Endotoxin-induced Oxidative Stress Research Articles

Inhalation of ferrate-disinfected Escherichia coli caused lung injury via endotoxin-induced oxidative stress and inflammation response

Ferrate (Fe(VI)) is an environmentally friendly disinfectant that is widely used to eradicate microbes in reclaimed water. However, the potential health risks associated with inhalation of Fe(VI)-treated bacteria-laden reclaimed water remains uncertain. We aimed to explore the inhalation hazards and potential mechanisms of K2FeO4-treated Escherichia coli (E. coli, ATCC 25922). Our findings indicated that Fe(VI) disinfection induced a dose- and time-dependent E. coli inactivation, accompanied by a rapid release of the bacterial endotoxin, lipopolysaccharide (LPS). Scanning electron microscopy (SEM) observations indicate that Fe(VI)-induced endotoxin production consists of at least two stages: initial binding of endotoxin to bacteria and subsequent dissociation to release free endotoxin. Furthermore, Fe(VI) disinfection was not able to effectively eliminate pure or E. coli-derived endotoxins. The E. coli strain used in this study lacks lung infection capability, thus the inhalation of bacteria alone failed to induce severe lung injury. However, mice inhaled exposure to Fe(VI)-treated E. coli showed severe impairment of lung structure and function. Moreover, we observed an accumulation of neutrophil/macrophage recruitment, cell apoptosis, and ROS generation in the lung tissue of mice subjected to Fe(VI)-treated E. coli. RNA sequencing (RNA-seq) and PCR results revealed that genes involved with endotoxin stimuli, cell apoptosis, antioxidant defence, inflammation response, chemokines and their receptors were upregulated in response to Fe(VI)-treated E. coli. In conclusion, Fe(VI) is ineffective in eliminating endotoxins and can trigger secondary hazards owing to endotoxin release from inactivated bacteria. Aerosol exposure to Fe(VI)-treated E. coli causes considerable damage to lung tissue by inducing oxidative stress and inflammatory responses.

Protective Effects of Aqueous Extract of Bay Leaf (Laurus Nobilis) on Endotoxin-Induced Oxidative Stress in Rabbits

ABSTRACT The protective effect of oral co-administration of Laurus nobilis on Escherichia coli endotoxin-exposed rabbits was studied. Twenty-five (25) rabbits were randomized into five groups containing five rabbits each – Group A, 500 Endotoxin Unit (EU) kg−1 bw, Group B, 500 EU kg−1 bw + 6.6 mg kg−1 bw extract, Group C, 500 EU kg−1 bw + 3.3 mg kg−1 bw extract, Group D, 500 EU kg−1 bw + Ascorbic acid (100 mg kg−1 bw) and Group E (0 EU kg−1 bw). The rabbits were pre-administered with the bay leaf extract in the first 7 days, then endotoxin oral administration was started and repeated daily for 21 d. At the end of days 7 and 21, assays for the serum superoxide dismutase, glutathione S-transferase, reduced glutathione, catalase, and malondialdehyde were done. The animals were sacrificed to collect kidneys and liver. Histopathological analysis of the liver and kidneys showed that exposure to 500 EU kg−1 bw endotoxin for 21 d + bay leaf extract at 6.6 and 3.3 mg kg−1 bw increased specific activities of superoxide dismutase, glutathione S-transferase, and reduced glutathione and catalase compared to the negative control. There was a decrease in the concentration of malondialdehyde in groups treated with the aqueous extract of bay leaf.

A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19

The global scientific community is striving to understand the pathophysiological mechanisms and develop effective therapeutic strategies for COVID-19. Despite overwhelming data, there is limited knowledge about the molecular mechanisms involved in the prominent cytokine storm syndrome and multiple organ failure and fatality in COVID-19 cases. The aim of this work is to investigate the possible role of of α-lipoic acid (ALA) and palmitoylethanolamide (PEA), in countering the mechanisms in overproduction of reactive oxygen species (ROS), and inflammatory cytokines. An in vitro model of lipopolysaccharide (LPS)-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome has been used. In this model of acute lung injury, the combination effects of ALAPEA, administered before and after LPS injury, were investigated. Our data demonstrated that a combination of 50 µM ALA + 5 µM PEA can reduce ROS and nitric oxide (NO) levels modulating the major cytokines involved on COVID-19 infection when administered either before or after LPS-induced damage. The best outcome was observed when administered after LPS, thus reinforcing the hypothesis that ALA combined with PEA to modulate the key point of cytokine storm syndrome. This work supports for the first time that the combination of ALA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and acting as a powerful antioxidant.

Withanolides from Withania somnifera Ameliorate Neutrophil Infiltration in Endotoxin-Induced Peritonitis by Regulating Oxidative Stress and Inflammatory Cytokines.

Identification of novel anti-inflammatory strategies are needed to avoid the side effects associated with the currently available therapies. Use of anti-inflammatory herbal remedies is gaining attention. The purpose of the present investigation was to evaluate the pharmacological potential of the withanolide-rich root extracts of the medical plant Withania somnifera (L.) Dunal using in vivo and in vitro models of endotoxin-induced inflammation and oxidative stress. The pharmacological effects of W. somnifera root extracts were evaluated using a mouse model of endotoxin (lipopolysaccharide)-induced peritonitis and various relevant human cell lines. HPLC analysis of the W. somnifera root extracts identified the presence of various bioactive withanolides. In vivo challenge of mice with endotoxin resulted in the infiltration of various leukocytes, specifically neutrophils, along with monocytes and lymphocytes into the peritoneal cavity. Importantly, prophylactic treatment with W. somnifera inhibited the migration of neutrophils, lymphocytes, and monocytes and decreased the release of interleukin-1β, TNF-α, and interleukin-6 cytokines into the peritoneal cavity as identified by ELISA. Liver (glutathione peroxidase, glutathione, glutathione disulfide, superoxide dismutase, malondialdehyde, myeloperoxidase) and peritoneal fluid (nitrite) biochemical analysis revealed the antioxidant profile of W. somnifera. Similarly, in human HepG2 cells, W. somnifera significantly modulated the antioxidant levels. In THP-1 cells, W. somnifera decreased the secretion of interleukin-6 and TNF-α. In HEK-Blue reporter cells, W. somnifera inhibited TNF-α-induced nuclear factor-κB/activator protein 1 transcriptional activity. Our findings suggest the pharmacological effects of root extracts of W. somnifera rich in withanolides inhibit neutrophil infiltration, oxidative hepatic damage, and cytokine secretion via modulating the nuclear factor-κB/activator protein 1 pathway.

Effect of Propofol and Fentanyl on Brain Oxidative Stress after Systemic Lipopolysaccharide Injection in Rats

Systemic inflammation causes brain oxidative stress, a prerequisite for neurodegeneration. In this study, we investigated the effect of the anesthetic agents propofol and fentanyl on brain oxidative stress during mild systemic endotoxemia induced by lipopolysaccharide (LPS) endotoxin. For this purpose, rats were administered LPS (400 μg/kg, intraperitoneally; i.p.), treated at the same time with different doses of propofol or fentanyl, i.p., and euthanized 4 h later. Other groups were treated with the saline, only propofol, or only fentanyl. Oxidative stress markers including malondialdehyde (MDA), nitric oxide (NO), and reduced glutathione (GSH) were determined. In addition, nuclear factor kappaB (NF-kB), paraoxonase-1 (PON-1), and butyrylcholinesterase (BChE) activities were measured in the brain tissue. Results showed that compared with the saline group, administration of LPS caused a marked and significant increase in brain MDA and NO combined with depletion of GSH and decreased PON-1 and BChE activities. Additionally, the active form of NF-kB was significantly increased in the brain of LPS only-treated rats. Treatment with propofol or fentanyl led to a marked and significant decrease in the levels of brain MDA and NO together with a significant increase in GSH and restoration of PON-1 and BChE activities. Furthermore, lower levels of active form of NF-kB were found following treatment with propofol or fentanyl compared with those in the LPS only group. Collectively, these results suggest that propofol and fentanyl exhibit an antioxidant action and attenuate the endotoxin-induced brain oxidative stress.

Rhubarb-Aconite Decoction (RAD) Drug-Containing Serum Alleviated Endotoxin-Induced Oxidative Stress Injury and Inflammatory Response in Caco-2 Cells In Vitro.

Rhubarb-Aconite Decoction (RAD), a famous Chinese medicine prescription, has been widely used for treating intestinal injury. However, the effect of RAD on intestinal epithelial cells is unclear. The aim of this study was to investigate the effects of RAD drug-containing serum on the oxidative stress injury and inflammatory response induced by endotoxin (ET) in Caco-2 cells in vitro. Lipid peroxide malondialdehyde (MDA), lactate dehydrogenase (LDH), caspase-11, tumor necrosis factor-α(TNF-α), interleukin-3(IL-3), and cytokeratin (CK)18, adenosine triphosphate (ATP) activity, and intracellular free calcium ion levels were measured. The results showed that ET triggered the activation of caspase-11 and the massive release of TNF-α, increased the inhibitory rate of cell growth, MDA, and LDH expressions in Caco-2 cells. Moreover, RAD drug-containing serum could inhibit caspase-11 activation, decrease the release of TNF-α and IL-3, reduce intracellular free calcium ion, and enhance CK 18 expression and ATP activity. These novel findings demonstrated that ET-induced oxidative stress injury and inflammatory response of Caco-2 cells were improved by RAD drug-containing serum, indicating that RAD may be a good choice for the treatment of intestinal injury.

Effects of Tempol in Lipopolysaccharide-Induced Liver Injury

Objective: Sepsis leads to conditions such as inflammatory and anti-inflammatory process, circulatory abnormalities, cellular and humoral reactions. Endotoxin-induced oxidative stress causes injury in the liver. The aim of this study was to evaluate the effects of a radical scavenger Tempol in lipopolysaccharide (LPS)-induced liver injury in rats. Materials and Methods: Male Wistar rats were divided into four groups: Control, LPS (15 mg/kg), LPS + Tempol group (100 mg/kg Tempol, three hours after LPS administration) and Tempol (100 mg/kg). Blood glucose and body temperature were measured during the experiment. Superoxide dismutase (SOD), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and C-reactive protein (CRP) levels were measured in plasma or liver tissue. Furthermore, histopathological changes and myeloperoxidase-stained leukocytes infiltration were assessed in liver tissue. Results: LPS caused tissue damage and leukocytes infiltration, increased AST, ALT and CRP levels, and decreased body temperature, blood glucose and SOD levels. Tempol reduced AST and ALT levels and increased SOD levels. Tempol did not prevent tissue damage, leukocytes infiltration and increment of CRP levels. There were no changes in body temperature and blood glucose levels. Conclusion: The present study suggests that tempol may have antioxidant properties in LPS-induced liver injury. These results may contribute to a better understanding of the role of tempol and basic mechanisms of underlying oxidative stressrelated liver injury for further investigations.

Protective effects of aqueous extract of Cryptolepis Sanguinolenta on endotoxin-induced oxidative stress in Wistar rats

The protective effect of oral co-administration of Cryptolepis sanguinolenta and E. coli endotoxin to rats was studied on liver and kidney function indices and antioxidant status in rats. Thirty-five (35) rats were randomized into 7 groups containing 5 rats each- Group A distilled water, Group Ascorbic acid and Endotoxin, Group C Endotoxin dose (50 EU/kg bw), Group D 50 mg/kg body weight (bw) of Cryptolepis sanguinolenta extract only and Group (E-G) 25, 50 and 100 mg/kg bw Cryptolepis sanguinolenta extract plus 50 EU/kg bw endotoxin respectively. The oral administration was repeated for 21 days at 11:30 am daily. Rectal temperatures of the rats were taken at an interval of 30 mins, 60 mins, 90 mins and 120 mins post administration. At the end of the 21 days, the animals were sacrificed and the serum, kidney and liver was obtained. Specific activities of alanine transaminase, aspartate transaminase, alkaline phosphatase as well as concentrations of creatinine and urea in the serum were determined. Activites of superoxide dismutase and catalase were also determined. Also assayed for was malondialdehyde concentration. Histopathological analysis was carried out on the liver and kidney from each test groups. Results show that exposure to 50 EU/ml endotoxin for 21 days plus extract at 50 and 100 mg/kg BW significantly (P

Esculetin Protects Human Retinal Pigment Epithelial Cells from Lipopolysaccharide-induced Inflammation and Cell Death

ABSTRACTPurpose: Age-related macular degeneration (AMD) is the most common cause of visual loss. The dry AMD is characterized by retinal pigment epithelium (RPE) death and changes in AMD lead to severe loss of vision. Coumarin-derived esculetin has a number of therapeutic and pharmacological effects such as anti-inflammatory and antioxidant with various mechanisms. The purpose of this study was to investigate the effects of esculetin treatment on lipopolysaccharide (LPS)-induced inflammation, oxidative stress, and cell survival.Material and methods: Human RPE cells (ARPE-19) were incubated for 24–72 h with 5 μg/ml LPS to induce inflammation and oxidative stress. Esculetin (5 μM) was used to protect the cells from LPS-induced damage. The cell viability was evaluated by quantitative 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide test. Interleukin 6 (IL-6), IL-12, and vascular endothelial growth factor (VEGF) levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-1β, tumor necrosis factor receptor (TNFR), TNF-related apoptosis-inducing ligand (TRAIL), catalase, glutathione peroxidase (GPx), superoxide dismutase 1 (CuZnSOD) and SOD2 (MnSOD) mRNA expressions were analyzed by RT-quantitative polymerase chain reaction. Apoptosis was monitored by cell-based cytometer. NF-kappa B (NF-κB) p65/RelA levels were determined by ELISA, and NF-κB protein expression and extracellular signal-regulated kinase (ERK1/2) phosphorylation were evaluated by Western blot analysis.Results: Esculetin treatment significantly suppressed LPS-induced cell death mediated by apoptosis and necrosis in a concentration-dependent manner. While LPS caused significant inflammation with cytokine increase in cells, esculetin reduced the expression of LPS-induced cytokines, VEGF, TNFR, and TRAIL. Furthermore, exposure to LPS increased the expression of GPx and mitochondrial MnSOD, leading to oxidative stress in the cells. Esculetin treatment attenuated phosphorylation of ERK1/2 and NF-κB expression mediated by LPS.Conclusions: These results suggest that esculetin may be an alternative treatment option for endotoxin-induced inflammation and oxidative stress, which therefore may inhibit the development of LPS-mediated AMD.

Idh1 protects murine hepatocytes from endotoxin-induced oxidative stress by regulating the intracellular NADP(+)/NADPH ratio.

Isocitrate dehydrogenase-1 (Idh1) is an important metabolic enzyme that produces NADPH by converting isocitrate to α-ketoglutarate. Idh1 is known to reduce reactive oxygen species (ROS) induced in cells by treatment with lipopolysaccharide (LPS) in vitro. Here, we used Idh1-deficient knockout (Idh1 KO) mice to investigate the role of Idh1 in antioxidant defense in vivo. Idh1 KO mice showed heightened susceptibility to death induced by LPS and exhibited increased serum levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. The serum of LPS-injected Idh1 KO mice also contained elevated levels of AST, a marker of inflammatory liver damage. Furthermore, after LPS injection, livers of Idh1 KO mice showed histological evidence of elevated oxidative DNA damage compared with livers of wild-type (WT) mice. Idh1 KO livers showed a faster and more pronounced oxidative stress than WT livers. In line with that, Idh1 KO hepatocytes showed higher ROS levels and an increase in the NADP+/NADPH ratio when compared with hepatocytes isolated from WT mice. These results suggest that Idh1 has a physiological function in protecting cells from oxidative stress by regulating the intracellular NADP+/NADPH ratio. Our findings suggest that stimulation of Idh1 activity may be an effective therapeutic strategy for reducing oxidative stress during inflammatory responses, including the early stages of septic shock.

Biomarkers of oxidative stress study VI. Endogenous plasma antioxidants fail as useful biomarkers of endotoxin-induced oxidative stress

This is the newest report in a series of publications aiming to identify a blood-based antioxidant biomarker that could serve as an in vivo indicator of oxidative stress. The goal of the study was to test whether acutely exposing Göttingen mini pigs to the endotoxin lipopolysaccharide (LPS) results in a loss of antioxidants from plasma. We set as a criterion that a significant effect should be measured in plasma and seen at both doses and at more than one time point. Animals were injected with two doses of LPS at 2.5 and 5µg/kg iv. Control plasma was collected from each animal before the LPS injection. After the LPS injection, plasma samples were collected at 2, 16, 48, and 72h. Compared with the controls at the same time point, statistically significant losses were not found for either dose at multiple time points in any of the following potential markers: ascorbic acid, tocopherols (α, δ, γ), ratios of GSH/GSSG and cysteine/cystine, mixed disulfides, and total antioxidant capacity. However, uric acid, total GSH, and total Cys were significantly increased, probably because LPS had a harmful effect on the liver. The leakage of substances from damaged cells into the plasma may have increased plasma antioxidant concentrations, making changes difficult to interpret. Although this study used a mini-pig animal model of LPS-induced oxidative stress, it confirmed our previous findings in different rat models that measurement of antioxidants in plasma is not useful for the assessment of oxidative damage in vivo.

Astragalin inhibits airway eotaxin-1 induction and epithelial apoptosis through modulating oxidative stress-responsive MAPK signaling.

BackgroundEotaxin proteins are a potential therapeutic target in treating the peribronchial eosinophilia associated with allergic airway diseases. Since inflammation is often associated with an increased generation of reactive oxygen species (ROS), oxidative stress is a mechanistically imperative factor in asthma. Astragalin (kaempferol-3-O-glucoside) is a flavonoid with anti-inflammatory activity and newly found in persimmon leaves and green tea seeds. This study elucidated that astragalin inhibited endotoxin-induced oxidative stress leading to eosinophilia and epithelial apoptosis in airways.MethodsAirway epithelial BEAS-2B cells were exposed to lipopolysaccharide (LPS) in the absence and presence of 1–20 μM astragalin. Western blot and immunocytochemical analyses were conducted to determine induction of target proteins. Cell and nuclear staining was also performed for ROS production and epithelial apoptosis.ResultsWhen airway epithelial cells were exposed to 2 μg/ml LPS, astragalin nontoxic at ≤20 μM suppressed cellular induction of Toll-like receptor 4 (TLR4) and ROS production enhanced by LPS. Both LPS and H2O2 induced epithelial eotaxin-1 expression, which was blocked by astragalin. LPS activated and induced PLCγ1, PKCβ2, and NADPH oxidase subunits of p22phox and p47phox in epithelial cells and such activation and induction were demoted by astragalin or TLR4 inhibition antagonizing eotaxin-1 induction. H2O2-upregulated phosphorylation of JNK and p38 MAPK was dampened by adding astragalin to epithelial cells, while this compound enhanced epithelial activation of Akt and ERK. H2O2 and LPS promoted epithelial apoptosis concomitant with nuclear condensation or caspase-3 activation, which was blunted by astragalin.ConclusionsAstragalin ameliorated oxidative stress-associated epithelial eosinophilia and apoptosis through disturbing TLR4-PKCβ2-NADPH oxidase-responsive signaling. Therefore, astragalin may be a potent agent antagonizing endotoxin-induced oxidative stress leading to airway dysfunction and inflammation.

An Anti-Interleukin-2 Receptor Drug Attenuates T- Helper 1 Lymphocytes-Mediated Inflammation in an Acute Model of Endotoxin-Induced Uveitis

The aim of the present study was to evaluate the anti-inflammatory efficacy of Daclizumab, an anti-interleukin-2 receptor drug, in an experimental uveitis model upon a subcutaneous injection of lipopolysaccharide into Lewis rats, a valuable model for ocular acute inflammatory processes. The integrity of the blood-aqueous barrier was assessed 24 h after endotoxin-induced uveitis by evaluating two parameters: cell count and protein concentration in aqueous humors. The histopathology of all the ocular structures (cornea, lens, sclera, choroid, retina, uvea, and anterior and posterior chambers) was also considered. Enzyme-linked immunosorbent assays of the aqueous humor samples were performed to quantify the levels of the different chemokine and cytokine proteins. Similarly, a biochemical analysis of oxidative stress-related markers was also assessed. The inflammation observed in the anterior chamber of the eyes when Daclizumab was administered with endotoxin was largely prevented since the aqueous humor protein concentration substantially lowered concomitantly with a significant reduction in the uveal and vitreous histopathological grading. Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon-γ, also significantly reduced with related anti-oxidant systems recovery. Daclizumab treatment in endotoxin-induced uveitis reduced Th1 lymphocytes-related cytokines, such as Interleukin-2 and Interferon gamma, by about 60–70% and presented a preventive role in endotoxin-induced oxidative stress. This antioxidant protective effect of Daclizumab may be related to several of the observed Daclizumab effects in our study, including IL-6 cytokine regulatory properties and a substantial concomitant drop in INFγ. Concurrently, Daclizumab treatment triggered a significant reduction in both the uveal histopathological grading and protein concentration in aqueous humors, but not in cellular infiltration.

Citric Acid Effects on Brain and Liver Oxidative Stress in Lipopolysaccharide-Treated Mice

Citric acid is a weak organic acid found in the greatest amounts in citrus fruits. This study examined the effect of citric acid on endotoxin-induced oxidative stress of the brain and liver. Mice were challenged with a single intraperitoneal dose of lipopolysaccharide (LPS; 200 μg/kg). Citric acid was given orally at 1, 2, or 4 g/kg at time of endotoxin injection and mice were euthanized 4 h later. LPS induced oxidative stress in the brain and liver tissue, resulting in marked increase in lipid peroxidation (malondialdehyde [MDA]) and nitrite, while significantly decreasing reduced glutathione, glutathione peroxidase (GPx), and paraoxonase 1 (PON1) activity. Tumor necrosis factor-alpha (TNF-α) showed a pronounced increase in brain tissue after endotoxin injection. The administration of citric acid (1-2 g/kg) attenuated LPS-induced elevations in brain MDA, nitrite, TNF-α, GPx, and PON1 activity. In the liver, nitrite was decreased by 1 g/kg citric acid. GPx activity was increased, while PON1 activity was decreased by citric acid. The LPS-induced liver injury, DNA fragmentation, serum transaminase elevations, caspase-3, and inducible nitric oxide synthase expression were attenuated by 1-2 g/kg citric acid. DNA fragmentation, however, increased after 4 g/kg citric acid. Thus in this model of systemic inflammation, citric acid (1-2 g/kg) decreased brain lipid peroxidation and inflammation, liver damage, and DNA fragmentation.

Effects of afferent and efferent denervation of vagal nerve on endotoxin-induced oxidative stress in rats

This study investigated the role of vagal innervation in oxidative stress after systemic administration of lipopolysaccharide (LPS) endotoxin. Control rats and rats subjected to bilateral subdiaphragmatic vagotomy, perivagal capsaicin application (5mg/ml) or cholinergic receptor blockade with subcutaneous atropine (1mg/kg), were intraperitoneally injected with 300μg/kg of LPS and euthanized 4h later. Results indicated that; (1) surgical vagotomy and sensory denervation by perivagal capsaicin increased brain oxidative stress and decreased reduced glutathione in basal condition (saline-treated rats) and following endotoxin challenge; (2) oxidative stress decreased after cholinergic blockade with atropine in endotoxemic rats; (3) nitric oxide decreased by abdominal vagotomy, sensory deafferentation and cholinergic blockade after endotoxin injection; (4) liver lipid peroxidation decreased after surgical vagotomy and cholinergic blockade but increased after sensory deafferentation; (5) liver reduced glutathione decreased following vagotomy and sensory denervation in basal state and by cholinergic blockade in basal state and during endotoxemia; (6) nitric oxide increased by vagotomy in basal state and by sensory denervation and cholinergic blockade in basal state and during endotoxemia; (7) liver histological damage increased by subdiaphragmatic vagotomy, sensory denervation or cholinergic blockade. These findings suggest that: (1) sensory fibers (signals from the periphery) running in the vagus nerves are important in maintaining the redox status of the brain; (2) capsaicin vagal sensory nerves are likely to maintain nitric oxide tone in basal conditions; (3) the vagus nerve modulates liver redox status and nitric oxide release, (4) the vagus nerve mediates protective role in the liver with both cholinergic and capsaicin-sensitive mechanisms being involved.

Lipoic acid lessens Th1-mediated inflammation in lipopolysaccharide-induced uveitis reducing selectively Th1 lymphocytes-related cytokines release

Inflammation results in the production of free radicals. We evaluated the anti-inflammatory and antioxidant capacity of lipoic acid in an experimental uveitis model upon a subcutaneous injection of endotoxin into Lewis rats. The role of oxidative stress in the endotoxin-induced uveitis model is well-known. Besides, the Th1 response classically performs a central part in the immunopathological process of experimental autoimmune uveitis. Exogenous sources of lipoic acid have been shown to exhibit antioxidant and anti-inflammatory properties. Our results show that lipoic acid treatment plays a preventive role in endotoxin-induced oxidative stress at 24 h post-administration and reduced Th1 lymphocytes-related cytokines by approximately 50–60%. Simultaneously, lipoic acid treatment caused a significant reduction in uveal histopathological grading and in the protein concentration in aqueous humors, but not in cellular infiltration.

The inducible soybean glyceollin phytoalexins with multifunctional health-promoting properties

The glyceollins are soybean-derived phytoalexins that accumulate in the seeds in response to various extrinsic factors. Several elicitors such as fungi, UV irradiation and physical injury have been demonstrated to alter the secondary metabolome of soybeans via induction of glyceollin synthesis and accumulation. The pterocarpan phytoalexins have exhibited antiestrogenic activity against estrogen receptor-mediated cellular processes. As a result, the glyceollins display anticancer activities against breast and ovarian cancers through inhibition of tumor growth and progression, and also by inducing cell cycle arrest in the cancer cells. Moreover, glyceollins were found to exhibit antimicrobial activity against pathogenic fungi, cellular antioxidant activities against endotoxin-induced oxidative stress, and regulatory effects on glucose metabolism and endotoxin-induced inflammatory response. The soybean-derived compounds warrant further studies to evaluate detailed molecular mechanisms during aberrant cellular processes, safety and efficacy in animal disease models and human subjects, and potential use for food preservation. The bioactivity of glyceollins can result in the enrichment of soybean with these phytoalexins for improved health functions and other novel applications.

Effect of Taurine on Brain 8-hydroxydeoxyguanosine and 3-nitrotyrosine Levels in Endotoxemia

Taurine is a sulfur-containing β-amino acid that is found in milimolar concentrations in most mammalian tissues and plasma. It was shown to have cytoprotective effects in many in vitro and in vivo studies and these actions are often attributed to an antioxidant mechanism. In this study, we aimed to investigate the effect of acute taurine administration on endotoxin-induced oxidative and nitrosative stress in brain. Fourty adult male guinea pigs were divided into four groups: control, taurine, endotoxemia, and endotoxemia + taurine. Taurine (300mg/kg), lipopolysaccharide (LPS, 4mg/kg), or taurine plus LPS was administered intraperitoneally. After 6h of incubation, when highest blood levels of taurine and endotoxin were attained, the animals were killed and brain tissue samples were collected. 3-Nitrotyrosine (3-NT), 8-hydroxydeoxyguanosine (8-OHdG) and taurine levels were measured using high-performance liquid chromatography methods. LPS administration significantly increased 3-NT, 8-OHdG levels, and dramatically reduced taurine concentrations in brain tissue compared to control group. The groups in which taurine was administered alone or with LPS, contradiction to well-known antioxidant effect, taurine caused elevated concentrations of 3-NT and 8-OHdG compared to both control and endotoxemia groups. In conclusion, endotoxemia leads to tyrosine nitration and DNA base modification that can be assessed by 3-NT and 8-OHdG, respectively. Taurine did not exhibit any antioxidant effect; moreover, it may contribute to neuronal damage at this dose. Thus, we can suggest that lower dose of taurine administration may be benefial for neuronal protection or adversely taurine administration may have toxic effect at all doses.

Insulin Suppresses Endotoxin-Induced Oxidative, Nitrosative, and Inflammatory Stress in Humans

OBJECTIVETo investigate whether insulin reduces the magnitude of oxidative, nitrosative, and inflammatory stress and tissue damage responses induced by endotoxin (lipopolysaccharide [LPS]).RESEARCH DESIGN AND METHODSNine normal subjects were injected intravenously with 2 ng/kg LPS prepared from Escherichia coli. Ten others were infused with insulin (2 units/h) for 6 h in addition to the LPS injection along with 100 ml/h of 5% dextrose to maintain normoglycemia.RESULTSLPS injection induced a rapid increase in plasma concentrations of nitric oxide metabolites, nitrite and nitrate (NOM), and thiobarbituric acid–reacting substances (TBARS), an increase in reactive oxygen species (ROS) generation by polymorphonuclear leukocytes (PMNLs), and marked increases in plasma free fatty acids, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibition factor (MIF), C-reactive protein, resistin, visfatin, lipopolysaccharide binding protein (LBP), high mobility group-B1 (HMG-B1), and myoglobin concentrations. The coinfusion of insulin led to a total elimination of the increase in NOM, free fatty acids, and TBARS and a significant reduction in ROS generation by PMNLs and plasma MIF, visfatin, and myoglobin concentrations. Insulin did not affect TNF-α, MCP-1, IL-6, LBP, resistin, and HMG-B1 increases induced by the LPS.CONCLUSIONSInsulin reduces significantly several key mediators of oxidative, nitrosative, and inflammatory stress and tissue damage induced by LPS. These effects of insulin require further investigation for its potential use as anti-inflammatory therapy for endotoxemia.

Comparison of the Acute Effects of anti-TNF-alpha Drugs on a Uveitis Experimental Model

Purpose: To compare histopathological and biochemical effects of the anti-TNF-alpha drugs adalimumab and infliximab in a uveitis experimental model.Methods: Histopathological evaluation was performed 24 h after endotoxin (200 μg into the footpad) and drug administration, as well as biochemical analysis of oxidative stress-related markers in the aqueous humor.Results: Severe inflammation was found in rat anterior chamber of the eye 24 h after endotoxin. Only infliximab administration partially prevented the endotoxin-induced disruption of the blood–aqueous barrier, as well as the increase in Rantes and MCP-1 concentration in aqueous humor. Both drugs ameliorated the histopathological score after endotoxin. Biochemical analysis revealed that both drugs protected against endotoxin-induced oxidative stress, restoring all markers to control levels, except infliximab, which failed to restore GSH concentration.Conclusions: Both anti-TNF-alpha drugs were effective in reducing histopathological inflammation but their mechanism of action appears to be different.