Beneficial effects of Oltipraz, nuclear factor - erythroid – 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model

Polat, Emre Can; Beşiroğlu, Hüseyin; Özcan, Levent; Ötünçtemur, Alper; Eruyar, Ahmet Tuğrul; Somay, Adnan; Özbay, Nurver; Çekmen, Mustafa; Eraldemır, Ceyla; Özbek, Emin

doi:10.1590/s1677-5538.ibju.2018.0232

Cited by 9 publications

(7 citation statements)

References 32 publications

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“…Nrf2 exerts cytoprotective and antiapoptotic effects, and is found present as an inactive complex in the cytoplasm with Keap1. In the nucleus, Nrf2 activates the expression of the HO-1 gene, which subsequently alleviates oxidative stress-induced cellular damage ( 8 , 14 ). In addition, HO-1 is a phase II detoxifying enzyme and an anti-inflammatory reactive protein ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have found that the severity of CP-induced nephrotoxicity is related to the activation of NF-κB, and conversely, the inflammatory response and severity of nephrotoxicity can be attenuated through the inhibition of NF-κB activity ( 12 , 13 ). In addition, numerous studies have suggested a role for nuclear factor E2-related factor 2 (Nrf2) in the regulation of physiological processes that serve to inhibit the development and progression of CP-induced renal damage ( 14 , 15 ). It has been reported that the absence of Nrf2 exacerbates CP-induced nephrotoxicity, whilst the pharmacological activation of Nrf2 has been observed to inhibit CP-mediated nephrotoxicity ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

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Treatment with catalpol protects against cisplatin‑induced renal injury through Nrf2 and NF‑κB signaling pathways

Zhang

Liu

et al. 2020

Exp Ther Med

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Cisplatin (CP) is one of the most widely used chemotherapy drugs for cancer treatment, but it often leads to nephrotoxicity. It is well known that catalpol exhibits antioxidant and anti-inflammatory functions, thus the present study aimed to investigate the potential protective effects of catalpol on CP-induced kidney injury in rats, in addition to determining the underlying mechanisms. Sprague-Dawley rats were treated with 25, 50 or 100 mg/kg catalpol for two days, injected with 20 mg/kg cisplatin and catalpol on day 3 and sacrificed on day 4. The histological analysis of isolated kidney tissues was performed using hematoxylin and eosin staining, cleaved caspase-3 expression levels were analyzed using western blotting and the expression levels of inflammatory cytokines in the tissues, including tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-8, IL-10 and inducible nitric oxide synthase (iNOS) were evaluated using ELISAs. Furthermore, the mRNA and protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), kelch-like ECH-associated protein 1 (Keap1), NF-κB and inhibitory κB (IκB) were determined using reverse transcription-quantitative PCR and western blotting, respectively. The results revealed that the treatment with catalpol prevented the histopathological injury and renal dysfunction caused by CP. In addition, catalpol significantly suppressed the CP-induced apoptosis of tubular cells, inhibited the CP-induced upregulation of TNF-α, IL-1β, IL-6, IL-8 and iNOS and promoted the production of the anti-inflammatory cytokine IL-10. Additionally, the mRNA and protein expression levels of Nrf2, HO-1 and IκB in the kidney tissues were increased, whereas the expression levels of Keap1 and NF-κB were significantly decreased following the treatment with catalpol. In conclusion, these results suggested that catalpol may inhibit CP-induced renal injury and suppress the associated inflammatory response through activating the Nrf2 and inhibiting the NF-κB signaling pathways, respectively.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Treatment with catalpol protects against cisplatin‑induced renal injury through Nrf2 and NF‑κB signaling pathways

Zhang

Liu

et al. 2020

Exp Ther Med

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“…Oltipraz, 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione is an inducer of Nrf2 that has exhibited antioxidant, anticancer, and regenerative properties in different animal models and clinical trials by inducing the NQO1 isoenzyme [33,34,35,36]. Treatment with oltipraz also prevents insulin resistance and obesity associated with type 2 diabetes [37], and attenuates heart failure [38], renal and liver fibrosis [39,40], and kidney injury [41]. The effects of oltipraz on the nociceptive responses and depressive-like behaviors that accompany chronic pain and on microglial activation and subsequent induced pain signaling pathways in the spinal and supraspinal regions of sciatic nerve-injured animals have not yet been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

Díaz

Polo

Gallardo

et al. 2019

JCM

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Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-κB (NF-κB) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of κBα (p-IκBα), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain.

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“…A phase 2a study showed that 24-week oltipraz treatment significantly reduced the liver fat content in patients with NAFLD (PMK-N01GI1) [ 56 ] ( Table 1 ). Oltipraz ameliorated renal fibrosis in a unilateral ureteral obstruction rat model [ 57 ]. However, human studies for diabetic nephropathy or CKD are not planned.…”

Section: Common Drug Pipelines For Nafld/nash and Diabetic Nephropmentioning

confidence: 99%

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Sumida

Yoneda

Toyoda

et al. 2020

IJMS

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Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called “diabetic hepatopathy or diabetic liver disease”. NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

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Beneficial effects of Oltipraz, nuclear factor - erythroid – 2 - related factor 2 (Nrf2), on renal damage in unilateral ureteral obstruction rat model

Cited by 9 publications

References 32 publications

Treatment with catalpol protects against cisplatin‑induced renal injury through Nrf2 and NF‑κB signaling pathways

Treatment with catalpol protects against cisplatin‑induced renal injury through Nrf2 and NF‑κB signaling pathways

Analgesic and Antidepressant Effects of Oltipraz on Neuropathic Pain in Mice by Modulating Microglial Activation

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

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