The effect of compound DM509 on kidney fibrosis in the conditions of the experimental model

Stavniichuk, Anna; Savchuk, Olexiy; Khan, Abdul Hye; Jankiewicz, Wojciech K.; Imig, John D.; Merk, Daniel

doi:10.17721/1728_2748.2020.80.10-15

Cited by 5 publications

(13 citation statements)

References 18 publications

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“…Considering the complexity of CKD pathogenesis involving different cell types and changes of multiple signal pathways, multi-target drugs (MTD) emerge as a useful tool; for example, soluble epoxide hydrolase (SHE)-based PTUPB (with cyclo-oxygenase 2 (COX2) inhibitor), PB394 (with PPARγ agonist), and DM509 (with farnesoid X receptor agonist) to alleviate fibrosis, inflammatory response, and oxidative stress from CKD related to DM, hypertension, hyperlipidemia, or other etiologies [ 166 , 167 , 168 ].…”

Section: Specific Issues Of Ckdmentioning

confidence: 99%

Chronic Kidney Disease: Strategies to Retard Progression

Yan

Chao

Lin

2021

IJMS

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Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.

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Section: Specific Issues Of Ckdmentioning

confidence: 99%

Chronic Kidney Disease: Strategies to Retard Progression

Yan

Chao

Lin

2021

IJMS

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“…The promise of FXR activation to treat cardiovascular and kidney fibrosis is dampened by unwanted increases in cholesterol levels in humans (Mudaliar et al, 2013;Neuschwander-Tetri et al, 2015). Dual modulating drugs with FXR agonism have avoided this problem and are demonstrating promising actions to combat kidney and cardiovascular diseases (Miyazaki-Anzai et al, 2010;Stavniichuk et al, 2020).…”

Section: Ppars and Fxr In Hypertensionmentioning

confidence: 99%

Peroxisome proliferator-activated receptors, farnesoid X receptor, and dual modulating drugs in hypertension

Imig

2023

Front. Physiol.

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Hypertension characterized by an elevated blood pressure is a cardiovascular disease that afflicts greater than one in every three adults worldwide. Nuclear receptors are large superfamily of DNA-binding transcription factors that target genes to regulate metabolic and cardiovascular function. Drugs have been developed for nuclear receptors such as peroxisome proliferator-activated receptors (PPARα and PPARγ) and farnesoid X receptor (FXR). PPARα, PPARγ, and FXR agonists are used clinically to treat lipid disorders and metabolic diseases. Evidence from clinical studies and animal hypertension models have demonstrated that PPARα, PPARγ, and FXR agonism can lower blood pressure and decrease end organ damage which could be useful for the treatment of hypertension in patients with metabolic diseases. Unfortunately, PPAR and FXR agonists have unwanted clinical side effects. There have been recent developments to limit side effects for PPAR and FXR agonists. Combining PPAR and FXR agonism with soluble epoxide hydrolase (sEH) inhibition or Takeda G protein receptor 5 (TGR5) agonism has been demonstrated in preclinical studies to have actions that would decrease clinical side effects. In addition, these dual modulating drugs have been demonstrated in preclinical studies to have blood pressure lowering, anti-fibrotic, and anti-inflammatory actions. There is now an opportunity to thoroughly test these novel dual modulators in animal models of hypertension associated with metabolic diseases. In particular, these newly developed dual modulating PPAR and FXR drugs could be beneficial for the treatment of metabolic diseases, organ fibrosis, and hypertension.

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“…55 DM509 had anti-inflammatory actions with reductions in TGF-β, tumor necrosis factor- (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) levels in the UUO mice. 55 With this highly promising in vivo profile, DM509 stands as a potential lead candidate for preclinical evaluation to combat organ fibrosis and kidney diseases.…”

Section: Dm509mentioning

confidence: 99%

“…Moreover, curative treatment with DM509 counteracted pre-established NASH in diet-induced obese mice with anti-inflammatory and remarkable antifibrotic effects widely exceeding OCA as standard of care (54). Experimental studies in UUO mice revealed that DM509 decreased renal fibrosis and injury (55). DM509 had anti-inflammatory actions with reductions in TGF- β , TNF α , IL-1 β , and IL-6 levels in the UUO mice (55).…”

Section: Progress With Multi-target Drugs For Kidney Diseasesmentioning

confidence: 99%

“…Experimental studies in UUO mice revealed that DM509 decreased renal fibrosis and injury (55). DM509 had anti-inflammatory actions with reductions in TGF- β , TNF α , IL-1 β , and IL-6 levels in the UUO mice (55). With this highly promising in vivo profile, DM509 stands as a lead potential candidate for preclinical evaluation to combat organ fibrosis and kidney diseases.…”

Section: Progress With Multi-target Drugs For Kidney Diseasesmentioning

confidence: 99%

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Multi-Target Drugs for Kidney Diseases

2021

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Kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), and glomerular nephritis can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell-signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past ten years, in silico design of drugs has allowed for multi-target drugs to go quickly from concept to reality. Several multi-target drugs have been successfully made that target arachidonic acid pathways and transcription factors to treat inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal transforming growth factor-β (TGF-β) signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.

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The effect of compound DM509 on kidney fibrosis in the conditions of the experimental model

Cited by 5 publications

References 18 publications

Chronic Kidney Disease: Strategies to Retard Progression

Chronic Kidney Disease: Strategies to Retard Progression

Peroxisome proliferator-activated receptors, farnesoid X receptor, and dual modulating drugs in hypertension

Multi-Target Drugs for Kidney Diseases

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