Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats

AbstractDoxorubicin (DOX) chemotherapy is associated with the release of inflammatory cytokines from macrophages. This has been suggested to be, in part, due to DOX-mediated leakage of endotoxins from gut microflora, which activate Toll-like receptor 4 (TLR4) signaling in macrophages, causing severe inflammation. However, the direct function of DOX on macrophages is still unknown. In the present study, we tested the hypothesis that DOX alone is incapable of stimulating inflammatory response in macrophages. Then, we compared the anti-inflammatory effects of curcumin (CUR), resveratrol (RES) and sulforaphane (SFN) against lipopolysaccharide/interferon-gamma (LPS/IFN-γ)-mediated inflammation in the absence or presence of DOX. For this purpose, RAW 264.7 cells were stimulated with LPS/IFN-γ (10 ng/mL/10 U/mL) in the absence or presence of DOX (0.1 µM). Our results showed that DOX alone is incapable of stimulating an inflammatory response in RAW 264.7 macrophages. Furthermore, after 24 h of incubation with LPS/IFN-γ, a significant increase in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) mRNA levels was observed. Similarly, nitric oxide (NO) production and TNF-α and IL-6 protein levels were significantly upregulated. Moreover, in LPS/IFN-γ-treated macrophages, the microRNAs (miRNAs) miR-146a, miR-155, and miR-21 were significantly overexpressed. Interestingly, upon testing CUR, RES, and SFN against LPS/IFN-γ-mediated inflammation, only SFN was able to significantly reverse the LPS/IFN-γ-mediated induction of iNOS, TNF-α and IL-6 and attenuate miR-146a and miR-155 levels. In conclusion, SFN, at the transcriptional and posttranscriptional levels, exhibits potent immunomodulatory action against LPS/IFN-γ-stimulated macrophages, which may indicate SFN as a potential treatment for DOX-associated inflammation.

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Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.273.3.l504 ◽

1997 ◽

Vol 273 (3) ◽

pp. L504-L512 ◽

Cited By ~ 2

Author(s):

Y. C. Huang ◽

P. W. Fisher ◽

E. Nozik-Grayck ◽

C. A. Piantadosi

Keyword(s):

Nitric Oxide ◽

Lung Injury ◽

Average Rate ◽

Ischemia Reperfusion ◽

Oxidant Stress ◽

No Production ◽

Protective Effects ◽

Lung Weight ◽

Edema Formation ◽

No Donors

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

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Nitric oxide preconditioning regulates endothelial monolayer integrity via the heat shock protein 90-soluble guanylate cyclase pathway

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00498.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. H893-H903 ◽

Cited By ~ 14

Author(s):

Galina N. Antonova ◽

Connie M. Snead ◽

Alexander S. Antonov ◽

Christiana Dimitropoulou ◽

Richard C. Venema ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Heat Shock ◽

Heat Shock Protein ◽

Cell Injury ◽

Soluble Guanylate Cyclase ◽

Heat Shock Protein 90 ◽

Protective Effects ◽

No Donor ◽

Spermine Nonoate

Large (pathological) amounts of nitric oxide (NO) induce cell injury, whereas low (physiological) NO concentrations often ameliorate cell injury. We tested the hypotheses that pretreatment of endothelial cells with low concentrations of NO (preconditioning) would prevent injury induced by high NO concentrations. Apoptosis, induced in bovine aortic endothelial cells (BAECs) by exposing them to either 4 mM sodium nitroprusside (SNP) or 0.5 mM N-(2-aminoethyl)- N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) for 8 h, was abolished by 24-h pretreatment with either 100 μM SNP, 10 μM spermine NONOate, or 100 μM 8-bromo-cGMP (8-Br-cGMP). Repair of BAECs following wounding, measured as the recovery rate of transendothelial electrical resistance, was delayed by 8-h exposure to 4 mM SNP, and this delay was significantly attenuated by 24-h pretreatment with 100 μM SNP. NO preconditioning produced increased association and expression of soluble guanyl cyclase (sGC) and heat shock protein 90 (HSP90). The protective effect of NO preconditioning, but not the injurious effect of 4 mM SNP, was abolished by either a sGC activity inhibitor 1H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one (ODQ) or a HSP90 binding inhibitor (radicicol) and was mimicked by 8-Br-cGMP. We conclude that preconditioning with a low dose of NO donor accelerates repair and maintains endothelial integrity via a mechanism that includes the HSP90/sGC pathway. HSP90/sGC may thus play a role in the protective effects of NO-generating drugs from injurious stimuli.

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Quantitative Proteomic Analysis of Plasma after Remote Ischemic Conditioning in a Rhesus Monkey Ischemic Stroke Model

Biomolecules ◽

10.3390/biom11081164 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1164

Author(s):

Siying Song ◽

Linlin Guo ◽

Di Wu ◽

Jingfei Shi ◽

Yunxia Duan ◽

...

Keyword(s):

Lipid Metabolism ◽

Rhesus Monkey ◽

Proteomic Analysis ◽

Complement C3 ◽

Protective Effects ◽

Plasma Proteome ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Metabolism Regulation ◽

Induced Changes

Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled populations, and sample times. This study aimed to examine the RIC-induced changes in the plasma proteome using rhesus monkey models of strokes. Methods: Two adult rhesus monkeys with autologous blood clot-induced middle cerebral artery (MCA) occlusion underwent RIC interventions twice a week for five consecutive weeks. Each RIC treatment included five cycles of five minutes of ischemia alternating with five minutes of reperfusion of the forearm. The blood samples were taken from the median cubital vein of the monkeys at baseline and immediately after each week’s RIC stimulus. The plasma samples were isolated for a proteomic analysis using mass spectrometry (MS). Results: Several proteins related to lipid metabolism (Apolipoprotein A-II and Apolipoprotein C-II), coagulation (Fibrinogen alpha chain and serpin), immunoinflammatory responses (complement C3 and C1), and endovascular hemostasis (basement membrane-specific heparan sulfate proteoglycan) were significantly modulated after the RIC intervention. Many of these induced changes, such as in the lipid metabolism regulation and anticoagulation responses, starting as early as two weeks following the RIC intervention. The complementary activation and protection of the endovascular cells occurred more than three weeks postintervention. Conclusions: Multiple protective effects were induced by RIC and involved lipid metabolism regulation (anti-atherogenesis), anticoagulation (antithrombosis), complement activation, and endovascular homeostasis (anti-inflammation). In conclusion, this study indicates that RIC results in significant modulations of the plasma proteome. It also provides ideas for future research and screening targets.

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Partial protective effects of melatonin on cadmium-induced changes in hematological characteristics in rats

Biotechnic & Histochemistry ◽

10.1080/10520295.2021.1925965 ◽

2021 ◽

pp. 1-7

Author(s):

İhsan Kısadere ◽

Mehmet Faruk Aydın ◽

İlknur Ündağ

Keyword(s):

Protective Effects ◽

Induced Changes

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Nitric oxide decreases lung liquid production via guanosine 3′,5′-cyclic monophosphate

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2001.280.5.l923 ◽

2001 ◽

Vol 280 (5) ◽

pp. L923-L929 ◽

Cited By ~ 6

Author(s):

James J. Cummings ◽

Huamei Wang

Keyword(s):

Nitric Oxide ◽

Pulmonary Epithelium ◽

Fetal Sheep ◽

Cgmp Analog ◽

Pulmonary Arterial ◽

Series Of Experiments ◽

Lung Liquid ◽

Tracer Dilution ◽

Induced Changes

We studied the role of cGMP in nitric oxide (NO)-induced changes in lung liquid production ( J v ) in chronically instrumented fetal sheep. Forty-five studies were done in which J v was measured by a tracer dilution technique. Left pulmonary arterial flow (Qlpa) was measured by a Doppler flow probe. There were two series of experiments. In the first, we gave 8-bromo-cGMP, a cGMP analog, by either the pulmonary vascular or intraluminal route; in the second, we used agents to inhibit or enhance endogenous cGMP activity. When infused directly into the pulmonary circulation, 8-bromo-cGMP significantly increased Qlpa but had no effect on J v. Conversely, when instilled into the lung liquid, 8-bromo-cGMP had no effect on Qlpa but significantly reduced J v. Inhibition of guanylate cyclase activity with methylene blue totally blocked, whereas phosphodiesterase inhibition with Zaprinast significantly enhanced, the effect of instilled NO on J v. Thus the reduction in lung liquid caused by NO appears to be mediated by cGMP, perhaps through a direct effect on the pulmonary epithelium.

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