced CKD rats. Additionally, RC administration also down-regulated TGF-β1, JNK, p38 and ERK.
In conclusion, RC may reduce inflammation in adenine induced CKD rats, improve extracellular matrix (ECM) components deposition, and diminish epithelial-mesenchymal transition (EMT) marker protein levels. Furthermore, RC intervention significantly reduces the release of inflammatory cytokines and inhibits the TGF-β1/MAPK signaling pathway. Based on the results, RC might be useful in the treatment of adenine induced renal fibrosis.
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•RC ameliorates RIF in CKD rats by inhibiting inflammatory cell infiltration and reducing levels of inflammatory cytokines.•RC effectively inhibits the accumulation of the ECM and the EMT process in renal interstitial fibrosis.•RC inhibits the inflammatory response and EMT process by suppressing the TGF-β1/MAPK signaling pathway.
A forward intensity model for the prediction of corporate defaults over different future periods is proposed. Maximum pseudo-likelihood analysis is then conducted on a large sample of the US ...industrial and financial firms spanning the period 1991–2011 on a monthly basis. Several commonly used factors and firm-specific attributes are shown to be useful for prediction at both short and long horizons. Our implementation also factors in momentum in some variables and documents their importance in default prediction. The model’s prediction is very accurate for shorter horizons. Its accuracy deteriorates somewhat when the horizon is increased to two or three years, but the performance still remains reasonable. The forward intensity model is also amenable to aggregation, which allows for an analysis of default behavior at the portfolio and/or economy level.
Circular RNAs (circRNAs) regulate various biological activities and have been shown to play crucial roles in hepatocellular carcinoma (HCC) progression. However, only a few coding circRNAs have been ...identified in cancers, and their roles in HCC remain elusive. This study aimed to identify coding circRNAs and explore their function in HCC.
CircMAP3K4 was selected from the CIRCpedia database. We performed a series of experiments to determine the characteristics and coding capacity of circMAP3K4. We then used in vivo and in vitro assays to investigate the biological function and mechanism of circMAP3K4 and its protein product, circMAP3K4-455aa, in HCC.
We found circMAP3K4 to be an upregulated circRNA with coding potential in HCC. IGF2BP1 recognized the circMAP3K4 N6-methyladenosine modification and promoted its translation into circMAP3K4-455aa. Functionally, circMAP3K4-455aa prevented cisplatin-induced apoptosis in HCC cells by interacting with AIF, thus protecting AIF from cleavage and decreasing its nuclear distribution. Moreover, circMAP3K4-455aa was degraded through the ubiquitin-proteasome E3 ligase MIB1 pathway. Clinically, a high level of circMAP3K4 is an independent prognostic factor for adverse overall survival and adverse disease-free survival of HCC patients.
CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, circMAP3K4 encoded circMAP3K4-455aa, protected HCC cells from cisplatin exposure, and predicted worse prognosis of HCC patients. Targeting circMAP3K4-455aa may provide a new therapeutic strategy for HCC patients, especially for those with chemoresistance. CircMAP3K4 is a highly expressed circRNA in HCC. Driven by m6A modification, IGF2BP1 facilitates circMAP3K4 peptide translation, then the circMAP3K4 peptide inhibits AIF cleavage and nuclear distribution, preventing HCC cells from cell death under stress and promoting HCC progression.
Elaphuri Davidiani Cornu (EDC) is the antler of the male Père David's deer, which has been reported to have multiple biological activities, and its use as a traditional Chinese medicine (TCM) in ...China has been known for thousands of years. However, EDC is difficult to distinguish from other related species–derived antlers in powder or extract form in TCM clinic use, such as Cervus elaphus Cornu (CEC) and Cervus nippon Cornu (CNC), both derived from Cervidae and easily confused with EDC. In this study, a strategy using peptidomics combined with mathematics set analysis was used to identify EDC‐specific peptide biomarkers, and four specific peptide biomarkers (Pep‐E1–E4) were identified and validated. Pep‐E1, Pep‐E3, and Pep‐E4 could be exclusively detected in EDC samples, with relative peak areas of 0.298 ± 0.060, 0.039 ± 0.015, and 0.037 ± 0.008, whereas Pep‐E2 showed relative peak area of 0.516 ± 0.101 in EDC, 0.132 ± 0.026 in CEC, and 0.136 ± 0.047 in CNC samples, respectively. These four peptides are applicable to distinguish EDC from CEC and CNC, which is of great significance for the quality control of EDC.
Goat horn (Caprae Hircus Cornu, GH) has been used as a substitute for Saiga antelope horn (Saigae Tataricae Cornu, SAH) in the clinic and the pharmaceutical industry. In the present study, peptides ...released from SAH and GH under simulated gastric and intestinal digestion were identified. The results showed that most of the peptides released from SAH and GH under simulated gastrointestinal digestion were hydrophilic, and over 75% of the peptides from keratins (KRTs) were hydrophilic. In total, over 58% of the identified peptides were released from KRTs, and were from the four main regions of KRTs. The peptide features and the peptide release profiles from KRTs in SAH and GH were similar, which may provide a method for the identification of sustainable alternatives to replace the threatened SAH, and provide further evidence of the feasibility of using GH as a replacement for SAH based on their peptidomic analysis.
Scutellariae Radix (SR) and Coptidis Rhizoma (CR) have often been combined to cure type 2 diabetes mellitus (T2DM) in the clinical practice for over thousands of years, but their compatibility ...mechanism is not clear. Mitogen-activated protein kinase (MAPK) signaling pathway has been suggested to play a critical role during the process of inflammation, insulin resistance, and T2DM. This study was designed to investigate their compatibility effects on T2DM rats and explore the underlying mechanisms by analyzing the metabolic profiling and MAPK/PI3K/Akt signaling pathway.
The compatibility effects of SR and CR were evaluated with T2DM rats induced by a high-fat diet (HFD) along with a low dose of streptozocin (STZ). Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to discover potential biomarkers. The levels of pro-inflammatory cytokines; biochemical indexes in serum, and the activities of key enzymes related to glycometabolism in liver were assessed by ELISA kits. qPCR was applied to examine mRNA levels of key targets in MAPK and insulin signaling pathways. Protein expressions of p65; p-p65; phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); phosphorylated-PI3K (p-PI3K); protein kinase B (Akt); phosphorylated Akt (p-Akt) and glucose transporter 2 (Glut2) in liver were investigated by Western blot analysis.
Remarkably, hyperglycaemia, dyslipidemia, inflammation, and insulin resistance in T2DM were ameliorated after oral administration of SR and CR, particularly their combined extracts. The effects of SR, CR, low dose of combined extracts (LSC) and high dose of combined extracts (HSC) on pro-inflammatory cytokine transcription in T2DM rats showed that the MAPK pathway might account for the phenomenon with down-regulation of MAPK (P38 mitogen-activated protein kinases (P38), extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK)) mRNA, and protein reduction in p-P65. While mRNA levels of key targets such as insulin receptor substrate 1 (IRS1), PI3K, Akt2, and Glut2 in the insulin signaling pathway were notably up-modulated, phosphorylations of PI3K, Akt, and expression of Glut2 were markedly enhanced. Moreover, the increased activities of phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), glucose 6-phosphatase (G6Pase), and glycogen phosphorylase (GP) were highly reduced and the decreased activities of glucokinase (GK), phosphofructokinase (PFK), pyruvate kinase (PK), and glycogen synthase (GS) in liver were notably increased after treatment. Further investigation indicated that the metabolic profiles of plasma and urine were clearly improved in T2DM rats. Fourteen potential biomarkers (nine in plasma and five in urine) were identified. After intervention, these biomarkers returned to normal level to some extent.
The results showed that SR, CR, and combined extract groups were normalized. The effects of combined extracts were more remarkable than single herb treatment. Additionally, this study also showed that the metabonomics method is a promising tool to unravel how traditional Chinese medicines work.
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