Compound 48/80, a mast cell degranulator, causes oxidative damage by enhancing vitamin C synthesis via reduced glutathione depletion and lipid peroxidation through neutrophil infiltration in rat livers

Y, Ohta; Yashiro, Koji; Ohashi, Koji; Horikoshi, Yosuke; Kusumoto, Chiaki; Matsura, Tatsuya

doi:10.3164/jcbn.16-89

Cited by 9 publications

(5 citation statements)

References 44 publications

(66 reference statements)

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“…C48/80 has been used to produce experimental anaphylactic shock, because this compound is known to increase histamine release from plasma or tissue (22,23) and an additional nitric oxide release from endothelial cells (24). Our data showed that this compound was effective in inducing anaphylactic shock in rats since blood pressure decreased after C48/80 administration.…”

Section: Discussionmentioning

confidence: 57%

Effects of NO/cGMP inhibitors in a rat model of anaphylactoid shock

Albuquerque

Ferreira

Carvalho

et al. 2020

Braz J Med Biol Res

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Anaphylactic shock can be defined as an acute syndrome, and it is the most severe clinical manifestation of allergic diseases. Anaphylactoid reactions are similar to anaphylactic events but differ in the pathophysiological mechanism. Nitric oxide (NO) inhibitors during anaphylaxis suggest that NO might decrease the signs and symptoms of anaphylaxis but exacerbate associated vasodilation. Therefore, blocking the effects of NO on vascular smooth muscle by inhibiting the guanylate cyclase (GC) would be a reasonable strategy. This study aimed to investigate the effects of NO/cGMP pathway inhibitors methylene blue (MB), N o-nitro-L-arginine methyl ester hydrochloride (L-NAME), and indigo carmine (IC) in shock induced by compound 48/80 (C48/80) in rats. The effect was assessed by invasive blood pressure measurement. Shock was initiated by C48/80 intravenous bolus injection 5 min before (prophylactic) or after (treatment) the administration of the inhibitors MB (3 mg/kg), L-NAME (1 mg/kg), and IC (3 mg/kg). Of the groups that received drugs as prophylaxis for shock, only the IC group did not present the final systolic blood pressure (SBP) better than the C48/80 group. Regarding shock treatment with the drugs tested, all groups had the final SBP similar to the C48/80group. Altogether, our results suggested that inhibition of GC and NO synthase in NO production pathway was not sufficient to revert hypotension or significantly improve survival.

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Section: Discussionmentioning

confidence: 57%

Effects of NO/cGMP inhibitors in a rat model of anaphylactoid shock

Albuquerque

Ferreira

Carvalho

et al. 2020

Braz J Med Biol Res

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“…It is known, for example, that ROS participate in mast cell intracellular signaling [77] and that mast cell degranulators such as acrolein, for example, are able to promote ROS generation [78]. In addition, it was recently demonstrated that Ket was able to control the oxidative damage determined by the compound 48/80, which is a well-known mast cell activator, in rat livers [79]. We also found out that the inflammasome platform was significantly downregulated by Ket therapy, as indicated by reduced levels of NLRP3, caspase-1 and IL-1β mRNA.…”

Section: Discussionmentioning

confidence: 99%

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

et al. 2020

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Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by extensive inflammation, demyelination, axonal loss and gliosis. Evidence indicates that mast cells contribute to immunopathogenesis of both MS and experimental autoimmune encephalomyelitis (EAE), which is the most employed animal model to study this disease. Considering the inflammatory potential of mast cells, their presence at the CNS and their stabilization by certain drugs, we investigated the effect of ketotifen fumarate (Ket) on EAE development. EAE was induced in C57BL/6 mice by immunization with MOG 35-55 and the animals were injected daily with Ket from the seventh to the 17th day after disease induction. This early intervention with Ket significantly reduced disease prevalence and severity. The protective effect was concomitant with less NLRP3 inflammasome activation, rebalanced oxidative stress and also reduced T cell infiltration at the CNS. Even though Ket administration did not alter mast cell percentage at the CNS, it decreased the local CPA3 and CMA1 mRNA expression that are enzymes typically produced by these cells. Evaluation of the CNS-barrier permeability indicated that Ket clearly restored the permeability levels of this barrier. Ket also triggered an evident lymphadenomegaly due to accumulation of T cells that produced higher levels of encephalitogenic cytokines in response to in vitro stimulation with MOG. Altogether these findings reinforce the concept that mast cells are particularly relevant in MS immunopathogenesis and that Ket, a known stabilizer of their activity, has the potential to be used in MS control.

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“…McNeil et al (2015), identified that C48/80 could target MRGPRX2 to activate mast cells. Some other research also indicated that C48/80 could induce itch (Dondalska et al, 2020) and cause hepatic oxidative damage (Ohta et al, 2017) or oxidative stress (Kaida et al, 2010). Similar to C48/80, SP is identified as an agonist of MRGPRX2 (Green et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Silibinin attenuated pseudo‐allergic reactions and mast cell degranulation via PLCγ and PI3K/Akt signaling pathway

Wang

Dang

et al. 2023

Phytotherapy Research

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Anaphylaxis is a type of potentially fatal hypersensitivity reaction resulting from the activation of mast cells. Many endogenous or exogenous factors could cause this reaction. Silibinin is the main chemical component of silymarin and has been reported to have pharmacological activities. However, the anti‐allergic reaction effect of silibinin has not yet been investigated. This study aimed to evaluate the effect of silibinin to attenuate pseudo‐allergic reactions in vivo and to investigate the underlying mechanism in vitro. In this study, calcium imaging was used to assess Ca2+ mobilization. The levels of cytokines and chemokines, released by stimulated mast cells, were measured using enzyme immunoassay kits. The activity of silibinin was evaluated in a mouse model of passive cutaneous anaphylaxis (PCA). Western blotting was used to explore the related molecular signaling pathways. In results, silibinin markedly inhibited mast cell degranulation, calcium mobilization, and preventing the release of cytokines and chemokines in a dose‐dependent manner via the PLCγ and PI3K/Akt signaling pathway. Silibinin also attenuated PCA in a dose‐dependent manner. In summary, silibinin has an anti‐pseudo‐allergic pharmacological activity, which makes it a potential candidate for the development of a novel agent to arrest pseudo‐allergic reactions.

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Compound 48/80, a mast cell degranulator, causes oxidative damage by enhancing vitamin C synthesis via reduced glutathione depletion and lipid peroxidation through neutrophil infiltration in rat livers

Cited by 9 publications

References 44 publications

Effects of NO/cGMP inhibitors in a rat model of anaphylactoid shock

Effects of NO/cGMP inhibitors in a rat model of anaphylactoid shock

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

Silibinin attenuated pseudo‐allergic reactions and mast cell degranulation via PLCγ and PI3K/Akt signaling pathway

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