Studies have suggested that prenatal exposure to inflammation increases the risk of neuropsychiatric disorders, including anxiety, depression, and cognitive dysfunction. Because of anatomical and ...hormonal alterations, pregnant women frequently experience sleep dysfunction, which can enhance the inflammatory response. The aim of this study was to explore the effects of maternal sleep deprivation on prenatal inflammation exposure-induced behavioral phenotypes in offspring and identify the associated mechanisms.
Pregnant mice received an intraperitoneal injection of lipopolysaccharide (LPS) on gestational day 15 and were subsequently subjected to sleep deprivation during gestational days 15-21. Anxiety-like behavior was evaluated by the open field test and the elevated plus maze test. Depression-like behavior was assessed by the tail suspension test and the forced swimming test. Cognitive function was determined using the Morris water maze test. The levels of markers of inflammation and synaptic function were examined employing general molecular biological techniques.
The results showed that prenatal exposure to LPS resulted in anxiety- and depression-like symptoms and learning and memory deficits, and these effects were exacerbated by maternal sleep deprivation. Furthermore, maternal sleep deprivation aggravated the prenatal LPS exposure-induced increase in the expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α and decrease in the levels of postsynaptic density-95 and synaptophysin in the hippocampus.
Collectively, these results suggested that maternal sleep deprivation exacerbates anxiety, depression, and cognitive impairment induced by prenatal LPS exposure, effects that were associated with an inflammatory response and synaptic dysfunction.
High-performance amorphous silica-alumina (ASA) is an important acid material in the chemical industry. In this work, we successfully synthesized mesoporous ASA with enhanced specific surface area, ...Lewis acidity and total acidity by pH-swing method. The morphology and structure of ASA were systematically investigated. With the increase of SiO2 content from 20.1% to 67.0%, the morphology of ASA varied considerably from fibrous to granular, and the specific surface area decreased from 436 to 306 m2 g−1. Meanwhile, the gradual increase of surface silanol groups facilitated the formation of pseudo-bridged silanol groups and promoted the formation of Brønsted acid sites (BAS). Furthermore, the concentration of BAS was found to increase with increasing tetra- and penta-coordinated aluminum and decrease with increasing octa-coordinated aluminum. In addition, the acidity-activity relationship was also explored by applying the as-synthesized ASA samples directly to the cracking reaction of cumene. The results showed that the activity of ASA was proportional to the concentration of BAS. The pH-swing method can controllably synthesize ASA materials with different structures and acidity for petrochemical industry.
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Background. Peripheral arterial disease (PAD) is a typical disease of atherosclerosis, most commonly influencing the lower extremities. In patients with PAD, revascularization remains a preferred ...treatment strategy. Buyang Huanwu decoction (BHD) is a popular Chinese herbal prescription which has showed effects of cardiovascular protection through conducting antioxidant, antiapoptotic, and anti-inflammatory effects. Here, we intend to study the effect of BHD on promoting revascularization via the Akt/GSK3β/NRF2 pathway in diabetic hindlimb ischemia (HLI) model of mice. Materials and Methods. All db/db mice (n=60) were randomly divided into 6 groups by table of random number. (1) Sham group (N=10): 7-0 suture thread passed through the underneath of the femoral artery and vein without occlusion. The remaining 5 groups were treated differently on the basis of the HLI (the femoral artery and vein from the inguinal ligament to the knee joint were transected and the vascular stump was ligated with 7-0 silk sutures) model: (2) HLI+NS group (N=15): 0.2 ml NS was gavaged daily for 3 days before modeling and 14 days after occlusion; (3) HLI+BHD group (N=15): 0.2 ml BHD (20 g/kg/day) was gavaged daily for 3 days before modeling and 14 days after occlusion; (4) HLI+BHD+sh-NC group (N=8): local injection of adenovirus vector carrying the nonsense shRNA (Ad-GFP) in the hindlimbs of mice before treatment; (5) HLI+BHD+sh-NRF2 group (N=8): knockdown of NRF2 in the hindlimbs of mice by local intramuscular injection of adenovirus vector carrying NRF2 shRNA (Ad-NRF2-shRNA) before treatment; and (6) HLI+BHD+LY294002 group (N=4): intravenous injection of LY294002 (1.5 mg/kg) once a day for 14 days on the basis of the HLI+BHD group. Laser Doppler examination, vascular cast, and immunofluorescence staining were applied to detect the revascularization of lower limbs in mice. Western blot analysis was used to detect the expression of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor- (TNF-) α, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone-1 (NQO-1), catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase-3 beta (p-GSK3β). HE staining was used to assess the level of muscle tissue damage and inflammation in the lower extremities. Local multipoint injection of Ad-NRF2-shRNA was used to knock down NRF2, and qPCR was applied to detect the mRNA level of NRF2. The blood glucose, triglyceride, cholesterol, MDA, and SOD levels of mice were tested using corresponding kits. The SPSS 20.0 software and GraphPad Prism 6.05 were used to do all statistics. Values of P<0.05 were considered as statistically significant. Results and Conclusions. BHD could enhance the revascularization of lower limbs in HLI mice, while BHD has no effect on blood glucose and lipid level in db/db mice (P>0.05). BHD could elevate the protein expression of VEGF, HO-1, NQO-1, and CAT (P<0.05) and decrease the expression of IL-1β, IL-6, and TNF-α (P<0.05) in HLI mice. Meanwhile, BHD could activate NRF2 and promote the phosphorylation of AKT/GSK3β during revascularization (P<0.05). In contrast, knockdown of NRF2 impaired the protective effects of BHD on HLI (P<0.05). LY294002 inhibited the upregulation of NRF2 activated by BHD through inhibiting the phosphorylation of the AKT/GSK3β pathway (P<0.05). The present study demonstrated that BHD could promote revascularization on db/db mice with HLI through targeting antioxidation, anti-inflammation, and angiogenesis via the AKT/GSK3β/NRF2 pathway.
Time‐dependent increases in cue‐induced nicotine and methamphetamine craving during abstinence were recently reported in human drug‐dependent individuals. In the present study, we sought to determine ...whether this ‘incubation of craving’ phenomenon also occurs in alcoholics. Four groups of 80 inpatient adult male alcoholics were assessed in a single session (between‐group design) for cue‐induced alcohol craving at 7, 14, 30 and 60 days of abstinence. Another group that included 19 patients was repeatedly tested for cue‐induced alcohol craving at the same abstinence days as above. Other psychological and physiological measures were assessed at the four abstinence timepoints. Cue‐induced alcohol craving measured with visual analogue scales was the highest at 60 days of abstinence both between and within groups. However, heart rate, blood pressure and skin conductance responses did not differ between abstinent groups. These results provide evidence of the incubation of alcohol craving in humans, extending previous reports with smokers and methamphetamine addicts.
Time‐dependent increases in cue‐induced nicotine and methamphetamine craving during abstinence were recently reported in human drug‐dependent individuals. In the present study, we sought to determine whether this “incubation of craving” phenomenon also occurs in alcoholics. We found that cue‐induced alcohol craving was the highest at 60 days of abstinence both between and within groups. These results provide evidence of the incubation of alcohol craving in humans, extending previous reports with smokers and methamphetamine addicts.
A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated ...conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results.
To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke.
A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke.
The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma).
Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke.
Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76).
In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.
Radix Salviae miltiorrhizae, danshen root (danshen), is one of the widely used Chinese herbal medicines in clinics, containing rich phenolic compounds. Salvianolic acid is the main active compound ...responsible for the pharmacologic effects of danshen. Here, we aimed to evaluate the effects of salvianolic acid on cardioprotection through promoting angiogenesis in experimental myocardial infarction. Studies of salvianolic acid in animal models of myocardial infarction were obtained from 6 databases until April 2016. The outcome measures were vascular endothelium growth factor (VEGF), blood vessel density (BVD), and myocardial infarct size. All the data were analyzed using Rev-Man 5.3 software. Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P<0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving BVD compared with the control group (P<0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P<0.01). In conclusion, these findings demonstrated that salvianolic acid can exert cardioprotection through promoting angiogenesis in animal models of myocardial infarction.
This paper introduces a class of differential fuzzy variational inequalities, the model provides an efficient approach for solving many dynamic multi-objective optimization problems in fuzzy ...environments. An existence theorem of the Carathéodory weak solution for the model is established under some suitable assumptions. An algorithm, supported by the convergence analysis, is developed to find the solution. In addition, some examples are given to illustrate the application and the algorithm.
Alzheimer's disease (AD) shows cognitive impairments in clinic, which is multifactorial with different etiopathogenic mechanisms such as Aβ deposition, neuroinflammation and neuronal dystrophy ...involved. Therefore, multi-targets drugs with neuroprotective, anti-amyloidogenic and anti-inflammatory properties will be effective in AD treatment. Epigallocatechin-3-gallate (EGCG) possesses a broad spectrum of pharmacological activities in the prevention and treatment of multiple neurodegenerative diseases. In the present study, we showed that oral administration of EGCG (50 mg/kg) for 4 months significantly attenuated the cognitive deficits in APP/PS1 transgenic mice, which served as AD model. Moreover, EGCG induced an improvement in dendritic integrity and expression levels of synaptic proteins in the brain of APP/PS1 mice. And EGCG exerted obvious anti-inflammatory effects, which was manifested by alleviating microglia activation, decreasing pro-inflammatory cytokine (IL-1β) and increasing anti-inflammatory cytokines (IL-10, IL-13). Furthermore, β-amyloid (Aβ) plaques were markedly reduced in the hippocampus of 6-month old APP/PS1 mice after EGCG treatment. In conclusion, these findings indicate that EGCG improves AD-like cognitive impairments through neuroprotective, anti-amyloidogenic and anti-inflammatory effects, thus is a promising therapeutic candidate for AD.
Background. Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. The idea of therapeutic angiogenesis in ischemic myocardium is a promising strategy for MI ...patients. Buyang Huanwu decoction (BHD), a famous Chinese herbal prescription, exerted antioxidant, antiapoptotic, and anti-inflammatory effects, which contribute to cardio-/cerebral protection. Here, we aim to investigate the effects of BHD on angiogenesis through the caveolin-1 (Cav-1)/vascular endothelial growth factor (VEGF) pathway in MI model of mice. Materials and Methods. C57BL/6 mice were randomly divided into 3 groups by the table of random number: (1) sham-operated group (sham, n=15), (2) AMI group (AMI+sham, n=20), and (3) BHD-treated group (AMI+BHD, n=20). 2,3,5-Triphenyltetrazolium chloride solution stain was used to determine myocardial infarct size. Myocardial histopathology was tested using Masson staining and hematoxylin-eosin staining. CD31 immunofluorescence staining was used to analyze the angiogenesis in the infarction border zone. Western blot analysis, immunofluorescence staining, and/or real-time quantitative reverse transcription polymerase chain reaction was applied to test the expression of Cav-1, VEGF, vascular endothelial growth factor receptor 2 (VEGFR2), and/or phosphorylated extracellular signal-regulated kinase (p-ERK). All statistical analyses were performed using the SPSS 20.0 software and GraphPad Prism 6.05. Values of P<0.05 were considered as statistically significant. Results and Conclusion. Compared with the AMI group, the BHD-treated group showed a significant improvement in the heart weight/body weight ratio, echocardiography images, cardiac function, infarct size, Mason staining of the collagen deposition area, and density of microvessel in the infarction border zone (P<0.05). Compared with the AMI group, BHD promoted the expression of Cav-1, VEGF, VEGFR2, and p-ERK in the infarction border zone after AMI. BHD could exert cardioprotective effects on the mouse model with AMI through targeting angiogenesis via Cav-1/VEGF signaling pathway.
A high level of LDL-C (low-density lipoprotein cholesterol) is a major risk factor for cardiovascular disease. The E3 ubiquitin ligase named IDOL (inducible degrader of the LDLR LDL receptor; also ...known as MYLIP myosin regulatory light chain interacting protein) mediates degradation of LDLR through ubiquitinating its C-terminal tail. But the expression profile of IDOL differs greatly in the livers of mice and humans. Whether IDOL is able to regulate LDL-C levels in humans remains to be determined. Approach and Results: By using whole-exome sequencing, we identified a nonsynonymous variant rs149696224 in the
gene that causes a G51S (Gly-to-Ser substitution at the amino acid site 51) from a Chinese Uygur family. Large cohort analysis revealed IDOL G51S carriers (+/G51S) displayed significantly higher LDL-C levels. Mechanistically, the G51S mutation stabilized IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL(G51S) exhibited a stronger ability to promote ubiquitination and degradation of LDLR. Adeno-associated virus-mediated expression of IDOL(G51S) in mouse liver decreased hepatic LDLR and increased serum levels of LDL-C, total cholesterol, and triglyceride.
Our study demonstrates that IDOL(G51S) is a gain-of-function variant responsible for high LDL-C in both humans and mice. These results suggest that IDOL is a key player regulating cholesterol level in humans.
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