Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe最新文献

Reactive oxygen species (ROS) play roles in physiological processes and pathological conditions. Higher ROS levels induce oxidative distress and cytotoxic responses, such as chronic inflammatory conditions and cancer. While the cellular responses of various cell types to cytotoxic pro-oxidative conditions have been well studied in the past decades, much less is known about the cellular gene and expression profiles that are a priori associated with subsequent cellular demise to oxidative stress. To this end, we used 25 human cancer cell lines of different origins and established the inhibitory concentration (IC₂₅) of hypochlorous acid (HOCl), an oxidant readily produced by neutrophils frequently present in many inflamed tissues, including cancer. The HOCl sensitivity varied throughout the 25 cell lines investigated, showing a more than 5-fold difference between the most sensitive and resistant types. In parallel, we investigated untreated cells and their basal gene expression using transcriptomic microarray and performed correlation analyses to HOCl IC₂₅ values of all cell lines. Transcriptomic analyses and functional classification of significant correlating genes revealed reduced expression of tumor protein p53 signaling network members, including BAX, CDKN1A (p21), and BTG2, as well as the p53 gene (TP53) itself to associate with cell line sensitivity to HOCl toxicity. Further, baseline surface membrane expression analysis of 33 inflammation- and redox-related molecules identified nitric oxide (NO) synthase 2 and the ER-stress-associated chaperone calreticulin to correlate significantly with HOCl resistance. We identified targets associated with HOCl sensitivity. Nevertheless, further studies are needed to map gene and protein expression patterns associated with oxidative stress-induced cytotoxicity.

m-Ditrifluoromethyl-diphenyl diselenide [DFDD (m-CF₃-C₆H₄Se)₂] is a disubstituted diaryl analog of diphenyl diselenide [DPDS (C₆H₅Se)₂] in which a hydrogen atom on each aromatic ring is replaced by trifluoromethyl group (-CF₃). Herein, we investigated the effect of the -CF₃ group introduction on the GPx mimetic and antioxidant properties of DPDS. Animals were euthanized, brains were removed, and used for lipid peroxidation, cerebral sodium pump activity and thiols assays in vitro. Results showed that DFDD utilizes exogenous thiols [dithiol treitol (DTT), cysteine (Cys) and glutathione (GSH)] to reduce hydroperoxides. Furthermore, DFDD only protected against deoxyribose degradation in the presence of DTT. DFDD also exerted marked (p< 0.05) inhibitory effect on Fe²⁺or H₂O₂ or fenton reaction-induced lipid peroxidation in rat cerebral tissue homogenate. In addition, DFDD simultaneously (p< 0.05) inhibited pump activity and lipid peroxidation in cerebral tissue homogenate assaulted with prooxidants with proportionate depletion of thiol in the reaction system. This assay was repeated in the presence of DTT or Cys-or GSH and results revealed that enzyme's activity was not inhibited indicating that DFDD switched from enzymes's thiols to the oxidation of medium's thiols. It is rational to conclude that the introduction of -CF₃ group to the aromatic rings of DFDD does not abolish its GPx mimetic and antioxidant properties and these still rely on thiols of cerebral electrogenic sodium pump. DFDD could be a suitable candidate for relative pharmacological effect and weak toxicity consequent to its possession of high electron withdrawing group. However, further research is needed in this regard.

Keratin is a central component of human hair proteins, which explicitly possesses many cysteine residues (Cys-SH). For a long time, these Cys-SH residues were believed to contribute to human hair strength by forming intra- and inter-molecular disulfide bond crosslinks. However, we detected that many polysulfide bonds (R-SS_(n)H or R-SS_(n)S-R') exist in keratin. Polysulfide is one of the reactive sulfur and supersulfides, similar to cysteine persulfide (Cys-SSH), that regulates oxidative stress and redox signaling. In the present study, we elucidated the distribution of polysulfide in human hair and the reaction of polysulfide to various oxidative stress, such as heat shock and ultraviolet radiation. The decrease of the polysulfides in hair leads to the loss of antioxidant activity. Additionally, we demonstrated the effect of sulfur supplementation on human hair strength and hair cuticle structure. All types of oxidative stresses decreased the polysulfide in human hair, and hair polysulfide positively correlated with human hair strength. Intriguingly, sulfur supplementation improved human hair strength and the structure of hair cuticles. In conclusion, polysulfide in human hair keratin contributes to hair strength and antioxidant activity against oxidative stresses such as ultraviolet radiation and maintains hair homeostasis.

The placenta plays a critical role in nutrient-waste exchange between the maternal and fetal circulation, and thus impacts fetal growth and development. We have previously shown that nano-titanium dioxide (nano-TiO₂) inhalation exposure during gestation decreased fetal female pup and placenta mass [1], which persists in the following generation [2]. In utero exposed females, once mated, their offspring's placentas had increased capacity for H₂O₂ production. Generation of oxidants such as hydrogen peroxide (H₂O₂), have been shown to impact cyclooxygenase activity, specifically metabolites such as prostacyclin (PGI₂) or thromboxane (TXA₂). Therefore, we hypothesized that maternal nano-TiO₂ inhalation exposure during gestation results in alterations in placental production of prostacyclin and thromboxane mediated by enhanced H₂O₂ production in a sexually dimorphic manner. Pregnant Sprague-Dawley rats were exposed to nano-TiO₂ aerosols or filtered air (sham-control) from gestational day (GD) 10–19. Dams were euthanized on GD 20, and fetal serum and placental tissue were collected based on fetal sex. Fetal placental zones (junctional zone (JZ) and labyrinth zone (LZ)) were assessed for xanthine oxidoreductase (XOR) activity, H₂O₂, and catalase activity, as well as 6-keto-PGF_1α and TXB₂ levels. Nano-TiO₂ exposed fetal female LZ demonstrated significantly greater XOR activity compared to exposed males. Exposed fetal female LZ also demonstrated significantly diminished catalase activity compared to sham-control females. Exposed fetal female LZ had significantly increased abundance of 6-keto-PGF_1α compared to sham-control females and increased TXB₂ compared to exposed males. In the aggregate these data indicate that maternal nano-TiO₂ inhalation exposure has a greater impact on redox homeostasis and PGI₂/TXA₂ balance in the fetal female LZ. Future studies need to address if treatment with an XO inhibitor during gestation can prevent diminished fetal female growth during maternal nano-TiO₂ inhalation exposure.

Cancer cells are very diverse but mostly share a common metabolic property: they are strongly glycolytic even though oxygen is available. Herein, the metabolic abnormalities of cancer cells are interpreted as modifications of the electric currents in redox reactions. A lower current in the electron transport chain, an increase of the concentration of reduced cofactors and a partial reversal of the tricarboxylic acid cycle are physical characteristics of several forms of cancer. The existence of electric short-circuits between oxidative branches and reductive branches of the metabolic network argue in favor of an electronic approach of cancer in the nanoscopic scale. These changes of electron flows induce a pseudo-hypoxia and the Warburg effect through succinate production and divert electrons from oxygen to biosynthetic pathways. This new look at cancer may have potential therapeutic applications.

Nicotine undergoes metabolism, converting into the oxidized metabolite cotinine, which can persist in the body for several weeks and potentially lead to fatal conditions, such as cancer. Conventional nicotine replacement therapy provides additional nicotine to the body, thereby increasing the chance of accumulating the toxic metabolite cotinine. Consequently, we proposed a hypothesis: converting cotinine back into nicotine using a suitable reducing agent, such as ascorbic acid, could be a practical approach. This conversion would allow cotinine to be reutilized for its central nervous system effects before its eventual elimination from the body. In the current study, we examined this hypothesis by using plasma samples from smokers. Volunteers (both non-smokers and smokers) were screened and recruited for this study. In the initial time- and dose-dependent studies, we incubated plasma samples from non-smokers with cotinine and ascorbic acid. Changes in cotinine and nicotine levels were quantified using HPLC-PDA. Based on the findings of these experiments, we selected a concentration of 1 µM ascorbic acid and incubated it with plasma samples from 25 smokers for 10 min. A time-dependent study revealed that nicotine was detected in non-smokers' plasma samples after a 10-minute incubation with 28.38 µM of both cotinine and ascorbic acid. In a subsequent dose-dependent study, the maximum concentration of nicotine was observed at 1 µM ascorbic acid. Among the 25 samples of smokers’ plasma, the mean nicotine concentration increased from 0.565 ± 0.196 to 1.937 ± 0.622 µM (P = 0.0081), while cotinine levels decreased from 1.278 ± 0.253 to 0.754 ± 0.137 µM (P = 0.0087). This study conclusively demonstrated that ascorbic acid, at a specified concentration, effectively converts cotinine back into nicotine in smokers' plasma. Importantly, this conversion did not occur in water or in the absence of ascorbic acid in the plasma, indicating enzyme involvement.

Background and Aim

Pollution and lifestyle changes expose mankind to a number of toxicants such as polycyclic aromatic hydrocarbons that may cause life-threatening diseases. The present study was undertaken to explicate the protective role of Acetyl-11-Keto-Beta Boswellic Acid (AKBA), if any, in containing benzo(a)pyrene (BaP) induced alterations on hepatic membrane dynamics and lipidiome in female rats.

Experimental procedure

The animals were divided into five groups viz. Normal control, Vehicle treated, BaP treated, AKBA treated and BaP + AKBA treated. To induce hepatotoxicity, BaP was administered orally at a dose level of 50 mg/kg b.wt. dissolved in olive oil twice a week for 4 weeks. AKBA was supplemented to animals four weeks prior to BaP treatment and continued for 8 weeks at a dose level of 50 mg/kg b.wt. thrice a week. Certain key indices that included oxidative stress biomarkers, lipid profile of membranes, membrane fluidity parameters and activities of ATPases were studied.

Results and Conclusion

The results showed that benzo(a)pyrene treatment resulted in a significant increase in the levels of lipid peroxidation (LPO) and ROS but caused a significant decrease in the levels of total lipids, phospholipids, cholesterol, glycolipids and activities of ATPases. Hepatic membrane fluidity as assessed by 1,6-Diphenyl-1,3,5-hexatriene (DPH) and Pyrene fluorescence probes was significantly increased in rats intoxicated with BaP. Interestingly, AKBA supplementation to BaP treated rats appreciably contained altered membrane dynamics and lipidiome as well as modulated hepatotoxicity by skirmishing activities of oxidative stress markers and also improved hepatic histoarchitecture. Our study thus concludes that AKBA can be used as a prophylactic intervention in providing protection to hepatocytes as it maintains membrane integrity in conditions of BaP induced toxicity.

Lung cancer is the main cause of cancer-related deaths throughout the world. Its treatment involves intensive cycles of chemotherapy and radiotherapy, which are associated with serious adverse effects. EGCG, an active component of green tea/white tea, regulates cell molecular pathways of apoptosis, angiogenesis, proliferation, differentiation, and self-renewal ability of cancer stem cells. It also acts as a pro-oxidant that can cause cell death in cancer cells via apoptosis. It can control lung carcinogenesis by altering the molecules involved in multiple signal transduction pathways like Ras-GTPase, ERK, COX2, VEGF, and protein kinases. Moreover, it can also affect other signalling molecules or pathways such as DNMT1, MAPK, NF-κB, Bcl/Bax, HIF-1α, EGFR, Akt/PI3, Wnt/β-catenin, caspases, NEAT1, TGF-β, HDGF, and CLOCK. Recent studies on cell lines and animals have focused on the role of EGCG in enhancing the efficacy of chemotherapeutic drugs and reducing their adverse effects. The low bioavailability and rapid metabolism of EGCG can act as a hurdle in the translation of this agent from lab to bedside. The uses of synthetic agents such as COMT inhibitors and nano-drug delivery tools have been shown to enhance the plasma levels of EGCG and its cancer preventive and therapeutic ability.

The anthracycline anticancer drug doxorubicin (Dox) is widely prescribed for treating lung, ovary, breast, lymphoma, sarcoma, and pediatric cancer. Mechanistically, Dox intercalates the DNA and inhibits the topoisomerase II enzyme in fast-proliferating cancer. The clinical application of Dox is limited due to its cardiotoxicity, including congestive heart failure, alterations in myocardial structure, arrhythmia, and left ventricular dysfunction. Dox causes cardiotoxicity via various mechanisms, including oxidative stress, mitochondrial dysfunctioning, deranged Ca²⁺ homeostasis, inflammation, fibrosis, downregulating AMPK, etc. Betaine is a zwitterion-based drug known as N, N, N trimethylglycine that regulates the methionine cycle and homocysteine (a risk factor for cardiovascular disease) detoxification through betaine-homocysteine methyltransferases. Betaine is nontoxic and has several beneficial effects in different disease models. Betaine treatment decreases the amyloid β generation, reduces obesity, improves steatosis and fibrosis, and activates AMP-activated protein kinase (AMPK). Further, betaine downregulates 8‑hydroxy-2-deoxyguanosine, malondialdehyde, and upregulates catalases, glutathione peroxidase, and superoxide dismutase activity. Therefore, we hypothesized that betaine might be a rational drug candidate to effectively combat Dox-associated oxidative stress, inflammation, and mitochondrial dysfunction.

Macrophages are characterised by their high plasticity and ability to adapt their phenotype and functionality in response to environmental cues, resulting in a spectrum of activation states the two extremes of which are M1 and M2. Reactive oxygen species, such as hydrogen peroxide, are among the cues that impact macrophage polarisation. Moreover, high levels of hydrogen peroxide play a role in the phagocytic response executed by M1 macrophages. Therefore, macrophages must balance the need to shield themselves from the harmful effects of hydrogen peroxide bursts with the ability to interpret hydrogen peroxide signals from the surroundings and initiate a cellular response. Peroxiredoxins (PRDX) are proteins capable of performing both roles. Specifically, PRDX1 and PRDX5 have been demonstrated to safeguard macrophages against reactive oxygen species while also impacting their polarisation status. Previously conducted studies did not differentiate between the polarisation state of macrophages or investigate the signalling events triggered by PRDXs. In this study, we utilised bone marrow-derived murine macrophages polarised to the M1 and M2 states. Our findings revealed that the expression of PRDX1 was significantly higher in M1 macrophages than in M2 and unpolarised macrophages. Moreover, we present evidence that in M1 macrophages, PRDX1 interacts with ASK1, its established interaction partner, and also binds to other proteins that regulate the cellular antioxidant response. Interestingly, we found that pharmacological elevation of hydrogen peroxide levels leads to an increase in PRDX1 expression on the mRNA level, but not in the highly related PRDX2 expression. Taken together, our findings suggest that PRDX1 plays a critical role in macrophage antioxidant defence and redox signalling, and provide scope for exploring redox-signalling proteins as highly sought-after candidates for macrophage repolarisation.