Atypical Cognitive Impairment and Recovery in Two Colorectal Cancer Patients.

Cognitive impairment in cancer patients can be caused by various factors; in approximately 30% of cancer patients, the symptoms appear before starting treatment. Paraneoplastic limbic encephalitis (PLE) is a rare disease associated with an autoimmune response, and is characterized by memory loss, depression, and personality changes; it is one of the potential causes of cognitive dysfunction in cancer patients. Two patients were previously diagnosed with mild cognitive impairment and maintained clinical stability; after suffering a rapid change in personality and sudden cognitive decline, colorectal cancer was diagnosed within a few months. The patients did not meet the diagnostic criteria for PLE in several tests. The symptoms improved after the underlying cancer was treated, and the patients returned to their previous stable state. Sudden cognitive impairment may appear as an early cancer symptom, and PLE is considered an atypical cause for these symptoms. However, in patients with unexplained PLE-like symptoms who do not meet the diagnostic criteria for PLE, probable etiologies to be considered are the gut-brain connection, CD8+ T-cell-mediated limbic encephalitis, and somatic mutations in dementia-related genes. Currently, few studies have investigated these symptoms, and further research will offer significant therapeutic strategies for cognitive impairment in cancer patients.

Linalyl acetate prevents hypertension-related ischemic injury.

Ischemic stroke remains an important cause of disability and mortality. Hypertension is a critical risk factor for the development of ischemic stroke. Control of risk factors, including hypertension, is therefore important for the prevention of ischemic stroke. Linalyl acetate (LA) has been reported to have therapeutic effects in ischemic stroke by modulating intracellular Ca2+ concentration and having anti-oxidative properties. The preventive efficacy of LA has not yet been determined. This study therefore investigated the preventive efficacy of LA in rat aortas exposed to hypertension related-ischemic injury, and the mechanism of action of LA.Hypertension was induced in vivo following ischemic injury to the aorta induced by oxygen-glucose deprivation and reoxygenation in vitro. Effects of LA were assayed by western blotting, by determining concentrations of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) and by vascular contractility assays. LA significantly reduced systolic blood pressure in vivo. In vitro, LA suppressed ischemic injury-induced expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox, as well as ROS production, LDH release, and ROS-induced endothelial nitric oxide synthase suppression. These findings indicate that LA has anti-hypertensive properties that can prevent hypertension-related ischemic injury and can prevent NADPH oxidase-induced production of ROS.

Linalyl acetate restores endothelial dysfunction and hemodynamic alterations in diabetic rats exposed to chronic immobilization stress.

Although stress is one of the risk factors of diabetes, few studies have assessed the effects of stress on diabetic rats. This study, therefore, analyzed differences in cardiovascular-related factors among control, nonstressed diabetic, and stressed diabetic rats as well as assessed the effects of linalyl acetate (LA) on stressed diabetic rats. Male Sprague-Dawley rats were subjected to immobilization stress throughout the experimental period, and diabetes was induced on day 15 by a single injection of streptozotocin. After confirming the induction of diabetes, stressed diabetic rats were administered LA (10 or 100 mg/kg) or metformin (500 mg/kg) for the last 7 days. Compared with nonstressed diabetic rats, stressed diabetic rats had significantly lower body weight, body fat percentage, ACh-induced vasorelaxation, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and NF-κB expression as well as increased serum nitrite concentration. Although metformin increased serum insulin concentration significantly, 100 mg/kg LA showed only an increasing tendency. However, treatment with 100 mg/kg LA not only reduced serum glucose and NF-κB expression, but also restored ACh-induced vasorelaxation, SBP, DBP, HR, AMP-activated protein kinase expression, and serum nitrite almost to control levels. Importantly, 100 mg/kg LA was more effective than metformin in ameliorating serum glucose, endothelial nitric oxide synthase expression, HR, and serum nitrite. These findings suggest that chronic stress can aggravate endothelial dysfunction and hemodynamic alterations in diabetes and that LA may have potent therapeutic efficacy in diabetic patients with cardiovascular disease complications or chronic stress. NEW & NOTEWORTHY To our knowledge, this is the first study to assess the effects of linalyl acetate (LA) on cardiovascular-related factors in diabetic rats exposed to chronic stress. Treatment with LA restored acetylcholine-induced vasorelaxation, blood pressure, heart rate, and AMP-activated protein kinase and serum nitrite levels. The present results suggest that LA may have potent therapeutic efficacy in diabetic patients with complications of cardiovascular disease or chronic stress.

Codonopsis lanceolata extract prevents hypertension in rats.

BACKGROUND: Codonopsis lanceolata, a plant with antioxidant, anti-cancer, anti-inflammatory and blood lipid improving effects, has been widely used as a therapeutic agent in traditional medicine. PURPOSE: The present study investigated the ability of an ethanol extract of Codonopsis lanceolata (ECL) to prevent hypertension in hypertensive rats. METHODS: Rats were orally administered daily doses of 0 mg/kg, 200 mg/kg and 400 mg/kg ECL for 3 weeks. As a positive control, rats were orally administered 10 mg/kg/day nifedipine. Hypertension was induced by immobilization stress for 2 h/day and by administration of 0.8 mg/kg/day nicotine for 3 weeks, followed by injection of 3 mg/kg nicotine on the day of sacrifice. Blood pressure and heart rate were measured using a volume pressure recording system. Vasoconstriction and vasodilation of aortic cross sections were measured with a physiological recorder. Neutrophil counts in bronchoalveolar lavage fluid were estimated with an automated cell counter. RESULTS: Treatment with both dosages of ECL significantly reduced systolic blood pressure (SBP) in hypertensive rats. Both doses of ECL tended to increase ACh- and SNP-induced vascular relaxation in hypertensive rats. Treatment with 200 mg/kg ECL significantly reduced neutrophil in hypertensive rats. CONCLUSIONS: These results suggest that ECL is effective in reducing SBP and inflammation in hypertensive conditions.

Cardiovascular effects of linalyl acetate in acute nicotine exposure.

BACKGROUD: Smoking is a risk factor for cardiovascular diseases as well as pulmonary dysfunction. In particular, adolescent smoking has been reported to have a higher latent risk for cardiovascular disease. Despite the risk to and vulnerability of adolescents to smoking, the mechanisms underlying the effects of acute nicotine exposure on adolescents remain unknown. This study therefore evaluated the mechanism underlying the effects of linalyl acetate on cardiovascular changes in adolescent rats with acute nicotine exposure. METHODS: Parameters analyzed included heart rate (HR), systolic blood pressure, lactate dehydrogenase (LDH) activity, vascular contractility, and nitric oxide levels. RESULTS: Compared with nicotine alone, those treated with nicotine plus 10 mg/kg (p = 0.036) and 100 mg/kg (p = 0.023) linalyl acetate showed significant reductions in HR. Moreover, the addition of 1 mg/kg (p = 0.011), 10 mg/kg (p = 0.010), and 100 mg/kg (p = 0.011) linalyl acetate to nicotine resulted in significantly lower LDH activity. Nicotine also showed a slight relaxation effect, followed by a sustained recontraction phase, whereas nicotine plus linalyl acetate or nifedipine showed a constant relaxation effect on contraction of mouse aorta (p < 0.001). Furthermore, nicotine-induced increases in nitrite levels were decreased by treatment with linalyl acetate (p < 0.001). CONCLUSIONS: Taken together, our findings suggest that linalyl acetate treatment resulted in recovery of cell damage and cardiovascular changes caused by acute nicotine-induced cardiovascular disruption. Our evaluation of the influence of acute nicotine provides potential insights into the effects of environmental tobacco smoke and suggests linalyl acetate as an available mitigating agent.

Anti-inflammatory effects of trans-anethole in a mouse model of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that is generally characterized by progressive and irreversible airflow obstruction and alveolar destruction. Long-term treatment with current medications has been associated with various adverse effects, indicating a need for alternative approaches for the prevention and treatment of COPD. This study investigated the mechanism underlying the effects of trans-anethole in a mouse model of COPD induced by porcine pancreatic elastase (PPE) and lipopolysaccharide (LPS). BALB/c mice were orally administered trans-anethole (62.5, 125, 250, or 500mg/kg) 2h before intranasal challenge with 1.2 units of PPE and 7µg of LPS. Lactate dehydrogenase (LDH) activity, cell counts, lung histology, cytokine production, and blood pressure were analyzed. Trans-anethole reduced LDH activity and inflammatory cell counts, including macrophage, neutrophil, and lymphocyte counts. trans-anethole 125mg/kg restored the histopathological changes induced in mouse lungs by PPE and LPS. trans-anethole reduced the serum concentrations of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as significantly reducing blood pressure during chronic inflammation. Trans-anethole ameliorated chronic lung inflammation in a mouse model of COPD by reducing the serum concentrations of pro-inflammatory cytokines such as TNF-α and IL-6, and by reducing blood pressure. The present results indicate that trans-anethole may be a potential therapeutic agent for prophylaxis and treatment in patients with chronic lung inflammation.

Foeniculum vulgare Mill. increases cytosolic Ca2+ concentration and inhibits store-operated Ca2+ entry in vascular endothelial cells.

This study assessed the effects of essential oil of Foeniculum vulgare Mill. (fennel oil) and of trans-anethole, the main component of fennel oil, on extracellular Ca2+-induced store-operated Ca2+ entry (SOCE) into vascular endothelial (EA) cells and their mechanisms of action. Components of fennel oil were analyzed by gas chromatography-mass spectrometry. Cytosolic Ca2+ concentration ([Ca2+]c) in EA cells was determined using Fura-2 fluorescence. In the presence of extracellular Ca2+, fennel oil significantly increased [Ca2+]c in EA cells; this increase was significantly inhibited by the Ca2+ channel blockers La3+ and nifedipine. In contrast, fennel oil induced [Ca2+]c was significantly lower in Ca2+-free solution, suggesting that fennel oil increases [Ca2+]c mainly by enhancing Ca2+ influx into EA cells. [Ca2+]c mobilization by trans-anethole was similar to that of fennel oil. Moreover, SOCE was suppressed by fennel oil and trans-anethole. SOCE was also attenuated by lanthanum (La3+), a non-selective cation channel (NSC) blocker; 2-aminoethoxydiphenyl borane (2-APB), an inositol 1,4,5-triphosphate (IP3) receptor inhibitor and SOCE blocker; and U73122, an inhibitor of phospholipase C (PLC). Further, SOCE was more strongly inhibited by La3+ plus fennel oil or trans-anethole than by La3+ alone. These findings suggest that fennel oil and trans-anethole significantly inhibit SOCE-induced [Ca2+]c increase in vascular endothelial cells and that these reactions may be mediated by NSC, IP3-dependent Ca2+ mobilization, and PLC activation.

Antioxidant activity of linalool in patients with carpal tunnel syndrome.

BACKGROUND: Carpal tunnel syndrome (CTS) is a common peripheral neuropathy and ischemic-reperfusion injury. Oxidative stress is considered a major cause of CTS. Linalool, a component of essential oils, has antioxidant activity. This study was designed to determine the effects of linalool inhalation on oxidative stress in patients with CTS. METHODS: This double-blind, placebo-controlled study assessed the effects of linalool inhalation on oxidative stress in patients with CTS. Thirty-seven subjects, with and without CTS, were randomized to inhalation of 1% linalool or carrier oil. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, systolic blood pressure (sBP), diastolic blood pressure (dBP) and pulse rate were analyzed. RESULTS: DPPH inhibition was significantly higher in both experimental groups than in their respective controls. Moreover inhalation of linalool reduced sBP, dBP and pulse rate in the CTS group, and pulse rate in the non-CTS group. However, there were no significant differences among the study groups in nitrite levels, sBP, dBP and pulse rate. CONCLUSIONS: Inhalation of linalool increases antioxidative activity and reduces blood pressure and pulse rate in patients with CTS.

Eucalyptol suppresses matrix metalloproteinase-9 expression through an extracellular signal-regulated kinase-dependent nuclear factor-kappa B pathway to exert anti-inflammatory effects in an acute lung inflammation model.

OBJECTIVES: The acute lung injury (ALI) model is characterised by a severe acute inflammatory response in the lungs that represents the pathogenesis of acute respiratory distress syndrome (ARDS). In this study, we sought to elucidate the anti-inflammatory mechanism of eucalyptol in relation to tissue remodelling in acute lung inflammation. METHODS: BALB/C mice were intraperitoneally injected with eucalyptol (100, 200 or 400 mg/kg) or dexamethasone (1 mg/kg) 1 h before intratracheal challenge with lipopolysaccharide (LPS; 1.5 mg/kg) and sacrificed after 4 h. The anti-inflammatory effects of eucalyptol were assessed by determining cell counts, measuring cytokine and nitric oxide production and performing Western blotting and histological analyses. KEY FINDINGS: Eucalyptol attenuated inflammation-associated increases in cell numbers, matrix metalloproteinase-9 (MMP-9) expression, production of cytokines (tumour necrosis factor-α and interleukin-6) and nitric oxide, and nuclear factor-kappa B (NF-κB) and phosphorylated extracellular signal-regulated kinase protein levels induced by LPS in bronchoalveolar lavage fluid from ALI mice. Furthermore, pretreatment with 400 mg/kg eucalyptol prevented LPS-induced histopathological changes. Collectively, these results indicate that eucalyptol acts through a mechanism involving decreased MMP-9 expression and an extracellular signal-regulated kinase-dependent NF-κB pathway to exert anti-inflammatory actions in acute lung inflammation. CONCLUSIONS: Thus, eucalyptol may be a potentially important agent in the treatment of pulmonary inflammation.

Foeniculum vulgare Mill. Protects against Lipopolysaccharide-induced Acute Lung Injury in Mice through ERK-dependent NF-κB Activation.

Foeniculum vulgare Mill. (fennel) is used to flavor food, in cosmetics, as an antioxidant, and to treat microbial, diabetic and common inflammation. No study to date, however, has assessed the anti-inflammatory effects of fennel in experimental models of inflammation. The aims of this study were to investigate the anti-inflammatory effects of fennel in model of lipopolysaccharide (LPS)-induced acute lung injury. Mice were randomly assigned to seven groups (n=7~10). In five groups, the mice were intraperitoneally injected with 1% Tween 80-saline (vehicle), fennel (125, 250, 500µl/kg), or dexamethasone (1 mg/kg), followed 1 h later by intratracheal instillation of LPS (1.5 mg/kg). In two groups, the mice were intraperitoneally injected with vehicle or fennel (250µl/kg), followed 1 h later by intratracheal instillation of sterile saline. Mice were sacrificed 4 h later, and bronchoalveolar lavage fluid (BALF) and lung tissues were obtained. Fennel significantly and dose-dependently reduced LDH activity and immune cell numbers in LPS treated mice. In addition fennel effectively suppressed the LPS-induced increases in the production of the inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, with 500µl/kg fennel showing maximal reduction. Fennel also significantly and dose-dependently reduced the activity of the proinflammatory mediator matrix metalloproteinase 9 and the immune modulator nitric oxide (NO). Assessments of the involvement of the MAPK signaling pathway showed that fennel significantly decreased the LPS-induced phosphorylation of ERK. Fennel effectively blocked the inflammatory processes induced by LPS, by regulating pro-inflammatory cytokine production, transcription factors, and NO.

Effects of Salvia sclarea on chronic immobilization stress induced endothelial dysfunction in rats.

BACKGROUND: Although Salvia sclarea (clary sage) is widely used in aromatherapy and has antioxidant and antimicrobial properties, its mechanisms of action remain poorly understood. We therefore assessed whether clary sage is effective in treating endothelial dysfunction induced by chronic immobilization stress in rats. METHODS: Rats were intraperitoneally injected with almond oil, clary sage oil (5%, 10% or 20%), or nifedipine once daily, followed by immobilization stress (2 h/day) for 14 days. Systolic blood pressure (SBP) and heart rate (HR) were measured, as were serum concentrations of corticosterone (CORT); a biomarker of chronic stress, malondialdehyde (MDA); a biomarker of oxidative stress. Nitric oxide production was assessed by nitrite assays, and eNOS level, a biomarker of endothelial dysfunction, was measured by western blotting. Endothelial dysfunction was also assayed by measuring the effect of clary sage on the contraction of rat aortae. RESULTS: Treatment with 5% (p = 0.029), 10% (p = 0.008), and 20% (p = 0.008) clary sage significantly reduced SBP and treatment with 20% clary sage significantly reduced HR (p = 0.039) compared with the chronic immobilization stress group. Clary sage decreased CORT serum concentration (10%, p = 0.026; 20%, p = 0.012) and MDA (10%, p = 0.007; 20%, p = 0.027), findings similar to those observed with nifedipine. In addition, 20% clary sage significantly increased nitric oxide production (p <0.001) and eNOS expression level (p <0.001) and relaxed aortic rings in rats subjected to chronic immobilization stress. CONCLUSIONS: Clary sage treatment of rats subjected to immobilization stress contributed to their recovery from endothelial dysfunction by increasing NO production and eNOS level as well as by decreasing oxidative stress. Appropriate concentration of clary sage may result in recovery from endothelial dysfunction. These findings indicate that clary sage oil may be effective in the prevention and treatment of stress-induced cardiovascular diseases.

Effects of Inhalation of Essential Oil of Citrus aurantium L. var. amara on Menopausal Symptoms, Stress, and Estrogen in Postmenopausal Women: A Randomized Controlled Trial.

This study aimed to investigate the effects of inhalation of the essential oil of Citrus aurantium L. var. amara (neroli oil) on menopausal symptoms, stress, and estrogen in postmenopausal women. Sixty-three healthy postmenopausal women were randomized to inhale 0.1% or 0.5% neroli oil or almond oil (control) for 5 minutes twice daily for 5 days. Menopause-related symptoms, as determined by the Menopause-Specific Quality of Life Questionnaire (MENQOL); sexual desire visual analog scale (VAS); serum cortisol and estrogen concentrations, blood pressure, pulse, and stress VAS, were measured before and after inhalation. Compared with the control group, the two neroli oil groups showed significant improvements in the physical domain score of the MENQOL and in sexual desire. Systolic blood pressure was significantly lower in the group inhaling 0.5% neroli oil than in the control group. Compared with the control group, the two neroli oil groups showed significantly lower diastolic blood pressure and tended to improve pulse rate and serum cortisol and estrogen concentrations. These findings indicate that inhalation of neroli oil helps relieve menopausal symptoms, increase sexual desire, and reduce blood pressure in postmenopausal women. Neroli oil may have potential as an effective intervention to reduce stress and improve the endocrine system.

Effects of 1,8-cineole on hypertension induced by chronic exposure to nicotine in rats.

OBJECTIVES: The monoterpenic oxide 1,8-cineole is a major component of many essential oils. We investigated its effects on systolic blood pressure (SBP) and oxidative stress in rats chronically exposed to nicotine. METHODS: Male Sprague-Dawley rats (100-120 g) were intraperitoneally injected with 0.8 mg/kg/day nicotine for 21 days, followed by 3 mg/kg nicotine the next day. Rats were subsequently injected intraperitoneally with 0.01, 0.1 and 1 mg/kg 1,8-cineole, or 10 mg/kg nifedipine. SBP was measured using a tail cuff transducer, plasma nitrite concentration was measured colorimetrically, and plasma corticosterone concentration was measured by enzyme immunoassay. KEY FINDINGS: We found that 0.1 mg/kg 1,8-cineole significantly reduced SBP, and that 1.0 mg/kg 1,8-cineole significantly increased plasma nitrite concentrations, compared with rats chronically exposed to nicotine alone. Rats chronically exposed to nicotine showed a significant increase in lipid peroxidation levels, an elevation significantly antagonized by treatment with 0.01 mg/kg and 0.1 mg/kg 1,8-cineole. Chronic exposure to nicotine also significantly increased plasma corticosterone levels, but this effect was not diminished by treatment with 1,8-cineole. CONCLUSIONS: These results indicate that 1,8-cineole may lower blood pressure, and that this antihypertensive effect may be associated with the regulation of nitric oxide and oxidative stress in rats chronically exposed to nicotine.

Anti-inflammatory effects of anethole in lipopolysaccharide-induced acute lung injury in mice.

AIMS: Anethole, the major component of the essential oil of star anise, has been reported to have antioxidant, antibacterial, antifungal, anti-inflammatory, and anesthetic properties. In this study, we investigated the anti-inflammatory effects of anethole in a mouse model of acute lung injury induced by lipopolysaccharide (LPS). MAIN METHODS: BALB/C mice were intraperitoneally administered anethole (62.5, 125, 250, or 500 mg/kg) 1 h before intratracheal treatment with LPS (1.5 mg/kg) and sacrificed after 4 h. The anti-inflammatory effects of anethole were assessed by measuring total protein and cell levels and inflammatory mediator production and by histological evaluation and Western blot analysis. KEY FINDINGS: LPS significantly increased total protein levels; numbers of total cells, including macrophages and neutrophils; and the production of inflammatory mediators such as matrix metalloproteinase 9 (MMP-9), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) in bronchoalveolar lavage fluid. Anethole (250 mg/kg) decreased total protein concentrations; numbers of inflammatory cells, including neutrophils and macrophages; and the inflammatory mediators MMP-9, TNF-α and NO. In addition, pretreatment with anethole decreased LPS-induced histopathological changes. The anti-inflammatory mechanism of anethole in LPS-induced acute lung injury was assessed by investigating the effects of anethole on NF-κB activation. Anethole suppressed the activation of NF-κB by blocking IκB-α degradation. SIGNIFICANCE: These results, showing that anethole prevents LPS-induced acute lung inflammation in mice, suggest that anethole may be therapeutically effective in inflammatory conditions in humans.

Comparison of the biological activity between ultrafine and fine titanium dioxide particles in RAW 264.7 cells associated with oxidative stress.

Ultrafine or fine titanium dioxide (TiO(2)) particles are widely used in the production of white pigments, for sunscreens, and in cleanup techniques. However, currently knowledge is deficient concerning cellular responses to these particles. The study evaluated and compared the biological activity of ultrafine and fine TiO(2) particles in RAW 264.7 macrophages according to an oxidative stress paradigm. In vitro exposure of macrophages to ultrafine or fine TiO(2) in the range of 0.5-200 microg/ml did not significantly alter cell viability. However, ultrafine TiO(2) enhanced intracellular generation of reactive oxygen species (ROS) to a greater extent than fine TiO(2) at each exposure concentration. Ultrafine TiO(2) induced ERK1/2 activation in a concentration-dependent manner, while the fine TiO(2)-induced changes were minimal. Phosphorylation of ERK1/2 occurred following 10 min exposure to higher concentrations of ultrafine TiO(2) (> or = 25 microg/ml). Similarly, ultrafine TiO(2) exposure significantly enhanced tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 secretion in a concentration-dependent manner, and its potency was higher than fine TiO(2). These findings suggest that when exposure concentration is based upon equivalent mass, ultrafine TiO(2) exerts greater biological activity as measured by ROS generation, ERK 1/2 activation, and proinflammatory mediator secretion in RAW 264.7 macrophages than fine TiO(2).

Inhibition of SRC tyrosine kinases suppresses activation of nuclear factor-kappaB, and serine and tyrosine phosphorylation of IkappaB-alpha in lipopolysaccharide-stimulated raw 264.7 macrophages.

Involvement of protein tyrosine kinases (PTK) in lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF-kappaB) activation has been demonstrated. Studies investigated the role of PTK and the underlying mechanisms by which PTK play a role in LPS induction of pathways leading to NF-kappaB activation in macrophages. Inhibitors of PTK-genistein, herbimycin A, or AG126-blocked LPS-induced NF-kappaB activation. Genistein also blocked pervanadate-induced NF-kappaB activation. Furthermore, Src TK selective inhibitors-damnacanthal or PP1-blocked LPS-induced NF-kappaB activation over a range of nanomolar concentrations. Genistein, damnacanthal, or PP1 blocked the LPS-induced serine phosphorylation, the degradation of IkappaB-alpha, and the consequent translocation of the p65 subunit of NF-kappaB to the nucleus. In addition to serine phosphorylation of IkappaB-alpha, LPS-induced NF-kappaB activation also required tyrosine phosphorylation of IkappaB-alpha. These TK inhibitors blocked substantially LPS induction of tyrosine phosphorylation of IkappaB-alpha. Furthermore, cSrc and Lck were physically associated with IkappaB-alpha. These results suggest that the LPS-induced NF-kappaB pathways are dependent on both serine and tyrosine phosphorylation of IkappaB-alpha, and that Src TK, such as cSrc and Lck, are key components of the LPS signaling pathway through at least two different mechanisms associated with NF-kappaB activation.

Inhibition of c-Jun NH2-terminal kinase or extracellular signal-regulated kinase improves lung injury.

BACKGROUND: Although in vitro studies have determined that the activation of mitogen-activated protein (MAP) kinases is crucial to the activation of transcription factors and regulation of the production of proinflammatory mediators, the roles of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in acute lung injury have not been elucidated. METHODS: Saline or lipopolysaccharide (LPS, 6 mg/kg of body weight) was administered intratracheally with a 1-hour pretreatment with SP600125 (a JNK inhibitor; 30 mg/kg, IO), or PD98059 (an MEK/ERK inhibitor; 30 mg/kg, IO). Rats were sacrificed 4 hours after LPS treatment. RESULTS: SP600125 or PD98059 inhibited LPS-induced phosphorylation of JNK and ERK, total protein and LDH activity in BAL fluid, and neutrophil influx into the lungs. In addition, these MAP kinase inhibitors substantially reduced LPS-induced production of inflammatory mediators, such as CINC, MMP-9, and nitric oxide. Inhibition of JNK correlated with suppression of NF-kappaB activation through downregulation of phosphorylation and degradation of IkappaB-alpha, while ERK inhibition only slightly influenced the NF-kappaB pathway. CONCLUSION: JNK and ERK play pivotal roles in LPS-induced acute lung injury. Therefore, inhibition of JNK or ERK activity has potential as an effective therapeutic strategy in interventions of inflammatory cascade-associated lung injury.

Iron tetrakis (N-methyl-4'-pyridyl) porphyrinato inhibits proliferative activity of thymocytes by blocking activation of p38 mitogen-activated protein kinase, nuclear factor-kappaB, and interleukin-2 secretion.

Iron tetrakis (N-methyl-4'-pyridyl) porphyrinato (FeTMPyP) has been demonstrated to be a potent scavenger of reactive oxygens and to have antiinflammatory activities. However, the effects of FeTMPyP on the function of T cells have not been illustrated. The objective of this study was to determine whether treatment of thymocytes with FeTMPyP inhibited the proliferative activity in response to various mitogens and, if so, to further characterize the mechanism of FeTMPyP immune modulation. The results indicate that treatment of thymocytes with FeTMPyP resulted in dose-dependent inhibition of thymocyte proliferation stimulated by concanawalin (Con) A-, Interleukin (IL)-1beta; or lipopdy socchande-exposed macrophage supernatant. FeTMPyP treatment also inhibited Con A- or IL-1beta-induced DNA-binding activity of NF-kappaB and IL-2 secretion by thymocytes. Both the p38 MAP kinase inhibitor SB203580 and the extracellular signal-regulated protein kinases inhibitor PD98059 blocked proliferative activity in Con A-stimulated thymocytes, while SB203580 but not PD98059 blocked nuclear factor (NF)-kappaB activation. FeTMPyP inhibited the activation and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in response to Con A. These data suggest that FeTMPyP downregulates the proliferative activity by inhibition of p38 MAPK activation, NF-kappaB activation, and IL-2 secretion during mitogenic stimulation of thymocytes. Therefore, further studies concerning the effects of FeTMPyP on the human diseases associated with both inflammatory disorders and immunologic overactivation are warranted.

Phosphoinositide 3-kinase activity leads to silica-induced NF-kappaB activation through interacting with tyrosine-phosphorylated I(kappa)B-alpha and contributing to tyrosine phosphorylation of p65 NF-kappaB.

The role of the subunits of phosphoinositide (PI) 3-kinase in NF-kappaB activation in silica-stimulated RAW 264.7 cells was investigated. Results indicate that PI3-kinase activity was increased in response to silica. The p85alpha subunit of PI3-kinase interacted with tyrosine-phosphorylated I(kappa)B-alpha in silica-stimulated cells. PI3-kinase specific inhibitors, such as wortmannin and LY294003, substantially blocked both silica-induced PI3-kinase and NF-kappaB activation. The inhibition of NF-KB activation by PI3-kinase inhibitors was also observed in pervanadate-stimulated but not in LPS-stimulated cells. Furthermore, tyrosine phosphorylation of NF-kappaB p65 was enhanced in cells stimulated with silica, pervanadate or LPS, and wortmannin substantially inhibited the phosphorylation event induced by the first two stimulants but not LPS. Antioxidants, such as superoxide dismutase (SOD), N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), blocked silica-induced PI3-kinase activation, suggesting that reactive oxygen species may be important regulatory molecules in NF-kappaB activation by mediating PI3-kinase activation. Our data suggest that p85 and p110 subunits of PI3-kinase play a role in NF-kappaB activation through interaction with tyrosine-phosphorylated I(kappa)B-alpha and contributing to tyrosine phosphorylation of p65 NF-kappaB.

Time course for inhibition of lipopolysaccharide-induced lung injury by genistein: relationship to alteration in nuclear factor-kappaB activity and inflammatory agents.

OBJECTIVE: This study determined the time course for inhibition of lipopolysaccharide-induced acute lung injury following a single dose of genistein. In addition, the study investigated whether a multiple dosing schedule with genistein retained the inhibitory effects on acute lung injury, nuclear factor-kappaB activation, and production of nuclear factor-kappaB-dependent inflammatory agents, such as matrix metalloproteinase-9 and nitric oxide. DESIGN: Prospective, randomized, laboratory study. SETTING: Experimental laboratory at a university. SUBJECTS: Rats weighing 280-300 g. INTERVENTIONS: Saline or lipopolysaccharide (6 mg/kg of body weight) administered intratracheally with a single dose of genistein (50 mg/kg) or a multiple dosing schedule with genistein (16 mg/kg every 6 hrs for 2 days with lipopolysaccharide treatment at 24 hrs after the first administration of genistein). MEASUREMENTS AND MAIN RESULTS: A 2-hr pretreatment with genistein (a single dose) inhibited biochemical lung injury variables as well as neutrophil infiltration with a maximal inhibition at 4 hrs after lipopolysaccharide treatment. These inhibitory effects of genistein declined with time and were no longer significant by 14-24 hrs after lipopolysaccharide treatment. The multiple dosing schedule with genistein retained significant inhibitory effects on biochemical lung injury variables and the number of neutrophils in the bronchoalveolar lavage fluid at 24 hrs after lipopolysaccharide treatment compared with a single pretreatment with genistein. The multiple dosing schedule with genistein also enhanced the inhibition of induced nuclear factor-kappaB activity as well as matrix metalloproteinase-9 activity and nitric oxide production at 24 hrs after lipopolysaccharide treatment. CONCLUSIONS: This study reports the time course of the inhibitory effects of a single genistein pretreatment on acute lung injury with the maximal effects at 4 hrs after lipopolysaccharide treatment. However, a multiple dosing schedule with genistein retained the inhibitory effect on acute lung injury at 24 hrs after lipopolysaccharide treatment. The mechanisms by which genistein exerts an inhibitory effect on acute lung injury may involve the suppression of nuclear factor-kappaB activation, matrix metalloproteinase-9 activity, and NO production.