摘要:
Female smokers are more likely to relapse than male smokers, but little is known about sex differences in nicotine withdrawal. Therefore, male and female rats were prepared with minipumps that contained nicotine or saline and sex differences in precipitated and spontaneous nicotine withdrawal were investigated. The intracranial self-stimulation (ICSS) procedure was used to assess mood states. Elevations in brain reward thresholds reflect a deficit in reward function. Anxiety-like behavior was investigated after the acute nicotine withdrawal phase in a large open field and the elevated plus maze test. The nicotinic receptor antagonist mecamylamine elevated the brain reward thresholds of the nicotine-treated rats but did not affect those of the saline-treated control rats. A low dose of mecamylamine elevated the brain reward thresholds of the nicotine-treated male rats but not those of the females. Mecamylamine also precipitated more somatic withdrawal signs in the nicotine-treated male than female rats. Minipump removal elevated the brain reward thresholds of the nicotine-treated rats for about 36h but did not affect those of the saline-treated rats. There was no sex difference in the reward deficit during spontaneous nicotine withdrawal. In addition, the nicotine-treated male and female rats did not display increased anxiety-like behavior three to four days after minipump removal. In conclusion, these studies suggest that relatively low doses of a nicotinic receptor antagonist induce a greater reward deficit and more somatic withdrawal signs in male than female rats, but there is no sex difference in the reward deficit during spontaneous withdrawal.
摘要:
BACKGROUND: The skin bridge in the perforator-plus flap is considered as an additional source for arterial input and venous drainage apart from the perforator. However, its exact role requires further elucidation. MATERIALS AND METHODS: Forty rats that underwent flap elevation with a size of 9 x 3 cm on the dorsum were evenly divided into a perforators-intact group with an intact vascular pedicle, an artery-deficient group with the artery ligated, a vein-deficient group with the vein ligated, and a perforators-deficient group with both vessels ligated. The blood perfusion was measured using a laser Doppler flowmeter. On the seventh day, the necrosis rate of the flaps was calculated and the diameter of vessels in the skin bridge was measured. RESULTS: The perfusion pattern was similar between the perforators-intact group and vein-deficient group, as well as between the perforators-deficient group and artery-deficient group. The blood perfusion was much more robust in the perforators-intact and vein-deficient groups. The necrosis rate in the perforators-deficient group (26 +/- 1%) was not significantly different from that in the artery-deficient group (29 +/- 1%), both of which was significantly larger than that in the perforator-intact (11 +/- 3%) and vein-deficient groups (12 +/- 4%) (P < 0.001). The venous network of the skin base in the vein-deficient and perforators-deficient groups dilated dramatically, whereas the arterial network in the artery-deficient and perforators-deficient groups had a very modest expansion. CONCLUSIONS: The skin base in a perforator-plus flap is much more important as an additional route for vein drainage than for arterial input.
期刊:
American Journal of Human Genetics,2019年105(1):166-176 ISSN:0002-9297
通讯作者:
Shen, Lu;Jin, Peng
作者机构:
[Tian, Yun; Sun, Qi-Ying; Yi, Fang; Tang, Bei-Sha; Zhou, Ya-Fang; Xu, Hong-Wei] Cent S Univ, Xiangya Hosp, Dept Geriatr, Changsha 410008, Hunan, Peoples R China.;[Zeng, Sheng; Jiao, Bin; Liu, Zhen; Chen, Zhao; Jiang, Hong; Zhou, Chao-Jun; Yan, Xin-Xiang; Hou, Xuan; Guo, Ji-Feng; Tang, Bei-Sha; Long, Hong-Yu; Wang, Jun-Ling; Shen, Lu] Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China.;[Tian, Yun; Tang, Bei-Sha; Shen, Lu] Cent S Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Hunan, Peoples R China.;[Xia, Kun; Hu, Zheng-Mao; Huang, Wen; Duan, Ran-Hui] Cent S Univ, Sch Life Sci, Ctr Med Genet, Changsha 410008, Hunan, Peoples R China.;[Kong, Ha Eun; Li, Yujing; Shafik, Andrew Mark; Allen, Emily G.; Jin, Peng] Emory Univ, Sch Med, Dept Human Genet, Whitehead Res Bldg,Room 305A,615 Michael St, Atlanta, GA 30322 USA.
通讯机构:
[Shen, Lu] C;[Jin, Peng] E;Cent S Univ, Xiangya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China.;Cent S Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Hunan, Peoples R China.;Emory Univ, Sch Med, Dept Human Genet, Whitehead Res Bldg,Room 305A,615 Michael St, Atlanta, GA 30322 USA.
摘要:
Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.
期刊:
IMMUNOLOGY AND CELL BIOLOGY,2019年97(2):134-141 ISSN:0818-9641
通讯作者:
Tang, Chao-Ke
作者机构:
[Tang, Chao-Ke; Yu, Xiao-Hua] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov,Med Res Expt Ct, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Da-Wei] Univ Alberta, Dept Pediat, Edmonton, AB T6G 2S2, Canada.;[Zhang, Da-Wei] Univ Alberta, Grp Mol & Cell Biol Lipids, Edmonton, AB T6G 2S2, Canada.;[Zheng, Xi-Long] Univ Calgary, Libin Cardiovasc Inst Alberta, Cumming Sch Med, Hlth Sci Ctr,Dept Biochem & Mol Biol, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada.;[Tang, Chao-Ke] Univ South China, Inst Cardiovasc Res, Hengyang 421001, Hunan, Peoples R China.
通讯机构:
[Tang, Chao-Ke] U;Univ South China, Inst Cardiovasc Res, Hengyang 421001, Hunan, Peoples R China.
关键词:
inflammation;IRG1;itaconate;IκBζ;Nrf2;SDH
摘要:
Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis-aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide-treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti-inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IkappaBzeta translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro- to an anti-inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.
摘要:
This study was conducted to observe the effect and possible mechanism of TO901317 in vivo and in vitro to provide a new basis for the targeted therapy of hepatocellular carcinoma (HCC). The expressions of liver X receptor (LXR)-alpha, glucose transporter (Glut)-1, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinase (MMP)-9 were analyzed from HCC public database (NCBI PubMed database). The result showed that LXR alpha was downregulated, whereas Glut1. PCNA. and MMP9 were upregulated in human HCC compared with normal liver. Furthermore. LXR alpha mRNA was negatively correlated with Glut1 mRNA. At the same time, HCC cells were cultivated in vitro and axillary injected in nude mice to establish the xenograft model. The xenograft in the TO901317-treated group was slower and smaller than the control group. The protein expression of LXR alpha, Glut1, and MMP9 could be detected by Western blot and glucose level. As a result. TO901317 could inhibit the cell proliferation of HCC in a dose-dependent manner by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. With the increase of TO901317 concentration, the cellular glucose concentration and ATP level were gradually decreased. Western blot results showed TO901317 could upregulate LXR alpha expression but downregulate MMP9 and Glut1 expression. Transwell and wound-healing analysis confirmed that, by increasing the concentration of TO901317. the cell invasion and migration were both decreased. LXR alpha small-interfering RNA (siRNA) could relieve the suppression effect of TO901317 on the cell invasion and migration and the expression of LXR alpha, Glut1, and MMP9. The glucose concentration was also raised. TO901317 could repress the progress of HCC cells by reducing the glucose concentration. upregulating LXR alpha expression. but downregulating the expression of Glut1 and MMP9. NEW & NOTEWORTHY This subject confirmed that TO901317, a specific liver X receptor agonist, could inhibit the progression of liver cancer through upregulating liver X receptor-alpha, downregulating the expression of glucose transporter-1 and matrix metalloproteinase-9, and decreasing the glucose content in SMMC-7721 and HepG2 cells.
摘要:
The present study focused on the novel roles and the underlying mechanisms of miR-135b in pyroptosis of MPP+-induced Parkinson's disease (PD). We established an in vitro PD model induced by MPP+. Our results demonstrated miR-135b was lower while FoxO1 was inversely higher in MPP+-treated SH-SY5Y and PC-12 cells. Luciferase reporter assay showed FoxO1 was a downstream target of miR-135b. MiR-135b mimics suppressed MPP+-induced pyroptosis and the upregulation of TXNIP, NLRP3, Caspase-1, ASC, GSDMD(Nterm) and IL-1 beta. Moreover, FoxO1 overexpression had no effect on miR-135b but reversed its own downregulation caused by miR-135b mimics. Meanwhile, overexpression of FoxO1 abolished the inhibitory effects of miR-135b on pyroptosis and reversed the downregulation of pyroptotic genes and LDH release. In summary, miR-135b played a protective role in Parkinson's disease via inhibiting pyroptosis by targeting FoxO1. MiR-135b might serve as a potential therapeutic target in the treatment of Parkinson's disease. (C) 2019 Elsevier Ltd. All rights reserved.
摘要:
Type 2 diabetes mellitus (T2DM) is a chronic degenerative endocrine and metabolic disease with high mortality and morbidity, yet lacks effective therapeutics. We recently generated a novel fusion peptide INSR-IgG4Fc, Yiminsu (YMS), to facilitate the high-affinity binding and transportation of insulin. Thus, the aim of the present study was to determine whether the novel recombinant peptide, YMS, could contribute to restoring insulin sensitivity and glycaemic control in insulin resistance models and revealing its underlying mechanism. Palmitic acid (PA)-treated LO2 cells and high fat diet (HFD)-fed mice were treated with YMS. Therapeutic effects of YMS were measured using Western blotting, ELISA, qPCR, Histology and transmission electron microscopy. We observed that YMS treatment effectively improved insulin signaling in PA-treated LO2 cells and HFD-fed mice. Notably, YMS could significantly reduce serum levels of glucose, triglycerides, fatty acids and cholesterol without affecting the serum insulin levels. Moreover, our data demonstrated that YMS could restore glucose and lipid homeostasis via facilitating insulin transportation and reactivating PI3K/Akt signaling in both PA-treated cells and liver, gastrocnemius and brown fat of HFD-fed mice. Additionally, we noticed that the therapeutic effects of YMS was similar as rosiglitazone, a well-recognized insulin sensitizer. Our findings suggested that YMS is a potentially candidate for pharmacotherapy for metabolic disorders associated with insulin resistance, particularly in T2DM.
作者:
Wang Pan;Xu Gao-Sheng;Ma Wei;Ye Dong-Mei;Li Yu-Xuan;...
期刊:
生物化学与生物物理进展,2019年46(3):238-247 ISSN:1000-3282
通讯作者:
Zhang Zhi-Wei
作者机构:
[Li Yu-Xuan; Wang Pan; Zhang Zhi-Wei; Ye Dong-Mei] Univ South China, Canc Res Inst, Hengyang Med Coll, Hengyang 421001, Peoples R China.;[Li Yu-Xuan; Wang Pan; Zhang Zhi-Wei; Ye Dong-Mei] Key Lab Canc Cellular & Mol Pathol Hunan Prov, Hengyang 421001, Peoples R China.;[Ma Wei; Xu Gao-Sheng] Yueyang Maternal & Child Hlth Hosp, Yueyang 421001, Peoples R China.;[Xiao Yi-Yang; Luo Wei-Ru] Univ South China, Clin Med Excellent Undergrad Med Coll, Hengyang 421001, Peoples R China.
通讯机构:
[Zhang Zhi-Wei] U;[Zhang Zhi-Wei] K;Univ South China, Canc Res Inst, Hengyang Med Coll, Hengyang 421001, Peoples R China.;Key Lab Canc Cellular & Mol Pathol Hunan Prov, Hengyang 421001, Peoples R China.
摘要:
We conducted a meta-analysis to evaluate the effect of probiotic combined with aminosalicylic on induction remission maintenance treatment of ulcerative colitis (UC). We conducted systematic searches in several Chinese and English databases from inception to June 2018, screening randomized controlled trials about effect of probiotics combined with aminosalicylic acid on UC. The evaluation indicator was the rate of remission. The relative risk (RR) and 95% confidence interval (CI) were calculated. A total of 27 studies with 1942 patients were included. The results indicated that the remission rate was significantly higher in the group using probiotics combined with aminosalicylic acid than that in the group using aminosalicylic acid alone (RR = 1.40, 95% CI: 1.27–1.53, P=0.000). The subgroup analysis indicated that probiotics combined with aminosalicylic acid can significantly elevate the remission rate in both mild to moderate (RR = 1.33, 95% CI: 1.16–1.54, P=0.000) and active stage (RR = 1.40, 95% CI: 1.27–1.64, P=0.000) UC. In different number of bacterium, drug types and treatment periods, the combination with probiotics can significantly increase the remission rate UC. The funnel plot shows slight publication bias. Probiotics in conjunction with aminosalicylic can obviously increase the clinical remission rate of activity UC than drug alone. There was no significant difference between combined with mesalazine group and salicylazosulfapyridine group. c 2019 The Author(s).