Monomethyl fumarate alleviates sepsis-induced hepatic dysfunction by regulating TLR-4/NF-κB signalling pathway

Shalmani, Armin Azadkhah; Ghahremani, Mohammad Hossein; Jeivad, Fereshteh; Shadboorestan, Amir; Hassanzadeh, Gholamreza; Beh-Pajooh, Abbas; Ganbari-Erdi, Mikhriy; Kasirzadeh, Sara; Mojtahedzadeh, Mojtaba; Sabzevari, Omid

doi:10.1016/j.lfs.2018.11.010

Cited by 16 publications

(6 citation statements)

References 31 publications

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“…Although both these studies were descriptive in nature as neither evaluated in detail the underlying mode of action, they provide evidence that DMF might be used successfully for the clinical management of sepsis. This is supported by a study by Shalmani et al [79] in which it was reported that 50 mg/kg (i.p.) MMF treatment improved sepsis-induced liver dysfunction by regulating the TLR-4/NF-κB signaling pathway.…”

Section: Sepsissupporting

confidence: 73%

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

Jadeja¹,

Powell²,

Martin³

2020

Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications

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The medicinal benefit of salts of fumaric acid and its esters (FAE), known as fumarates (mono and dimethyl fumarate), was realized many years ago. Early on, FAE were derived from plants and mushrooms (e.g., Fumaria officinalis, Boletus fomentarius var. pseudo-igniarius). The FAE containing formulation Fumaderm ® was licensed in Germany for the treatment of psoriasis in 1994. Recently, a clinical formulation of dimethyl fumarate known as BG12 (Tecfidera) was approved for use in the United States, New Zealand, Australia, European Union, Switzerland, and Canada for the treatment of multiple sclerosis. Others and we have assessed the potential benefit of FAE in a number of disease conditions that are diverse with respect to etiology but unified with regard to the involvement of inflammation and oxidative stress. Hence, a FAE-based drug with robust anti-oxidative and anti-inflammatory effects that is already US-FDA approved is a perfect contender for repurposing and rapid clinical implementation for their management. There is a burgeoning literature on the use of FAE in the prevention and treatment of diseases, other than psoriasis and MS, in which oxidative stress and/or inflammation are prominent. This chapter highlights critical information gleaned from these studies, exposes lacunae of potential importance, and provides related perspectives.Keywords: fumaric acid esters, oxidative stress, Nrf2, antioxidant Drug Repurposing Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation:… DOI: http://dx.doi.org/10.5772/intechopen.91915 in which oxidative stress and/or inflammation are prominent. The present review highlights critical information gleaned from these studies and exposes and provides perspectives on lacunae of potential importance. Pharmacokinetics of fumaric acid estersDimethyl fumarate (PubChem CID: 637568), described as a "white crystalline compound with a fruit-like taste" [19], is a dimethyl ester of fumaric acid with the official chemical name of trans-1,2-ethylene carboxylic acid dimethyl ester [20]. Because of its rapid degradation by intestinal esterase, DMF does not cross the intestinal wall in significant amounts [21]. Thus, because of its short-lived activity, evidence of direct, sustained anti-inflammatory or antioxidant effects derived directly from DMF is limited [22]. Instead, monomethyl fumarate (MMF; PubChem CID: 21721168), the product of DMF metabolism by intestinal esterase, is said to be the main active metabolite [23]. This is confirmed by pharmacokinetic studies that demonstrate following oral DMF intake, serum concentrations of MMF peak within 2-2.5 h and its half-life is approximately 1 h [24]. Further, the ingestion of DMF along with a high fat/high-calorie diet was found to interfere with intestinal absorption, delaying the systemic peak of MMF significantly [16,17]. Following doses of delayed-release DMF of up to 240 mg, the mean C max of MMF in healthy human subjects was 1.43 μg/ml with a corresponding MMF area under the curve of 2.41 μg h/ml. ...

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Section: Sepsissupporting

confidence: 73%

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

Jadeja¹,

Powell²,

Martin³

2020

Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications

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“…A recent study has shown that in a similar in vivo model, the administration of FOs alone led to ~70% survival at 48 h following CLP induction (29). Dexamethasone alleviated the induction of inflammation caused by sepsis and reduced the extent of lipid peroxidation (30). In the present study, dexamethasone was used as a positive control.…”

Section: Discussionmentioning

confidence: 99%

Fish oils protects against cecal ligation and puncture‑induced septic acute kidney injury via the regulation of inflammation, oxidative stress and apoptosis

Lin¹,

Jin²,

Shan³

2019

Int J Mol Med

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Septic acute kidney injury (AKI) is usually caused by sepsis. ω3 fatty acid has been reported to suppress sepsis-induced organ dysfunction to a certain degree. The present study aimed to investigate the effects of ω3 fatty acid in septic renal injury. Sprague Dawley rats were used to establish a cecal ligation and puncture (CLP) model in order to mimic the development of septic injury. The rats were treated with dexamethasone and fish oils (FOs) for 4 days prior to CLP. Alterations in the morphology of the tissues, the renal function and the induction of inflammation, oxidative stress and apoptosis were evaluated. The effects of FOs on nuclear factor-κB (NF-κB), JAK2/STAT3 and p38-MAPK were determined. The rats of the CLP model group exhibited low survival rates and increased expression of serum creatine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 and of proinflammatory cytokines. In addition, the levels of the markers of oxidative injury and apoptosis were increased. The induction of renal injury was notably reversed by administration of dexamethasone and FOs. The expression levels of the protein markers involved in inflammation and apoptosis were measured and the results indicated that FOs inhibited JAK/STAT3 and p-38MAPK signaling, while they concomitantly increased the expression of NF-κB. The present study highlighted that FOs improve CLP-induced mortality and renal injury by inhibiting inflammation, oxidative stress and apoptosis.

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“…Newly synthesized I κ B α translocates into the nucleus and terminates NF- κ B activation by binding to the activated dimer. NF- κ Bi level increases in response to inflammation and decreases when appropriate treatment is given [ 5 ]. Furthermore, the NF- κ B signaling pathway has been reported to play a role in hepatic injury [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

β-Sitosterol Alters the Inflammatory Response in CLP Rat Model of Sepsis by Modulation of NFκB Signaling

Kasirzadeh

Ghahremani

Setayesh

et al. 2021

BioMed Research International

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Purpose. Sepsis originates from the host inflammatory response, especially to bacterial infections, and is considered one of the main causes of death in intensive care units. Various agents have been developed to inhibit mediators of the inflammatory response; one prospective agent is β-sitosterol (βS), a phytosterol with a structure similar to cholesterol. This study is aimed at evaluating the effects of βS on the biomarkers of inflammation and liver function in cecal ligation and puncture- (CLP-) induced septic rats. Methods. Thirty male Wistar rats were divided equally into six groups as follows: sham, CLP, CLP+dexamethasone (DX, 0.2 mg/kg), CLP+βS (1 mg/kg), CLP+imipenem (IMI, 20 mg/kg), and CLP+IMI (20 mg/kg)+βS (1 mg/kg). Serum levels of IL-1β, IL-6, IL-10, AST, ALT, and liver glutathione (GSH) were assessed by ELISA. Liver expression levels of TNF-α and NF-κBi mRNAs were evaluated by RT-qPCR. Results. Serum concentrations of IL-1β, IL-6, IL-10, ALT, and AST and mRNA levels of TNF-α and NF-κBi were all significantly higher in septic rats than in normal rats ( p < 0.05 ). Liver GSH content was markedly lower in the CLP group than that in the sham group. βS-treated rats had remarkably lower levels of IL-1β, IL-6, IL-10, TNF-α, NF-κBi, AST, and ALT (51.79%, 62.63%, 41.46%, 54.35%, 94.37%, 95.30%, 34.87%, and 46.53% lower, respectively) and greater liver GSH content (35.71% greater) compared to the CLP group ( p < 0.05 ). Conclusion. βS may play a protective role in the septic process by mitigating inflammation. This effect is at least partly mediated by inhibition of the NF-κB signaling pathway. Thus, βS can be considered as a supplementary treatment in septic patients.

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Monomethyl fumarate alleviates sepsis-induced hepatic dysfunction by regulating TLR-4/NF-κB signalling pathway

Cited by 16 publications

References 31 publications

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

Fish oils protects against cecal ligation and puncture‑induced septic acute kidney injury via the regulation of inflammation, oxidative stress and apoptosis

β-Sitosterol Alters the Inflammatory Response in CLP Rat Model of Sepsis by Modulation of NFκB Signaling

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