Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin‐deficient mdx mice

Micheletto, Maria Laura Jorge; Hermes, Túlio de Almeida; Bertassoli, Bruno Machado; Petri, Giuliana; Perez, Matheus Moreira; Fonseca, Fernando Luiz Affonso; Carvalho, Alzira Alves de Siqueira; Feder, David

doi:10.1111/iep.12383

Cited by 3 publications

(4 citation statements)

References 82 publications

(164 reference statements)

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“…The four limb hanging test is a valuable method for measuring the motor function of dystrophic animals, even with different degrees of skeletal muscle pathology 38,48,49 . Studies demonstrate that oxidative stress has a direct relationship with muscle function, since as the production of ROS increases, the tetanic force of the skeletal muscle fibre is compromised 50 .…”

Section: Discussionmentioning

confidence: 99%

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Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy

Hermes,

Fratini,

Nascimento

et al. 2024

Int J Experimental Path

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Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti‐inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight‐week‐old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF‐κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF‐κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.

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Section: Discussionmentioning

confidence: 99%

“…The disease manifests itself differently in the various types of muscles of mdx mice, varying according to age and even the therapies used 35,36,48 . The TA muscle first manifests signs of muscle necrosis around 21 days, and this is more pronounced than in QUA 32 .…”

Section: Discussionmentioning

confidence: 99%

Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy

Hermes,

Fratini,

Nascimento

et al. 2024

Int J Experimental Path

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“…The importance of the TGFβ pathway in the DMD phenotype may have several clinical implications: first, drug development aimed at the downregulation of TGFβ signaling to reduce muscle fibrosis. This approach includes angiotensin 1–7, halofuginone, anti-TGFβ1 antibodies, ixazomib, and angiotensin-II type 1 receptor blockers, which antagonize or downmodulate the TGFβ pathway with promising results in animal models [ 47 , 48 , 49 , 50 , 51 ]. However, some of these drugs have produced undesirable pleiotropic effects, which might be a problem in achieving a clinical benefit [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

et al. 2021

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The transforming growth factor beta (TGFβ) pathway could modulate the Duchenne muscular dystrophy (DMD) phenotype. This meta-analysis aims to estimate the association of genetic variants involved in the TGFβ pathway, including the latent transforming growth factor beta binding protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP1) genes, among others, with age of loss of ambulation (LoA) and cardiac function in patients with DMD. Meta-analyses were conducted for the hazard ratio (HR) of LoA for each genetic variant. A subgroup analysis was performed in patients treated exclusively with glucocorticoids. Eight studies were included in the systematic review and four in the meta-analyses. The systematic review suggests a protective effect of LTBP4 haplotype IAAM (recessive model) for LoA. It is also suggested that the SPP1 rs28357094 genotype G (dominant model) is associated with early LoA in glucocorticoids-treated patients. The meta-analysis of the LTBP4 haplotype IAAM showed a protective association with LoA, with an HR = 0.78 (95% CI: 0.67–0.90). No association with LoA was observed for the SPP1 rs28357094. The LTBP4 haplotype IAAM is associated with a later LoA, especially in the Caucasian population, while the SPP1 rs28357094 genotype G could be associated with a poor response to glucocorticoids. Future research is suggested for SPP1 rs11730582, LTBP4 rs710160, and THBS1 rs2725797.

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“…It can cause several hepatic diseases and also fetal harm. In a mouse model for Duchenne muscular dystrophy, it was shown that Ixazomib reduced inflammation in muscles and increased the number of fibres [53]. The expression of dystrophin and utrophin was increased, and the expression of osteopontin and transforming growth factor beta (TGF-β) decreased [53].…”

Section: Ubiquitin-mediated Proteasome Degradation System (Ups)mentioning

confidence: 99%

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

et al. 2021

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As a multifactorial and multiorgan syndrome, cancer cachexia is associated with decreased tolerance to antitumor treatments and increased morbidity and mortality rates. The current approaches for the treatment of this syndrome are not always effective and well established. Drug repurposing or repositioning consists of the investigation of pharmacological components that are already available or in clinical trials for certain diseases and explores if they can be used for new indications. Its advantages comparing to de novo drugs development are the reduced amount of time spent and costs. In this paper, we selected drugs already available or in clinical trials for non-cachexia indications and that are related to the pathways and molecular components involved in the different phenotypes of cancer cachexia syndrome. Thus, we introduce known drugs as possible candidates for drug repurposing in the treatment of cancer-induced cachexia.

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Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin‐deficient mdx mice

Cited by 3 publications

References 82 publications

Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy

Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates

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