Vasculogenic mimicry (VM), defined as a capability of aggressive tumor Cells to mimic embryonic vasculogenic networks, caused poor prognosis in hepatocellular carcinoma (HCC). Rho kinases (ROCK), ...p21-activated kinase (PAK), hypoxia or epithelial-mesenchymal transition (EMT) contributed to the VM potential. However, the details underlying these biological behaviors have not been completely elucidated.
Kaplan-Meier analysis was conducted to predict relationship with hypoxia Inducible factor (HIF-1α), EMT related markers: Vimentin and patient prognosis. CD34/periodic acid-Schiff (PAS) double staining was examined to differentiate VM-positive (VM+) and VM-negative (VM-) samples. Cells were cultured under controlled hypoxic environments (1% O2) or normoxic conditions. The effect of hypoxia on RhoA/ROCK, Rac1/PAK and EMT were evaluated by real time-qPCR and western blot. HIF-1α small interfering RNA (siRNA), overexpressed or short hairpin RNA (shRNA) of ROCK and kinase inhibitors were used to explore the effect of HIF-1α, RhoA/ROCK, Rac1/PAK and Vimentin on VM.
HIF-1α or Vimentin was upregulated in VM+ HCC tissues, compared to non-cancerous tissues (P < 0.01), and patients with high expression of HIF-1α or Vimentin had worse prognosis (P < 0.001). We showed hypoxia induced RhoA/ROCK and Rac1/PAK signaling transduction, and EMT could be repressed by HIF-1α siRNA. Notably, RhoA/ROCK or Rac1/PAK stabilized HIF-1α in hypoxia, whereas HIF-1α did not significantly altered RhoA/ROCK or Rac1/PAK signaling in hypoxia. Moreover, we found distinct roles of ROCK1, ROCK2 and PAK in regulating Vimentin phosphorylation.
RhoA/ROCK and Rac/PAK signaling played crucial roles in hypoxia-induced VM via Ser72 and Ser56 Vimentin phosphorylation in HCC.
Downregulating transcription of the oncogene c-MYC is a feasible strategy for cancer therapy. Stabilization of the G-quadruplex structure present in the c-MYC promoter can suppress c-MYC ...transcription. Thus, far, several ligands targeting this structure have been developed. However, most have shown no selectivity for the c-MYC G-quadruplex over other G-quadruplexes, leading to uncertain side effects. In this study, through structural modification of aryl-substituted imidazole/carbazole conjugates, a brand-new, four-leaf clover-like ligand called IZCZ-3 was found to preferentially bind and stabilize the c-MYC G-quadruplex. Further intracellular studies indicated that IZCZ-3 provoked cell cycle arrest and apoptosis and thus inhibited cell growth, primarily by blocking c-MYC transcription through specific targeting of the promoter G-quadruplex structure. Notably, IZCZ-3 effectively suppressed tumor growth in a mouse xenograft model. Accordingly, this work provides an encouraging example of a selective small molecule that can target one particular G-quadruplex structure, and the selective ligand might serve as an excellent anticancer agent.
This study investigated the antioxidant effects of whey protein peptide on learning and memory in aging C57BL/6N mice. A total of 72 SPF male C57BL/6N mice were used. Twelve mice were randomly ...selected as the control group, and the other mice were intraperitoneally injected with D-galactose (100 mg/kg body weight for 6 weeks), during which, the mice in the control group were intraperitoneally injected with the same amount of normal saline. After 6 weeks, the blood was taken from the epicanthus and the serum MDA level was measured, according to which, the mice were randomly divided into the model control group, the whey protein group (1.5 g/kg body weight), and three Whey protein peptide (WHP) intervention groups (0.3 g/kg body weight, 1.5 g/kg body weight, 3.0 g/kg body weight). The water solution of the test sample was administered by oral gavage every day. The intervention period was 30 days, during which, the model control group, the whey protein group, and the whey protein peptide group continued receiving intraperitoneal injections of D-galactose, while the control group continued receiving intraperitoneal injections of normal saline. After the intervention, behavioral experiments were conducted in the following order: open field test, water maze test, and new object recognition test. After the behavioral experiment, the morphology of hippocampal formation was observed by HE staining and TUNEL labeling. Oxidative stress-related indexes in the serum, liver, and brain were detected. Expression levels of the cholinergic system-related enzymes and proinflammatory cytokines in brain tissue were detected. Western blot was used to detect the expression of synaptic plasticity-related proteins in the mouse brain. The results showed that WHP could significantly improve the accumulation of MDA and PC, increase the activities of SOD and GSH-Px, resist oxidative stress injury, and enhance the potential of endogenous antioxidant defense mechanisms. WHP can significantly improve the decline of aging-related spatial exploration, body movement, and spatial and non-spatial learning/memory ability. Its specific mechanism may be related to reducing the degeneration of hippocampal nerve cells, reducing the apoptosis of nerve cells, improving the activity of AChE, reducing the expression of inflammatory factors (TNF-α and IL-1β) in brain tissue, reducing oxidative stress injury, and improving the expression of p-CaMKⅡ and BDNF synaptic plasticity protein. These results indicate that WHP can improve aging-related oxidative stress, as well as learning and memory impairment.
The short-term prediction of single well production can provide direct data support for timely guiding the optimization and adjustment of oil well production parameters and studying and judging oil ...well production conditions. In view of the coupling effect of complex factors on the daily output of a single well, a short-term prediction method based on a multi-agent hybrid model is proposed, and a short-term prediction process of single well output is constructed. First, CEEMDAN method is used to decompose and reconstruct the original data set, and the sliding window method is used to compose the data set with the obtained components. Features of components by decomposition are described as feature vectors based on values of fuzzy entropy and autocorrelation coefficient, through which those components are divided into two groups using cluster algorithm for prediction with two sub models. Optimized online sequential extreme learning machine and the deep learning model based on encoder-decoder structure using self-attention are developed as sub models to predict the grouped data, and the final predicted production comes from the sum of prediction values by sub models. The validity of this method for short-term production prediction of single well daily oil production is verified. The statistical value of data deviation and statistical test methods are introduced as the basis for comparative evaluation, and comparative models are used as the reference model to evaluate the prediction effect of the above multi-agent hybrid model. Results indicated that the proposed hybrid model has performed better with MAE value of 0.0935, 0.0694 and 0.0593 in three cases, respectively. By comparison, the short-term prediction method of single well production based on multi-agent hybrid model has considerably improved the statistical value of prediction deviation of selected oil well data in different periods. Through statistical test, the multi-agent hybrid model is superior to the comparative models. Therefore, the short-term prediction method of single well production based on a multi-agent hybrid model can effectively optimize oilfield production parameters and study and judge oil well production conditions.
The aim of this study was to clarify the anti-fatigue effect of peanut oligopeptides (POPs) in mice and to investigate its possible underlying mechanism. A total of 150 male ICR mice were randomly ...assigned into five groups: control, whey protein (0.50 g/kg·bw), and three peanut peptide groups (0.25, 0.50, and 1.00 g/kg·bw). All the mice were treated with intra-gastric administration for 30 days. Following the intervention, a weight-loaded swimming test, blood lactate concentration, glycogen content, the activities of antioxidant factors and energy metabolism enzymes, and the function of mitochondria in the skeletal muscle were examined. The results show that POP intervention significantly prolonged the exhaustive swimming time, decreased blood lactate concentration levels, regulated the process of energy metabolism, and increased the level of antioxidant enzymes, muscle glycogen, and expressions of mtTFA and NRF-1 in the mitochondria of the gastrocnemius muscle. The results suggest that POPs produce an anti-fatigue effect in the animals, and they may exert this effect through the mechanism of improving the animals' antioxidant capacity to reduce oxidative damage levels and regulating the process of energy metabolism.
The contamination of dental unit waterlines (DUWLs) poses a significant risk of cross-infection in dentistry. Although chemical disinfectants have been effective in reducing number of bacteria, they ...do have limitations.
This study aimed to investigate the potential of chlorogenic acid, a natural substance with broadspectrum antibacterial properties, for treating DUWLs. Over a period of three months, we analyzed the microbial communities in 149 DUWLs samples collected from 5 dental units using high-throughput pyrophosphate sequencing.
The results revealed that chlorogenic acid treatment had a significant impact on the microbial community profile in the DUWLs, with the most significant changes occurring within the first 15 days and stabilization observed in the last 30 days. The predominant genera detected in the samples were Bacteroides, Lactobacillus, Streptococcus, Methylobacterium, and Phreatobacter. Additionally, the relative abundance of certain beneficial bacteria, such as Alloprevotella, Roseburia, and Blautia, increased, while the presence of opportunistic pathogens like Mycobacteria significantly decreased. The functional prediction analysis using the KEGG database indicated a decrease in the pathogenicity of the bacterial community in the DUWLs following chlorogenic acid treatment.
This study introduces a novel approach for the prevention and treatment of infections associated with dental care.
The discovery and application of environment-sensitive genic male sterile (EGMS) rice germplasm provide an easy method for hybrid rice breeding and have made great contributions to hybrid rice ...production. Typically, the photoperiod- and thermo-sensitive GMS (P/TGMS) lines utilized in two-line hybrid systems are male sterile under long day or/and high temperature but fertile under short day or/and low temperature conditions. However, YannongS (YnS), a reverse TGMS (rTGMS) line, is sterile under low temperature (<29°C) and fertile under high temperature (>29.5°C). Here, we report a genetic study on the rTGMS trait in YnS. Interestingly, the F1 plants of the cross between YnS and a cultivar, L422, were male sterile at 22°C and completely fertile at 27°C. Moreover, the segregation ratio of fertile and sterile individuals in YnS/L422 F2 populations changed from 1:3.05 to 2.95:1 when the ambient temperature increased, showing that the rTGMS trait exhibits semi-dominance in YnS. We further found a locus on chromosome 10, termed RTMS10, which controls the rTGMS trait in YnS. We then finely mapped RTMS10 to a ∼68 kb interval between markers ID13116 and ID1318 by YnS/L422 BC6F2 populations. A near iso-genic line (NIL) NL1 from the BC6F3 generation was developed and the pollen of NL1 became abnormal from the meiosis stage under low temperature. In summary, we identified an rTGMS locus, RTMS10, and provided co-segregated markers, which could help to accelerate molecular breeding of rTGMS lines and better understand the rTGMS trait in rice.
Radiation therapy is widely used in the treatment of tumor diseases, but it can also cause serious damage to the body, so it is necessary to find effective nutritional supplements. The main purpose ...of this study is to evaluate the protective effect of whey hydrolysate peptides (WHPs) against
Coγ radiation damage in mice and explore the mechanism. BALB/c mice were given WHPs by oral gavage administration for 14 days. Then, some mice underwent a 30-day survival test after 8 Gy radiation, and other mice received 3.5 Gy radiation to analyze the changes in body weight, hematology and bone marrow DNA after three and 14 days. In addition, through further analysis of the level of oxidative stress and intestinal barrier function, the possible mechanism of the radioprotective effect of WHPs was explored. The study found WHPs can prolong survival time, restore body weight, and increase the number of peripheral blood white blood cells and bone marrow DNA content in irradiated mice. In addition, WHPs can significantly improve the antioxidant capacity, inhibit pro-inflammatory cytokines and protect the intestinal barrier. These results indicate that WHPs have a certain radioprotective effect in mice, and the main mechanism is related to reducing oxidative damage.
How to control the spatial distribution of nanoparticles to meet different performance requirements is a constant challenge in the field of polymer nanocomposites. Current studies have been focused ...on the flexible polymer chain systems. In this study, the rigid polyimide (PI) chain grafted silica particles with different grafting chain lengths and grafting densities were prepared by “grafting to” method, and the influence of polymerization degree of grafted chains (
N
), matrix chains (
P
), and grafting density (
σ
) on the spatial distribution of nanoparticles in the PI matrix was explored. The glass transition temperature (
T
g
) of PI composites was systematically investigated as well. The results show that silica particles are well dispersed in polyamic acid composite systems, while aggregation and small clusters appear in PI nanocomposites after thermal imidization. Besides, the particle size has no impact on the spatial distribution of nanoparticles. When
σ
·
N
0.5
≪ (
N/P
)
2
, the grafted and matrix chains interpenetrate, and the frictional resistance of the segment increases, resulting in restricted relaxation kinetics and
T
g
increase of the PI composite system. In addition, smaller particle size and longer grafted chains are beneficial to improving
T
g
of composites. These results are all propitious to complete the microstructure control theory of nanocomposites and make a theoretical foundation for the high performance and multi-function of PI nanocomposites.
PDF
