Vascular feature as a modulator of the aging brain.

The cerebral functional reorganization and declined cognitive function of aging might associate with altered vascular features. Here, we explored the altered cerebral hierarchical functional network of 2 conditions (task-free and naturalistic stimuli) in older adults and its relationship with vascular features (systemic microvascular and perfusion features, measured by magnetic resonance imaging) and behavior. Using cerebral gradient analysis, we found that compressive gradient of resting-state mainly located on the primary sensory-motor system and transmodal regions in aging, and further compress in these regions under the continuous naturalistic stimuli. Combining cerebral functional gradient, vascular features, and cognitive performance, the more compressive gradient in the resting-state, the worse vascular state, the lower cognitive function in older adults. Further modulation analysis demonstrated that both vascular features can regulate the relationship between gradient scores in the insula and behavior. Interestingly, systemic microvascular oxygenation also can modulate the relationship between cerebral gradient and cerebral perfusion. Furthermore, the less alteration of the compressive gradient with naturalistic stimuli came with lower cognitive function. Our findings demonstrated that the altered cerebral hierarchical functional structure in aging was linked with changed vascular features and behavior, offering a new framework for studying the physiological mechanism of functional connectivity in aging.

N-n-Butyl haloperidol iodide ameliorates liver fibrosis and hepatic stellate cell activation in mice.

N-n-Butyl haloperidol iodide (F2) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl4) or thioacetamide (TAA). The mice received F2 (0.75, 1.5 or 3 mg·kg-1·d-1, ip) for 4 weeks of fibrosis induction. We showed that F2 administration dose-dependently ameliorated CCl4- or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-ß receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-ß1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F2 (0.1, 1, 10 µM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F2 inhibited TGF-ß/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-ß signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-ß1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-ß signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-ß signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-ß1. F2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.

Influence of Sliding Time Window Size Selection Based on Heart Rate Variability Signal Analysis on Intelligent Monitoring of Noxious Stimulation under Anesthesia.

In recent decades, little progress of objective evaluation of pain and noxious stimulation has been achieved under anesthesia. Some researches based on medical signals have failed to provide a general understanding of this problem. This paper presents a feature extraction method for heart rate variability signals, aiming at further improving the evaluation of noxious stimulation. In the process of data processing, the empirical mode decomposition is used to decompose and recombine heart rate variability signals, and the sliding time window approach is used to extract the signal features of noxious stimulation, respectively. The influence of window size on feature extraction is studied by changing the window size. By comparing the results, the feature extraction in the process of data processing is valuable, and the selection of window size has a significant impact. With the increase of selected window sizes, we can get better detection results. But for the best choice of window size, to ensure the accuracy of the results and to make it easy to use, then, we need to get just a suitable window size.

[Assessment of the Effect of Pain on Autonomic Nervous System in Human Body Using Heart Rate Variability Analysis].

The purpose of this study is to discuss the feasibility of establishing capsaicin pain model and the possibility to evaluate different degrees of pain by the heart rate variability (HRV). It also aims to investigate the changes of autonomic nervous activity of volunteers during the process of pain caused by capsaicin. A total of 30 volunteers were selected, who were physically and mentally healthy, into the study. To assess the effects of capsaicin on the healthy volunteers, we recorded the Visual Analogue Scale (VAS) scores after the capsaicin stimulus. Additionally, the electrocardiogram signals and HRV analysis index before and after stimulating were also recorded, respectively. More specifically, the HRV analysis indexes included the time domain index, the frequency domain index, and the nonlinear analysis index. The results demonstrated that the activity of the autonomic nerves was enhanced in the process of capsaicin stimulus, especially for the sympathetic nerve, which exhibited a significantly differences in HRV. In conclusion, the degree of pain can be reflected by the HRV. It is feasible to establish a capsaicin pain model. And in further experiments, HRV analysis could be used as a reference index for quantitative evaluation of pain.

[Experimental research on heart rate variability analysis with application of acquisition system of R peak of electrocardiosignal based on sound card].

This study designed an audio signal acquisition system to achieve real-time detection of R peak for heart rate variability (HRV) analysis, substituting ECG-specific data acquisition board with sound card. It is proved that the R peak with low frequency can be gathered by sound card. The comparison with PowerLab signal acquisition system has shown that the acquisition system of R peak could accurately detect the R peak. The R peak detected by sound card and PowerLab signal acquisition system completely overlap each other, while RR intervals has no difference. The HRV analysis was accurate and reliable with the RR interval from sound card. This low cost, high performance, strong compatibility and easy upgraded acquisition system of R peak compared with the traditional data acquisition board has the value of practical uses and might have broad applications in the future.

Effects of ghrelin on the intracellular calcium concentration in rat aorta vascular smooth muscle cells.

BACKGROUND/AIMS: Ghrelin has been regarded as a cardioprotective factor with complicated mechanisms. Whether ghrelin is vasodilative or vasoconstrictive in nature is controversial, and the effects of ghrelin on intracellular calcium concentration are still unclear. To explore the mechanisms involved in the vasoactive regulation of ghrelin at the cellular level, we investigated the effects of ghrelin on calcium concentrations in rat aorta vascular smooth muscle cells (VSMCs). METHODS: We obtained VSMCs via cell culture and stained the cells with Furo-2 AM. Western blotting was used to verify growth hormone secretagogue receptor (GHS-R1a) expression in VSMCs. The intracellular calcium variations affected by ghrelin and the interactions of ghrelin with angiotensin II (AngII), Sq22536, and potassium chloride (KCl) were observed using a calcium imaging and analysis system. RESULTS: Western blotting revealed good GHS-R1a expression in VSMCs. The most prominent finding in the present study was that ghrelin inhibited the AngII-induced increase in the calcium concentration. This inhibition was reversed by the adenylate cyclase inhibitor Sq22536 and the GHS-R1a antagonist (D-Lys(3))- GHRP-6. This finding revealed the potential vasodilative effects of ghrelin at the cellular level. We did not observe any effects of ghrelin on intracellular calcium concentrations in resting VSMCs or the increase of calcium concentration induced by KCl. CONCLUSION: Ghrelin inhibited the increase in the intracellular calcium concentration of rat aorta VSMCs induced by AngII, which may depend on the activation of the cAMP/PKA pathway.

Isoflavonoids from Ficus benjamina and their inhibitory activity on BACE1.

Examination of an active extract of the fruit of Ficus benjamina var. nuda (Miq.) Barrett has led to the isolation of six new isoflavones and two coumarano-chroman-4-ones, along with fifteen known compounds. The structures of the eight new compounds were elucidated on the basis of extensive NMR experiments and mass spectrometric measurements. The inhibitory activity of the compounds on the proteolytic cleavage of amyloid precursor protein by the aspartic protease BACE1 was evaluated. Both coumarano-chroma-4-ones and some isoflavones showed moderate activity in this assay.

Intelligent monitoring of noxious stimulation during anaesthesia based on heart rate variability analysis.

Research based on medical signals has received significant attention in recent years. If the patients' states can be accurately monitored based on medical signals, it greatly benefits both doctors and patients. This paper proposes a method to extract signal features from heart rate variability signals and classify patients' states using the long short-term memory network and enable effective monitoring of noxious stimulation. For data processing, the heart rate variability signal is decomposed and recombined by the empirical mode decomposition method, and the signal features of the noxious stimulation are extracted by the sliding time window method. Compared with the average accuracy of direct classifications, the classification accuracy based on the proposed method is proved more accurate. The model based on the extracted features proposed can realize the classification of consciousness and general anaesthesia with an accuracy rate of more than 90% and accurately estimate the occurrence of tracheal intubation stimulation. Furthermore, this study shows that combining the deep learning neural network with the extracted more effective signal features under different states and stresses can classify the states with high accuracy. Therefore, it is promising to apply the deep learning method in researching the autonomic nervous system.

[Application of 5-second heart rate variability parameter based on poincare plot in real-time monitoring of the autonomic nervous system activity].

This study designed one index of HRV from Poincaré plot named 5SSD1 by the present authors, which can describe the characteristics of the heart rate dynamics with 5-second data. We also investigated the feasibility of its clinical application in real-time monitoring of the activity of autonomic nervous system. We studied 20 patients scheduled for oral maxillofacial surgery. ECG recording was obtained when kept awake and anesthetic states, respectively. We calculated the correlation coefficients between the 5SSD1 and the other quantitative indicators, such as 5-minute HRV in the time domain, the frequency domain, and the Poincaré plot families. The correlation between 5SSD1 and indicators, such as rMSSD, HF and SD1 of 5-minute HRV was significantly high, with r=0.995, 0.895, 0.996, respectively, at P<0.01 for all. However, the correlation between 5SSD1 and the other indicators of 5-minute HRV was relatively poor. It was proved that 5SSD1 could be used to assess the activities of the autonomic nervous system in real-time, and the stable and reliable results might play more roles in the clinical applications.

LRP1 receptor-mediated immunosuppression of α-MMC on monocytes.

Alpha-MMC is a type I ribosome-inactivating protein purified from bitter gourd that has strong anti-tumour and antiviral activity. Alpha-MMC also has immunosuppressive effects, but the mechanism of these immunosuppressive effects remains unclear. It is reported that the binding of α-MMC to its specific cell membrane LRP1 receptor is key to its biological effects. In this study, we investigated the effect of α-MMC on cytotoxicity and cytokine release regulation in three immune cells, human monocyte THP-1 cells, B-lymphocyte WIL2 cells and T-lymphocyte H9 cells, and explored the correlation between this effect and LRP1 receptor distribution on these three cell types. We demonstrate that α-MMC has a significant effect of apoptosis induction and cytokine release in THP-1 cells but has no effect on WIL2-S and H9 cells. Specifically, at a non-cytotoxic dose (80 µg/ml), α-MMC regulates THP-1 cells by inhibiting IL-1ß, IL-2, IL-8, IL-9, IL-12, MIP-1α/ß, MCP-1 and TNF-α expression and enhancing IL-1ra and RANTES expression, resulting in the inhibition of cellular immune function. Subsequent experiments showed that the cytokine expression regulated by α-MMC can be blocked by silencing the LRP1 receptor of α-MMC. Further research indicated that phosphorylation of 9 signalling proteins of the MAPK pathway was significantly regulated by α-MMC and was blocked by LRP1 silencing. We conclude that the regulation of cytokine expression induced by α-MMC in monocyte THP-1 cells is mediated by the LRP1 receptor, likely via the MAPK signalling pathway. Our results suggest that the inhibition effect on monocytes/macrophages mediates the immunosuppressive function of α-MMC. Due to the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes/macrophages, α-MMC may be used for killing Tumour-Associated Macrophages (M2 subtypes) or inhibiting their cytokine release in the tumour microenvironment.

[Distraction osteogenesis for correction of cleft palate in rhesus-histological and fluorescent labeling study].

OBJECTIVE: To investigate the mechanism of new bone formation in the distraction osteogenesis (DO) for correction of cleft palate (CP) in rhesus. METHODS: CP was created by operation in 23 rhesus. The CP was corrected with DO in 21 animals as experimental group. The distraction rate was 0.8 mm per day, two times a day. The bone fragments were fixed after cleft closure, every 3 animals were sacrificed to get specimen after 1, 2, 4, 6, 8, 12, 24 weeks of fixation. 6 days before sacrifice, tetracycline was administrated for labeling (30 mg/kg). RESULTS: The hard and soft tissue def of fixation. At the same time, the bone volume and calcification between the distraction gap increased. The cleft in the control group could not b ect was successfully closed with DO by intramembrane osteogenesis. The new formed bone was remodeling and became maturation during the period e corrected spontaneously. CONCLUSIONS: The DO can successfully correct both the soft and hard tissue defect in CP by intramembrane osteogenesis. The fixation is important for remodeling and maturation of the new formed bone.

[Ultrastructural and element spectrometric analysis of distraction osteogenesis for reconstruction of cleft palate in rhesus macaque model].

OBJECTIVE: To study the ultrastructure and Ca/P element spectrometry of distraction osteogenesis (DO) for reconstruction of cleft palate (CP), so as to explore the osteogenesis and remodeling of new bone in situ. METHODS: 23 rhesus macaques were operated to establish animal models of CP. 2 monkeys didn't received DO as controls. The other 21 monkeys in experimental group underwent DO to correct both bony and soft tissue defects in palate. The distraction was performed at a rate of 0.8 mm/d, twice a day until the cleft was closed. After fixation for 1, 2, 4, 6, 8, 12, 24 weeks, every 3 animals were sacrificed to get the specimens at the distraction gap. The scanning electron microscopic study and Ca, P elements spectrometric analysis were adopted. There were also two unoperated animals as sham group. RESULTS: After fixation for 1-2 weeks, the distraction gap was full of collagen fibers oriented along vector of distraction. Few trabeculae was seen at the margin area. After fixation for 4-6 weeks, active osteogenesis was presented with new formed bone trabeculae and abundant cellular component. After fixation for 8-12 weeks, the new formed bone became mature and couldn't distinguish from the normal bone. 24 weeks later, the bone between the distraction gap had a similar structure to the normal bone. Elements spectrometric analysis results indicated that in early stage of osteogenesis, the P and S peaks were relatively high while the Ca peak was much lower. During the late stage, the S peak was obviously decreased, and Ca/P ratio increased to normal level as in the empty control group. CONCLUSIONS: The CP can be corrected by DO. The new bone between the distraction gap is formed and remodeled through intramembraneous osteogenesis.

[Expression of osteopontin and osteocalcin during distraction osteogenesis on rhesus with cleft palate].

OBJECTIVE: To study the mechanism of new bone formation and remodeling of distraction osteogenesis (DO) by analysis of the expression of osteopontin (OPN) and osteocalcin (OC). METHODS: Rhesus were operated to reconstruct the animal model of cleft palate (CP). The CP was closed by DO in experimental group(n = 21). After consolidation of 1, 2, 4, 6, 8, 12, 24 weeks, every 3 animals were killed to collect the specimens, respectively. The OPN and OC and their mRNA were detected quantitatively by Real-time RT-PCR and ELISA, respectively. The animals in control group (n = 2) and sham group (n = 2) were used as control. RESULTS: The mRNA expression of OPN increased since 2nd week of consolidation and reached the peak at 4th week (7.59 +/- 0.37). The mRNA expression of OC was up-regulated since 4th week, and reach the peak at 6th week (7.94 +/- 0.31). Then they decreased to about the level in sham group at 24th week (P > 0.05). The OPN and OC were highly expressed during 4 to 6 weeks of consolidation. During 8 to 12 weeks, they decreased like their mRNA expression. CONCLUSION: The intramembraneous new bone formation after DO can reconstruct the bone defect of CP. The new formed bone can be remodeled to be quite normal bone tissue.