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Cilostazol protects diabetic rats from vascular inflammation via nuclear factor-kappa B-dependent down-regulation of vascular cell adhesion molecule-1 expression.
Gao Ling;Wang Furong;Wang Bo;Gong Bendi;Zhang Jie;Zhang Xiumei;Zhao Jiaju
J Pharmacol Exp Ther 2006年 318卷1期 页码:53-8
Animals|Diabetes Mellitus, Experimental/drug therapy/metabolism|Down-Regulation/drug effects/physiology|Endothelium, Vascular/drug effects/metabolism|Gene Expression Regulation/drug effects/physiology|Male|NF-kappa B/antagonists & inhibitors/metabolism|Rats|Rats, Sprague-Dawley|Tetrazoles/pharmacology/therapeutic use|Vascular Cell Adhesion Molecule-1/biosynthesis|Vascular Diseases/metabolism/prevention & contro
Vascular cell adhesion molecule (VCAM)-1 plays a critical role in the initiation and development of vascular inflammation and selective inhibition of adhesion molecules expressed by endothelial cells may present a new therapeutic strategy for the treatment of vascular complications associated with diabetes mellitus. Increasing evidence indicates that cilostazol, a cAMP phosphodiesterase inhibitor, reduces VCAM-1 expression on endothelial cells. In this study, we have tested the effect of cilostazol on the development of vascular inflammation in rats with streptozotocin-induced diabetes and determined the mechanism by which cilostazol prevents diabetes-induced vascular inflammation in the aorta. Diabetic rats were treated with different dose of cilostazol (27 or 9 mg/kg/day) for 8 weeks, and aortae were removed for the evaluation of vascular inflammation. The VCAM-1 protein expression and VCAM-1 mRNA transcripts were analyzed by immunohistochemical staining and in situ hybridization assay, respectively. Our results demonstrated that cilostazol treatment prevents the overexpression of VCAM-1 and protects diabetic rats from vascular inflammation. More importantly, our mechanistic studies suggested that cilostazol controls the VCAM-1 overexpression via inhibiting the activation of nuclear factor-kappaB.
Chronic palmitate exposure inhibits AMPKalpha and decreases glucose-stimulated insulin secretion from beta-cells: modulation by fenofibrate.
Sun Ying;Ren Meng;Gao Guan-qi;Gong Bendi;Xin Wei;Guo Hua;Zhang Xiu-juan;Gao Ling;Zhao Jia-ju
Acta Pharmacol Sin 2008年 29卷4期 页码:443-50
AMP-Activated Protein Kinases/antagonists & inhibitors|Animals|Cell Culture Techniques|Cell Line, Tumor|Cells, Cultured|Dose-Response Relationship, Drug|Fenofibrate/pharmacology|Glucose/pharmacology|Insulin/secretion|Insulin-Secreting Cells/drug effects/metabolism|Insulinoma/metabolism|Islets of Langerhans/cytology/drug effects/physiology|Luminescence|Luminescent Measurements|Male|PPAR alpha/metabolism|Palmitates/pharmacology|Rats|Rats, Wista
Adenosine monophosphate-activated protein kinase (AMPK), a vital regulator of glucose metabolism, may affect insulin secretion in beta-cells. However, the role of AMPK in beta-cell lipotoxicity remains unclear. Fenofibrate has been reported to regulate lipid homeostasis and is involved in insulin secretion in pancreatic beta-cells. In the present study, we aimed to investigate the effect of palmitate on AMPK expression and glucose-stimulated insulin secretion (GSIS) in rat islets and INS-1 beta-cell, as well as the effect of fenofibrate on AMPK and GSIS in INS-1 cells treated with palmitate.
Peroxynitrite induces apoptosis of mouse cochlear hair cells via a Caspase-independent pathway in vitro
Cao, ZX;Yang, QQ;Yin, HY;Qi, Q;Li, HR;Sun, GY;Wang, HL;Liu, WW;Li, JF
APOPTOSIS 2017年 22卷11期 页码:1419-1430 影响因子:3.592
CISPLATIN-INDUCED OTOTOXICITY; ORGANOTYPIC CULTURES; HEARING-LOSS; RAT; GENES; DEATH; MICE; AIF; AGE
Peroxynitrite (ONOO-) is a potent and versatile oxidant implicated in a number of pathophysiological processes. The present study was designed to investigate the effect of ONOO- on the cultured cochlear hair cells (HCs) of C57BL/6 mice in vitro as well as the possible mechanism underlying the action of such an oxidative stress. The in vitro primary cultured cochlear HCs were subjected to different concentrations of ONOO-, then, the cell survival and morphological changes were examined by immunofluorescence and transmission electron microscopy (TEM), the apoptosis was determined by Terminal deoxynucleotidyl transferase dUNT nick end labeling (TUNEL) assay, the mRNA expressions of Caspase-3, Caspase-8, Caspase-9, Apaf1, Bcl-2, and Bax were analyzed by RT-PCR, and the protein expressions of Caspase-3 and AIF were assessed by immunofluorescence. This work demonstrated that direct exposure of primary cultured cochlear HCs to ONOO- could result in a base-to-apex gradient injury of HCs in a concentration-dependent manner. Furthermore, ONOO- led to much more losses of outer hair cells than inner hair cells mainly through the induction of apoptosis of HCs as evidenced by TEM and TUNEL assays. The mRNA expressions of Caspase-8, Caspase-9, Apaf1, and Bax were increased and, meanwhile, the mRNA expression of Bcl-2 was decreased in response to ONOO- treatment. Of interesting, the expression of Caspase-3 had no significant change, whereas, the expression alteration of AIF was observed. These results suggested that ONOO- can effectively damage the survival of cochlear HCs via triggering the apoptotic pathway. The findings from this work suggest that ONOO--induced apoptosis is mediated, at least in part, via a Caspase-independent pathway in cochlear HCs.
Prevalence of Mutations in Deafness-Causing Genes in Cochlear Implanted Patients with Profound Nonsyndromic Sensorineural Hearing Loss in Shandong Province, China
Luo, JF;Bai, XH;Zhang, FG;Xiao, Y;Gu, LT;Han, YC;Fan, ZM;Li, JF;Xu, L;Wang, HB
ANNALS OF HUMAN GENETICS 2017年 81卷6期 页码:258-266
ENLARGED VESTIBULAR AQUEDUCT; PENDRED-SYNDROME; GJB2 MUTATIONS; CONNEXIN-26 MUTATIONS; SLC26A4 MUTATIONS; JAPANESE; IDENTIFICATION; FREQUENCIES; POPULATION; IMPAIRMENT
The mutations of GJB2, SLC26A4, and mtDNA12SrRNA are the most common inherited causes of nonsyndromic sensorineural hearing loss (NSHL) in China, yet previous genetic screenings were mainly carried on patients with moderate-to-profound impairment. We aimed to detect the mutation frequencies in NSHL population within a more specified range of severity. Patients with profound NSHL who had undergone cochlear implantation in the Shandong Provincial Hospital (Shandong, China) were recruited. The majority (n = 472) were between 0.7 and 6 years old, and the remaining (n = 63) were between 6 and 70 years old. In total, 115 mutation alleles of the three genes were screened with SNP scan assay. Of the patients, 19.44% (104/535) were found to have GJB2 mutations, and the most common allele was c.235delC, followed by c.299_300delAT and c.109G>A. SLC26A4 mutations were detected in 13.46% patients (72/535), and the most common allele was c.919-2A>G (IVS7-2A>G), followed by c.1174A>T and c.2168A>G. Seven patients (1.31%) carried mutations in mtDNA12SrRNA, with the alleles of m.1555A>G and m.1494C>T. We found the allele frequency of c.109G>A (GJB2) was relatively lower in the profound NSHL population in comparison to the moderate-to-profound ones, and the c.1174A>T (SLC26A4) relatively higher. It suggests those mutations may be connected with the degree of deafness, which needs more observations and analyses to support.
Different contributions of lipid profiles and BMI to the natural history of type 2 diabetes: a 3-year cohort study in China
Liu, L;Guan, XL;Yuan, ZS;Zhao, M;Li, Q;Zhang, X;Zhang, HQ;Zheng, DM;Xu, J;Gao, L;Guan, QB;Zhao, JJ
DIABETES-METABOLISM RESEARCH AND REVIEWS 2017年 33卷
MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3
Bian, HJ;Li, FF;Wang, WW;Zhao, Q;Gao, SS;Ma, JC;Li, X;Ren, WH;Qin, CY;Qi, JN
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 2017年 40卷5期 页码:1495-1503
IFN-BETA PRODUCTION; ACTIN CYTOSKELETON; IN-VIVO; CELLS; REORGANIZATION; RECOGNITION; VINCRISTINE; INHIBITION; ENDOTOXIN; LEUKEMIA
Toll-like receptor 3 (TLR3) and TLR4 utilize adaptor proteins to activate mitogen-activated protein kinase (MAPK), resulting in the acute but transient inflammatory response aimed at the clearance of pathogens. In the present study, it was demonstrated that macrophage activation by lipopolysaccharide (LPS) or poly(I:C), leading to changes in cell morphology, differed significantly between the mouse macrophage cell line RAW264.7 and mouse primary peritoneal macrophages. Moreover, the expression of alpha- and beta-tubulin was markedly decreased following LPS stimulation. By contrast, alpha- and beta-tubulin expression were only mildly increased following poly(I:C) treatment. However, the expression of beta-actin and GAPDH was not significantly affected. Furthermore, it was verified that vincristine pretreatment abrogated the cytoskeleton rearrangement and decreased the synthesis and secretion of proinflammatory cytokines and migration of macrophages caused by LPS. Finally, it was observed that the MAPK/p38 signaling pathway regulating cytoskeleton rearrangement may participate in LPS-induced macrophage cytokine production and migration. Overall, the findings of the present study indicated that MAPK/p38 regulation of the cytoskeleton, particularly tubulin proteins, plays an important role in LPS-induced inflammatory responses via alleviating the synthesis and secretion of proinflammatory cytokines and inhibiting the migration of macrophages.
FKBP51 decreases cell proliferation and increases progestin sensitivity of human endometrial adenocarcinomas by inhibiting Akt
Dong, J;Jiao, YL;Mu, WL;Lu, BR;Wei, MY;Sun, LY;Hu, SN;Cui, B;Liu, XW;Chen, ZJ;Zhao, YR
ONCOTARGET 2017年 8卷46期 页码:80405-80415 影响因子:5.008
RECEPTOR COMPLEXES; CDK INHIBITORS; CANCER; PATHWAY; THERAPY; PROTEINS; BINDING; REGULATORS; CARCINOMA; GROWTH
In this study, we investigated the role of FK506 binding protein 51 (FKBP51) in human endometrial adenocarcinoma progression. Immunohistochemical analysis showed decreased FKBP51 expression in endometrial adenocarcinoma tissues. Moreover, higher FKBP51 expression was observed in the normal secretory phase than in proliferative-phase endometrial tissues. FKBP51-shRNA transfected KLE cells showed high Ser473-phospho Akt with decreased p21 and p27 levels, which promoted S-G(2)/M phase cell cycle progression and proliferation. Conversely, FKBP51 overexpressing Ishikawa cells showed low Ser473-phospho Akt, which led to increased p21 and p27 levels and, in turn, G(0)/G(1) cell cycle arrest and decreased cell proliferation. FKBP51 overexpression in progesterone receptor-positive Ishikawa cells sensitized them to medroxyprogesterone acetate (MPA; progestin) treatment by repressing Akt signaling. Conversely, FKBP51-shRNA knockdown in RL95-2 cells attenuated progestin sensitivity. These findings indicate FKBP51 inhibits cell proliferation and promotes progestin sensitivity in endometrial adenocarcinoma by decreasing Akt signaling.
New perspectives of physiological and pathological functions of nucleolin (NCL)
Jia, WY;Yao, ZY;Zhao, JJ;Guan, QB;Gao, L
LIFE SCIENCES 2017年 186卷 页码:1-10
CELL-SURFACE NUCLEOLIN; PRE-RIBOSOMAL-RNA; PENTAMERIC PSEUDOPEPTIDE HB-19; POLYMERASE-I TRANSCRIPTION; SELF-CLEAVING ACTIVITY; REPLICATION PROTEIN-A; BREAST-CANCER CELLS; MESSENGER-RNA; EXPRESSED NUCLEOLIN; COMPLEX-FORMATION
Nucleolin (NCL) is a multifunctional protein that mainly localized in the nucleolus, it is also found in the nucleoplasm, cytoplasm and cell membrane. The three main structural domains allow the interaction of NCL with different proteins and RNA sequences. Moreover, specific post-translational modifications and its shuttling property also contribute to its multifunctionality. NCL has been demonstrated to be involved in a variety of aspects such as ribosome biogenesis, chromatin organization and stability, DNA and RNA metabolism, cytokinesis, cell proliferation, angiogenesis, apoptosis regulation, stress response and microRNA processing. NCL has been increasingly implicated in several pathological processes, especially in tumorigenesis and viral infection, which makes NCL a potential target for the development of anti-tumor and anti-viral strategies. In this review, we present an overview on the structure, localizations and various functions of NCL, and further describe how the multiple functions of NCL are correlated to its multiple cellular distributions.
MiR-320 inhibits the growth of glioma cells through downregulating PBX3
Pan, CC;Gao, H;Zheng, N;Gao, Q;Si, YQ;Zhao, YR
BIOLOGICAL RESEARCH 2017年 50卷
COLORECTAL-CANCER; SIGNALING PATHWAY; PROSTATE-CANCER; PROLIFERATION; GLIOBLASTOMA; MICRORNAS; SUPPRESSES; APOPTOSIS; MIGRATION; INVASION
Background: MiR-320 is downregulated in multiple cancers, including glioma and acts as tumor suppressor through inhibiting tumor cells proliferation and inducing apoptosis. PBX3 (Pre-B cell leukemia homeobox 3), a putative target gene of miR-320, has been reported to be upregulated in various tumors and promote tumor cell growth through regulating MAKP/ERK pathway. This study aimed to verify whether miR-320 influences glioma cells growth through regulating PBX3.;-;Methods: Twenty-four human glioma and paired adjacent nontumorous tissues were collected for determination of miR-320 and PBX3 expression using RT-qPCR and western blot assays. Luciferase reporter assay was performed to verify the interaction between miR-320 and its targeting sequence in the 3' UTR of PBX3 in glioma cells U87 and U251. Increased miR-320 level in U87 and U251 cells was achieved through miR-320 mimic transfection and the effect of which on glioma cells growth, proliferation, cell cycle, apoptosis and activation of Raf-1/MAPK pathway was determined using MTT, colony formation, flow cytometry and western blot assays. PBX3 knockdown was performed using shPBX3 and the influence on MAPK pathway activation was evaluated.;-;Results: MiR-320 downregulation and PBX3 upregulation was found in glioma tissues. Luciferase reporter assays identified miR-320 directly blinds to the 3' UTR of PBX3 in glioma cells. MiR-320 mimic transfection suppressed glioma cells proliferation, and induced cell cycle arrest and apoptosis. Both miR-320 overexpression and PBX3 knockdown inhibited Raf-1/MAPK activation.;-;Conclusion: MiR-320 may suppress glioma cells growth and induced apoptosis through the PBX3/Raf-1/MAPK axis, and miR-320 oligonucleotides may be a potential cancer therapeutic for glioma.
Spag6 Mutant Mice Have Defects in Development and Function of Spiral Ganglion Neurons, Apoptosis, and Higher Sensitivity to Paclitaxel
Li, XF;Xu, L;Sun, GY;Wu, XM;Bai, XH;Li, JF;Strauss, JF;Zhang, ZB;Wang, HB
SCIENTIFIC REPORTS 2017年 7卷
MICROTUBULE-ASSOCIATED PROTEIN; MINIMAL RESIDUAL DISEASE; GROWTH; CANCER; EXPRESSION; GENES; CELLS; IDENTIFICATION; REGENERATION; MIGRATION
Mammalian Sperm Associated Antigen 6 (SPAG6) is the orthologue of Chlamydomonas PF16, a protein localized in the axoneme central apparatus. Recent studies showed that Spag6 has a role in brain neuronal proliferation and differentiation. The mammalian spiral ganglion neurons (SGNs) are specialzed bipolar neurons in the inner ear. However, the role of SPAG6 in SGN has not been elucidated. Therefore, We hypothesized that a Spag6 knockout would affect the development and function of SGNs. We utilized Spag6-deficient mice and SGN explants to define the role of SPAG6. On postnatal day 30 (P30) mutant mice had lower SGN density compared to their wild-type littermates, and more apoptosis was evident in the mutants. Increased Bax expression, a disturbed distribution of cytochrome c, and cleaved caspase-3 positive staining indicated that increased apoptosis involved a mitochondrial pathway. Transmission electron microscopy revealed abnormalities in the ultrastructure of mutant SGNs as early as P7. In vitro, lack of SPAG6 affected the growth of neurites and growth cones. Additionally, SPAG6 deficiency decreased synapse density in SGN explants. Finally, Spag6 mutant SGNs were more sensitive to the microtubule stabilizing agent, paclitaxel. These findings suggest that Spag6 plays a crucial role in SGN development and function.
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