Hongqiao Zhang's research while affiliated with University of Southern California and other places

Publications (74)

Article
Background: HNE (4-hydroxy-2-nonenal), a primary α, β-unsaturated aldehyde product of lipid peroxidation, is implicated in the pathogenesis and progression of Alzheimer's disease (AD). HNE level in the brain increases with aging and is higher in AD hippocampus than age-matched controls. Upon HNE exposure, cells usually can upregulate HNE detoxific...
Article
Background: Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood-brain barrier weakening, which may augment neurotoxic effec...
Article
Oxidative stress is a component of many diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer disease and cancer. Although numerous small molecules evaluated as antioxidants have exhibited therapeutic potential in preclinical studies, clinical trial results have been disappointing. A greater understanding of the mech...
Article
Background: Air pollution is widely associated with accelerated cognitive decline at later ages and risk of Alzheimer's disease (AD). Correspondingly, rodent models demonstrate the neurotoxicity of ambient air pollution and its components. Our studies with nano-sized particulate matter (nPM) from urban Los Angeles collected since 2009 have shown p...
Article
4-hydroxynonenal (HNE, 4-hydroxy-2-nonenal) is a primary α,β-unsaturated aldehyde product of lipid peroxidation. The accumulation of HNE increases with aging and the mechanisms are mainly attributable to increased oxidative stress and decreased capacity of HNE elimination. In this review article, we summarize the studies on age-related change of HN...
Article
Glutathione (GSH) plays critical roles in the inflammatory response by acting as the master substrate for antioxidant enzymes and an important anti-inflammatory agent. In the early phase of the inflammatory response of macrophages, GSH content is decreased due to the down regulation of the catalytic subunit of glutamate cysteine ligase (GCLC). In t...
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The neurotoxicity of air pollution is undefined for sex and APOE alleles. These major risk factors of Alzheimer's disease (AD) were examined in mice given chronic exposure to nPM, a nano-sized subfraction of urban air pollution. In the cerebral cortex, female mice had twofold more genes responding to nPM than males. Transcriptomic responses to nPM...
Chapter
4-Hydroxenonenal (HNE) is one of the major α,β-unsaturated aldehyde products of lipid peroxidation. HNE can form conjugates with macromolecules, including protein, and thereby alter their function. HNE and its conjugation with proteins are increased in aging and age-related diseases. To elucidate how HNE is involved in these aging-related pathophys...
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Air pollution (AirP) is associated with many neurodevelopmental and neurological disorders in human populations. Rodent models show similar neurotoxic effects of AirP particulate matter (PM) collected by different methods or from various sources. However, controversies continue on the identity of the specific neurotoxic components and mechanisms of...
Article
Exposure to urban ambient particulate matter (PM) is associated with risk of Alzheimer's disease and accelerated cognitive decline in normal aging. Assessment of the neurotoxic effects caused by urban PM is complicated by variations of composition from source, location, and season. We compared several in vitro cell-based assays in relation to their...
Article
Nrf2 is the master transcription factor regulating the basal and inducible expression of antioxidant genes. With aging, the basal Nrf2 activity is increased but oxidant/electrophile-enhanced activation of Nrf2 signaling is diminished, and these changes are accompanied by an increased expression of Bach1, a repressor of Nrf2 signaling. In this limit...
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The Nrf2 signal transduction pathway plays a major role in adaptive responses to oxidative stress and in maintaining adaptive homeostasis, yet Nrf2 signaling undergoes a significant age-dependent decline that is still poorly understood. We used mouse embryonic fibroblasts (MEFs) cultured under hyperoxic conditions of 40% O 2 , as a model of acceler...
Article
In response to oxidative stress, cells usually expand a wide suite of defense mechanisms as part of adaptive homeostasis. Included in the array of adaptive responses is increased expression and activity of 20S proteasomes, immunoproteasomes, and PA28 (11S) proteasomal activator that enable efficient and rapid removal of oxidatively damaged proteins...
Article
Rett syndrome is a rare, female-specific genetic disease that is caused by an X-linked dominant mutation of the methyl-CPG-binding protein 2 (MECP2) gene, involved in chromatin architecture and often functioning as transcriptional repressor. MECP2 mutation is the leading cause behind the most prevalent form of female-specific cognitive disability....
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Evidence indicates that oxidative stress plays a central role in the pathogenesis of harmful effects caused by airborne nanoparticle (ANP), a health hazard associated with various diseases. Carbon nanoparticles are a major component of urban ANP, and usually adsorbs transition metals especially iron and organics on the surface. Nuclear factor eryth...
Article
Glutathione (GSH), the most abundant non-protein antioxidant thiol in cells, also plays a key role in mediating the inflammatory response. Its content is reduced in the early phase of the inflammatory response of macrophages due to decreased expression of the catalytic subunit of glutamate cysteine ligase (GCLC). How GCLC is down regulated during t...
Article
The elderly are more susceptible to sepsis, which is often fatal, and caused by infection and characterized by systemic inflammation and oxidative stress. Blood monocytes are effector immune cells that play critical roles in the pathogenesis of sepsis through producing large amount of pro-inflammatory cytokines and oxidants. In this study we examin...
Article
Silica nanoparticles with iron on their surface (SiFeP) induce the production of oxidants and pro-inflammatory cytokines in epithelial cells. Crosstalk between the nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and NF-κB signaling was found in response to SiFeP exposure. However, little is known about the age-related change in interaction...
Article
How macrophages maintain redox homeostasis in the inflammatory process, in which a large amount of oxidants are produced, remains elusive. In this study, we investigated the temporal changes in the intracellular glutathione (GSH), the master antioxidant, and the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH biosynt...
Article
How macrophages maintain redox homeostasis in the inflammatory process, in which a large amount of oxidants are produced, remains elusive. In this study, we investigated the temporal changes in the intracellular glutathione (GSH), the master antioxidant, and the expression of glutamate cysteine ligase (GCL), the rate-limiting enzyme for GSH biosynt...
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Evidence from animal studies suggests that stress-induced increases in Nrf2-regulated antioxidant gene expression, a critical mechanism of cellular protection, declines with aging. This study examined whether this also occurs in humans. We measured the basal and inducible levels of Nrf2-regulated antioxidant genes in human bronchial epithelial (HBE...
Article
Silica and iron are major constituents in ambient particulate matter, and iron is a common impurity in many engineered nanomaterials. The purpose of this work was to determine the pro-inflammatory and other biological effects and mechanism of particle size and iron presence under low dose, non-cytotoxic conditions that are likely to approximate act...
Article
Silica nanoparticles with iron on their surface cause the production of oxidants and stimulate an inflammatory response in macrophages. Nuclear factor erythroid-derived 2 -like factor 2 (Nrf2) signaling and its regulated antioxidant genes play critical roles in maintaining redox homeostasis. In this study we investigated the regulation of four repr...
Article
4-hydroxy-2-nonenal (HNE), a major non-saturated aldehyde product of lipid peroxidation, has been extensively studied as a signaling messenger. In these studies a wide range of HNE concentrations have been used, ranging from the unstressed plasma concentration to far beyond what would be found in actual pathophysiological condition. In addition, ac...
Article
Studies have demonstrated that airborne nanoparticulate matter causes oxidative stress, inflammation, and induces an Nrf2-regulated adaptive response. However, the contribution of particulate components to these biologic effects and how Nrf2 signaling is activated need to be further clarified. In this study, we focused on silica and iron, two commo...
Article
4-Hydroxy-2-nonenal (HNE), one of the major α, β-unsaturated aldehydes produced during lipid peroxidation, is a potent messenger in mediating signaling pathways. Lipid peroxidation and HNE production appear to increase with aging. Although the cause and effect relation remains arguable, aging is associated with significant changes in diverse signal...
Article
Oxidation of critical signaling protein cysteines regulated by H2O2 has been considered to involve sulfenic acid (RSOH) formation. RSOH may subsequently form either a sulfenyl amide (RSNHR′) with a neighboring amide, or a mixed disulfide (RSSR′) with another protein cysteine or glutathione. Previous studies have claimed that RSOH can be detected as...
Article
Increasing oxidative stress, a major characteristic of aging, has been implicated in variety of age-related pathologies. In aging, oxidant production from several sources is increased while antioxidant enzymes, the primary lines of defense, are decreased. Repair systems, including the proteasomal degradation of damaged proteins also declines. Impor...
Article
Transforming growth factor-β1 (TGF-β) is involved in multiple cellular processes through Src activation. In the canonical pathway, Src activation is initiated by pTyr530 dephosphorylation followed by a conformational change allowing Tyr419 auto-phosphorylation. A non-canonical pathway in which oxidation of cysteine allows bypassing of pTyr530 depho...
Article
Transforming growth factor-β (TGF-β1 is involved in multiple cellular processes including epithelial-mesenchymal transition (EMT), and many of them are mediated through activating Src kinase, a non-receptor tyrosine kinase. How TGF-β1activates Src remains largely unknown. In the classic pathway Src activation is initiated by dephosphorylation of pT...
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Although the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) regulated expression of multiple antioxidant and cytoprotective genes through the electrophile responsive element (EpRE) is well established, interaction of Nrf2/EpRE with Nrf1, a closely-related transcription factor, is less well understood. Due to either proteolysis or al...
Article
3244 Introduction The United States Armed Forces estimate that sickle cell trait (SCT) conveys a 30-fold risk of sudden cardiac death and a 200-fold risk of rhabdomyolysis following exertion in recruits during basic training. Catastrophic cardiovascular collapse in African Americans with SCT has been the leading cause of death in NCAA football pla...
Article
Glutathione (GSH) is the most abundant antioxidant and a major detoxification agent in cells. It is synthesized through two-enzyme reaction catalyzed by glutamate cysteine ligase and glutathione synthetase, and its level is well regulated in response to redox change. Accumulating evidence suggests that GSH may play important roles in cell signaling...
Article
Many xenobiotic detoxifying (phase II) enzymes are induced by sublethal doses of environmental toxicants. However, these adaptive mechanisms have not been studied in response to vehicular-derived airborne nano-sized particulate matter (nPM). Because aging is associated with increased susceptibility to environmental toxicants, we also examined the e...
Article
Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of lung fibrosis and cancer metastasis, two conditions associated with cigarette smoke (CS). CS has been reported to promote the EMT process. CS is the major cause of lung cancer and nearly half of lung cancer patients are active smokers. Nonetheless, the mechanism whereby CS...
Article
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The ability to adapt to acute oxidative stress (e.g. H(2)O(2), peroxynitrite, menadione, and paraquat) through transient alterations in gene expression is an important component of cellular defense mechanisms. We show that such adaptation includes Nrf2-dependent increases in cellular capacity to degrade oxidized proteins that are attributable to in...
Article
Multidrug-resistant protein-3 (MRP3), a membrane-bound transporter, facilitates efflux of toxic compounds, including certain chemotherapies, out of cells. Aberrant MRP3 expression has been linked to drug resistance in non-small cell lung carcinoma (NSCLC). We sought to determine if tumor MRP3 expression patterns correlate with the mutational status...
Article
Resveratrol, a polyphenolic compound rich in grapes and red wine, has been reported to protect cells against oxidative damage and cell death by increasing cellular antioxidant/detoxification capacity. Cigarette smoking is a major risk factor for respiratory diseases and oxidative damage is implicated in its pathogenesis. Here we investigated the en...
Article
The electrophile response element (EpRE) is essential for regulation of many genes involved in protection against toxic agents. Putative EpRE core sequences (TGAnnnnGC) are localized in 5'-flanking regions (5'-UTR) of these genes but specificity of the internal bases and whether location affects function has not been refined. The catalytic subunit...
Article
gamma-Glutamyl transpeptidase (GGT) catalyzes the transfer of the glutamyl moiety from glutathione, and glutathione S-conjugates to acceptors to form another amide or to water to produce free glutamate. Functionally, GGT plays important roles in glutathione homeostasis and mercapturic acid metabolism. The expression of GGT is increased as an adapti...
Article
Phase II enzymes are induced primarily through the common electrophile response element (EpRE) signaling. Studies performed in different cell types and with different inducer appear to indicate variation in the upstream signaling pathways involved in the induction of these phase II genes. Nonetheless, whether variation in signaling among phase II g...
Article
Multidrug-resistant proteins (MRPs) are members of the ATP-binding cassette superfamily that facilitate detoxification by transporting toxic compounds, including chemotherapeutic drugs, out of cells. Chemotherapy, radiation, and other xenobiotic stresses have been shown to increase levels of select MRPs, although the underlying mechanism remains la...
Article
Resveratrol has been shown to protect against oxidative stress through modulating antioxidant capacity. In this study, we investigated resveratrol-mediated induction of glutathione (GSH) and glutamate cysteine ligase (GCL), and the combined effect of resveratrol and 4-hydroxynonenal (HNE) on GSH synthesis in cultured HBE1 human bronchial epithelial...
Article
This review is the introduction to a special issue concerning, glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. Here, the functions and GSH and the sources...
Article
During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactiv...
Article
Heme oxygenase-1 (HO-1) catalyzes the rate limiting reaction of heme metabolism and plays critical roles in resistance to oxidative stress and other cellular functions. It is well known that HO-1 is induced in response to various stresses; however, the signaling pathways involved remain incompletely elucidated. Acrolein is an alpha,beta-unsaturated...
Article
Silica particle-associated inflammation is implicated in the genesis of several pulmonary diseases, including silicosis and lung cancer. In this study we investigated the role of phosphatidylcholine-specific phospholipase C (PC-PLC) in silica-stimulated induction of TNF-alpha and IL-1beta and how PC-PLC activity is regulated by silica in a rat alve...
Article
4-Hydroxynonenal (HNE), a major electrophilic product of lipid peroxidation, is regarded as both a marker of oxidative stress and a mediator of oxidative damage. At subtoxic concentrations, however, this compound has been shown to be a signalling molecule that can induce the expression of various antioxidant/detoxification enzymes, including glutam...
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The role of H2O2 as a second messenger in signal transduction pathways is well established. We show here that the NADPH oxidase-dependent production of O2*(-) and H2O2 or respiratory burst in alveolar macrophages (AM) (NR8383 cells) is required for ADP-stimulated c-Jun phosphorylation and the activation of JNK1/2, MKK4 (but not MKK7) and apoptosis...
Article
Up-regulation of activity of gamma-glutamyl transpeptidase (GGT) has been reported to occur in the Parkinsonian substantia nigra, the area of the brain affected by the disease. Increased GGT activity has been hypothesized to play a role in subsequent mitochondrial complex I (CI) inhibition by increasing cysteine as substrate for cellular uptake. In...
Article
gamma-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNA V is controlled by promoter 5. Previously we found that GGT mRNA V-2 was responsible for the induction of GGT in rat...
Article
Full-text available
Gamma-glutamyl transpeptidase (GGT) plays critical roles in glutathione homeostasis and metabolism. Rat GGT is a single-copy gene from which seven types of GGT mRNA with a common protein encoding sequence, but different 5'-untranslated regions, may be transcribed. We previously showed that type V-2 was the predominant form of GGT mRNA in rat L2 epi...
Article
Glutathione (GSH) is the most abundant nonprotein thiol in cells and has multiple biological functions. Glutathione biosynthesis by way of the γ‐glutamyl cycle is important for maintaining GSH homeostasis and normal redox status. As the only enzyme of the cycle located on the outer surface of plasma membrane, γ‐glutamyl transpeptidase (GGT) plays k...
Article
gamma-Glutamyl transpeptidase (GGT) plays key roles in the metabolism of glutathione. Previous studies have shown that GGT expression was increased by oxidants, but the mechanism remains unclear. In the present study, the effects of 4-hydroxy-2-nonenal (HNE), an electrophilic end product of lipid peroxidation, on GGT expression were investigated in...
Article
Glutathione (GSH) is the most abundant nonprotein thiol in cells and has multiple biological functions. Glutathione biosynthesis by way of the gamma-glutamyl cycle is important for maintaining GSH homeostasis and normal redox status. As the only enzyme of the cycle located on the outer surface of plasma membrane, gamma-glutamyl transpeptidase (GGT)...
Article
Glutathione (GSH) is the primary nonprotein thiol in the cell. It has many important roles in cell function, including regulating redox-dependent signal transduction pathways. The content of GSH within the cell varies with stress. In many cases, a process involving GSH synthesis results in adaptation to subsequent stressors. Sustained increases in...
Article
Full-text available
Dietary use of curcumin, the active component of tumeric, one of the most widely used spices, is linked to several beneficial health effects, although the underlying molecular mechanisms remain largely unknown. Correlations have been established between curcumin exposure and increases in enzymes for glutathione synthesis, particularly glutamate-cys...
Article
Glutathione is the most abundant non-protein thiol in the cell, with roles in cell cycle regulation, detoxification of xenobiotics, and maintaining the redox tone of the cell. The glutathione content is controlled at several levels, the most important being the rate of de novo synthesis, which is mediated by two enzymes, glutamate cysteine ligase (...
Article
Full-text available
In A549 cell culture, significant variability was found in sensitivity to actinomycin D. Using limiting dilution, actinomycin D-susceptible (G4S) and -resistant (D3R) subclones were isolated. G4S cells were also susceptible to protein synthesis inhibitors, a redox cycling quinone, and an electrophile with concomitant activation of caspases 3 and 9....

Citations

... More recently, Mack's team found that nPM exposure altered working memory in a mouse model of carotid artery disease; however, exposure did not affect working memory in healthy mice. 5 "These are the types of outcomes we can look for in patients," Mack says. "We think exposure to particulate matter may cause Experiments using rodent models are yielding evidence of how exposure to particulate matter may affect stroke risk in humans. ...
... They serve as signaling molecules, and are generated by the immune system as a defense against pathogens (Radi 2004(Radi , 2013. However, if present in high concentrations they cannot be handled by the protective mechanisms based on antioxidants, and oxidative stress occurs (Sies 2020;Forman and Zhang 2021). This state is implicated, for example, in diabetes mellitus type 2, or in many neurodegenerative diseases (Ježek et al. 2017;Sies 2020;Forman and Zhang 2021). ...
... The results of this study should be interpreted within the framework of the reported decreases in potency of recent Los Angeles nPM samples (18). Histochemistry studies were performed on mice exposed to nPM batches collected in 2015 and 2016, while MRI studies were performed on mice exposed to nPM batches collected in 2018 (batch 6,7). ...
... Reactive oxygen species (ROS), especially hydrogen peroxide (H 2 O 2 ) are recognized as associated with tumor metastasis [36][37][38]. TGF-β-related signaling promotes hydrogen peroxide production in several types of cells [39][40][41]. Simultaneously, H 2 O 2 enhances TGF-β-mediated EMT via SMAD and MEK/ERK signaling [42]. To determine if intracellular H 2 O 2 participate in the TGF-β1-related inhibition of cell migration, we first measured H 2 O 2 level in cells with LAE supplement for 48 hours. ...
... Further, the qPCR assay showed that Tfrc and ferroportin-1 (Fpn1) mRNAs were increased, while ferritin light chain 1 (Ftl1), Ho1, and Mt1g mRNAs were Accepted Article decreased in pregnant DHT+INS-exposed rats compared to pregnant control rats (Fig. 3G). GPX4 inactivation and/or GSH shortage induces lipid oxidation, which is directly responsible for ferroptosis [27,30], and 4-Hydroxynonenal (4-HNE) is a cytotoxic aldehydic product of lipid peroxidation (a marker of ferroptosis) [47,48]. We found that in comparison with control rats (Fig. 4A and 4B), pregnant DHT+INSexposed rats exhibited increased uterine lipid peroxidation as evidenced by increased 4-HNE-modified protein levels (Fig. 4A) and increased 4-HNE immunoreactivity (Fig. 4D). ...
... Clinical evidence suggests that lung injury is generally accompanied by rapid alveolar injury, pulmonary infiltrates, uncontrolled inflammatory response, and excessive oxidative stress [3]. Among those, the abnormal inflammatory response plays a vital role in the process of lung injury, and is mainly represented by elevated concentrations of harmful reactive oxygen species (ROS) and insufficient cellular anti-inflammatory defenses [4]. High levels of ROS are frequently found in patients with lung injury, and can affect inflammatory signaling pathways-especially toll-like receptors/myeloid differentiation primary response 88/nuclear factor-kappa B (TLR4/MyD88/NF-κB) [5,6]. ...
... We speculate that young females had a larger pro-inflammatory response that could be ameliorated by ibuprofen treatment. It is shown that young females have larger inflammatory responses to environmental stressors such as air pollution (Haghani et al. 2020). We expect a similar female excess of response to traumatic injuries. ...
... Characteristics of 4-HNE. 4-HNE is considered one of the major mediators of oxidative stress in cells and tissues, that collectively lead to cell senescence by affecting the expression of various senescence-related signaling pathways [38] (such as NF-κB, Nrf2, Akt/PKB, and mTOR), as shown in Figure 2. The combination of the two conjugated functional groups of 4-HNE, the carbonyl group (-C =0), and a double bond (C2/C3, -C=C-) facilitates the reaction of 4-HNE with biological molecules (including lipids, nucleic acids, and proteins) [39]. A mass spectrometry-based proteomic analysis of oxidative stress found that the electrophilic double bond and nucleophilic amino acid residues on proteins enable 4-HNE to form Michael adducts with lysine (Lys) [40], histidine (His) [41], and cysteine (Cys) [42] residues to increase the molecular masses of these amino acids by 156 Da (the molecular mass of HNE), or form Schiffbase adducts with its aldehyde group and Lys to an increase in the mass by 138 Da (Schiff-base formation with a net loss of water) [43,44]. ...
... Silica-based dusts may not only drive pulmonary inflammation, but also cause neuroinflammatory impacts in an autoimmune model [5]. Furthermore, mental health impacts and depression have been linked to short-term exposure to PM and a depressive-like response in mice due to inflammation in the brain [11,12]. More specifically, there is a neuroand immunologic association among stress, inflammation, and air pollution exposures [13][14][15][16]. ...
... Some mechanisms have been revealed.