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Results in Journal Free Radical Biology and Medicine: 22,348

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Yujia Li, Chun Jin, Min Shen, Zhenyi Wang, Shanzhong Tan, Anping Chen, Shijun Wang, Jiangjuan Shao, Feng Zhang, Sciprofile linkZili Zhang, et al.
Published: 15 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.008

Abstract:
Currently, the existing treatments have not cured the liver fibrosis thoroughly. Ferroptosis is a newly discovered way of cell death, which is closely related to many diseases. Previous studies have shown that ferroptosis plays an important role in the occurrence and development of liver fibrosis, but the further mechanism remains to be discovered. LX-2 cells were used as the research object, fibrosis activation index was detected by Western blot, PCR and Immunofluorescence, ferroptosis was detected by kits, the binding and interaction between IRP2 (iron regulatory protein 2) and STUB1 (STIP1 homology and U-box containing protein 1) were detected by Immunoprecipitation and ubiquitin test, and IRP2 knockdown mice were constructed by interfering plasmid to verify the results of in vitro experiment. Our research showed that ART (artemether) had a good anti-fibrosis effect in vivo and in vitro, and ferroptosis played an important role in this process. Further studies have found that ART could lead to the accumulation of IRP 2 a in hepatic stellate cell by inhibiting the ubiquitination of it, thus inducing the increase of iron in HSC (hepatic stellate cell), which could product a large number of ROS (reactive oxide species), resulting the occurrence of ferroptosis in cells. Our findings provided an experimental basis for ART to become a drug for the treatment of liver fibrosis. Our results show that IRP2-Iron-ROS axis is necessary for ART to induce ferroptosis in HSC and play an anti-fibrotic effect.
Anca Grivei, Kurt T.K. Giuliani, Xiangju Wang, Sciprofile linkJacobus Ungerer, Leo Francis, Kirsten Hepburn, George T. John, Pedro F.H. Gois, Andrew J. Kassianos, Sciprofile linkHelen Healy
Published: 14 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.011

Abstract:
Acute kidney injury (AKI) is a life-threatening complication of rhabdomyolysis. The pathophysiological mechanisms of rhabdomyolysis-induced AKI (RIAKI) have been extensively studied in the murine system, yet clinical translation of this knowledge to humans is lacking. In this study, we investigated the cellular and molecular pathways of human RIAKI. Renal biopsy tissue from a RIAKI patient was examined by quantitative immunohistochemistry (Q-IHC) and compared to healthy kidney cortical tissue. We identified myoglobin casts and uric acid localised to sites of histological tubular injury, consistent with the diagnosis of RIAKI. These pathological features were associated with tubular oxidative stress (4-hydroxynonenal staining), regulated necrosis/necroptosis (phosphorylated mixed-lineage kinase domain-like protein staining) and inflammation (tumour necrosis factor (TNF)-α staining). Expression of these markers was significantly elevated in the RIAKI tissue compared to the healthy control. A tubulointerstitial inflammatory infiltrate accumulated adjacent to these sites of RIAKI oxidative injury, consisting of macrophages (CD68), dendritic cells (CD1c) and T lymphocytes (CD3). Foci of inflammasome activation were co-localised with these immune cell infiltrate, with significantly increased staining for adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) and active caspase-1 in the RIAKI tissue compared to the healthy control. Our clinical findings identify multiple pathophysiological pathways previously only reported in murine RIAKI, providing first evidence in humans linking deposition of myoglobin and presence of uric acid to tubular oxidative stress/necroptosis, inflammasome activation and necroinflammation.
Sciprofile linkJie Zhang, Zhi-Wei Ye, Wei Chen, John Culpepper, Haiming Jiang, Lauren Ball, Shikhar Mehrotra, Anna Blumental-Perry, Kenneth D. Tew, Sciprofile linkDanyelle M. Townsend
Published: 13 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.013

Abstract:
Multiple myeloma (MM) cells have high rates of secretion of proteins rich in disulfide bonds and depend upon compartmentalized redox balance for accurate protein folding. The proteasome inhibitor bortezomib (Btz) is a successful frontline treatment for the disease, but its long-term efficacy is restricted by the acquisition of resistance. We found that MM cell lines resistant to Btz maintain high levels of oxidative stress and are cross resistant to endoplasmic reticulum (ER) stress-inducing agents thapsigargin (ThG), and tunicamycin (TuM). Moreover, cells expressing high/wild type levels of glutathione S-transferase P (GSTP) are more resistant than Gstp1/p2 knockout cells. In agreement, basal levels of S-glutathionylated proteins and redox regulation enzymes, including GSTP are elevated at mRNA and protein levels in resistant cells. GSTP mediated S-glutathionylation (SSG) regulates the activities of a number of redox active ER proteins. Here we demonstrated that the post-translational modification determines the balance between foldase and ATPase activities of the binding immunoglobulin protein (BiP), with Cys41-SSG important for ATPase, and Cys420-SSG for foldase. BiP expression and S-glutathionylation are increased in clinical specimens of bone marrow from MM patients compared to non-cancerous samples. Preventing S-glutathionylation in MM cells with a GSTP specific inhibitor restored BiP activities and reversed resistance to Btz. Therefore, S-glutathionylation of BiP confreres pro-survival advantages and represents a novel mechanism of drug resistance in MM cells. We conclude that altered GSTP expression leads to S-glutathionylation of BiP, and contributes to acquired resistance to Btz in MM.
Published: 12 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.08.027

Abstract:
Tocochromanols (tocopherols and plastochromanol-8), isoprenoid quinone (plastoquinone-9 and plastoquinol-9) and carotenoids (xanthophylls), are lipid-soluble antioxidants in the chloroplasts, which play an important defensive role against photooxidative stress in plants. In this study, the interplay between the antioxidant activities of those compounds in excess light stress was analysed in wild-type (WT) Arabidopsis thaliana and in a tocopherol cyclase mutant (vte1), a homogentisate phytyl transferase mutant (vte2) and a tocopherol cyclase overexpressor (VTE1oex). The results reveal a strategy of cooperation and replacement between α-tocopherol, plastochromanol-8, plastoquinone-9 and zeaxanthin. In the first line of defence (non-radical mechanism), singlet oxygen is either physically or chemically quenched by α-tocopherol; however, when α-tocopherol is absent or consumed, zeaxanthin and plastoquinone-9/plastoquinol-9 can provide an alternative protection against singlet oxygen toxicity either by functional replacement of α-tocopherol by zeaxanthin for the physical quenching or by functional replacement of α-tocopherol by plastoquinone-9 for the chemical quenching. When singlet oxygen escapes this first line of defence, it oxidizes lipids and forms lipid hydroperoxides, which are oxidized to lipid peroxyl radicals by ferric iron. In the second line of defence (radical mechanism), lipid peroxyl radicals are scavenged by α-tocopherol. After its consumption, plastochromanol-8 overtakes this function. We provide a comprehensive description of the reaction pathways underlying the non-radical and radical antioxidant activities of α-tocopherol, carotenoids, plastoquinone-9/plastoquinol-9 and plastochromanol-8. The interplay between the different plastid lipid-soluble antioxidants in the non-radical and the radical mechanism provides step by step insights into protection against photooxidative stress in higher plants.
Mario S.P. Correia, Abhishek Jain, Wafa Alotaibi, Paul Young Tie Yang, Sciprofile linkAna Rodriguez-Mateos, Sciprofile linkDaniel Globisch
Published: 11 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.006

Abstract:
The gut microbiome converts dietary compounds that are absorbed in the gastrointestinal tract and further metabolized by the human host. Sulfated metabolites are a major compound class derived from this co-metabolism and have been linked to disease development. In the present multidisciplinary study, we have investigated human urine samples from a dietary intervention study with 22 individuals collected before and after consumption of a polyphenol rich breakfast. These samples were analyzed utilizing our method combining enzymatic metabolite hydrolysis using an arylsulfatase and mass spectrometric metabolomics. Key to this study is the validation of 235 structurally diverse sulfated metabolites. We have identified 48 significantly upregulated metabolites upon dietary intervention including 11 previously unknown sulfated metabolites for this diet. We observed a large variation in subjects based on their potential to sulfate metabolites, which may be the foundation for classification of subjects as high and low sulfate metabolizers in future large cohort studies. The reported sulfatase-based method is a robust tool for the discovery of unknown microbiota-derived metabolites in human samples.
Sciprofile linkGema Pereira-Caro, Sciprofile linkMichael N. Clifford, Thelma Polyviou, Sciprofile linkIziar A. Ludwig, Hani Alfheeaid, José Manuel Moreno-Rojas, Sciprofile linkAda L. Garcia, Dalia Malkova, Alan Crozier
Published: 11 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.007

Abstract:
The health benefits of orange juice (OJ) consumption are attributed in part to the circulating flavanone phase II metabolites and their microbial-derived ring fission phenolic catabolites. The present study investigated these compounds in the bloodstream after acute intake of 500 mL of OJ. Plasma samples obtained at 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h after OJ intake were analysed by HPLC-HR-MS. Eleven flavanone metabolites and 36 phenolic catabolites were identified and quantified in plasma. The main metabolites were hesperetin-3´-sulfate with a peak plasma concentration (Cmax) of 80 nmol/L, followed by hesperetin-7-glucuronide (Cmax 24 nmol/L), hesperetin-3´-glucuronide (Cmax 18 nmol/L) and naringenin-7-glucuronide (Cmax 21 nmol/L). Among the main phenolic catabolites to increase in plasma after OJ consumption were 3´-methoxycinnamic acid-4´-sulfate (Cmax 19 nmol/L), 3-hydroxy-3-(3′-hydroxy-4′-methoxyphenyl)propanoic acid (Cmax 20 nmol/L), 3-(3′-hydroxy-4′-methoxyphenyl)propanoic acid (Cmax 19 nmol/L), 3-(4′-hydroxyphenyl)propanoic acid (Cmax 25 nmol/L), and 3-(phenyl)propanoic acid (Cmax 19 nmol/L), as well as substantial amounts of phenylacetic and hippuric acids. The comprehensive plasma pharmacokinetic profiles that were obtained are of value to the design of future ex vivo cell studies, aimed at elucidating the mechanisms underlying the potential health benefits of OJ consumption. This trial was registered at clinicaltrials.gov as NCT02627547.
Published: 11 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.010

Abstract:
The trace element zinc plays an indispensable role in human health and diseases including cancer due to its antioxidant properties. While zinc supplements have been used for cancer prevention, zinc is also a risk factor for cancer development. It is still unclear how zinc plays a role in ovarian cancer. To understand how zinc contributes to ovarian tumor growth and metastasis, we examined whether zinc contributes to tumor metastasis by regulating epithelial to mesenchymal transition (EMT) using ovarian cancer cells in vitro. Cell migration and invasion were examined using transwell plates and EMT markers were examined using Western blot. Primary ovarian tumor growth and metastasis were assessed using orthotopic ovarian cancer mouse models in vivo. Zinc promoted EMT, while TPEN (N, N, N’, N’-tetrakis-(2-pyridylmethyl)-ethylenediamine), a membrane-permeable selective zinc chelator, inhibited EMT in a dose dependent manner in ovarian cancer cells. Moreover, zinc promoted ovarian cancer cell migration and invasion, while TPEN inhibited cell migration and invasion. Zinc activated expression of the metal response transcriptional factor-1 (MTF-1), while TPEN inhibited MTF-1 expression in a dose dependent manner. Knockout of MTF-1 inhibited zinc-induced cell migration, invasion and augmented the inhibitory effect of TPEN on cell migration and invasion. Loss of MTF-1 attenuated zinc-induced ERK1/2 and AKT activation and augmented the effect of TPEN in attenuating the ERK1/2 and AKT pathways. TPEN effectively inhibited primary ovarian tumor growth and metastasis in an orthotopic ovarian cancer mouse model by suppressing EMT. zinc contributes to ovarian tumor metastasis by promoting EMT through a MTF-1 dependent pathway. Zinc depletion by TPEN may be a novel approach for ovarian cancer therapy by inhibiting EMT and attenuating the ERK1/2 and AKT pathways.
Yu-Shiuan Cheng, Mikhail Linetsky, Haoting Li, Naji Ayyash, Anthony Gardella, Sciprofile linkRobert G. Salomon
Published: 10 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.009

Abstract:
Oxidation of docosahexaenoate (DHA)-containing phospholipids in the cell plasma membrane leads to release of the α,β-unsaturated aldehyde 4-hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone which is capable of inducing retinal pigmented epithelial (RPE) cell dysfunction. Previously, HOHA lactone was shown to induce apoptosis and angiogenesis, and to activate the alternative complement pathway. RPE cells metabolize HOHA lactone through enzymatic conjugation with glutathione (GSH). Competing with this process is the adduction of HOHA lactone to protein lysyl residues generating 2-(ω-carboxyethyl)pyrrole (CEP) derivatives that have pathological relevance to age-related macular degeneration (AMD). We now find that HOHA lactone induces mitochondrial dysfunction. It decreases ATP levels, mitochondrial membrane potentials, enzymatic activities of mitochondrial complexes, depletes GSH and induces oxidative stress in RPE cells. The present study confirmed that pyridoxamine and other primary amines, which have been shown to scavenge γ-ketoaldehydes formed by carbohydrate or lipid peroxidation, are ineffective for scavenging the α,β-unsaturated aldehydes. Histidyl hydrazide (HH), that has both hydrazide and imidazole nucleophile functionalities, is an effective scavenger of HOHA lactone and it protects ARPE-19 cells against HOHA lactone-induced cytotoxicity. The HH α-amino group is not essential for this electrophile trapping activity. The Nα-acyl L-histidyl hydrazide derivatives with 2- to 7-carbon acyl groups with increasing lipophilicities are capable of maintaining the effectiveness of HH in protecting ARPE-19 cells against HOHA lactone toxicity, which potentially has therapeutic utility for treatment of age related eye diseases.
Alessandro Corti, Sciprofile linkEugenia Belcastro, Silvia Dominici, Emilia Maellaro, Sciprofile linkAlfonso Pompella
Published: 9 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.005

Abstract:
Having long been regarded as just a member in the cellular antioxidant systems, as well as a clinical biomarker of hepatobiliary diseases and alcohol abuse, gamma-glutamyltransferase (GGT) enzyme activity has been highlighted by more recent research as a critical factor in modulation of redox equilibria within the cell and in its surroundings. Moreover, due to the prooxidant reactions which can originate during its metabolic function in selected conditions, experimental and clinical studies are increasingly involving GGT in the pathogenesis of several important disease conditions, such as atherosclerosis, cardiovascular diseases, cancer, lung inflammation, neuroinflammation and bone disorders. The present article is an overview of the laboratory findings that have prompted an evolution in interpretation of the significance of GGT in human pathophysiology.
Stephanie Bellmaine, Alisa Schnellbaecher, Sciprofile linkAline Zimmer
Published: 8 September 2020
Free Radical Biology and Medicine; doi:10.1016/j.freeradbiomed.2020.09.002

Abstract:
Tryptophan is one of the essential mammalian amino acids, and is thus a required component in human nutrition, animal feeds, and cell culture media. However, this aromatic amino acid is highly susceptible to oxidation and is known to degrade into multiple products during manufacturing, storage and processing. Many physical and chemical processes contribute to the degradation of this compound, primarily via oxidation or cleavage of the highly reactive indole ring. The central contributing factors are reactive oxygen species, such as singlet oxygen, hydrogen peroxide, and hydroxyl radicals; light and photosensitizers; metals; and heat. In a multi-component mixture, tryptophan also commonly reacts with carbonyl-containing compounds, leading to a wide variety of products. The purpose of this review is to summarize the current state of knowledge regarding the degradation and interaction products of tryptophan in complex liquid solutions and in proteins. For the purposes of context, a brief summary of the key pathways in tryptophan metabolism will be included, along with common methods and issues in tryptophan manufacturing. The review will focus on the conditions that lead to tryptophan degradation, the products generated in these processes, their known biological effects, and methods which may be applied to stabilize the amino acid.
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