scholarly journals Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1113
Author(s):  
Pamela Maher
Keyword(s):  
Transition Metals ◽  
Neurodegenerative Diseases ◽  
Dependent Manner ◽  
Copper Binding ◽  
Drug Candidates ◽  
Beneficial Effects ◽  
Anti Inflammatory ◽  
Dose Dependent

Alterations occur in the homeostasis of the transition metals iron (Fe2+) and copper (Cu2+) during aging and these are further amplified in neurodegenerative diseases, including Alzheimer’s disease (AD). These observations suggest that the most effective drug candidates for AD might be those that can reduce these alterations. The flavonoid fisetin has both neuroprotective and anti-inflammatory activity both in vitro and in vivo and can bind both iron and copper suggesting that its chelating activity might play a role in its beneficial effects. To test this idea, the effects of iron and copper on both the neuroprotective and anti-inflammatory activities of fisetin were examined. It is shown that while fisetin can reduce the potentiation of cell death by iron and copper in response to treatments that lower glutathione levels, it is much less effective when the metals are combined with other inducers of oxidative stress. In addition, iron but not copper reduces the anti-inflammatory effects of fisetin in a dose-dependent manner. These effects correlate with the ability of iron but not copper to block the induction of the antioxidant transcription factor, Nrf2, by fisetin. In contrast, although the flavanone sterubin also binds iron, the metal has no effect on sterubin’s ability to induce Nrf2 or protect cells from toxic or pro-inflammatory insults. Together, these results suggest that while iron and copper binding could contribute to the beneficial effects of neuroprotective compounds in the context of neurodegenerative diseases, the consequences of this binding need to be fully examined for each compound.

The N-Terminal Domain of Thrombomodulin Sequesters HMGB1: A Novel Anti-Inflammatory Mechanism.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3435-3435
Author(s):  
Kazuhiro Abeyama ◽  
Yasushi Yoshimoto ◽  
Ikuro Maruyama
Keyword(s):  
Protein C ◽  
Statistical Significance ◽  
Dependent Manner ◽  
Protective Effects ◽  
Binding Studies ◽  
Terminal Domain ◽  
Anti Inflammatory ◽  
Dose Dependent

Abstract Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC), the latter an enzyme with potent anti-coagulant and anti-inflammatory properties. We have found that the N-terminal, lectin-like domain (D1) of thrombomodulin has unique anti-inflammatory properties. Thrombomodulin, via D1, binds high mobility group-B1 DNA binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing leukocyte activation in vitro, and ultraviolet radiation-induced cutaneous inflammation and lipopolysaccharide-induced lethality in vivo. Our data also demonstrate anti-inflammatory properties of a peptide spanning the D1 domain of TM and suggest its therapeutic potential. These findings highlight a novel mechanism through which an endothelial cofactor, TM, suppresses inflammation; i.e., sequestration of mediators thereby preventing their interaction with cell surface receptors on effector cells in the vasculature. Results: TM binds HMGB1 and prevents expression of pro-inflammatory activity. Our co-culture studies of leukocytes and HUVEC, and results in the cutaneous irritation model suggested that early release of a mediator, such as HMGB1, might contribute importantly to cellular activation in inflammation at later time points. In this context, TM might have the ability to decrease HMGB1-mediated inflammatory events. Binding studies using surface plasmon resonance (SPR), performed to directly assess the interaction of TM and immobilized HMGB1, demonstrated dose-dependent binding in the nanomolar range (Kd ~232 nM). Furthermore, addition of rhs-TM decreased, in a dose-dependent manner, the binding of HMGB1 to RAGE through the its N-terminal domain, but not anti-coagulant domain. TM and the N-terminal-derived TM peptide have anti-inflammatory effects in settings where HMGB1 is a likely key mediator. In HMGB1-mediated skin inflammation model, systemic administration of rhs-TM, its lectin-like domain and sRAGE resulted in a significant blunting of the inflammatory response. In contrast, the effect of anti-coagulant domain, although showing a trend toward decreased ear swelling, did not achieve statistical significance (anticoagulant domain has anti-inflammatory effects in vivo that probably reflect its ability to support thrombin-mediated activation of protein C; the latter does not occur in vitro after inactivation of the protein C zymogen by heat treatment). In view of recent data suggesting a link between HMGB1 released from injured tissue and endotoxin-induced lethality in mice, we also tested whether rhs-TM and its lectin-like domain might also have protective effects in this model. We employed a dose of intraperitoneal (IP) LPS (10 mg/kg) resulting in 100% lethality by 96 hrs. Systemic (IP) treatment of animals with anti-HMGB1 IgY had a protective effect with respect to lethality at 4 days, whereas the same regimen of nonimmune IgY was without effect. Similarly, IP administration of rhs-TM and its N-teminal lectin domain, but not anti-coagulant domain had complete protective effects compared with anti-HMGB1 IgY. Conclusion: Our findings have elucidated an unexpected anti-inflammatory property of TM residing in the D1 domain, namely binding of HMGB1.

scholarly journals Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Paulo José Basso ◽  
Helioswilton Sales-Campos ◽  
Viviani Nardini ◽  
Murillo Duarte-Silva ◽  
Vanessa Beatriz Freitas Alves ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Predictive Biomarker ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Anti Inflammatory

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara-/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.

scholarly journals Anti-inflammatory Effect of the Peptide LKEKK

2021 ◽  
Vol 6 (5) ◽  
Keyword(s):  
High Specificity ◽  
Dependent Manner ◽  
Thymosin Α1 ◽  
Tnf Α ◽  
Normal Human ◽  
Anti Inflammatory ◽  
Interferon Α2 ◽  
Dose Dependent

We have established that the peptide LKEKK (Np5) corresponding to the sequence 16-20 of thymosin-α1 and to the sequence 131-135 of interferon-α2, in the concentration range 50 300 µg/ear reduces in a dose-dependent manner phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin edema in mice .Tested in parallel peptide with inverted sequence (iNp5, KKEKL, 150-300 µg/ear) was inactive, indicating high specificity of the Np5 action. In the concentration range of 5 20 µM Np5 significantly decrease the TNF-α-induced production by normal human keranocytes of pro-inflammatory mediators IL-6 and IL-1β. Thus, Np5t has a pronounced anti-inflammatory activity in vivo and in vitro.

Antioxidant, Anti-inflammatory, and Analgesic Activities of Citrus reticulata Blanco Leaves Extracts: An In Vivo and In Vitro Study

2018 ◽  
Vol 16 (S1) ◽  
pp. S130-S142
Author(s):  
M. Nasri ◽  
F. Bedjou ◽  
D. Porras ◽  
S. Martínez-Flórez
Keyword(s):  
Second Phase ◽  
Citrus Reticulata ◽  
Dependent Manner ◽  
Dpph Radical ◽  
Huh7 Cells ◽  
Anti Inflammatory ◽  
Response Expression ◽  
Dose Dependent

Citrus species are cultivated and consumed widely. Citrus have been investigated for their pharmacological activity and human health. Their beneficial effects include antibacterial, analgesic, anti-inflammatory, and antitumoral effects. This studywas designed to evaluate the analgesic effect and the antioxidant and anti-inflammatory activities of Citrus reticulata Blanco leaves extracts (ECR) in cell and animal models. Antioxidant, anti-inflammatory, and antinociceptive activities were evaluated in mice using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical inhibition, xylene-induced ear edema, formalin assay and acetic acid-writhing response. Expression of antiinflammatory genes was measured in lipopolysaccharide (LPS)-treated Huh7 cells. ECR showed a significant DPPH radical scavenging activity. No behavioral changes or deaths were observed in mice at doses less than 2,000 mg/kg body weight. Different concentrations of methanolic and aqueous extracts (100–500 mg/kg body wt.) reduced the duration of linking behavior in the second phase of the formalin chemical nociception assay and decreased the number of acetic acidinduced writhing responses in mice, indicating significant analgesic activity. ECR also diminished xylene-induced ear swelling in mice, suggesting an In Vivo anti-inflammatory action. No toxicity of ECR in the range of 0.1–10 μg/ml was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Cell treatment with LPS-induced oxidative/ nitrosative stress as assessed by flow cytometry as the fluorescence of 2′,7′-dichlorofluorescein. This effect was significantly inhibited in a dose-dependent manner by ECR. Administration of ECR caused a dose-dependent inhibition of cytochrome P450 2E1, inducible nitric oxide synthase, tumor necrosis factor α, and interleukin-6 expression in LPS-treated cells. The present study demonstrates that extracts of Citrus reticulata leaves are safe, having antioxidant, anti-inflammatory, and analgesic effects both In Vivo and In Vitro.

scholarly journals Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 630 ◽  
Author(s):  
Sarah A. Scuderi ◽  
Alessio Ardizzone ◽  
Irene Paterniti ◽  
Emanuela Esposito ◽  
Michela Campolo
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Fumaric Acid ◽  
Dimethyl Fumarate ◽  
Related Factor ◽  
Nuclear Factor ◽  
Beneficial Effects ◽  
Anti Inflammatory

Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.

scholarly journals Scrutinizing pharmacological efficiency for Acacia auriculiformis by experimental and computational approach

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shafinaz Nur ◽  
Md. Mohotasin Hossain ◽  
Nadia Islam ◽  
Abu Montakim Tareq ◽  
Nujhat Binte Hanif ◽  
...  
Keyword(s):  
Protein Denaturation ◽  
Acacia Auriculiformis ◽  
Dependent Manner ◽  
Binding Interaction ◽  
Standard Drug ◽  
Brine Shrimp Lethality Assay ◽  
Anti Inflammatory ◽  
Dose Dependent

Abstract Background The study sought to investigate the biological efficacy of methanol leave extract of Acacia auriculiformis (MEAA) via in vitro, in vivo, in silico approaches. The in vitro cytotoxicity was evaluated through brine shrimp lethality assay, and anti-inflammatory activity was determined by membrane stabilisation and protein denaturation methods (BSA and egg albumin). The in vivo antipyretic activity was examined via Brewer’s yeast induced pyrexia model. Results A. auriculiformis extract unveiled moderate cytotoxicity with significant anti-inflammatory efficacy (p < 0.001) compared to standard drug. This extract also exhibited dose-dependent time of paralysis and death for the worm (p < 0.001) in the anthelmintic test which was directly proportional to employed concentrations. A notable percentage of clot lysis effect (36.42 ± 1.95%, p < 0.001) was also observed for MEAA in human blood compared to control. However, this extract significantly (p < 0.05) reduced fever in a dose-dependent manner during the antipyretic experiment. Besides, in computer-aided investigations, two compounds (2,4-ditert-butylphenol and 3-hydroxy-β-damascone) revealed the best binding interaction with six proteins for cytotoxicity, inflammation, helminthic, thrombolytic and pyretic effect. Moreover, these two compounds satisfy Lipinski’s ‘Rule of Five’ and revealed drug-likeness profiles in the toxicological study. Conclusions These findings disclosed that methanol leaves extract of A. auriculiformis might be a potent source for anti-inflammatory, anti-helminthic, thrombolytic and antipyretic agents.

Aprotinin Reduces Nitric Oxide Production in Vitro and in Vivo in a Dose-Dependent Manner

1998 ◽  
Vol 94 (5) ◽  
pp. 505-509 ◽  
Author(s):  
N. L. Bruda ◽  
B. J. Hurlbert ◽  
G. E. Hill
Keyword(s):  
Nitric Oxide ◽  
Cardiopulmonary Bypass ◽  
Interleukin 1 ◽  
Dependent Manner ◽  
Group 3 ◽  
Anti Inflammatory ◽  
Group 2 ◽  
Dose Dependent

1. Cardiopulmonary bypass is associated with an increase in nitric oxide concentrations, and plasma levels of tumour necrosis factor and interleukin-1. Aprotinin, a serine protease inhibitor, commonly used during cardiopulmonary bypass to reduce blood loss, has been demonstrated to exhibit significant anti-inflammatory effects during and after cardiopulmonary bypass. 2. Airway nitric oxide was measured during cardiopulmonary bypass in 10 controls (Group 1), 10 subjects receiving half-dose aprotinin (Group 2) and 10 patients receiving full-dose aprotinin (Group 3). In vitro, a murine bronchial epithelial cell line (LA-4) was cultured with cytomix (a combination of tumour necrosis factor, interleukin-1, and (γ-interferon) with and without aprotinin in increasing concentrations. Nitrite concentrations, the stable and measureable end-product of nitric oxide oxidative metabolism, were measured in the culture supernatant by chemiluminescence. 3. Airway nitric oxide concentrations were increased after 50 min cardiopulmonary bypass compared with that measured at 5 min in controls (53 ± 5 versus 29 ± 3 ppb, P < 0.05) but not in the aprotinin-treated groups (25 ± 4 versus 14 ± 5, Group 2; 21 ± 6 versus 15 ± 3 ppb, Group 3). 4. In a dose-dependent manner, nitrite levels (means ± S.E.M.) were significantly reduced by aprotinin at 500 and 1000 units/ml when compared with cells cultured in the presence of cytomix alone (P < 0.05). 5. These data demonstrate that aprotinin, in a dose-responsive manner, reduces nitric oxide production in vivo and reduces cytokine-induced nitrite production by murine bronchial epithelial cells in vitro. Since increased airway nitric oxide is found in inflammatory lung diseases, like asthma, and anti-inflammatory therapy reduces the concentration of airway nitric oxide, these data support the concept that aprotinin is anti-inflammatory during cardiopulmonary bypass.

scholarly journals Anti-inflammatory Effect of the Peptide LKEKK

2021 ◽  
Vol 6 (5) ◽  
Keyword(s):  
High Specificity ◽  
Dependent Manner ◽  
Thymosin Α1 ◽  
Tnf Α ◽  
Normal Human ◽  
Anti Inflammatory ◽  
Interferon Α2 ◽  
Dose Dependent

We have established that the peptide LKEKK (Np5) corresponding to the sequence 16-20 of thymosin-α1 and to the sequence 131-135 of interferon-α2, in the concentration range 50 300 µg/ear reduces in a dose-dependent manner phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin edema in mice .Tested in parallel peptide with inverted sequence (iNp5, KKEKL, 150-300 µg/ear) was inactive, indicating high specificity of the Np5 action. In the concentration range of 5 20 µM Np5 significantly decrease the TNF-α-induced production by normal human keranocytes of pro-inflammatory mediators IL-6 and IL-1β. Thus, Np5t has a pronounced anti-inflammatory activity in vivo and in vitro.

scholarly journals Anti-Inflammatory and Antinociceptive Activities of Untreated, Germinated, and Fermented Mung Bean Aqueous Extract

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Norlaily Mohd Ali ◽  
Hamidah Mohd Yusof ◽  
Swee-Keong Yeap ◽  
Wan-Yong Ho ◽  
Boon-Kee Beh ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Mung Bean ◽  
Inflammatory Mediator ◽  
Dependent Manner ◽  
Antinociceptive Effects ◽  
Anti Inflammatory ◽  
Dose Dependent ◽  
Ear Oedema

Evaluation of anti-inflammatory and antinociceptive activities of untreated mung bean (MB), germinated mung bean (GMB), and fermented mung bean (FMB) was performed on bothin vitro(inhibition of inflammatory mediator, nitric oxide(NO)) andin vivo(inhibition of ear oedema and reduction of response to pain stimulus) studies. Results showed that both GMB and FMB aqueous extract exhibited potent anti-inflammatory and antinociceptive activities in a dose-dependent manner.In vitroresults showed that GMB and FMB were potent inflammatory mediator (NO) inhibitors at both 2.5 and 5 mg/mL. Furtherin vivostudies showed that GMB and FMB aqueous extract at 1000 mg/kg can significantly reduce ear oedema in mice caused by arachidonic acid. Besides, both 200 mg/kg and 1000 mg/kg concentrations of GMB and FMB were found to exhibit potent antinociceptive effects towards hotplate induced pain. With these, it can be concluded that GMB and FMB aqueous extract exhibited potential anti-inflammatory and antinociceptive effects.

scholarly journals Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xuxing Shen ◽  
Chao Wu ◽  
Meng Lei ◽  
Qing Yan ◽  
Haoyang Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Serum Enzyme ◽  
Herg Channels ◽  
Anti Tumor Activity ◽  
Dose Dependent

AbstractCarfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

Sign in / Sign up

Export Citation Format

Share Document