Acute O-GlcNAcylation prevents inflammation-induced vascular dysfunction

Acute increases in cellular protein O-linked N-acetyl-glucosamine ( O-GlcNAc) modification ( O-GlcNAcylation) have been shown to have protective effects in the heart and vasculature. We hypothesized that d-glucosamine (d-GlcN) and Thiamet-G, two agents that increase protein O-GlcNAcylation via different mechanisms, inhibit TNF-α-induced oxidative stress and vascular dysfunction by suppressing inducible nitric oxide (NO) synthase (iNOS) expression. Rat aortic rings were incubated for 3h at 37°C with d-GlcN or its osmotic control l-glucose (l-Glc) or with Thiamet-G or its vehicle control (H2O) followed by the addition of TNF-α or vehicle (H2O) for 21 h. After incubation, rings were mounted in a myograph to assess arterial reactivity. Twenty-four hours of incubation of aortic rings with TNF-α resulted in 1) a hypocontractility to 60 mM K+ solution and phenylephrine, 2) blunted endothelium-dependent relaxation responses to ACh and substance P, and 3) unaltered relaxing response to the Ca2+ ionophore A-23187 and the NO donor sodium nitroprusside compared with aortic rings cultured in the absence of TNF-α. d-GlcN and Thiamet-G pretreatment suppressed the TNF-α-induced hypocontractility and endothelial dysfunction. Total protein O-GlcNAc levels were significantly higher in aortic segments treated with d-GlcN or Thiamet-G compared with controls. Expression of iNOS protein was increased in TNF-α-treated rings, and this was attenuated by pretreatment with either d-GlcN or Thiamet-G. Dense immunostaining for nitrotyrosylated proteins was detected in the endothelium and media of the aortic wall, suggesting enhanced peroxynitrite production by iNOS. These findings demonstrate that acute increases in protein O-GlcNAcylation prevent TNF-α-induced vascular dysfunction, at least in part, via suppression of iNOS expression.

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Protective effects of active hexose correlated compound in a rat model of liver injury after hepatectomy

Functional Foods in Health and Disease ◽

10.31989/ffhd.v6i11.305 ◽

2016 ◽

Vol 6 (11) ◽

pp. 702 ◽

Cited By ~ 1

Author(s):

Richi Nakatake ◽

Yoshito Tanaka ◽

Yosuke Ueyama ◽

Hirokazu Miki ◽

Morihiko Ishizaki ◽

...

Keyword(s):

Nitric Oxide ◽

Liver Injury ◽

Rat Model ◽

Inflammatory Mediators ◽

Nuclear Factor ◽

Protective Effects ◽

Tnf Α ◽

Oxide Synthase ◽

Necrosis Factor ◽

Inducible Nitric Oxide

Background: Recent evidence has indicated that a functional food, active hexose correlated compound (AHCC), has liver-protective effects via suppression of inflammatory mediators, such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α.Objective: This study aimed to investigate whether AHCC has beneficial effects in a rat model of endotoxin-induced liver injury after partial hepatectomy, in addition to clarifying the mechanisms of action of AHCC.Methods: Rats were treated with 70% of partial hepatectomy and lipopolysaccharide (PH/LPS) to induce acute liver injury. A normal diet with or without 2% AHCC was administered orally 10 days before 70% hepatectomy. Inflammatory mediators were analyzed.Results: AHCC improved the survival rate by 70% in PH/LPS rats. AHCC prevented an increase in serum transaminase levels, and histopathological changes and apoptosis in the liver. AHCC reduced iNOS mRNA and protein expression in the liver, resulting in inhibition of nitric oxide production. AHCC also reduced TNF-α, cytokine-induced neutrophil chemoattractant-1, and interleukin-6 mRNA expression, but enhanced expression of interleukin-10. An electrophoretic mobility shift assay with hepatic nuclear extracts demonstrated that AHCC reduced the activation of nuclear factor (NF)-κB induced by PH/LPS treatment.Conclusion: AHCC inhibits induction of inflammatory mediators, including iNOS and TNF-α, in part through inhibition of NF-κB activation in a rat model of liver injury. Our findings suggest that AHCC prevents postoperative liver failure after liver resection.Keywords: active hexose correlated compound, inducible nitric oxide synthase, liver injury, nuclear factor-κB, tumor necrosis factor-α

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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00761.2013 ◽

2014 ◽

Vol 306 (7) ◽

pp. H1001-H1010 ◽

Cited By ~ 13

Author(s):

Livius V. d'Uscio ◽

Tongrong He ◽

Anantha Vijay R. Santhanam ◽

Li-Jung Tai ◽

Ronald M. Evans ◽

...

Keyword(s):

Vascular Function ◽

Vascular Dysfunction ◽

Vascular Endothelial Cell ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Superoxide Anion Production ◽

No Donor ◽

Peroxisome Proliferator Activated Receptor ◽

Specific Deletion

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ−/− mice) were generated using loxP/Cre technology. ePPARδ−/− mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium ( Z)-1-( N, N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ−/− mice ( P < 0.05). In ePPARδ−/− mouse aortas, phosphorylation of endothelial NO synthase at Ser1177 was significantly decreased ( P < 0.05). However, basal levels of cGMP were unexpectedly increased ( P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ−/− mice ( P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta ( P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ−/− mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.

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Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

Clinical Science ◽

10.1042/cs20120232 ◽

2012 ◽

Vol 124 (5) ◽

pp. 333-342 ◽

Cited By ~ 10

Author(s):

Kathleen M. Lukaszewicz ◽

John R. Falck ◽

Vijaya L. Manthati ◽

Julian H. Lombard

Keyword(s):

Vascular Function ◽

Vascular Dysfunction ◽

Cerebral Arteries ◽

Dienoic Acid ◽

Brown Norway ◽

No Donor ◽

Middle Cerebral Arteries ◽

No Bioavailability ◽

Relaxation Responses

The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NGnitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.

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Differential inducible nitric oxide synthase expression in systemic and pulmonary vessels after endotoxin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.278.5.r1232 ◽

2000 ◽

Vol 278 (5) ◽

pp. R1232-R1239 ◽

Cited By ~ 19

Author(s):

Edward J. Pulido ◽

Brian D. Shames ◽

David A. Fullerton ◽

Brett C. Sheridan ◽

Craig H. Selzman ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Western Blot ◽

Inducible Nitric Oxide Synthase ◽

Vascular Dysfunction ◽

Inos Expression ◽

Pulmonary Vessels ◽

Oxide Synthase ◽

Inos Inhibition ◽

Inducible Nitric Oxide

Inducible nitric oxide synthase (iNOS) is associated with vascular hypocontractility in systemic vessels after endotoxin lipopolysaccharide (LPS) administration. Although lung iNOS is increased after LPS, its role in the pulmonary circulation is unclear. We hypothesized that whereas iNOS upregulation is responsible for LPS-induced vascular dysfunction in systemic vessels, iNOS does not play a significant role in the pulmonary artery (PA). Using isolated aorta (AO) and PA rings, we examined the effect of nonselective NOS inhibition [ N G-monomethyl-l-arginine (l-NMMA); 100 μmol/l] and selective iNOS inhibition (aminoguanidine, AG; 100 μmol/l) on α1-adrenergic-mediated vasoconstriction (phenylephrine; 10− 9 to 10− 3 M) after LPS ( Salmonella typhimurium, 20 mg/kg ip). We also determined the presence of iNOS using Western blot and immunohistochemistry. LPS markedly impaired AO contractility (maximal control tension 1,076 ± 33 mg vs. LPS 412 ± 39 mg, P < 0.05), but PA contractility was unchanged (control 466 ± 29 mg vs. LPS 455 ± 27 mg, P > 0.05). Selective iNOS inhibition restored the AO's response to vasoconstriction (LPS + AG 1,135 ± 54 mg, P > 0.05 vs. control and P < 0.05 vs. LPS), but had no effect on the PA (LPS + AG 422 ± 38 mg, P > 0.05 vs. control and LPS). Western blot and immunohistochemistry revealed increased iNOS expression in the AO after LPS, but iNOS was not detected in the PA. Our results suggest that differential iNOS expression after LPS in systemic and pulmonary vessels contributes to the phenomenon of sepsis/endotoxemia-induced systemic hypotension and pulmonary hypertension.

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Short-Term Regulation of Tumor Necrosis Factor-α-Induced Lipolysis in 3T3-L1 Adipocytes Is Mediated through the Inducible Nitric Oxide Synthase/Nitric Oxide-Dependent Pathway

Endocrinology ◽

10.1210/en.2009-0403 ◽

2009 ◽

Vol 150 (11) ◽

pp. 4892-4900 ◽

Cited By ~ 14

Author(s):

Chih-Chan Lien ◽

Lo-Chun Au ◽

Ying-Lan Tsai ◽

Low-Tone Ho ◽

Chi-Chang Juan

Keyword(s):

Nitric Oxide ◽

Guanylyl Cyclase ◽

Inos Expression ◽

No Production ◽

Short Term ◽

Hairpin Rna ◽

Tnf Α ◽

Short Hairpin ◽

Dependent Pathway ◽

Inducible Nitric Oxide

TNF-α has several effects on adipocytes that may be related to the development of type 2 diabetes in obese subjects. Many studies demonstrated that long-term treatment with TNF-α increases lipolysis in adipocytes. However, the short-term (<4 h) effects of TNF-α on lipolysis have not been well investigated. The aim of this study was to investigate the short-term regulatory mechanism of TNF-α-induced lipolysis in 3T3-L1 adipocytes. Well-differentiated 3T3-L1 adipocytes were used. Lipolysis was determined by measuring glycerol release. Expression of inducible nitric oxide (iNOS) and nitric oxide (NO) production were measured, respectively, by Western blots and the Griess reagent. A selective iNOS inhibitor (s-ethylisothiourea · HBr), an adenylyl cyclase inhibitor (SQ22536), and a guanylyl cyclase inhibitor (LY83583) were used to investigate the involvement of iNOS, cAMP, and cGMP in TNF-α-induced lipolysis. Transient transfection with iNOS short hairpin RNA was performed to confirm the involvement of iNOS in TNF-α-induced lipolysis. Phosphorylation of hormone-sensitive lipase (HSL) was measured by immunoprecipitation and Western blotting. Results showed that short-term TNF-α treatment significantly increased lipolysis, iNOS expression, and NO production in a time- and dose-dependent manner. Furthermore, treatment with the NO donor S-nitroso-N-acetylpenicillamine also stimulated lipolysis and HSL phosphorylation in 3T3-L1 adipocytes. Moreover, pretreatment with inhibitors of iNOS and guanylate cyclase, but not an adenylate cyclase inhibitor, abolished TNF-α-induced lipolysis and HSL phosphorylation. Suppression of TNF-α-induced iNOS expression using short hairpin RNA significantly reduced TNF-α-induced lipolysis. In conclusion, short-term TNF-α treatment induces lipolysis in 3T3-L1 adipocytes by increasing iNOS expression and NO production, which activates the guanylyl cyclase/cGMP-dependent pathway and induces phosphorylation of HSL.

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Comparing the protective effects of resveratrol, curcumin and sulforaphane against LPS/IFN-γ-mediated inflammation in doxorubicin-treated macrophages

Scientific Reports ◽

10.1038/s41598-020-80804-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haidy A. Saleh ◽

Eman Ramdan ◽

Mohey M. Elmazar ◽

Hassan M. E. Azzazy ◽

Anwar Abdelnaser

Keyword(s):

Nitric Oxide ◽

Inflammatory Response ◽

Raw 264.7 Cells ◽

Inos Mrna ◽

No Production ◽

Raw 264.7 ◽

Mrna Levels ◽

Protective Effects ◽

Tnf Α ◽

Ifn Γ

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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Phytowaste as nutraceuticals in boosting public health

Clinical Phytoscience ◽

10.1186/s40816-021-00260-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chinyere S. Dike ◽

Chinna N. Orish ◽

Chukwuemeka R. Nwokocha ◽

Francis D. Sikoki ◽

Bolaji B. Babatunde ◽

...

Keyword(s):

Animal Studies ◽

Fruits And Vegetables ◽

Protective Effects ◽

Bioactive Substances ◽

Environment Friendly ◽

Human Trial ◽

Production Improvement ◽

Tnf Α ◽

Therapeutic Activities ◽

Seed Extracts

AbstractThe utilization of bioactive constituent of peels and seeds provide an effective, environment friendly and inexpensive therapy for different forms of human disease, and the production, improvement and documentation of novel nutraceuticals. This review systematically presents findings and further understanding of the reported benefits and therapeutic applications of peel and seed extracts on innovative cell culture and animal studies, as well as phased clinical human trial research. The extracts of seed and peels were reported to possess high quantities of bioactive substances with antioxidative, antidiabetic, hepatorenal protective, antithyroidal, anti-inflammatory, antibacterial, cardiovascular protective, neuro-protective effects, anticancer and wound healing activities. Therapeutic activities of the bioactive substances of peel and seed extracts include elevation of Superoxide dismutase (SOD), GSH-Px, t-GPx, Catalase and GST activities, with the suppression of MDA levels, hydroperoxide generation and lipid peroxidized products, the extracts also regulate inflammatory mediators and cytokines as they are reported to suppress the secretion of inflammatory cytokines, which include; IL-1β, PGE2, TGF-β and TNF-α and induces apoptosis and cell differentiation. This review revealed the therapeutic importance and best utilization of peels and seed extracts of fruits and vegetables.

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Alleviation of Oxidative Stress in Dental Pulp Cells Following 4-Hexylresorcinol Administration in a Rat Model

Applied Sciences ◽

10.3390/app11083637 ◽

2021 ◽

Vol 11 (8) ◽

pp. 3637

Author(s):

Jun-Ho Chang ◽

Dae-Won Kim ◽

Seong-Gon Kim ◽

Tae-Woo Kim

Keyword(s):

Oxidative Stress ◽

Dental Pulp ◽

Therapeutic Effects ◽

Protective Effects ◽

Mandibular Incisor ◽

Tnf Α ◽

Total Antioxidant ◽

Pulp Cells ◽

Pre Treatment

Damaged dental pulp undergoes oxidative stress and 4-hexylresorcinol (4HR) is a well-known antioxidant. In this study, we aimed to evaluate the therapeutic effects of a 4HR ointment on damaged dental pulp. Pulp cells from rat mandibular incisor were cultured and treated with 4HR or resveratrol (1–100 μM). These treatments (10–100 μM) exerted a protective effect during subsequent hydrogen peroxide treatments. The total antioxidant capacity and glutathione peroxidase activity were significantly increased following 4HR or resveratrol treatment (p < 0.05), while the expression levels of TNF-α and IL1β were decreased following the exposure to 4HR pre-treatment in an in vitro model. Additionally, the application of 4HR ointment in an exposed dental pulp model significantly reduced the expression of TNF-α and IL1β (p < 0.05). Conclusively, 4HR exerted protective effects against oxidative stress in dental pulp tissues through downregulating TNF-α and IL1β.

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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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In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

Scientific Reports ◽

10.1038/s41598-021-94228-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rosangela Montanaro ◽

Alessio D’Addona ◽

Andrea Izzo ◽

Carlo Ruosi ◽

Vincenzo Brancaleone

Keyword(s):

Inflammatory Markers ◽

In Vitro Study ◽

Inos Expression ◽

Beneficial Effects ◽

Tnf Α ◽

Inflammatory State ◽

Anti Inflammatory ◽

Underlying Mechanisms ◽

Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

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