AVE 0991 Suppresses Astrocyte-Mediated Neuroinflammation of Alzheimer's Disease by Enhancing Autophagy.

Purpose: Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimer's disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimer's disease. Materials and Methods: APP/PS1 mice and Aß-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aß in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. Results: We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aß deposition, neuronal death, and cognitive deficits in APP/PS1 Alzheimer's disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. Conclusion: These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

Angiotensin IV suppresses inflammation in the brains of rats with chronic cerebral hypoperfusion.

INTRODUCTION: This study aimed to evaluate the influence of central angiotensin IV (Ang IV) infusion on chronic cerebral hypoperfusion (CCH)-related neuropathological changes including amyloid-ß (Aß), hyperphosphorylated tau (p-tau) and the inflammatory response. MATERIALS AND METHODS: Rats with CCH received central infusion of Ang IV, its receptor AT4R antagonist divalinal-Ang IV or artificial cerebrospinal fluid for six weeks. During this procedure, the systolic blood pressure (SBP) was monitored, and the levels of Aß42, p-tau and pro-inflammatory cytokines in the brain were detected. RESULTS: Rats with CCH exhibited higher levels of Aß42, p-tau and pro-inflammatory cytokines in the brain when compared with controls. Infusion of Ang IV significantly reduced the expression of pro-inflammatory cytokines in the brains of rats with CCH. Meanwhile, the reduction of pro-inflammatory cytokines levels caused by Ang IV was reversed by divalinal-Ang IV. During the treatment, the SBP in rats was not significantly altered. CONCLUSION: This study demonstrates for the first time that Ang IV dose-dependently suppresses inflammation through AT4R in the brains of rats with CCH, which is independent from SBP. These findings suggest that Ang IV/AT4R may represent a potential therapeutic target for CCH-related neurological diseases.

AVE0991, a nonpeptide analogue of Ang-(1-7), attenuates aging-related neuroinflammation.

During the aging process, chronic neuroinflammation induced by microglia is detrimental for the brain and contributes to the etiology of several aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a newly identified axis of renin-angiotensin system, ACE2/Ang-(1-7)/MAS1 axis plays a crucial role in modulating inflammatory responses under various pathological conditions. However, its relationship with aging-related neuroinflammation is less studied so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we revealed that the neuroinflammation in the aged brain might be attributed to a decreased level of Ang-(1-7). More importantly, we provided evidence that AVE0991, a nonpeptide analogue of Ang-(1-7), attenuated the aging-related neuroinflammation via suppression of microglial-mediated inflammatory response through a MAS1 receptor-dependent manner. Meanwhile, this protective effect might be ascribed to the M2 activation of microglia induced by AVE0991. Taken together, these findings reveal the association of Ang-(1-7) with the inflammatory response in the aged brain and uncover the potential of its nonpeptide analogue AVE0991 in attenuation of aging-related neuroinflammation.

Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice.

In vitro and in vivo studies have demonstrated that lithium treatment can protect neurons against excitotoxic and ischemic damage. Yet the possible beneficial effect of chronic low dose lithium on a model of traumatic brain injury (TBI) has not been intensively investigated. In this study, lithium (1 mmol/kg) was given daily, intraperitonealy, for 14 days before the onset of moderate controlled TBI and was continued until the mice were sacrificed. The results showed that in brain injured animals, chronic lithium treatment attenuated the loss of hemispheric tissue, cerebral edema and the expression of pro-inflammatory cytokine interleukin-1ß. The neuronal degeneration in hippocampal CA3 and dentate gyrus sub-regions was also attenuated in the chronic lithium-treated mice as shown by Fluoro-Jade B staining. Moreover, chronic lithium treatment enhanced spatial learning and memory performance of injured mice in the Morris water maze. Our current study extended the protective role of lithium in the model of TBI and suggested that chronic lithium treatment might be a helpful therapeutic strategy for brain injury with multiple beneficial effects.

[Observation of fast track surgery in patients with gastric cancer].

OBJECTIVE: To investigate the effects of fast track surgery on patients with gastric cancer in perioperative period. METHODS: Ninety-two patients with gastric cancer undergone radical operations were randomly divided into two groups: fast track group (n=46, fast track surgery) and control group(n=46, traditional surgery). Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C reaction protein (CRP) in the 92 patients were assayed preoperatively and at day 1, 3, 7 postoperatively, and the resting energy expenditure (REE) was also measured by indirect calorimetry in the morning. The postoperative hospital stay, duration of fever, medical cost, postoperative time of flatus and postoperative complications were recorded and compared respectively. RESULTS: At postoperative day 1 and 3, serum levels of TNF-alpha were (12.67+/-2.68) fmmol/L and (13.19+/-2.75) fmmol/L in fast track group, (14.74+/-3.18) fmmol/L and (15.56+/-2.99) fmmol/L in control group; serum levels of IL-6 were (112.52+/-24.73) ng/L and (129.03+/-22.75) ng/L in fast track group, (123.90+/-22.52) ng/L and (142.67+/-20.33) ng/L in control group. The levels of IL-6 and TNF-alpha in fast track group were significantly lower than those in control group (all P<0.05). At postoperative day 1, 3 and 7, serum levels of CRP in fast track group were significantly lower than those in control group [d1(56.20+/-11.47) g/L vs (71.07+/-17.32) g/L, d3(136.09+/-19.78) g/L vs (157.78+/-28.18) g/L, d7 (48.53+/-12.95) g/L vs (64.72+/-19.73) g/L] (all P<0.05). At postoperative day 1 and day 3, the REE in fast track group were significantly lower those than in control group [d1(5713.96+/-619.44) kJ/d vs (6176.04+/-614.46) kJ/d, d3 (5298.49+/-639.36) kJ/d vs (5627.94+/-656.72) kJ/d] (all P<0.05). The postoperative duration of fever [2(2.0-3.0) d vs 4(2.8-4.0) d], postoperative time of flatus [3(2.0-4.0) d vs 4(3.8-5.0) d], postoperative hospital stay [6(6.0-7.0) d vs 8(7.0-8.3) d] and treatment expense [(27 201+/-3857) Chinese yuan vs (31 006+/-3555) Chinese yuan] in fast track group were also significantly lower than those in control group (P<0.01). There were no significant differences in complications between the two groups(P>0.05). The quality of life score on discharge in fast track group was significantly higher than that in control group (15.74+/-1.82 vs 14.67+/-1.27, P<0.01). CONCLUSION: Fast track surgery can ameliorate stress reaction, decrease postoperative patients' REE during perioperative period and accelerate the rehabilitation of patients with gastric cancer.

[Effects of intensive insulin therapy on insulin resistance and serum proteins after radical gastrectomy].

OBJECTIVE: To investigate the effects of intensive insulin therapy on insulin resistance(IR) and serum proteins after radical gastrectomy. METHODS: Twenty-two gastric cancer patients were randomly divided into the control (n=11) and intensive insulin therapy group (n=11), and underwent distal radical subtotal gastrectomy under epidural anesthesia. Fasting blood glucose (FBG), fasting insulin (FINS) and serum proteins were assayed preoperatively and at day 1, 3, 7 postoperatively. Insulin resistance index was calculated using homeostasis model assessment (HOMA). The length of hospital stay and postoperative complications were recorded respectively. RESULTS: (1)The levels of FBG, FINS, lnHOMA-IR (P<0.01,P<0.05) and the incidence of insulin resistance were remarkably decreased by intensive insulin therapy after the surgical procedure.(2)The levels of serum transferrin (TRF), prealbumin (PRE) and retinal binding protein (RBP) in the intensive insulin therapy group were significantly improved as compared to control group after operation(P<0.05). (3) The duration of fever, antibiotic use, passage of gas by anus, length of hospital stay and the occurrence of postoperative complications were also significantly lower than those in control group(P<0.01,P<0.05). CONCLUSION: Compared to routine therapy, the intensive insulin therapy has more beneficial effects on the patients undergone distal radical subtotal gastrectomy in decreasing the insulin resistance, improving the status of nutrition and preventing postoperative complications.