Nrf2 signaling in diabetic nephropathy, cardiomyopathy and neuropathy: Therapeutic targeting, challenges and future prospective

Hashemi, Mehrdad; Zandieh, Mohammad Arad; Ziaolhagh, Setayesh; Mojtabavi, Sarah; Sadi, Farzaneh Hasani; Koohpar, Zeinab Khazaei; Ghanbarirad, Maryam; Haghighatfard, Arvin; Behroozaghdam, Mitra; Khorrami, Ramin; Nabavi, Noushin; Ren, Jun; Reíter, Russel J.; Salimimoghadam, Shokooh; Rashidi, Mohsen; Hushmandi, Kiavash; Taheriazam, Afshin; Entezari, Maliheh

doi:10.1016/j.bbadis.2023.166714

Cited by 16 publications

(12 citation statements)

References 209 publications

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“…In summary, activation of SIRT1 and Nrf2 signaling markedly enhances expression of antioxidant enzymes, attenuates oxidative damage, and is, thus, beneficial by retarding cardiac fibrosis induced by diabetes ( 37 ). The chronic supplementation of diabetic rats with YNJ substantially prevents the development of cardiac remodeling, which is at least in part mediated by the SIRT1/Nrf2/NQO1 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

YuNü-Jian attenuates diabetes-induced cardiomyopathy: integrating network pharmacology and experimental validation

Wang¹,

Liu²,

Zhu³

et al. 2023

Front. Endocrinol.

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IntroductionDiabetic cardiomyopathy (DCM) is one of the most prevalent complications of diabetes with complex pathogenesis. YuNü-Jian (YNJ) is a traditional Chinese medicinal formula widely used for diabetes with hypoglycemic and cardioprotective effects. This study aims to investigate the actions and mechanisms of YNJ against DCM which has never been reported.MethodsNetwork pharmacology approach was used to predict the potential pathways and targets of YNJ on DCM. Molecular docking between hub targets and active components of YNJ was performed and visualized by AutoDock Vina and PyMOL. Then type 2 diabetic model was employed and intervened with YNJ for 10 weeks to further validate these critical targets.ResultsFirst, a total of 32 main ingredients of YNJ were identified and 700 potential targets were screened to construct herb-compound-target network. Then 94 differentially expressed genes of DCM were identified from GEO database. After that, PPI network of DCM and YNJ were generated from which hub genes (SIRT1, Nrf2, NQO1, MYC and APP) were assessed by topology analysis. Next, functional and pathway analysis indicated that the candidate targets were enriched in response to oxidative stress and Nrf2 signaling pathway. Furthermore, molecular docking revealed strong affinity between core targets and active components of YNJ. Finally, in rats with type 2 diabetes, YNJ obviously attenuated cardiac collagen accumulation and degree of fibrosis. Meanwhile, YNJ significantly upregulated protein expression of SIRT1, Nrf2 and NQO1 in diabetic myocardium.DiscussionCollectively, our findings suggested that YNJ could effectively ameliorate cardiomyopathy induced by diabetes possibly through SIRT1/Nrf2/NQO1 signaling.

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Section: Discussionmentioning

confidence: 99%

YuNü-Jian attenuates diabetes-induced cardiomyopathy: integrating network pharmacology and experimental validation

Wang¹,

Liu²,

Zhu³

et al. 2023

Front. Endocrinol.

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“…For example, SIRT1 presented as a predominant regulator to promote Nrf2 expression in diabetic complications treatment. 33 Astragaloside IV activated not only SIRT1/NRF2 signaling to inhibit oxidative stress but also SIRT1 to suppress NLRP3-mediated inflammatory cytokines releasing, including IL-1, TNF-α, and IL-6. 35 In line with these previous findings, our results also suggested that SNS might activate SIRT1/NRF2 signaling to promote SOD2 transcription and then ameliorate LPS-induced inflammatory injuries.…”

Section: Discussionmentioning

confidence: 99%

“…The Sirtuin family acts as the NAD + cofactor which belongs to class III Histone deacetylase (HDAC) . As the first cataloged member of the Sirtuin family, SIRT1 exhibits various bioactivities in anti-inflammation, antioxidant, and antitumor. , SIRT1 deletion caused excessive inflammation and oxidative stress in multiple organs, which subsequently contribute to chronic inflammatory diseases . These previous studies reasoned us to investigate the effect of SNS on regulating SIRT1 expression and its activities.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating studies had indicated that NRF2 served as a key downstream target of SIRT1 that played important roles in antioxidative stress and immunomodulation. For example, SIRT1 presented as a predominant regulator to promote Nrf2 expression in diabetic complications treatment . Astragaloside IV activated not only SIRT1/NRF2 signaling to inhibit oxidative stress but also SIRT1 to suppress NLRP3-mediated inflammatory cytokines releasing, including IL-1, TNF-α, and IL-6 .…”

Section: Discussionmentioning

confidence: 99%

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Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation via SIRT1-NRF2 Signaling

Lin,

Deng,

Gong

et al. 2023

ACS Omega

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Macrophage-mediated inflammation plays essential roles in multiple-organ injury. Sinensetin (SNS) at least exhibits anti-inflammation, antioxidant, and antitumor properties. However, the underlying mechanism of SNS-targeted macrophage-mediated inflammation remains elusive. In the present study, our results showed that SNS suppressed lipopolysaccharide (LPS)-induced inflammation to ameliorate lung and liver injuries. Mechanistically, SNS significantly inhibited M1-type macrophage polarization and its NLRP3 inflammasome formation to significantly decrease tumor necrosis factor α (TNFα) and IL-6 expression, while increasing IL-10 expression. Moreover, SNS interacted and activated SIRT1 to promote NRF2 and its target gene SOD2 transcription, which subsequently decreased LPS-induced inflammation. SIRT1 knockdown impaired the effects of SNS on the inhibition of macrophage polarization, NLRP3 inflammasome formation, and NRF2/SOD2 signaling. Taken together, our results showed that SNS is a potential and promising natural active ingredient to ameliorate inflammatory injury via activating SIRT1/NRF2/SOD2 signaling.

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“…It has been discovered, however, that Nrf2’s involvement is not limited to antioxidant effects alone. As stated in the introduction, Nrf2 also plays a key role in the regulation of programmed cell death, and this role is closely linked to mitochondria [ 52 ]. Nrf2 can affect apoptosis by regulating mitochondrial ROS expression, and ferroptosis by regulating mitochondrial accumulation of Fe 2+ , ROS and lipid peroxides [ 17 , 27 , 52 – 57 ].…”

Section: The Structure and Regulation Of Nrf2mentioning

confidence: 99%

Nrf2: a dark horse in doxorubicin-induced cardiotoxicity

Zhao¹,

Zheng²,

Sun³

et al. 2023

Cell Death Discov.

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Being a broad-spectrum anticancer drug, doxorubicin is indispensable for clinical treatment. Unexpectedly, its cardiotoxic side effects have proven to be a formidable obstacle. Numerous studies are currently devoted to elucidating the pathological mechanisms underlying doxorubicin-induced cardiotoxicity. Nrf2 has always played a crucial role in oxidative stress, but numerous studies have demonstrated that it also plays a vital part in pathological mechanisms like cell death and inflammation. Numerous studies on the pathological mechanisms associated with doxorubicin-induced cardiotoxicity demonstrate this. Several clinical drugs, natural and synthetic compounds, as well as small molecule RNAs have been demonstrated to prevent doxorubicin-induced cardiotoxicity by activating Nrf2. Consequently, this study emphasizes the introduction of Nrf2, discusses the role of Nrf2 in doxorubicin-induced cardiotoxicity, and concludes with a summary of the therapeutic modalities targeting Nrf2 to ameliorate doxorubicin-induced cardiotoxicity, highlighting the potential value of Nrf2 in doxorubicin-induced cardiotoxicity.

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Nrf2 signaling in diabetic nephropathy, cardiomyopathy and neuropathy: Therapeutic targeting, challenges and future prospective

Cited by 16 publications

References 209 publications

YuNü-Jian attenuates diabetes-induced cardiomyopathy: integrating network pharmacology and experimental validation

YuNü-Jian attenuates diabetes-induced cardiomyopathy: integrating network pharmacology and experimental validation

Sinensetin Attenuated Macrophagic NLRP3 Inflammasomes Formation via SIRT1-NRF2 Signaling

Nrf2: a dark horse in doxorubicin-induced cardiotoxicity

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