Chronic stress accelerates the process of gastric precancerous lesions in rats.

Background: Gastrointestinal cancers account for 20% of all deaths worldwide. Gastric cancer (GC) patients are susceptible to psychological change, especially depression which is commonly induced by chronic stress. Gastric precancerous lesions (GPL) is an important prodromal stage in the occurrence of gastric cancer. Chronic stress influences the prognosis of GC and may influence the process of GPL as well. Methods: Sixty SD rats were randomly divided into a control group, GPL group, and GPL+CUMS group. In the GPL group, 200µg/mL N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) free drinking method combined with intermittent fasting was applied to establish the GPL animal model. Based on this, we combined the GPL rats with chronic unpredicted mild stress (CUMS) to establish a comprehensive model. We then evaluated their behavior by open field tests and sucrose preference tests. We tested the IL-6, IL-10, TNF-α, Ghrelin, Leptin and Somatostatin (SS) levels in serum and observed the expression of Ghrelin and Gastrokine 2(GKN2) in the gastric mucosa of rats with tumors by immunofluorescence. Results: Our results showed that GPL and GPL+CUMS rats all displayed a significantly decreased total distance and mean velocity traveled in the open field test. The percentages of sucrose preference were significantly decreased in the GPL+CUMS group compared to the control group. In addition, IL-6 and TNF-α were significantly increased in both the GPL and GPL+CUMS groups. Furthermore, the GPL+CUMS group showed significantly increased TNF-α levels in serum compared to the GPL rats. Our results showed that the expression of NF-κB, p53, and BCL-2 were significantly increased while BAX was reduced in the GPL and GPL+CUMS groups. Moreover, Ghrelin and Leptin levels in serum were significantly decreased in the GPL and GPL+CUMS groups. SS levels in serum were significantly increased in the GPL+CUMS group. Additionally, we found that the GPL+CUMS rats with tumors not only had strong expression of GKN2 on the luminal side and the lamina propria of the gastric mucosa and tumor, but also had expression of Ghrelin on the luminal side of the gastric mucosa. The areas that showed strong expression of GKN2 and Ghrelin, are all located around the blood vessels in the tumor. Conclusions: GPL rats under chronic stress would aggravate the conditions of GPL, shorten the process of GPL, and increase the risk of tumorigenesis. In addition, the close monitoring of the mental health of cancer survivors and precancerous lesion patients is suggested to be of great significance in the prevention and treatment of cancer.

Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice.

The natural polyamine spermidine and spermine have been reported to ameliorate aging and aging-induced dementia. However, the mechanism is still confused. An aging model, the senescence accelerated mouse-8 (SAMP8), was used in this study. Novel object recognition and the open field test results showed that oral administration of spermidine, spermine and rapamycin increased discrimination index, modified number, inner squares distance and times. Spermidine and spermine increased the activity of SOD, and decreased the level of MDA in the aging brain. Spermidine and spermine phosphorylate AMPK and regulate autophagy proteins (LC3, Beclin 1 and p62). Spermidine and spermine balanced mitochondrial and maintain energy for neuron, with the regulation of MFN1, MFN2, DRP1, COX IV and ATP. In addition, western blot results (Bcl-2, Bax and Caspase-3, NLRP3, IL-18, IL-1ß) showed that spermidine and spermine prevented apoptosis and inflammation, and elevate the expression of neurotrophic factors, including NGF, PSD95and PSD93 and BDNF in neurons of SAMP8 mice. These results indicated that the effect of spermidine and spermine on anti-aging is related with improving autophagy and mitochondrial function.

Carnosine ameliorates age-related dementia via improving mitochondrial dysfunction in SAMP8 mice.

Dementia is a kind of age-related neurodegenerative disease. Carnosine, an endogenous dipeptide consisting of ß-alanine and l-histidine, has been shown to have neuroprotective effects. However, the exact mechanism is still obscure. In this study, senescence-accelerated mouse prone 8 (SAMP8) mice, an age-related animal model, were used. Carnosine (100 and 200 mg kg-1 day-1) was orally administered to the mice once daily for six weeks. Behavioral tests, western blotting, and detection kits were used to evaluate the potential effects of carnosine on SAMP8 mice. Open-field and new object recognition experiments have shown that carnosine improved cognitive deficits in SAMP8 mice. Carnosine decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), increased the activity of superoxide dismutase (SOD) and the level of adenosine triphosphate (ATP) in SAMP8 mice. Concomitantly, western blotting results proved that carnosine increased the protein expressions of Mitofusin-1, Mitofusin-2, and Bcl-2 and reduced the protein expressions of P-Drp1, Bax, cleaved Caspase-3 and NLRP3 inflammasomes in the hippocampus of SAMP8 mice. The present data provided evidence that carnosine might improve cognitive impairment in SAMP8 mice through modulating mitochondrial dysfunction.

Ligustilide improves aging-induced memory deficit by regulating mitochondrial related inflammation in SAMP8 mice.

Alzheimer's disease (AD) is an age-related neurodegenerative disease. The main active component in Angelica sinensis, ligustilide, has been reported to have the protective effect on AD. Whether ligustilide could protect against age-induced dementia is still unknown. In this study, we used an aging model, SAMP8 mice to investigate the neuroprotective effect of ligustilide. The behavioral tests (Morris water maze, object recognition task, open field test and elevated plus maze) results showed that ligustilide could improve the memory deficit in SAMP8 mice. For mechanism study, we found that the protein level of P-Drp1 (fission) was decreased and the levels of Mfn1 and Mfn2 (fusion) were increased after ligustilide treatment in animals and cells. Ligustilide increased P-AMPK and ATP levels. Malondialdehyde and superoxide dismutase activity results indicated that ligustilide exerts antioxidant effects by reducing the level of oxidative stress markers. In addition, ligustilide improved neural function and alieved apoptosis and neuroinflammation. These findings have shown that ligustilide treatment improves mitochondrial function in SAMP8 mice, and improves memory loss.

Sodium tanshinone IIA sulfonate protects against Aß1-42-induced cellular toxicity by modulating Aß-degrading enzymes in HT22 cells.

ß-Amyloid (Aß) plays an important role in the pathogenesis of Alzheimer's disease (AD). However, there is still no effective Aß-targeting drugs for AD treatment. In this study, we explored the effect and mechanism of Sodium Tanshinone IIA Sulfonate (STS) on AD. Aß-treated HT22 cells, an immortalized mouse hippocampal neuronal cell line, were employed. Different dosages of STS (0.1, 1 and 10 µM) were selected. STS improved cell viability and protected against Aß-induced apoptosis in a dose-dependent manner. Furthermore, the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were decreased, while the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were significantly increased after STS treatment. STS decreased the levels of phosphorylate PKR-like (p-PERK), phosphorylate eukaryotic initiation factor 2 (p-eIF2α), phosphorylate inositol-requiring enzyme (p-IRE1α), X-box binding protein 1 (XBP1) and binding immunoglobulin heavy chain protein (Bip), while increased protein disulfide isomerase (PDI) levels in Aß-treated HT22 cells. In addition, the levels of insulin degrading enzymes (IDE) and Nepterrilysin (NEP) (or call it CD10) were significantly increased after STS treatment. Taken together, these results indicated that STS might be effective in treating AD via increasing the levels of Aß-degrading enzymes.

Long non-coding RNA TCONS_00000200 as a non-invasive biomarker in patients with intracranial aneurysm.

We performed long non-coding RNA (lncRNA) microarray assay to identify lncRNAs with differential expression between patients with intracranial aneurysm (IA) and healthy control individuals to evaluate their potential use as biomarkers of IA. Arraystar Human lncRNA Microarray v3.0 was performed to identify differentially expressed lncRNAs and mRNAs in plasma samples (4 ml). lncRNAs with the most pronounced differential expression were used to select gene markers, and results were validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Plasma levels of TCONS_00000200 (fold change: 2.28) and ENST00000511927 (fold change: 2.50) were significantly higher in IA patients than in healthy individuals (P<0.001), and plasma levels of ENST00000421997 (fold change: 0.45) and ENST00000538202 (fold change: 0.43) were significantly lower in IA patients than in healthy individuals (P<0.001). qRT-PCR confirmed the same trends of up- and down-regulation of these four lncRNAs. A receiver operating characteristic (ROC) curve for TCONS_00000200 showed that the area under the curve (AUC) was 0.963 (95% confidence interval, 0.919-1.000), optimal cut-off point was 0.0081, sensitivity was 90.0%, and specificity was 96.7%. These results indicate that the lncRNA TCONS_00000200 is differentially expressed in the plasma of IA patients and could serve as a biomarker of IA.

From Analysis of Ischemic Mouse Brain Proteome to Identification of Human Serum Clusterin as a Potential Biomarker for Severity of Acute Ischemic Stroke.

Ischemic stroke is a devastating neurological disease that can cause permanent brain damage, but to date, few biomarkers are available to reliably assess the severity of injury during acute onset. In this study, quantitative proteomic analysis of ischemic mouse brain detected the increase in expression levels of clusterin (CLU) and cystatin C (CST3). Since CLU is a secretary protein, serum samples (n = 70) were obtained from acute ischemic stroke (AIS) patients within 24 h of stroke onset and together with 70 matched health controls. Analysis of CLU levels indicated significantly higher levels in AIS patients than healthy controls (14.91 ± 4.03 vs. 12.79 ± 2.22 ng/L; P = 0.0004). Analysis of serum CST3 also showed significant increase in AIS patients as compared with healthy controls (0.90 ± 0.19 vs. 0.84 ± 0.12 ng/L; P = 0.0064). The serum values of CLU were also positively correlated with the NIH Stroke Scale (NIHSS) scores, the time interval after stroke onset, as well as major stroke risk factors associated with lipid profile. These data demonstrate that elevated levels of serum CLU and CST3 are independently associated with AIS and may serve as peripheral biomarkers to aid clinical assessment of AIS and its severity. This pilot study thus contributes to progress toward preclinical proteomic screening by using animal models and allows translation of results from bench to bedside.