12 results on '"Li, Hailing"'
Search Results
2. High glucose induced human umbilical vein endothelial cell injury: involvement of protein tyrosine nitration
- Author
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Zhao, Yuling, Lu, Naihao, Li, Hailing, Zhang, Yan, Gao, Zhonghong, and Gong, Yuefa
- Published
- 2008
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3. Y12 nitration of human calcitonin (hCT): A promising strategy to produce non-aggregation bioactive hCT.
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Ye, Huixian, Li, Hailing, and Gao, Zhonghong
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NITRATION , *CALCITONIN , *DRUG design , *PEPTIDE hormones - Abstract
Irreversible aggregation can extremely limit the bioavailability and therapeutic activity of peptide-based drugs. There is therefore an urgent demand of effective strategy to control peptide aggregation. Recently, we found that tyrosine nitration at certain sites of peptide can effectively inhibit its aggregation. This minor modification may be an ideal strategy to the rational design of peptide-based drugs with low aggregation propensity yet without loss of bioactivity. Human calcitonin (hCT) is such a peptide hormone known for its hypocalcaemic effect but has limited pharmaceutical potential due to a high tendency to aggregate. In this study, by using multiple techniques including Fluorescence, TEM, Nu-PAGE and CD, we demonstrated that Y12 nitration of hCT would significantly inhibit its self-assembles, and we also found that this modification would not only reduce the cytotoxicity induced by peptide aggregation, but also had little effect on its potency. This finding may provide a novel strategy for clinically application of hCT instead of sCT. Tyr12 nitration of hCT could be a useful strategy for inhibiting its aggregation but not reducing the hypocalcaemic activity. Image 1 • Tyrosine nitration could effectively inhibit the formation of hCT fibril. • The low aggregation propensity of hCT (3 N) makes it less cytotoxicity than hCT. • hCT (3 N) could still maintain the approximately equally potency compared with hCT. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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4. Triosephosphate isomerase tyrosine nitration induced by heme-NaNO2-H2O2 or peroxynitrite: Effects of different natural phenolic compounds.
- Author
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Gao, Wanxia, Zhao, Jie, Li, Hailing, and Gao, Zhonghong
- Abstract
Peroxynitrite and heme peroxidases (or heme)-H
2 O2 -NaNO2 system are the two common ways to cause protein tyrosine nitration in vitro, but the effects of antioxidants on reducing these two pathways-induced protein nitration and oxidation are controversial. Both nitrating systems can dose-dependently induce triosephosphate isomerase (TIM) nitration, however, heme-H2 O2 -NaNO2 was less destructive to protein secondary structures and led to more nitrated tyrosine residue than 3-morpholinosydnonimine hydrochloride (SIN-1, a peroxynitrite donor). Both of desferrioxamine and catechin could inhibit TIM nitration induced by heme-H2 O2 -NaNO2 and SIN-1 and protein oxidation induced by SIN-1, but promoted heme-H2 O2 -NaNO2 -induced protein oxidation. Moreover, the antagonism of natural phenolic compounds on SIN-1-induced tyrosine nitration was consistent with their radical scavenging ability, but no similar consensus was found in heme-H2 O2 -NaNO2 -induced nitration. Our results indicated that peroxynitrite and heme-H2 O2 -NaNO2 -induced protein nitration was different, and the later one could be a better model for anti-nitration compounds screening. [ABSTRACT FROM AUTHOR]- Published
- 2017
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5. Heme and Cu2+-induced vasoactive intestinal peptide (VIP) tyrosine nitration: A possible molecular mechanism for the attenuated anti-inflammatory effect of VIP in inflammatory diseases.
- Author
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Zeng, Lizhen, Zhang, Xuan, Xia, Mengyang, Ye, Huixian, Li, Hailing, and Gao, Zhonghong
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VASOACTIVE intestinal peptide , *NITRATION , *HEME , *TYROSINE , *DRUG target , *NITRATE reductase , *NEUROPEPTIDES - Abstract
Vasoactive intestinal peptide (VIP) is a neuropeptide that play an important role in immunoregulation and anti-inflammation. Numerous inflammatory/autoimmune disorders are associated with decreased VIP binding ability to receptors and diminished VIP activation of cAMP generation in immune cells. However, the mechanisms linking oxidative/nitrative stress to VIP immune dysfunction remain unknown. It has been reported that the elevated heme or Cu2+ in inflammatory diseases can cause oxidative and nitrative damage to nearby biological targets under high oxidative stress conditions, which affects the structure and activity of linked peptides or proteins. Thus, the VIP down-regulated immune response may be interfered by redox metal catalyzed VIP tyrosine nitration. To explore this, we systematically investigated the possibility of heme or Cu2+ to catalyze VIP tyrosine nitration. The results showed that Tyr10 and Tyr22 of VIP can both be nitrated in heme/H 2 O 2 /NO 2 − system as well as in Cu2+/H 2 O 2 /NO 2 − system. Then, we used synthetic mutant VIPs with tyrosine residues substituted by 3-nitrotyrosine to study the impact of tyrosine nitration on VIP activity in SHSY-5Y cells. Our findings demonstrated that VIP nitration dramatically decreased the content of its α-helix and random coil, suggesting that VIP nitration might reduce its affinity to the receptor. This was further confirmed in the cAMP assay. The results showed that 10 nM of these tyrosine nitrated VIPs could significantly (p < 0.01) decrease cAMP secretion compared to the wild type VIP. Our data reveal that the attenuation of the neuroprotective effect of VIP in inflammation-related diseases might be attributed to metal-catalyzed VIP tyrosine nitration. [Display omitted] • Vasoactive intestinal peptide (VIP) is prone to bind to heme or Cu2+. • Heme or Cu2+ can catalyze the nitration of Tyr10 and Tyr22 residues in VIP in the presence of H 2 O 2 and NO 2 −. • Tyrosine nitration of VIP reduced the content of its active monomer structure and influenced the production of cAMP in cells. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Tyrosine nitration of glucagon impairs its function: Extending the role of heme in T2D pathogenesis.
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Yin, Xiaoying, Ni, Guoqi, Zhang, Xuan, Fu, Shitao, Li, Hailing, and Gao, Zhonghong
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INSULIN receptors , *INSULIN , *NITRATION , *CELLULAR signal transduction , *HEME , *TYROSINE , *HEMOPROTEINS - Abstract
New studies raise the possibility that the higher glucagon (GCG) level present in type 2 diabetes (T2D) is a compensatory mechanism to enhance β-cell function, rather than induce dysregulated glucose homeostasis, due to an important role for GCG that acts directly within the pancreas on insulin secretion by intra-islet GCG signaling. However, in states of poorly controlled T2D, pancreatic α cell mass increases (overproduced GCG) in response to insufficient insulin secretion, indicating decreased local GCG activity. The reason for this decrease is not clear. Recent evidence has uncovered a new role of heme in cellular signal transduction, and its mechanism involves reversible binding of heme to proteins. Considering that protein tyrosine nitration in diabetic islets increases and glucose-stimulated insulin secretion (GSIS) decreases, we speculated that heme modulates GSIS by transient interaction with GCG and catalyzing its tyrosine nitration, and the tyrosine nitration may impair GCG activity, leading to loss of intra-islet GCG signaling and markedly impaired insulin secretion. Data presented here elucidate a novel role for heme in disrupting local GCG signaling in diabetes. Heme bound to GCG and induced GCG tyrosine nitration. Two tyrosine residues in GCG were both sensitive to the nitrating species. Further, GCG was also demonstrated to be a preferred target peptide for tyrosine nitration by co-incubation with BSA. Tyrosine nitration impaired GCG stimulated cAMP-dependent signaling in islet β cells and decreased insulin release. Our results provided a new role of heme for impaired GSIS in the pathological process of diabetes. The possible mechanism of intra-islet GCG activity impairment in diabetes. Since the majority of beta cells in human islets are in direct contact with alpha cells, there is a functional crosstalk between these two major islet cell types. Mechanistically, the positive effect of GCG on beta cell function is achieved by GCG binding to G protein-coupled receptors (GPCRs) (including GLP-1 receptor and GCG receptor), that are expressed in beta cells, and the activation of GPCRs signaling to stimulate the production of cAMP that acts as a necessary cofactor to support glucose-stimulated insulin secretion (GSIS) (the mechanism of GCG maintaining "β-cell tone" is shown as "Normal"). We proposed that tyrosine nitration of GCG may be one of the reason for a diminished intra-islet paracrine hormone action of GCG in diabetes. Heme bound to GCG promotes the probability of GCG tyrosine nitration in the presence of H 2 O 2 and NO 2 −. Tyrosine nitration may affect the structure of GCG, leading to impaired affinity for GPCRs, thereby decreased the stimulatory effect of GCG on insulin secretion from pancreatic beta cells (defective intra-islet GCG action due to that heme-induced GCG tyrosine nitration is shown as "Natrative stress"). [Display omitted] • Glucagon (GCG) is prone to bind to heme • Heme catalyzes GCG tyrosine nitration in the presence of H 2 O 2 and NO 2 − • GCG is a preferred target protein for tyrosine nitration • Tyrosine nitration impaired GCG's role in intra-islet paracrine signaling, which ultimately impaired insulin secretion [ABSTRACT FROM AUTHOR]
- Published
- 2024
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7. Nitration of hIAPP promotes its toxic oligomer formation and exacerbates its toxicity towards INS-1 cells.
- Author
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Zhao, Jie, Wu, Jinming, Yang, Zhen, Ouyang, Lei, Zhu, Lihua, Gao, Zhonghong, and Li, Hailing
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NITRATION , *AMYLIN , *HYDROGEN bonding , *ATOMIC force microscopes , *REACTIVE nitrogen species , *TYPE 2 diabetes - Abstract
Abstract Amyloid formation of human islet amyloid polypeptide (hIAPP) is one of the most common pathological features of type 2 diabetes (T2D). Increasing evidences have shown that the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) play an important role in the development of the T2D. Interestingly, our previous studies indicated that heme could bind to hIAPP, and the complex might induce the nitration of tyrosine residue (Y37) of hIAPP in the presence of hydrogen peroxide and nitrite. However, it remains unclear about effect of the nitration on the implicated function of hIAPP in the development of T2D. In this study, fluorescent assays, transmission electron microscopy (TEM), atomic force microscope (AFM) were used to demonstrate that nitration of hIAPP significantly decreased its fibril formation. But the decreased fibril formation was not through the diminished aggregation of hIAPP monomer as suggested by the results of circular dichroism spectroscopy (CD) and gel electrophoresis assay. Surface-enhanced raman spectroscopy (SERS) indicated that nitration of hIAPP impaired the intermolecular hydrogen bonding. On the basis of these results, we hypothesize that nitration of hIAPP may block the intermolecular hydrogen bonding, leading to the inhibition of its fibril formation. In addition, cytotoxicity study of native and modified hIAPP was also performed on INS-1 cells, which revealed exacerbated toxicity of hIAPP by its nitration. The findings in this study that nitration of hIAPP promotes its oligomer formation and thus exacerbates its cytotoxicity suggests a possible link between the nitrite (or the sum of nitrite and nitrate) levels and T2D, and ameliorated nitration of hIAPP by diminishing nitrative stress might be a promising therapeutic strategy for T2D. Graphical abstract Nitration of hIAPP remarkably decreased its fibril formation by blocking its intermolecular hydrogen bonding and π-π stacking interactions. Image 1 Highlights • The tyrosine (Y37) in hIAPP is prone to nitration in the presence of heme, H 2 O 2 and NO 2 −. • Nitration of hIAPP decreases its aggregation. • Nitration of hIAPP enhances its cytotoxicity toward ISN-1 cells. • Nitration of hIAPP blocks the intermolecular hydrogen bonding. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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8. 5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride (FeTPPS), a peroxynitrite decomposition catalyst, catalyzes protein tyrosine nitration in the presence of hydrogen peroxide and nitrite.
- Author
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Zhang, Pengfei, Ma, Lu, Yang, Zhen, Li, Hailing, and Gao, Zhonghong
- Subjects
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IRON chlorides , *PROTEIN-tyrosine kinases , *PEROXYNITRITE , *NITRATION , *HYDROGEN peroxide - Abstract
5,10,15,20-Tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride (FeTPPS) is a water-soluble heme analog, which has been used as a scavenger of peroxynitrite in many studies. Similar to heme, it may also possess pseudo-peroxidase activity that could cause protein tyrosine nitration through the peroxidase-H 2 O 2 -NO 2 − pathway. In this paper, we used western blotting and spectrophotometry analysis to study the capability of FeTPPS in catalyzing protein tyrosine nitration. Furthermore, the capability of FeTPPS in catalyzing protein nitration in tissue homogenate and cultured cells was also investigated. Our results showed that FeTPPS induced bovine serum albumin (BSA) nitration in the presence of H 2 O 2 and NaNO 2 , and the reaction was dose-, time- and pH-dependent. In acidic condition, more protein was nitrated by FeTPPS than heme, which corresponded to their peroxidase activities. Meanwhile, our results also confirmed the catalytic effect of FeTPPS on protein tyrosine nitration in rat brain homogenate and human hepatocellular carcinoma (HepG2) cells. At the end of this study, we used liquid chromatography (LC)–tandem mass spectrometry (MS/MS) to investigate differences of site selectivity between heme and FeTPPS catalyzed protein tyrosine nitration. The result indicated that FeTPPS tended to catalyze tyrosine residues locating in more hydrophilic sites, whereas heme was more likely to induce nitration of tyrosine residues locating in relatively hydrophobic environment. Taken together, this is the first report that FeTPPS is an effective and convenient nitration catalyzer in vitro , and this study confirms that the hydrophilicity of the nitrating agents would play an important role in nitration site selection. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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9. Insulin enhances the peroxidase activity of heme by forming heme-insulin complex: Relevance to type 2 diabetes mellitus.
- Author
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Huang, Yi, Yang, Zhen, Xu, Huan, Zhang, Pengfei, Gao, Zhonghong, and Li, Hailing
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GENETICS of type 2 diabetes , *HEME , *CAPILLARY electrophoresis technique , *HISTIDINE metabolism , *INSULIN genetics - Abstract
Evidences have implicated the involvement of heme in the type 2 diabetes mellitus (T2Dm) pathogenesis, but possible mediators linking between heme and diabetes are still poorly understood. Here, we explored a potential mechanism that linked heme, insulin and diabetes. Our results demonstrated the formation of heme-insulin complex by two classical methods, i.e. UV–vis and capillary electrophoresis-frontal analysis (CE-FA). UV–vis results implied heme binding insulin via bis-histidine sites, and CE-FA further revealed that, when insulin uses two sites binding with heme, this interaction occurs at high affinity (K d = 3.13 × 10 −6 M). Molecule docking supported that histidine-B5 of insulin binds with heme-Fe. In addition to that, tyrosine-B26, phenylalanine-B1 and valine-B2 are also contributed to binding heme. The binding amplified the peroxidase activity of heme itself. Under oxidative and nitrative stress, it affects pathogenesis of diabetes from two aspects: promoting insulin cross-linking that leads to permanent loss of insulin functionality on one hand, and enhancing protein tyrosine nitration that may result in inactivation of proteins associated with diabetes on the other hand. This study suggested that the enhanced peroxidase activity of heme through binding with insulin might be a previously unrecognized contributor to the pathogenesis of T2Dm in some heme-associated disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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10. Interaction of glyceraldehyde-3-phosphate dehydrogenase and heme: The relevance of its biological function.
- Author
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Huang, Yi, Zhang, Pengfei, Yang, Zhen, Wang, Peipei, Li, Hailing, and Gao, Zhonghong
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HEMOPROTEINS , *CARBONYLATION , *NITRATION , *GLYCERALDEHYDEPHOSPHATE dehydrogenase , *TYROSINE , *HEME - Abstract
GAPDH was speculated to function as a transient trap to reduce the potential toxicity of free heme by a specific and reversible binding with heme. Up to now, there has been lack of studies focused on this effect. In this paper, the efficiency of GAPDH-heme complex on catalyzing protein carbonylation and nitration, the cross-linking of heme to protein formation, and cytotoxicity of GAPDH-heme were studied. It was found that the binding of GAPDH could inhibit H 2 O 2 -mediated degradation of heme. Peroxidase activity of GAPDH-heme complex was higher than that of free heme, but significantly lower than that of HSA-heme. Catalytic activity of heme corresponded complex toward tyrosine oxidation/nitration was decreased in the order of HSA-heme, heme and GAPDH-heme. GAPDH also inhibited heme-H 2 O 2 -NO 2 - induced protein carbonylation. No covalent bond was formed between heme and GAPDH after treated with H 2 O 2 . GAPDH was more effective than HSA on protecting cells against heme-NO 2 - -H 2 O 2 induced cytotoxicity. These results indicate that binding of GAPDH inhibits the activity of heme in catalyzing tyrosine nitration and protects the coexistent protein against oxidative damage, and the mechanism is different from that of HSA. This study may help clarifying the protective role of GAPDH acting as a chaperone in heme transfer to downstream areas. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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11. Association of cardiac injury with iron-increased oxidative and nitrative modifications of the SERCA2a isoform of sarcoplasmic reticulum Ca2+-ATPase in diabetic rats.
- Author
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Li, Xueli, Li, Wenliang, Gao, Zhonghong, and Li, Hailing
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HEART injuries , *SARCOPLASMIC reticulum , *ADENOSINE triphosphatase , *DIABETES complications , *OXIDATIVE stress , *LABORATORY rats - Abstract
The role of iron in the etiology of diabetes complications is not well established. Thus, this study was performed to test whether the iron-induced increase of oxidative/nitrative damage is involved in SERCA2a-related diabetic heart complication. Four randomly divided groups of rats were used: normal control group; iron overload group; diabetes group, and diabetic plus iron overload group. Iron supplementation stimulated cardiomyocyte hypertrophy and led to an increase in cardiac protein carbonyls, nitrotyrosine (3-NT) formation, and iNOS protein expression, thus resulting in abnormal myocardium calcium homeostasis of diabetic rats. The levels of SECA2a oxidation/nitration were significantly increased in the iron overload diabetic rats, along with a decrease in SECA2a expression and activity. In order to elucidate the possible role of iron in SERCA2a dysfunction, the effects of iron (Fe 3+ or hemin) on peroxynitrite (ONOO − ) induced SERCA2a oxidation and nitration were further investigated in vitro. It was found that tyrosine nitration played more important role in SERCA2a inactivation than thiol oxidation. These results present a potential mechanism in which iron exacerbates the diabetes-induced oxidative/nitrative modification of SERCA2a, which may cause functional deficits in the myocyte associated with diabetic cardiac dysfunction. Our findings may help to further understand the role of iron in the pathogenesis of diabetic complications. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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12. Iron overload-induced rat liver injury: Involvement of protein tyrosine nitration and the effect of baicalin
- Author
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Zhang, Yan, Huang, Yi, Deng, Xiaorong, Xu, Yan, Gao, Zhonghong, and Li, Hailing
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LIVER injuries , *THERAPEUTICS , *IRON in the body , *PROTEIN-tyrosine kinases , *FLAVONOIDS , *DRUG efficacy , *IMMUNOHISTOCHEMISTRY , *LABORATORY rats - Abstract
Abstract: Baicalin has been reported to protect against liver injury in iron-overload mice, however, the mechanisms underlying the hepatoprotective properties of baicalin are poorly understood. In this study, we systematically studied the protective effect of baicalin on iron overload induced liver injury, as well as the underlying mechanism based on nitrative stress in rat model. We found that when iron overload rats (500mgiron/kg) were fed baicalin-containing diet (0.3% and 1% w/w) for 45days, baicalin dose dependently protected against iron overload induced liver injury, including alleviation of hepatic pathological damage, decrease of SOD activity, iron content, carbonyl content, and the thiobarbituric acid-reactive substances level in hepatic tissues. It also increased serum iron content, SH content and GPx activity, decreased serum ALT and AST activities. Immunohistochemistry and immunoprecipitation analysis revealed that baicalin could also inhibit iron overload induced protein tyrosine nitration in liver. Moreover, in iron overload rat liver, we found that baicalin decreased the iron overload increased level of glutathione-S-transferases (GSTs) expression, oxidation and nitration. These results suggest that not only oxidative stress, but also nitrative stress, is involved in iron overload induced liver injury, and the underlying mechanism might partially relate to the involvement of GSTs expression and post-translational modification. Baicalin can effectively prevent iron overload caused abnormality and can be a candidate medicine for iron overload diseases. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
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